A Phase II, Randomized, Double-Blind Trial of Varenicline for the Treatment of Cocaine Dependence
Phase: PHASE2
Conditions: Cocaine Dependence
Sponsor: University of Pennsylvania

 
Version 13 02/15/2017 
University of Pennsylvania 
 
 
 
A Phase II, Randomized, Double-Blind Trial of Varenicline for the 
Treatment of Cocaine Dependence 
 
Principal Investigator 
Kyle Kampman, M.D. 
Department of Psychiatry 
Treatment Research Center 
3535 Market Street, Suite 500 
Philadelphia, PA 19104 
215-746-2764 
 
Regulatory Sponsor: 
 
Kyle Kampman, M.D.Department of Psychiatry 
Treatment Research Center 
3535 Market Street, Suite 500Philadelphia, PA 19104 
215-746-2764 
Funding Sponsor: 
NIDA 
Study Product: 
Varenicline (Chantix™) 
Protocol Version Number: 
ChC2 v.13 
IND Number: 
77,735 
 
Date: 
Version 1, 10/17/2011 
Amended: 
Version 2, 05/11/2012 
Amended: 
Version 3, 06/28/2012 
Amended: 
Version 4, 07/31/2012 
Amended: 
Amended: 
Amended: 
Amended: 
Amended: 
Amended: 
Amended: 
Amended: 
Version 5, 08/21/2012 
Version 6, 01/22/2013 
Version 7, 07/11/2013 
Version 8, 08/25/2014 
Version 9, 02/17/2015 
Version 10, 04/21/2015 
Version 11, 03/24/2016 
Version 12, 07/25/2016 
Administrative 
Change: 
 
Version 13, 02/01/2017 
• Version 13 Correction 02/15/2017 
• IRB approved 28 Jan 2019 
 
 
 
 

 
 
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CONFIDENTIAL 
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CONFIDENTIAL 
 
This document is confidential and the property of the University of Pennsylvania.  No part 
of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 
 
 

 
 
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Signature Page 
 
 
I agree to conduct this clinical trial according to the principles and methods set forth in this protocol 
and in accordance with GCP, and applicable regulatory requirements. 
 
________________________                                        _____________________ 
Kyle Kampman, M.D.                                                       Date 
Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table of Contents 
STUDY SUMMARY ..................................................................................................................... 1 
1 
INTRODUCTION................................................................................................................. 2 
1.1 
BACKGROUND .................................................................................................................. 2 
1.2 
INVESTIGATIONAL AGENT ............................................................................................... 3 
1.3 
DOSE RATIONALE AND RISK/BENEFITS............................................................................ 4 
2 
STUDY OBJECTIVES ......................................................................................................... 9 
3 
STUDY DESIGN ................................................................................................................... 9 
3.1 
GENERAL DESIGN .......................................................................................................... 11 
3.2 
PRIMARY STUDY ENDPOINTS ........................................................................................... 9 
3.3 
SECONDARY STUDY ENDPOINTS .................................................................................... 10 
3.4 
PRIMARY SAFETY ENDPOINTS........................................................................................ 10 
4 
SUBJECT SELECTION AND WITHDRAWAL ............................................................ 10 
4.1 
INCLUSION CRITERIA ..................................................................................................... 10 
4.2 
EXCLUSION CRITERIA ...................................................................................................... 9 
4.3 
SUBJECT RECRUITMENT AND SCREENING ...................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS............................................................................... 13 
4.4.1 When and How to Withdraw Subjects ....................................................................... 13 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects ......................................... 14 
5 
STUDY DRUG .................................................................................................................... 14 
5.1 
DESCRIPTION ................................................................................................................. 14 
5.2 
TREATMENT REGIMEN ................................................................................................... 14 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................... 16 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................. 16 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................. 16 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................ 16 
5.7 
PACKAGING ................................................................................................................... 17 
5.8 
BLINDING OF STUDY DRUG ............................................................................................ 15 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN.......................................................... 17 
5.9.1 Receipt of Drug Supplies .......................................................................................... 17 
5.9.2 Storage ...................................................................................................................... 17 
5.9.3 Dispensing of Study Drug ......................................................................................... 17 
5.9.4 Return or Destruction of Study Drug ........................................................................ 17 
6 
STUDY PROCEDURES .................................................................................................... 18 
6.1 
VISIT 1 ........................................................................................................................... 24 
6.2 
VISIT 2 ........................................................................................................................... 24 
6.3 
VISIT 3 ........................................................................................................................... 24 
6.4 
FIRST VISIT OF THE WEEK, RANDOMIZED MEDICATION PHASE ..................................... 24 
6.5 
SECOND VISIT OF THE WEEK, RANDOMIZED MEDICATION PHASE ................................. 26 
6.6 
THIRD VISIT OF THE WEEK, RANDOMIZED MEDICATION PHASE .................................... 26 
6.7 
END OF RANDOMIZED MEDICATION PHASE ................................................................... 26 
7 
STATISTICAL PLAN ........................................................................................................ 28 

