David Weinstock, MD

Photo courtesy of the

Dana-Farber Cancer Institute

A type II JAK2 inhibitor has shown activity against B-cell acute lymphoblastic leukemia (B-ALL) in preclinical experiments.

The inhibitor, known as CHZ868, works by binding JAK2 into a tightly clenched position, which prevents the protein from functioning.

Researchers tested CHZ868 in samples from patients with CRLF2-rearranged B-ALL, in mice with the disease, and in mice implanted with human B-ALL tissue.

“In each case, we saw good activity: leukemia cells died, JAK2 signaling was suspended, and survival rates increased,” said David Weinstock, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“When we combined CHZ868 with the steroid dexamethasone, the killing of leukemia cells was much more extensive, and the animals lived longer than they did with CHZ868 alone.”

Dr Weinstock and his colleagues reported these results in Cancer Cell. Some of the researchers involved in this work are employees of, or have received research funding from, Novartis.

The team found that CHZ868 inhibited JAK2 signaling in B-ALL, both in vitro and in vivo. CHZ868 could overcome persistent JAK2 signaling where type I JAK2 inhibitors (BSK805 and BVB808) could not.

However, the researchers also identified a mutation—JAK2 L884P—that conferred resistance to CHZ868 and another type II JAK2 inhibitor, BBT594.

Nevertheless, CHZ868 suppressed the growth of CRLF2-rearranged human B-ALL cells and improved survival in mice with human or murine B-ALL.

CHZ868 worked synergistically with dexamethasone to induce apoptosis in JAK2-dependent B-ALL. The combination also improved survival in mice with B-ALL, when compared to either dexamethasone or CHZ868 alone.

The researchers noted that, when given at 30 mg/kg/day, CHZ868 was tolerated in NSG mice for up to 25 days and in immunocompetent mice for up to 44 days. And the drug had “essentially no effects” on peripheral blood counts.

This result and the tolerability of dexamethasone make CHZ868 and dexamethasone a “particularly attractive” combination that should be investigated in clinical trials, the team said.

They also speculated that CHZ868 or other type II JAK2 inhibitors could prove effective against malignancies other than B-ALL.

“JAK2 abnormalities are found in some cases of triple-negative breast cancer and Hodgkin lymphoma,” Dr Weinstock noted. “The success of CHZ868 in B-ALL suggests that it, or a compound that works by a similar mechanism, may also be effective in these cancers.”

David Weinstock, MD

Photo courtesy of the

Dana-Farber Cancer Institute

A type II JAK2 inhibitor has shown activity against B-cell acute lymphoblastic leukemia (B-ALL) in preclinical experiments.

The inhibitor, known as CHZ868, works by binding JAK2 into a tightly clenched position, which prevents the protein from functioning.

Researchers tested CHZ868 in samples from patients with CRLF2-rearranged B-ALL, in mice with the disease, and in mice implanted with human B-ALL tissue.

“In each case, we saw good activity: leukemia cells died, JAK2 signaling was suspended, and survival rates increased,” said David Weinstock, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“When we combined CHZ868 with the steroid dexamethasone, the killing of leukemia cells was much more extensive, and the animals lived longer than they did with CHZ868 alone.”

Dr Weinstock and his colleagues reported these results in Cancer Cell. Some of the researchers involved in this work are employees of, or have received research funding from, Novartis.

The team found that CHZ868 inhibited JAK2 signaling in B-ALL, both in vitro and in vivo. CHZ868 could overcome persistent JAK2 signaling where type I JAK2 inhibitors (BSK805 and BVB808) could not.

However, the researchers also identified a mutation—JAK2 L884P—that conferred resistance to CHZ868 and another type II JAK2 inhibitor, BBT594.

Nevertheless, CHZ868 suppressed the growth of CRLF2-rearranged human B-ALL cells and improved survival in mice with human or murine B-ALL.

CHZ868 worked synergistically with dexamethasone to induce apoptosis in JAK2-dependent B-ALL. The combination also improved survival in mice with B-ALL, when compared to either dexamethasone or CHZ868 alone.

The researchers noted that, when given at 30 mg/kg/day, CHZ868 was tolerated in NSG mice for up to 25 days and in immunocompetent mice for up to 44 days. And the drug had “essentially no effects” on peripheral blood counts.

This result and the tolerability of dexamethasone make CHZ868 and dexamethasone a “particularly attractive” combination that should be investigated in clinical trials, the team said.

They also speculated that CHZ868 or other type II JAK2 inhibitors could prove effective against malignancies other than B-ALL.

“JAK2 abnormalities are found in some cases of triple-negative breast cancer and Hodgkin lymphoma,” Dr Weinstock noted. “The success of CHZ868 in B-ALL suggests that it, or a compound that works by a similar mechanism, may also be effective in these cancers.”

David Weinstock, MD

Photo courtesy of the

Dana-Farber Cancer Institute

A type II JAK2 inhibitor has shown activity against B-cell acute lymphoblastic leukemia (B-ALL) in preclinical experiments.

The inhibitor, known as CHZ868, works by binding JAK2 into a tightly clenched position, which prevents the protein from functioning.

Researchers tested CHZ868 in samples from patients with CRLF2-rearranged B-ALL, in mice with the disease, and in mice implanted with human B-ALL tissue.

“In each case, we saw good activity: leukemia cells died, JAK2 signaling was suspended, and survival rates increased,” said David Weinstock, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“When we combined CHZ868 with the steroid dexamethasone, the killing of leukemia cells was much more extensive, and the animals lived longer than they did with CHZ868 alone.”

Dr Weinstock and his colleagues reported these results in Cancer Cell. Some of the researchers involved in this work are employees of, or have received research funding from, Novartis.

The team found that CHZ868 inhibited JAK2 signaling in B-ALL, both in vitro and in vivo. CHZ868 could overcome persistent JAK2 signaling where type I JAK2 inhibitors (BSK805 and BVB808) could not.

However, the researchers also identified a mutation—JAK2 L884P—that conferred resistance to CHZ868 and another type II JAK2 inhibitor, BBT594.

Nevertheless, CHZ868 suppressed the growth of CRLF2-rearranged human B-ALL cells and improved survival in mice with human or murine B-ALL.

CHZ868 worked synergistically with dexamethasone to induce apoptosis in JAK2-dependent B-ALL. The combination also improved survival in mice with B-ALL, when compared to either dexamethasone or CHZ868 alone.

The researchers noted that, when given at 30 mg/kg/day, CHZ868 was tolerated in NSG mice for up to 25 days and in immunocompetent mice for up to 44 days. And the drug had “essentially no effects” on peripheral blood counts.

This result and the tolerability of dexamethasone make CHZ868 and dexamethasone a “particularly attractive” combination that should be investigated in clinical trials, the team said.

They also speculated that CHZ868 or other type II JAK2 inhibitors could prove effective against malignancies other than B-ALL.

“JAK2 abnormalities are found in some cases of triple-negative breast cancer and Hodgkin lymphoma,” Dr Weinstock noted. “The success of CHZ868 in B-ALL suggests that it, or a compound that works by a similar mechanism, may also be effective in these cancers.”

Hematopoietic stem cells

in the bone marrow

Shortening the G1 phase of the cell cycle can improve the production and function of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.

When investigators shortened the G1 phase in human HSCs, they found the cells were better able to resist differentiation in vitro and exhibited enhanced engraftment in vivo.

However, these benefits only occurred when the team shortened the early phase of G1, not the late phase.

Claudia Waskow, PhD, of Technische Universitaet Dresden in Germany, and her colleagues conducted this research to determine whether the function of human HSCs is controlled by the kinetics of cell-cycle progression.

The investigators knew that the body’s pool of HSCs is maintained through self-renewing divisions tightly regulated by enzymatically active cyclin (CCN)/cyclin-dependent kinase (CDK) complexes.

So they enforced expression of functional CCND1–CDK4 complexes, which are important for progression through the early G1 phase of the cell cycle, and CCNE1–CDK2 complexes, which are key in the transition from the G1 phase to the S phase.

Overexpression of CCND1–CDK4 complexes (also referred to as elevated 4D) promoted the transit from G0 to G1 and successfully shortened the G1 phase. However, the total length of the cell cycle did not change much, as the G2 or M phase was prolonged slightly.

The investigators also found that elevated 4D levels protected HSCs from differentiation-inducing signals in vitro and provided a “competitive advantage” in vivo.

When they transplanted HSCs with elevated 4D into mice, the team observed improved donor-leukocyte engraftment but no increase in the HSC pool. They said the improvement in engraftment was based on an elevated output of myeloid cells.

In contrast to elevated 4D, overexpression of CCNE1–CDK2 (also referred to as elevated 2E) conferred detrimental effects. Elevated 2E did accelerate cell-cycle progression, but it led to the loss of functional HSCs and poor engraftment.

The investigators said a large proportion of cells with elevated 2E contained fragmented DNA and underwent apoptosis after transduction.

In addition, many HSCs with elevated 2E exited G0 and shifted to the S–G2–M phases of the cell cycle. The G1 phase was significantly shortened, and the time HSCs spent in each cycle was reduced.

Dr Waskow and her colleagues said these results suggest transit velocity through the early and late G1 phase is an important regulator of HSC function and therefore makes an essential contribution to the maintenance of hematopoiesis.

Furthermore, alterations of G1 transition kinetics may be the basis for functional defects observed in HSCs from old mice or elderly humans.

Hematopoietic stem cells

in the bone marrow

Shortening the G1 phase of the cell cycle can improve the production and function of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.

