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Vaping-associated lung injury cases exceed 1,000
More than 1,000 cases of vaping-associated lung injury have been reported in 48 states and the U.S. Virgin Islands, according to a telebriefing by the Centers for Disease Control and Prevention.
As of Oct. 1, there have been 1,080 confirmed and probable cases of lung injury associated with the use of e-cigarettes, or vaping, said Anne Schuchat, MD, principal deputy director of the CDC. The latest figures were also reported in a statement issued by the CDC.
Dr. Schuchat said 18 related deaths in 15 states have been confirmed, and additional deaths are under investigation.
“As we have continued to get data for additional cases, the trends we reported last week persist,” Dr. Schuchat said (MMWR. 2019 Sep 27;68[39];860-4).
“Most patients reported a history of using THC [tetrahydrocannabinol]-containing products, and most patients are male and young people.” Of the 1,080 cases identified, approximately 70% are male, roughly 80% are younger than 35 years of age, and 37% are under 21 years of age. The patients’ median age is 23 years (range, 13-75 years). Among patients who have died, the median age is 50 years (range, 27-71 years).
The CDC now has information from 578 patients on the substances used in vaping products in the 90 days before symptom onset. About 78% of these patients reported using THC-containing products, and 37% reported exclusive use of THC-containing products. Roughly 58% of patients reported using nicotine-containing products, and 17% reported exclusive use of nicotine-containing products.
“I wish we had more answers regarding the specific harmful products or components that are causing these illnesses,” Dr. Schuchat said. She noted that THC-containing products appear to be the most commonly used, but these products don’t appear to be the only culprit. Additionally, in a report released recently in the New England Journal of Medicine (2019 Sep 9. doi: 10.1056/NEJMoa1911614), THC-containing products bought “off the street” were commonly used by patients with lung injuries. However, the CDC can’t say for certain if it’s safer for consumers to buy THC-containing products from a licensed dispensary.
The CDC has deployed staff to several states to help investigate the lung injuries, reached out to the clinical community to increase awareness of the injuries, and worked with clinicians and medical examiners to review assessments of patients who have developed these injuries, including those who have died. The CDC has also convened clinical professional societies to “help strengthen the detection, reporting, and management of cases,” Dr. Schuchat said.
In addition, the CDC has joined with the Food and Drug Administration and other public health partners to develop a laboratory plan for “continued testing of products, aerosol testing of substances produced by the products, and clinical pathology lung specimens from patients,” Dr. Schuchat said.
The FDA is also working to gather more information about vaping-associated lung injuries. The FDA is trying to obtain “critical details” about the specific products or substances that may be involved, said Judy McMeekin, PharmD, deputy associate commissioner for regulatory affairs at the FDA.
“There does not currently appear to be one product or substance involved in all of the cases,” Dr. McMeekin said. “We are leaving no stone unturned and following all potential leads regarding any particular product, constituent, or compound that may be at issue.”
The FDA has collected more than 440 samples of vaping devices and products from 18 states. The agency is still analyzing these samples, but a preliminary analysis has shown that some products contain THC concentrations ranging from 14% to 76%, and some products contain a combination of THC and vitamin E acetate ranging from 31% to 88%.
For information about the collection of vaping products for possible testing by the FDA, email [email protected]. For information about collection and submission of clinical specimens for possible testing by the CDC, see the Healthcare Provider webpage.
Clinicians and health officials who have questions about this outbreak can email [email protected]. All others with questions about this outbreak can contact CDC-INFO at 800-232-4636 or submit information at the Contact CDC-INFO page.
More than 1,000 cases of vaping-associated lung injury have been reported in 48 states and the U.S. Virgin Islands, according to a telebriefing by the Centers for Disease Control and Prevention.
As of Oct. 1, there have been 1,080 confirmed and probable cases of lung injury associated with the use of e-cigarettes, or vaping, said Anne Schuchat, MD, principal deputy director of the CDC. The latest figures were also reported in a statement issued by the CDC.
Dr. Schuchat said 18 related deaths in 15 states have been confirmed, and additional deaths are under investigation.
“As we have continued to get data for additional cases, the trends we reported last week persist,” Dr. Schuchat said (MMWR. 2019 Sep 27;68[39];860-4).
“Most patients reported a history of using THC [tetrahydrocannabinol]-containing products, and most patients are male and young people.” Of the 1,080 cases identified, approximately 70% are male, roughly 80% are younger than 35 years of age, and 37% are under 21 years of age. The patients’ median age is 23 years (range, 13-75 years). Among patients who have died, the median age is 50 years (range, 27-71 years).
The CDC now has information from 578 patients on the substances used in vaping products in the 90 days before symptom onset. About 78% of these patients reported using THC-containing products, and 37% reported exclusive use of THC-containing products. Roughly 58% of patients reported using nicotine-containing products, and 17% reported exclusive use of nicotine-containing products.
“I wish we had more answers regarding the specific harmful products or components that are causing these illnesses,” Dr. Schuchat said. She noted that THC-containing products appear to be the most commonly used, but these products don’t appear to be the only culprit. Additionally, in a report released recently in the New England Journal of Medicine (2019 Sep 9. doi: 10.1056/NEJMoa1911614), THC-containing products bought “off the street” were commonly used by patients with lung injuries. However, the CDC can’t say for certain if it’s safer for consumers to buy THC-containing products from a licensed dispensary.
The CDC has deployed staff to several states to help investigate the lung injuries, reached out to the clinical community to increase awareness of the injuries, and worked with clinicians and medical examiners to review assessments of patients who have developed these injuries, including those who have died. The CDC has also convened clinical professional societies to “help strengthen the detection, reporting, and management of cases,” Dr. Schuchat said.
In addition, the CDC has joined with the Food and Drug Administration and other public health partners to develop a laboratory plan for “continued testing of products, aerosol testing of substances produced by the products, and clinical pathology lung specimens from patients,” Dr. Schuchat said.
The FDA is also working to gather more information about vaping-associated lung injuries. The FDA is trying to obtain “critical details” about the specific products or substances that may be involved, said Judy McMeekin, PharmD, deputy associate commissioner for regulatory affairs at the FDA.
“There does not currently appear to be one product or substance involved in all of the cases,” Dr. McMeekin said. “We are leaving no stone unturned and following all potential leads regarding any particular product, constituent, or compound that may be at issue.”
The FDA has collected more than 440 samples of vaping devices and products from 18 states. The agency is still analyzing these samples, but a preliminary analysis has shown that some products contain THC concentrations ranging from 14% to 76%, and some products contain a combination of THC and vitamin E acetate ranging from 31% to 88%.
For information about the collection of vaping products for possible testing by the FDA, email [email protected]. For information about collection and submission of clinical specimens for possible testing by the CDC, see the Healthcare Provider webpage.
Clinicians and health officials who have questions about this outbreak can email [email protected]. All others with questions about this outbreak can contact CDC-INFO at 800-232-4636 or submit information at the Contact CDC-INFO page.
More than 1,000 cases of vaping-associated lung injury have been reported in 48 states and the U.S. Virgin Islands, according to a telebriefing by the Centers for Disease Control and Prevention.
As of Oct. 1, there have been 1,080 confirmed and probable cases of lung injury associated with the use of e-cigarettes, or vaping, said Anne Schuchat, MD, principal deputy director of the CDC. The latest figures were also reported in a statement issued by the CDC.
Dr. Schuchat said 18 related deaths in 15 states have been confirmed, and additional deaths are under investigation.
“As we have continued to get data for additional cases, the trends we reported last week persist,” Dr. Schuchat said (MMWR. 2019 Sep 27;68[39];860-4).
“Most patients reported a history of using THC [tetrahydrocannabinol]-containing products, and most patients are male and young people.” Of the 1,080 cases identified, approximately 70% are male, roughly 80% are younger than 35 years of age, and 37% are under 21 years of age. The patients’ median age is 23 years (range, 13-75 years). Among patients who have died, the median age is 50 years (range, 27-71 years).
The CDC now has information from 578 patients on the substances used in vaping products in the 90 days before symptom onset. About 78% of these patients reported using THC-containing products, and 37% reported exclusive use of THC-containing products. Roughly 58% of patients reported using nicotine-containing products, and 17% reported exclusive use of nicotine-containing products.
“I wish we had more answers regarding the specific harmful products or components that are causing these illnesses,” Dr. Schuchat said. She noted that THC-containing products appear to be the most commonly used, but these products don’t appear to be the only culprit. Additionally, in a report released recently in the New England Journal of Medicine (2019 Sep 9. doi: 10.1056/NEJMoa1911614), THC-containing products bought “off the street” were commonly used by patients with lung injuries. However, the CDC can’t say for certain if it’s safer for consumers to buy THC-containing products from a licensed dispensary.
The CDC has deployed staff to several states to help investigate the lung injuries, reached out to the clinical community to increase awareness of the injuries, and worked with clinicians and medical examiners to review assessments of patients who have developed these injuries, including those who have died. The CDC has also convened clinical professional societies to “help strengthen the detection, reporting, and management of cases,” Dr. Schuchat said.