 
 
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7.1 
SAMPLE SIZE DETERMINATION ...................................................................................... 28 
7.2 
STATISTICAL METHODS ................................................................................................. 28 
7.3 
SUBJECT POPULATION(S) FOR ANAYLSIS ....................................................................... 30 
8 
SAFETY AND ADVERSE  EVENTS ............................................................................... 30 
8.1 
DEFINITIONS .................................................................................................................. 30 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................. 32 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ................................................................... 32 
8.3.1 Study Sponsor Notification by Investigator .............................................................. 32 
8.3.2 EC/IRB Notification by Investigator ......................................................................... 33 
8.3.3 FDA Notification by Sponsor .................................................................................... 33 
8.4 
UNBLINDING PROCEDURES ............................................................................................ 33 
8.5 
STOPPING RULES............................................................................................................ 32 
8.6 
MEDICAL MONITORING ................................................................................................. 33 
 
9 
DATA HANDLING AND RECORD KEEPING ............................................................. 34 
9.1 
CONFIDENTIALITY ......................................................................................................... 34 
9.2 
SOURCE DOCUMENTS .................................................................................................... 34 
9.3 
CASE REPORT FORMS .................................................................................................... 34 
9.4 
RECORDS RETENTION .................................................................................................... 35 
10 STUDY MONITORING, AUDITING, AND INSPECTING ......................................... 35 
10.1 
STUDY MONITORING PLAN ............................................................................................ 35 
10.2 
AUDITING AND INSPECTING ........................................................................................... 43 
11 ETHICAL CONSIDERATIONS ....................................................................................... 44 
12 STUDY FINANCES............................................................................................................ 44 
12.1 
FUNDING SOURCE .......................................................................................................... 44 
12.2 
CONFLICT OF INTEREST .................................................................................................. 44 
12.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................. 44 
13 PUBLICATION PLAN ...................................................................................................... 45 
14 REFERENCES .................................................................................................................... 46 
15 ATTACHMENTS ............................................................................................................... 49 

 
 
page 1 
 
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Study Summary 
Title 
A Phase II Randomized, Double-blind, Placebo-Controlled,  Trial of 
Varenicline (Chantix™) for the Treatment of Cocaine Dependence 
Short Title 
Chantix for Cocaine Dependence 
Protocol Number 
ChC2 Version 13, 01/27/2017 
Phase 
Phase II 
Methodology 
Randomized, double-blind, placebo-controlled  trial 
Study Duration 
5 years 
Study Center(s) 
Single-center – University of Pennsylvania Treatment Research Center 
Objectives 
To determine the efficacy of varenicline (Chantix™) for the treatment of 
cocaine dependence 
Number of Subjects 
200 
Diagnosis and Main 
Inclusion Criteria 
Cocaine dependence.  Men and women ages 18-65. Subjects must have current 
DSM IV diagnosis of cocaine dependence and a recent history of cocaine use. 
Subjects must be in good health and psychiatrically stable.  They must have no 
other current substance dependence except nicotine or alcohol. 
Study Product, Dose, 
Route, Regimen 
Varenicline (Chantix™), oral 1.0 mg BID. 
Duration 
of 
administration 
12 weeks 
Reference therapy 
Placebo 
Statistical 
Methodology 
 
