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

Philippe HJ Hoogsteder 0 Daniel Kotz 0 Paul I van Spiegel 2 Wolfgang Viechtbauer 0 Ruth Brauer 0 Paul D Kessler 1 Matthew W Kalnik 1 Raafat EF Fahim 1 Onno CP van Schayck 0 0 CAPHRI School for Public Health and Primary Care, Department of General Practice, Maastricht University , P.O. Box 616, Maastricht 6200, MD , The Netherlands 1 Nabi Biopharmaceuticals , Rockville, Maryland , USA 2 Department of Pulmonary Medicine, Slotervaart Hospital , Amsterdam , The Netherlands 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 NicVAXW co-administered with varenicline (ChampixW) 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 NicVAXW 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 NicVAXW 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) - Background Tobacco use is the leading preventable cause of death in the world. Currently, about 1 billion people smoke of which eventually half will die from smoking-related diseases [1]. Worldwide, approximately 6 million people die from smoking each year, including more than 600,000 non-smokers who die from secondhand smoke [1]. Although smokers are generally aware of the health consequences of smoking they have major difficulties to stop smoking [2]. Without the use of effective therapies, less than 5% of the smokers are able to stay abstinent for one year after a quit attempt [3]. Nicotine is responsible for the addictive mechanism of tobacco use and the difficulties that smokers encounter when trying to quit smoking and remain abstinent. After inhalation of cigarette smoke, nicotine almost immediately travels to the blood stream and crosses the bloodbrain barrier within 10 to 20 seconds [4]. At this point the nicotine molecule acts on several neurotransmitter systems where it activates 42 nicotinic acetylcholine receptors and the dopamine reward system responsible for the reinforcing and addictive effects of nicotine [5]. Pharmacotherapy treatment for smoking cessation focuses on minimizing the nicotine withdrawal effects by substitution of the nicotine reward effects or by attenuating the reinforcing effects of tobacco [6,7]. Currently available therapies such as nicotine replacement therapy (NRT), psychotropic drugs, and partial nicotine acetylcholine agonists, in combination with behavioral support, can increase abstinence rates to a maximum of 20 to 25% after one year [6,8-10]. NRT reduces withdrawal by replacement of nicotine, which might result from abrupt cessation of nicotine use [6] while psychotropic drugs, such as bupropion and nortriptyline cause a blockade of neuronal re-uptake of several neurotransmitters like norepinephrine, serotonine, and dopamine [8]. Blockage of this biology of nicotine addiction will reduce the reinforcing effect of nicotine and withdrawal symptoms [8]. A more recent developed treatment strategy is the use of partial nicotine acetylcholine agonists like varenicline and cytisine, which stimulate the release of sufficient dopamine to reduce craving and withdrawal while simultaneously acting as a partial antagonist by blocking the binding and consequent reinforcing effects of inhaled nicotine [11,12]. Since the majority of smokers who attempt to quit still fail to achieve long-term abstinence, and most smokers relapse in the first 8 days, the need for better cessation approaches is of major importance [3]. A potential new treatment approach in smoking cessation and relapse prevention is nicotine vaccination, in which smokers who want to quit smoking receive multiple injections of a nicotine conjugate vaccine. Nicotine vaccination: mechanism of action Nicotine vaccination is a new therapy which is based on active immunization against the, otherwise, non-immunogenic, nicotine molecule. For this purpose, the small nicotine molecule is conjugated to a much larger carrier protein to induce and activate the immune system to produce highly specific nicotine antibodies [13]. These antibodies sequester nicotine in the blood stream, after inhaling tobacco products, and the resulting antigen-antibody molecule becomes too large to cross the bloodbrain barrier [14]. By preventing large amounts of nicotine reaching the central nervous system, nicotine vaccination is believed to attenuate the rewarding effect of nicotine [15]. The nicotine conjugate vaccine NicVAXW, developed by Nabi Biopharmaceuticals, was initially developed as an aid in smoking cessation. For this purpose, multiple injections are administered prior to the planned quit date resulting in a gradual increase in anti-nicotine antibodies which helps smokers in gradually reducing the number of cigarettes and eventually achieve complete abstinence [16]. Nicotine vaccines could also be used to prevent relapse. Hence, vaccinated ex-smokers who lapse (i.e., take a puff of a cigarette, have a positive smoking status for 1 week after a period of abstinence) are expected to experience diminished reward from nicotine inhalation which could prevent a full blown relapse (i.e., a positive smoking status for at least 2 weeks after a period of abstinence) [17]. The effects of a brief exposure to a p (...truncated)