When investigators shortened the G1 phase in human HSCs, they found the cells were better able to resist differentiation in vitro and exhibited enhanced engraftment in vivo.

However, these benefits only occurred when the team shortened the early phase of G1, not the late phase.

Claudia Waskow, PhD, of Technische Universitaet Dresden in Germany, and her colleagues conducted this research to determine whether the function of human HSCs is controlled by the kinetics of cell-cycle progression.

The investigators knew that the body’s pool of HSCs is maintained through self-renewing divisions tightly regulated by enzymatically active cyclin (CCN)/cyclin-dependent kinase (CDK) complexes.

So they enforced expression of functional CCND1–CDK4 complexes, which are important for progression through the early G1 phase of the cell cycle, and CCNE1–CDK2 complexes, which are key in the transition from the G1 phase to the S phase.

Overexpression of CCND1–CDK4 complexes (also referred to as elevated 4D) promoted the transit from G0 to G1 and successfully shortened the G1 phase. However, the total length of the cell cycle did not change much, as the G2 or M phase was prolonged slightly.

The investigators also found that elevated 4D levels protected HSCs from differentiation-inducing signals in vitro and provided a “competitive advantage” in vivo.

When they transplanted HSCs with elevated 4D into mice, the team observed improved donor-leukocyte engraftment but no increase in the HSC pool. They said the improvement in engraftment was based on an elevated output of myeloid cells.

In contrast to elevated 4D, overexpression of CCNE1–CDK2 (also referred to as elevated 2E) conferred detrimental effects. Elevated 2E did accelerate cell-cycle progression, but it led to the loss of functional HSCs and poor engraftment.

The investigators said a large proportion of cells with elevated 2E contained fragmented DNA and underwent apoptosis after transduction.

In addition, many HSCs with elevated 2E exited G0 and shifted to the S–G2–M phases of the cell cycle. The G1 phase was significantly shortened, and the time HSCs spent in each cycle was reduced.

Dr Waskow and her colleagues said these results suggest transit velocity through the early and late G1 phase is an important regulator of HSC function and therefore makes an essential contribution to the maintenance of hematopoiesis.

Furthermore, alterations of G1 transition kinetics may be the basis for functional defects observed in HSCs from old mice or elderly humans.

Hematopoietic stem cells

in the bone marrow

Shortening the G1 phase of the cell cycle can improve the production and function of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.

When investigators shortened the G1 phase in human HSCs, they found the cells were better able to resist differentiation in vitro and exhibited enhanced engraftment in vivo.

However, these benefits only occurred when the team shortened the early phase of G1, not the late phase.

Claudia Waskow, PhD, of Technische Universitaet Dresden in Germany, and her colleagues conducted this research to determine whether the function of human HSCs is controlled by the kinetics of cell-cycle progression.

The investigators knew that the body’s pool of HSCs is maintained through self-renewing divisions tightly regulated by enzymatically active cyclin (CCN)/cyclin-dependent kinase (CDK) complexes.

So they enforced expression of functional CCND1–CDK4 complexes, which are important for progression through the early G1 phase of the cell cycle, and CCNE1–CDK2 complexes, which are key in the transition from the G1 phase to the S phase.

Overexpression of CCND1–CDK4 complexes (also referred to as elevated 4D) promoted the transit from G0 to G1 and successfully shortened the G1 phase. However, the total length of the cell cycle did not change much, as the G2 or M phase was prolonged slightly.

The investigators also found that elevated 4D levels protected HSCs from differentiation-inducing signals in vitro and provided a “competitive advantage” in vivo.

When they transplanted HSCs with elevated 4D into mice, the team observed improved donor-leukocyte engraftment but no increase in the HSC pool. They said the improvement in engraftment was based on an elevated output of myeloid cells.

In contrast to elevated 4D, overexpression of CCNE1–CDK2 (also referred to as elevated 2E) conferred detrimental effects. Elevated 2E did accelerate cell-cycle progression, but it led to the loss of functional HSCs and poor engraftment.

The investigators said a large proportion of cells with elevated 2E contained fragmented DNA and underwent apoptosis after transduction.

In addition, many HSCs with elevated 2E exited G0 and shifted to the S–G2–M phases of the cell cycle. The G1 phase was significantly shortened, and the time HSCs spent in each cycle was reduced.

Dr Waskow and her colleagues said these results suggest transit velocity through the early and late G1 phase is an important regulator of HSC function and therefore makes an essential contribution to the maintenance of hematopoiesis.

Furthermore, alterations of G1 transition kinetics may be the basis for functional defects observed in HSCs from old mice or elderly humans.

Red and white blood cells

The American Society of Clinical Oncology (ASCO) has updated its clinical practice guideline on hematopoietic colony-stimulating factors (CSFs).

The guideline includes recommendations on the use of CSFs in the context of lymphoma, solid tumor malignancies, pediatric leukemia, and hematopoietic stem cell transplant.

There are no recommendations pertaining to adults with acute myeloid leukemia or myelodysplastic syndromes.

ASCO’s previous guideline on CSFs was issued in 2006. For the update, an ASCO expert panel conducted a formal systematic review of relevant articles from the medical literature published from October 2005 through September 2014.

Key recommendations from the resulting guideline are as follows.

Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia.

For patients with lymphomas or solid tumors, primary prophylaxis with a CSF should be given during all cycles of chemotherapy in patients who have an approximately 20% or higher risk for febrile neutropenia on the basis of patient-, disease-, and treatment-related factors.

However, clinicians should also consider using chemotherapy regimens that do not require CSF administration but are as effective as regimens that do require a CSF.

Patients with lymphomas or solid tumors should receive secondary febrile neutropenia prophylaxis with a CSF if they experienced a neutropenic complication from a previous cycle of chemotherapy (for which they did not receive primary prophylaxis) when a reduced dose or treatment delay may compromise disease-free survival, overall survival, or treatment outcome.

However, the guideline also says that, in many clinical situations, dose reductions or delays may be a reasonable alternative.

CSFs should not be routinely used for patients with neutropenia who are afebrile or as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.

Dose-dense regimens with CSF support should only be used within an appropriately designed clinical trial or if use of the regimen is supported by convincing efficacy data. The guideline says that, for non-Hodgkin lymphoma, data on the value of dose-dense regimens with CSF support are limited and conflicting.

In the context of transplant, CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral blood stem cells. To reduce the duration of severe neutropenia, CSFs should be administered after autologous stem cell transplant and may be administered after allogeneic stem cell transplant.

CSFs should be avoided in patients receiving concomitant chemotherapy and radiation, particularly involving the mediastinum. CSFs may be considered in patients receiving radiation alone if the clinician expects prolonged treatment delays due to neutropenia.

Patients who are exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, should promptly receive CSFs or pegylated granulocyte CSFs.

Clinicians should consider prophylactic CSF for patients with diffuse aggressive lymphoma who are 65 or older and are receiving curative chemotherapy (R-CHOP), particularly if they have comorbidities.

The guideline also says the use of CSFs in pediatric patients will almost always be guided by clinical protocols. But CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute myeloid leukemia who do not have an infection.

For more details, see the complete guideline. ASCO said it encourages feedback on its guidelines from oncologists, practitioners, and patients through the ASCO Guidelines Wiki.

Red and white blood cells

The American Society of Clinical Oncology (ASCO) has updated its clinical practice guideline on hematopoietic colony-stimulating factors (CSFs).

The guideline includes recommendations on the use of CSFs in the context of lymphoma, solid tumor malignancies, pediatric leukemia, and hematopoietic stem cell transplant.

There are no recommendations pertaining to adults with acute myeloid leukemia or myelodysplastic syndromes.

ASCO’s previous guideline on CSFs was issued in 2006. For the update, an ASCO expert panel conducted a formal systematic review of relevant articles from the medical literature published from October 2005 through September 2014.

Key recommendations from the resulting guideline are as follows.

Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia.

For patients with lymphomas or solid tumors, primary prophylaxis with a CSF should be given during all cycles of chemotherapy in patients who have an approximately 20% or higher risk for febrile neutropenia on the basis of patient-, disease-, and treatment-related factors.

However, clinicians should also consider using chemotherapy regimens that do not require CSF administration but are as effective as regimens that do require a CSF.

Patients with lymphomas or solid tumors should receive secondary febrile neutropenia prophylaxis with a CSF if they experienced a neutropenic complication from a previous cycle of chemotherapy (for which they did not receive primary prophylaxis) when a reduced dose or treatment delay may compromise disease-free survival, overall survival, or treatment outcome.

However, the guideline also says that, in many clinical situations, dose reductions or delays may be a reasonable alternative.

CSFs should not be routinely used for patients with neutropenia who are afebrile or as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.

Dose-dense regimens with CSF support should only be used within an appropriately designed clinical trial or if use of the regimen is supported by convincing efficacy data. The guideline says that, for non-Hodgkin lymphoma, data on the value of dose-dense regimens with CSF support are limited and conflicting.

In the context of transplant, CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral blood stem cells. To reduce the duration of severe neutropenia, CSFs should be administered after autologous stem cell transplant and may be administered after allogeneic stem cell transplant.

CSFs should be avoided in patients receiving concomitant chemotherapy and radiation, particularly involving the mediastinum. CSFs may be considered in patients receiving radiation alone if the clinician expects prolonged treatment delays due to neutropenia.

Patients who are exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, should promptly receive CSFs or pegylated granulocyte CSFs.

Clinicians should consider prophylactic CSF for patients with diffuse aggressive lymphoma who are 65 or older and are receiving curative chemotherapy (R-CHOP), particularly if they have comorbidities.

