Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.

The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.

In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.

Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”

Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”

Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.

He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.

Nevertheless, the response rate was “quite impressive for this patient population.”

He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”

“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.

Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
 

Response rate, PFS, and OS

Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.

LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.

The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.

They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.

From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.

Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.

A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.

Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.

The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.

Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.

However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”

The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.

The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.

Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.

Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.

The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
 

LEAP presents challenges

Dr. Chmielowski would like to see treatment in this setting individualized somehow.

“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.

Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.

However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.

The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.  

This article first appeared on Medscape.com.

Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.

The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.

In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.

Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”

Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”

Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.

He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.

Nevertheless, the response rate was “quite impressive for this patient population.”

He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”

“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.

Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
 

Response rate, PFS, and OS

Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.

LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.

The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.

They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.

From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.

Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.

A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.

Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.

The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.

Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.

However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”

The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.

The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.

Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.

Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.

The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
 

LEAP presents challenges

Dr. Chmielowski would like to see treatment in this setting individualized somehow.

“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.

Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.

However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.

The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.  

This article first appeared on Medscape.com.

Patients with advanced melanoma who have progressed on anti–programmed death 1/PD-ligand 1 (PD-L1) immunotherapy could substantially extend their overall survival (OS) with a combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and pembrolizumab (Keytruda), suggests an open-label, single arm study.

The research was presented Sept. 19 at the European Society for Medical Oncology Virtual Congress 2020.

In LEAP-004 trial, over 100 patients with stage 3 or 4 melanoma who had progressed after immunotherapy were given lenvatinib plus pembrolizumab, which yielded a median progression-free survival (PFS) of more than 4 months and a median OS of more than a year. Median follow-up was 12 months.

Presenting the findings, Ana Maria Arance Fernandez, MD, PhD, Hospital Clínic de Barcelona, Spain, said lenvatinib plus pembrolizumab has “promising” antitumor activity in patients with advanced melanoma with confirmed progression on a PD-1 inhibitor given alone or in combination. “These results are encouraging given the stringent definition of progression on prior anti-PD-1 therapy and the enrollment of poor-risk patients.”

Dr. Arance Fernandez added that “these data support lenvatinib plus pembrolizumab as a potential treatment regimen for this population of high unmet medical need.”

Bartosz Chmielowski, MD, PhD, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was not involved in the study, discussed the findings.

He highlighted that the patients were not randomly assigned in LEAP-004, with all of them receiving the same therapy.

Nevertheless, the response rate was “quite impressive for this patient population.”

He also drew comparison with previous data with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in a similar population, noting that the overall survival was less than half that seen in the current trial, “which makes these results even more important.”

“It tells us that this combination might be an option with disease progression on anti-PD-1,” Dr. Chmielowski noted.

Dr. Arance Fernandez pointed out that patients with advanced melanoma who progress on standard-of-care treatment with anti-PD-1 therapy or a cytotoxic T-lymphocyte–associated protein 4 (CTLA4) inhibitor plus anti-PD-1 “have very limited therapeutic options available and there is no approved regimen in this indication.”
 

Response rate, PFS, and OS

Previous studies have indicated that adding an anti-PD-1 drug to lenvatinib achieves superior antitumor activity than either treatment alone, with promising results in phase 1/2b data in pretreated metastatic melanoma.

LEAP-004 therefore enrolled patients with unresectable stage 3 or 4 melanoma, who had disease progression within 12 weeks of their last dose of anti-PD-(L)1 therapy either alone or with a CTLA4 inhibitor. There was no limit on the number of prior treatments.

The patients received pembrolizumab 200 mg IV for up to 35 cycles plus lenvatinib 20 mg daily until progression, unacceptable toxicity, or patient or physician decision.

They were imaged at baseline and every 9 weeks through to week 54, then every 12 weeks until week 102, and then every 24 weeks.

From February to September 2019, 103 patients were enrolled, all of whom received at least one dose of lenvatinib plus pembrolizumab. The median age of the patients was 63 years, and 53.4% were male.

Dr. Arance Fernandez pointed out that this was a high-risk population, with 20.4% having a lactate dehydrogenase level twice the upper limit of normal and 14.6% having brain metastasis, while the median sum of target lesions was 100 mm.

A BRAFv600 mutation was identified in 36.9% of patients, and 64.1% were PD-L1 positive.

Nearly one third (28.2%) had received a prior anti-CTLA4 plus anti-PD-(L)1 combination, and 19.5% had undergone four or more prior lines of therapy.

The overall response rate to lenvatinib plus pembrolizumab was 21.4%, with 1.9% having a complete response and 19.4% a partial response. This was seen across subgroups, including by age and disease stage.

Dr. Arance Fernandez said the overall response rate was even higher in patients who had previously been treated with an anti-CTLA4 plus anti-PD-(L)1 combination, at 31%.

However, Dr. Chmielowski warned that “we must interpret this result with caution since only 29 patients were in this subpopulation.”

The median duration of response (per blinded independent committee review) across the study population was 6.3 months, with 72.6% still responding at 6 months.

The median PFS was 4.2 months with the combination therapy, with 41.7% of patients progression free at 6 months, and 26.2% at 9 months.

Median overall survival was 13.9 months, with 77.3% of patients still alive at 6 months and 65.4% alive at 9 months.

Although 96.1% of patients experienced at least one treatment-related adverse event of any grade, only 44.7% had grade 3 or higher events, and only in 7.8% of cases did that lead to treatment discontinuation.

The most common adverse events were hypertension (56.3%), diarrhea (35.9%), nausea (34%), and hypothyroidism (33%), although, in the vast majority of cases, these events were grade 1 or 2.
 

LEAP presents challenges

Dr. Chmielowski would like to see treatment in this setting individualized somehow.

“It will be also important to come up with personalized immunotherapy so that, based on the mechanism of resistance in patient populations, we would be able to choose the subsequent treatments,” he commented.

Dr. Arance Fernandez explained that lenvatinib inhibits multiple tyrosine kinases involved in angiogenesis, cell proliferation, and immune modulation, and has demonstrated immunomodulatory activity in the tumor microenvironment.

However, Dr. Arance Fernandez noted that, as resistance to immunotherapy is “multifactorial,” it may be that a combination treatment will be more effective in these patients.

The study was funded by Merck. Dr. Arance Fernandez has financial ties to Merck and multiple other drug companies. Dr. Chmielowski has financial ties to Merck Serono and multiple other companies.  

This article first appeared on Medscape.com.

The companies behind three major COVID-19 vaccines in development released the protocols of their trials, outlining their expectations for participant enrollment, benchmarks for vaccine efficacy, and more details about the makeup of each product.

Typically, manufacturers guard the specifics of preclinical vaccine trials. This rare move follows calls for greater transparency. For example, the American Medical Association wrote a letter in late August asking the Food and Drug Administration to keep physicians informed of their COVID-19 vaccine review process.

On September 17, ModernaTx released the phase 3 trial protocol for its mRNA-1273 SARS-CoV-2 vaccine. In short order, on September 19, Pfizer/BioNTech shared their phase 1/2/3 trial vaccine protocol. AstraZeneca, which is developing a vaccine along with Oxford University, also released its protocol.

The AstraZeneca vaccine trial made headlines recently for having to be temporarily halted because of unexpected illnesses that arose in two participants, according to the New York Times and other sources.

“I applaud the release of the clinical trial protocols by the companies. The public trust in any COVID-19 vaccine is paramount, especially given the fast timeline and perceived political pressures of these candidates,” Robert Kruse, MD, PhD, told Medscape Medical News when asked to comment.
 

AstraZeneca takes a shot at transparency

The three primary objectives of the AstraZeneca AZD1222 trial outlined in the 110-page protocol include estimating the efficacy, safety, tolerability, and reactogenicity associated with two intramuscular doses of the vaccine in comparison with placebo in adults.

The projected enrollment is 30,000 participants, and the estimated primary completion date is Dec. 2, 2020, according to information on clinicaltrials.gov.

“Given the unprecedented global impact of the coronavirus pandemic and the need for public information, AstraZeneca has published the detailed protocol and design of our AZD1222 clinical trial,” the company said in a statement. “As with most clinical development, protocols are not typically shared publicly due to the importance of maintaining confidentiality and integrity of trials.

“AstraZeneca continues to work with industry peers to ensure a consistent approach to sharing timely clinical trial information,” the company added.
 

Moderna methodology

The ModernaTX 135-page protocol outlines the primary trial objectives of evaluating efficacy, safety, and reactogenicity of two injections of the vaccine administered 28 days apart. Researchers also plan to randomly assign 30,000 adults to receive either vaccine or placebo. The estimated primary completion date is Oct. 27, 2022.

A statement that was requested from ModernaTX was not received by press time.
 

Pfizer protocol

In the Pfizer/BioNTech vaccine trial, researchers plan to evaluate different doses in different age groups in a multistep protocol. The trial features 20 primary safety objectives, which include reporting adverse events and serious adverse events, including any local or systemic events.

Efficacy endpoints are secondary objectives. The estimated enrollment is 29,481 adults; the estimated primary completion date is April 19, 2021.

“Pfizer and BioNTech recognize that the COVID-19 pandemic is a unique circumstance, and the need for transparency is clear,” Pfizer spokesperson Sharon Castillo told Medscape Medical News. By making the full protocol available, “we believe this will reinforce our long-standing commitment to scientific and regulatory rigor that benefits patients,” she said.

“Based on current infection rates, Pfizer and BioNTech continue to expect that a conclusive read-out on efficacy is likely by the end of October. Neither Pfizer nor the FDA can move faster than the data we are generating through our clinical trial,” Castillo said.

If clinical work and regulatory approval or authorization proceed as planned, Pfizer and BioNTech expect to supply up to 100 million doses worldwide by the end of 2020 and approximately 1.3 billion doses worldwide by the end of 2021.

Pfizer is not willing to sacrifice safety and efficacy in the name of expediency, Castillo said. “We will not cut corners in this pursuit. Patient safety is our highest priority, and Pfizer will not bring a vaccine to market without adequate evidence of safety and efficacy.”
 

A positive move

“COVID-19 vaccines will only be useful if many people are willing to receive them,” said Kruse, a postgraduate year 3 resident in the Department of Pathology at Johns Hopkins Medicine in Baltimore, Maryland.

“By giving the general public along with other scientists and physicians the opportunity to critique the protocols, everyone can understand what the metrics would be for an early look at efficacy,” Kruse said. He noted that information could help inform a potential FDA emergency use authorization.

Kruse has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The companies behind three major COVID-19 vaccines in development released the protocols of their trials, outlining their expectations for participant enrollment, benchmarks for vaccine efficacy, and more details about the makeup of each product.

Typically, manufacturers guard the specifics of preclinical vaccine trials. This rare move follows calls for greater transparency. For example, the American Medical Association wrote a letter in late August asking the Food and Drug Administration to keep physicians informed of their COVID-19 vaccine review process.

On September 17, ModernaTx released the phase 3 trial protocol for its mRNA-1273 SARS-CoV-2 vaccine. In short order, on September 19, Pfizer/BioNTech shared their phase 1/2/3 trial vaccine protocol. AstraZeneca, which is developing a vaccine along with Oxford University, also released its protocol.