In addition, the CDC has joined with the Food and Drug Administration and other public health partners to develop a laboratory plan for “continued testing of products, aerosol testing of substances produced by the products, and clinical pathology lung specimens from patients,” Dr. Schuchat said.
The FDA is also working to gather more information about vaping-associated lung injuries. The FDA is trying to obtain “critical details” about the specific products or substances that may be involved, said Judy McMeekin, PharmD, deputy associate commissioner for regulatory affairs at the FDA.
“There does not currently appear to be one product or substance involved in all of the cases,” Dr. McMeekin said. “We are leaving no stone unturned and following all potential leads regarding any particular product, constituent, or compound that may be at issue.”
The FDA has collected more than 440 samples of vaping devices and products from 18 states. The agency is still analyzing these samples, but a preliminary analysis has shown that some products contain THC concentrations ranging from 14% to 76%, and some products contain a combination of THC and vitamin E acetate ranging from 31% to 88%.
For information about the collection of vaping products for possible testing by the FDA, email [email protected]. For information about collection and submission of clinical specimens for possible testing by the CDC, see the Healthcare Provider webpage.
Clinicians and health officials who have questions about this outbreak can email [email protected]. All others with questions about this outbreak can contact CDC-INFO at 800-232-4636 or submit information at the Contact CDC-INFO page.
One-third of patients with severe asthma are overusing corticosteroids
MADRID – if data from a Dutch study presented at the annual congress of the European Respiratory Society are representative of practice elsewhere.
“The main message from our study is that OCS overuse is common and unnecessary in the majority of asthma patients,” reported Katrien A.B. Eger, MD, Amsterdam University Medical Centre.
In this study, 5,002 patients on high doses of inhaled corticosteroids (ICS), defined as at least 500 mcg/day, were identified in a pharmacy database in the Netherlands. These patients were asked to complete a questionnaire to determine how many had severe asthma and had received rescue or maintenance OCS in the past year.
Drawing from the pharmacy database, it could be determined that 29% of the 2,312 patients who responded to the questionnaire were taking harmfully high doses of OCS as well as high doses of ICS. For this study, harmful exposure was defined as a cumulative intake of 420 mg of prednisone-equivalent OCS over a 1-year period. The median cumulative 1-year exposure, according to Dr. Eger, was 750 mg of prednisone equivalent.
In this population, the investigators then calculated ICS medication adherence based on prescription refills. In addition, a subset of this population was evaluated for inhaler technique.
On the basis of these calculations, 47.4% of patients with harmful OCS exposure were found not to be adherent to their prescribed ICS. Of those who were adherent, 53.9% were found not be taking their inhaled steroids appropriately,
When these numbers are put together, the data suggest “78.1% of high OCS users are either nonadherent or using poor inhalation techniques, which means there is a big potential for treatment optimization,” Dr. Eger said.
Yet even among the 21.9% who were adherent and using good inhaler technique, identifying a group who presumably require OCS for exacerbations, the study found that only 46.1% had been prescribed a biologic, which Dr. Eger considers an important steroid-sparing option. She conceded that many of those not on a biologic might not be candidates, but she believes this is another missed opportunity for reducing OCS exposure.
“In the Netherlands, we have very good access to health care, and biologics are available to anyone who needs them,” said Dr. Eger, explaining that access to these drugs is not a barrier.
The evidence overall is that not enough is being done to ensure that asthma patients are being protected from the risks of OCS, according to Dr. Eger. Citing evidence that adverse events associated with OCS begin with a cumulative lifetime prednisone-equivalent exposure of only 500 mg, she believes that clinicians should be more aggressive in intervening.
“We know that there are both acute and chronic complications associated with OCS that involve a range of organ systems,” Dr. Eger said. She listed osteoporosis, diabetes mellitus, hypertension, and adrenal insufficiency as examples. Rescue OCS, even if used sparingly, can drive risk of OCS complications attributable to the importance of cumulative exposure.
In the session where these data were presented, the moderator, Guy Brusselle, MD, professor of asthma and immunology, Ghent (Belgium) University, labeled them “important.” However, he quibbled with Dr. Eger’s assertion that biologics represent a major opportunity to reduce OCS exposure.
“By suggesting that biologics are not being used often enough, there is an assumption that all of these patients have type 2 inflammatory asthma,” Dr. Brusselle said. “I think it makes more sense to emphasize steroid-sparing strategies, not just biologics.”
Dr. Eger did not disagree, but she emphasized that steroid-sparing alternatives are just one strategy to reduce OCS exposure, and ensuring that patients are adherent to prescribed ICS therapies and are using them correctly might have an even greater impact.
Dr. Eger reports no potential conflicts of interest.
MADRID – if data from a Dutch study presented at the annual congress of the European Respiratory Society are representative of practice elsewhere.
“The main message from our study is that OCS overuse is common and unnecessary in the majority of asthma patients,” reported Katrien A.B. Eger, MD, Amsterdam University Medical Centre.
In this study, 5,002 patients on high doses of inhaled corticosteroids (ICS), defined as at least 500 mcg/day, were identified in a pharmacy database in the Netherlands. These patients were asked to complete a questionnaire to determine how many had severe asthma and had received rescue or maintenance OCS in the past year.
Drawing from the pharmacy database, it could be determined that 29% of the 2,312 patients who responded to the questionnaire were taking harmfully high doses of OCS as well as high doses of ICS. For this study, harmful exposure was defined as a cumulative intake of 420 mg of prednisone-equivalent OCS over a 1-year period. The median cumulative 1-year exposure, according to Dr. Eger, was 750 mg of prednisone equivalent.
In this population, the investigators then calculated ICS medication adherence based on prescription refills. In addition, a subset of this population was evaluated for inhaler technique.
On the basis of these calculations, 47.4% of patients with harmful OCS exposure were found not to be adherent to their prescribed ICS. Of those who were adherent, 53.9% were found not be taking their inhaled steroids appropriately,
When these numbers are put together, the data suggest “78.1% of high OCS users are either nonadherent or using poor inhalation techniques, which means there is a big potential for treatment optimization,” Dr. Eger said.
Yet even among the 21.9% who were adherent and using good inhaler technique, identifying a group who presumably require OCS for exacerbations, the study found that only 46.1% had been prescribed a biologic, which Dr. Eger considers an important steroid-sparing option. She conceded that many of those not on a biologic might not be candidates, but she believes this is another missed opportunity for reducing OCS exposure.
“In the Netherlands, we have very good access to health care, and biologics are available to anyone who needs them,” said Dr. Eger, explaining that access to these drugs is not a barrier.
The evidence overall is that not enough is being done to ensure that asthma patients are being protected from the risks of OCS, according to Dr. Eger. Citing evidence that adverse events associated with OCS begin with a cumulative lifetime prednisone-equivalent exposure of only 500 mg, she believes that clinicians should be more aggressive in intervening.
“We know that there are both acute and chronic complications associated with OCS that involve a range of organ systems,” Dr. Eger said. She listed osteoporosis, diabetes mellitus, hypertension, and adrenal insufficiency as examples. Rescue OCS, even if used sparingly, can drive risk of OCS complications attributable to the importance of cumulative exposure.
In the session where these data were presented, the moderator, Guy Brusselle, MD, professor of asthma and immunology, Ghent (Belgium) University, labeled them “important.” However, he quibbled with Dr. Eger’s assertion that biologics represent a major opportunity to reduce OCS exposure.
“By suggesting that biologics are not being used often enough, there is an assumption that all of these patients have type 2 inflammatory asthma,” Dr. Brusselle said. “I think it makes more sense to emphasize steroid-sparing strategies, not just biologics.”
Dr. Eger did not disagree, but she emphasized that steroid-sparing alternatives are just one strategy to reduce OCS exposure, and ensuring that patients are adherent to prescribed ICS therapies and are using them correctly might have an even greater impact.
Dr. Eger reports no potential conflicts of interest.
MADRID – if data from a Dutch study presented at the annual congress of the European Respiratory Society are representative of practice elsewhere.
“The main message from our study is that OCS overuse is common and unnecessary in the majority of asthma patients,” reported Katrien A.B. Eger, MD, Amsterdam University Medical Centre.
In this study, 5,002 patients on high doses of inhaled corticosteroids (ICS), defined as at least 500 mcg/day, were identified in a pharmacy database in the Netherlands. These patients were asked to complete a questionnaire to determine how many had severe asthma and had received rescue or maintenance OCS in the past year.
Drawing from the pharmacy database, it could be determined that 29% of the 2,312 patients who responded to the questionnaire were taking harmfully high doses of OCS as well as high doses of ICS. For this study, harmful exposure was defined as a cumulative intake of 420 mg of prednisone-equivalent OCS over a 1-year period. The median cumulative 1-year exposure, according to Dr. Eger, was 750 mg of prednisone equivalent.
In this population, the investigators then calculated ICS medication adherence based on prescription refills. In addition, a subset of this population was evaluated for inhaler technique.
