Efficacy of the nicotine vaccine 3'-AmNic-rEPA (NicVAX) co-administered with varenicline and counselling for smoking cessation: a randomized placebo-controlled trial.

BACKGROUND AND AIMS: Nicotine vaccination has been proposed as a possible treatment to aid smoking cessation. First efficacy results of the nicotine vaccine 3'-AmNic-rEPA (NicVAX) showed that only a subgroup of the top 30% antibody responders achieved higher abstinence rates than placebo. The present study examined the efficacy of adding NicVAX versus placebo to varenicline and behavioural support as an aid in smoking cessation and relapse prevention. DESIGN: Randomized placebo-controlled trial. SETTING: Two research centres (Maastricht University Medical Centre and Slotervaart Hospital) in the Netherlands. PARTICIPANTS: A total of 558 smokers were assigned randomly to six injections with NicVAX (n = 278) or placebo (n = 280) both co-administered with open label varenicline and behavioural support. MEASURES: Outcomes were prolonged carbon monoxide-validated abstinence from weeks 9 to 52 (primary) and weeks 37 to 52 (secondary). We also performed a pre-planned subgroup analysis in the top 30% antibody responders. FINDINGS: There was no difference in abstinence rates between NicVAX and placebo from weeks 9 to 52 [27.7 versus 30.0%, odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.62-1.29] or weeks 37 to 52 (33.8 versus 33.2%, OR = 1.03, 95% CI = 0.73-1.46). The top 30% antibody responders, compared to the placebo group, showed a non-significant tendency towards higher abstinence rates from weeks 37 to 52 (42.2 versus 33.2%, OR = 1.47, 95% CI = 0.89-2.42). CONCLUSION: The nicotine vaccine, NicVAX, does not appear to improve the chances of stopping smoking when given in addition to varenicline and behavioural support.

The efficacy and safety of a nicotine conjugate vaccine (NicVAX®) or placebo co-administered with varenicline (Champix®) for smoking cessation: study protocol of a phase IIb, double blind, randomized, placebo controlled trial.

BACKGROUND: A potential new treatment in smoking cessation and relapse prevention is nicotine vaccination which is based on active immunization against the nicotine molecule. This immunization will elicit the immune system to produce nicotine-specific antibodies that sequester nicotine in the blood stream, after inhaling tobacco products. The resulting antibody-antigen is too large to cross the blood-brain barrier and is therefore postulated to attenuate the rewarding effect of nicotine by preventing the latter from reaching its receptors in the brain and causing the release of dopamine. The aim of this paper is to describe the design of a phase IIb, multi-center, double blind, randomized, placebo controlled trial to assess the efficacy of the nicotine vaccine NicVAX® co-administered with varenicline (Champix®) and intensive counseling as an aid in smoking cessation and relapse prevention. METHODS/DESIGN: Two centers will include a total of 600 smokers who are motivated to quit smoking. At week -2 these smokers will be randomized, in a 1:1 ratio, to either 6 injections of NicVAX® or placebo, both co-administered with 12-weeks of varenicline treatment, starting at week 0. The target quit day will be set after 7 days of varenicline treatment at week 1. Smokers will be followed up for 54 weeks. The primary outcome is defined as biochemically validated prolonged smoking abstinence from week 9 to 52. Secondary outcomes include safety, immunogenicity, smoking abstinence from week 37 to 52, abstinence from week 9 to 24, abstinence in the subset of subjects with the highest antibody response, and lapse/relapse rate. DISCUSSION: This is the first study to assess the efficacy of a nicotine conjugate vaccine in combination with an evidence-based smoking cessation pharmacotherapy (varenicline) to quit smoking. Although NicVAX® is primarily designed as an aid to smoking cessation, our study is designed to explore its potential to maintain abstinence and prevent relapse. The results of this trial will give a unique insight in the potential of nicotine vaccination for relapse prevention. TRIAL REGISTRATION: ClinicalTrials.gov: (NCT00995033).

Nicotine vaccines to assist with smoking cessation: current status of research.

Tobacco smoking causes cardiovascular, respiratory and malignant disease, and stopping smoking is among the key medical interventions to lower the worldwide burden of these disorders. However, the addictive properties of cigarette smoking, including nicotine inhalation, render most quit attempts unsuccessful. Recommended therapies, including combinations of counselling and medication, produce long-term continuous abstinence rates of no more than 30%. Thus, more effective treatment options are needed. An intriguing novel therapeutic concept is vaccination against nicotine. The basic principle of this approach is that, after entering the systemic circulation, a substantial proportion of nicotine can be bound by antibodies. Once bound to antibodies, nicotine is no longer able to cross the blood-brain barrier. As a consequence, the rewarding effects of nicotine are diminished, and relapse to smoking is less likely to occur. Animal studies indicate that antibodies profoundly change the pharmacokinetics of the drug and can interfere with nicotine self-administration and impact on the severity of withdrawal symptoms. To date, five phase I/II clinical trials using vaccines against nicotine have been published. Results have been disappointing in that an increase in quit rates was only observed in small groups of smokers displaying particularly high antibody titres. The failure of encouraging preclinical data to completely translate to clinical studies may be partially explained by shortcomings of animal models of addiction and an incomplete understanding of the complex physiological and behavioural processes contributing to tobacco addiction. This review summarizes the current status of research and suggests some directions for the future development of vaccines against nicotine. Ideally, these vaccines could one day become part of a multifaceted approach to treating tobacco addiction that includes counselling and pharmacotherapy.

Electrocardiographic findings in women with a recent history of pre-eclampsia.

OBJECTIVE: To assess the prevalence of electrocardiographic (ECG) abnormalities after a pregnancy complicated by pre-eclampsia and/or syndrome of hemolysis, elevated liver enzymes and low platelets (PE) and to compare the ECG characteristics, at least six months after pregnancy, between primiparous early-onset PE women with and without recurrent PE. DESIGN: Longitudinal observational study. SETTING: Tertiary referral centre in The Netherlands from 1996 to 2008. SAMPLE: Six hundred and fifty-eight formerly pre-eclamptic women. For our second objective, we used a subgroup of 79 primiparae with a history of early-onset PE. METHODS: Data were obtained during a postpartum screening program for women with hypertensive disorders during pregnancy. MAIN OUTCOME MEASURES: Electrocardiographic abnormalities in PE women and characteristics of the ECG in women with recurrent PE after a first pregnancy complicated by early-onset PE. RESULTS: The ECG of 13 (2.0%), two (0.3%) and two (0.3%) former patients suggested ischemia, left ventricular hypertrophy and left atrial enlargement, respectively. Primiparae with recurrent PE in their second pregnancy differed from their counterparts with an uneventful second pregnancy by a leftward deviation of both the P- and the R-axes of 11° (p= 0.022) and 12° (p= 0.021), respectively, with a prolonged QT interval (p= 0.025). CONCLUSIONS: The prevalence of ECG abnormalities in women with a recent history of PE was low and did not differ appreciably from that in a large population of healthy women of comparable age. The ECGs in primiparae with a history of early-onset PE who developed recurrent PE in their second pregnancy differed slightly from women with an uneventful second pregnancy, probably related to potential confounders.