The AstraZeneca vaccine trial made headlines recently for having to be temporarily halted because of unexpected illnesses that arose in two participants, according to the New York Times and other sources.

“I applaud the release of the clinical trial protocols by the companies. The public trust in any COVID-19 vaccine is paramount, especially given the fast timeline and perceived political pressures of these candidates,” Robert Kruse, MD, PhD, told Medscape Medical News when asked to comment.
 

AstraZeneca takes a shot at transparency

The three primary objectives of the AstraZeneca AZD1222 trial outlined in the 110-page protocol include estimating the efficacy, safety, tolerability, and reactogenicity associated with two intramuscular doses of the vaccine in comparison with placebo in adults.

The projected enrollment is 30,000 participants, and the estimated primary completion date is Dec. 2, 2020, according to information on clinicaltrials.gov.

“Given the unprecedented global impact of the coronavirus pandemic and the need for public information, AstraZeneca has published the detailed protocol and design of our AZD1222 clinical trial,” the company said in a statement. “As with most clinical development, protocols are not typically shared publicly due to the importance of maintaining confidentiality and integrity of trials.

“AstraZeneca continues to work with industry peers to ensure a consistent approach to sharing timely clinical trial information,” the company added.
 

Moderna methodology

The ModernaTX 135-page protocol outlines the primary trial objectives of evaluating efficacy, safety, and reactogenicity of two injections of the vaccine administered 28 days apart. Researchers also plan to randomly assign 30,000 adults to receive either vaccine or placebo. The estimated primary completion date is Oct. 27, 2022.

A statement that was requested from ModernaTX was not received by press time.
 

Pfizer protocol

In the Pfizer/BioNTech vaccine trial, researchers plan to evaluate different doses in different age groups in a multistep protocol. The trial features 20 primary safety objectives, which include reporting adverse events and serious adverse events, including any local or systemic events.

Efficacy endpoints are secondary objectives. The estimated enrollment is 29,481 adults; the estimated primary completion date is April 19, 2021.

“Pfizer and BioNTech recognize that the COVID-19 pandemic is a unique circumstance, and the need for transparency is clear,” Pfizer spokesperson Sharon Castillo told Medscape Medical News. By making the full protocol available, “we believe this will reinforce our long-standing commitment to scientific and regulatory rigor that benefits patients,” she said.

“Based on current infection rates, Pfizer and BioNTech continue to expect that a conclusive read-out on efficacy is likely by the end of October. Neither Pfizer nor the FDA can move faster than the data we are generating through our clinical trial,” Castillo said.

If clinical work and regulatory approval or authorization proceed as planned, Pfizer and BioNTech expect to supply up to 100 million doses worldwide by the end of 2020 and approximately 1.3 billion doses worldwide by the end of 2021.

Pfizer is not willing to sacrifice safety and efficacy in the name of expediency, Castillo said. “We will not cut corners in this pursuit. Patient safety is our highest priority, and Pfizer will not bring a vaccine to market without adequate evidence of safety and efficacy.”
 

A positive move

“COVID-19 vaccines will only be useful if many people are willing to receive them,” said Kruse, a postgraduate year 3 resident in the Department of Pathology at Johns Hopkins Medicine in Baltimore, Maryland.

“By giving the general public along with other scientists and physicians the opportunity to critique the protocols, everyone can understand what the metrics would be for an early look at efficacy,” Kruse said. He noted that information could help inform a potential FDA emergency use authorization.

Kruse has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The companies behind three major COVID-19 vaccines in development released the protocols of their trials, outlining their expectations for participant enrollment, benchmarks for vaccine efficacy, and more details about the makeup of each product.

Typically, manufacturers guard the specifics of preclinical vaccine trials. This rare move follows calls for greater transparency. For example, the American Medical Association wrote a letter in late August asking the Food and Drug Administration to keep physicians informed of their COVID-19 vaccine review process.

On September 17, ModernaTx released the phase 3 trial protocol for its mRNA-1273 SARS-CoV-2 vaccine. In short order, on September 19, Pfizer/BioNTech shared their phase 1/2/3 trial vaccine protocol. AstraZeneca, which is developing a vaccine along with Oxford University, also released its protocol.

The AstraZeneca vaccine trial made headlines recently for having to be temporarily halted because of unexpected illnesses that arose in two participants, according to the New York Times and other sources.

“I applaud the release of the clinical trial protocols by the companies. The public trust in any COVID-19 vaccine is paramount, especially given the fast timeline and perceived political pressures of these candidates,” Robert Kruse, MD, PhD, told Medscape Medical News when asked to comment.
 

AstraZeneca takes a shot at transparency

The three primary objectives of the AstraZeneca AZD1222 trial outlined in the 110-page protocol include estimating the efficacy, safety, tolerability, and reactogenicity associated with two intramuscular doses of the vaccine in comparison with placebo in adults.

The projected enrollment is 30,000 participants, and the estimated primary completion date is Dec. 2, 2020, according to information on clinicaltrials.gov.

“Given the unprecedented global impact of the coronavirus pandemic and the need for public information, AstraZeneca has published the detailed protocol and design of our AZD1222 clinical trial,” the company said in a statement. “As with most clinical development, protocols are not typically shared publicly due to the importance of maintaining confidentiality and integrity of trials.

“AstraZeneca continues to work with industry peers to ensure a consistent approach to sharing timely clinical trial information,” the company added.
 

Moderna methodology

The ModernaTX 135-page protocol outlines the primary trial objectives of evaluating efficacy, safety, and reactogenicity of two injections of the vaccine administered 28 days apart. Researchers also plan to randomly assign 30,000 adults to receive either vaccine or placebo. The estimated primary completion date is Oct. 27, 2022.

A statement that was requested from ModernaTX was not received by press time.
 

Pfizer protocol

In the Pfizer/BioNTech vaccine trial, researchers plan to evaluate different doses in different age groups in a multistep protocol. The trial features 20 primary safety objectives, which include reporting adverse events and serious adverse events, including any local or systemic events.

Efficacy endpoints are secondary objectives. The estimated enrollment is 29,481 adults; the estimated primary completion date is April 19, 2021.

“Pfizer and BioNTech recognize that the COVID-19 pandemic is a unique circumstance, and the need for transparency is clear,” Pfizer spokesperson Sharon Castillo told Medscape Medical News. By making the full protocol available, “we believe this will reinforce our long-standing commitment to scientific and regulatory rigor that benefits patients,” she said.

“Based on current infection rates, Pfizer and BioNTech continue to expect that a conclusive read-out on efficacy is likely by the end of October. Neither Pfizer nor the FDA can move faster than the data we are generating through our clinical trial,” Castillo said.

If clinical work and regulatory approval or authorization proceed as planned, Pfizer and BioNTech expect to supply up to 100 million doses worldwide by the end of 2020 and approximately 1.3 billion doses worldwide by the end of 2021.

Pfizer is not willing to sacrifice safety and efficacy in the name of expediency, Castillo said. “We will not cut corners in this pursuit. Patient safety is our highest priority, and Pfizer will not bring a vaccine to market without adequate evidence of safety and efficacy.”
 

A positive move

“COVID-19 vaccines will only be useful if many people are willing to receive them,” said Kruse, a postgraduate year 3 resident in the Department of Pathology at Johns Hopkins Medicine in Baltimore, Maryland.

“By giving the general public along with other scientists and physicians the opportunity to critique the protocols, everyone can understand what the metrics would be for an early look at efficacy,” Kruse said. He noted that information could help inform a potential FDA emergency use authorization.

Kruse has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Hurricane Sally recently crossed the Gulf of Mexico and landed with torrential rainfalls along the Alabama coast. A little rainfall is important for crops; too much leads to devastation. As physicians, we need data in order to help manage patients’ illnesses and to help to keep them healthy. Our fear though is that too much data provided too quickly may have the opposite effect.

Personal monitoring devices

When I bought my first Fitbit 7 years ago, I was enamored with the technology. The Fitbit was little more than a step tracker, yet I proudly wore its black rubber strap on my wrist. It was my first foray into wearable technology, and it felt quite empowering to have an objective way to track my fitness beyond just using my bathroom scale. Now less than a decade later, that Fitbit looks archaic in comparison with the wrist-top technology currently available.

As I write this, the world’s largest technology company is in the process of releasing its sixth-generation Apple Watch. In addition to acting as a smartphone, this new device, which is barely larger than a postage stamp, offers GPS-based movement tracking, the ability to detect falls, continuous heart rate monitoring, a built-in EKG capable of diagnosing atrial fibrillation, and an oxygen saturation sensor. These features weren’t added thoughtlessly. Apple is marketing this as a health-focused device, with their primary advertising campaign claiming that “the future of health is on your wrist,” and they aren’t the only company making this play.

Along with Apple, Samsung, Withings, Fitbit, and other companies continue to bring products to market that monitor our activity and provide new insights into our health. Typically linked to smartphone-based apps, these devices record all of their measurements for later review, while software helps interpret the findings to make them actionable. From heart rate tracking to sleep analysis, these options now provide access to volumes of data that promise to improve our wellness and change our lives. Of course, those promises will only be fulfilled if our behavior is altered as a consequence of having more detailed information. Whether that will happen remains to be seen.
 

Health system–linked devices

Major advancements in medical monitoring technology are now enabling physicians to get much deeper insight into their patients’ health status. Internet-connected scales, blood pressure cuffs, and exercise equipment offer the ability to upload information into patient portals and integrate that information into EHRs. New devices provide access to information that previously was impossible to obtain. For example, wearable continuous blood glucose monitors, such as the FreeStyle Libre or DexCom’s G6, allow patients and physicians to follow blood sugar readings 24 hours a day. This provides unprecedented awareness of diabetes control and relieves the pain and inconvenience of finger sticks and blood draws. It also aids with compliance because patients don’t need to remember to check their sugar levels on a schedule.

Other compliance-boosting breakthroughs, such as Bluetooth-enabled asthma inhalers and cellular-connected continuous positive airway pressure machines, assist patients with managing chronic respiratory conditions. Many companies are developing technologies to manage acute conditions as well. One such company, an on-demand telemedicine provider called TytoCare, has developed a $299 suite of instruments that includes a digital stethoscope, thermometer, and camera-based otoscope. In concert with a virtual visit, their providers can remotely use these tools to examine and assess sick individuals. This virtual “laying on of hands” may have sounded like science fiction and likely would have been rejected by patients just a few years ago. Now it is becoming commonplace and will soon be an expectation of many seeking care.

We as clinicians need to learn how best to adapt to the new world and integrate these new sources of health data into our practices. But if we are to be successful, everyone must acknowledge that this revolution in health care brings many challenges along with it. One of those is the deluge of data that connected devices provide.
 

Information overload

There is such a thing as “too much of a good thing.” Described by journalist David Shenk as “data smog” in his 1997 book of the same name, the idea is clear: There is only so much information we can assimilate.

Even after years of using EHRs and with government-implemented incentives that promote “meaningful use,” physicians are still struggling with EHRs. Additionally, many have expressed frustration with the connectedness that EHRs provide and lament their inability to ever really “leave the office.” As more and more data become available to physicians, the challenge of how to assimilate and act on those data will continue to grow. The addition of patient-provided health statistics will only make information overload worse, with clinicians will feeling an ever-growing burden to know, understand, and act on this information.