On the basis of these calculations, 47.4% of patients with harmful OCS exposure were found not to be adherent to their prescribed ICS. Of those who were adherent, 53.9% were found not be taking their inhaled steroids appropriately,
When these numbers are put together, the data suggest “78.1% of high OCS users are either nonadherent or using poor inhalation techniques, which means there is a big potential for treatment optimization,” Dr. Eger said.
Yet even among the 21.9% who were adherent and using good inhaler technique, identifying a group who presumably require OCS for exacerbations, the study found that only 46.1% had been prescribed a biologic, which Dr. Eger considers an important steroid-sparing option. She conceded that many of those not on a biologic might not be candidates, but she believes this is another missed opportunity for reducing OCS exposure.
“In the Netherlands, we have very good access to health care, and biologics are available to anyone who needs them,” said Dr. Eger, explaining that access to these drugs is not a barrier.
The evidence overall is that not enough is being done to ensure that asthma patients are being protected from the risks of OCS, according to Dr. Eger. Citing evidence that adverse events associated with OCS begin with a cumulative lifetime prednisone-equivalent exposure of only 500 mg, she believes that clinicians should be more aggressive in intervening.
“We know that there are both acute and chronic complications associated with OCS that involve a range of organ systems,” Dr. Eger said. She listed osteoporosis, diabetes mellitus, hypertension, and adrenal insufficiency as examples. Rescue OCS, even if used sparingly, can drive risk of OCS complications attributable to the importance of cumulative exposure.
In the session where these data were presented, the moderator, Guy Brusselle, MD, professor of asthma and immunology, Ghent (Belgium) University, labeled them “important.” However, he quibbled with Dr. Eger’s assertion that biologics represent a major opportunity to reduce OCS exposure.
“By suggesting that biologics are not being used often enough, there is an assumption that all of these patients have type 2 inflammatory asthma,” Dr. Brusselle said. “I think it makes more sense to emphasize steroid-sparing strategies, not just biologics.”
Dr. Eger did not disagree, but she emphasized that steroid-sparing alternatives are just one strategy to reduce OCS exposure, and ensuring that patients are adherent to prescribed ICS therapies and are using them correctly might have an even greater impact.
Dr. Eger reports no potential conflicts of interest.
REPORTING FROM ERS 2019
Six factors predicted benefit from asthma triple therapy
MADRID – Two newly published but previously reported phase 3 trials associated triple therapy in a single inhaler with a 23% reduction (P = .008) in asthma exacerbations relative to a two-drug inhaler, but fresh data from a prespecified analysis presented at the annual congress of the European Respiratory Society has identified those patients most likely to benefit.
“Six easily identifiable factors appear to be associated with the most prominent response to treatment and may help in the treatment step-up decision at the point of care,” reported Dave Singh, MD, professor in the division of infection, immunity, and respiratory medicine, University of Manchester (England).
The primary results of these trials were presented several months ago at the 2019 American Thoracic Society (ATS) meeting, but the full data were published on the day that Dr. Singh spoke at the ERS.
To identify predictors of response, the pooled analysis of TRIMARIN and TRIGGER was prespecified. Both of these trials, which were similarly designed, compared a single inhaler of inhaled corticosteroids (ICS), long-acting beta agonist (LABA), and long-acting muscarinic antagonist (LAMA) to a single ICS/LABA inhaler.
On the basis of risk for severe exacerbations, greater protection from triple therapy relative to a conventional ICS/LABA inhaler was identified for those with a high degree of reversibility (defined as greater than 400 mL) relative to those with a lower degree (RR, 0.729; P = .024), those with a body mass index less than 25 kg/m2 relative to a higher BMI (RR, 0.570; P = .005), those with only one exacerbation in the previous 12 months relative to those with more (RR, 0.731; P = .009), never-smokers relative to those with smoking history (RR, 0.764; P = .013), those younger than age 65 years relative to older (RR, 0.770; P = .17), and males relative to females (RR, 0.651; P = .009).
“This gives us six factors to consider when you are thinking about stepping up to triple therapy and are trying to determine which patients would benefit the most,” Dr. Singh said.
Both the TRIMARIN and the TRIGGER trials were double blind and placebo controlled. In both, the experimental arm was a single inhaler triple therapy of the ICS beclomethasone, the LABA formoterol, and the LAMA glycopyrronium. The control arm was a single inhaler combination of beclomethasone and formoterol. All inhalers were used twice daily.
TRIMARIN, with 171 participating sites in 16 countries, randomized 1,155 patients to the triple-drug inhaler with a moderate dose of ICS (100 mcg) or to the ICS/LABA inhaler. In TRIGGER, with 221 sites in 17 countries, 1,437 patients were randomized to one of three arms. Both the triple-drug inhaler arm and the ICS/LABA arm contained a higher dose of ICS (200 mcg) than in TRIMARIN. In an open-label third arm, patients also received the higher dose of ICS plus LABA and a second inhaler with tiotropium. The formoterol dose in all arms of both studies was 6 mcg.
As reported at the ATS and now published in the Lancet, the reduction in exacerbations on single inhaler triple therapy relative to ICS/LABA was significant when the data were pooled (even though the reduction in the TRIGGER study fell short of statistical significance). The median improvement in lung function for single inhaler triple therapy relative to ICS/LABA was significant in both TRIMARIN (57 mL; P = .008) and TRIGGER (73 mL; P = .0025).
In discussing the new pooled analysis of response predictors in TRIMARIN/TRIGGER, the ERS-invited discussant, Celeste M. Porsbjerg, MD, Bispebjerg Hospital, Copenhagen, expressed particular interest in reversibility. A positive reversibility test to salbutamol was an entry criterion for both trials, but Dr. Porsbjerg pointed out that a greater response in those with the highest reversibility suggests these patients have a phenotype in which bronchodilation is a more important driver of disease than is inflammation.
While conceding that this was possible, Dr. Singh cautioned that he considers these predictors of response to be “exploratory.” He believes that the TRIMARIN/TRIGGER studies were not designed to tease out the relative importance of mechanisms of asthma in response to the assigned therapies. However, he believes the response predictor analysis is a step in this direction, which might be valuable for better individualizing therapy.
The studies were funded by Chiesi Farmaceutici. Dr. Singh reports no potential conflicts of interest.
Virchow JC et al. Lancet. 2019 Sep 30. doi. org/10.1016/S0140-6736(19)32215-9.
MADRID – Two newly published but previously reported phase 3 trials associated triple therapy in a single inhaler with a 23% reduction (P = .008) in asthma exacerbations relative to a two-drug inhaler, but fresh data from a prespecified analysis presented at the annual congress of the European Respiratory Society has identified those patients most likely to benefit.
“Six easily identifiable factors appear to be associated with the most prominent response to treatment and may help in the treatment step-up decision at the point of care,” reported Dave Singh, MD, professor in the division of infection, immunity, and respiratory medicine, University of Manchester (England).
The primary results of these trials were presented several months ago at the 2019 American Thoracic Society (ATS) meeting, but the full data were published on the day that Dr. Singh spoke at the ERS.
To identify predictors of response, the pooled analysis of TRIMARIN and TRIGGER was prespecified. Both of these trials, which were similarly designed, compared a single inhaler of inhaled corticosteroids (ICS), long-acting beta agonist (LABA), and long-acting muscarinic antagonist (LAMA) to a single ICS/LABA inhaler.
On the basis of risk for severe exacerbations, greater protection from triple therapy relative to a conventional ICS/LABA inhaler was identified for those with a high degree of reversibility (defined as greater than 400 mL) relative to those with a lower degree (RR, 0.729; P = .024), those with a body mass index less than 25 kg/m2 relative to a higher BMI (RR, 0.570; P = .005), those with only one exacerbation in the previous 12 months relative to those with more (RR, 0.731; P = .009), never-smokers relative to those with smoking history (RR, 0.764; P = .013), those younger than age 65 years relative to older (RR, 0.770; P = .17), and males relative to females (RR, 0.651; P = .009).
“This gives us six factors to consider when you are thinking about stepping up to triple therapy and are trying to determine which patients would benefit the most,” Dr. Singh said.
Both the TRIMARIN and the TRIGGER trials were double blind and placebo controlled. In both, the experimental arm was a single inhaler triple therapy of the ICS beclomethasone, the LABA formoterol, and the LAMA glycopyrronium. The control arm was a single inhaler combination of beclomethasone and formoterol. All inhalers were used twice daily.
TRIMARIN, with 171 participating sites in 16 countries, randomized 1,155 patients to the triple-drug inhaler with a moderate dose of ICS (100 mcg) or to the ICS/LABA inhaler. In TRIGGER, with 221 sites in 17 countries, 1,437 patients were randomized to one of three arms. Both the triple-drug inhaler arm and the ICS/LABA arm contained a higher dose of ICS (200 mcg) than in TRIMARIN. In an open-label third arm, patients also received the higher dose of ICS plus LABA and a second inhaler with tiotropium. The formoterol dose in all arms of both studies was 6 mcg.
