User login
Benefits of peanut desensitization may not last
based on data from a phase 2 randomized trial of individuals with confirmed peanut allergies.
Previous studies have shown that desensitization to peanuts can be successful, but sustained response to oral immunotherapy after treatment reduction or discontinuation has not been well studied, wrote R. Sharon Chinthrajah, MD, of Stanford (Calif.)University, and colleagues.
“We found that OIT with peanut was able to desensitise people with peanut allergy to 4,000 mg of peanut protein, but that discontinuation of peanut, or even a reduction to 300 mg daily, increased the likelihood of regaining clinical reactivity to peanut,” they wrote. “With peanut allergy therapies in varying stages of clinical development, and some nearing [Food and Drug Administration] approval, vital questions remain regarding the durability of treatment effects and the appropriate maintenance doses.”
In the Peanut Oral Immunotherapy Study: Safety Efficacy and Discovery (POISED), published in The Lancet, the researchers randomized 120 participants to three groups:
• 60 patients built up to a maintenance dose of 4,000 mg of peanut protein for 104 weeks followed by total discontinuation (peanut-0).
• 35 patients built up to a maintenance dose of 4,000 mg of peanut protein for 104 weeks followed by a 300-mg maintenance dose of peanut protein in the form of peanut flour (peanut-300).
• 25 patients to an oat flour placebo.
All participants were trained on how and when to use epinephrine autoinjector devices to treat allergic symptoms such as respiratory problems (cough, shortness of breath, or change in voice), widespread hives or erythema, repetitive vomiting, persistent abdominal pain, angioedema of the face, or feeling faint.
The primary outcome was passing a double-blind, placebo-controlled, food challenge (DBPCFC) to 4,000 mg of peanut protein, which was measured at baseline and at weeks 104, 117, 130, 143, and 156.
Overall, 35% of the peanut-0 group passed the challenge at 104 and 117 weeks, compared with 4% of the placebo group. At week 156 after discontinuing OIT, 13% of the peanut-0 group met the DBPCFC challenge, compared with 4% of the placebo group. However, 37% of participants randomized to a reduced peanut protein dose of 300 mg passed the challenge at 156 weeks, suggesting that more data are needed on optimal maintenance dosing strategies.
Baseline demographics were similar across all groups. The median age at study enrollment was 11 years and the median allergy duration was 9 years. The most common adverse events were mild gastrointestinal and respiratory problems. Adverse events decreased over time in all three groups.
“Higher levels of peanut-specific IgE to total IgE ratio, peanut sIgE, Ara h 1, Ara h 2, and Ara h 1 IgE to peanut-specific IgE ratio at baseline in participants were associated with increased frequencies of adverse events during active peanut OIT,” the researchers noted.
The study findings were limited by several factors including the ability of participants to tolerate 4,000 mg of peanut protein after achieving a maintenance dose but conducting serial testing only for those who passed the challenge. In addition, the results may be limited to peanut and not generalizable to other food allergies, the researchers said.
However, the results suggest that OIT remains a promising treatment for peanut allergies, and the association of biomarkers with clinical outcomes “might help the practitioner in identifying good candidates for OIT and those individuals who warrant increased vigilance against allergic reactions during OIT,” they said.
The National Institutes of Health supported the study. The researchers had no financial conflicts to disclose.
SOURCE: Chinthrajah RS et al. Lancet. 2019 Sep 12. doi: 10.1016/S0140-6736(19)31793-3.
based on data from a phase 2 randomized trial of individuals with confirmed peanut allergies.
Previous studies have shown that desensitization to peanuts can be successful, but sustained response to oral immunotherapy after treatment reduction or discontinuation has not been well studied, wrote R. Sharon Chinthrajah, MD, of Stanford (Calif.)University, and colleagues.
“We found that OIT with peanut was able to desensitise people with peanut allergy to 4,000 mg of peanut protein, but that discontinuation of peanut, or even a reduction to 300 mg daily, increased the likelihood of regaining clinical reactivity to peanut,” they wrote. “With peanut allergy therapies in varying stages of clinical development, and some nearing [Food and Drug Administration] approval, vital questions remain regarding the durability of treatment effects and the appropriate maintenance doses.”
In the Peanut Oral Immunotherapy Study: Safety Efficacy and Discovery (POISED), published in The Lancet, the researchers randomized 120 participants to three groups:
• 60 patients built up to a maintenance dose of 4,000 mg of peanut protein for 104 weeks followed by total discontinuation (peanut-0).
• 35 patients built up to a maintenance dose of 4,000 mg of peanut protein for 104 weeks followed by a 300-mg maintenance dose of peanut protein in the form of peanut flour (peanut-300).
• 25 patients to an oat flour placebo.
All participants were trained on how and when to use epinephrine autoinjector devices to treat allergic symptoms such as respiratory problems (cough, shortness of breath, or change in voice), widespread hives or erythema, repetitive vomiting, persistent abdominal pain, angioedema of the face, or feeling faint.
The primary outcome was passing a double-blind, placebo-controlled, food challenge (DBPCFC) to 4,000 mg of peanut protein, which was measured at baseline and at weeks 104, 117, 130, 143, and 156.
Overall, 35% of the peanut-0 group passed the challenge at 104 and 117 weeks, compared with 4% of the placebo group. At week 156 after discontinuing OIT, 13% of the peanut-0 group met the DBPCFC challenge, compared with 4% of the placebo group. However, 37% of participants randomized to a reduced peanut protein dose of 300 mg passed the challenge at 156 weeks, suggesting that more data are needed on optimal maintenance dosing strategies.
Baseline demographics were similar across all groups. The median age at study enrollment was 11 years and the median allergy duration was 9 years. The most common adverse events were mild gastrointestinal and respiratory problems. Adverse events decreased over time in all three groups.
“Higher levels of peanut-specific IgE to total IgE ratio, peanut sIgE, Ara h 1, Ara h 2, and Ara h 1 IgE to peanut-specific IgE ratio at baseline in participants were associated with increased frequencies of adverse events during active peanut OIT,” the researchers noted.
The study findings were limited by several factors including the ability of participants to tolerate 4,000 mg of peanut protein after achieving a maintenance dose but conducting serial testing only for those who passed the challenge. In addition, the results may be limited to peanut and not generalizable to other food allergies, the researchers said.
However, the results suggest that OIT remains a promising treatment for peanut allergies, and the association of biomarkers with clinical outcomes “might help the practitioner in identifying good candidates for OIT and those individuals who warrant increased vigilance against allergic reactions during OIT,” they said.
The National Institutes of Health supported the study. The researchers had no financial conflicts to disclose.
SOURCE: Chinthrajah RS et al. Lancet. 2019 Sep 12. doi: 10.1016/S0140-6736(19)31793-3.
based on data from a phase 2 randomized trial of individuals with confirmed peanut allergies.
Previous studies have shown that desensitization to peanuts can be successful, but sustained response to oral immunotherapy after treatment reduction or discontinuation has not been well studied, wrote R. Sharon Chinthrajah, MD, of Stanford (Calif.)University, and colleagues.
“We found that OIT with peanut was able to desensitise people with peanut allergy to 4,000 mg of peanut protein, but that discontinuation of peanut, or even a reduction to 300 mg daily, increased the likelihood of regaining clinical reactivity to peanut,” they wrote. “With peanut allergy therapies in varying stages of clinical development, and some nearing [Food and Drug Administration] approval, vital questions remain regarding the durability of treatment effects and the appropriate maintenance doses.”
In the Peanut Oral Immunotherapy Study: Safety Efficacy and Discovery (POISED), published in The Lancet, the researchers randomized 120 participants to three groups:
• 60 patients built up to a maintenance dose of 4,000 mg of peanut protein for 104 weeks followed by total discontinuation (peanut-0).
• 35 patients built up to a maintenance dose of 4,000 mg of peanut protein for 104 weeks followed by a 300-mg maintenance dose of peanut protein in the form of peanut flour (peanut-300).
• 25 patients to an oat flour placebo.
All participants were trained on how and when to use epinephrine autoinjector devices to treat allergic symptoms such as respiratory problems (cough, shortness of breath, or change in voice), widespread hives or erythema, repetitive vomiting, persistent abdominal pain, angioedema of the face, or feeling faint.
The primary outcome was passing a double-blind, placebo-controlled, food challenge (DBPCFC) to 4,000 mg of peanut protein, which was measured at baseline and at weeks 104, 117, 130, 143, and 156.