Unless we develop systems to sort, filter, and prioritize the flow of information, there is potential for liability from not acting on the amount of virtual information doctors receive. This new risk for already fatigued and overburdened physicians combined with an increase in the amount of virtual information at doctors’ fingertips may lead to the value of patient data being lost.
 

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

Hurricane Sally recently crossed the Gulf of Mexico and landed with torrential rainfalls along the Alabama coast. A little rainfall is important for crops; too much leads to devastation. As physicians, we need data in order to help manage patients’ illnesses and to help to keep them healthy. Our fear though is that too much data provided too quickly may have the opposite effect.

Personal monitoring devices

When I bought my first Fitbit 7 years ago, I was enamored with the technology. The Fitbit was little more than a step tracker, yet I proudly wore its black rubber strap on my wrist. It was my first foray into wearable technology, and it felt quite empowering to have an objective way to track my fitness beyond just using my bathroom scale. Now less than a decade later, that Fitbit looks archaic in comparison with the wrist-top technology currently available.

As I write this, the world’s largest technology company is in the process of releasing its sixth-generation Apple Watch. In addition to acting as a smartphone, this new device, which is barely larger than a postage stamp, offers GPS-based movement tracking, the ability to detect falls, continuous heart rate monitoring, a built-in EKG capable of diagnosing atrial fibrillation, and an oxygen saturation sensor. These features weren’t added thoughtlessly. Apple is marketing this as a health-focused device, with their primary advertising campaign claiming that “the future of health is on your wrist,” and they aren’t the only company making this play.

Along with Apple, Samsung, Withings, Fitbit, and other companies continue to bring products to market that monitor our activity and provide new insights into our health. Typically linked to smartphone-based apps, these devices record all of their measurements for later review, while software helps interpret the findings to make them actionable. From heart rate tracking to sleep analysis, these options now provide access to volumes of data that promise to improve our wellness and change our lives. Of course, those promises will only be fulfilled if our behavior is altered as a consequence of having more detailed information. Whether that will happen remains to be seen.
 

Health system–linked devices

Major advancements in medical monitoring technology are now enabling physicians to get much deeper insight into their patients’ health status. Internet-connected scales, blood pressure cuffs, and exercise equipment offer the ability to upload information into patient portals and integrate that information into EHRs. New devices provide access to information that previously was impossible to obtain. For example, wearable continuous blood glucose monitors, such as the FreeStyle Libre or DexCom’s G6, allow patients and physicians to follow blood sugar readings 24 hours a day. This provides unprecedented awareness of diabetes control and relieves the pain and inconvenience of finger sticks and blood draws. It also aids with compliance because patients don’t need to remember to check their sugar levels on a schedule.

Other compliance-boosting breakthroughs, such as Bluetooth-enabled asthma inhalers and cellular-connected continuous positive airway pressure machines, assist patients with managing chronic respiratory conditions. Many companies are developing technologies to manage acute conditions as well. One such company, an on-demand telemedicine provider called TytoCare, has developed a $299 suite of instruments that includes a digital stethoscope, thermometer, and camera-based otoscope. In concert with a virtual visit, their providers can remotely use these tools to examine and assess sick individuals. This virtual “laying on of hands” may have sounded like science fiction and likely would have been rejected by patients just a few years ago. Now it is becoming commonplace and will soon be an expectation of many seeking care.

We as clinicians need to learn how best to adapt to the new world and integrate these new sources of health data into our practices. But if we are to be successful, everyone must acknowledge that this revolution in health care brings many challenges along with it. One of those is the deluge of data that connected devices provide.
 

Information overload

There is such a thing as “too much of a good thing.” Described by journalist David Shenk as “data smog” in his 1997 book of the same name, the idea is clear: There is only so much information we can assimilate.

Even after years of using EHRs and with government-implemented incentives that promote “meaningful use,” physicians are still struggling with EHRs. Additionally, many have expressed frustration with the connectedness that EHRs provide and lament their inability to ever really “leave the office.” As more and more data become available to physicians, the challenge of how to assimilate and act on those data will continue to grow. The addition of patient-provided health statistics will only make information overload worse, with clinicians will feeling an ever-growing burden to know, understand, and act on this information.

Unless we develop systems to sort, filter, and prioritize the flow of information, there is potential for liability from not acting on the amount of virtual information doctors receive. This new risk for already fatigued and overburdened physicians combined with an increase in the amount of virtual information at doctors’ fingertips may lead to the value of patient data being lost.
 

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

Hurricane Sally recently crossed the Gulf of Mexico and landed with torrential rainfalls along the Alabama coast. A little rainfall is important for crops; too much leads to devastation. As physicians, we need data in order to help manage patients’ illnesses and to help to keep them healthy. Our fear though is that too much data provided too quickly may have the opposite effect.

Personal monitoring devices

When I bought my first Fitbit 7 years ago, I was enamored with the technology. The Fitbit was little more than a step tracker, yet I proudly wore its black rubber strap on my wrist. It was my first foray into wearable technology, and it felt quite empowering to have an objective way to track my fitness beyond just using my bathroom scale. Now less than a decade later, that Fitbit looks archaic in comparison with the wrist-top technology currently available.

As I write this, the world’s largest technology company is in the process of releasing its sixth-generation Apple Watch. In addition to acting as a smartphone, this new device, which is barely larger than a postage stamp, offers GPS-based movement tracking, the ability to detect falls, continuous heart rate monitoring, a built-in EKG capable of diagnosing atrial fibrillation, and an oxygen saturation sensor. These features weren’t added thoughtlessly. Apple is marketing this as a health-focused device, with their primary advertising campaign claiming that “the future of health is on your wrist,” and they aren’t the only company making this play.

Along with Apple, Samsung, Withings, Fitbit, and other companies continue to bring products to market that monitor our activity and provide new insights into our health. Typically linked to smartphone-based apps, these devices record all of their measurements for later review, while software helps interpret the findings to make them actionable. From heart rate tracking to sleep analysis, these options now provide access to volumes of data that promise to improve our wellness and change our lives. Of course, those promises will only be fulfilled if our behavior is altered as a consequence of having more detailed information. Whether that will happen remains to be seen.
 

Health system–linked devices

Major advancements in medical monitoring technology are now enabling physicians to get much deeper insight into their patients’ health status. Internet-connected scales, blood pressure cuffs, and exercise equipment offer the ability to upload information into patient portals and integrate that information into EHRs. New devices provide access to information that previously was impossible to obtain. For example, wearable continuous blood glucose monitors, such as the FreeStyle Libre or DexCom’s G6, allow patients and physicians to follow blood sugar readings 24 hours a day. This provides unprecedented awareness of diabetes control and relieves the pain and inconvenience of finger sticks and blood draws. It also aids with compliance because patients don’t need to remember to check their sugar levels on a schedule.

Other compliance-boosting breakthroughs, such as Bluetooth-enabled asthma inhalers and cellular-connected continuous positive airway pressure machines, assist patients with managing chronic respiratory conditions. Many companies are developing technologies to manage acute conditions as well. One such company, an on-demand telemedicine provider called TytoCare, has developed a $299 suite of instruments that includes a digital stethoscope, thermometer, and camera-based otoscope. In concert with a virtual visit, their providers can remotely use these tools to examine and assess sick individuals. This virtual “laying on of hands” may have sounded like science fiction and likely would have been rejected by patients just a few years ago. Now it is becoming commonplace and will soon be an expectation of many seeking care.

We as clinicians need to learn how best to adapt to the new world and integrate these new sources of health data into our practices. But if we are to be successful, everyone must acknowledge that this revolution in health care brings many challenges along with it. One of those is the deluge of data that connected devices provide.
 

Information overload

There is such a thing as “too much of a good thing.” Described by journalist David Shenk as “data smog” in his 1997 book of the same name, the idea is clear: There is only so much information we can assimilate.

Even after years of using EHRs and with government-implemented incentives that promote “meaningful use,” physicians are still struggling with EHRs. Additionally, many have expressed frustration with the connectedness that EHRs provide and lament their inability to ever really “leave the office.” As more and more data become available to physicians, the challenge of how to assimilate and act on those data will continue to grow. The addition of patient-provided health statistics will only make information overload worse, with clinicians will feeling an ever-growing burden to know, understand, and act on this information.

Unless we develop systems to sort, filter, and prioritize the flow of information, there is potential for liability from not acting on the amount of virtual information doctors receive. This new risk for already fatigued and overburdened physicians combined with an increase in the amount of virtual information at doctors’ fingertips may lead to the value of patient data being lost.
 

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of baricitinib tablets for adults with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Baricitinib (Olumiant) is already approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis.

If approved in Europe, it will be the first Janus kinase (JAK) inhibitor and first oral medication indicated to treat patients with AD.

The CHMP’s positive opinion on baricitinib for AD was based on three phase 3, randomized, double-blind, placebo-controlled studies where the JAK inhibitor was used alone or in combination with topical treatments in adults with moderate to severe AD for whom topical treatments were insufficient or not tolerated. In all three studies, baricitinib was shown to be more effective than placebo in achieving skin that is “clear” or “almost clear” at 16 weeks.

“Patients living with AD face difficulties on a daily basis, and this CHMP opinion marks an important milestone in providing adult AD patients with a new potential treatment option,” Thomas Bieber, MD, PhD, professor of dermatology and allergy, University of Bonn (Germany), said in a company news release.

The most common side effects with baricitinib in clinical trials include increased LDL cholesterol, upper respiratory tract infections, and headache.

Patients receiving baricitinib, particularly in combination with immunosuppressants, are at risk of developing serious infections that may lead to hospitalization or death. If a serious infection develops, baricitinib should be stopped until the infection is controlled.

The CHMP’s positive opinion will be sent to the European Commission, which will adopt a final decision regarding an European Union–wide marketing authorization. Once granted, each member state will make decisions about price and reimbursement, taking into account the potential role/use of baricitinib in the context of that country’s national health system.

A version of this story originally appeared on Medscape.com.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of baricitinib tablets for adults with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Baricitinib (Olumiant) is already approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis.

If approved in Europe, it will be the first Janus kinase (JAK) inhibitor and first oral medication indicated to treat patients with AD.

The CHMP’s positive opinion on baricitinib for AD was based on three phase 3, randomized, double-blind, placebo-controlled studies where the JAK inhibitor was used alone or in combination with topical treatments in adults with moderate to severe AD for whom topical treatments were insufficient or not tolerated. In all three studies, baricitinib was shown to be more effective than placebo in achieving skin that is “clear” or “almost clear” at 16 weeks.

“Patients living with AD face difficulties on a daily basis, and this CHMP opinion marks an important milestone in providing adult AD patients with a new potential treatment option,” Thomas Bieber, MD, PhD, professor of dermatology and allergy, University of Bonn (Germany), said in a company news release.

The most common side effects with baricitinib in clinical trials include increased LDL cholesterol, upper respiratory tract infections, and headache.

Patients receiving baricitinib, particularly in combination with immunosuppressants, are at risk of developing serious infections that may lead to hospitalization or death. If a serious infection develops, baricitinib should be stopped until the infection is controlled.

