LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.

A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.

LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)

The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.

Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.

The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.

There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.

The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).

The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,

But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.

Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.

But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.

There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).

Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.

“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.

LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.

[email protected]

MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.

A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.

LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)

The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.

Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.

The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.

There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.

The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).

The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,

But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.

Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.

But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.

There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).

Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.

“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.

LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.

[email protected]

MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.

A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.

LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)

The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.

Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.

The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.

There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.

The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).

The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,

But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.

Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.

But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.

There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).

Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.

“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.

LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.

[email protected]

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

[email protected]

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

[email protected]

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

[email protected]

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams

NEW YORK – In this first of four interviews, the new director of the National Institute of Mental Health, Joshua A. Gordon, MD, PhD, shares his thoughts about the emerging nosology of depression and whether it might be possible to identify and turn off genetic pathways implicated in depression without impacting creativity, sexual drive, and appetite.

Dr. Gordon is a practicing psychiatrist and a neuroscientist whose primary area of research is in the emerging field of optogenetics, which uses light to trace the genetically predetermined neurocircuitry of various mental states through the brain.

He steps into his leadership role with NIMH at a time when some have voiced concern that the institute has placed too much emphasis on future therapies, instead of on what can be done in the here and now to treat mental disorders.

Also in this series, Dr. Gordon discusses how, under his leadership, NIMH will balance the priorities of clinicians in everyday practice with those of researchers. He also explains the finer points of optogenetics. Currently, the technique is being studied only in mouse models; but if it makes it to human trials, researchers will explore the ability to switch on and off certain mental states.

Dr. Gordon talks about the ethical implications of optogenetics, as well as his belief in the biological basis of all thought and emotion, and how that guides the search for targeted treatments.

Finally, he’ll discuss what he believes NIMH’s top priorities should be, and whether he will blog as did his predecessor, Thomas R. Insel, MD.

[email protected]

On Twitter @whitneymcknight

NEW YORK – In this first of four interviews, the new director of the National Institute of Mental Health, Joshua A. Gordon, MD, PhD, shares his thoughts about the emerging nosology of depression and whether it might be possible to identify and turn off genetic pathways implicated in depression without impacting creativity, sexual drive, and appetite.

Dr. Gordon is a practicing psychiatrist and a neuroscientist whose primary area of research is in the emerging field of optogenetics, which uses light to trace the genetically predetermined neurocircuitry of various mental states through the brain.

He steps into his leadership role with NIMH at a time when some have voiced concern that the institute has placed too much emphasis on future therapies, instead of on what can be done in the here and now to treat mental disorders.

Also in this series, Dr. Gordon discusses how, under his leadership, NIMH will balance the priorities of clinicians in everyday practice with those of researchers. He also explains the finer points of optogenetics. Currently, the technique is being studied only in mouse models; but if it makes it to human trials, researchers will explore the ability to switch on and off certain mental states.

Dr. Gordon talks about the ethical implications of optogenetics, as well as his belief in the biological basis of all thought and emotion, and how that guides the search for targeted treatments.

Finally, he’ll discuss what he believes NIMH’s top priorities should be, and whether he will blog as did his predecessor, Thomas R. Insel, MD.

[email protected]

On Twitter @whitneymcknight

NEW YORK – In this first of four interviews, the new director of the National Institute of Mental Health, Joshua A. Gordon, MD, PhD, shares his thoughts about the emerging nosology of depression and whether it might be possible to identify and turn off genetic pathways implicated in depression without impacting creativity, sexual drive, and appetite.

Dr. Gordon is a practicing psychiatrist and a neuroscientist whose primary area of research is in the emerging field of optogenetics, which uses light to trace the genetically predetermined neurocircuitry of various mental states through the brain.

He steps into his leadership role with NIMH at a time when some have voiced concern that the institute has placed too much emphasis on future therapies, instead of on what can be done in the here and now to treat mental disorders.

Also in this series, Dr. Gordon discusses how, under his leadership, NIMH will balance the priorities of clinicians in everyday practice with those of researchers. He also explains the finer points of optogenetics. Currently, the technique is being studied only in mouse models; but if it makes it to human trials, researchers will explore the ability to switch on and off certain mental states.

Dr. Gordon talks about the ethical implications of optogenetics, as well as his belief in the biological basis of all thought and emotion, and how that guides the search for targeted treatments.

Finally, he’ll discuss what he believes NIMH’s top priorities should be, and whether he will blog as did his predecessor, Thomas R. Insel, MD.