As reported at the ATS and now published in the Lancet, the reduction in exacerbations on single inhaler triple therapy relative to ICS/LABA was significant when the data were pooled (even though the reduction in the TRIGGER study fell short of statistical significance). The median improvement in lung function for single inhaler triple therapy relative to ICS/LABA was significant in both TRIMARIN (57 mL; P = .008) and TRIGGER (73 mL; P = .0025).
In discussing the new pooled analysis of response predictors in TRIMARIN/TRIGGER, the ERS-invited discussant, Celeste M. Porsbjerg, MD, Bispebjerg Hospital, Copenhagen, expressed particular interest in reversibility. A positive reversibility test to salbutamol was an entry criterion for both trials, but Dr. Porsbjerg pointed out that a greater response in those with the highest reversibility suggests these patients have a phenotype in which bronchodilation is a more important driver of disease than is inflammation.
While conceding that this was possible, Dr. Singh cautioned that he considers these predictors of response to be “exploratory.” He believes that the TRIMARIN/TRIGGER studies were not designed to tease out the relative importance of mechanisms of asthma in response to the assigned therapies. However, he believes the response predictor analysis is a step in this direction, which might be valuable for better individualizing therapy.
The studies were funded by Chiesi Farmaceutici. Dr. Singh reports no potential conflicts of interest.
Virchow JC et al. Lancet. 2019 Sep 30. doi. org/10.1016/S0140-6736(19)32215-9.
MADRID – Two newly published but previously reported phase 3 trials associated triple therapy in a single inhaler with a 23% reduction (P = .008) in asthma exacerbations relative to a two-drug inhaler, but fresh data from a prespecified analysis presented at the annual congress of the European Respiratory Society has identified those patients most likely to benefit.
“Six easily identifiable factors appear to be associated with the most prominent response to treatment and may help in the treatment step-up decision at the point of care,” reported Dave Singh, MD, professor in the division of infection, immunity, and respiratory medicine, University of Manchester (England).
The primary results of these trials were presented several months ago at the 2019 American Thoracic Society (ATS) meeting, but the full data were published on the day that Dr. Singh spoke at the ERS.
To identify predictors of response, the pooled analysis of TRIMARIN and TRIGGER was prespecified. Both of these trials, which were similarly designed, compared a single inhaler of inhaled corticosteroids (ICS), long-acting beta agonist (LABA), and long-acting muscarinic antagonist (LAMA) to a single ICS/LABA inhaler.
On the basis of risk for severe exacerbations, greater protection from triple therapy relative to a conventional ICS/LABA inhaler was identified for those with a high degree of reversibility (defined as greater than 400 mL) relative to those with a lower degree (RR, 0.729; P = .024), those with a body mass index less than 25 kg/m2 relative to a higher BMI (RR, 0.570; P = .005), those with only one exacerbation in the previous 12 months relative to those with more (RR, 0.731; P = .009), never-smokers relative to those with smoking history (RR, 0.764; P = .013), those younger than age 65 years relative to older (RR, 0.770; P = .17), and males relative to females (RR, 0.651; P = .009).
“This gives us six factors to consider when you are thinking about stepping up to triple therapy and are trying to determine which patients would benefit the most,” Dr. Singh said.
Both the TRIMARIN and the TRIGGER trials were double blind and placebo controlled. In both, the experimental arm was a single inhaler triple therapy of the ICS beclomethasone, the LABA formoterol, and the LAMA glycopyrronium. The control arm was a single inhaler combination of beclomethasone and formoterol. All inhalers were used twice daily.
TRIMARIN, with 171 participating sites in 16 countries, randomized 1,155 patients to the triple-drug inhaler with a moderate dose of ICS (100 mcg) or to the ICS/LABA inhaler. In TRIGGER, with 221 sites in 17 countries, 1,437 patients were randomized to one of three arms. Both the triple-drug inhaler arm and the ICS/LABA arm contained a higher dose of ICS (200 mcg) than in TRIMARIN. In an open-label third arm, patients also received the higher dose of ICS plus LABA and a second inhaler with tiotropium. The formoterol dose in all arms of both studies was 6 mcg.
As reported at the ATS and now published in the Lancet, the reduction in exacerbations on single inhaler triple therapy relative to ICS/LABA was significant when the data were pooled (even though the reduction in the TRIGGER study fell short of statistical significance). The median improvement in lung function for single inhaler triple therapy relative to ICS/LABA was significant in both TRIMARIN (57 mL; P = .008) and TRIGGER (73 mL; P = .0025).
In discussing the new pooled analysis of response predictors in TRIMARIN/TRIGGER, the ERS-invited discussant, Celeste M. Porsbjerg, MD, Bispebjerg Hospital, Copenhagen, expressed particular interest in reversibility. A positive reversibility test to salbutamol was an entry criterion for both trials, but Dr. Porsbjerg pointed out that a greater response in those with the highest reversibility suggests these patients have a phenotype in which bronchodilation is a more important driver of disease than is inflammation.
While conceding that this was possible, Dr. Singh cautioned that he considers these predictors of response to be “exploratory.” He believes that the TRIMARIN/TRIGGER studies were not designed to tease out the relative importance of mechanisms of asthma in response to the assigned therapies. However, he believes the response predictor analysis is a step in this direction, which might be valuable for better individualizing therapy.
The studies were funded by Chiesi Farmaceutici. Dr. Singh reports no potential conflicts of interest.
Virchow JC et al. Lancet. 2019 Sep 30. doi. org/10.1016/S0140-6736(19)32215-9.
REPORTING FROM ERS 2019
Multicenter trial backs pirfenidone for unclassifiable interstitial lung disease
MADRID – according to results of a late breaker, placebo-controlled, multinational trial presented at the annual congress of the European Respiratory Society.
For preservation of lung function as monitored with forced vital capacity (FVC), pirfenidone provided a large and highly statistically significant advantage over placebo in a phase 2 trial that randomized 253 uILD patients to 2,403 mg pirfenidone or placebo, according to Toby M. Maher, MD, head of the Fibrosis Research Group for the National Heart and Lung Institute, Imperial College, London.
At 24 weeks, FVC lung function declined by just 17.8 mL in the pirfenidone group vs. 113 mL in the placebo group (P = .002). The results, published simultaneously with Dr. Maher’s ERS presentation in The Lancet Respiratory Medicine, are particularly encouraging because there are no currently approved treatments for uILD, according to Dr. Maher.
However, the data from this study, even though it was double blind and involved 70 participating centers in 14 countries, come with an asterisk. The significant FVC advantage was documented with in-hospital measurements, but this was a secondary, not the primary, endpoint. Measurements with hand-held spirometry, which was the primary endpoint, proved to be uninterpretable due to intra-individual variability.
“We had hoped that daily home spirometry would give us more information of the patient’s trajectory over time,” said Dr. Maher, who blames himself for selecting hand-held device measurements as the primary endpoint. In the end, the variability in the home hand-held spirometry data prevented the planned statistical testing.
“There were issues with the hand-held devices we had not anticipated,” Dr. Maher reported. However, hospital-based measurement, which has long been the “regulatory standard” in ILD trials “supports the conclusion that pirfenidone was effective.”
The conclusion is also supported by other secondary outcomes and analyses. For example, the categorical declines in FVC of greater than 5% (37.0% vs. 58.7%; P = .001) and greater than 10% (14.2% vs. 27.9%; P = .011) both favored pirfenidone. There were no between-group differences in progression-free survival at 24 weeks, but events were low in both study arms over this time period.
There was evidence of functional benefit for pirfenidone relative to placebo, such as a smaller decline in the 6-minute walk test (–2 vs. –26.7 M, P = .04). Treatment favoring pirfenidone over placebo was observed across subgroups defined by age, gender, baseline lung function, and presence or absence of interstitial pneumonia with autoimmune features.
Pirfenidone was generally well tolerated with side effects similar to those reported in other studies. The rate of treatment-related discontinuation was 12.6% on pirfenidone versus 0.8% on placebo. The most frequent adverse events, all of which were more common in the pirfenidone group, were gastrointestinal complaints (47.2% vs. 25.8%), rash (10.2% vs. 7.3%), and dizziness (7.9% vs. 0.8%). Rates of photosensitivity were higher in the experimental arm (7.9% vs. 1.8%), but low relative to previous studies, potentially because of greater emphasis on sun protection, Dr. Maher reported.
About 10%-15% of patients with ILD have an unclassifiable type, he noted. Although it is possible for uILD to be a missed diagnosis of an established ILD type, Dr. Maher reported that participating centers for this study were specifically selected for their expertise in ILD. He noted that more than 45% of patients were deemed uILD on the basis of biopsy.
The ERS-invited discussant of this trial, Martin Kolb, MD, professor of respirology, McMaster University, Hamilton, Ont., called the data “strong.” He suggested the data are particularly encouraging in the context of the lack of approved therapies for uILD.