The CHMP’s positive opinion will be sent to the European Commission, which will adopt a final decision regarding an European Union–wide marketing authorization. Once granted, each member state will make decisions about price and reimbursement, taking into account the potential role/use of baricitinib in the context of that country’s national health system.

A version of this story originally appeared on Medscape.com.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended approval of baricitinib tablets for adults with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Baricitinib (Olumiant) is already approved in the European Union and the United States to treat moderate to severe active rheumatoid arthritis.

If approved in Europe, it will be the first Janus kinase (JAK) inhibitor and first oral medication indicated to treat patients with AD.

The CHMP’s positive opinion on baricitinib for AD was based on three phase 3, randomized, double-blind, placebo-controlled studies where the JAK inhibitor was used alone or in combination with topical treatments in adults with moderate to severe AD for whom topical treatments were insufficient or not tolerated. In all three studies, baricitinib was shown to be more effective than placebo in achieving skin that is “clear” or “almost clear” at 16 weeks.

“Patients living with AD face difficulties on a daily basis, and this CHMP opinion marks an important milestone in providing adult AD patients with a new potential treatment option,” Thomas Bieber, MD, PhD, professor of dermatology and allergy, University of Bonn (Germany), said in a company news release.

The most common side effects with baricitinib in clinical trials include increased LDL cholesterol, upper respiratory tract infections, and headache.

Patients receiving baricitinib, particularly in combination with immunosuppressants, are at risk of developing serious infections that may lead to hospitalization or death. If a serious infection develops, baricitinib should be stopped until the infection is controlled.

The CHMP’s positive opinion will be sent to the European Commission, which will adopt a final decision regarding an European Union–wide marketing authorization. Once granted, each member state will make decisions about price and reimbursement, taking into account the potential role/use of baricitinib in the context of that country’s national health system.

A version of this story originally appeared on Medscape.com.

Adding palbociclib to letrozole significantly prolonged progression-free survival (PFS) in a phase 2 trial of patients with advanced or recurrent estrogen receptor (ER)–positive endometrial cancer.

This was the first randomized trial to evaluate the efficacy of a CDK4/6 inhibitor in combination with an aromatase inhibitor in patients with advanced or recurrent ER-positive endometrial cancer, noted study investigator Mansoor Raza Mirza, MD, PhD, of Rigshospitalet Copenhagen University Hospital.

Dr. Mirza presented results from this study, ENGOT-EN3-NSGO/PALEO, at the European Society for Medical Oncology Virtual Congress 2020.

Palbociclib is a selective inhibitor of CDK4/, both of which are involved in cell-cycle transitions, Dr. Mirza explained. He observed that endometrial endometrioid adenocarcinomas are hormone dependent, and endocrine treatment with an aromatase inhibitor is well established. Palbociclib has been shown to be superior, when combined with letrozole, to letrozole alone in ER-positive breast cancer.

For the ENGOT-EN3-NSGO/PALEO study, investigators enrolled 77 patients with ER-positive advanced/recurrent endometrial cancer. Patients had received at least one prior systemic therapy, no prior endocrine therapy (except medroxyprogesterone acetate and megestrol acetate), and no prior CDK inhibitor.

Patients were randomized 1:1 to receive oral letrozole (2.5 mg on days 1-28) and either palbociclib (125 mg on days 1-21) or placebo (125 mg on days 1-21) in a 28-day cycle until progression. Baseline characteristics were similar between the treatment arms.
 

Efficacy

Of the 77 patients enrolled, 73 were evaluable. The primary endpoint was PFS.

The median PFS in the intention-to-treat population was 3.0 months in the placebo arm and 8.3 months in the palbociclib arm (hazard ratio, 0.56; 95% confidence interval, 0.32-0.98; P = .0376).

Looking at stratification factors, PFS was higher in the palbociclib arm among the large majority (about 85%) of patients who had received no prior medroxyprogesterone acetate or megestrol acetate (HR, 0.55; 95% CI, 0.29-01.04; P = .0615) and among patients with relapsed disease (HR, 0.61; 95% CI, 0.34-1.09; P = .0916).

The disease control rate at 24 weeks, a secondary endpoint, was 63.6% in the palbociclib arm and 37.8% in the placebo arm.
 

Safety

Adverse events were more frequent in the palbociclib arm, with neutropenia being the most common.

Rates of adverse event–related dose reduction (to 100 mg or 75 mg) were 36% in the palbociclib arm and 3% in the placebo arm.

Adverse event–related discontinuation rates were 25% and 19% for palbociclib and letrozole, respectively, in the palbociclib arm and 14% and 11% for placebo and letrozole, respectively, in the placebo arm.

“The toxicity of palbociclib plus letrozole combination therapy was manageable, with most patients remaining on treatment until disease progression,” Dr. Mirza said.

He noted that an analysis of patient-reported outcomes revealed no detrimental effect on quality of life with the combination therapy.
 

Next steps

“Compared with placebo plus letrozole, the combination of palbociclib plus letrozole demonstrated clinically meaningful improvement in PFS,” Dr. Mirza said. “These results merit a phase 3 validation trial.”

“There is a huge rationale for using this drug in endometrial cancer,” commented study discussant Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of Sacred Hearth in Rome.

Dr. Lorusso said hormone receptor expression, which has been identified as a strong predictor of CDK4/6 inhibitor activity, is present in up to 90% of patients with type 1 and in about 65% of patients with type 2 endometrial cancer.

Response rates, in experience with aromatase inhibitors, have been “quite disappointing, in the 10%-20% range,” Dr. Lorusso said, with “dismal prognosis” and guidelines stating that “no standard second-line treatment has been identified.”

This research was sponsored by investigators, but Pfizer provided a study grant. Dr. Mirza disclosed relationships with Pfizer, AstraZeneca, Biocad, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Oncology Adventure, Roche, Seattle Genetics, Sera Prognostics, Sotio, GlaxoSmithKline, Zai Lab, and Boehringer Ingelheim. Dr. Lorusso disclosed relationships with AstraZeneca, Biocad, Clovis Oncology, Genmab, Merck, Roche, Tesaro, Amgen, Immunogen, and Pharma Mar.

SOURCE: Mirza MR et al. ESMO 2020, Abstract LBA28.

Adding palbociclib to letrozole significantly prolonged progression-free survival (PFS) in a phase 2 trial of patients with advanced or recurrent estrogen receptor (ER)–positive endometrial cancer.

This was the first randomized trial to evaluate the efficacy of a CDK4/6 inhibitor in combination with an aromatase inhibitor in patients with advanced or recurrent ER-positive endometrial cancer, noted study investigator Mansoor Raza Mirza, MD, PhD, of Rigshospitalet Copenhagen University Hospital.

Dr. Mirza presented results from this study, ENGOT-EN3-NSGO/PALEO, at the European Society for Medical Oncology Virtual Congress 2020.

Palbociclib is a selective inhibitor of CDK4/, both of which are involved in cell-cycle transitions, Dr. Mirza explained. He observed that endometrial endometrioid adenocarcinomas are hormone dependent, and endocrine treatment with an aromatase inhibitor is well established. Palbociclib has been shown to be superior, when combined with letrozole, to letrozole alone in ER-positive breast cancer.

For the ENGOT-EN3-NSGO/PALEO study, investigators enrolled 77 patients with ER-positive advanced/recurrent endometrial cancer. Patients had received at least one prior systemic therapy, no prior endocrine therapy (except medroxyprogesterone acetate and megestrol acetate), and no prior CDK inhibitor.

Patients were randomized 1:1 to receive oral letrozole (2.5 mg on days 1-28) and either palbociclib (125 mg on days 1-21) or placebo (125 mg on days 1-21) in a 28-day cycle until progression. Baseline characteristics were similar between the treatment arms.
 

Efficacy

Of the 77 patients enrolled, 73 were evaluable. The primary endpoint was PFS.

The median PFS in the intention-to-treat population was 3.0 months in the placebo arm and 8.3 months in the palbociclib arm (hazard ratio, 0.56; 95% confidence interval, 0.32-0.98; P = .0376).

Looking at stratification factors, PFS was higher in the palbociclib arm among the large majority (about 85%) of patients who had received no prior medroxyprogesterone acetate or megestrol acetate (HR, 0.55; 95% CI, 0.29-01.04; P = .0615) and among patients with relapsed disease (HR, 0.61; 95% CI, 0.34-1.09; P = .0916).

The disease control rate at 24 weeks, a secondary endpoint, was 63.6% in the palbociclib arm and 37.8% in the placebo arm.
 

Safety

Adverse events were more frequent in the palbociclib arm, with neutropenia being the most common.

Rates of adverse event–related dose reduction (to 100 mg or 75 mg) were 36% in the palbociclib arm and 3% in the placebo arm.

Adverse event–related discontinuation rates were 25% and 19% for palbociclib and letrozole, respectively, in the palbociclib arm and 14% and 11% for placebo and letrozole, respectively, in the placebo arm.

“The toxicity of palbociclib plus letrozole combination therapy was manageable, with most patients remaining on treatment until disease progression,” Dr. Mirza said.

He noted that an analysis of patient-reported outcomes revealed no detrimental effect on quality of life with the combination therapy.
 

Next steps

“Compared with placebo plus letrozole, the combination of palbociclib plus letrozole demonstrated clinically meaningful improvement in PFS,” Dr. Mirza said. “These results merit a phase 3 validation trial.”

“There is a huge rationale for using this drug in endometrial cancer,” commented study discussant Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of Sacred Hearth in Rome.

Dr. Lorusso said hormone receptor expression, which has been identified as a strong predictor of CDK4/6 inhibitor activity, is present in up to 90% of patients with type 1 and in about 65% of patients with type 2 endometrial cancer.

Response rates, in experience with aromatase inhibitors, have been “quite disappointing, in the 10%-20% range,” Dr. Lorusso said, with “dismal prognosis” and guidelines stating that “no standard second-line treatment has been identified.”

This research was sponsored by investigators, but Pfizer provided a study grant. Dr. Mirza disclosed relationships with Pfizer, AstraZeneca, Biocad, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Oncology Adventure, Roche, Seattle Genetics, Sera Prognostics, Sotio, GlaxoSmithKline, Zai Lab, and Boehringer Ingelheim. Dr. Lorusso disclosed relationships with AstraZeneca, Biocad, Clovis Oncology, Genmab, Merck, Roche, Tesaro, Amgen, Immunogen, and Pharma Mar.

SOURCE: Mirza MR et al. ESMO 2020, Abstract LBA28.

Adding palbociclib to letrozole significantly prolonged progression-free survival (PFS) in a phase 2 trial of patients with advanced or recurrent estrogen receptor (ER)–positive endometrial cancer.

This was the first randomized trial to evaluate the efficacy of a CDK4/6 inhibitor in combination with an aromatase inhibitor in patients with advanced or recurrent ER-positive endometrial cancer, noted study investigator Mansoor Raza Mirza, MD, PhD, of Rigshospitalet Copenhagen University Hospital.

Dr. Mirza presented results from this study, ENGOT-EN3-NSGO/PALEO, at the European Society for Medical Oncology Virtual Congress 2020.