[email protected]

On Twitter @whitneymcknight

BOSTON – When it comes to chemical denervation, it is best to aim for modulation rather than paralysis, according to Anthony Rossi, MD.

Showing an image of a woman making an exaggerated facial expression, he noted that her treatment had left her overparalyzed in certain areas while other areas were moving. “It’s hard to figure out what she’s trying to emote and what she’s trying to express,” Dr. Rossi of Memorial Sloan Kettering Cancer Center, New York, said at the American Academy of Dermatology summer meeting.

“When we think about facial expressions and when we think about muscles, they work in tandem together, so if things are overparalyzed then some muscles won’t work while others will take over and it will create a perplexed look,” he explained.

A computer analysis of college students demonstrating various facial expressions that represent different emotions identified 21 unique expressions that used a combination of muscles that were different from all other expressions. “There were 6 basic expressions and 15 compound expressions. So as humans, we just need to know we’re using all these facial muscles to convey our message to the world,” Dr. Rossi said.

This finding has particular implications when treating younger versus older patients, he noted.

Younger patients are coming in for cosmetic procedures in increasing numbers, and use of chemical denervation in these patients, compared with in older patients, may be more likely to change facial expressions and appearance. “In the older patient, it may be appropriate to do more cosmetic procedures, but in the younger patient, even the tiniest amount of change can really have a drastic effect on their look,” he said.

As with any surgical or cosmetic case, good patient selection is important for improving patient satisfaction, as is management of patient expectations, he added.

Dr. Rossi compared photos of two women, both in their 40s. One was toxin naive, but the other – despite having scleroderma and undergoing chemotherapy for breast cancer – looked much more “refreshed.” The difference was that the second patient received regular filler and neurotoxin injections, he explained.

To achieve a comparable cosmetic result in the toxin-naive patient, multiple procedures are needed, and procedures should be staged over time, he said.

He noted that it is important to take photos to show patients; photos look different from a mirror image. In addition, static and dynamic rhytids will respond differently to treatment, he pointed out. Static, etched-in rhytids may take longer to correct and may require repeat injections, whereas dynamic rhytids will respond well to neurotoxins, he added.

Combination treatments, such as those incorporating fillers and/or laser resurfacing, may also be needed. “I like to stage my cosmetic procedures,” he said. Staging may not always be possible, but he prefers to allow 2 weeks for a neurotoxin to take effect before adding more neurotoxin or filler.

Among other “pearls” that Dr. Rossi offered for improving outcomes and patient satisfaction were warning patients in advance that static rhytids may require filler in addition to neurotoxin injection, checking for and photographing baseline asymmetry (such as a crooked smile) prior to treatment to avoid blaming the treatment after the fact, and tailoring injections to the patient.

For example, for a particularly expressive individual, it is important to maintain natural movement. For this type of patient, “a standard injection pattern may not work. You still want to give her some natural movement,” he said, explaining that the injection pattern in such a patient would “be more unique, more spread out.

“I usually use multiple rows of injections, but I tend to keep the units that I’m using at a lower dosage so there is some movement, and we don’t drop her brow too much,” he said.

A possible aesthetic trend toward more natural movement – “less frozen, less paralysis” – was suggested by a 2015 retrospective chart review, led by Alastair Carruthers, MD, of the University of British Columbia, Vancouver, showing a decreasing number of units of onabotulinumtoxinA being used over time. In 5,112 treatment sessions in 194 patients over an average of 9 years, the mean dose for forehead lines steadily decreased over time (Dermatol Surg. 2015 Jun;41[6]:693-701).

Dr. Rossi disclosed that he has served on an advisory board for Allergan.

[email protected]

BOSTON – When it comes to chemical denervation, it is best to aim for modulation rather than paralysis, according to Anthony Rossi, MD.

Showing an image of a woman making an exaggerated facial expression, he noted that her treatment had left her overparalyzed in certain areas while other areas were moving. “It’s hard to figure out what she’s trying to emote and what she’s trying to express,” Dr. Rossi of Memorial Sloan Kettering Cancer Center, New York, said at the American Academy of Dermatology summer meeting.

“When we think about facial expressions and when we think about muscles, they work in tandem together, so if things are overparalyzed then some muscles won’t work while others will take over and it will create a perplexed look,” he explained.

A computer analysis of college students demonstrating various facial expressions that represent different emotions identified 21 unique expressions that used a combination of muscles that were different from all other expressions. “There were 6 basic expressions and 15 compound expressions. So as humans, we just need to know we’re using all these facial muscles to convey our message to the world,” Dr. Rossi said.