Despite the fact that benefit of pirfenidone was not established on the primary endpoint, Dr. Maher contended that this is a positive study that can be used to design future investigations. “When we use the normal standard endpoint for the study, we see a clear benefit of pirfenidone over placebo.”
Dr. Maher reported no potential conflicts of interest.
SOURCE: Maher TM et al. Lancet Respir Med. 2019 Sep 29. doi: 10.1016/S2213-2600(19)30341-8.
MADRID – according to results of a late breaker, placebo-controlled, multinational trial presented at the annual congress of the European Respiratory Society.
For preservation of lung function as monitored with forced vital capacity (FVC), pirfenidone provided a large and highly statistically significant advantage over placebo in a phase 2 trial that randomized 253 uILD patients to 2,403 mg pirfenidone or placebo, according to Toby M. Maher, MD, head of the Fibrosis Research Group for the National Heart and Lung Institute, Imperial College, London.
At 24 weeks, FVC lung function declined by just 17.8 mL in the pirfenidone group vs. 113 mL in the placebo group (P = .002). The results, published simultaneously with Dr. Maher’s ERS presentation in The Lancet Respiratory Medicine, are particularly encouraging because there are no currently approved treatments for uILD, according to Dr. Maher.
However, the data from this study, even though it was double blind and involved 70 participating centers in 14 countries, come with an asterisk. The significant FVC advantage was documented with in-hospital measurements, but this was a secondary, not the primary, endpoint. Measurements with hand-held spirometry, which was the primary endpoint, proved to be uninterpretable due to intra-individual variability.
“We had hoped that daily home spirometry would give us more information of the patient’s trajectory over time,” said Dr. Maher, who blames himself for selecting hand-held device measurements as the primary endpoint. In the end, the variability in the home hand-held spirometry data prevented the planned statistical testing.
“There were issues with the hand-held devices we had not anticipated,” Dr. Maher reported. However, hospital-based measurement, which has long been the “regulatory standard” in ILD trials “supports the conclusion that pirfenidone was effective.”
The conclusion is also supported by other secondary outcomes and analyses. For example, the categorical declines in FVC of greater than 5% (37.0% vs. 58.7%; P = .001) and greater than 10% (14.2% vs. 27.9%; P = .011) both favored pirfenidone. There were no between-group differences in progression-free survival at 24 weeks, but events were low in both study arms over this time period.
There was evidence of functional benefit for pirfenidone relative to placebo, such as a smaller decline in the 6-minute walk test (–2 vs. –26.7 M, P = .04). Treatment favoring pirfenidone over placebo was observed across subgroups defined by age, gender, baseline lung function, and presence or absence of interstitial pneumonia with autoimmune features.
Pirfenidone was generally well tolerated with side effects similar to those reported in other studies. The rate of treatment-related discontinuation was 12.6% on pirfenidone versus 0.8% on placebo. The most frequent adverse events, all of which were more common in the pirfenidone group, were gastrointestinal complaints (47.2% vs. 25.8%), rash (10.2% vs. 7.3%), and dizziness (7.9% vs. 0.8%). Rates of photosensitivity were higher in the experimental arm (7.9% vs. 1.8%), but low relative to previous studies, potentially because of greater emphasis on sun protection, Dr. Maher reported.
About 10%-15% of patients with ILD have an unclassifiable type, he noted. Although it is possible for uILD to be a missed diagnosis of an established ILD type, Dr. Maher reported that participating centers for this study were specifically selected for their expertise in ILD. He noted that more than 45% of patients were deemed uILD on the basis of biopsy.
The ERS-invited discussant of this trial, Martin Kolb, MD, professor of respirology, McMaster University, Hamilton, Ont., called the data “strong.” He suggested the data are particularly encouraging in the context of the lack of approved therapies for uILD.
Despite the fact that benefit of pirfenidone was not established on the primary endpoint, Dr. Maher contended that this is a positive study that can be used to design future investigations. “When we use the normal standard endpoint for the study, we see a clear benefit of pirfenidone over placebo.”
Dr. Maher reported no potential conflicts of interest.
SOURCE: Maher TM et al. Lancet Respir Med. 2019 Sep 29. doi: 10.1016/S2213-2600(19)30341-8.
MADRID – according to results of a late breaker, placebo-controlled, multinational trial presented at the annual congress of the European Respiratory Society.
For preservation of lung function as monitored with forced vital capacity (FVC), pirfenidone provided a large and highly statistically significant advantage over placebo in a phase 2 trial that randomized 253 uILD patients to 2,403 mg pirfenidone or placebo, according to Toby M. Maher, MD, head of the Fibrosis Research Group for the National Heart and Lung Institute, Imperial College, London.
At 24 weeks, FVC lung function declined by just 17.8 mL in the pirfenidone group vs. 113 mL in the placebo group (P = .002). The results, published simultaneously with Dr. Maher’s ERS presentation in The Lancet Respiratory Medicine, are particularly encouraging because there are no currently approved treatments for uILD, according to Dr. Maher.
However, the data from this study, even though it was double blind and involved 70 participating centers in 14 countries, come with an asterisk. The significant FVC advantage was documented with in-hospital measurements, but this was a secondary, not the primary, endpoint. Measurements with hand-held spirometry, which was the primary endpoint, proved to be uninterpretable due to intra-individual variability.
“We had hoped that daily home spirometry would give us more information of the patient’s trajectory over time,” said Dr. Maher, who blames himself for selecting hand-held device measurements as the primary endpoint. In the end, the variability in the home hand-held spirometry data prevented the planned statistical testing.
“There were issues with the hand-held devices we had not anticipated,” Dr. Maher reported. However, hospital-based measurement, which has long been the “regulatory standard” in ILD trials “supports the conclusion that pirfenidone was effective.”
The conclusion is also supported by other secondary outcomes and analyses. For example, the categorical declines in FVC of greater than 5% (37.0% vs. 58.7%; P = .001) and greater than 10% (14.2% vs. 27.9%; P = .011) both favored pirfenidone. There were no between-group differences in progression-free survival at 24 weeks, but events were low in both study arms over this time period.
There was evidence of functional benefit for pirfenidone relative to placebo, such as a smaller decline in the 6-minute walk test (–2 vs. –26.7 M, P = .04). Treatment favoring pirfenidone over placebo was observed across subgroups defined by age, gender, baseline lung function, and presence or absence of interstitial pneumonia with autoimmune features.
Pirfenidone was generally well tolerated with side effects similar to those reported in other studies. The rate of treatment-related discontinuation was 12.6% on pirfenidone versus 0.8% on placebo. The most frequent adverse events, all of which were more common in the pirfenidone group, were gastrointestinal complaints (47.2% vs. 25.8%), rash (10.2% vs. 7.3%), and dizziness (7.9% vs. 0.8%). Rates of photosensitivity were higher in the experimental arm (7.9% vs. 1.8%), but low relative to previous studies, potentially because of greater emphasis on sun protection, Dr. Maher reported.
About 10%-15% of patients with ILD have an unclassifiable type, he noted. Although it is possible for uILD to be a missed diagnosis of an established ILD type, Dr. Maher reported that participating centers for this study were specifically selected for their expertise in ILD. He noted that more than 45% of patients were deemed uILD on the basis of biopsy.
The ERS-invited discussant of this trial, Martin Kolb, MD, professor of respirology, McMaster University, Hamilton, Ont., called the data “strong.” He suggested the data are particularly encouraging in the context of the lack of approved therapies for uILD.
Despite the fact that benefit of pirfenidone was not established on the primary endpoint, Dr. Maher contended that this is a positive study that can be used to design future investigations. “When we use the normal standard endpoint for the study, we see a clear benefit of pirfenidone over placebo.”
Dr. Maher reported no potential conflicts of interest.
SOURCE: Maher TM et al. Lancet Respir Med. 2019 Sep 29. doi: 10.1016/S2213-2600(19)30341-8.
REPORTING FROM ERS 2019
Lefamulin found noninferior to moxifloxacin for bacterial pneumonia
Persistent high rates of bacterial resistance to current treatments have created the need for more options, especially for the treatment of community-acquired bacterial pneumonia (CABP), which remains a leading cause of hospitalization and death in the United States, wrote Elizabeth Alexander, MD, of Nabriva Therapeutics in King of Prussia, Penn., and colleagues. Lefamulin, “the first pleuromutilin antibiotic approved for intravenous and oral use in humans,” has demonstrated activity against many CABP-causing pathogens, including some not susceptible to other classes of antimicrobials, they noted.
Findings of Lefamulin Evaluation Against Pneumonia 2 (LEAP2) were published in JAMA. In this study, the researchers randomized 370 patients to 600 mg of oral lefamulin every 12 hours for 5 days and 368 patients to 400 mg of oral moxifloxacin every 24 hours for 7 days.
Early clinical response rates at 96 hours were 90.8% for both medications (difference of 0.1%). In addition, the rates of clinical response success were similar between the groups in both the modified intent-to-treat population (87.5% with lefamulin and 89.1% with moxifloxacin) and the clinically evaluable population (89.7% with lefamulin and 93.6% with moxifloxacin).