Palbociclib is a selective inhibitor of CDK4/, both of which are involved in cell-cycle transitions, Dr. Mirza explained. He observed that endometrial endometrioid adenocarcinomas are hormone dependent, and endocrine treatment with an aromatase inhibitor is well established. Palbociclib has been shown to be superior, when combined with letrozole, to letrozole alone in ER-positive breast cancer.

For the ENGOT-EN3-NSGO/PALEO study, investigators enrolled 77 patients with ER-positive advanced/recurrent endometrial cancer. Patients had received at least one prior systemic therapy, no prior endocrine therapy (except medroxyprogesterone acetate and megestrol acetate), and no prior CDK inhibitor.

Patients were randomized 1:1 to receive oral letrozole (2.5 mg on days 1-28) and either palbociclib (125 mg on days 1-21) or placebo (125 mg on days 1-21) in a 28-day cycle until progression. Baseline characteristics were similar between the treatment arms.
 

Efficacy

Of the 77 patients enrolled, 73 were evaluable. The primary endpoint was PFS.

The median PFS in the intention-to-treat population was 3.0 months in the placebo arm and 8.3 months in the palbociclib arm (hazard ratio, 0.56; 95% confidence interval, 0.32-0.98; P = .0376).

Looking at stratification factors, PFS was higher in the palbociclib arm among the large majority (about 85%) of patients who had received no prior medroxyprogesterone acetate or megestrol acetate (HR, 0.55; 95% CI, 0.29-01.04; P = .0615) and among patients with relapsed disease (HR, 0.61; 95% CI, 0.34-1.09; P = .0916).

The disease control rate at 24 weeks, a secondary endpoint, was 63.6% in the palbociclib arm and 37.8% in the placebo arm.
 

Safety

Adverse events were more frequent in the palbociclib arm, with neutropenia being the most common.

Rates of adverse event–related dose reduction (to 100 mg or 75 mg) were 36% in the palbociclib arm and 3% in the placebo arm.

Adverse event–related discontinuation rates were 25% and 19% for palbociclib and letrozole, respectively, in the palbociclib arm and 14% and 11% for placebo and letrozole, respectively, in the placebo arm.

“The toxicity of palbociclib plus letrozole combination therapy was manageable, with most patients remaining on treatment until disease progression,” Dr. Mirza said.

He noted that an analysis of patient-reported outcomes revealed no detrimental effect on quality of life with the combination therapy.
 

Next steps

“Compared with placebo plus letrozole, the combination of palbociclib plus letrozole demonstrated clinically meaningful improvement in PFS,” Dr. Mirza said. “These results merit a phase 3 validation trial.”

“There is a huge rationale for using this drug in endometrial cancer,” commented study discussant Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of Sacred Hearth in Rome.

Dr. Lorusso said hormone receptor expression, which has been identified as a strong predictor of CDK4/6 inhibitor activity, is present in up to 90% of patients with type 1 and in about 65% of patients with type 2 endometrial cancer.

Response rates, in experience with aromatase inhibitors, have been “quite disappointing, in the 10%-20% range,” Dr. Lorusso said, with “dismal prognosis” and guidelines stating that “no standard second-line treatment has been identified.”

This research was sponsored by investigators, but Pfizer provided a study grant. Dr. Mirza disclosed relationships with Pfizer, AstraZeneca, Biocad, Clovis Oncology, Genmab, Karyopharm Therapeutics, Merck, Oncology Adventure, Roche, Seattle Genetics, Sera Prognostics, Sotio, GlaxoSmithKline, Zai Lab, and Boehringer Ingelheim. Dr. Lorusso disclosed relationships with AstraZeneca, Biocad, Clovis Oncology, Genmab, Merck, Roche, Tesaro, Amgen, Immunogen, and Pharma Mar.

SOURCE: Mirza MR et al. ESMO 2020, Abstract LBA28.

Persons with type 2 diabetes may be at heightened risk for developing vascular dementia than other types of dementia, a team of international researchers has found.

Compared with a nondiabetic control population, those with type 2 diabetes had a statistically significant 35% increased chance of having vascular dementia in a large observational study.

By comparison, the risk for nonvascular dementia was increased by a “more modest” 8%, said the researchers from the University of Glasgow and the University of Gothenburg (Sweden), while the risk for Alzheimer’s dementia appeared to be reduced by 8%.

The link between type 2 diabetes and dementia is not new, observed Carlos Celis-Morales, PhD, who presented the study’s findings at the virtual annual meeting of the European Association for the Study of Diabetes. With people living longer thanks to improved preventative strategies and treatments, there is a risk for developing other chronic conditions, such as dementia.

“A third of all dementia cases may be attributable to modifiable risk factors, among them type 2 diabetes, which accounts for 3.2% of all dementia cases,” said Dr. Celis-Morales, a research fellow at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences.

“Although we know that diabetes is linked to dementia, what we don’t know really well is how much of this association between diabetes and dementia outcomes are explained by modifiable and nonmodifiable risk factors,” Dr. Celis-Morales added.

“Diabetes and dementia share certain risk factors,” commented coinvestigator Naveed Sattar, MD, in a press release issued by the EASD. These include obesity, smoking, and lack of physical activity and might explain part of the association between the two conditions.

Dr. Sattar said that the heightened vascular dementia risk found in the study was “in itself an argument for preventive measures such as healthier lifestyle,” adding that “the importance of prevention is underscored by the fact that, for the majority of dementia diseases, there is no good treatment.”

Using data from the Swedish National Diabetes Register, the research team set out to determine the extent to which type 2 diabetes was associated with dementia and the incidence of different subtypes of dementia. They also looked to see if there were any associations with blood glucose control and what risk factors may be involved.

In total, data on 378,299 individuals with type 2 diabetes were compared with data on 1,886,022 similarly aged (average, 64 years) and gender-matched controls from the general population.

After a mean 7 years of follow-up, 10,143 people with and 46,479 people without type 2 diabetes developed dementia. Nonvascular dementia was the most common type of dementia recorded, followed by Alzheimer’s disease and then vascular dementia.

“Within type 2 diabetes individuals, poor glycemic [control] increased the risk of dementia especially for vascular dementia and nonvascular dementia. However, these associations were not as evident for Alzheimer’s disease,” Dr. Celis-Morales reported.

Comparing those with hemoglobin bA1c of less than 52 mmol/mol (7%) with those whose A1c was above 87 mmol/mol (10.1%), there was 93% increase in the risk for vascular dementia, a 67% increase in the risk for nonvascular dementia, and a 34% higher risk for Alzheimer’s disease–associated dementia.

“We have focused on high levels of HbA1c, but what happens if you have really low limits? It’s something we’re working on right now,” Dr. Celis-Morales said.

Importantly, cardiovascular-related risk factors – some of which, like systolic blood pressure and body weight, were potentially modifiable – accounted for more than 40% of the risk for dementia in type 2 diabetes. This suggests that a large percentage of the dementia risk could perhaps be addressed by identifying high-risk individuals and tailoring interventions accordingly.

“These are observational findings, so we need to be careful before we translate to any sort of recommendation,” Dr. Celis-Morales said.

The study was financed by the Swedish state under the agreement between the government and the county councils, the ALF agreement, as well as grant from the Novo Nordisk Foundation and the Swedish Association of Local Authorities and Regions. Dr. Celis-Morales and Dr. Sattar had no conflicts of interest.
 

SOURCE: Celis-Morales C et al. EASD 2020, Oral presentation 06.

Persons with type 2 diabetes may be at heightened risk for developing vascular dementia than other types of dementia, a team of international researchers has found.

Compared with a nondiabetic control population, those with type 2 diabetes had a statistically significant 35% increased chance of having vascular dementia in a large observational study.

By comparison, the risk for nonvascular dementia was increased by a “more modest” 8%, said the researchers from the University of Glasgow and the University of Gothenburg (Sweden), while the risk for Alzheimer’s dementia appeared to be reduced by 8%.

The link between type 2 diabetes and dementia is not new, observed Carlos Celis-Morales, PhD, who presented the study’s findings at the virtual annual meeting of the European Association for the Study of Diabetes. With people living longer thanks to improved preventative strategies and treatments, there is a risk for developing other chronic conditions, such as dementia.

“A third of all dementia cases may be attributable to modifiable risk factors, among them type 2 diabetes, which accounts for 3.2% of all dementia cases,” said Dr. Celis-Morales, a research fellow at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences.

“Although we know that diabetes is linked to dementia, what we don’t know really well is how much of this association between diabetes and dementia outcomes are explained by modifiable and nonmodifiable risk factors,” Dr. Celis-Morales added.

“Diabetes and dementia share certain risk factors,” commented coinvestigator Naveed Sattar, MD, in a press release issued by the EASD. These include obesity, smoking, and lack of physical activity and might explain part of the association between the two conditions.

Dr. Sattar said that the heightened vascular dementia risk found in the study was “in itself an argument for preventive measures such as healthier lifestyle,” adding that “the importance of prevention is underscored by the fact that, for the majority of dementia diseases, there is no good treatment.”

Using data from the Swedish National Diabetes Register, the research team set out to determine the extent to which type 2 diabetes was associated with dementia and the incidence of different subtypes of dementia. They also looked to see if there were any associations with blood glucose control and what risk factors may be involved.

In total, data on 378,299 individuals with type 2 diabetes were compared with data on 1,886,022 similarly aged (average, 64 years) and gender-matched controls from the general population.

After a mean 7 years of follow-up, 10,143 people with and 46,479 people without type 2 diabetes developed dementia. Nonvascular dementia was the most common type of dementia recorded, followed by Alzheimer’s disease and then vascular dementia.

“Within type 2 diabetes individuals, poor glycemic [control] increased the risk of dementia especially for vascular dementia and nonvascular dementia. However, these associations were not as evident for Alzheimer’s disease,” Dr. Celis-Morales reported.

Comparing those with hemoglobin bA1c of less than 52 mmol/mol (7%) with those whose A1c was above 87 mmol/mol (10.1%), there was 93% increase in the risk for vascular dementia, a 67% increase in the risk for nonvascular dementia, and a 34% higher risk for Alzheimer’s disease–associated dementia.

“We have focused on high levels of HbA1c, but what happens if you have really low limits? It’s something we’re working on right now,” Dr. Celis-Morales said.

Importantly, cardiovascular-related risk factors – some of which, like systolic blood pressure and body weight, were potentially modifiable – accounted for more than 40% of the risk for dementia in type 2 diabetes. This suggests that a large percentage of the dementia risk could perhaps be addressed by identifying high-risk individuals and tailoring interventions accordingly.

“These are observational findings, so we need to be careful before we translate to any sort of recommendation,” Dr. Celis-Morales said.

The study was financed by the Swedish state under the agreement between the government and the county councils, the ALF agreement, as well as grant from the Novo Nordisk Foundation and the Swedish Association of Local Authorities and Regions. Dr. Celis-Morales and Dr. Sattar had no conflicts of interest.
 

SOURCE: Celis-Morales C et al. EASD 2020, Oral presentation 06.

Persons with type 2 diabetes may be at heightened risk for developing vascular dementia than other types of dementia, a team of international researchers has found.

Compared with a nondiabetic control population, those with type 2 diabetes had a statistically significant 35% increased chance of having vascular dementia in a large observational study.