Overall, 35% of the peanut-0 group passed the challenge at 104 and 117 weeks, compared with 4% of the placebo group. At week 156 after discontinuing OIT, 13% of the peanut-0 group met the DBPCFC challenge, compared with 4% of the placebo group. However, 37% of participants randomized to a reduced peanut protein dose of 300 mg passed the challenge at 156 weeks, suggesting that more data are needed on optimal maintenance dosing strategies.
Baseline demographics were similar across all groups. The median age at study enrollment was 11 years and the median allergy duration was 9 years. The most common adverse events were mild gastrointestinal and respiratory problems. Adverse events decreased over time in all three groups.
“Higher levels of peanut-specific IgE to total IgE ratio, peanut sIgE, Ara h 1, Ara h 2, and Ara h 1 IgE to peanut-specific IgE ratio at baseline in participants were associated with increased frequencies of adverse events during active peanut OIT,” the researchers noted.
The study findings were limited by several factors including the ability of participants to tolerate 4,000 mg of peanut protein after achieving a maintenance dose but conducting serial testing only for those who passed the challenge. In addition, the results may be limited to peanut and not generalizable to other food allergies, the researchers said.
However, the results suggest that OIT remains a promising treatment for peanut allergies, and the association of biomarkers with clinical outcomes “might help the practitioner in identifying good candidates for OIT and those individuals who warrant increased vigilance against allergic reactions during OIT,” they said.
The National Institutes of Health supported the study. The researchers had no financial conflicts to disclose.
SOURCE: Chinthrajah RS et al. Lancet. 2019 Sep 12. doi: 10.1016/S0140-6736(19)31793-3.
FROM THE LANCET
CDC activates Emergency Operations Center to investigate vaping-associated lung injury
This move allows the CDC “to provide increased operational support” to CDC staff to meet the evolving challenges of the outbreak of vaping-related injuries and deaths, says a statement from the CDC.
“CDC has made it a priority to find out what is causing this outbreak,” noted CDC Director Robert Redfield, MD, in the statement.
The agency “continues to work closely with the U.S. Food and Drug Administration to collect information about recent e-cigarette product use, or vaping, among patients and to test the substances or chemicals within e-cigarette products used by case patients,” according to the statement.
The CDC provided email addresses and site addresses for gathering information and communicating about e-cigarettes.
Information about the collection of e-cigarettes for possible testing by FDA can be obtained through contacting FDAVapingSampleInquiries@fda.hhs.gov.
To communicate with CDC about this public health response, clinicians and health officials can contact LungDiseaseOutbreak@cdc.gov.
More information on the current outbreak related to e-cigarettes is available at https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html.
General information on electronic cigarette products, can be found at www.cdc.gov/e-cigarettes.
Individuals concerned about health risks of vaping should consider refraining from e-cigarette use while the cases of lung injury are being investigated, the CDC said.
This move allows the CDC “to provide increased operational support” to CDC staff to meet the evolving challenges of the outbreak of vaping-related injuries and deaths, says a statement from the CDC.
“CDC has made it a priority to find out what is causing this outbreak,” noted CDC Director Robert Redfield, MD, in the statement.
The agency “continues to work closely with the U.S. Food and Drug Administration to collect information about recent e-cigarette product use, or vaping, among patients and to test the substances or chemicals within e-cigarette products used by case patients,” according to the statement.
The CDC provided email addresses and site addresses for gathering information and communicating about e-cigarettes.
Information about the collection of e-cigarettes for possible testing by FDA can be obtained through contacting FDAVapingSampleInquiries@fda.hhs.gov.
To communicate with CDC about this public health response, clinicians and health officials can contact LungDiseaseOutbreak@cdc.gov.
More information on the current outbreak related to e-cigarettes is available at https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html.
General information on electronic cigarette products, can be found at www.cdc.gov/e-cigarettes.
Individuals concerned about health risks of vaping should consider refraining from e-cigarette use while the cases of lung injury are being investigated, the CDC said.
This move allows the CDC “to provide increased operational support” to CDC staff to meet the evolving challenges of the outbreak of vaping-related injuries and deaths, says a statement from the CDC.
“CDC has made it a priority to find out what is causing this outbreak,” noted CDC Director Robert Redfield, MD, in the statement.
The agency “continues to work closely with the U.S. Food and Drug Administration to collect information about recent e-cigarette product use, or vaping, among patients and to test the substances or chemicals within e-cigarette products used by case patients,” according to the statement.
The CDC provided email addresses and site addresses for gathering information and communicating about e-cigarettes.
Information about the collection of e-cigarettes for possible testing by FDA can be obtained through contacting FDAVapingSampleInquiries@fda.hhs.gov.
To communicate with CDC about this public health response, clinicians and health officials can contact LungDiseaseOutbreak@cdc.gov.
More information on the current outbreak related to e-cigarettes is available at https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html.
General information on electronic cigarette products, can be found at www.cdc.gov/e-cigarettes.
Individuals concerned about health risks of vaping should consider refraining from e-cigarette use while the cases of lung injury are being investigated, the CDC said.
Pulegone levels in e-liquids, smokeless tobacco products exceed FDA limits
A group of mint- and menthol-flavored e-liquids and smokeless tobacco products contained significantly more pulegone – a known carcinogen that causes hepatic carcinomas, pulmonary metaplasia, and other neoplasms – than the Food and Drug Administration considers acceptable, according to new findings.
Pulegone, an oil extract from mint plants such as peppermint, spearmint, and pennyroyal, was banned as a food additive by the agency in 2018, and the tobacco industry has taken steps to minimize pulegone levels in cigarettes because of the toxicity concerns.
Studies from the Centers for Disease Control and Prevention, however, have indicated that mint- and menthol-flavored e-cigarette liquids and smokeless tobacco products marketed in the United States contain substantial amounts of the substance, Sairam V. Jabba, DVM, PhD, and Sven-Eric Jordt, PhD, said in a research letter published in JAMA Internal Medicine.
Dr. Jabba and Dr. Jordt, both with the department of anesthesiology at Duke University, Durham, N.C., calculated the margin of exposure in five e-liquids (V2 Menthol, V2 Peppermint, Premium Menthol, South Beach Smoke Menthol, and South Beach Smoke Peppermint) and one smokeless tobacco product (Skoal Xtra Mint snuff) by dividing the no–observed adverse event level (13.39 mg/kg of bodyweight per day) by the mean human exposure to e-liquids or smokeless tobacco. The FDA considers margin-of-exposure values of 10,000 or less to require mitigation strategies.
The six products included in the analysis had pulegone concentration levels ranging from 25.7 to 119.0 mcg/g (a menthol cigarette has a pulegone concentration of 0.037-0.290 mcg/g). Based on those levels, light daily use (5 mL e-liquid, 10 g smokeless tobacco, half a pack of cigarettes) exposed e-cigarette users to 44-198 times more pulegone, compared with menthol cigarettes, and exposed smokeless tobacco users to 168-1,319 times as much pulegone. The margin of exposure ranged from 1,298 to 6,012, all below 10,000 threshhold the FDA deems acceptable.
For heavy daily use (20 mL e-liquid, 30 g smokeless tobacco, two packs of cigarettes), e-cigarette users were exposed to 282-1,608 times more pulegone, compared with menthol cigarettes; smokeless tobacco users were exposed to 126-990 times more pulegone. The margin of exposure ranged from 325 to 1,503.
The study findings “appear to establish health risks associated with pulegone intake and concerns that the FDA should address before suggesting mint- and menthol-flavored e-cigarettes and smokeless tobacco products as alternatives for people who use combustible tobacco products,” Dr. Jabba and Dr. Jordt concluded.
The study was funded by a grant from the National Institute of Environmental Health Sciences. Dr. Jordt reported receiving grants from the NIEHS and the National Institute on Drug Abuse, personal fees from Hydra Biosciences and Sanofi, and nonfinancial support from GlaxoSmithKline. Dr. Jabba reported no disclosures.
lfranki@mdedge.com
SOURCE: Jabba SV, Jordt S-E. JAMA Intern Med. 2019 Sep 16. doi: 10.1001/jamainternmed.2019.3649.
A group of mint- and menthol-flavored e-liquids and smokeless tobacco products contained significantly more pulegone – a known carcinogen that causes hepatic carcinomas, pulmonary metaplasia, and other neoplasms – than the Food and Drug Administration considers acceptable, according to new findings.
Pulegone, an oil extract from mint plants such as peppermint, spearmint, and pennyroyal, was banned as a food additive by the agency in 2018, and the tobacco industry has taken steps to minimize pulegone levels in cigarettes because of the toxicity concerns.