Gastrointestinal issues of diarrhea and nausea were the two most frequently reported treatment-emergent adverse events in both groups. Both conditions occurred more often in the lefamulin group, compared with the moxifloxacin group, but the differences were not significant (12.2% vs. 1.1% and 5.2% vs. 1.9%, respectively).
The study findings were limited by several factors including strict exclusion criteria that may limit the generalizability of the results, as well as a lack of testing for viral copathogens, low recovery of resistant pathogens, and possible misclassification of patient ethnicity, the researchers noted.
However, the results were strengthened by the randomized design, inclusion of patients with more severe CABP, and low rate of discontinuation, they said. The data support previous studies of lefamulin. Its lack of cross-resistance to other drug classes, coverage of typical and atypical CABP pathogens, and options for both oral and intravenous use suggest that it “may provide an alternative approach for the treatment of vulnerable patients,” the researchers said.
The study was supported by Nabriva Therapeutics. Dr. Alexander and several coauthors are employees of Nabriva Therapeutics and own stock in the company.
SOURCE: Alexander E et al. JAMA. 2019 Sep 27. doi:10.1001/jama.2019.15468.
“The development and approval of a new antibiotic is a rare occurrence and a reason to celebrate” given the scientific, regulatory, and economic challenges to antibiotic development, wrote Preeti N. Malani, MD, in an accompanying editorial. Lefamulin in both oral and intravenous forms was approved by the Food and Drug Administration in August 2019 for the treatment of community-acquired bacterial pneumonia, Dr. Malani said.
Lefamulin will likely be an expensive option. According to a manufacturer press release, lefamulin may cost $205/day for intravenous treatment and $275/day for oral treatment. “This is severalfold more than moxifloxacin or levofloxacin, which are the most commonly prescribed fluoroquinolones for CABP [community-acquired bacterial pneumonia],” said Dr. Malani. However, the addition of lefamulin to the array of antibiotics is important because of the persistent burden of bacterial pneumonia as an indication for antibiotic use, Dr. Malani emphasized.
Dr. Malani is affiliated with the University of Michigan, Ann Arbor, and serves as an associate editor of JAMA, but had no financial conflicts to disclose. These remarks were taken from an accompanying editorial (JAMA. 2019 Sep 27. doi:10.1001/jama.2019.16215).
“The development and approval of a new antibiotic is a rare occurrence and a reason to celebrate” given the scientific, regulatory, and economic challenges to antibiotic development, wrote Preeti N. Malani, MD, in an accompanying editorial. Lefamulin in both oral and intravenous forms was approved by the Food and Drug Administration in August 2019 for the treatment of community-acquired bacterial pneumonia, Dr. Malani said.
Lefamulin will likely be an expensive option. According to a manufacturer press release, lefamulin may cost $205/day for intravenous treatment and $275/day for oral treatment. “This is severalfold more than moxifloxacin or levofloxacin, which are the most commonly prescribed fluoroquinolones for CABP [community-acquired bacterial pneumonia],” said Dr. Malani. However, the addition of lefamulin to the array of antibiotics is important because of the persistent burden of bacterial pneumonia as an indication for antibiotic use, Dr. Malani emphasized.
Dr. Malani is affiliated with the University of Michigan, Ann Arbor, and serves as an associate editor of JAMA, but had no financial conflicts to disclose. These remarks were taken from an accompanying editorial (JAMA. 2019 Sep 27. doi:10.1001/jama.2019.16215).
“The development and approval of a new antibiotic is a rare occurrence and a reason to celebrate” given the scientific, regulatory, and economic challenges to antibiotic development, wrote Preeti N. Malani, MD, in an accompanying editorial. Lefamulin in both oral and intravenous forms was approved by the Food and Drug Administration in August 2019 for the treatment of community-acquired bacterial pneumonia, Dr. Malani said.
Lefamulin will likely be an expensive option. According to a manufacturer press release, lefamulin may cost $205/day for intravenous treatment and $275/day for oral treatment. “This is severalfold more than moxifloxacin or levofloxacin, which are the most commonly prescribed fluoroquinolones for CABP [community-acquired bacterial pneumonia],” said Dr. Malani. However, the addition of lefamulin to the array of antibiotics is important because of the persistent burden of bacterial pneumonia as an indication for antibiotic use, Dr. Malani emphasized.
Dr. Malani is affiliated with the University of Michigan, Ann Arbor, and serves as an associate editor of JAMA, but had no financial conflicts to disclose. These remarks were taken from an accompanying editorial (JAMA. 2019 Sep 27. doi:10.1001/jama.2019.16215).
Persistent high rates of bacterial resistance to current treatments have created the need for more options, especially for the treatment of community-acquired bacterial pneumonia (CABP), which remains a leading cause of hospitalization and death in the United States, wrote Elizabeth Alexander, MD, of Nabriva Therapeutics in King of Prussia, Penn., and colleagues. Lefamulin, “the first pleuromutilin antibiotic approved for intravenous and oral use in humans,” has demonstrated activity against many CABP-causing pathogens, including some not susceptible to other classes of antimicrobials, they noted.
Findings of Lefamulin Evaluation Against Pneumonia 2 (LEAP2) were published in JAMA. In this study, the researchers randomized 370 patients to 600 mg of oral lefamulin every 12 hours for 5 days and 368 patients to 400 mg of oral moxifloxacin every 24 hours for 7 days.
Early clinical response rates at 96 hours were 90.8% for both medications (difference of 0.1%). In addition, the rates of clinical response success were similar between the groups in both the modified intent-to-treat population (87.5% with lefamulin and 89.1% with moxifloxacin) and the clinically evaluable population (89.7% with lefamulin and 93.6% with moxifloxacin).
Gastrointestinal issues of diarrhea and nausea were the two most frequently reported treatment-emergent adverse events in both groups. Both conditions occurred more often in the lefamulin group, compared with the moxifloxacin group, but the differences were not significant (12.2% vs. 1.1% and 5.2% vs. 1.9%, respectively).
The study findings were limited by several factors including strict exclusion criteria that may limit the generalizability of the results, as well as a lack of testing for viral copathogens, low recovery of resistant pathogens, and possible misclassification of patient ethnicity, the researchers noted.
However, the results were strengthened by the randomized design, inclusion of patients with more severe CABP, and low rate of discontinuation, they said. The data support previous studies of lefamulin. Its lack of cross-resistance to other drug classes, coverage of typical and atypical CABP pathogens, and options for both oral and intravenous use suggest that it “may provide an alternative approach for the treatment of vulnerable patients,” the researchers said.
The study was supported by Nabriva Therapeutics. Dr. Alexander and several coauthors are employees of Nabriva Therapeutics and own stock in the company.
SOURCE: Alexander E et al. JAMA. 2019 Sep 27. doi:10.1001/jama.2019.15468.
Persistent high rates of bacterial resistance to current treatments have created the need for more options, especially for the treatment of community-acquired bacterial pneumonia (CABP), which remains a leading cause of hospitalization and death in the United States, wrote Elizabeth Alexander, MD, of Nabriva Therapeutics in King of Prussia, Penn., and colleagues. Lefamulin, “the first pleuromutilin antibiotic approved for intravenous and oral use in humans,” has demonstrated activity against many CABP-causing pathogens, including some not susceptible to other classes of antimicrobials, they noted.
Findings of Lefamulin Evaluation Against Pneumonia 2 (LEAP2) were published in JAMA. In this study, the researchers randomized 370 patients to 600 mg of oral lefamulin every 12 hours for 5 days and 368 patients to 400 mg of oral moxifloxacin every 24 hours for 7 days.
Early clinical response rates at 96 hours were 90.8% for both medications (difference of 0.1%). In addition, the rates of clinical response success were similar between the groups in both the modified intent-to-treat population (87.5% with lefamulin and 89.1% with moxifloxacin) and the clinically evaluable population (89.7% with lefamulin and 93.6% with moxifloxacin).
Gastrointestinal issues of diarrhea and nausea were the two most frequently reported treatment-emergent adverse events in both groups. Both conditions occurred more often in the lefamulin group, compared with the moxifloxacin group, but the differences were not significant (12.2% vs. 1.1% and 5.2% vs. 1.9%, respectively).
The study findings were limited by several factors including strict exclusion criteria that may limit the generalizability of the results, as well as a lack of testing for viral copathogens, low recovery of resistant pathogens, and possible misclassification of patient ethnicity, the researchers noted.
However, the results were strengthened by the randomized design, inclusion of patients with more severe CABP, and low rate of discontinuation, they said. The data support previous studies of lefamulin. Its lack of cross-resistance to other drug classes, coverage of typical and atypical CABP pathogens, and options for both oral and intravenous use suggest that it “may provide an alternative approach for the treatment of vulnerable patients,” the researchers said.
The study was supported by Nabriva Therapeutics. Dr. Alexander and several coauthors are employees of Nabriva Therapeutics and own stock in the company.