The guideline also says the use of CSFs in pediatric patients will almost always be guided by clinical protocols. But CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute myeloid leukemia who do not have an infection.

For more details, see the complete guideline. ASCO said it encourages feedback on its guidelines from oncologists, practitioners, and patients through the ASCO Guidelines Wiki.

Red and white blood cells

The American Society of Clinical Oncology (ASCO) has updated its clinical practice guideline on hematopoietic colony-stimulating factors (CSFs).

The guideline includes recommendations on the use of CSFs in the context of lymphoma, solid tumor malignancies, pediatric leukemia, and hematopoietic stem cell transplant.

There are no recommendations pertaining to adults with acute myeloid leukemia or myelodysplastic syndromes.

ASCO’s previous guideline on CSFs was issued in 2006. For the update, an ASCO expert panel conducted a formal systematic review of relevant articles from the medical literature published from October 2005 through September 2014.

Key recommendations from the resulting guideline are as follows.

Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia.

For patients with lymphomas or solid tumors, primary prophylaxis with a CSF should be given during all cycles of chemotherapy in patients who have an approximately 20% or higher risk for febrile neutropenia on the basis of patient-, disease-, and treatment-related factors.

However, clinicians should also consider using chemotherapy regimens that do not require CSF administration but are as effective as regimens that do require a CSF.

Patients with lymphomas or solid tumors should receive secondary febrile neutropenia prophylaxis with a CSF if they experienced a neutropenic complication from a previous cycle of chemotherapy (for which they did not receive primary prophylaxis) when a reduced dose or treatment delay may compromise disease-free survival, overall survival, or treatment outcome.

However, the guideline also says that, in many clinical situations, dose reductions or delays may be a reasonable alternative.

CSFs should not be routinely used for patients with neutropenia who are afebrile or as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.

Dose-dense regimens with CSF support should only be used within an appropriately designed clinical trial or if use of the regimen is supported by convincing efficacy data. The guideline says that, for non-Hodgkin lymphoma, data on the value of dose-dense regimens with CSF support are limited and conflicting.

In the context of transplant, CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral blood stem cells. To reduce the duration of severe neutropenia, CSFs should be administered after autologous stem cell transplant and may be administered after allogeneic stem cell transplant.

CSFs should be avoided in patients receiving concomitant chemotherapy and radiation, particularly involving the mediastinum. CSFs may be considered in patients receiving radiation alone if the clinician expects prolonged treatment delays due to neutropenia.

Patients who are exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, should promptly receive CSFs or pegylated granulocyte CSFs.

Clinicians should consider prophylactic CSF for patients with diffuse aggressive lymphoma who are 65 or older and are receiving curative chemotherapy (R-CHOP), particularly if they have comorbidities.

The guideline also says the use of CSFs in pediatric patients will almost always be guided by clinical protocols. But CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute myeloid leukemia who do not have an infection.

For more details, see the complete guideline. ASCO said it encourages feedback on its guidelines from oncologists, practitioners, and patients through the ASCO Guidelines Wiki.

Blood for transfusion

Photo by Elise Amendola

Results of a pilot study suggest a restrictive transfusion strategy may be safe for patients with acute upper gastrointestinal bleeding (AUGIB), but investigators say more research is needed.

In this study, known as TRIGGER, use of a restrictive transfusion strategy led to a 13% reduction in red blood cell (RBC) transfusions compared to the liberal strategy, but this difference was not statistically significant.

Likewise, there was no significant difference in clinical outcomes whether AUGIB patients received transfusions according to the restrictive strategy or the liberal one.

These results suggest a need for a large, randomized trial, according to investigators.

“If restrictive practice is proven to be safe in a large study, it could potentially safely reduce the use of red blood cell transfusions and produce cost savings . . . ,” said Vipul Jairath, MBChB, DPhil, of Oxford University Hospitals in the UK.

He and his colleagues conducted the TRIGGER trial and reported the results in The Lancet.

The study included 6 hospitals that had more than 20 AUGIB admissions monthly, more than 400 adult beds, 24-hour endoscopy, and onsite intensive care and surgery. Patients were eligible if they presented with new AUGIB (defined by hematemesis or melena) and were 18 or older. The only exclusion criterion was exsanguinating hemorrhage.

The investigators enrolled 936 patients—403 on the restrictive transfusion arm and 533 on the liberal arm. Patients in the restrictive arm were eligible to receive RBCs when their hemoglobin concentration fell below 80 g/L, with a post-transfusion target of 81-100 g/L.

Patients in the liberal arm were eligible for transfusion when their hemoglobin concentration fell below 100 g/L, with a post-transfusion target of 101-120 g/L. These thresholds were informed by UK transfusion practices.

Protocol adherence was 96% in the restrictive arm and 83% in the liberal arm. The mean last recorded hemoglobin concentration was 116 g/L for the restrictive arm and 118 g/L for the liberal arm.

The investigators noted that there was a 13% absolute reduction in the proportion of patients transfused in the restrictive arm, a reduction in the amount of RBCs transfused between the arms, and a separation in hemoglobin concentration between the arms, but none of these differences were significant.

In addition, there was no significant difference in clinical outcomes between the arms, although the trial was not powered to assess these outcomes.

All-cause mortality at day 28 was 7% in the liberal transfusion arm and 5% in the restrictive arm. The rate of serious adverse events at day 28 was 22% and 18%, respectively.

At hospital discharge, further bleeding had occurred in 6% of patients in the liberal arm and 4% in the restrictive arm. At day 28, further bleeding had occurred in 9% and 5%, respectively.

At discharge, thromboembolic or ischemic events had occurred in 5% of patients in the liberal arm and 3% in the restrictive arm. At day 28, these events had occurred in 7% and 4%, respectively.

At discharge, acute transfusion reactions had occurred in 2% of patients in the liberal arm and 1% in the restrictive arm, and infections had occurred in 24% and 26%, respectively.

By discharge, 38% of patients in the liberal arm and 32% in the restrictive arm had required some therapeutic intervention. Surgical or radiological intervention was required in 3% and 4%, respectively.

Considering these results, the investigators said the TRIGGER trial has paved the way for a phase 3 trial that could provide evidence to inform transfusion guidelines for patients with AUGIB.

Blood for transfusion

Photo by Elise Amendola

Results of a pilot study suggest a restrictive transfusion strategy may be safe for patients with acute upper gastrointestinal bleeding (AUGIB), but investigators say more research is needed.

In this study, known as TRIGGER, use of a restrictive transfusion strategy led to a 13% reduction in red blood cell (RBC) transfusions compared to the liberal strategy, but this difference was not statistically significant.

Likewise, there was no significant difference in clinical outcomes whether AUGIB patients received transfusions according to the restrictive strategy or the liberal one.

These results suggest a need for a large, randomized trial, according to investigators.

“If restrictive practice is proven to be safe in a large study, it could potentially safely reduce the use of red blood cell transfusions and produce cost savings . . . ,” said Vipul Jairath, MBChB, DPhil, of Oxford University Hospitals in the UK.

He and his colleagues conducted the TRIGGER trial and reported the results in The Lancet.

The study included 6 hospitals that had more than 20 AUGIB admissions monthly, more than 400 adult beds, 24-hour endoscopy, and onsite intensive care and surgery. Patients were eligible if they presented with new AUGIB (defined by hematemesis or melena) and were 18 or older. The only exclusion criterion was exsanguinating hemorrhage.

The investigators enrolled 936 patients—403 on the restrictive transfusion arm and 533 on the liberal arm. Patients in the restrictive arm were eligible to receive RBCs when their hemoglobin concentration fell below 80 g/L, with a post-transfusion target of 81-100 g/L.

Patients in the liberal arm were eligible for transfusion when their hemoglobin concentration fell below 100 g/L, with a post-transfusion target of 101-120 g/L. These thresholds were informed by UK transfusion practices.

Protocol adherence was 96% in the restrictive arm and 83% in the liberal arm. The mean last recorded hemoglobin concentration was 116 g/L for the restrictive arm and 118 g/L for the liberal arm.

The investigators noted that there was a 13% absolute reduction in the proportion of patients transfused in the restrictive arm, a reduction in the amount of RBCs transfused between the arms, and a separation in hemoglobin concentration between the arms, but none of these differences were significant.

In addition, there was no significant difference in clinical outcomes between the arms, although the trial was not powered to assess these outcomes.

All-cause mortality at day 28 was 7% in the liberal transfusion arm and 5% in the restrictive arm. The rate of serious adverse events at day 28 was 22% and 18%, respectively.

At hospital discharge, further bleeding had occurred in 6% of patients in the liberal arm and 4% in the restrictive arm. At day 28, further bleeding had occurred in 9% and 5%, respectively.

At discharge, thromboembolic or ischemic events had occurred in 5% of patients in the liberal arm and 3% in the restrictive arm. At day 28, these events had occurred in 7% and 4%, respectively.

At discharge, acute transfusion reactions had occurred in 2% of patients in the liberal arm and 1% in the restrictive arm, and infections had occurred in 24% and 26%, respectively.

By discharge, 38% of patients in the liberal arm and 32% in the restrictive arm had required some therapeutic intervention. Surgical or radiological intervention was required in 3% and 4%, respectively.

Considering these results, the investigators said the TRIGGER trial has paved the way for a phase 3 trial that could provide evidence to inform transfusion guidelines for patients with AUGIB.

Blood for transfusion

Photo by Elise Amendola

Results of a pilot study suggest a restrictive transfusion strategy may be safe for patients with acute upper gastrointestinal bleeding (AUGIB), but investigators say more research is needed.