By comparison, the risk for nonvascular dementia was increased by a “more modest” 8%, said the researchers from the University of Glasgow and the University of Gothenburg (Sweden), while the risk for Alzheimer’s dementia appeared to be reduced by 8%.

The link between type 2 diabetes and dementia is not new, observed Carlos Celis-Morales, PhD, who presented the study’s findings at the virtual annual meeting of the European Association for the Study of Diabetes. With people living longer thanks to improved preventative strategies and treatments, there is a risk for developing other chronic conditions, such as dementia.

“A third of all dementia cases may be attributable to modifiable risk factors, among them type 2 diabetes, which accounts for 3.2% of all dementia cases,” said Dr. Celis-Morales, a research fellow at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences.

“Although we know that diabetes is linked to dementia, what we don’t know really well is how much of this association between diabetes and dementia outcomes are explained by modifiable and nonmodifiable risk factors,” Dr. Celis-Morales added.

“Diabetes and dementia share certain risk factors,” commented coinvestigator Naveed Sattar, MD, in a press release issued by the EASD. These include obesity, smoking, and lack of physical activity and might explain part of the association between the two conditions.

Dr. Sattar said that the heightened vascular dementia risk found in the study was “in itself an argument for preventive measures such as healthier lifestyle,” adding that “the importance of prevention is underscored by the fact that, for the majority of dementia diseases, there is no good treatment.”

Using data from the Swedish National Diabetes Register, the research team set out to determine the extent to which type 2 diabetes was associated with dementia and the incidence of different subtypes of dementia. They also looked to see if there were any associations with blood glucose control and what risk factors may be involved.

In total, data on 378,299 individuals with type 2 diabetes were compared with data on 1,886,022 similarly aged (average, 64 years) and gender-matched controls from the general population.

After a mean 7 years of follow-up, 10,143 people with and 46,479 people without type 2 diabetes developed dementia. Nonvascular dementia was the most common type of dementia recorded, followed by Alzheimer’s disease and then vascular dementia.

“Within type 2 diabetes individuals, poor glycemic [control] increased the risk of dementia especially for vascular dementia and nonvascular dementia. However, these associations were not as evident for Alzheimer’s disease,” Dr. Celis-Morales reported.

Comparing those with hemoglobin bA1c of less than 52 mmol/mol (7%) with those whose A1c was above 87 mmol/mol (10.1%), there was 93% increase in the risk for vascular dementia, a 67% increase in the risk for nonvascular dementia, and a 34% higher risk for Alzheimer’s disease–associated dementia.

“We have focused on high levels of HbA1c, but what happens if you have really low limits? It’s something we’re working on right now,” Dr. Celis-Morales said.

Importantly, cardiovascular-related risk factors – some of which, like systolic blood pressure and body weight, were potentially modifiable – accounted for more than 40% of the risk for dementia in type 2 diabetes. This suggests that a large percentage of the dementia risk could perhaps be addressed by identifying high-risk individuals and tailoring interventions accordingly.

“These are observational findings, so we need to be careful before we translate to any sort of recommendation,” Dr. Celis-Morales said.

The study was financed by the Swedish state under the agreement between the government and the county councils, the ALF agreement, as well as grant from the Novo Nordisk Foundation and the Swedish Association of Local Authorities and Regions. Dr. Celis-Morales and Dr. Sattar had no conflicts of interest.
 

SOURCE: Celis-Morales C et al. EASD 2020, Oral presentation 06.

Two new protein biomarkers may serve as prognostic indicators for outcomes in chronic lymphocytic leukemia (CLL) patients, according to the results of a proteomic assessment of patients’ serum compared to their event-free survival (EFS).

The results were published in Experimental Hematology.

The study attempted to validate the prognostic ability of known proteomic markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL, according to Fatemeh Saberi Hosnijeh, MD, of Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and colleagues.

Baseline serum samples were taken from 51 CLL patients who were then treated with chemoimmunotherapy. The samples were analyzed for 360 proteomic markers, and those results were compared with patient EFS.

Study subjects were selected from patients enrolled in the HOVON 109 clinical trial, a phase 1/2 trial designed to assess the efficacy and safety of first-line therapy involving chlorambucil, rituximab,and lenalidomide in elderly patients and young frail patients with advanced CLL.

The patients assessed comprised 30 men and 21 women, and the median EFS for all patients was 23 months (ranging from 1.25 to 60.9 months).
 

Promising biomarkers

The researchers found that patients who had high serum levels of the proteins sCD23 (P = .026), sCD27 (P = .04), the serine peptidase inhibitor SPINT1 (P = .001), and the surface antigen protein LY9 (P = .0003) had a shorter EFS than those with marker levels below the median.

“Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients,” the researchers stated.

“Despite the relatively small number of available cases, which had an impact on statistical power, our pilot study identified SPINT1 and LY9 as promising independent prognostic proteomic markers next to sCD23 and sCD27 in patients treated for CLL. Further studies with larger sample sizes are required to validate these results,” the researchers concluded.

This research was supported by a grant from Gilead Sciences and an EU TRANSCAN/Dutch Cancer Society grant. The authors declared that they had no conflicts of interest.

[email protected]

SOURCE: Hosnijeh FS et al. Exp Hematol. 2020;89:55-60.

Two new protein biomarkers may serve as prognostic indicators for outcomes in chronic lymphocytic leukemia (CLL) patients, according to the results of a proteomic assessment of patients’ serum compared to their event-free survival (EFS).

The results were published in Experimental Hematology.

The study attempted to validate the prognostic ability of known proteomic markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL, according to Fatemeh Saberi Hosnijeh, MD, of Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and colleagues.

Baseline serum samples were taken from 51 CLL patients who were then treated with chemoimmunotherapy. The samples were analyzed for 360 proteomic markers, and those results were compared with patient EFS.

Study subjects were selected from patients enrolled in the HOVON 109 clinical trial, a phase 1/2 trial designed to assess the efficacy and safety of first-line therapy involving chlorambucil, rituximab,and lenalidomide in elderly patients and young frail patients with advanced CLL.

The patients assessed comprised 30 men and 21 women, and the median EFS for all patients was 23 months (ranging from 1.25 to 60.9 months).
 

Promising biomarkers

The researchers found that patients who had high serum levels of the proteins sCD23 (P = .026), sCD27 (P = .04), the serine peptidase inhibitor SPINT1 (P = .001), and the surface antigen protein LY9 (P = .0003) had a shorter EFS than those with marker levels below the median.

“Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients,” the researchers stated.

“Despite the relatively small number of available cases, which had an impact on statistical power, our pilot study identified SPINT1 and LY9 as promising independent prognostic proteomic markers next to sCD23 and sCD27 in patients treated for CLL. Further studies with larger sample sizes are required to validate these results,” the researchers concluded.

This research was supported by a grant from Gilead Sciences and an EU TRANSCAN/Dutch Cancer Society grant. The authors declared that they had no conflicts of interest.

[email protected]

SOURCE: Hosnijeh FS et al. Exp Hematol. 2020;89:55-60.

Two new protein biomarkers may serve as prognostic indicators for outcomes in chronic lymphocytic leukemia (CLL) patients, according to the results of a proteomic assessment of patients’ serum compared to their event-free survival (EFS).

The results were published in Experimental Hematology.

The study attempted to validate the prognostic ability of known proteomic markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL, according to Fatemeh Saberi Hosnijeh, MD, of Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and colleagues.

Baseline serum samples were taken from 51 CLL patients who were then treated with chemoimmunotherapy. The samples were analyzed for 360 proteomic markers, and those results were compared with patient EFS.

Study subjects were selected from patients enrolled in the HOVON 109 clinical trial, a phase 1/2 trial designed to assess the efficacy and safety of first-line therapy involving chlorambucil, rituximab,and lenalidomide in elderly patients and young frail patients with advanced CLL.

The patients assessed comprised 30 men and 21 women, and the median EFS for all patients was 23 months (ranging from 1.25 to 60.9 months).
 

Promising biomarkers

The researchers found that patients who had high serum levels of the proteins sCD23 (P = .026), sCD27 (P = .04), the serine peptidase inhibitor SPINT1 (P = .001), and the surface antigen protein LY9 (P = .0003) had a shorter EFS than those with marker levels below the median.

“Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients,” the researchers stated.

“Despite the relatively small number of available cases, which had an impact on statistical power, our pilot study identified SPINT1 and LY9 as promising independent prognostic proteomic markers next to sCD23 and sCD27 in patients treated for CLL. Further studies with larger sample sizes are required to validate these results,” the researchers concluded.

This research was supported by a grant from Gilead Sciences and an EU TRANSCAN/Dutch Cancer Society grant. The authors declared that they had no conflicts of interest.

[email protected]

SOURCE: Hosnijeh FS et al. Exp Hematol. 2020;89:55-60.

Survival of U.S. patients who received a kidney transplant improved during 2000-2018, but the extent of improvement among patients whose end-stage kidney disease linked with diabetes lagged behind patients with renal disease unrelated to diabetes, based on a review of more than 250,000 U.S. renal transplant recipients from that period.

Mohammed Haneefa Nizamudeen/Getty Images

After adjustment for several demographic and clinical baseline differences, as well as for several characteristics of the organ donor, the analysis showed that patients with type 2 diabetes (T2D) had a significant 64% higher mortality rate following kidney transplant compared with patients without diabetes, while patients with type 1 diabetes (T1D) had a significant 94% increased relative rate of death, Jessica Harding, PhD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

The analyses that Dr. Harding reported also showed that, throughout the period examined, mortality rates following kidney transplant remained several times greater than the death rate of similar Americans who did not undergo renal replacement. By 2017, the standardized mortality ratio for patients with T2D following a kidney transplant was roughly fourfold greater than in similarly aged Americans in the general population who did undergo a transplant, while for patients with T1D the standardized mortality ratio compared with the general population was about sevenfold higher.

“Important disparities” for survival following kidney transplantation based on a specific diabetes etiology exist among U.S. patients, and further research should examine ways to better reduce posttransplant mortality in patients with diabetes, especially those with T1D, concluded Dr. Harding, an epidemiologist in the division of transplantation, department of surgery, at Emory University, Atlanta.

Issues surrounding kidney transplantation and postsurgical survival among patients with diabetes are important because these patients remain very susceptible to developing end-stage kidney disease and need for renal replacement. Adequate management of hyperglycemia, hypertension, and the adverse cardiovascular effects of immunosuppressive drugs might provide effective strategies for further mortality reductions among patients with diabetes following kidney transplant, she suggested.

The study used data collected in the United States Renal Data System during January 2000–August 2018, and included 258,188 adults who underwent a first-time, single kidney transplant at a U.S. center. About 20,000 patients had T1D (8%), about 59,000 (23%) had T2D, and the remaining 69% had no diabetes diagnosis. The data allowed for survival monitoring during a median follow-up of just over 6 years, during which more than 72,000 of the tracked patients (28%) died. The Renal Data System entries for 2017 also showed that 47% of U.S. patients with new end-stage renal disease had a diabetes etiology, Dr. Harding said.

The study received no commercial funding. Dr. Harding had no disclosures.

[email protected]

SOURCE: Harding J. EASD 2020. Oral presentation 66.