This finding has particular implications when treating younger versus older patients, he noted.

Younger patients are coming in for cosmetic procedures in increasing numbers, and use of chemical denervation in these patients, compared with in older patients, may be more likely to change facial expressions and appearance. “In the older patient, it may be appropriate to do more cosmetic procedures, but in the younger patient, even the tiniest amount of change can really have a drastic effect on their look,” he said.

As with any surgical or cosmetic case, good patient selection is important for improving patient satisfaction, as is management of patient expectations, he added.

Dr. Rossi compared photos of two women, both in their 40s. One was toxin naive, but the other – despite having scleroderma and undergoing chemotherapy for breast cancer – looked much more “refreshed.” The difference was that the second patient received regular filler and neurotoxin injections, he explained.

To achieve a comparable cosmetic result in the toxin-naive patient, multiple procedures are needed, and procedures should be staged over time, he said.

He noted that it is important to take photos to show patients; photos look different from a mirror image. In addition, static and dynamic rhytids will respond differently to treatment, he pointed out. Static, etched-in rhytids may take longer to correct and may require repeat injections, whereas dynamic rhytids will respond well to neurotoxins, he added.

Combination treatments, such as those incorporating fillers and/or laser resurfacing, may also be needed. “I like to stage my cosmetic procedures,” he said. Staging may not always be possible, but he prefers to allow 2 weeks for a neurotoxin to take effect before adding more neurotoxin or filler.

Among other “pearls” that Dr. Rossi offered for improving outcomes and patient satisfaction were warning patients in advance that static rhytids may require filler in addition to neurotoxin injection, checking for and photographing baseline asymmetry (such as a crooked smile) prior to treatment to avoid blaming the treatment after the fact, and tailoring injections to the patient.

For example, for a particularly expressive individual, it is important to maintain natural movement. For this type of patient, “a standard injection pattern may not work. You still want to give her some natural movement,” he said, explaining that the injection pattern in such a patient would “be more unique, more spread out.

“I usually use multiple rows of injections, but I tend to keep the units that I’m using at a lower dosage so there is some movement, and we don’t drop her brow too much,” he said.

A possible aesthetic trend toward more natural movement – “less frozen, less paralysis” – was suggested by a 2015 retrospective chart review, led by Alastair Carruthers, MD, of the University of British Columbia, Vancouver, showing a decreasing number of units of onabotulinumtoxinA being used over time. In 5,112 treatment sessions in 194 patients over an average of 9 years, the mean dose for forehead lines steadily decreased over time (Dermatol Surg. 2015 Jun;41[6]:693-701).

Dr. Rossi disclosed that he has served on an advisory board for Allergan.

[email protected]

BOSTON – When it comes to chemical denervation, it is best to aim for modulation rather than paralysis, according to Anthony Rossi, MD.

Showing an image of a woman making an exaggerated facial expression, he noted that her treatment had left her overparalyzed in certain areas while other areas were moving. “It’s hard to figure out what she’s trying to emote and what she’s trying to express,” Dr. Rossi of Memorial Sloan Kettering Cancer Center, New York, said at the American Academy of Dermatology summer meeting.

“When we think about facial expressions and when we think about muscles, they work in tandem together, so if things are overparalyzed then some muscles won’t work while others will take over and it will create a perplexed look,” he explained.

A computer analysis of college students demonstrating various facial expressions that represent different emotions identified 21 unique expressions that used a combination of muscles that were different from all other expressions. “There were 6 basic expressions and 15 compound expressions. So as humans, we just need to know we’re using all these facial muscles to convey our message to the world,” Dr. Rossi said.

This finding has particular implications when treating younger versus older patients, he noted.

Younger patients are coming in for cosmetic procedures in increasing numbers, and use of chemical denervation in these patients, compared with in older patients, may be more likely to change facial expressions and appearance. “In the older patient, it may be appropriate to do more cosmetic procedures, but in the younger patient, even the tiniest amount of change can really have a drastic effect on their look,” he said.

As with any surgical or cosmetic case, good patient selection is important for improving patient satisfaction, as is management of patient expectations, he added.

Dr. Rossi compared photos of two women, both in their 40s. One was toxin naive, but the other – despite having scleroderma and undergoing chemotherapy for breast cancer – looked much more “refreshed.” The difference was that the second patient received regular filler and neurotoxin injections, he explained.

To achieve a comparable cosmetic result in the toxin-naive patient, multiple procedures are needed, and procedures should be staged over time, he said.