In this study, known as TRIGGER, use of a restrictive transfusion strategy led to a 13% reduction in red blood cell (RBC) transfusions compared to the liberal strategy, but this difference was not statistically significant.

Likewise, there was no significant difference in clinical outcomes whether AUGIB patients received transfusions according to the restrictive strategy or the liberal one.

These results suggest a need for a large, randomized trial, according to investigators.

“If restrictive practice is proven to be safe in a large study, it could potentially safely reduce the use of red blood cell transfusions and produce cost savings . . . ,” said Vipul Jairath, MBChB, DPhil, of Oxford University Hospitals in the UK.

He and his colleagues conducted the TRIGGER trial and reported the results in The Lancet.

The study included 6 hospitals that had more than 20 AUGIB admissions monthly, more than 400 adult beds, 24-hour endoscopy, and onsite intensive care and surgery. Patients were eligible if they presented with new AUGIB (defined by hematemesis or melena) and were 18 or older. The only exclusion criterion was exsanguinating hemorrhage.

The investigators enrolled 936 patients—403 on the restrictive transfusion arm and 533 on the liberal arm. Patients in the restrictive arm were eligible to receive RBCs when their hemoglobin concentration fell below 80 g/L, with a post-transfusion target of 81-100 g/L.

Patients in the liberal arm were eligible for transfusion when their hemoglobin concentration fell below 100 g/L, with a post-transfusion target of 101-120 g/L. These thresholds were informed by UK transfusion practices.

Protocol adherence was 96% in the restrictive arm and 83% in the liberal arm. The mean last recorded hemoglobin concentration was 116 g/L for the restrictive arm and 118 g/L for the liberal arm.

The investigators noted that there was a 13% absolute reduction in the proportion of patients transfused in the restrictive arm, a reduction in the amount of RBCs transfused between the arms, and a separation in hemoglobin concentration between the arms, but none of these differences were significant.

In addition, there was no significant difference in clinical outcomes between the arms, although the trial was not powered to assess these outcomes.

All-cause mortality at day 28 was 7% in the liberal transfusion arm and 5% in the restrictive arm. The rate of serious adverse events at day 28 was 22% and 18%, respectively.

At hospital discharge, further bleeding had occurred in 6% of patients in the liberal arm and 4% in the restrictive arm. At day 28, further bleeding had occurred in 9% and 5%, respectively.

At discharge, thromboembolic or ischemic events had occurred in 5% of patients in the liberal arm and 3% in the restrictive arm. At day 28, these events had occurred in 7% and 4%, respectively.

At discharge, acute transfusion reactions had occurred in 2% of patients in the liberal arm and 1% in the restrictive arm, and infections had occurred in 24% and 26%, respectively.

By discharge, 38% of patients in the liberal arm and 32% in the restrictive arm had required some therapeutic intervention. Surgical or radiological intervention was required in 3% and 4%, respectively.

Considering these results, the investigators said the TRIGGER trial has paved the way for a phase 3 trial that could provide evidence to inform transfusion guidelines for patients with AUGIB.

Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.^1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.^3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.^6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.⁸ However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.

Methods

Study Design and Participants

The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.

Data Collection

Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.

Isokinetic Evaluation

A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.

Statistical Analysis

Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.

Results

Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).

Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05). 

Comment

This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring  and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.

Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.⁶ Furthermore, Goulden et al⁹ reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.¹⁰ In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.

Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.^11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.

The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.¹³ Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).¹⁴ In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.

This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.

Conclusion

Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.

Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.^1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.^3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.^6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.⁸ However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.

Methods

Study Design and Participants

The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.

Data Collection

Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.

Isokinetic Evaluation

A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.

Statistical Analysis

Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.

Results

Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).

Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05). 

Comment

This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring  and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.

Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.⁶ Furthermore, Goulden et al⁹ reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.¹⁰ In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.

Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.^11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.

The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.¹³ Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).¹⁴ In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.

This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.

Conclusion

Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.

Isotretinoin is a vitamin A derivative that frequently is used in the treatment of acne vulgaris.^1,2 Although isotretinoin generally is associated with favorable effects, adverse effects also have been reported.^3-5 Musculoskeletal side effects can include myalgia, sacroiliitis, back pain, diffuse idiopathic skeletal hyperostosis, ligament and tendon calcifications, bone resorption, and reduced collagen synthesis.^6,7 Elevated creatine kinase (CK) levels also have been reported in 15% to 50% of patients with isotretinoin-induced myalgia.⁸ However, there are limited data available on the effects of isotretinoin treatment on muscle strength. The objective of this study was to evaluate the impact of isotretinoin on muscle strength, fatigue, and endurance using an isokinetic dynamometer.

Methods

Study Design and Participants

The study followed a pretest-posttest design including 27 patients with acne vulgaris who were treated with oral isotretinoin (age range, 18–40 years) as well as 26 control patients for comparison. Exclusion criteria were renal or liver disease, uncontrolled hypertension, heart failure, malignancy, thyroid and bone disorders (eg, parathyroid disease, osteomalacia), use of drugs that can affect skeletal metabolism (eg, corticosteroids, heparin, anticonvulsants), and history of trauma to and/or surgery of the lower extremities. All patients were informed of the study procedure and informed consent was obtained. The study protocol was approved by the local ethics committee.

Data Collection

Participant demographics and clinical features (eg, sex, age, body mass index [BMI]) were obtained. Participants in the treatment group received oral isotretinoin 0.5 mg/kg once daily for 1 month, followed by an increased dose of 1 mg/kg once daily for 2 months. Isokinetic measurements of the knee muscles were performed on the nondominant side at baseline and at 3-month follow-up. Reports of muscular side effects were noted during the course of treatment.

Isokinetic Evaluation

A calibrated isokinetic dynamometer was used to conduct isokinetic evaluations. After performing 5 submaximal warm-up contractions, concentric peak torque (PT) values of the quadriceps and hamstrings at 60° and 180° per second angular velocities (AVs), hamstring strength to quadriceps strength ratio (H:Q ratio), and muscle fatigue were evaluated. The isokinetic test protocol included 10 repeats at 60° per second, 15 seconds of rest, and 15 repeats at 180° per second.

Statistical Analysis

Data analysis was conducted using SPSS software version 20.0. Data were expressed as mean (standard deviation [SD]). After checking normal distribution with the Kolmogorov-Smirnov test, independent t tests were used to compare the baseline parameters between the treatment and control groups. Paired t tests and Wilcoxon signed rank tests were used to compare baseline and posttreatment values where appropriate. The results were for those who completed treatment. Statistical significance was set at P<.05.

Results

Twenty-seven participants (24 female; 3 male) with newly diagnosed acne vulgaris were enrolled in the treatment group along with 26 controls (23 female; 3 male). One of the participants in the treatment group did not tolerate isotretinoin due to headache and was excluded from the study. The mean (SD) age of the participants was 20.6 (1.6) years for the treatment group and 21.3 (1.5) years for the control group, and the mean (SD) BMI for both groups was 21.8 (2.8) and 21.5 (1.8), respectively. Participant demographics and isokinetic values at baseline are presented in Table 1. No significant differences between the treatment and control groups for participant sex, age, or BMI were noted (P>.05).

Of the 26 participants in the treatment group, 5 reported myalgia and nonspecific back pain. Isokinetic measurements of the treatment group obtained using the dynamometer are shown in Table 2. Although the PT of the hamstring and quadriceps at both 60° and 180° per second AV was decreased at 3-month follow-up, there was no significant difference compared to baseline (P>.05). Additionally, no significant difference in H:Q ratio or muscle fatigue was noted (P>.05), and no significant difference in isokinetic measurements was seen in participants with myalgia (n=5) at 3-month follow-up versus baseline (P>.05). 

Comment

This study aimed to investigate the short-term effects of isotretinoin treatment on muscle strength, fatigue, and endurance in patients with acne vulgaris, which has not been widely evaluated in the literature. Although maximal PT of the hamstring  and quadriceps in the isotretinoin treatment group was decreased at 3-month follow-up, there was no statistically significant difference in all parameters (ie, PT at 60° and 180° per second, H:Q ratio, muscle fatigue) versus baseline. These findings showed that systemic isotretinoin was not associated with muscle dysfunction in this patient population.

Myalgia, particularly associated with exercise, has been seen in approximately 50% of patients treated with isotretinoin.⁶ Furthermore, Goulden et al⁹ reported that patients with higher CK levels might be at an increased risk for developing rhabdomyolysis in the setting of isotretinoin treatment. High CK levels indicate serious muscular cell damage and are usually associated with release of myoglobin from muscular cells.¹⁰ In the current study, 5 participants reported myalgia and nonspecific back pain at 3-month follow-up; however, no participants reported muscle weakness. Differences in the isokinetic measurements of participants with myalgia at baseline and at 3-month follow-up were not statistically significant.

Muscles mainly consist of type I (slow oxidative), type IIA (fast oxidative), and type IIB (fast glycolytic) muscle fibers. Type I fibers produce low force and high endurance, type IIB fibers produce high force and low endurance, and type IIA fibers fall in between the two. At low AVs (eg, 60° per second), only type II fibers contract. As the AV increases (eg, 180° per second), only type II fibers contract. Consequently, the observation of a decrease in the isokinetic test parameters at low or high AVs indicate the decrease in type I or type II contracting muscle fibers.^11,12 In our study, the isokinetic values did not significantly change. As such, we concluded that isotretinoin treatment did not result in the reduction of muscle fibers in our patient population.

The H:Q ratio is the indicator of muscle balance and dynamic stabilization of the knee. It is calculated by dividing the PT of the hamstrings by the PT of the quadriceps in concentric motion.¹³ Additionally, muscle fatigue demonstrates the endurance of the contraction of type IIB fibers (anaerobic).¹⁴ In our study, isotretinoin treatment did not impact the H:Q ratio or muscle fatigue.