Survival of U.S. patients who received a kidney transplant improved during 2000-2018, but the extent of improvement among patients whose end-stage kidney disease linked with diabetes lagged behind patients with renal disease unrelated to diabetes, based on a review of more than 250,000 U.S. renal transplant recipients from that period.

Mohammed Haneefa Nizamudeen/Getty Images

After adjustment for several demographic and clinical baseline differences, as well as for several characteristics of the organ donor, the analysis showed that patients with type 2 diabetes (T2D) had a significant 64% higher mortality rate following kidney transplant compared with patients without diabetes, while patients with type 1 diabetes (T1D) had a significant 94% increased relative rate of death, Jessica Harding, PhD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

The analyses that Dr. Harding reported also showed that, throughout the period examined, mortality rates following kidney transplant remained several times greater than the death rate of similar Americans who did not undergo renal replacement. By 2017, the standardized mortality ratio for patients with T2D following a kidney transplant was roughly fourfold greater than in similarly aged Americans in the general population who did undergo a transplant, while for patients with T1D the standardized mortality ratio compared with the general population was about sevenfold higher.

“Important disparities” for survival following kidney transplantation based on a specific diabetes etiology exist among U.S. patients, and further research should examine ways to better reduce posttransplant mortality in patients with diabetes, especially those with T1D, concluded Dr. Harding, an epidemiologist in the division of transplantation, department of surgery, at Emory University, Atlanta.

Issues surrounding kidney transplantation and postsurgical survival among patients with diabetes are important because these patients remain very susceptible to developing end-stage kidney disease and need for renal replacement. Adequate management of hyperglycemia, hypertension, and the adverse cardiovascular effects of immunosuppressive drugs might provide effective strategies for further mortality reductions among patients with diabetes following kidney transplant, she suggested.

The study used data collected in the United States Renal Data System during January 2000–August 2018, and included 258,188 adults who underwent a first-time, single kidney transplant at a U.S. center. About 20,000 patients had T1D (8%), about 59,000 (23%) had T2D, and the remaining 69% had no diabetes diagnosis. The data allowed for survival monitoring during a median follow-up of just over 6 years, during which more than 72,000 of the tracked patients (28%) died. The Renal Data System entries for 2017 also showed that 47% of U.S. patients with new end-stage renal disease had a diabetes etiology, Dr. Harding said.

The study received no commercial funding. Dr. Harding had no disclosures.

[email protected]

SOURCE: Harding J. EASD 2020. Oral presentation 66.

Survival of U.S. patients who received a kidney transplant improved during 2000-2018, but the extent of improvement among patients whose end-stage kidney disease linked with diabetes lagged behind patients with renal disease unrelated to diabetes, based on a review of more than 250,000 U.S. renal transplant recipients from that period.

Mohammed Haneefa Nizamudeen/Getty Images

After adjustment for several demographic and clinical baseline differences, as well as for several characteristics of the organ donor, the analysis showed that patients with type 2 diabetes (T2D) had a significant 64% higher mortality rate following kidney transplant compared with patients without diabetes, while patients with type 1 diabetes (T1D) had a significant 94% increased relative rate of death, Jessica Harding, PhD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

The analyses that Dr. Harding reported also showed that, throughout the period examined, mortality rates following kidney transplant remained several times greater than the death rate of similar Americans who did not undergo renal replacement. By 2017, the standardized mortality ratio for patients with T2D following a kidney transplant was roughly fourfold greater than in similarly aged Americans in the general population who did undergo a transplant, while for patients with T1D the standardized mortality ratio compared with the general population was about sevenfold higher.

“Important disparities” for survival following kidney transplantation based on a specific diabetes etiology exist among U.S. patients, and further research should examine ways to better reduce posttransplant mortality in patients with diabetes, especially those with T1D, concluded Dr. Harding, an epidemiologist in the division of transplantation, department of surgery, at Emory University, Atlanta.

Issues surrounding kidney transplantation and postsurgical survival among patients with diabetes are important because these patients remain very susceptible to developing end-stage kidney disease and need for renal replacement. Adequate management of hyperglycemia, hypertension, and the adverse cardiovascular effects of immunosuppressive drugs might provide effective strategies for further mortality reductions among patients with diabetes following kidney transplant, she suggested.

The study used data collected in the United States Renal Data System during January 2000–August 2018, and included 258,188 adults who underwent a first-time, single kidney transplant at a U.S. center. About 20,000 patients had T1D (8%), about 59,000 (23%) had T2D, and the remaining 69% had no diabetes diagnosis. The data allowed for survival monitoring during a median follow-up of just over 6 years, during which more than 72,000 of the tracked patients (28%) died. The Renal Data System entries for 2017 also showed that 47% of U.S. patients with new end-stage renal disease had a diabetes etiology, Dr. Harding said.

The study received no commercial funding. Dr. Harding had no disclosures.

[email protected]

SOURCE: Harding J. EASD 2020. Oral presentation 66.

Children continue to represent an increasing proportion of reported COVID-19 cases in the United States, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The 38,516 child cases reported during the week ending Sept. 17 bring the cumulative number to 587,948, which is 10.3% of all COVID-19 cases. The previous week, children represented 10.0% of all cases, and that proportion has continued to rise throughout the pandemic, the AAP and CHA report shows.

Looking at just new cases for the latest week, the 38,000+ pediatric cases made up almost 17% of the 228,396 cases reported for all ages, compared with 16% and 15% the two previous weeks. For the weeks ending Aug. 13 and Aug. 6, the corresponding figures were 8% and 13%, based on the data in the AAP/CHA report, which cover 49 states (New York City but not New York state), the District of Columbia, Puerto Rico, and Guam.

The state with the highest proportion of child COVID-19 cases as of Sept. 17 was Wyoming, with 20.6%, followed by North Dakota at 18.3% and Tennessee at 17.9%. New York City has a cumulative rate of just 3.4%, but New Jersey is the state with the lowest rate at 3.6%. Florida comes in at 5.9% but is using an age range of 0-14 years for children, and Texas has a rate of 6.0% but has reported ages for only 8% of confirmed cases, the AAP and CHA noted.

Severe illness, however, continues to be rare in children. The overall hospitalization rate for children was down to 1.7% among the 26 jurisdictions providing ages as Sept. 17 – down from 1.8% the week before and 2.3% on Aug. 20. The death rate is just 0.02% among 43 jurisdictions, the report said.

[email protected]

Children continue to represent an increasing proportion of reported COVID-19 cases in the United States, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The 38,516 child cases reported during the week ending Sept. 17 bring the cumulative number to 587,948, which is 10.3% of all COVID-19 cases. The previous week, children represented 10.0% of all cases, and that proportion has continued to rise throughout the pandemic, the AAP and CHA report shows.

Looking at just new cases for the latest week, the 38,000+ pediatric cases made up almost 17% of the 228,396 cases reported for all ages, compared with 16% and 15% the two previous weeks. For the weeks ending Aug. 13 and Aug. 6, the corresponding figures were 8% and 13%, based on the data in the AAP/CHA report, which cover 49 states (New York City but not New York state), the District of Columbia, Puerto Rico, and Guam.

The state with the highest proportion of child COVID-19 cases as of Sept. 17 was Wyoming, with 20.6%, followed by North Dakota at 18.3% and Tennessee at 17.9%. New York City has a cumulative rate of just 3.4%, but New Jersey is the state with the lowest rate at 3.6%. Florida comes in at 5.9% but is using an age range of 0-14 years for children, and Texas has a rate of 6.0% but has reported ages for only 8% of confirmed cases, the AAP and CHA noted.

Severe illness, however, continues to be rare in children. The overall hospitalization rate for children was down to 1.7% among the 26 jurisdictions providing ages as Sept. 17 – down from 1.8% the week before and 2.3% on Aug. 20. The death rate is just 0.02% among 43 jurisdictions, the report said.

[email protected]

Children continue to represent an increasing proportion of reported COVID-19 cases in the United States, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

The 38,516 child cases reported during the week ending Sept. 17 bring the cumulative number to 587,948, which is 10.3% of all COVID-19 cases. The previous week, children represented 10.0% of all cases, and that proportion has continued to rise throughout the pandemic, the AAP and CHA report shows.

Looking at just new cases for the latest week, the 38,000+ pediatric cases made up almost 17% of the 228,396 cases reported for all ages, compared with 16% and 15% the two previous weeks. For the weeks ending Aug. 13 and Aug. 6, the corresponding figures were 8% and 13%, based on the data in the AAP/CHA report, which cover 49 states (New York City but not New York state), the District of Columbia, Puerto Rico, and Guam.

The state with the highest proportion of child COVID-19 cases as of Sept. 17 was Wyoming, with 20.6%, followed by North Dakota at 18.3% and Tennessee at 17.9%. New York City has a cumulative rate of just 3.4%, but New Jersey is the state with the lowest rate at 3.6%. Florida comes in at 5.9% but is using an age range of 0-14 years for children, and Texas has a rate of 6.0% but has reported ages for only 8% of confirmed cases, the AAP and CHA noted.

Severe illness, however, continues to be rare in children. The overall hospitalization rate for children was down to 1.7% among the 26 jurisdictions providing ages as Sept. 17 – down from 1.8% the week before and 2.3% on Aug. 20. The death rate is just 0.02% among 43 jurisdictions, the report said.

[email protected]

Maybe the hipsters patronizing trendy oxygen bars seeking elevation of mood back in the prepandemic era were actually onto something – because Israeli investigators have now shown in a pilot double-blind, placebo-controlled, randomized trial that breathing enriched oxygen on a nightly basis resulted in clinically meaningful symptomatic improvement in mild to moderate major depression.

Courtesy Dr. R. Haim Belmaker

“We saw a highly significant effect of normobaric hyperoxia therapy in lowering Hamilton Rating Scale for Depression scores,” R. Haim Belmaker, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

In addition, the patients on enriched oxygen also showed statistically significant and clinically meaningful improvements relative to sham-treated controls on the secondary endpoints of Clinical Global Impressions Scale, the World Health Organization–Five Well-Being Index, the Sheehan Disability Scale, and the Sense of Coherence Scale, added Dr. Belmaker, professor emeritus of psychiatry at the Ben Gurion University of the Negev in Beersheva, Israel.

Numerous PET imaging studies have documented diminished brain mitochondrial function in patients with depression or schizophrenia. And mitochondria need oxygen to do their work. Yet, the idea of administering enriched oxygen in an effort to boost mitochondrial energy metabolism has long been viewed with skepticism – even though it’s a simple and well-tolerated intervention – because of the fact that 90%-95% of the oxygen supply is carried bound to hemoglobin, and oxygen enrichment doesn’t further increase hemoglobin saturation in individuals with normal lung function. However, recently it has been shown that inspired enriched oxygen roughly doubles arterial oxygen tension, and while this doesn’t translate into anything close to a doubled oxygen supply to tissues, it may result in increased oxygen diffusion into brain tissue, the psychiatrist explained.

Normobaric hyperoxia therapy is not to be confused with hyperbaric oxygen therapy, which requires a special chamber to handle markedly increased atmospheric pressures and has some inherent dangers. Mobile bedside oxygen generator units for oxygen enrichment are commercially available over the counter. Those used in the Israeli study were about the size of a vacuum cleaner and weighed a little more than 40 lb. Much smaller, more convenient units are available as well, but are costlier.