He noted that it is important to take photos to show patients; photos look different from a mirror image. In addition, static and dynamic rhytids will respond differently to treatment, he pointed out. Static, etched-in rhytids may take longer to correct and may require repeat injections, whereas dynamic rhytids will respond well to neurotoxins, he added.

Combination treatments, such as those incorporating fillers and/or laser resurfacing, may also be needed. “I like to stage my cosmetic procedures,” he said. Staging may not always be possible, but he prefers to allow 2 weeks for a neurotoxin to take effect before adding more neurotoxin or filler.

Among other “pearls” that Dr. Rossi offered for improving outcomes and patient satisfaction were warning patients in advance that static rhytids may require filler in addition to neurotoxin injection, checking for and photographing baseline asymmetry (such as a crooked smile) prior to treatment to avoid blaming the treatment after the fact, and tailoring injections to the patient.

For example, for a particularly expressive individual, it is important to maintain natural movement. For this type of patient, “a standard injection pattern may not work. You still want to give her some natural movement,” he said, explaining that the injection pattern in such a patient would “be more unique, more spread out.

“I usually use multiple rows of injections, but I tend to keep the units that I’m using at a lower dosage so there is some movement, and we don’t drop her brow too much,” he said.

A possible aesthetic trend toward more natural movement – “less frozen, less paralysis” – was suggested by a 2015 retrospective chart review, led by Alastair Carruthers, MD, of the University of British Columbia, Vancouver, showing a decreasing number of units of onabotulinumtoxinA being used over time. In 5,112 treatment sessions in 194 patients over an average of 9 years, the mean dose for forehead lines steadily decreased over time (Dermatol Surg. 2015 Jun;41[6]:693-701).

Dr. Rossi disclosed that he has served on an advisory board for Allergan.

[email protected]

Adolescents who underwent cognitive-behavioral therapy (CBT) as part of postconcussion care reported significantly lower levels of postconcussive symptoms and depressive symptoms in a randomized trial of 49 patients aged 11-17 years. The report was published online Sept. 12 in Pediatrics.

“Affective symptoms, including depression and anxiety, commonly co-occur with cognitive and somatic symptoms and may prolong recovery from postconcussive symptoms, wrote Carolyn A. McCarty, PhD, of Seattle Children’s Hospital, Washington, and her colleagues. “The complexities of managing persistent postconcussive symptoms in conjunction with comorbid psychological symptoms create a significant burden for injured children and adolescents, their families, and schools” (Pediatrics. 2016. doi: 10.1542/peds.2016-0459).

©s-c-s/Thinkstock

To determine the impact of CBT on persistent symptoms in adolescents with concussions, the researchers randomized 49 patients to usual care or a collaborative care plan that included usual care plus CBT.

After 6 months, approximately 13% of the teens in the CBT group reported high levels of postconcussive symptoms, compared with 42% of controls. In addition, 78% of CBT patients reported a depressive symptom reduction of more than 50%, compared with 46% of controls.

Concussions were diagnosed by sports medicine or rehabilitative medicine specialists. The patients assigned to CBT received usual care management, CBT, and possible psychopharmacological consultation. Control patients received usual concussion care, generally defined as an initial visit with a sports medicine physician and assessments at 1, 3, and 6 months. Usual care also could include MRI, sleep medication, and subthreshold exercise, depending on the patient. No serious adverse events were reported. The average age of the patients was 15 years, approximately 65% were girls, and 76% were white.

Overall, 83% of the CBT patients and 87% of their parents were “very satisfied” with their care, compared with 46% of patients and 29% of parents in the control group.

“Although patients in both groups showed symptom reduction in the first 3 months, only those who received collaborative care demonstrated sustained improvements through 6 months of follow-up,” Dr. McCarty and her colleagues wrote.

The results were limited by several factors including the small size of the study, the researchers said. However, the findings “prompt more investigation into the role of affective symptoms in perpetuating physical symptoms secondary to prolonged recovery from sports-related concussion,” and also suggest that collaborative care can help improve persistent postconcussive symptoms in teens.

Dr. McCarty and her colleagues had no relevant financial conflicts to disclose. The Seattle Sports Concussion Research Collaborative supported the study.

Adolescents who underwent cognitive-behavioral therapy (CBT) as part of postconcussion care reported significantly lower levels of postconcussive symptoms and depressive symptoms in a randomized trial of 49 patients aged 11-17 years. The report was published online Sept. 12 in Pediatrics.