This study included a few important limitations. The sample size was small, particularly concerning the number of participants who reported myalgia. The lack of laboratory evaluations (eg, creatinine kinase) also was a limitation. Finally, the short study period limited the conclusions that could be drawn from the data.

Conclusion

Results from the current study revealed that systemic isotretinoin treatment did not alter muscle strength, fatigue, or endurance. Further studies taking into account histologic evaluations with larger sample sizes and long-term follow-up are needed.

Alevicyn SG Antipruritic Spray Gel

IntraDerm Pharmaceuticals, a division of Oculus Innovative Sciences, Inc, receives 510(k) clearance from the US Food and Drug Administration for Alevicyn SG Antipruritic Spray Gel with both prescription and over-the-counter indications. The Alevicyn SG prescription product manages and relieves the burning, itching, and pain experienced with dermatoses such as radiation dermatitis and atopic dermatitis. It also relieves the pain of first- and second-degree burns and helps to relieve dry waxy skin by maintaining a moist wound environment, which is beneficial to the healing process. The over-the-counter product relieves the burning and itching associated with many common types of skin irritation, lacerations, abrasions, and minor burns including sunburn. For more information, visit www.intraderm.com.
Promius Promise

Promius Pharma LLC announces that the Promius Promise program has been expanded to include Cloderm (clocortolone pivalate) Cream 0.1% and Trianex (triamcinolone acetonide) Ointment 0.05%, both for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. The Promius Promise program was created in 2013 to support patients. This program features a dedicated call center staff to educate patients about their insurance coverage and answer any questions they may have about their out-of-pocket cost, co-pay assistance, and prior authorizations. For more information, visit www.promiuspharma.com.
Radiesse

Merz North America, Inc, receives US Food and Drug Administration approval of Radiesse for correction of volume loss in the dorsum of the hands. Radiesse is an opaque dermal filler composed of calcium hydroxylapatite microspheres suspended in a water-based gel carrier. It provides an immediate volumizing effect and helps reduce the prominence of tendons and veins in the hands, delivering natural-looking results that can last up to 1 year. Radiesse also is indicated for subdermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. For more information, visit www.MerzUSA.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].

Alevicyn SG Antipruritic Spray Gel

IntraDerm Pharmaceuticals, a division of Oculus Innovative Sciences, Inc, receives 510(k) clearance from the US Food and Drug Administration for Alevicyn SG Antipruritic Spray Gel with both prescription and over-the-counter indications. The Alevicyn SG prescription product manages and relieves the burning, itching, and pain experienced with dermatoses such as radiation dermatitis and atopic dermatitis. It also relieves the pain of first- and second-degree burns and helps to relieve dry waxy skin by maintaining a moist wound environment, which is beneficial to the healing process. The over-the-counter product relieves the burning and itching associated with many common types of skin irritation, lacerations, abrasions, and minor burns including sunburn. For more information, visit www.intraderm.com.
Promius Promise

Promius Pharma LLC announces that the Promius Promise program has been expanded to include Cloderm (clocortolone pivalate) Cream 0.1% and Trianex (triamcinolone acetonide) Ointment 0.05%, both for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. The Promius Promise program was created in 2013 to support patients. This program features a dedicated call center staff to educate patients about their insurance coverage and answer any questions they may have about their out-of-pocket cost, co-pay assistance, and prior authorizations. For more information, visit www.promiuspharma.com.
Radiesse

Merz North America, Inc, receives US Food and Drug Administration approval of Radiesse for correction of volume loss in the dorsum of the hands. Radiesse is an opaque dermal filler composed of calcium hydroxylapatite microspheres suspended in a water-based gel carrier. It provides an immediate volumizing effect and helps reduce the prominence of tendons and veins in the hands, delivering natural-looking results that can last up to 1 year. Radiesse also is indicated for subdermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. For more information, visit www.MerzUSA.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].

Alevicyn SG Antipruritic Spray Gel

IntraDerm Pharmaceuticals, a division of Oculus Innovative Sciences, Inc, receives 510(k) clearance from the US Food and Drug Administration for Alevicyn SG Antipruritic Spray Gel with both prescription and over-the-counter indications. The Alevicyn SG prescription product manages and relieves the burning, itching, and pain experienced with dermatoses such as radiation dermatitis and atopic dermatitis. It also relieves the pain of first- and second-degree burns and helps to relieve dry waxy skin by maintaining a moist wound environment, which is beneficial to the healing process. The over-the-counter product relieves the burning and itching associated with many common types of skin irritation, lacerations, abrasions, and minor burns including sunburn. For more information, visit www.intraderm.com.
Promius Promise

Promius Pharma LLC announces that the Promius Promise program has been expanded to include Cloderm (clocortolone pivalate) Cream 0.1% and Trianex (triamcinolone acetonide) Ointment 0.05%, both for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. The Promius Promise program was created in 2013 to support patients. This program features a dedicated call center staff to educate patients about their insurance coverage and answer any questions they may have about their out-of-pocket cost, co-pay assistance, and prior authorizations. For more information, visit www.promiuspharma.com.
Radiesse

Merz North America, Inc, receives US Food and Drug Administration approval of Radiesse for correction of volume loss in the dorsum of the hands. Radiesse is an opaque dermal filler composed of calcium hydroxylapatite microspheres suspended in a water-based gel carrier. It provides an immediate volumizing effect and helps reduce the prominence of tendons and veins in the hands, delivering natural-looking results that can last up to 1 year. Radiesse also is indicated for subdermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. For more information, visit www.MerzUSA.com.

If you would like your product included in Product News, please e-mail a press release to the Editorial Office at [email protected].

Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.^1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.³ Reports of the gender distribution of the disease vary but often show female predominance.⁴ Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.¹         

The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.⁵ Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.² These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.⁶ The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.²

Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.⁷

Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.⁸ Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).⁹ Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.¹⁰ Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.¹¹ Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.¹²

In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.^13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.¹⁶

Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.¹⁷ Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.¹⁸ In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.¹⁹ The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.

We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.⁸

Methods

Study Design

This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.

Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.

The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.

Efficacy Evaluations

There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.

The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.

Safety

Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).

Statistical Analysis

Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)

Results

Study Participants

Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.

Figure 1. Study disposition and reasons for study discontinuation. Percentages of participants who discontinued prior to treatment randomization are based on the number of patients screened, whereas all other percentages are based on the number of participants randomized. After completion of treatment, all participants (including those who prematurely discontinued treatment) were invited to enter the follow-up phase.

Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.

Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.

Efficacy

Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F_1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.

Figure 2. Percentages of participants who had successful treatment outcomes based on investigator global assessment scores (clear or minimal) at weeks 4, 8, 12, and 16 (FU). P values were calculated from the Pearson c² test. Last observation carried forward was not applied to FU analysis. EoT indicates end of treatment; FU, after 4 weeks of follow-up without treatment.

Figure 3. Mean nominal change in inflammatory lesion count from baseline at weeks 4, 8, 12, and 16 (FU). P values were calculated from 2-sided t tests. Last observation carried forward was not applied to FU analysis. SD indicates standard deviation; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).

Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.

Safety

Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.

The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).

All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.

Comment

Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.

Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.

The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.²⁰

Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.

Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.⁸

Conclusion

The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.^17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.²² However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.¹⁸ The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.

Addendum

After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.

Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.

APPENDIX

Supplementary Methods

Supplementary Study Design

This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.

Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.

The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.

Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.

Additional Efficacy Evaluations

A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.

Additional Safety

Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.

Statistical Analysis

The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.

A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.

Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.⁸ To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.^1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.³ Reports of the gender distribution of the disease vary but often show female predominance.⁴ Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.¹         

The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.⁵ Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.² These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.⁶ The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.²

Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.⁷

Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.⁸ Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).⁹ Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.¹⁰ Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.¹¹ Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.¹²

In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.^13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.¹⁶

Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.¹⁷ Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.¹⁸ In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.¹⁹ The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.

We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.⁸

Methods

Study Design

This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.

Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.

The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.

Efficacy Evaluations

There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.

The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.

Safety

Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).

Statistical Analysis

Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)

Results

Study Participants

Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.

Figure 1. Study disposition and reasons for study discontinuation. Percentages of participants who discontinued prior to treatment randomization are based on the number of patients screened, whereas all other percentages are based on the number of participants randomized. After completion of treatment, all participants (including those who prematurely discontinued treatment) were invited to enter the follow-up phase.

Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.

Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.

Efficacy

Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F_1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.

Figure 2. Percentages of participants who had successful treatment outcomes based on investigator global assessment scores (clear or minimal) at weeks 4, 8, 12, and 16 (FU). P values were calculated from the Pearson c² test. Last observation carried forward was not applied to FU analysis. EoT indicates end of treatment; FU, after 4 weeks of follow-up without treatment.

Figure 3. Mean nominal change in inflammatory lesion count from baseline at weeks 4, 8, 12, and 16 (FU). P values were calculated from 2-sided t tests. Last observation carried forward was not applied to FU analysis. SD indicates standard deviation; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).

Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.

Safety

Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.

The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).

All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.

Comment

Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.

Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.

The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.²⁰

Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.

Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.⁸

Conclusion

The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.^17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.²² However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.¹⁸ The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.

Addendum

After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.

Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.

APPENDIX

Supplementary Methods

Supplementary Study Design

This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.

Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.

The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.

Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.

Additional Efficacy Evaluations

A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.

Additional Safety

Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.

Statistical Analysis

The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.

A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.

Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.⁸ To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Rosacea is a common dermatologic disorder that generally is characterized by erythema as well as papules and pustules on the cheeks, chin, forehead, and nose. Moreover, telangiectasia and burning or stinging sensations often occur.^1,2 These clinical manifestations and other related ones frequently lead to the perception of “sensitive skin.” Rosacea patients often experience low self-esteem, anxiety, and social embarrassment.³ Reports of the gender distribution of the disease vary but often show female predominance.⁴ Although it also occurs in darker skin types, rosacea is more common in individuals with lighter skin.¹         

The etiology of rosacea is not yet fully understood, but the underlying pathology has been attributed to dysregulated immune responses. Although the flares of a typical fluctuating disease course often are caused by exogenous triggers, there is evidence that an underlying genetic component predisposes some individuals to pathologic changes associated with the condition.⁵ Augmented immune activity and proinflammatory signaling appear to induce the infiltration of inflammatory elements into affected areas.² These regions show dilated vasculature and increased cutaneous blood flow secondary to inflammation. Systemic oxidative stress also may contribute to epidermal dysfunction, as the antioxidant capacity of the skin in patients with rosacea is depleted relative to that of healthy individuals. The biochemical and vascular changes characteristic of rosacea coincide with aberrant permeability of the stratum corneum.⁶ The resulting decreased hydration and water loss across the skin contribute to the sensitivity and irritation typical of the disease.²

Current guidelines for the optimal management of rosacea with papulopustular lesions recommend skin care, photoprotection, and topical therapy. Depending on the severity of disease and the likelihood of adherence to a topical regimen, use of oral agents may be warranted.⁷

Azelaic acid (AzA), an unbranched saturated dicarboxylic acid (1,7-heptanedicarboxylic acid) that occurs in plants, is one of several US Food and Drug Administration–approved topical agents for the treatment of inflammatory lesions in rosacea.⁸ Although the pathophysiology of rosacea is not yet fully understood, there is a growing consensus about the role of proinflammatory molecules (eg, kallikrein 5, cathelicidins) as well as reactive oxygen species (ROS).⁹ Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes through several pathways, including modulation of the signaling pathways of peroxisome proliferator-activated receptor g and nuclear factor kB, concurrent with the observed inhibition of proinflammatory cytokine secretion.¹⁰ Additionally, AzA can inhibit the release of ROS from neutrophils and also may reduce ROS by direct scavenging effects.¹¹ Further, AzA shows direct inhibition of kallikrein 5 in human keratinocytes as well as a reduction of the expression of kallikrein 5 and cathelicidin in murine skin and the facial skin of patients with rosacea.¹²

In a series of randomized trials in patients with papulopustular rosacea (PPR), AzA has shown clinical efficacy and safety as a topical treatment.^13-15 Based on these studies, a gel formulation of AzA with a 15% concentration has been approved for treating inflammatory papules and pustules of mild to moderate rosacea.¹⁶

Although AzA delivered in a gel matrix is an effective therapy, topical delivery of active pharmaceutical ingredients via foam is often preferred over traditional vehicles in patients with sensitive skin. Patient rationale for favoring foam includes improved appearance and ease of application, namely easier to spread with a reduced need to manipulate inflamed skin.¹⁷ Also, data reveal that patients may be more compliant with a treatment that meets their needs such as an optimized foam formulation.¹⁸ In addition, the lipid components of an optimized formulation are thought to contribute to an improved skin condition.¹⁹ The foam vehicle used in this study is a proprietary oil-in-water formulation that includes fatty alcohols and triglycerides. The novel delivery of AzA in a foam formulation will provide clinicians and patients with a new option for improved individualized care.

We report the primary results of a phase 3 study in patients with PPR comparing the efficacy and safety of twice-daily AzA foam 15% with vehicle foam. The phase 3 study builds on the results of a prior randomized double-blind trial (N=401) that demonstrated significant improvements relative to vehicle in therapeutic success rate (P=.017) and decreased inflammatory lesion count (ILC)(P<.001) among patients treated with AzA foam 15%.⁸

Methods

Study Design

This phase 3 randomized, double-blind, vehicle-controlled, parallel-group, multicenter study was conducted in patients with PPR according to Good Clinical Practice guidelines in 48 study centers in the United States. The objective was to evaluate a 12-week, twice-daily (morning and evening) course of AzA foam 15% versus vehicle.

Participants were men and women aged 18 years or older with moderate to severe PPR (as determined by investigator global assessment [IGA]) presenting with 12 to 50 papules and/or pustules and persistent erythema with or without telangiectasia. Informed consent was obtained from all participants before any study-related activities were carried out.

The study products were applied to the entire facial area each morning and evening at a dose of 0.5 g, thus administering 150 mg of AzA daily in the active arm of the trial (computerized randomization 1:1). The treatment period lasted 12 weeks, and participants were evaluated at baseline and weeks 4, 8, and 12. The follow-up period lasted 4 weeks following the end of treatment (EoT) and was concluded with one final end-of-study visit.

Efficacy Evaluations

There were 2 coprimary efficacy end points. Therapeutic success rate was evaluated using the IGA scale (clear, minimal, mild, moderate, or severe). Treatment success was defined as an IGA score of either clear or minimal (with at least a 2-step improvement) at EoT, whereas treatment failure was constituted by IGA scores of mild, moderate, or severe.

The second coprimary end point was the nominal change in ILC from baseline to EoT as determined by the total number of facial papules and pustules. Efficacy and safety parameters were evaluated at weeks 4, 8, and 12, as well as at the end of the 4-week follow-up period. Throughout the study, the investigator, participants, and all study personnel remained blinded.

Safety

Information about adverse events (AEs) was collected at each study visit, and AEs were graded according to seriousness (yes or no) and intensity (mild, moderate, or severe).

Statistical Analysis

Efficacy was confirmed by analysis of the treatment success rate at EoT with Cochran-Mantel-Haenszel test statistics, including a point estimate and 95% confidence interval (CI) for the odds ratio. Change in ILC at EoT was analyzed via an analysis of covariance model using treatment, center, and baseline lesion count as factors. (Additional methods can be found in the Appendix below.)

Results

Study Participants

Of the 1156 patients who were screened for eligibility, 961 were randomized to treatment with AzA foam (n=484) or vehicle (n=477)(Figure 1). Sixty-four (13.2%) participants in the AzA foam group and 79 (16.6%) in the vehicle group discontinued treatment before completing the study. The most common reasons for discontinuation were participant withdrawal from the study and lost to follow-up. Six (1.2%) participants from the AzA foam group and 12 (2.5%) from the vehicle group discontinued because of AEs. All safety and efficacy data presented are based on the full analysis set, which consisted of the 961 participants randomized to treatment.

Figure 1. Study disposition and reasons for study discontinuation. Percentages of participants who discontinued prior to treatment randomization are based on the number of patients screened, whereas all other percentages are based on the number of participants randomized. After completion of treatment, all participants (including those who prematurely discontinued treatment) were invited to enter the follow-up phase.

Demographic and baseline characteristics were balanced between the treatment groups (Table 1). The majority of participants were female (73.0%) and white (95.5%), reflecting the patient populations of independent studies that found a higher prevalence of rosacea in women and lighter skin types.4 There were no significant differences in baseline measures of PPR severity between the treatment groups. Participants in the AzA foam and vehicle groups had a mean ILC of 21.7 and 21.2, respectively, and 76.4% of participants had more than 14 lesions. All participants had an IGA score of moderate (86.8%) or severe (13.2%). Moderate or severe erythema was present in 91.5% of participants.

Treatment compliance, as measured by the percentage of expected doses that were actually administered, was 97.1% in the AzA foam group and 95.9% in the vehicle group.

Efficacy

Results from both primary end points demonstrated superior efficacy of AzA foam over vehicle. The AzA foam group achieved a greater IGA success rate at EoT compared with the vehicle group (32.0% vs 23.5%; Cochran-Mantel-Haenszel test center-adjusted P<.001; odds ratio, 1.6; 95% CI, 1.2-2.2). Treatment success rate was higher in the AzA foam group than in the vehicle group at every time point past baseline (Figure 2). Similarly, the decrease in mean nominal ILC values was greater in the AzA foam group at every time point after baseline (Figure 3), and the treatment difference at EoT was statistically significant in favor of AzA foam (-2.7, F_1,920=23.7, P<.001; 95% CI, -3.8 to -1.6). The divergence between treatment groups at week 4 reveals an onset of AzA effect early in the study.

Figure 2. Percentages of participants who had successful treatment outcomes based on investigator global assessment scores (clear or minimal) at weeks 4, 8, 12, and 16 (FU). P values were calculated from the Pearson c² test. Last observation carried forward was not applied to FU analysis. EoT indicates end of treatment; FU, after 4 weeks of follow-up without treatment.

Figure 3. Mean nominal change in inflammatory lesion count from baseline at weeks 4, 8, 12, and 16 (FU). P values were calculated from 2-sided t tests. Last observation carried forward was not applied to FU analysis. SD indicates standard deviation; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

Although the AzA foam group showed significantly better efficacy results than the vehicle group for the coprimary end points, participants in the vehicle group did show appreciable IGA success rates (23.5%) and changes in ILC (-10.3) at EoT (Figures 2 and 3).

Notably, the AzA foam group maintained better results than vehicle for both primary end points even at the end of the 4-week follow-up after EoT (Figures 2 and 3). Sensitivity analysis (data not shown) confirmed the findings from the full analysis set.