Dr. Belmaker reported on 51 adults with mild or moderate symptoms of major depressive disorder and a mean 11-year disease history who were randomized double blind to breathe either 35% oxygen or normal air – that is, 21% oxygen – at 1 atm pressure delivered from an investigator-supplied oxygen generator through standard plastic nasal prongs at a flow rate of 5 L/min for 7 hours nightly for 1 month.

“Controls heard the same flow and felt the same feeling on the face but were receiving 21% oxygen,” he noted.

Oxygen generator units are capable of enriching air to more than 90% oxygen; however, the investigators wanted to be cautious in a pilot study of an untested therapy, and they found evidence from both animal and human studies that 40% oxygen is reassuringly safe. Most participants were on stable doses of antidepressant medications. Study exclusion criteria included obesity, acute or chronic respiratory disease, psychosis, and suicidality.

The primary study endpoint was the change in Hamilton Rating Scale for Depression score at 1 month. From a mean baseline of 14.6, the score in the normobaric hyperoxia group dropped by more than 4 points while remaining unchanged in controls. In a subscale analysis, it was apparent that most of the improvement occurred in the anxiety and cognitive disturbance subscale domains, according to Dr. Belmaker.

Of note, all patients rated by blinded investigators as much improved or very much improved on the Clinical Global Impression scale came from the enriched oxygen group.

No treatment-related adverse events occurred in the study.

“We don’t know the mechanism of the benefit of oxygen on the brain. It’s complex. In stroke and acute MI we used to think oxygen was beneficial, but scientists now feel that it’s not,” the psychiatrist said. “This early data deserve replication with higher concentrations of oxygen, different time periods of application, and in different patient groups.”

He emphasized that, since individuals with physical illnesses – including sleep apnea and chronic obstructive pulmonary disease – were excluded from the study, it’s not possible to say whether normobaric hyperoxia therapy would have an antidepressant effect in such patients.

“I would be especially careful with the normobaric oxygen in any patients with any cardiovascular or hypertensive disease because the increased oxygen pressure can have the side effect of contracting cardiac capillaries as a reflex action. So I certainly cannot recommend applying this study in any patients with a physical disease at this point,” Dr. Belmaker emphasized.

He reported having no financial conflicts regarding the study, funded by a grant from the Brain and Behavior Research Foundation.

[email protected]

SOURCE: Belmaker RH. ECNP 2020, Session S.12.

Maybe the hipsters patronizing trendy oxygen bars seeking elevation of mood back in the prepandemic era were actually onto something – because Israeli investigators have now shown in a pilot double-blind, placebo-controlled, randomized trial that breathing enriched oxygen on a nightly basis resulted in clinically meaningful symptomatic improvement in mild to moderate major depression.

Courtesy Dr. R. Haim Belmaker

“We saw a highly significant effect of normobaric hyperoxia therapy in lowering Hamilton Rating Scale for Depression scores,” R. Haim Belmaker, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

In addition, the patients on enriched oxygen also showed statistically significant and clinically meaningful improvements relative to sham-treated controls on the secondary endpoints of Clinical Global Impressions Scale, the World Health Organization–Five Well-Being Index, the Sheehan Disability Scale, and the Sense of Coherence Scale, added Dr. Belmaker, professor emeritus of psychiatry at the Ben Gurion University of the Negev in Beersheva, Israel.

Numerous PET imaging studies have documented diminished brain mitochondrial function in patients with depression or schizophrenia. And mitochondria need oxygen to do their work. Yet, the idea of administering enriched oxygen in an effort to boost mitochondrial energy metabolism has long been viewed with skepticism – even though it’s a simple and well-tolerated intervention – because of the fact that 90%-95% of the oxygen supply is carried bound to hemoglobin, and oxygen enrichment doesn’t further increase hemoglobin saturation in individuals with normal lung function. However, recently it has been shown that inspired enriched oxygen roughly doubles arterial oxygen tension, and while this doesn’t translate into anything close to a doubled oxygen supply to tissues, it may result in increased oxygen diffusion into brain tissue, the psychiatrist explained.

Normobaric hyperoxia therapy is not to be confused with hyperbaric oxygen therapy, which requires a special chamber to handle markedly increased atmospheric pressures and has some inherent dangers. Mobile bedside oxygen generator units for oxygen enrichment are commercially available over the counter. Those used in the Israeli study were about the size of a vacuum cleaner and weighed a little more than 40 lb. Much smaller, more convenient units are available as well, but are costlier.

Dr. Belmaker reported on 51 adults with mild or moderate symptoms of major depressive disorder and a mean 11-year disease history who were randomized double blind to breathe either 35% oxygen or normal air – that is, 21% oxygen – at 1 atm pressure delivered from an investigator-supplied oxygen generator through standard plastic nasal prongs at a flow rate of 5 L/min for 7 hours nightly for 1 month.

“Controls heard the same flow and felt the same feeling on the face but were receiving 21% oxygen,” he noted.

Oxygen generator units are capable of enriching air to more than 90% oxygen; however, the investigators wanted to be cautious in a pilot study of an untested therapy, and they found evidence from both animal and human studies that 40% oxygen is reassuringly safe. Most participants were on stable doses of antidepressant medications. Study exclusion criteria included obesity, acute or chronic respiratory disease, psychosis, and suicidality.

The primary study endpoint was the change in Hamilton Rating Scale for Depression score at 1 month. From a mean baseline of 14.6, the score in the normobaric hyperoxia group dropped by more than 4 points while remaining unchanged in controls. In a subscale analysis, it was apparent that most of the improvement occurred in the anxiety and cognitive disturbance subscale domains, according to Dr. Belmaker.

Of note, all patients rated by blinded investigators as much improved or very much improved on the Clinical Global Impression scale came from the enriched oxygen group.

No treatment-related adverse events occurred in the study.

“We don’t know the mechanism of the benefit of oxygen on the brain. It’s complex. In stroke and acute MI we used to think oxygen was beneficial, but scientists now feel that it’s not,” the psychiatrist said. “This early data deserve replication with higher concentrations of oxygen, different time periods of application, and in different patient groups.”

He emphasized that, since individuals with physical illnesses – including sleep apnea and chronic obstructive pulmonary disease – were excluded from the study, it’s not possible to say whether normobaric hyperoxia therapy would have an antidepressant effect in such patients.

“I would be especially careful with the normobaric oxygen in any patients with any cardiovascular or hypertensive disease because the increased oxygen pressure can have the side effect of contracting cardiac capillaries as a reflex action. So I certainly cannot recommend applying this study in any patients with a physical disease at this point,” Dr. Belmaker emphasized.

He reported having no financial conflicts regarding the study, funded by a grant from the Brain and Behavior Research Foundation.

[email protected]

SOURCE: Belmaker RH. ECNP 2020, Session S.12.

Maybe the hipsters patronizing trendy oxygen bars seeking elevation of mood back in the prepandemic era were actually onto something – because Israeli investigators have now shown in a pilot double-blind, placebo-controlled, randomized trial that breathing enriched oxygen on a nightly basis resulted in clinically meaningful symptomatic improvement in mild to moderate major depression.

Courtesy Dr. R. Haim Belmaker

“We saw a highly significant effect of normobaric hyperoxia therapy in lowering Hamilton Rating Scale for Depression scores,” R. Haim Belmaker, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.

In addition, the patients on enriched oxygen also showed statistically significant and clinically meaningful improvements relative to sham-treated controls on the secondary endpoints of Clinical Global Impressions Scale, the World Health Organization–Five Well-Being Index, the Sheehan Disability Scale, and the Sense of Coherence Scale, added Dr. Belmaker, professor emeritus of psychiatry at the Ben Gurion University of the Negev in Beersheva, Israel.

Numerous PET imaging studies have documented diminished brain mitochondrial function in patients with depression or schizophrenia. And mitochondria need oxygen to do their work. Yet, the idea of administering enriched oxygen in an effort to boost mitochondrial energy metabolism has long been viewed with skepticism – even though it’s a simple and well-tolerated intervention – because of the fact that 90%-95% of the oxygen supply is carried bound to hemoglobin, and oxygen enrichment doesn’t further increase hemoglobin saturation in individuals with normal lung function. However, recently it has been shown that inspired enriched oxygen roughly doubles arterial oxygen tension, and while this doesn’t translate into anything close to a doubled oxygen supply to tissues, it may result in increased oxygen diffusion into brain tissue, the psychiatrist explained.

Normobaric hyperoxia therapy is not to be confused with hyperbaric oxygen therapy, which requires a special chamber to handle markedly increased atmospheric pressures and has some inherent dangers. Mobile bedside oxygen generator units for oxygen enrichment are commercially available over the counter. Those used in the Israeli study were about the size of a vacuum cleaner and weighed a little more than 40 lb. Much smaller, more convenient units are available as well, but are costlier.

Dr. Belmaker reported on 51 adults with mild or moderate symptoms of major depressive disorder and a mean 11-year disease history who were randomized double blind to breathe either 35% oxygen or normal air – that is, 21% oxygen – at 1 atm pressure delivered from an investigator-supplied oxygen generator through standard plastic nasal prongs at a flow rate of 5 L/min for 7 hours nightly for 1 month.

“Controls heard the same flow and felt the same feeling on the face but were receiving 21% oxygen,” he noted.

Oxygen generator units are capable of enriching air to more than 90% oxygen; however, the investigators wanted to be cautious in a pilot study of an untested therapy, and they found evidence from both animal and human studies that 40% oxygen is reassuringly safe. Most participants were on stable doses of antidepressant medications. Study exclusion criteria included obesity, acute or chronic respiratory disease, psychosis, and suicidality.

The primary study endpoint was the change in Hamilton Rating Scale for Depression score at 1 month. From a mean baseline of 14.6, the score in the normobaric hyperoxia group dropped by more than 4 points while remaining unchanged in controls. In a subscale analysis, it was apparent that most of the improvement occurred in the anxiety and cognitive disturbance subscale domains, according to Dr. Belmaker.

Of note, all patients rated by blinded investigators as much improved or very much improved on the Clinical Global Impression scale came from the enriched oxygen group.

No treatment-related adverse events occurred in the study.

“We don’t know the mechanism of the benefit of oxygen on the brain. It’s complex. In stroke and acute MI we used to think oxygen was beneficial, but scientists now feel that it’s not,” the psychiatrist said. “This early data deserve replication with higher concentrations of oxygen, different time periods of application, and in different patient groups.”

He emphasized that, since individuals with physical illnesses – including sleep apnea and chronic obstructive pulmonary disease – were excluded from the study, it’s not possible to say whether normobaric hyperoxia therapy would have an antidepressant effect in such patients.

“I would be especially careful with the normobaric oxygen in any patients with any cardiovascular or hypertensive disease because the increased oxygen pressure can have the side effect of contracting cardiac capillaries as a reflex action. So I certainly cannot recommend applying this study in any patients with a physical disease at this point,” Dr. Belmaker emphasized.

He reported having no financial conflicts regarding the study, funded by a grant from the Brain and Behavior Research Foundation.

[email protected]

SOURCE: Belmaker RH. ECNP 2020, Session S.12.