Studies from the Centers for Disease Control and Prevention, however, have indicated that mint- and menthol-flavored e-cigarette liquids and smokeless tobacco products marketed in the United States contain substantial amounts of the substance, Sairam V. Jabba, DVM, PhD, and Sven-Eric Jordt, PhD, said in a research letter published in JAMA Internal Medicine.
Dr. Jabba and Dr. Jordt, both with the department of anesthesiology at Duke University, Durham, N.C., calculated the margin of exposure in five e-liquids (V2 Menthol, V2 Peppermint, Premium Menthol, South Beach Smoke Menthol, and South Beach Smoke Peppermint) and one smokeless tobacco product (Skoal Xtra Mint snuff) by dividing the no–observed adverse event level (13.39 mg/kg of bodyweight per day) by the mean human exposure to e-liquids or smokeless tobacco. The FDA considers margin-of-exposure values of 10,000 or less to require mitigation strategies.
The six products included in the analysis had pulegone concentration levels ranging from 25.7 to 119.0 mcg/g (a menthol cigarette has a pulegone concentration of 0.037-0.290 mcg/g). Based on those levels, light daily use (5 mL e-liquid, 10 g smokeless tobacco, half a pack of cigarettes) exposed e-cigarette users to 44-198 times more pulegone, compared with menthol cigarettes, and exposed smokeless tobacco users to 168-1,319 times as much pulegone. The margin of exposure ranged from 1,298 to 6,012, all below 10,000 threshhold the FDA deems acceptable.
For heavy daily use (20 mL e-liquid, 30 g smokeless tobacco, two packs of cigarettes), e-cigarette users were exposed to 282-1,608 times more pulegone, compared with menthol cigarettes; smokeless tobacco users were exposed to 126-990 times more pulegone. The margin of exposure ranged from 325 to 1,503.
The study findings “appear to establish health risks associated with pulegone intake and concerns that the FDA should address before suggesting mint- and menthol-flavored e-cigarettes and smokeless tobacco products as alternatives for people who use combustible tobacco products,” Dr. Jabba and Dr. Jordt concluded.
The study was funded by a grant from the National Institute of Environmental Health Sciences. Dr. Jordt reported receiving grants from the NIEHS and the National Institute on Drug Abuse, personal fees from Hydra Biosciences and Sanofi, and nonfinancial support from GlaxoSmithKline. Dr. Jabba reported no disclosures.
lfranki@mdedge.com
SOURCE: Jabba SV, Jordt S-E. JAMA Intern Med. 2019 Sep 16. doi: 10.1001/jamainternmed.2019.3649.
A group of mint- and menthol-flavored e-liquids and smokeless tobacco products contained significantly more pulegone – a known carcinogen that causes hepatic carcinomas, pulmonary metaplasia, and other neoplasms – than the Food and Drug Administration considers acceptable, according to new findings.
Pulegone, an oil extract from mint plants such as peppermint, spearmint, and pennyroyal, was banned as a food additive by the agency in 2018, and the tobacco industry has taken steps to minimize pulegone levels in cigarettes because of the toxicity concerns.
Studies from the Centers for Disease Control and Prevention, however, have indicated that mint- and menthol-flavored e-cigarette liquids and smokeless tobacco products marketed in the United States contain substantial amounts of the substance, Sairam V. Jabba, DVM, PhD, and Sven-Eric Jordt, PhD, said in a research letter published in JAMA Internal Medicine.
Dr. Jabba and Dr. Jordt, both with the department of anesthesiology at Duke University, Durham, N.C., calculated the margin of exposure in five e-liquids (V2 Menthol, V2 Peppermint, Premium Menthol, South Beach Smoke Menthol, and South Beach Smoke Peppermint) and one smokeless tobacco product (Skoal Xtra Mint snuff) by dividing the no–observed adverse event level (13.39 mg/kg of bodyweight per day) by the mean human exposure to e-liquids or smokeless tobacco. The FDA considers margin-of-exposure values of 10,000 or less to require mitigation strategies.
The six products included in the analysis had pulegone concentration levels ranging from 25.7 to 119.0 mcg/g (a menthol cigarette has a pulegone concentration of 0.037-0.290 mcg/g). Based on those levels, light daily use (5 mL e-liquid, 10 g smokeless tobacco, half a pack of cigarettes) exposed e-cigarette users to 44-198 times more pulegone, compared with menthol cigarettes, and exposed smokeless tobacco users to 168-1,319 times as much pulegone. The margin of exposure ranged from 1,298 to 6,012, all below 10,000 threshhold the FDA deems acceptable.
For heavy daily use (20 mL e-liquid, 30 g smokeless tobacco, two packs of cigarettes), e-cigarette users were exposed to 282-1,608 times more pulegone, compared with menthol cigarettes; smokeless tobacco users were exposed to 126-990 times more pulegone. The margin of exposure ranged from 325 to 1,503.
The study findings “appear to establish health risks associated with pulegone intake and concerns that the FDA should address before suggesting mint- and menthol-flavored e-cigarettes and smokeless tobacco products as alternatives for people who use combustible tobacco products,” Dr. Jabba and Dr. Jordt concluded.
The study was funded by a grant from the National Institute of Environmental Health Sciences. Dr. Jordt reported receiving grants from the NIEHS and the National Institute on Drug Abuse, personal fees from Hydra Biosciences and Sanofi, and nonfinancial support from GlaxoSmithKline. Dr. Jabba reported no disclosures.
lfranki@mdedge.com
SOURCE: Jabba SV, Jordt S-E. JAMA Intern Med. 2019 Sep 16. doi: 10.1001/jamainternmed.2019.3649.
FROM JAMA INTERNAL MEDICINE
Key clinical point: Mint- and menthol-flavored e-liquids and smokeless tobacco contain levels of pulegone that are much higher than those deemed acceptable by the Food and Drug Administration.
Major finding:
Study details: An assessment of pulegone in five e-liquids and one brand of smokeless tobacco.
Disclosures: The study was funded by a grant from the National Institute of Environmental Health Sciences. Dr. Jordt reported receiving grants from the NIEHS and the National Institute on Drug Abuse, personal fees from Hydra Biosciences and Sanofi, and nonfinancial support from GlaxoSmithKline. Dr. Jabba reported no disclosures.
Source: Jabba SV, Jordt S-E. JAMA Intern Med. 2019 Sep 16. doi: 10.1001/jamainternmed.2019.3649.
Peanut allergy pill gets thumbs-up from FDA advisory panel
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
A pill designed to desensitize peanut-allergic children and teenagers may be on the way.
aged 4-17 years old with a confirmed peanut allergy. Conditions for approval include stipulations that a black-box warning and medication use guide are included in the packaging, the panel said. The FDA usually follows the recommendations of its advisory panels.
The committee members voted 7-2 that the drug was effective and 8-1 that it was safe.
John Kelso, MD, the sole dissenter on safety, voiced concerns about the dearth of long-term follow-up in Aimmune Therapeutic’s body of research and the finding that children who received the treatment during the dose-escalation and maintenance periods had twice the number of allergic reactions requiring epinephrine, compared with those who received placebo. There are no long-term safety data to rely on yet, he added.
“Efficacy has not been demonstrated, except on the day the peanut challenge is administered,” said Dr. Kelso, an allergist at the Scripps Clinic, San Diego, adding that only long-term follow-up data would fully convince him that the drug’s benefits outweigh the risks.
In the discussion, however, other committee members pointed out that new drugs are often approved without long-term efficacy and safety data. Those data are extrapolated from clinical trials, and only real-world experience will confirm the data, they noted.
Company representatives did not explicitly address the potential cost of the therapy, but a recent review by the Institute for Clinical and Economic Review estimated the cost to be $4,200 a year. Palforzia would have to be taken every day, for an unknown amount of time, to maintain peanut tolerance.
“Using prices from analysts for AR101 ($4,200 a year), we estimated that only 41% of eligible patients could be treated in a given year without exceeding ICER’s budget impact threshold,” the institute concluded in a publicly released analysis.
Palforzia comes in individual packs of capsules filled with peanut protein, not flour. The capsules come in doses of 0.5, 1, 10, 20, and 100, and 300 mg. A single-dose sachet contains 300 mg. Treatment begins with 0.5-6 mg over 1 day and escalates every 2 weeks until 300 mg is reached or there is a reaction requiring epinephrine. Passing at least a 300-mg dose was the requirement for exiting the escalation phase and moving on to the daily, year-long maintenance phase.
The four efficacy studies presented showed that 96% of patients tolerated 300 mg, 84% tolerated 600 mg, and 63% 1,000 mg – about 10 times the reactive dose observed in the placebo controls.
