A Fmri Study on the Effects of a Conjugate Vaccine and Placebo on CNS Activation and Behavior Following a Nicotine Challenge
Condition: Nicotine Dependency; Smoking
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      In this study the effects of a nicotine challenge on brain activity, behavior and mood will
      be evaluated in two groups of healthy volunteers who have a smoking habbit: The first group
      will undergo a series of treatments with NicVax, aimed at producing nicotine antibodies in
      the body and preventing nicotine to enter the brain. The second group will receive a placebo
      treatment. This pre-treatment (vaccination) will take place over a 18-week period. All
      participants will then undergo two days of testing. On each day the subjects will perform a
      number of psychomotor and memory tests after a challenge with nicotine (gum) or placebo(gum).
      Also brain activity will be studied in an fMRI scanner. We expect to see an effect on brain
      activation and performance only in the placebo-vaccinated group. The Nicvax vaccinated group
      should show activation and performance comparable to that after challenge with placebo(gum)
      as in this group nicotine should not cross the blood brain barrier and enter the brain
    

Detailed description: 
      Rationale: To develop a more effective treatment for nicotine addiction is a public health
      priority. In order to do so a better understanding is needed of the mechanisms 1) underlying
      nicotine addiction and 2) the way treatments alter the way nicotine transiently and
      permanently alters multiple cognitive and executive functions. Most effects of nicotine on
      the Central Nervous System (CNS) are directly mediated by nicotine molecules. Treatment with
      3'aminomethylnicotine P. aeruginosa r-Exoprotein A Conjugate Vaccine (NicVAX™) stimulates the
      production of nicotine specific antibodies. These antibodies bind the small nicotine
      molecules, preventing them to cross the Blood Brain Barrier (BBB) and thus preventing CNS
      stimulation. A nicotine challenge given after vaccination will show no or diminished direct
      effects of nicotine on CNS stimulation. The blocking effects of the nicotine specific
      antibodies will be evaluated on several cognitive tasks and on reactivity to smoking-related
      cues.

      Objective: Main aim; to show that NicVAX attenuates nicotine induced CNS effects on brain
      activation and cognitive performance relative to placebo. The secondary aim is to evaluate
      how these changes in CNS stimulation alter subjective measures and the addictive properties
      of nicotine.

      Study design: within-subject cross-over double-blind placebo controlled study. Study
      population: 48 current smokers, male, age 25-40, at least smoking 10 cigarettes /day the last
      year, in general good health. Additional criteria; 1) No contra-indications for MRI 2) No
      history of cognitive deficits or brain trauma 3) No use of psychoactive medication 4) No
      contra-indications for nicotine gum.

      Intervention (if applicable): The group will be randomized in two sub-populations. 1) 28
      volunteers will receive five injections of 3'aminomethylnicotine P. aeruginosa r-Exoprotein A
      Conjugate Vaccine (NicVAX™), 2) 20 smokers will receive five injections placebo. On test days
      both groups will be given a nicotine challenge; a chewing gum either containing nicotine
      (2mg) or a placebo.

      Main study parameters/endpoints: correlation between nicotine specific antibody and 1) the
      BOLD response during resting state, during the smoking-cue reactivity paradigm and during
      task performance; in regions of interest associated with the specific tasks; 2) the number of
      correct response and the reaction time; 3) correlation between nicotine specific antibody and
      subjective signs of nicotine addiction, measured with several questionnaires.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: participants will complete a medical screening questionnaire (15-30 min) and
      will undergo a medical screening (45 min; 2 blood samples, a urine sample and an
      electrocardiogram). Informed consent will be obtained. All participants will be vaccinated
      with NicVAX or Placebo 5 times on day 0, 28, 56, 84 and 112 (4 weeks in between each
      injection) During the training session (Day 0; ±1,5 hour) the inclusion/exclusion criteria
      and baseline laboratory results will be reviewed to ensure that no changes to the
      participants health and eligibility status occurred since the Screening Visit. Participants
      will be randomized and receive either one dose NicVAX 400µ in 1 ml or a placebo
      intramuscular. The cognitive fMRI task will be trained in a dummy scanner, and questionnaires
      will be completed. Subsequent vaccinations (days 28, 56, 84 and 112) should be given in the
      alternating deltoid muscle. Participants will be observed for 60 minutes to monitor possible
      adverse events. Adverse events, vital signs and concomitant medications will be recorded.
      During each test session (days 133, 140) participants will complete 5 questionnaires (30
      minute total) and will perform several cognitive tasks inside the fMRI scanner (scan session
      in total ~85 min). The last test session (day 140) three blood samples (5-8 ml each) will be
      taken for nicotine-specific antibody assessment and to monitor changes. In total the study
      will take 18 hours to complete. The participants will be paid 10 euro/hr as compensation. The
      risk of vaccination, fMRI scanning and of administration of nicotine 2mg gum (delivering a
      dose of approximately 1-1.5 mg nicotine to the bloodstream) is negligible for carefully
      screened participants. The nicotine specific-antibody vaccine has been clinically tested on
      several occasions; the safety profile was favourable. Local reactogenicity was generally mild
      to moderate and subsided spontaneously. Vaccinated subjects with the highest antibody levels
      (top 30%) smoked less cigarettes per day and reported a higher abstinence rate than placebo
      subjects, establishing proof-of-concept. The group receiving the vaccine could therefore in
      theory reduce smoking/exposure to tobacco smoke and have consequential health benefits.
    

Intervention name(s): vaccination with Nicvax
Intervention type(s): Biological
Intervention description(s): 5 vaccinations of NicVax 400ug (1 ml) over a 18 week period or matching placebo.
Other intervention name(s): NicVAX is a P. earoginosa r-Exoprotein conjugate vaccine.
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Keywords: fmri smoking vaccination mood