“Affective symptoms, including depression and anxiety, commonly co-occur with cognitive and somatic symptoms and may prolong recovery from postconcussive symptoms, wrote Carolyn A. McCarty, PhD, of Seattle Children’s Hospital, Washington, and her colleagues. “The complexities of managing persistent postconcussive symptoms in conjunction with comorbid psychological symptoms create a significant burden for injured children and adolescents, their families, and schools” (Pediatrics. 2016. doi: 10.1542/peds.2016-0459).

©s-c-s/Thinkstock

To determine the impact of CBT on persistent symptoms in adolescents with concussions, the researchers randomized 49 patients to usual care or a collaborative care plan that included usual care plus CBT.

After 6 months, approximately 13% of the teens in the CBT group reported high levels of postconcussive symptoms, compared with 42% of controls. In addition, 78% of CBT patients reported a depressive symptom reduction of more than 50%, compared with 46% of controls.

Concussions were diagnosed by sports medicine or rehabilitative medicine specialists. The patients assigned to CBT received usual care management, CBT, and possible psychopharmacological consultation. Control patients received usual concussion care, generally defined as an initial visit with a sports medicine physician and assessments at 1, 3, and 6 months. Usual care also could include MRI, sleep medication, and subthreshold exercise, depending on the patient. No serious adverse events were reported. The average age of the patients was 15 years, approximately 65% were girls, and 76% were white.

Overall, 83% of the CBT patients and 87% of their parents were “very satisfied” with their care, compared with 46% of patients and 29% of parents in the control group.

“Although patients in both groups showed symptom reduction in the first 3 months, only those who received collaborative care demonstrated sustained improvements through 6 months of follow-up,” Dr. McCarty and her colleagues wrote.

The results were limited by several factors including the small size of the study, the researchers said. However, the findings “prompt more investigation into the role of affective symptoms in perpetuating physical symptoms secondary to prolonged recovery from sports-related concussion,” and also suggest that collaborative care can help improve persistent postconcussive symptoms in teens.

Dr. McCarty and her colleagues had no relevant financial conflicts to disclose. The Seattle Sports Concussion Research Collaborative supported the study.

Adolescents who underwent cognitive-behavioral therapy (CBT) as part of postconcussion care reported significantly lower levels of postconcussive symptoms and depressive symptoms in a randomized trial of 49 patients aged 11-17 years. The report was published online Sept. 12 in Pediatrics.

“Affective symptoms, including depression and anxiety, commonly co-occur with cognitive and somatic symptoms and may prolong recovery from postconcussive symptoms, wrote Carolyn A. McCarty, PhD, of Seattle Children’s Hospital, Washington, and her colleagues. “The complexities of managing persistent postconcussive symptoms in conjunction with comorbid psychological symptoms create a significant burden for injured children and adolescents, their families, and schools” (Pediatrics. 2016. doi: 10.1542/peds.2016-0459).

©s-c-s/Thinkstock

To determine the impact of CBT on persistent symptoms in adolescents with concussions, the researchers randomized 49 patients to usual care or a collaborative care plan that included usual care plus CBT.

After 6 months, approximately 13% of the teens in the CBT group reported high levels of postconcussive symptoms, compared with 42% of controls. In addition, 78% of CBT patients reported a depressive symptom reduction of more than 50%, compared with 46% of controls.

Concussions were diagnosed by sports medicine or rehabilitative medicine specialists. The patients assigned to CBT received usual care management, CBT, and possible psychopharmacological consultation. Control patients received usual concussion care, generally defined as an initial visit with a sports medicine physician and assessments at 1, 3, and 6 months. Usual care also could include MRI, sleep medication, and subthreshold exercise, depending on the patient. No serious adverse events were reported. The average age of the patients was 15 years, approximately 65% were girls, and 76% were white.

Overall, 83% of the CBT patients and 87% of their parents were “very satisfied” with their care, compared with 46% of patients and 29% of parents in the control group.

“Although patients in both groups showed symptom reduction in the first 3 months, only those who received collaborative care demonstrated sustained improvements through 6 months of follow-up,” Dr. McCarty and her colleagues wrote.

The results were limited by several factors including the small size of the study, the researchers said. However, the findings “prompt more investigation into the role of affective symptoms in perpetuating physical symptoms secondary to prolonged recovery from sports-related concussion,” and also suggest that collaborative care can help improve persistent postconcussive symptoms in teens.

Dr. McCarty and her colleagues had no relevant financial conflicts to disclose. The Seattle Sports Concussion Research Collaborative supported the study.

