Results of EAGLES trial for Chantix/Champix (varenicline) published in The Lancet shows no significant increase in serious neuropsychiatric events.-Pfizer

Pfizer Inc.has announced results published in The Lancet from the largest clinical trial of approved smoking cessation medicines, called EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study). This smoking cessation trial included 8,144 adult smokers and was designed to compare the neuropsychiatric safety of Chantix/Champix (varenicline) and bupropion with placebo and nicotine patch in adult smokers with and without a history of psychiatric disorders. The authors concluded that the trial did not show a significant increase in the incidence of the composite primary safety endpoint of serious neuropsychiatric adverse events with Chantix/Champix or bupropion compared to placebo and nicotine patch. Differences between incidence rates were considered significant if their associated 95% confidence intervals (CIs) were entirely above or below zero.

Approximately half of the trial participants had a history of psychiatric disorders, either past and in remission or present and clinically stable. The psychiatric diagnoses included primarily depressive, bipolar, anxiety and psychotic disorders. The EAGLES trial also included an efficacy objective to determine smoking abstinence rates in patients treated with Chantix/Champix or bupropion, relative to placebo, during the last four weeks of the 12-week treatment period. Continuous abstinence was also evaluated relative to the nicotine patch. In addition, longer-term abstinence through a 12-week non-treatment follow-up period (weeks 9-24) was evaluated for all treatments. The results showed that patients with and without a history of psychiatric disorders taking Chantix/Champix had significantly higher continuous abstinence rates than patients treated with bupropion or nicotine patch during both time periods. Patients treated with each of the medications had higher abstinence rates than those treated with placebo. This is the first placebo-controlled trial of this size to directly compare the efficacy of Chantix/Champix, bupropion and nicotine patch to help people quit smoking.

The primary safety endpoint of the EAGLES trial was defined as the occurrence of at least one treatment-emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment-emergent moderate or severe adverse event of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior or completed suicide. The incidence of the primary safety endpoint in patients without a history of psychiatric disorders was 1.3% (Chantix/Champix), 2.2% (bupropion), 2.5% (nicotine patch) and 2.4% (placebo). The incidence rates in patients with a history of psychiatric disorders were 6.5% (Chantix/Champix), 6.7% (bupropion), 5.2% (nicotine patch) and 4.9% (placebo). In patients without a history of psychiatric disorders, the Chantix/Champix–placebo and bupropion–placebo risk differences (RDs) for the primary safety endpoint were ?1.28 (95% CI ?2.40 to ?0.15) and ?0.08 (?1.37 to 1.21), respectively. The RDs for Chantix/Champix-nicotine patch and bupropion-nicotine patch comparisons were ?1.07 (?2.21 to 0.08) and 0.13 (?1.19 to 1.45), respectively. In patients with a history of psychiatric disorders, the Chantix/Champix–placebo and bupropion–placebo RDs were 1.59 (?0.42 to 3.59) and 1.78 (?0.24 to 3.81), respectively; the RDs for Chantix/Champix -nicotine patch and bupropion-nicotine patch comparisons were 1.22 (?0.81 to 3.25) and 1.42 (?0.63 to 3.46), respectively. Across both patient cohorts, 95% CIs associated with these RDs were lower than or included zero. There were more neuropsychiatric adverse events in the psychiatric cohort than the non-psychiatric cohort across all treatment arms including placebo.

EAGLES is a multi-center, parallel-group, post-authorization safety study/post-marketing requirement (PASS/PMR), which was conducted in 16 countries by Pfizer in collaboration with GlaxoSmithKline. The trial was conducted at the request of, and designed in consultation with, the FDA and the European Medicines Agency (EMA) to compare the risk of clinically significant neuropsychiatric events, including but not limited to suicidality, in individuals using Chantix/Champix, bupropion, nicotine replacement therapy or placebo as aids to smoking cessation over 12 weeks of treatment, and to determine whether individuals with a history of psychiatric disorders are at greater risk for developing clinically significant neuropsychiatric events compared to individuals without a history of psychiatric disorders while using Chantix/Champix or bupropion as an aid to smoking cessation. Data limitations included: the findings may not generalize to smokers with untreated or unstable psychiatric disease, and the trial had limited power to detect rare neuropsychiatric events.

Comment:Authors conclude no significant increase in serious neuropsychiatric adverse events with Chantix/Champix relative to placebo or nicotine patch. Smokers treated with Chantix/Champix had significantly higher quit rates than those treated with bupropion, nicotine patch or placebo.