“Only 125 mg of peanut protein – the amount in about half a peanut kernel – can be enough to provoke a reaction,” said Daniel Adelman, MD, chief medical officer of Aimmune. If patients can tolerate 600 mg of protein – the equivalent of two kernels, accidental ingestion will result in a “predictable, manageable” reaction.
“This is truly a clinically significant result for patients and families who report lives dictated by the allergy,” Dr. Adelman said.
Consistent manufacturing processes and positive safety data should reassure clinicians and patients that they are receiving a safe, effective, and well-regulated treatment, he added.
The capsule, however, is not a panacea. The company advises that families continue with the peanut avoidance diet. “It’s important to remember that reactive episodes can occur with dosing, and accidental exposures can occur at unpredictable times, away from home, and despite the best efforts at avoidance,” Dr. Adelman said. “This is not a drug for everyone, but it is an effective desensitization tool and would clearly be the first therapy to treat a food allergy, providing statistically significant and clinically important improvement. Outcomes align with patients’ goals.”
Safety was assessed in 709 treated patients who received the medication and 292 who received placebo. Treatment-related adverse events were most common in initial dosing: 89% of the treatment group and 58% of the placebo group experienced at least one adverse event during that time. Adverse events were mostly mild to moderate and decreased in severity over the study period. They included abdominal pain (45% active vs. 18% placebo), throat irritation (40% vs. 17%), pruritus (33% vs. 20%), vomiting (37% vs. 16%), cough (32% vs. 24%), nausea (32% vs. 14%), urticaria (28% vs. 19%), and upper abdominal pain (30% vs. 14%).
Discontinuations caused by these adverse events were infrequent, with only 1.8% of participants who were taking the active capsule and 1% of those taking placebo discontinuing the study product during initial dose escalation. Only the severe systemic allergic reactions were considered to be anaphylaxis, and they had to affect at least two body systems.
Respiratory events were more common in those in the active group, especially in children with asthma. These events included cough, wheezing, dyspnea, dysphonia, throat irritation and tightness, and exercise-induced asthma. There was, however, no “concerning change” in asthma control.
Systemic allergic reactions and anaphylaxis were more common in the active-dose group. Systemic reactions during dose escalation occurred in 9.4% of active patients and 3.8% those taking placebo. During the maintenance phase, they occurred in 8.7% and 1.7% of patients, respectively. Three patients in the active group had a serious systemic reaction – two during up-dosing and one during maintenance.
During initial dose escalation and up-dosing combined, 6.1% of patients in the active group and 3.1% in the placebo group had a systemic reaction requiring epinephrine. This was most often administered outside of the clinic.
There were 12 cases of eosinophilic esophagitis, all of which resolved after withdrawal from the study medication.
Aimmune submitted a risk-management proposal that includes the following:
- The first dose of each progressive dose must be administered in a facility that is equipped to treat systemic allergic reactions.
- Families must have a valid prescription for injectable epinephrine before treatment starts and must demonstrate that they know how to use it.
- There must be distribution controls in every pharmacy that dispenses the product.
- Packaging will be dose specific to ensure proper at-home administration.
- Pharmacologic questionnaires will be used as data collection instruments.
- Professional and patient-focused labeling will include a medication guide and educational material.
Palforzia is not the only peanut desensitization product in the works. DBC Technology has resubmitted its biologics license application to the FDA in the hope of getting approval for its peanut allergy treatment, the Viaskin Peanut patch.
The patch is designed to desensitize allergic children aged 4-11 years through a skin-patch method known as epicutaneous immunotherapy. Results from two controlled clinical trials were included in the submission. The company is also investigating the potential of this form of skin-patch therapy for milk and egg allergies.
Correction, 9/15/19: An earlier version of this article did not clearly state that the panel recommended approval rather than granted approval for the drug.
FROM THE FDA ALLERGENIC PRODUCTS ADVISORY COMMITTEE MEETING
FDA issues warning for CDK 4/6 inhibitors
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
The Food and Drug Administration is warning that the entire class of the cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors used to treat advanced breast cancer may cause rare but severe inflammation of the lungs.
“We reviewed CDK 4/6 inhibitors cases from completed and ongoing clinical trials undertaken by manufacturers and their postmarket safety databases that described specific types of inflammation of the lungs, called interstitial lung disease and pneumonitis. Across the entire drug class, there were reports of serious cases, including fatalities,” the FDA said in a press statement.
The overall benefit of CDK 4/6 inhibitors, however, is still greater than the risks when used as prescribed, the agency said.
CDK 4/6 inhibitors are used in combination with hormone therapies to treat adults with hormone receptor–positive, human epidermal growth factor 2–negative advanced or metastatic breast cancer that has spread to other parts of the body. The FDA approved the CDK 4/6 inhibitors palbociclib (Ibrance) in 2015 and ribociclib (Kisqali) and abemaciclib (Verzenio) in 2017, based on improvements in progression-free survival.
Health care professionals should monitor patients regularly for pulmonary symptoms indicative of interstitial lung disease and/or pneumonitis. Signs and symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded. Interrupt CDK 4/6 inhibitor treatment in patients who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe interstitial lung disease and/or pneumonitis, the FDA said.
Benralizumab trials cast doubt on eosinophil depletion’s role in COPD treatment
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
and eosinophilic inflammation, according to results from two phase 3 trials. The data were published in the New England Journal of Medicine.
Benralizumab, an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody, is approved for the treatment of patients with severe eosinophilic asthma. To assess whether the treatment may prevent COPD exacerbations, Gerard J. Criner, MD, chair and professor of thoracic medicine and surgery at Temple University in Philadelphia and colleagues conducted two randomized, double-blind, parallel-group studies: GALATHEA and TERRANOVA. Researchers enrolled patients with frequent moderate or severe COPD exacerbations and blood eosinophil counts of at least 220 per mm3.
A 56-week treatment period
“An eosinophil threshold of 220 per mm3 was selected on the basis of the phase 2 trial of benralizumab in patients with COPD, in which modeling of annual exacerbations according to baseline blood eosinophil count indicated that patients with eosinophil counts above a similar threshold were more likely to have a response to benralizumab,” the authors wrote. “The doses selected were 30 mg, the approved dose for asthma treatment; 100 mg, to inform the safety margin; and 10 mg (in TERRANOVA), to evaluate the dose-efficacy relationship.”
Patients received placebo or benralizumab via subcutaneous injection every 4 weeks for the first three doses, then every 8 weeks for the rest of the 56-week treatment period. The primary end point was the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56.
The primary analysis populations included 1,120 patients in GALATHEA and 1,545 patients in TERRANOVA. Most patients were white men, and the average age was 65 years. The percentages of patients with current asthma (5.4% in GALATHEA and 3.3% in TERRANOVA) or past asthma (8.3% in GALATHEA and 6.1% in TERRANOVA) were low.
In GALATHEA, the estimated annualized exacerbation rates were 1.19 per year in the 30-mg benralizumab group, 1.03 per year in the 100-mg benralizumab group, and 1.24 per year in the placebo group. Compared with placebo, the rate ratio was 0.96 for 30 mg of benralizumab and 0.83 for 100 mg of benralizumab.
In TERRANOVA, the estimated annualized exacerbation rates for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year, 1.21 per year, 1.09 per year, and 1.17 per year, respectively. The corresponding rate ratios were 0.85, 1.04, and 0.93. “At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial,” the researchers said. “Types and frequencies of adverse events were similar with benralizumab and placebo.”
Depletion of eosinophils in blood and sputum
By week 4, benralizumab substantially depleted blood eosinophils. In addition, treatment substantially depleted sputum eosinophils by week 24. “However, in contrast to the results in benralizumab-treated patients with severe eosinophilic asthma, this eosinophil depletion did not correspond to a significant difference in the rate of exacerbations. This finding, together with the effect on eosinophils – with minimal effect on the COPD exacerbation rate – that was observed in the mepolizumab trials, suggests that eosinophil depletion is unlikely to ameliorate exacerbation outcomes for the majority of patients with COPD,” Dr. Criner and his coauthors concluded. “Future investigation is required to identify additional clinical factors or biomarkers that may characterize the patients with COPD who are most likely to benefit from anti–interleukin-5 receptor antibody therapy.”
The trials were sponsored by AstraZeneca, which manufactures benralizumab (Fasenra), and by Kyowa Hakko Kirin. One author is supported by the National Institute for Health Research Manchester Biomedical Research Centre. The authors’ disclosures included grants and personal fees from AstraZeneca and other pharmaceutical companies.