WAIKOLOA, HI. – For gunshot wounds, the current “cardiac box” was the poorest predictor of cardiac injury, results from a single-center retrospective study demonstrated.

“We determined that, from a statistical standpoint, the cardiac box should be redefined to include the area of the thorax that extends from the clavicle to xiphoid and from the anterior midline to the posterior midline of the left thorax,” Bryan C. Morse, MD, said in an interview in advance of the annual meeting of the American Association for the Surgery of Trauma. “The classic cardiac box is inadequate to discriminate whether a gunshot wound will create a cardiac injury.”

Dr. Morse of Emory University and Grady Memorial Hospital, Atlanta, and his associates recently published their experience with penetrating cardiac injuries over the past 36 years and documented an increase in the number of cardiac injuries from gunshots over the past 10 years (J. Trauma Acute Care Surg. 2016 Jul 6. doi: 10.1097/TA.0000000000001165). They also noted that several of these injuries were caused by penetrating thoracic wounds outside the cardiac box.

The cardiac box is currently defined as the area of the chest overlying the heart, bounded by the midclavicular lines (laterally) and from the clavicles to the tip of the xiphoid. “Surgical teaching dictates that penetrating injuries (i.e. stab wounds and gunshot wounds) in the box have the highest likelihood of cardiac injury and thereby mandate further evaluation,” Dr. Morse said. “These studies, however, are based on small patient sample sizes in which the majority were stab wound victims and underwent minimal statistical scrutiny.”

In what he said is the largest study of its kind, Dr. Morse and his associates conducted a retrospective review of trauma registry data from Grady’s trauma center and autopsy reports to identify patients with penetrating thoracic gunshot wounds and cardiac injury from 2011 to 2013 and to evaluate the relationship between penetrating injuries and the likelihood of a cardiac injury. Using a circumferential grid system around the thorax, the researchers employed logistic regression analysis to compare differences in rates of cardiac injury from entrance/exit wounds in the cardiac box, versus outside the box. They repeated the process to identify potential regions that yield improved predictions for cardiac injury over the current definition of the cardiac box.

Over the 3-year study period, 263 patients sustained 735 penetrating thoracic wounds, of which 80% were gunshot wounds (GSWs). Most of the patients were males (89%) with a median of two injuries each. After stab wounds were excluded, 277 GSWs to the thorax were included for study and 95 (34%) injured the heart. Of the 233 GSWs entering the cardiac box, 30% caused cardiac injury while, of the 44 GSWs outside the cardiac box, 32% penetrated the heart, suggesting that the current cardiac box is a poor predictor of cardiac injury relative to the thoracic non–cardiac box regions (OR 1.1; P = .71).

The researchers observed that the regions from the anterior to the posterior midline of the left thorax provided the highest positive predictive value, with a sensitivity of 90% and a specificity of 31%, making this region the most statistically significant discriminator of cardiac injury (OR, 4.4; P less than .01). This finding was primarily based on the fact that gunshots to the left lateral chest (an area not currently included in the box) had a high rate of cardiac injury (41%; OR, 1.4).

“The current cardiac box is unable to discriminate between gunshot wounds that will cause a cardiac injury and those that will not,” Dr. Morse said. “Any gunshot wound to the chest can cause a cardiac injury. While clinically relevant box borders would include the left chest, the bottom line for surgeons is to think outside the current cardiac box.”

The improved cardiac box that he and his associates proposed includes the area from the clavicles to the xiphoid and from the anterior to the posterior midline over the left thorax. “While this may be intuitive, it is not what we as surgeons have been teaching,” he said. “Finally, gunshots to areas such as the right posterior and posterolateral chest were associated with rates of cardiac injury greater than 30% despite their distance from the heart. This led us to conclude that a gunshot anywhere to the chest should be considered to potentially cause a cardiac injury.”

Dr. Morse acknowledged certain limitations of the study, including the fact that the study excluded graze wounds and gunshots above the clavicles and below the xiphoid. “However, a small percentage of these did cause cardiac injuries, which emphasizes the point that gunshot wounds from any entrance can cause cardiac injury.”

Invited discussant Nicholas Namias, MD, professor and chief of the division of acute care surgery at Jackson Memorial Hospital, Miami, said that the study by Dr. Morse and his associates “confirms what Dr. [Grace] Rozycki showed 20 years ago: Forget the [cardiac] box; it’s dead. Just throw an ultrasound probe on.”

Dr. Morse reported having no relevant financial disclosures.

