Novel Smoking Cessation Drug for Schizophrenia

Objective:

This is a Proof of Concept study planned over nearly 2 years to determine the potential
efficacy of a novel drug for smokers with schizophrenia.

This study will assess 60 smokers with a diagnosis of either schizophrenia or schizoaffective
disorder with high quit interest on their ability to quit during a week-long attempt to
abstain while receiving a novel drug vs. placebo, using a within-subjects cross-over design.

Research Plan:

Active drug or placebo will be provided to participants in double-blind fashion.

Study participation will last 6 weeks after subjects enter the study following the screening
and physical exam sessions (about 8 weeks total). Participants will engage in two identical
study phases, each involving visits over 3 weeks and varying only in whether active drug or
placebo is administered. The 3 weeks will involve: baseline visits, dose run-up (week 2), and
week 3 (for abstinence assessments). The first week of each period will be a baseline week in
which they smoke normally without any medication. During week 2, subjects will begin the dose
run-up of active drug or placebo, increasing over 4 days from 1 tablet of 50 mg once daily to
100 mg b.i.d. (two 50 mg tablets twice/day), which will continue through the second and third
weeks. Active drug or placebo will be administered in counter-balanced order in a cross-over
design. During week 3, subjects will be instructed to try to abstain on each day, i.e.
Mon-Friday. Most visits will last 60 mins and involve psychiatric assessments (including
psychopathology and neurological and other side effects) ratings, providing an expired breath
carbon monoxide (CO) measure that assesses smoking exposure in the past 24 hrs, as well as
completing brief self-report measures of craving, withdrawal, and mood. On week 3 of each
phase, one visit will involve cognitive testing. On Fri of week 3, subjects will discontinue
all medication and resume ad lib smoking prior to the next study period, involving the same
3-week procedure (but with the other medication condition): baseline, dose run-up, full dose
administration plus abstinence assessment. Note that active medication will be taken during
only one period, with placebo taken during the other period. Pill counts will be used to
measure adherence.

Primary and secondary dependent measures are described separately in this report.

Psychopathology will be assessed using standard rating scales to evaluate psychoses and
general psychopathology and severity of illness ratings, and suicide rating scales. These and
clinical impressions of patients in the study will assist in monitoring for stability or
worsening of psychoses or suicidal behavior and/or the need to exit patients from the study.

Laboratory and EKG monitoring at the beginning and end of the study will also be part of the
subject safety procedures.

Patients will be offered their choice of one of the FDA approved smoking cessation agents,
i.e. nicotine replacement therapy, bupropion or varenicline for a 3-month period upon
completion of the study. If patients decline open-label smoking cessation participation, they
will be requested to come in for one post-study visit, 14 ± 4 days later. At the first
post-study visit, if there are no adverse events, their participation will end.

Methods:

The novel drug or placebo will be administered double-blind in counter-balanced order in a
cross-over design. This is not a clinical trial that assesses long term smoking cessation but
a within-subjects comparison of the short-term effects of this drug on abstinence and
abstinence symptoms over a week-long period, relative to placebo.

Significance:

This study addresses an important question of whether the novel drug shows potential efficacy
for smoking cessation, relative to placebo, in smokers with schizophrenia. This procedure
could have enormous implications for accelerating the development of this medication and
similar compounds to help people quit smoking by increasing the efficiency of early
medication evaluation.

Inclusion Criteria: List the specific criteria for inclusion of potential subjects.

- Men or women of any race, ages 18 to 65 years, (≥18 years, ≤ 66 years)

- Willing to provide written informed consent

- MINI (Sheehan et al 1998, 2008) chart and/or clinician consensus affirmed DSM IV TR or
(DSM -V) diagnoses of schizophrenia or schizoaffective disorder.

- Patients whose PANSS total scores have been stable for ≥ 4 weeks (clinician and/or
subject affirmed) and at ≤ 70

- No recent ( ≤ 3months) hospitalization, aggression, or suicidal attempts

- Stable doses of antipsychotic medication, ≥ 4 weeks

Smoking Inclusion Criteria:

- Smoke ≥ 5 cigarettes/day

- Smoking cigarettes ≥ 1 year

Exclusion Criteria:

Smoking/Nicotine Exclusions:

- Use of smokeless tobacco or snuff or chewing tobacco

- Use of e-cigarettes, or any non-tobacco nicotine products (e.g. nicotine gum,
lozenges, patch, etc.)

- Current enrollment or plans to enroll in another smoking cessation program. (Bupropion
use for depression will be assessed on a case by case basis)

Alcohol/Illicit Substance Exclusion Criteria:

- Recent alcohol or substance dependence (≤ 3 months)

- Current alcohol consumption that exceeds 15 standard drinks/week or greater than 2
standard drinks daily

Medical Exclusion Criteria:

- Women who are pregnant, planning a pregnancy, or lactating; all female participants
shall undergo a pregnancy test at screening and will be excluded if positive.

- Serious or unstable medical disorder within the past 3 months (assessed by the
investigators)

- Epilepsy

- Current diagnosis (within last 6-months) of abnormal cardiac rhythms; unstable
cardiovascular disease e.g. stroke, myocardial infarction in the last 6 months

- Evidence impaired liver function test (LFT) defined as serum glutamate oxaloacetate
transaminase (SGOT) (AST) or serum glutamate pyruvate transaminase (SGPT) (ALT) or
alkaline phosphatase greater than 1x the upper limit of normal, or bilirubin 1x the
upper limit of normal

- Evidence of kidney failure defined as: Serum creatinine > 1.8 mg/dl for males and 1.6
mg/dl for females.

- Any subject with a history of hematological cancers examples: leukemia, lymphoma etc.
will be excluded.

- Any clinically significant hematological laboratory abnormality (chronic low-grade
laboratory values just above or below the reference range that are without clinical
significance will be permitted) will be grounds for exclusion.

Medication Exclusion Criteria:

- Current use or recent discontinuation (within last 14-days) of the following
medications: any form of smoking cessation medication (Bupropion except when used for
Depressive Disorders on a case by case basis, Varenicline, NRT); and (b)
opiate-containing medications for chronic pain. Potent CYP 3A4 inhibitors will be
reviewed for exclusion, see below.

- In view of novel drug being a moderate CYP3A4 inhibitor, any subjects receiving the
following narrow therapeutic index CYP3A4 substrates will be excluded: Alfentanil,
astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl,
pimozide, quinidine, sirolimus, tacrolimus, terfenadine.

- In view of the impact of clozapine on smoking cessation, patients receiving clozapine
will be excluded.

- Stable medical conditions examples: hypertension, diabetes, dyslipidemia etc that are
treated and ongoing and patients are not receiving the exclusionary drugs noted above
will be considered for inclusion on a case by case basis.