SOURCE: Criner GJ et al. N Engl J Med. 2019;382(11):1023-34. doi: 10.1056/NEJMoa1905248.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Short Takes
Pharmacist-led intervention reduced inappropriate medication prescriptions
An outpatient pharmacy-led intervention of notifying prescribing physicians to discontinue inappropriate Beers Criteria medications resulted in a greater discontinuation of inappropriate medications for older adults at 6 months, compared with the control group (43% vs. 12% discontinuation).
Citation: Martin P et al. Effect of a pharmacist-led educational intervention on inappropriate medication prescriptions in older adults: The D-PRESCRIBE randomized clinical trial. JAMA. 2018;320(18):1889-98.
Omadacycline noninferior for community-acquired pneumonia and acute bacterial soft tissue skin infections
Randomized, double-blind, double-dummy trials showed omadacycline is a noninferior alternative to moxifloxacin for the treatment of community-acquired pneumonia and to linezolid for acute bacterial soft-tissue skin infections.
Citation: Nuzyra (omadacycline) [package insert]. Boston, MA: Paratek Pharmaceuticals. 2018.
Lack of evidence to support low-salt diet in adult heart failure patients
Systematic review of multiple databases demonstrated there is limited high-quality evidence to support current guidelines that recommend a low-salt diet to heart failure patients.
Citation: Mahtani KR et al. Reduced salt intake for heart failure: A systematic review. JAMA Int Med. 2018;178(12):1693-700.
Magnesium for rate control in rapid atrial fibrillation
Randomized, controlled trial demonstrated that intravenous magnesium sulfate in combination with atrioventricular (AV) nodal blocking agents resulted in better rate control for atrial fibrillation with rapid ventricular response than did placebo given in combination with AV nodal blocking agents.
Citation: Bouida W et al. Low-dose magnesium sulfate versus high-dose in the early management of rapid atrial fibrillation: Randomized controlled double-blind study (LOMAGHI Study). Acad Emerg Med. 2019 Feb;26(2):183-91.
Low versus intermediate tidal volume strategy on ventilator-free days in ICU patients without ARDS
Randomized, clinical trial of low tidal volume versus intermediate tidal volume strategies in invasively ventilated patients without accute respiratory distress syndrome (ARDS) demonstrated no difference in number of ventilator-free days, ICU length of stay, hospital length of stay, incidence of ventilator-associated adverse events (ARDS, pneumonia, severe atelectasis, pneumothorax), or 28-day mortality.
Citation: Writing Group for the PReVENT Investigators, Simonis FD, Serpa Neto A. Effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS: A randomized clinical trial. JAMA. 2018;320(18):1872-80.
Pharmacist-led intervention reduced inappropriate medication prescriptions
An outpatient pharmacy-led intervention of notifying prescribing physicians to discontinue inappropriate Beers Criteria medications resulted in a greater discontinuation of inappropriate medications for older adults at 6 months, compared with the control group (43% vs. 12% discontinuation).
Citation: Martin P et al. Effect of a pharmacist-led educational intervention on inappropriate medication prescriptions in older adults: The D-PRESCRIBE randomized clinical trial. JAMA. 2018;320(18):1889-98.
Omadacycline noninferior for community-acquired pneumonia and acute bacterial soft tissue skin infections
Randomized, double-blind, double-dummy trials showed omadacycline is a noninferior alternative to moxifloxacin for the treatment of community-acquired pneumonia and to linezolid for acute bacterial soft-tissue skin infections.
Citation: Nuzyra (omadacycline) [package insert]. Boston, MA: Paratek Pharmaceuticals. 2018.
Lack of evidence to support low-salt diet in adult heart failure patients
Systematic review of multiple databases demonstrated there is limited high-quality evidence to support current guidelines that recommend a low-salt diet to heart failure patients.
Citation: Mahtani KR et al. Reduced salt intake for heart failure: A systematic review. JAMA Int Med. 2018;178(12):1693-700.
Magnesium for rate control in rapid atrial fibrillation
Randomized, controlled trial demonstrated that intravenous magnesium sulfate in combination with atrioventricular (AV) nodal blocking agents resulted in better rate control for atrial fibrillation with rapid ventricular response than did placebo given in combination with AV nodal blocking agents.
Citation: Bouida W et al. Low-dose magnesium sulfate versus high-dose in the early management of rapid atrial fibrillation: Randomized controlled double-blind study (LOMAGHI Study). Acad Emerg Med. 2019 Feb;26(2):183-91.
Low versus intermediate tidal volume strategy on ventilator-free days in ICU patients without ARDS
Randomized, clinical trial of low tidal volume versus intermediate tidal volume strategies in invasively ventilated patients without accute respiratory distress syndrome (ARDS) demonstrated no difference in number of ventilator-free days, ICU length of stay, hospital length of stay, incidence of ventilator-associated adverse events (ARDS, pneumonia, severe atelectasis, pneumothorax), or 28-day mortality.
Citation: Writing Group for the PReVENT Investigators, Simonis FD, Serpa Neto A. Effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS: A randomized clinical trial. JAMA. 2018;320(18):1872-80.
Pharmacist-led intervention reduced inappropriate medication prescriptions
An outpatient pharmacy-led intervention of notifying prescribing physicians to discontinue inappropriate Beers Criteria medications resulted in a greater discontinuation of inappropriate medications for older adults at 6 months, compared with the control group (43% vs. 12% discontinuation).
Citation: Martin P et al. Effect of a pharmacist-led educational intervention on inappropriate medication prescriptions in older adults: The D-PRESCRIBE randomized clinical trial. JAMA. 2018;320(18):1889-98.
Omadacycline noninferior for community-acquired pneumonia and acute bacterial soft tissue skin infections
Randomized, double-blind, double-dummy trials showed omadacycline is a noninferior alternative to moxifloxacin for the treatment of community-acquired pneumonia and to linezolid for acute bacterial soft-tissue skin infections.
Citation: Nuzyra (omadacycline) [package insert]. Boston, MA: Paratek Pharmaceuticals. 2018.
Lack of evidence to support low-salt diet in adult heart failure patients
Systematic review of multiple databases demonstrated there is limited high-quality evidence to support current guidelines that recommend a low-salt diet to heart failure patients.
Citation: Mahtani KR et al. Reduced salt intake for heart failure: A systematic review. JAMA Int Med. 2018;178(12):1693-700.
Magnesium for rate control in rapid atrial fibrillation
Randomized, controlled trial demonstrated that intravenous magnesium sulfate in combination with atrioventricular (AV) nodal blocking agents resulted in better rate control for atrial fibrillation with rapid ventricular response than did placebo given in combination with AV nodal blocking agents.
Citation: Bouida W et al. Low-dose magnesium sulfate versus high-dose in the early management of rapid atrial fibrillation: Randomized controlled double-blind study (LOMAGHI Study). Acad Emerg Med. 2019 Feb;26(2):183-91.
Low versus intermediate tidal volume strategy on ventilator-free days in ICU patients without ARDS
Randomized, clinical trial of low tidal volume versus intermediate tidal volume strategies in invasively ventilated patients without accute respiratory distress syndrome (ARDS) demonstrated no difference in number of ventilator-free days, ICU length of stay, hospital length of stay, incidence of ventilator-associated adverse events (ARDS, pneumonia, severe atelectasis, pneumothorax), or 28-day mortality.
Citation: Writing Group for the PReVENT Investigators, Simonis FD, Serpa Neto A. Effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS: A randomized clinical trial. JAMA. 2018;320(18):1872-80.
Educating teens, young adults about dangers of vaping
Physicians have been alarmed about the vaping craze for quite some time. This alarm has grown louder in the wake of news that electronic cigarettes have been associated with a mysterious lung disease.
Public health officials have reported that there have been 530 cases of vaping-related respiratory disease,1 and as of press time at least seven deaths had been attributed to vaping*. On Sept. 6, 2019, the Food and Drug Administration, Centers for Disease Control and Prevention, and other health officials issued an investigation notice on vaping and e-cigarettes,2 cautioning teenagers, young adults, and pregnant women to avoid e-cigarettes completely and cautioning all users to never buy e-cigarettes off the street or from social sources.
A few days later, on Sept. 9, the FDA’s Center for Tobacco Products issued a warning letter to JUUL Labs, makers of a popular e-cigarette, for illegal marketing of modified-risk tobacco products.3 Then on Sept. 10, health officials in Kansas reported that a sixth person has died of a lung illness related to vaping.4
Researchers have found that 80% of those diagnosed with the vaping illness used products that contained THC, the psychoactive ingredient in marijuana, 61% had used nicotine products, and 7% used cannabidiol (CBD) products. Vitamin E acetate is another substance identified in press reports as tied to the severe lung disease.
