EAGLES Study Results Released

Results have been published in The Lancet from the largest placebo-controlled trial of approved smoking cessation pharmacotherapy, called EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study).

EAGLES is a multi-center, parallel group, post-authorization, safety study/post-marketing requirement (PASS/PMR) and is the largest trial to date to compare both the safety and efficacy of varenicline and bupropion to nicotine patch and placebo.

Study authors concluded that neither varenicline nor bupropion significantly increased the incidence of serious neuropsychiatric side effects compared to nicotine patch and placebo.

These results bode well for pharmaceutical giants Pfizer and GlaxoSmithKline, who collaborated to fund the trial and are the makers of Chantix (varenicline) and Zyban (bupropion), respectively.

Lead study investigator Robert M. Anthenelli, MD, Professor of Psychiatry, University of California San Diego, said, “This is an important study. It provides more detailed information that supports other studies done before that point to these medications being safe in psychiatrically stable smokers.”

“Smoking is one of the leading preventable causes of death worldwide, and the benefits of quitting are immediate and substantial,” said Freda Lewis-Hall, M.D., DFAPA, Chief Medical Officer and EVP, Pfizer Inc., in an April 22 Pfizer press release. “These data from the EAGLES study build on the large body of clinical evidence characterizing the neuropsychiatric safety and efficacy of Chantix/Champix, which supports Chantix/Champix as an important treatment option for people who want to quit smoking.”1


The trial was conducted at the request of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) following concerns about the neuropsychiatric safety of the non-nicotine medications varenicline and bupropion.

“There’s been a reluctance to use some of the smoking cessation aids – especially for smokers with psychiatric disorders – for fear that they would somehow spark more neuropsychiatric adverse events,” Anthenelli explained.

According to Anthenelli, the trial was a huge undertaking. EAGLES assessed 8,144 motivated-to-quit adult smokers at 140 centers in 16 countries.

About half of the participants had a history of a past or current stable psychiatric condition, primarily including a depressive, bipolar, anxiety, or psychotic disorder. The other half of the participants did not have a history of a psychiatric condition. Anthenelli noted that an important feature of the trial was its randomized, double-blind, triple-dummy design.

For 12 weeks participants were treated with either varenicline, bupropion, a nicotine patch, or placebo, receiving brief cessation counseling after each visit. All patients were assessed to determine if they experienced moderate to severe neuropsychiatric adverse events during and after treatment.

SEE ALSO: Helping Patients Stop Smoking

The Results

Study data did not demonstrate a significant increase in the occurrence of the composite primary safety endpoint of serious neuropsychiatric adverse events associate with the use of varenicline or bupropion. Differences between occurrence rates were considered significant if their associated 95% confidence intervals (CIs) were completely above or below zero.

The primary safety endpoint was defined as the incidence of at least one treatment-emergent adverse event of anxiety, depression, feeling abnormal, or hostility at the severe level, and the occurrence of at least one treatment-emergent adverse event of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior or completed suicide at the moderate to severe level.

EAGLES authors also investigated whether smokers with a history of psychiatric disorders are at greater risk for developing clinically significant neuropsychiatric side effects compared to individuals without a history of psychiatric disorders. For smokers without psychiatric disorders, moderate to severe side effects were reported in 1.3 % on varenicline, 2.2% on bupropion, 2.5% on nicotine patch, and 2.4% on placebo. Higher rates of neuropsychiatric side effects were experienced in smokers with psychiatric disorders (6.5% on varenicline, 6.7% on bupropion, 5.2% on nicotine patch, and 4.9% on placebo). Among the trial participants, the most common side effects of each treatment were nausea (25%, varenicline), insomnia (12%, bupropion), abnormal dreams (12%, nicotine patch) and headache (10%, placebo).2

Smoking abstinence rates were evaluated in patients treated with varenicline or bupropion relative to nicotine patch or placebo during weeks 9-12 and continued abstinence rates were evaluated during a non-treatment, follow-up period from weeks 12-24. Smokers with and without a history of psychiatric disorders treated with each of the three smoking cessation medications had significantly superior continued abstinence rates than those treated with placebo. Of the three smoking cessation methods, varenicline was found to be the most effective for continued abstinence.

“The reality is that these medicines are under-used,” Anthenelli said. “Up to two-thirds of smokers who make a quit attempt do so without using support of either medications or counseling. The recommendation for the best way to quit smoking, especially if you’re a moderate to heavy smoker, is to combine one of the approved medications/pharmacotherapies with counseling. Our problem is that most people who need the medicines and the counseling don’t choose to use them. Part of that is because of the concerns and fears of using these medicines. We hope our study helps allay some of those concerns.” Study data were limited to participants with stable psychiatric disorders, so findings might not apply to those with untreated or unstable psychiatric disorders. The study also could not fully detect rare neuropsychiatric events.

Further Research

Plans are already underway for secondary analyses of the data. Anthenelli said, “It’s an incredibly rich database. About half of the sample are people who don’t have a psychiatric disorder; the other half of the sample do have psychiatric illness. We have a large number of participants who have various mood disorders, anxiety disorders, and psychotic disorders such as schizophrenia, so plans are under way to do secondary data analyses – especially in those psychiatric sub-cohorts. We’re very excited about that because less is known about the safety and efficacy of the first-line medications in these special subpopulations of smokers.”

1. Pfizer. CHANTIX/CHAMPIX (Varenicline) Results From the Largest Global Clinical Trial of Smoking Cessation Medicines Published in The Lancet. Press release.
2. Anthenelli RM, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled trial. The Lancet, 2016 DOI: 10.1016/S0140-6736(16)30272-0

Kirsten Malenke is a staff writer at ADVANCE. Contact:kmalenke@advanceweb.com.

About The Author