SOURCE: Alexander E et al. JAMA. 2019 Sep 27. doi:10.1001/jama.2019.15468.
FROM JAMA
Vitamin C infusion falls short for sepsis and ARDS patients
Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.
“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.
To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.
In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.
Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.
The average age of the patients was 55 years, and 54% were men.
The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.
No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.
“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.
The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.
The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.
SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.
Although none of the primary outcomes was significant, “the difference in mortality is tantalizing and likely to spur much debate,” wrote Emily B. Brant, MD, and Derek C. Angus, MD, in an accompanying editorial.
“However, this outcome was one of many secondary outcomes, and although reported as statistically significant, that finding was without adjustment for multiple comparisons,” they said.
The study was well-designed, and resulted in the collection of considerable patient data, they said. Previous studies have suggested that approximately 40% of sepsis patients are vitamin C deficient, and vitamin C is considered safe and inexpensive, which may be reason to pursue research in this area, they added.
Study design for addition research should keep in mind the timing and dosage that were limitations in the current study; the lack of effect on organ dysfunction may have occurred because vitamin C was given too late, they said.
Researchers planning further evaluation might “reconsider optimal dosing and timing, as well as the likelihood that any potential benefits may only accrue to subsets of patients, given the underlying heterogeneity of sepsis,” they concluded (JAMA. 2019 Oct 1; 322:1257-8).
Dr. Brant and Dr. Angus are affiliated with the department of critical care medicine, University of Pittsburgh. Dr. Angus serves as a associate editor for JAMA and disclosed receiving consulting fees from Ferring, Bristol-Myers Squibb, and Beckman Coulter; holding stock in Alung Technologies; and holding pending patents for selepressin and for proteomic biomarkers of sepsis in elderly patients. Dr. Brant had no financial conflicts to disclose.
Although none of the primary outcomes was significant, “the difference in mortality is tantalizing and likely to spur much debate,” wrote Emily B. Brant, MD, and Derek C. Angus, MD, in an accompanying editorial.
“However, this outcome was one of many secondary outcomes, and although reported as statistically significant, that finding was without adjustment for multiple comparisons,” they said.
The study was well-designed, and resulted in the collection of considerable patient data, they said. Previous studies have suggested that approximately 40% of sepsis patients are vitamin C deficient, and vitamin C is considered safe and inexpensive, which may be reason to pursue research in this area, they added.
Study design for addition research should keep in mind the timing and dosage that were limitations in the current study; the lack of effect on organ dysfunction may have occurred because vitamin C was given too late, they said.
Researchers planning further evaluation might “reconsider optimal dosing and timing, as well as the likelihood that any potential benefits may only accrue to subsets of patients, given the underlying heterogeneity of sepsis,” they concluded (JAMA. 2019 Oct 1; 322:1257-8).
Dr. Brant and Dr. Angus are affiliated with the department of critical care medicine, University of Pittsburgh. Dr. Angus serves as a associate editor for JAMA and disclosed receiving consulting fees from Ferring, Bristol-Myers Squibb, and Beckman Coulter; holding stock in Alung Technologies; and holding pending patents for selepressin and for proteomic biomarkers of sepsis in elderly patients. Dr. Brant had no financial conflicts to disclose.
Although none of the primary outcomes was significant, “the difference in mortality is tantalizing and likely to spur much debate,” wrote Emily B. Brant, MD, and Derek C. Angus, MD, in an accompanying editorial.
“However, this outcome was one of many secondary outcomes, and although reported as statistically significant, that finding was without adjustment for multiple comparisons,” they said.
The study was well-designed, and resulted in the collection of considerable patient data, they said. Previous studies have suggested that approximately 40% of sepsis patients are vitamin C deficient, and vitamin C is considered safe and inexpensive, which may be reason to pursue research in this area, they added.
Study design for addition research should keep in mind the timing and dosage that were limitations in the current study; the lack of effect on organ dysfunction may have occurred because vitamin C was given too late, they said.
Researchers planning further evaluation might “reconsider optimal dosing and timing, as well as the likelihood that any potential benefits may only accrue to subsets of patients, given the underlying heterogeneity of sepsis,” they concluded (JAMA. 2019 Oct 1; 322:1257-8).
Dr. Brant and Dr. Angus are affiliated with the department of critical care medicine, University of Pittsburgh. Dr. Angus serves as a associate editor for JAMA and disclosed receiving consulting fees from Ferring, Bristol-Myers Squibb, and Beckman Coulter; holding stock in Alung Technologies; and holding pending patents for selepressin and for proteomic biomarkers of sepsis in elderly patients. Dr. Brant had no financial conflicts to disclose.
Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.
“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.
To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.
In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.
Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.
The average age of the patients was 55 years, and 54% were men.
The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.
No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.
“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.
The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.
The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.
SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.
Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.
“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.
To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.
In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.
Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.
The average age of the patients was 55 years, and 54% were men.
The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.
No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.
“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.
The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.
The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.
SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.
FROM JAMA
Key clinical point: Vitamin C infusion failed to improve outcomes for patients with ARDS and sepsis.
Major finding: The average SOFA score to measure organ failure changed by 3 points in the vitamin C group vs. 3.5 points in the placebo group.
Study details: The data come from a randomized trial of 167 adults with ARDS and sepsis.
Disclosures: The study was supported by the National Heart, Lung, and Blood Institute, the National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Tech School of Medicine, the NHLBI, and study materials from McGuff Pharmaceuticals.
Source: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi: 10.1001/jama.2019.11825.
TKI preserved lung function in patients with fibrosing interstitial disease
MADRID – according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.
The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).
Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.
On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).
In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.
“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).
The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”
However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.
The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.
A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.
In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.
More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.
The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”
Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.
SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.
MADRID – according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.
The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).
Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.
On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).
In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.
“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).
The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”
However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.
The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.
A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.
In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.
More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.
The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”
Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.
SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.
MADRID – according to findings from a phase 3, placebo-controlled trial presented at the annual congress of the European Respiratory Society.
The trial, called INBUILD, enrolled patients who had a progressive lung disease with a fibrosing phenotype, such as interstitial pneumonia with autoimmune features (IPAF) or noninterstitial pneumonia (NSIP), on the premise that these conditions might share a pathology responsive to a common therapy, explained Kevin R. Flaherty, MD, of National Jewish Health, Denver. The INBUILD trial was a randomized, double-blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries. A total of 663 patients underwent randomization and received at least one dose of nintedanib (332) or placebo (331).
Patients with fibrosing lung disease affecting more than 10% of lung volume were randomized to 150 mg twice daily of nintedanib, which inhibits intracellular growth factors implicated in fibrosis and is already indicated for IPF, or matching placebo.
On the primary endpoint of change in forced vital capacity (FVC) at 52 weeks, those in the nintedanib arm lost lung function at a rate that was less than half that of those randomized to placebo (–80.8 vs. –187.8 mL/year; P less than .001).
In a preplanned stratification, the protection from nintedanib against a decline in lung function was found to be at least as good in those with a usual interstitial pneumonia (UIP-like) pattern of fibrosis on baseline imaging (–82.9 vs. –211.1 mL/year), compared with those with other fibrotic patterns (–79.0 vs. –154.2 mL/year). The UIP-like subgroup represented about 60% of those enrolled.
“The relative protection from decline in lung function supports the hypothesis that progressive fibrosing interstitial lung diseases have a similar pathobiologic mechanism,” said Dr. Flaherty. Results from the INBUILD were published simultaneously with his ERS presentation (N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681).
The curves documenting change of lung function in favor of nintedanib relative to placebo separated within 12 weeks of treatment initiation, according to Dr. Flaherty. The ERS-invited discussant, Martin Kolb, MD, PhD, professor of respirology, McMaster University, Hamilton, Ont., called the reductions in loss of lung function “profound” and “very impactful.”
However, despite these reductions, there was no significant difference in quality of life as measured with the King’s Brief Interstitial Lung Disease (KBILD) questionnaire, which was a secondary outcome. The problem was that there was little change in KBILD in either group at 52 weeks, limiting the ability to show differences.
The rates of death were numerically lower at 52 weeks in the nintedanib arm for the study overall (4.8% vs. 5.1%) and for the UIP-like subgroup (5.3% vs. 7.8%), but the differences did not reach statistical significance.
A suggestion of benefit was derived from a design feature of INBUILD that called for patients to remain on blinded therapy until all enrolled patients completed the trial. When the effect of nintedanib was evaluated in this extended analysis, the event curves for the combined endpoint of interstitial lung disease or death separated and approached significance.
In this extended analysis, which suggests that clinical benefit is likely to accrue after longer periods of treatment, “we saw similar trends when we looked at mortality as an independent outcome,” Dr. Flaherty reported.
More patients in the nintedanib group discontinued therapy because of adverse events (19.6% vs. 10.3%), but Dr. Flaherty characterized the rate of serious adverse events as “similar.” He made this statement even though several adverse events, particularly those involving the gastrointestinal tract, such as diarrhea (66.9% vs. 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% vs. 5.1%), and abdominal pain (10.2% vs. 2.4%), were higher in the nintedanib arm.