Hypothesis 1: Cocaine use will be measured with three-times-weekly urine 
benzoylecgonine (BE) levels and self-reports of use from the Time Line Follow 
Back, combined to yield daily use/no-use indicators for each study day. We plan 
to use a mixed effects model.   Mixed-effects models have two parts: a fixed 
effects component (comprising the explanatory variables included in the model) 
that describes the mean values of the outcomes across the time points, and a 
random-effects component defining the variances and covariances of the 
outcomes.  In our models, the primary fixed effects are group, and time, together 
with possible interaction terms. The effect of time will be broken into linear, 
quadratic and, possibly, cubic, trends across the 13 weeks.  A generalized 
estimating equations (GEE) model will be used to model the effects of 
medication group and time on the log-odds of use across the treatment period.  
The explanatory variables in these models will be a binary factor for medication, 
and terms for time effects, and group by time interaction 
 

 
 
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Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
1.1 Background 
Therapies with both partial agonist and antagonist properties (e.g., buprenorphine) are 
highly effective in treating opiate abuse and dependence.  By both providing a low level of 
reinforcement and down-grading any “high” associated with concurrent administration of the 
abused drug, such therapies promote both initial and sustained abstinence.  Unlike treatment for 
opioid dependence, currently there are no efficacious pharmacotherapies for cocaine dependence.  
Based on the efficacy of partial agonists and antagonists in opioid treatment, by extension 
psychostimulants such as methylphenidate may be considered to be good candidates for treating 
cocaine dependence.  However, that such psychostimulants are in and of themselves abusable 
drugs makes them relatively impractical treatment alternatives. 
 
 
Increased acetylcholine release in the midbrain due to psychostimulant use (e.g., nicotine 
or cocaine) appears to increase dopamine and glutamate activity.  It is believed that acetylcholine 
release in the midbrain triggers both pre-synaptic α7 receptors found on glutamatergic terminals 
(GLU) and post-synaptic α2β4 receptors found on dopamine cell bodies (DA).  It is hypothesized 
that this interaction of the cholinergic, dopaminergic and glutamatergic systems in midbrain 
structures (e.g., nucleus accumbens, ventral tegmental area, amygdala and prefrontal cortex) is 
responsible for the development of psychostimulant abuse and dependence (c.f., Kelley 2002).  As 
such, reduction in cholinergic activity at α7 and α2β4 receptors would likely reduce dopaminergic 
and glutamatergic activity in the midbrain, potentially halting or reversing the neural processes 
associated with development of psychostimulant abuse and dependence. 
 
Based on varenicline’s specific affinity for the nicotinic acetylcholine receptors that are 
implicated in cocaine reward circuitry (c.f., Schoffelmeer et al., 2002), it appears to be a good 
candidate for treatment of cocaine dependence.  In addition to its partial agonist activity at 
heteromeric α2β4 nicotinic acetylcholine receptors, varenicline has also been shown to be a full 
agonist at homomeric α7 nicotinic acetylcholine receptors (Mihalak et al., 2006).  That full 
agonism at α7 may be key in reducing cocaine withdrawal and craving during early cocaine 
abstinence, and thus reducing relapse, as α7 receptors are implicated in the neural reward circuitry 
activated by cocaine use.  In addition, varenicline’s ability to occupy the α7 and α2β4 nicotinic 
receptors, effectively blocking cocaine, would reduce the high derived from cocaine ingested 
during varenicline treatment.  Evidence in support of this comes from the specific α7 antagonist 
methyllycaconitine, which attenuates the reinforcing effects of cocaine (Panagis et al., 2000). 
 
Varenicline (Chantix™) is a partial agonist for the α2β4 nicotinic acetylcholine receptor 
subtypes.  It has demonstrated efficacy as a treatment for smoking cessation (Oncken et al., 2006; 
Nides et al., 2006) and relapse prevention (Tonstad et al., 2006). Varenicline partially mimics 
nicotine’s dopamine agonist properties, providing some reinforcement that mirrors that of nicotine, 
and thus reduces nicotine withdrawal and craving.  In rat studies, extracellular dopamine in the 
nucleus accumbens after varenicline dosing was about half what is typically seen with acute 

 
 
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nicotine dose administration.  In addition to its partial agonist effects, varenicline acts as an 
antagonist in the presence of nicotine, effectively downgrading nicotine-derived reinforcement 
(Johnson 2006).  Based on its specific affinity for receptors implicated in both nicotine and cocaine 
reward, varenicline may work both for initiating and maintaining cocaine abstinence. 
In contrast to the abuse liability associated with psychostimulants, less than 1 in 1000 
subjects in the varenicline Phase III clinical trials reported euphoria with varenicline treatment, 
and any reports of increased positive subjective effects due to increased dosing are accompanied 
by reports of increased negative subjective effects, indicating a relatively low abuse liability for 
varenicline.  In addition, there are no indications that tolerance to varenicline develops with 
repeated dosing. 
In our recently completed pilot trial of varenicline for cocaine dependence we found that 
varenicline reduced cocaine use as compared to placebo (Plebani et al., 2011).  In addition, 
varenicline reduced cocaine reinforcement. 
 
