An fMRI-study on the effects of NicVAX® and placebo on Central Nervous System activation and behaviour following a nicotine challenge.

Cigarette smoking is implicated in 20.000 (15%) of all deaths per year in the
Netherlands. Most smokers are aware of the health consequences and want to
quit, but have difficulty doing so. Only 3-5% of smokers who quit on their own
are successful. Since the vast majority of those who attempt to quit will fail,
the need for better approaches to smoking cessation is clear and urgent.
Most effects of nicotine on the Central Nervous System (CNS) are directly
mediated by nicotine molecules. A safe and effective means of blocking the
effects of nicotine would be of considerable interest as a potential treatment
for tobacco use and may be especially effective in the prevention of relapse.
Treatment with 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.

Main aim; to show that NicVAX attenuates nicotine induced CNS effects on brain
activation and cognitive performance relative to placebo.
The secondary aim; to evaluate how these changes in CNS stimulation alter
subjective measures and the addictive properties of nicotine.

To the best of our knowledge this will be the first fMRI study that
investigates the effects of a nicotine challenge on brain activation after
vaccination resulting in nicotine specific antibodies to attenuate these
effects, while simultaneous evaluating the effects on cognitive performance,
craving and mood.

Nicotine dependency and mood will be evaluated on every visit to the research
centre; nicotine dependency will be evaluated again 6 months after vaccination
to evaluate long term abstinence in correlation to brain activation in
different testing conditions.
The results will help explain: (1) that NicVAX prevents the CNS effects of a
nicotine challenge, (2) how direct effects of nicotine on the CNS might
contribute to dependence, (3) whether smoking is sustained by transient
enhanced performance or (4) to avoid cognitive deficits during abstinence; (5)
how vaccination resulting in specific antibodies alters the CNS response to
nicotine and the addictive properties of nicotine

within-subject cross-over (nicotine challenge) double-blind placebo controlled
(vaccine) study

The group will be randomised in two subgroups, one will recieve 5 injections
with NicVAX, 4 weeks inbetween in the alternating deltoid muscle, the other
group will recieve placebo vaccinations.
On the fMRI scanning sessions a nicotine challenge or placebo will be given in
the form of Nicotine 2 mg chewing gum (randomised order).

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). All participants will be vaccinated with NicVAX or
Placebo 5 times on day 0, 28, 56, 84, 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, 112) should be given in the alternating deltoid muscle.
Participants will be observed for 30 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 vaccination
session (day 140) three blood samples will be taken for nicotine-specific
antibody assessment and to monuitor any hematological/chemical changes (5 ml
each).
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; in these studies no major side-effects were reported. Local
reactogenicity was mild to moderate and subsided spontaneously. The vaccine is
associated with a decrease in smoked cigarettes per day and a higher success
rate in quitting attempts; with lower relapse rates. The group receiving the
vaccine could therefore in theory reduce smoking/exposure to tobacco smoke and
have consequential health benefits.
There will be a financiaol compensation for time of 10.- per hour and a bonus
of 35 euro for each scanning session. The maximum amount of payment is 380 euro
per subject.