Safety

Adverse events were experienced by 149 (30.8%) participants in the AzA foam group and 119 (24.9%) in the vehicle group. The most common noncutaneous AEs (>1% of participants) reported during AzA foam treatment were nasopharyngitis, headache, upper respiratory tract infection, and influenza. In the vehicle group, the most common noncutaneous AEs reported were nasopharyngitis and headache. Drug-related AEs (relationship assessed by the investigator) were reported slightly more often in the AzA foam group (7.6%) than in the vehicle group (4.6%). Drug-related AEs were predominantly cutaneous and occurred at the site of application (Table 2). Drug-related cutaneous AEs were more common in the AzA foam group (7.0%) than in the vehicle group (4.4%). Although serious AEs were more common in the vehicle group, all were regarded as unrelated to the study medication. A single death occurred in the vehicle group due to an accident unrelated to the study drug.

The most frequent drug-related AEs in participants treated with AzA foam versus vehicle were application-site pain (3.5% vs 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). The classical rosacea symptom of stinging is subsumed under the term application-site pain, according to MedDRA (Medical Dictionary for Regulatory Activities).

All other drug-related AEs occurred at a frequency of less than 1% in participants from both groups. Serious AEs were rare and unrelated to treatment, with 3 AEs reported in the AzA foam group and 4 in the vehicle group. Adverse events leading to study drug withdrawal occurred in less than 2% of participants and were more common in the vehicle group (2.5%) than in the AzA foam group (1.2%). Of the 3 drug-related AEs leading to withdrawal in the AzA foam group, 2 were due to cutaneous reaction and 1 was due to a burning sensation. The number of active drug-related cutaneous AEs was highest during the first 4 weeks of treatment and declined over the course of the study (eFigure).

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

More than 96% of AEs were resolved by the end of the study. Of the participants experiencing AEs that did not resolve during the course of the study, 16 were in the AzA foam group and 10 in the vehicle group. Six unresolved AEs were drug related, with 3 occurring in each treatment group. Unresolved drug-related cutaneous AEs in the AzA foam group were pain, pruritus, and dryness at the application site.

Comment

Overall, the results from this phase 3 trial demonstrate that the new foam formulation of AzA was efficacious and safe in a 12-week, twice-daily course of treatment for moderate to severe PPR. The AzA foam formulation was significantly superior to vehicle (P<.001) for both primary efficacy end points. Participants in the AzA foam group achieved therapeutic success at a higher rate than the vehicle group, and the change in nominal ILC at EoT was significantly greater for participants treated with AzA foam than for those treated with vehicle (P<.001). Differences between the 2 treatment groups for the coprimary end point measures arose early in the study, demonstrating that symptoms were rapidly controlled. Between weeks 8 and 12 (EoT), the rate of increase of beneficial effects in the AzA foam group remained high, while the vehicle group showed a notable slowing. There was no indication of any rebound effect in overall disease severity subsequent to EoT. After 4 weeks of follow-up, there was still a beneficial treatment effect present in favor of the AzA foam group, as indicated by the persistence of improvements in both coprimary end point measures throughout the follow-up period.

Analyses of alternative populations and secondary end points (data not shown) supported the efficacy results reported here. There was no indication of irregular study center effects, and the sensitivity analyses demonstrated robustness of the data for the observed treatment effects.

The use of vehicle foam alone appeared to be beneficial in reducing ILC and improving IGA rating, which suggests that the properties of the new foam formulation are favorable for the inflamed lesional skin of rosacea. Of note, other dermatology studies, including trials in rosacea, have reported therapeutic effects of vehicle treatment that may be attributable to the positive effects of skin care with certain formulations.²⁰

Azelaic acid foam was well tolerated in the current study. More than 93% of AEs in either treatment group were of mild or moderate severity. The incidence of drug-related AEs was low in both groups and mainly occurred at the application site. There were no drug-related severe or serious AEs. The low incidence of reported drug-related noncutaneous AEs in the AzA foam group (dysgeusia in 1 patient and headache in 2 patients) supports the known favorable systemic tolerance profile of AzA.

Although most drug-related AEs occurred at the application site, they were generally transient, with the majority of events in the AzA foam group lasting no more than 1 hour. Most cutaneous AEs developed early in the study. In the AzA foam group, the prevalence of drug-related cutaneous AEs dropped at every time interval as the study progressed (eFigure). Very few AEs of any type persisted through the end of the study. These safety results were accompanied by a high compliance rate and a high participation rate throughout the course of the study. Taken together, the available data for this AzA foam formulation support a favorable tolerability profile. The results of this study are consistent with and expand on data from an earlier investigation of similar design.⁸

Conclusion

The development of an AzA foam formulation with higher lipid content was intended to expand the treatment options available to physicians and patients who are managing rosacea. Most topical dermatologic treatments are currently delivered in classical formulations such as creams or gels, but patients who use topical therapies have rated messiness and ease of application among the most important characteristics affecting quality of life.^17,21 Foam formulations may offer improvements in this regard; ease of application may minimize unnecessary manipulation of inflamed skin and contribute to a high level of user satisfaction.²² However, the design of the current study was limited to evaluating only the AzA foam formulation versus a foam vehicle, and direct comparisons of clinical efficacy and tolerability to other AzA topical preparations were not performed. Nonetheless, patients have previously reported that they would be more likely to comply with a recommended course of dermatologic foam therapy than other topical formulations.¹⁸ The proposed foam formulation was designed to attend to the specific needs of the dry and sensitive skin in rosacea by combining the demonstrated efficacy properties exhibited by AzA gel 15% with the good tolerability and acceptability of a lipid-containing foam formulation. Development of this formulation was targeted to obtain a product that would be highly spreadable, dry quickly, and be easy to apply. The available data for this AzA foam formulation support the value of this option in the topical treatment of rosacea. The success in reduction of overall disease severity, lack of any rebound after EoT, and the observed tolerability and high adherence rates suggest that this novel formulation is a useful addition to current treatment options for rosacea.

Addendum

After release of the study data for unblinding and statistical evaluation, the following inconsistency regarding patient distribution was noted: 1 participant was incorrectly evaluated as part of the AzA foam analysis group when in fact this patient was randomized to vehicle and was treated throughout the study with vehicle. This participant did not experience any AE and did not show any IGA improvement at the EoT. As this single case did not have an impact on the statistical conclusions or interpretation of the results, the released study data have not been changed. This deviation was described as a database erratum in the study report.

Acknowledgement—Editorial support through inVentiv Medical Communications, New York, New York, was provided by Bayer HealthCare Pharmaceuticals Inc.

APPENDIX

Supplementary Methods

Supplementary Study Design

This study met all local legal and regulatory requirements and was conducted according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Before the start of the study and implementation, the protocol and all amendments were approved by the appropriate independent ethics committee or institutional review board at each study site. Two protocol amendments were implemented before the first participant visit.

Exclusion criteria included the presence of dermatoses that could interfere with rosacea diagnosis or evaluation, facial laser surgery or topical use of any medication to treat rosacea within 6 weeks before randomization, systemic use of any medications to treat rosacea, and known unresponsiveness to AzA treatment. Further standard exclusion criteria included alcohol or drug use or parallel participation in other clinical studies, which were necessary to exclude undue influence on study evaluations and/or participant safety. The study was conducted by qualified investigators at 48 centers in the United States.

The investigational product was filled in identical containers according to the randomization list generated by a computer program using blocks. Complete blocks of study medication were distributed to the centers. Eligible participants were randomized 1:1 into either AzA foam or vehicle treatment groups by assignment of a randomization number at baseline. A blind investigational product under the same randomization number was dispensed to and returned from participants by study personnel who were not involved in the assessments. Blinding was achieved by using labels on the investigational products that did not allow identification of the true medication.

Compliance was evaluated from participant diaries as well as the number of expected doses and actually applied doses.

Additional Efficacy Evaluations

A number of secondary variables (not reported here) were assessed, including changes in other manifestations of PPR, as well as participant assessments of treatment response, tolerability, cosmetic preferences, and quality of life.

Additional Safety

Investigators reported a yes or no response as to whether there was a reasonable causal relationship between AEs and treatment. Moreover, AEs that began at the start of or during treatment were considered treatment emergent. Cutaneous AEs were further assessed regarding location and duration. An AE was deemed local if it occurred at the application site and transient if it subsided within 60 minutes of onset.

Statistical Analysis

The primary efficacy analyses presented here were based on the full analysis set of participants who were randomized and had medication dispensed. For participants with no EoT value, the last nonmissing value was used including baseline (last-observation-carried-forward methodology). Participants who discontinued treatment prematurely because of lack of efficacy were considered to be treatment failures, regardless of the reported IGA score. Statistical significance was needed for both coprimary efficacy variables at a 1-sided 2.5% significance level to show confirmed superiority of AzA foam versus vehicle.

A number of sensitivity analyses were performed, including an analysis of the coprimary end points using observed data, analysis of the per-protocol population of participants who did not prematurely discontinue treatment and had no major protocol deviations, subgroup analyses, and the use of statistical methods to investigate the effect of missing observations. Analyses of success rate and nominal change in ILC were repeated for each postbaseline visit using χ² and t tests, respectively. All summary and statistical analyses were performed according to the study protocol (unchanged after the start of the study) using SAS version 9.2.

Results from a prior study provided the basis for the sample size, which was calculated to show a significant difference in both primary efficacy end points with a power of 90%.⁸ To allow for dropouts, 480 participants in each treatment group were to be randomized for a total of 960 participants.

eFigure. Number of active drug-related cutaneous AEs at each study interval (full analysis set). AE indicates adverse event; EoT, end of treatment; FU, after 4 weeks of follow-up without treatment.