1.2 Investigational Agent 
(Taken from Chantix™ Package insert 
 
CHANTIX™ tablets contain the active ingredient, varenicline (as the tartrate salt), which is a 
partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes. 
Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid 
with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3- 
h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. 
Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of 
C13H13N3 • C4H6O6. 
 
Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine 
receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of 
varenicline’s activity at a sub-type of the nicotinic receptor where its binding produces agonist 
activity, while simultaneously preventing nicotine binding to α4β2 receptors. 
Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline 
binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated 
activity, but at a significantly lower level than nicotine. Varenicline blocks the ability of nicotine 
to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, 
believed to be the neuronal mechanism underlying reinforcement and reward experienced upon 
smoking. Varenicline is highly selective and binds more potently to α4β2 receptors than to other 
common nicotinic receptors (>500-fold α3β4, >3500-fold α7, >20,000-fold α1βγδ), or to 
nonnicotinic receptors and transporters (>2000-fold). Varenicline also binds with moderate 
affinity (Ki = 350 nM) to the 5-HT3 receptor. 
 
Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral 
administration. Following administration of multiple oral doses of varenicline, steady-state 
conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits 
linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of 
varenicline was virtually complete after oral administration and systemic availability was high. 
Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein 

 
 
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binding of varenicline is low (≤20%) and independent of both age and renal function. 
 
Metabolism/Elimination 
The elimination half-life of varenicline is approximately 24 hours. Varenicline undergoes 
minimal metabolism with 92% excreted unchanged in the urine. Renal elimination of varenicline 
is primarily through glomerular filtration along with active tubular secretion possibly via the 
organic cation transporter, OCT2. 
 
Pharmacokinetics In Special Patient Populations 
There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, 
gender, smoking status, or use of concomitant medications, as demonstrated in specific 
pharmacokinetic studies and in population pharmacokinetic analyses. 
 
1.3 
Dose Rationale and Risk/Benefits 
For the proposed trial, we chose a dose of 2.0 mg per day (1.0 mg BID) for several reasons. 
First, that dose has shown the best outcomes in smoking cessation trails with varenicline.  In 
addition, few side effects are reported at that dose, making it both safe and efficacious. 
 
Potential Risks:  The potential risks of this study include adverse reactions to varenicline, cocaine 
and the small risk incurred by venipuncture. 
 
Most adverse effects from varenicline have been mild and transient and have rarely required the 
withdrawal of therapy. 
 
Common side effects are categorized below: 
GASTROINTESTINAL 
Nausea, Abdominal Pain, Flatulence, Dyspepsia, Vomiting, Constipation, Gastroesophageal reflux 
disease, Dry mouth 
PSYCHIATRIC DISORDERS 
Insomnia, Abnormal dreams, Sleep disorder, Nightmare 
NERVOUS SYSTEM 
Headache, Dysgeusia, Somnolence, Lethargy 
GENERAL DISORDERS 
Fatigue/Malaise/Asthenia 
RESPIR/THORACIC/MEDIAST 
Rhinorrhea, Dyspnoea, Upper Respiratory Tract Disorder 
SKIN/SUBCUTANEOUS TISSUE 
Rash, Pruritis 
METABOLISM & NUTRITION 
Increased appetite, Decreased appetite/Anorexia 
 
Treatment-emergent adverse events reported by participants during Chantix clinical trials: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS. Infrequent: Anemia, 
Lymphadenopathy. Rare: Leukocytosis, Thrombocytopenia, Splenomegaly. 
CARDIAC DISORDERS. Infrequent: Angina pectoris, Arrhythmia, Bradycardia, Ventricular 

 
 