Most of the patients affected are adolescents and young adults, with the average age of 19 years.5 This comes as vaping among high school students rose 78% between 2017 and 2018.6 According the U.S. surgeon general, one in five teens vapes. Other data show that teen use of e-cigarettes comes with most users having never smoked a traditional cigarette.7 Teens and young adults frequently borrow buy* e-cigarette “pods” from gas stations but borrow and purchase from friends or peers. In addition, young people are known to alter the pods to insert other liquids, such as CBD and other marijuana products.
Teens and young adults are at higher risk for vaping complications. Their respiratory and immune systems are still developing. In addition to concerns about the recent surge of respiratory illnesses, nicotine is known to also suppress the immune system, which makes people who use it more susceptible to viral and bacterial infections – and also making it harder for them to recover.
In addition nicotine hyperactivates the reward centers of the brain, which can trigger addictive behaviors. Because the brains of young adults are not yet fully developed until at or after age 26, nicotine use before this can “prime the pump” of a still-developing brain, thereby increasing the likelihood for addiction to harder drugs. Nicotine has been shown to disrupt sleep patterns, which are critical for mental and physical health. Lastly, research shows that smoking increases the risks of various psychiatric disorders, such as depression and anxiety. My teen and young adult patients have endlessly debated with me the idea that smoking – either nicotine or marijuana – eases their anxiety or helps them get to sleep. I tell them that, in the long run, the data show that smoking makes those problems worse.8-11
Nationally, we are seeing an explosion of multistate legislation pushing marijuana as a health food. E-cigarettes have followed as the “healthy” alternative to traditional tobacco. As clinicians, we must counter those messages.
Finally, our world is now filled with smartphones, sexting, and social media overuse. An entire peer group exists that knows life only with constant electronic stimulation. It is not without irony that our national nicotine obsessions have morphed from paper cigarettes to electronic versions. This raises questions: Are teens and young adults using e-cigarettes because of boredom? Are we witnessing a generational ADHD borne from restlessness that stems from lives with fewer meaningful face-to-face human interactions?
In addition to educating our teens and young adults about the physical risks tied to vaping, we need to teach them to build meaning into their lives that exists outside of this digital age.
Dr. Jorandby is chief medical officer of Lakeview Health in Jacksonville, Fla. She trained in addiction psychiatry at Yale University, New Haven, Conn.
References
1. CDC. Outbreak of lung injury associated with e-cigarette use, or vaping. 2019 Sep 19.
2. CDC. Outbreak of lung illness associated with using e-cigarette products. Investigation notice. 2019 Sep 6.
3. FDA. Warning letter, JUUL Labs. 2019 Sep 9.
4. Sixth person dies of vaping-related illness. The Hill. 2019 Sep 10.
5. Layden JE. Pulmonary illness related to cigarette use in Illinois and Wisconsin – preliminary report. N Engl J Med. 2019 Sep 6. doi: 10.1056/NEJMoa1911614.
6. Cullen KA et al. CDC. MMWR. 2018 Nov 16;67(45):1276-7.
7. National Academies of Sciences, Engineering, and Medicine. Public health consequences of e-cigarettes. 2018.
8. Patton GC et al. Am J Public Health. 1996 Feb;86(2):225-30.
9. Leventhal AM et al. J Psychiatr Res. 2016 Feb;73:71-8.
10. Levine A et al. J Am Acad Child Adolesc Psychiatry. 2017 Mar;56(3):214-2.
11. Leadbeater BJ et al. Addiction. 2019 Feb;114(2):278-93.
* This column was updated 9/24/2019.
Physicians have been alarmed about the vaping craze for quite some time. This alarm has grown louder in the wake of news that electronic cigarettes have been associated with a mysterious lung disease.
Public health officials have reported that there have been 530 cases of vaping-related respiratory disease,1 and as of press time at least seven deaths had been attributed to vaping*. On Sept. 6, 2019, the Food and Drug Administration, Centers for Disease Control and Prevention, and other health officials issued an investigation notice on vaping and e-cigarettes,2 cautioning teenagers, young adults, and pregnant women to avoid e-cigarettes completely and cautioning all users to never buy e-cigarettes off the street or from social sources.
A few days later, on Sept. 9, the FDA’s Center for Tobacco Products issued a warning letter to JUUL Labs, makers of a popular e-cigarette, for illegal marketing of modified-risk tobacco products.3 Then on Sept. 10, health officials in Kansas reported that a sixth person has died of a lung illness related to vaping.4
Researchers have found that 80% of those diagnosed with the vaping illness used products that contained THC, the psychoactive ingredient in marijuana, 61% had used nicotine products, and 7% used cannabidiol (CBD) products. Vitamin E acetate is another substance identified in press reports as tied to the severe lung disease.
Most of the patients affected are adolescents and young adults, with the average age of 19 years.5 This comes as vaping among high school students rose 78% between 2017 and 2018.6 According the U.S. surgeon general, one in five teens vapes. Other data show that teen use of e-cigarettes comes with most users having never smoked a traditional cigarette.7 Teens and young adults frequently borrow buy* e-cigarette “pods” from gas stations but borrow and purchase from friends or peers. In addition, young people are known to alter the pods to insert other liquids, such as CBD and other marijuana products.
Teens and young adults are at higher risk for vaping complications. Their respiratory and immune systems are still developing. In addition to concerns about the recent surge of respiratory illnesses, nicotine is known to also suppress the immune system, which makes people who use it more susceptible to viral and bacterial infections – and also making it harder for them to recover.
In addition nicotine hyperactivates the reward centers of the brain, which can trigger addictive behaviors. Because the brains of young adults are not yet fully developed until at or after age 26, nicotine use before this can “prime the pump” of a still-developing brain, thereby increasing the likelihood for addiction to harder drugs. Nicotine has been shown to disrupt sleep patterns, which are critical for mental and physical health. Lastly, research shows that smoking increases the risks of various psychiatric disorders, such as depression and anxiety. My teen and young adult patients have endlessly debated with me the idea that smoking – either nicotine or marijuana – eases their anxiety or helps them get to sleep. I tell them that, in the long run, the data show that smoking makes those problems worse.8-11
Nationally, we are seeing an explosion of multistate legislation pushing marijuana as a health food. E-cigarettes have followed as the “healthy” alternative to traditional tobacco. As clinicians, we must counter those messages.
Finally, our world is now filled with smartphones, sexting, and social media overuse. An entire peer group exists that knows life only with constant electronic stimulation. It is not without irony that our national nicotine obsessions have morphed from paper cigarettes to electronic versions. This raises questions: Are teens and young adults using e-cigarettes because of boredom? Are we witnessing a generational ADHD borne from restlessness that stems from lives with fewer meaningful face-to-face human interactions?
In addition to educating our teens and young adults about the physical risks tied to vaping, we need to teach them to build meaning into their lives that exists outside of this digital age.
Dr. Jorandby is chief medical officer of Lakeview Health in Jacksonville, Fla. She trained in addiction psychiatry at Yale University, New Haven, Conn.
References
1. CDC. Outbreak of lung injury associated with e-cigarette use, or vaping. 2019 Sep 19.
2. CDC. Outbreak of lung illness associated with using e-cigarette products. Investigation notice. 2019 Sep 6.
3. FDA. Warning letter, JUUL Labs. 2019 Sep 9.
4. Sixth person dies of vaping-related illness. The Hill. 2019 Sep 10.
5. Layden JE. Pulmonary illness related to cigarette use in Illinois and Wisconsin – preliminary report. N Engl J Med. 2019 Sep 6. doi: 10.1056/NEJMoa1911614.
6. Cullen KA et al. CDC. MMWR. 2018 Nov 16;67(45):1276-7.
7. National Academies of Sciences, Engineering, and Medicine. Public health consequences of e-cigarettes. 2018.
8. Patton GC et al. Am J Public Health. 1996 Feb;86(2):225-30.
9. Leventhal AM et al. J Psychiatr Res. 2016 Feb;73:71-8.
10. Levine A et al. J Am Acad Child Adolesc Psychiatry. 2017 Mar;56(3):214-2.
11. Leadbeater BJ et al. Addiction. 2019 Feb;114(2):278-93.
* This column was updated 9/24/2019.
Physicians have been alarmed about the vaping craze for quite some time. This alarm has grown louder in the wake of news that electronic cigarettes have been associated with a mysterious lung disease.
Public health officials have reported that there have been 530 cases of vaping-related respiratory disease,1 and as of press time at least seven deaths had been attributed to vaping*. On Sept. 6, 2019, the Food and Drug Administration, Centers for Disease Control and Prevention, and other health officials issued an investigation notice on vaping and e-cigarettes,2 cautioning teenagers, young adults, and pregnant women to avoid e-cigarettes completely and cautioning all users to never buy e-cigarettes off the street or from social sources.