The use of gauges to expand or alter the shape of the earlobe is a relatively popular trend in this day and age. However, as with tattoos, patients sometimes request removal of this physical alteration out of regret or a change in lifestyle. Managing these patients poses a challenge for dermatologists due to the variable degree of tissue ptosis left behind.

Collins et al published a retrospective review in JAMA Facial Plastic Surgery (2015;17:144-148) of their last 20 patients treated for earlobe reconstruction that had at least 1 year of follow-up. The earlobe deformities were classified as small, medium, or large. Small defects were those that were small enough to be treated with an elliptical excision and primary closure. Medium defects were those that had a disruption of the natural curve of the inferior earlobe and a more distinct soft tissue loss of the lobule. A primary closure of this type of defect may cause an unnaturally long lobule. The authors suggested excising the opening and then using a posterior-based advancement flap to restore the natural earlobe contour while improving some of the soft tissue loss. Large defects were those with a lot of volume loss and tissue redundancy. These defects required a wedge excision of the elongated piercing site and a posterior-superior–based advancement flap with 2 arms to it.

Results showed that all 20 patients did well after at least 1 year without the need for further reconstruction or excisional scar revision. Two patients did undergo dermabrasion at 1 year to help blend the final scar.

What’s the issue?

Trends such as the placement of earlobe gauges may wane at some point, resulting in a number of patients seeking our help to repair their earlobes. The approach presented in this study tailors the method of repair to the size of the defect. By doing so, one can hope to restore the natural shape and volume to achieve a natural-appearing earlobe. Have you seen an increase in the number of patients seeking this type of repair?

We want to know your views! Tell us what you think.

The use of gauges to expand or alter the shape of the earlobe is a relatively popular trend in this day and age. However, as with tattoos, patients sometimes request removal of this physical alteration out of regret or a change in lifestyle. Managing these patients poses a challenge for dermatologists due to the variable degree of tissue ptosis left behind.

Collins et al published a retrospective review in JAMA Facial Plastic Surgery (2015;17:144-148) of their last 20 patients treated for earlobe reconstruction that had at least 1 year of follow-up. The earlobe deformities were classified as small, medium, or large. Small defects were those that were small enough to be treated with an elliptical excision and primary closure. Medium defects were those that had a disruption of the natural curve of the inferior earlobe and a more distinct soft tissue loss of the lobule. A primary closure of this type of defect may cause an unnaturally long lobule. The authors suggested excising the opening and then using a posterior-based advancement flap to restore the natural earlobe contour while improving some of the soft tissue loss. Large defects were those with a lot of volume loss and tissue redundancy. These defects required a wedge excision of the elongated piercing site and a posterior-superior–based advancement flap with 2 arms to it.

Results showed that all 20 patients did well after at least 1 year without the need for further reconstruction or excisional scar revision. Two patients did undergo dermabrasion at 1 year to help blend the final scar.

What’s the issue?

Trends such as the placement of earlobe gauges may wane at some point, resulting in a number of patients seeking our help to repair their earlobes. The approach presented in this study tailors the method of repair to the size of the defect. By doing so, one can hope to restore the natural shape and volume to achieve a natural-appearing earlobe. Have you seen an increase in the number of patients seeking this type of repair?

We want to know your views! Tell us what you think.

The use of gauges to expand or alter the shape of the earlobe is a relatively popular trend in this day and age. However, as with tattoos, patients sometimes request removal of this physical alteration out of regret or a change in lifestyle. Managing these patients poses a challenge for dermatologists due to the variable degree of tissue ptosis left behind.

Collins et al published a retrospective review in JAMA Facial Plastic Surgery (2015;17:144-148) of their last 20 patients treated for earlobe reconstruction that had at least 1 year of follow-up. The earlobe deformities were classified as small, medium, or large. Small defects were those that were small enough to be treated with an elliptical excision and primary closure. Medium defects were those that had a disruption of the natural curve of the inferior earlobe and a more distinct soft tissue loss of the lobule. A primary closure of this type of defect may cause an unnaturally long lobule. The authors suggested excising the opening and then using a posterior-based advancement flap to restore the natural earlobe contour while improving some of the soft tissue loss. Large defects were those with a lot of volume loss and tissue redundancy. These defects required a wedge excision of the elongated piercing site and a posterior-superior–based advancement flap with 2 arms to it.

Results showed that all 20 patients did well after at least 1 year without the need for further reconstruction or excisional scar revision. Two patients did undergo dermabrasion at 1 year to help blend the final scar.

What’s the issue?

Trends such as the placement of earlobe gauges may wane at some point, resulting in a number of patients seeking our help to repair their earlobes. The approach presented in this study tailors the method of repair to the size of the defect. By doing so, one can hope to restore the natural shape and volume to achieve a natural-appearing earlobe. Have you seen an increase in the number of patients seeking this type of repair?

We want to know your views! Tell us what you think.

Head contact with other players, not with the ball, is the main source of concussions among high-school soccer players of both sexes, according to a report published online July 13 in JAMA Pediatrics.

Several studies have shown that “heading” the ball during soccer practices and games is responsible for many soccer-related concussions, and some have called for banning such heading, especially among children and adolescents, to make the sport safer. But until now, no large study has examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts cannot be considered evidence based, said R. Dawn Comstock, Ph.D., an epidemiologist at the University of Colorado Denver, Aurora, and her associates.

©James Boulette/iStockphoto.com

The investigators performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games which required medical attention and restricted the athlete’s participation for 1 or more days. They assessed nationally representative samples of 100 high schools every year for a 9-year period. There were 627 concussions during 1,393,753 athletic exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athletic exposures among boys (2.78 per 10,000 exposures).

The most common mechanism of concussion was player-to-player contact among both boys (68.8% of concussions) and girls (51.3% of concussions). In contrast, contact with the ball accounted for 17% of concussions among boys and 29% among girls.

The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post (JAMA Pediatr. 2015 July 13 [doi:10.1001/jamapediatrics.2015.1062]).

“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism (i.e., in preventing concussion injuries) unless such a ban is combined with concurrent efforts to reduce athlete-athlete contact throughout the game,” Dr. Comstock and her associates said.

Moreover, “it may be culturally more tolerable to the soccer community to attempt to reduce athlete-athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, they added.

Head contact with other players, not with the ball, is the main source of concussions among high-school soccer players of both sexes, according to a report published online July 13 in JAMA Pediatrics.

Several studies have shown that “heading” the ball during soccer practices and games is responsible for many soccer-related concussions, and some have called for banning such heading, especially among children and adolescents, to make the sport safer. But until now, no large study has examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts cannot be considered evidence based, said R. Dawn Comstock, Ph.D., an epidemiologist at the University of Colorado Denver, Aurora, and her associates.

©James Boulette/iStockphoto.com

The investigators performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games which required medical attention and restricted the athlete’s participation for 1 or more days. They assessed nationally representative samples of 100 high schools every year for a 9-year period. There were 627 concussions during 1,393,753 athletic exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athletic exposures among boys (2.78 per 10,000 exposures).

The most common mechanism of concussion was player-to-player contact among both boys (68.8% of concussions) and girls (51.3% of concussions). In contrast, contact with the ball accounted for 17% of concussions among boys and 29% among girls.

The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post (JAMA Pediatr. 2015 July 13 [doi:10.1001/jamapediatrics.2015.1062]).

“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism (i.e., in preventing concussion injuries) unless such a ban is combined with concurrent efforts to reduce athlete-athlete contact throughout the game,” Dr. Comstock and her associates said.

Moreover, “it may be culturally more tolerable to the soccer community to attempt to reduce athlete-athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, they added.

Head contact with other players, not with the ball, is the main source of concussions among high-school soccer players of both sexes, according to a report published online July 13 in JAMA Pediatrics.

Several studies have shown that “heading” the ball during soccer practices and games is responsible for many soccer-related concussions, and some have called for banning such heading, especially among children and adolescents, to make the sport safer. But until now, no large study has examined the exact mechanism of head injuries among school-aged soccer players, so such prevention efforts cannot be considered evidence based, said R. Dawn Comstock, Ph.D., an epidemiologist at the University of Colorado Denver, Aurora, and her associates.

©James Boulette/iStockphoto.com

The investigators performed a retrospective analysis of data from a large, Internet-based sports injury surveillance study, focusing on concussions sustained during soccer practices or games which required medical attention and restricted the athlete’s participation for 1 or more days. They assessed nationally representative samples of 100 high schools every year for a 9-year period. There were 627 concussions during 1,393,753 athletic exposures among girls (4.50 per 10,000 exposures) and 442 concussions during 1,592,238 athletic exposures among boys (2.78 per 10,000 exposures).

The most common mechanism of concussion was player-to-player contact among both boys (68.8% of concussions) and girls (51.3% of concussions). In contrast, contact with the ball accounted for 17% of concussions among boys and 29% among girls.

The number and types of concussion symptoms were the same, regardless of whether the concussion was caused by player-to-player contact or player-to-ball contact. However, symptom resolution time was slightly but significantly longer for both boys and girls when the concussion was caused by collision with a ball or goal post (JAMA Pediatr. 2015 July 13 [doi:10.1001/jamapediatrics.2015.1062]).

“We postulate that banning heading from soccer will have limited effectiveness as a primary prevention mechanism (i.e., in preventing concussion injuries) unless such a ban is combined with concurrent efforts to reduce athlete-athlete contact throughout the game,” Dr. Comstock and her associates said.

Moreover, “it may be culturally more tolerable to the soccer community to attempt to reduce athlete-athlete contact across all phases of play through better enforcement of existing rules, enhanced education of athletes on the rules of the game, and improved coaching of activities such as heading,” rather than simply banning heading, they added.