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extrasystoles, Myocardial infarction, Palpitations, Tachycardia. Rare: Atrial fibrillation, Cardiac 
flutter, Coronary artery disease, Cor pulmonale, Acute coronary syndrome. 
EAR AND LABYRINTH DISORDERS. Infrequent: Tinnitus, Vertigo. Rare: Deafness, 
Meniere’s disease. 
ENDOCRINE DISORDERS. Infrequent: Thyroid gland disorders. 
EYE DISORDERS. Infrequent: Conjunctivitis, Dry eye, Eye irritation, Vision blurred, Visual 
disturbance, Eye pain. Rare: Acquired night blindness, Blindness transient, Cataract subcapsular, 
Ocular vascular disorder, Photophobia, Vitreous floaters. 
GASTROINTESTINAL DISORDERS Frequent: Diarrhea, Gingivitis. Infrequent: 
Dysphagia, Enterocolitis, Eructation, Gastritis, Gastrointestinal hemorrhage, Mouth ulceration, 
Esophagitis. Rare: Gastric ulcer, Intestinal obstruction, Pancreatitis acute. 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS. Frequent: 
Chest pain, Influenza like illness, Edema, Thirst. Infrequent: Chest discomfort, Chills, Pyrexia. 
HEPATOBILIARY DISORDERS. Infrequent: Gall bladder disorder. 
IMMUNE SYSTEM DISORDERS. Infrequent: Hypersensitivity. Rare: Drug 
hypersensitivity. 
INVESTIGATIONS. Frequent: Liver function test abnormal, Weight increased. Infrequent: 
Electrocardiogram abnormal, Muscle enzyme increased, Urine analysis abnormal. 
METABOLISM AND NUTRITION DISORDERS. Infrequent: Diabetes mellitus, 
Hyperlipidemia, Hypokalemia. Rare: Hyperkalemia, Hypoglycemia. 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS. Frequent: 
Arthralgia, Back pain, Muscle cramp, Musculoskeletal pain, Myalgia. Infrequent: Arthritis, 
Osteoporosis. Rare: Myositis. 
NERVOUS SYSTEM DISORDERS. Frequent: Disturbance in attention, Dizziness, Sensory 
disturbance. Infrequent: Amnesia, Migraine, Parosmia, Psychomotor hyperactivity, Restless 
legs syndrome, Syncope, Tremor. Rare: Balance disorder, Cerebrovascular accident, 
Convulsion, Dysarthria, Facial palsy, Mental impairment, Multiple sclerosis, Nystagmus, 
Psychomotor skills impaired, Transient ischemic attack, Visual field defect. 
PSYCHIATRIC DISORDERS. Frequent: Anxiety, Depression, Emotional disorder, 
Irritability, Restlessness. Infrequent: Aggression, Agitation, Disorientation, Dissociation, Libido 
decreased, Mood swings, Thinking abnormal. Rare: Bradyphrenia, Euphoric mood, 
Hallucination, Psychotic disorder, Suicidal ideation. 
Serious neuropsychiatric events, including, but not limited to depression, suicidal 
ideation, suicide attempt and completed suicide have been reported in patients taking 
Chantix. 
RENAL AND URINARY DISORDERS. Frequent: Polyuria. Infrequent: Nephrolithiasis, 
Nocturia, Urine abnormality, Urethral syndrome. Rare: Renal failure acute, Urinary retention. 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS. Frequent: Menstrual disorder. 
Infrequent: Erectile dysfunction. Rare: Sexual dysfunction. 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS. Frequent: Epistaxis, 
Respiratory disorders. Infrequent: Asthma. Rare: Pleurisy, Pulmonary embolism. 
 
 

 
 
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SERIOUS SKIN REACTIONS 
There have been postmarketing reports of rare but serious skin reactions, including Stevens-
Johnson Syndrome and erythema multiforme, in patients using CHANTIX 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS. Frequent: Hyperhidrosis. 
Infrequent: Acne, Dermatitis, Dry skin, Eczema, Erythema, Psoriasis, Urticaria. Rare: 
Photosensitivity reaction. 
VASCULAR DISORDERS. Frequent: Hot flush, Hypertension. Infrequent: Hypotension, 
Peripheral ischemia, Thrombosis. 
 
The U.S. Food and Drug Administration (FDA) notified the public that varenicline may be 
associated with a small, increased risk of certain cardiovascular adverse events in patients 
who have cardiovascular disease. History of significant heart disease or dysfunction is 
exclusionary criteria for this study. 
 