A few days later, on Sept. 9, the FDA’s Center for Tobacco Products issued a warning letter to JUUL Labs, makers of a popular e-cigarette, for illegal marketing of modified-risk tobacco products.3 Then on Sept. 10, health officials in Kansas reported that a sixth person has died of a lung illness related to vaping.4
Researchers have found that 80% of those diagnosed with the vaping illness used products that contained THC, the psychoactive ingredient in marijuana, 61% had used nicotine products, and 7% used cannabidiol (CBD) products. Vitamin E acetate is another substance identified in press reports as tied to the severe lung disease.
Most of the patients affected are adolescents and young adults, with the average age of 19 years.5 This comes as vaping among high school students rose 78% between 2017 and 2018.6 According the U.S. surgeon general, one in five teens vapes. Other data show that teen use of e-cigarettes comes with most users having never smoked a traditional cigarette.7 Teens and young adults frequently borrow buy* e-cigarette “pods” from gas stations but borrow and purchase from friends or peers. In addition, young people are known to alter the pods to insert other liquids, such as CBD and other marijuana products.
Teens and young adults are at higher risk for vaping complications. Their respiratory and immune systems are still developing. In addition to concerns about the recent surge of respiratory illnesses, nicotine is known to also suppress the immune system, which makes people who use it more susceptible to viral and bacterial infections – and also making it harder for them to recover.
In addition nicotine hyperactivates the reward centers of the brain, which can trigger addictive behaviors. Because the brains of young adults are not yet fully developed until at or after age 26, nicotine use before this can “prime the pump” of a still-developing brain, thereby increasing the likelihood for addiction to harder drugs. Nicotine has been shown to disrupt sleep patterns, which are critical for mental and physical health. Lastly, research shows that smoking increases the risks of various psychiatric disorders, such as depression and anxiety. My teen and young adult patients have endlessly debated with me the idea that smoking – either nicotine or marijuana – eases their anxiety or helps them get to sleep. I tell them that, in the long run, the data show that smoking makes those problems worse.8-11
Nationally, we are seeing an explosion of multistate legislation pushing marijuana as a health food. E-cigarettes have followed as the “healthy” alternative to traditional tobacco. As clinicians, we must counter those messages.
Finally, our world is now filled with smartphones, sexting, and social media overuse. An entire peer group exists that knows life only with constant electronic stimulation. It is not without irony that our national nicotine obsessions have morphed from paper cigarettes to electronic versions. This raises questions: Are teens and young adults using e-cigarettes because of boredom? Are we witnessing a generational ADHD borne from restlessness that stems from lives with fewer meaningful face-to-face human interactions?
In addition to educating our teens and young adults about the physical risks tied to vaping, we need to teach them to build meaning into their lives that exists outside of this digital age.
Dr. Jorandby is chief medical officer of Lakeview Health in Jacksonville, Fla. She trained in addiction psychiatry at Yale University, New Haven, Conn.
References
1. CDC. Outbreak of lung injury associated with e-cigarette use, or vaping. 2019 Sep 19.
2. CDC. Outbreak of lung illness associated with using e-cigarette products. Investigation notice. 2019 Sep 6.
3. FDA. Warning letter, JUUL Labs. 2019 Sep 9.
4. Sixth person dies of vaping-related illness. The Hill. 2019 Sep 10.
5. Layden JE. Pulmonary illness related to cigarette use in Illinois and Wisconsin – preliminary report. N Engl J Med. 2019 Sep 6. doi: 10.1056/NEJMoa1911614.
6. Cullen KA et al. CDC. MMWR. 2018 Nov 16;67(45):1276-7.
7. National Academies of Sciences, Engineering, and Medicine. Public health consequences of e-cigarettes. 2018.
8. Patton GC et al. Am J Public Health. 1996 Feb;86(2):225-30.
9. Leventhal AM et al. J Psychiatr Res. 2016 Feb;73:71-8.
10. Levine A et al. J Am Acad Child Adolesc Psychiatry. 2017 Mar;56(3):214-2.
11. Leadbeater BJ et al. Addiction. 2019 Feb;114(2):278-93.
* This column was updated 9/24/2019.
Trump administration finalizing ban on flavored e-cigarettes
The Food and Drug Administration is finalizing a compliance policy that will target flavored e-cigarettes and aim to clear the market of unauthorized, non–tobacco-flavored e-cigarette products, U.S. Department of Health & Human Services Secretary Alex M. Azar II announced Sept. 11.
“The Trump administration is making it clear that we intend to clear the market of flavored e-cigarettes to reverse the deeply concerning epidemic of youth e-cigarette use that is impacting children, families, schools, and communities,” Mr. Azar said in a statement. “We will not stand idly by as these products become an on-ramp to combustible cigarettes or nicotine addiction for a generation of youth.”
The announcement comes as the Centers for Disease Control and Prevention and state health departments track hundreds of lung-related illnesses that are linked to the use of e-cigarettes. At least 450 cases have been reported in 33 states and one jurisdiction. Diagnoses include lipoid pneumonia, alveolar hemorrhage, and cryptogenic organizing pneumonia, according to a Sept. 6 press briefing by Ileana Arias, PhD, CDC acting deputy director for non-infectious diseases. Six deaths associated with the illnesses have been reported thus far.
Details of new regulatory action will be forthcoming and will outline enforcement policy for non–tobacco-flavored e-cigarette products that lack premarket authorization, HHS officials said. According to federal rules, all electronic nicotine delivery system (ENDS) products must file premarket tobacco product applications with the FDA within 2 years. Many ENDS products currently on the market are not being legally marketed and are subject to government action, according to the Trump administration.
“Once finalized, this compliance policy will serve as a powerful tool that the FDA can use to combat the troubling trend of youth e-cigarette use,” Ned Sharpless, MD, acting FDA commissioner, said in the statement. “We must act swiftly against flavored e-cigarette products that are especially attractive to children. Moreover, if we see a migration to tobacco-flavored products by kids, we will take additional steps to address youth use of these products.”
Federal officials noted that preliminary numbers from the National Youth Tobacco Survey show a continued rise in youth e-cigarette use, with more than a quarter of high school students current e-cigarette users in 2019. The overwhelming majority of youth e-cigarette users cited the use of fruit, menthol, or mint flavors, according to the preliminary data, which have not yet been published.
According to 2018 survey data, e-cigarette use increased from 12% to 21% among high school students and from 3% to 5% among middle school students from 2017 to 2018. There were 1.5 million more youth e-cigarette users in 2018 than in 2017, and youth who were using e-cigarettes were using them more often, according to the survey.
The Food and Drug Administration is finalizing a compliance policy that will target flavored e-cigarettes and aim to clear the market of unauthorized, non–tobacco-flavored e-cigarette products, U.S. Department of Health & Human Services Secretary Alex M. Azar II announced Sept. 11.
“The Trump administration is making it clear that we intend to clear the market of flavored e-cigarettes to reverse the deeply concerning epidemic of youth e-cigarette use that is impacting children, families, schools, and communities,” Mr. Azar said in a statement. “We will not stand idly by as these products become an on-ramp to combustible cigarettes or nicotine addiction for a generation of youth.”
The announcement comes as the Centers for Disease Control and Prevention and state health departments track hundreds of lung-related illnesses that are linked to the use of e-cigarettes. At least 450 cases have been reported in 33 states and one jurisdiction. Diagnoses include lipoid pneumonia, alveolar hemorrhage, and cryptogenic organizing pneumonia, according to a Sept. 6 press briefing by Ileana Arias, PhD, CDC acting deputy director for non-infectious diseases. Six deaths associated with the illnesses have been reported thus far.
Details of new regulatory action will be forthcoming and will outline enforcement policy for non–tobacco-flavored e-cigarette products that lack premarket authorization, HHS officials said. According to federal rules, all electronic nicotine delivery system (ENDS) products must file premarket tobacco product applications with the FDA within 2 years. Many ENDS products currently on the market are not being legally marketed and are subject to government action, according to the Trump administration.
“Once finalized, this compliance policy will serve as a powerful tool that the FDA can use to combat the troubling trend of youth e-cigarette use,” Ned Sharpless, MD, acting FDA commissioner, said in the statement. “We must act swiftly against flavored e-cigarette products that are especially attractive to children. Moreover, if we see a migration to tobacco-flavored products by kids, we will take additional steps to address youth use of these products.”