The INBUILD trial demonstrates that nintedanib preserves lung function in fibrosing lung diseases other than IPF. In his review of this paper, Dr. Kolb pointed out that non-IPF etiologies represent about 75% of interstitial lung diseases. For these patients “we have no drugs, so there is a big medical need.”
Dr. Flaherty reports no potential conflicts of interest. The study was funded by Boehringer-Ingelheim, which produces nintedanib.
SOURCE: Flaherty KR et al. N Engl J Med. 2019 Sep 29. doi: 10.1056/NEJMoa1908681.
REPORTING FROM ERS 2019
CDC reports most vaping lung disease linked to THC-containing cartridges
and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.
The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.
The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.
Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.
Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.
Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.
Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.
“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”
Dr. Schuchat drew her data from two reports issued in the Morbidity and Mortality Weekly Report: a national case update by Peter A. Briss, MD, chair of CDC’s Lung Injury Response Epidemiology/Surveillance Group, and colleagues, and a regional report coauthored by Dr. Layden of cases in Illinois and Wisconsin.
In the national report, 514 patients self-reported their history of e-cigarette and vaping use. Among those, 395 (76.9%) reported using THC-containing products, and 292 (56.8%) reported using nicotine-containing products in the 30 days preceding symptom onset. Almost half (210; 40.9%) reported using both THC- and nicotine-containing products.
But there appeared to be no clear pattern of use, said Dr. Briss, who also participated in the briefing. More than a third (185; 36.0%) reported exclusive use of THC-containing products, and 82 (16.0%) reported exclusive use of nicotine-containing products.
The regional report added additional details.
Among the 86 patients who self-reported details, there were 234 unique cases of e-cigarette or THC vaping in 87 brands.
“Patients reported using numerous products and brands,” Dr. Layden noted. “Those who reported using THC products used an average of 2.1 different products and those who reported using nicotine products used about 1.3 different ones. Some patients reported using up to seven different brands, and these were used at least daily and sometimes numerous times in the day.”
According to the MMWR regional report, among the urinary THC screens obtained for 32 patients, “29 (91%) were positive for THC. One of these patients reported smoking combustible marijuana. Urinary THC levels for four patients who reported using THC-containing products exceeded 400 ng/ml, indicating intensive use of THC or THC-containing products.”
About 40% of THC users and 65% of nicotine-product users reported using the product at least five times a day; 52% said they used combustible marijuana in addition to the vapes, and 24% reported also smoking combustible tobacco.
There was a very low level of concomitant drug use. Two patients reported using LSD; one reported misusing dextroamphetamine-amphetamine (Adderall), and one reported misusing oxycodone. Two tested positive for benzodiazepines and opioids, and one each for only benzodiazepines, only opioids, only amphetamines. One patient screened positive for unidentified narcotics.
and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.
The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.
The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.
Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.
Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.
Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.
Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.
“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”
Dr. Schuchat drew her data from two reports issued in the Morbidity and Mortality Weekly Report: a national case update by Peter A. Briss, MD, chair of CDC’s Lung Injury Response Epidemiology/Surveillance Group, and colleagues, and a regional report coauthored by Dr. Layden of cases in Illinois and Wisconsin.
In the national report, 514 patients self-reported their history of e-cigarette and vaping use. Among those, 395 (76.9%) reported using THC-containing products, and 292 (56.8%) reported using nicotine-containing products in the 30 days preceding symptom onset. Almost half (210; 40.9%) reported using both THC- and nicotine-containing products.
But there appeared to be no clear pattern of use, said Dr. Briss, who also participated in the briefing. More than a third (185; 36.0%) reported exclusive use of THC-containing products, and 82 (16.0%) reported exclusive use of nicotine-containing products.
The regional report added additional details.
Among the 86 patients who self-reported details, there were 234 unique cases of e-cigarette or THC vaping in 87 brands.
“Patients reported using numerous products and brands,” Dr. Layden noted. “Those who reported using THC products used an average of 2.1 different products and those who reported using nicotine products used about 1.3 different ones. Some patients reported using up to seven different brands, and these were used at least daily and sometimes numerous times in the day.”
According to the MMWR regional report, among the urinary THC screens obtained for 32 patients, “29 (91%) were positive for THC. One of these patients reported smoking combustible marijuana. Urinary THC levels for four patients who reported using THC-containing products exceeded 400 ng/ml, indicating intensive use of THC or THC-containing products.”
About 40% of THC users and 65% of nicotine-product users reported using the product at least five times a day; 52% said they used combustible marijuana in addition to the vapes, and 24% reported also smoking combustible tobacco.
There was a very low level of concomitant drug use. Two patients reported using LSD; one reported misusing dextroamphetamine-amphetamine (Adderall), and one reported misusing oxycodone. Two tested positive for benzodiazepines and opioids, and one each for only benzodiazepines, only opioids, only amphetamines. One patient screened positive for unidentified narcotics.
and most products used were prepackaged, prefilled cartridges, according to new data released by the Centers for Disease Control and Prevention.
The majority of these products (66%) were THC-containing cartridges marketed under the brand name Dank. Dank cartridges are available at legal dispensaries and online in areas where they are legal. The Dank company posted a statement on its website warning buyers about fake cartridges and showing images of genuine cartridges. However, 89% of the cartridges were obtained on the street, from dealers, online, or from friends or social contacts, Jennifer Layden, MD, of the Illinois Department of Public Health said during a CDC telebriefing.
The illness was first recognized in Wisconsin and Illinois. Marijuana is illegal in Wisconsin; Illinois licensed recreational marijuana in 2009.
Other commonalties among cases have also emerged, Anne Schuchat, MD, deputy director of CDC, said during the call. More than two-thirds of the 805 confirmed or probable cases were male, and the median age was 23 years. The illness crosses age barriers, she said. About 62% were 18-24 years of age, and 54% under age 25. However, among the 12 deaths so far reported, the median age was 50 years. The age range was wide, from 27 to 71 years. Dr. Schuchat said data about medical comorbidities potentially linking the deaths is not yet available, although it is part of the ongoing investigation.
Other clinical commonalities included intensive use of THC-containing products and, in a small number of cases, concomitant use of benzodiazepenes, opioids, and narcotics.
Cases have now emerged in 46 states and in the U.S. Virgin Islands, although the number reported each week is dropping. However, this decrease may not represent a drop in newly occurring cases, but instead reflect delays in clinical recognition or reporting to local health departments, Dr. Schuchat said.
Regardless of the recent decline in reported cases, she said, the epidemic is serious, far reaching, and ongoing.
“I want to stress that this is a serious, life-threatening disease occurring mostly in otherwise healthy young people. These illnesses and deaths are occurring in the context of a dynamic marketplace with mix of products with mixes of ingredients, including potentially illicit substances. Users don’t know what’s in them and cannot tell from the ingredients listed on the packaging.”
Dr. Schuchat drew her data from two reports issued in the Morbidity and Mortality Weekly Report: a national case update by Peter A. Briss, MD, chair of CDC’s Lung Injury Response Epidemiology/Surveillance Group, and colleagues, and a regional report coauthored by Dr. Layden of cases in Illinois and Wisconsin.
In the national report, 514 patients self-reported their history of e-cigarette and vaping use. Among those, 395 (76.9%) reported using THC-containing products, and 292 (56.8%) reported using nicotine-containing products in the 30 days preceding symptom onset. Almost half (210; 40.9%) reported using both THC- and nicotine-containing products.
But there appeared to be no clear pattern of use, said Dr. Briss, who also participated in the briefing. More than a third (185; 36.0%) reported exclusive use of THC-containing products, and 82 (16.0%) reported exclusive use of nicotine-containing products.
The regional report added additional details.
Among the 86 patients who self-reported details, there were 234 unique cases of e-cigarette or THC vaping in 87 brands.
“Patients reported using numerous products and brands,” Dr. Layden noted. “Those who reported using THC products used an average of 2.1 different products and those who reported using nicotine products used about 1.3 different ones. Some patients reported using up to seven different brands, and these were used at least daily and sometimes numerous times in the day.”
According to the MMWR regional report, among the urinary THC screens obtained for 32 patients, “29 (91%) were positive for THC. One of these patients reported smoking combustible marijuana. Urinary THC levels for four patients who reported using THC-containing products exceeded 400 ng/ml, indicating intensive use of THC or THC-containing products.”
About 40% of THC users and 65% of nicotine-product users reported using the product at least five times a day; 52% said they used combustible marijuana in addition to the vapes, and 24% reported also smoking combustible tobacco.
There was a very low level of concomitant drug use. Two patients reported using LSD; one reported misusing dextroamphetamine-amphetamine (Adderall), and one reported misusing oxycodone. Two tested positive for benzodiazepines and opioids, and one each for only benzodiazepines, only opioids, only amphetamines. One patient screened positive for unidentified narcotics.