[email protected]

WAIKOLOA, HI. – For gunshot wounds, the current “cardiac box” was the poorest predictor of cardiac injury, results from a single-center retrospective study demonstrated.

“We determined that, from a statistical standpoint, the cardiac box should be redefined to include the area of the thorax that extends from the clavicle to xiphoid and from the anterior midline to the posterior midline of the left thorax,” Bryan C. Morse, MD, said in an interview in advance of the annual meeting of the American Association for the Surgery of Trauma. “The classic cardiac box is inadequate to discriminate whether a gunshot wound will create a cardiac injury.”

Dr. Morse of Emory University and Grady Memorial Hospital, Atlanta, and his associates recently published their experience with penetrating cardiac injuries over the past 36 years and documented an increase in the number of cardiac injuries from gunshots over the past 10 years (J. Trauma Acute Care Surg. 2016 Jul 6. doi: 10.1097/TA.0000000000001165). They also noted that several of these injuries were caused by penetrating thoracic wounds outside the cardiac box.

The cardiac box is currently defined as the area of the chest overlying the heart, bounded by the midclavicular lines (laterally) and from the clavicles to the tip of the xiphoid. “Surgical teaching dictates that penetrating injuries (i.e. stab wounds and gunshot wounds) in the box have the highest likelihood of cardiac injury and thereby mandate further evaluation,” Dr. Morse said. “These studies, however, are based on small patient sample sizes in which the majority were stab wound victims and underwent minimal statistical scrutiny.”

In what he said is the largest study of its kind, Dr. Morse and his associates conducted a retrospective review of trauma registry data from Grady’s trauma center and autopsy reports to identify patients with penetrating thoracic gunshot wounds and cardiac injury from 2011 to 2013 and to evaluate the relationship between penetrating injuries and the likelihood of a cardiac injury. Using a circumferential grid system around the thorax, the researchers employed logistic regression analysis to compare differences in rates of cardiac injury from entrance/exit wounds in the cardiac box, versus outside the box. They repeated the process to identify potential regions that yield improved predictions for cardiac injury over the current definition of the cardiac box.

Over the 3-year study period, 263 patients sustained 735 penetrating thoracic wounds, of which 80% were gunshot wounds (GSWs). Most of the patients were males (89%) with a median of two injuries each. After stab wounds were excluded, 277 GSWs to the thorax were included for study and 95 (34%) injured the heart. Of the 233 GSWs entering the cardiac box, 30% caused cardiac injury while, of the 44 GSWs outside the cardiac box, 32% penetrated the heart, suggesting that the current cardiac box is a poor predictor of cardiac injury relative to the thoracic non–cardiac box regions (OR 1.1; P = .71).

The researchers observed that the regions from the anterior to the posterior midline of the left thorax provided the highest positive predictive value, with a sensitivity of 90% and a specificity of 31%, making this region the most statistically significant discriminator of cardiac injury (OR, 4.4; P less than .01). This finding was primarily based on the fact that gunshots to the left lateral chest (an area not currently included in the box) had a high rate of cardiac injury (41%; OR, 1.4).

“The current cardiac box is unable to discriminate between gunshot wounds that will cause a cardiac injury and those that will not,” Dr. Morse said. “Any gunshot wound to the chest can cause a cardiac injury. While clinically relevant box borders would include the left chest, the bottom line for surgeons is to think outside the current cardiac box.”

The improved cardiac box that he and his associates proposed includes the area from the clavicles to the xiphoid and from the anterior to the posterior midline over the left thorax. “While this may be intuitive, it is not what we as surgeons have been teaching,” he said. “Finally, gunshots to areas such as the right posterior and posterolateral chest were associated with rates of cardiac injury greater than 30% despite their distance from the heart. This led us to conclude that a gunshot anywhere to the chest should be considered to potentially cause a cardiac injury.”

Dr. Morse acknowledged certain limitations of the study, including the fact that the study excluded graze wounds and gunshots above the clavicles and below the xiphoid. “However, a small percentage of these did cause cardiac injuries, which emphasizes the point that gunshot wounds from any entrance can cause cardiac injury.”

Invited discussant Nicholas Namias, MD, professor and chief of the division of acute care surgery at Jackson Memorial Hospital, Miami, said that the study by Dr. Morse and his associates “confirms what Dr. [Grace] Rozycki showed 20 years ago: Forget the [cardiac] box; it’s dead. Just throw an ultrasound probe on.”

Dr. Morse reported having no relevant financial disclosures.