Federal officials noted that preliminary numbers from the National Youth Tobacco Survey show a continued rise in youth e-cigarette use, with more than a quarter of high school students current e-cigarette users in 2019. The overwhelming majority of youth e-cigarette users cited the use of fruit, menthol, or mint flavors, according to the preliminary data, which have not yet been published.
According to 2018 survey data, e-cigarette use increased from 12% to 21% among high school students and from 3% to 5% among middle school students from 2017 to 2018. There were 1.5 million more youth e-cigarette users in 2018 than in 2017, and youth who were using e-cigarettes were using them more often, according to the survey.
The Food and Drug Administration is finalizing a compliance policy that will target flavored e-cigarettes and aim to clear the market of unauthorized, non–tobacco-flavored e-cigarette products, U.S. Department of Health & Human Services Secretary Alex M. Azar II announced Sept. 11.
“The Trump administration is making it clear that we intend to clear the market of flavored e-cigarettes to reverse the deeply concerning epidemic of youth e-cigarette use that is impacting children, families, schools, and communities,” Mr. Azar said in a statement. “We will not stand idly by as these products become an on-ramp to combustible cigarettes or nicotine addiction for a generation of youth.”
The announcement comes as the Centers for Disease Control and Prevention and state health departments track hundreds of lung-related illnesses that are linked to the use of e-cigarettes. At least 450 cases have been reported in 33 states and one jurisdiction. Diagnoses include lipoid pneumonia, alveolar hemorrhage, and cryptogenic organizing pneumonia, according to a Sept. 6 press briefing by Ileana Arias, PhD, CDC acting deputy director for non-infectious diseases. Six deaths associated with the illnesses have been reported thus far.
Details of new regulatory action will be forthcoming and will outline enforcement policy for non–tobacco-flavored e-cigarette products that lack premarket authorization, HHS officials said. According to federal rules, all electronic nicotine delivery system (ENDS) products must file premarket tobacco product applications with the FDA within 2 years. Many ENDS products currently on the market are not being legally marketed and are subject to government action, according to the Trump administration.
“Once finalized, this compliance policy will serve as a powerful tool that the FDA can use to combat the troubling trend of youth e-cigarette use,” Ned Sharpless, MD, acting FDA commissioner, said in the statement. “We must act swiftly against flavored e-cigarette products that are especially attractive to children. Moreover, if we see a migration to tobacco-flavored products by kids, we will take additional steps to address youth use of these products.”
Federal officials noted that preliminary numbers from the National Youth Tobacco Survey show a continued rise in youth e-cigarette use, with more than a quarter of high school students current e-cigarette users in 2019. The overwhelming majority of youth e-cigarette users cited the use of fruit, menthol, or mint flavors, according to the preliminary data, which have not yet been published.
According to 2018 survey data, e-cigarette use increased from 12% to 21% among high school students and from 3% to 5% among middle school students from 2017 to 2018. There were 1.5 million more youth e-cigarette users in 2018 than in 2017, and youth who were using e-cigarettes were using them more often, according to the survey.
Consider triple therapy for the management of COPD
Background: The Global Initiative for Obstructive Lung Disease (GOLD) recommends triple therapy with inhaled corticosteroids, long-acting beta2-adrenoceptor agonists (LABA), and long-acting muscarinic receptor antagonists (LAMA) for patients with severe COPD who have frequent exacerbations despite treatment with a LABA and LAMA. Triple therapy has been shown to improve forced expiratory volume in 1 second (FEV1), but its effect on preventing exacerbations has not been well documented in previous meta-analyses.
Study design: Meta-analysis.
Setting: Studies published on PubMed, Embase, Cochrane Library website, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases.
Synopsis: 21 randomized, controlled trials of triple therapy in stable cases of moderate to very severe COPD were included in this meta-analysis. Triple therapy was associated with a significantly greater reduction in the rate of COPD exacerbations, compared with dual therapy of LAMA and LABA (rate ratio, 0.78; 95% confidence interval, 0.70-0.88), inhaled corticosteroid and LABA (rate ratio, 0.77; 95% CI, 0.66-0.91), or LAMA monotherapy (rate ratio, 0.71; 95% CI, 0.60-0.85). Triple therapy was also associated with greater improvement in FEV1.
There was a significantly higher incidence of pneumonia in patients using triple therapy, compared with those using dual therapy (LAMA and LABA), and there also was a trend toward increased pneumonia incidence with triple therapy, compared with LAMA monotherapy. Triple therapy was not shown to improve survival; however, most trials lasted less than 6 months, which limits their analysis of survival outcomes.
Bottom line: In patients with advanced COPD, triple therapy is associated with lower rates of COPD exacerbations and improved lung function, compared with dual therapy or monotherapy.
Citation: Zheng Y et al. Triple therapy in the management of chronic obstructive pulmonary disease: Systemic review and meta-analysis. BMJ. 2018;363:k4388.
Dr. Chace is an associate physician in the division of hospital medicine at the University of California, San Diego.
Background: The Global Initiative for Obstructive Lung Disease (GOLD) recommends triple therapy with inhaled corticosteroids, long-acting beta2-adrenoceptor agonists (LABA), and long-acting muscarinic receptor antagonists (LAMA) for patients with severe COPD who have frequent exacerbations despite treatment with a LABA and LAMA. Triple therapy has been shown to improve forced expiratory volume in 1 second (FEV1), but its effect on preventing exacerbations has not been well documented in previous meta-analyses.
Study design: Meta-analysis.
Setting: Studies published on PubMed, Embase, Cochrane Library website, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases.
Synopsis: 21 randomized, controlled trials of triple therapy in stable cases of moderate to very severe COPD were included in this meta-analysis. Triple therapy was associated with a significantly greater reduction in the rate of COPD exacerbations, compared with dual therapy of LAMA and LABA (rate ratio, 0.78; 95% confidence interval, 0.70-0.88), inhaled corticosteroid and LABA (rate ratio, 0.77; 95% CI, 0.66-0.91), or LAMA monotherapy (rate ratio, 0.71; 95% CI, 0.60-0.85). Triple therapy was also associated with greater improvement in FEV1.
There was a significantly higher incidence of pneumonia in patients using triple therapy, compared with those using dual therapy (LAMA and LABA), and there also was a trend toward increased pneumonia incidence with triple therapy, compared with LAMA monotherapy. Triple therapy was not shown to improve survival; however, most trials lasted less than 6 months, which limits their analysis of survival outcomes.
Bottom line: In patients with advanced COPD, triple therapy is associated with lower rates of COPD exacerbations and improved lung function, compared with dual therapy or monotherapy.
Citation: Zheng Y et al. Triple therapy in the management of chronic obstructive pulmonary disease: Systemic review and meta-analysis. BMJ. 2018;363:k4388.
Dr. Chace is an associate physician in the division of hospital medicine at the University of California, San Diego.
Background: The Global Initiative for Obstructive Lung Disease (GOLD) recommends triple therapy with inhaled corticosteroids, long-acting beta2-adrenoceptor agonists (LABA), and long-acting muscarinic receptor antagonists (LAMA) for patients with severe COPD who have frequent exacerbations despite treatment with a LABA and LAMA. Triple therapy has been shown to improve forced expiratory volume in 1 second (FEV1), but its effect on preventing exacerbations has not been well documented in previous meta-analyses.
Study design: Meta-analysis.
Setting: Studies published on PubMed, Embase, Cochrane Library website, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases.
Synopsis: 21 randomized, controlled trials of triple therapy in stable cases of moderate to very severe COPD were included in this meta-analysis. Triple therapy was associated with a significantly greater reduction in the rate of COPD exacerbations, compared with dual therapy of LAMA and LABA (rate ratio, 0.78; 95% confidence interval, 0.70-0.88), inhaled corticosteroid and LABA (rate ratio, 0.77; 95% CI, 0.66-0.91), or LAMA monotherapy (rate ratio, 0.71; 95% CI, 0.60-0.85). Triple therapy was also associated with greater improvement in FEV1.
There was a significantly higher incidence of pneumonia in patients using triple therapy, compared with those using dual therapy (LAMA and LABA), and there also was a trend toward increased pneumonia incidence with triple therapy, compared with LAMA monotherapy. Triple therapy was not shown to improve survival; however, most trials lasted less than 6 months, which limits their analysis of survival outcomes.
Bottom line: In patients with advanced COPD, triple therapy is associated with lower rates of COPD exacerbations and improved lung function, compared with dual therapy or monotherapy.
Citation: Zheng Y et al. Triple therapy in the management of chronic obstructive pulmonary disease: Systemic review and meta-analysis. BMJ. 2018;363:k4388.
Dr. Chace is an associate physician in the division of hospital medicine at the University of California, San Diego.