[email protected]

WAIKOLOA, HI. – For gunshot wounds, the current “cardiac box” was the poorest predictor of cardiac injury, results from a single-center retrospective study demonstrated.

“We determined that, from a statistical standpoint, the cardiac box should be redefined to include the area of the thorax that extends from the clavicle to xiphoid and from the anterior midline to the posterior midline of the left thorax,” Bryan C. Morse, MD, said in an interview in advance of the annual meeting of the American Association for the Surgery of Trauma. “The classic cardiac box is inadequate to discriminate whether a gunshot wound will create a cardiac injury.”

Dr. Morse of Emory University and Grady Memorial Hospital, Atlanta, and his associates recently published their experience with penetrating cardiac injuries over the past 36 years and documented an increase in the number of cardiac injuries from gunshots over the past 10 years (J. Trauma Acute Care Surg. 2016 Jul 6. doi: 10.1097/TA.0000000000001165). They also noted that several of these injuries were caused by penetrating thoracic wounds outside the cardiac box.

The cardiac box is currently defined as the area of the chest overlying the heart, bounded by the midclavicular lines (laterally) and from the clavicles to the tip of the xiphoid. “Surgical teaching dictates that penetrating injuries (i.e. stab wounds and gunshot wounds) in the box have the highest likelihood of cardiac injury and thereby mandate further evaluation,” Dr. Morse said. “These studies, however, are based on small patient sample sizes in which the majority were stab wound victims and underwent minimal statistical scrutiny.”

In what he said is the largest study of its kind, Dr. Morse and his associates conducted a retrospective review of trauma registry data from Grady’s trauma center and autopsy reports to identify patients with penetrating thoracic gunshot wounds and cardiac injury from 2011 to 2013 and to evaluate the relationship between penetrating injuries and the likelihood of a cardiac injury. Using a circumferential grid system around the thorax, the researchers employed logistic regression analysis to compare differences in rates of cardiac injury from entrance/exit wounds in the cardiac box, versus outside the box. They repeated the process to identify potential regions that yield improved predictions for cardiac injury over the current definition of the cardiac box.

Over the 3-year study period, 263 patients sustained 735 penetrating thoracic wounds, of which 80% were gunshot wounds (GSWs). Most of the patients were males (89%) with a median of two injuries each. After stab wounds were excluded, 277 GSWs to the thorax were included for study and 95 (34%) injured the heart. Of the 233 GSWs entering the cardiac box, 30% caused cardiac injury while, of the 44 GSWs outside the cardiac box, 32% penetrated the heart, suggesting that the current cardiac box is a poor predictor of cardiac injury relative to the thoracic non–cardiac box regions (OR 1.1; P = .71).

The researchers observed that the regions from the anterior to the posterior midline of the left thorax provided the highest positive predictive value, with a sensitivity of 90% and a specificity of 31%, making this region the most statistically significant discriminator of cardiac injury (OR, 4.4; P less than .01). This finding was primarily based on the fact that gunshots to the left lateral chest (an area not currently included in the box) had a high rate of cardiac injury (41%; OR, 1.4).

“The current cardiac box is unable to discriminate between gunshot wounds that will cause a cardiac injury and those that will not,” Dr. Morse said. “Any gunshot wound to the chest can cause a cardiac injury. While clinically relevant box borders would include the left chest, the bottom line for surgeons is to think outside the current cardiac box.”

The improved cardiac box that he and his associates proposed includes the area from the clavicles to the xiphoid and from the anterior to the posterior midline over the left thorax. “While this may be intuitive, it is not what we as surgeons have been teaching,” he said. “Finally, gunshots to areas such as the right posterior and posterolateral chest were associated with rates of cardiac injury greater than 30% despite their distance from the heart. This led us to conclude that a gunshot anywhere to the chest should be considered to potentially cause a cardiac injury.”

Dr. Morse acknowledged certain limitations of the study, including the fact that the study excluded graze wounds and gunshots above the clavicles and below the xiphoid. “However, a small percentage of these did cause cardiac injuries, which emphasizes the point that gunshot wounds from any entrance can cause cardiac injury.”

Invited discussant Nicholas Namias, MD, professor and chief of the division of acute care surgery at Jackson Memorial Hospital, Miami, said that the study by Dr. Morse and his associates “confirms what Dr. [Grace] Rozycki showed 20 years ago: Forget the [cardiac] box; it’s dead. Just throw an ultrasound probe on.”

Dr. Morse reported having no relevant financial disclosures.

[email protected]

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”