In a controlled clinical trial of CHANTIX administered to patients with stable cardiovascular 
disease, with approximately 350 patients per treatment arm, certain cardiovascular events were 
reported more frequently in patients treated with CHANTIX than in patients treated with 
placebo. These included treatment-emergent events (on-treatment or 30 days after treatment) of 
angina pectoris (13 patients in the varenicline arm vs. 7 in the placebo arm), and the serious 
cardiovascular events of nonfatal MI (4 vs. 1) and nonfatal stroke (2 vs. 0). During non-treatment 
follow up to 52 weeks, serious cardiovascular events included nonfatal myocardial infarction (3 
vs. 2), need for coronary revascularization (7 vs. 2), hospitalization for angina pectoris (6 vs. 4), 
transient ischemic attack (1 vs. 0), new diagnosis of peripheral vascular disease (PVD) or 
admission for a PVD procedure (5 vs. 2). Serious cardiovascular events occurring over the 52 
weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by an 
independent blinded committee. CHANTIX was not studied in patients with unstable 
cardiovascular disease or cardiovascular events occurring within two months before screening. 
Patients should be advised to notify a health care provider of new or worsening symptoms of 
cardiovascular disease. 
 
Black Box Warning 
WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS 
Serious neuropsychiatric events including, but not limited to, depression, suicidal ideation, 
suicide attempt, and completed suicide have been reported in patients taking CHANTIX. Some 
reported cases may have been complicated by the symptoms of nicotine withdrawal in patients 
who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, 
rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation 
attempt without medication. However, some of these symptoms have occurred in patients taking 
CHANTIX who continued to smoke. 
All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms 
including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, 
including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of 
pre-existing psychiatric illness and completed suicide, have been reported in some patients 
attempting to quit smoking while taking CHANTIX in the postmarketing experience. When 
symptoms were reported, most were during CHANTIX treatment, but some were following 
discontinuation of CHANTIX therapy. 

 
 
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These events have occurred in patients with and without pre- existing psychiatric disease. 
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major 
depressive disorder did not participate in the premarketing studies of CHANTIX, and the safety 
and efficacy of CHANTIX in such patients has not been established. 
Advise patients and caregivers that the patient should stop taking CHANTIX and contact a 
healthcare provider immediately if agitation, hostility, depressed mood, or changes in behavior 
or thinking that are not typical for the patient are observed, or if the patient develops suicidal 
ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after 
discontinuation of CHANTIX was reported, although in some cases the symptoms persisted; 
therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. 
The risks of CHANTIX should be weighed against the benefits of its use. CHANTIX has been 
demonstrated to increase the likelihood of abstinence from smoking for as long as one year 
compared to treatment with placebo. The health benefits of quitting smoking are immediate and 
substantial.  
 
 
Drug Interactions 
Based on varenicline characteristics and clinical experience to date, CHANTIX has no clinically 
meaningful pharmacokinetic drug interactions. 
 
Prior research examining the attenuating effects of the nicotinic acetylcholine receptor 
antagonist methyllcaconitine (MLA) on cocaine-derived reinforcement in rats showed no adverse 
interactions between cocaine and MLA (Panagis et al., 2000).  Evidence for the lack of 
interactive effect between acetylcholine agonists and cocaine comes from prior research 
investigating the acetylcholinesterase inhibitor donepezil (Aricept®) as a treatment for cocaine 
dependence (Kampman et al., 2005).  In that study, there were no adverse events stemming from 
the concurrent use of cocaine and donepezil.  Taken together, these studies suggest that the 
partial agonist activity, as well as the antagonist activity of varenicline on nicotinic acetylcholine 
receptors should not interact in a clinically meaningful way with cocaine.   
In our recently completed pilot trials of varenicline for cocaine dependence and varenicline 
for alcohol dependence, we have encountered no medication associated serious adverse events.  
A total of 77 participants have been randomized in our varenicline for cocaine dependence (n = 
37) or varenicline alcohol dependence (n = 40) pilot trials.  There have been no medication 
associated serious adverse events in either trial.  Adverse events have been mainly mild.  
Adverse events possibly related to study medication reported by at least 5% of participants, 
including placebo treated participants, are: nausea (15%), aches and pains (13%), sedation 
(13%), diarrhea (10%) headache (8%), insomnia (8%) and vomiting (6%).  Significant 
interactions between varenicline and cocaine, alcohol and the combination of cocaine and 
alcohol were not noted in the varenicline for cocaine dependence trial. There were no reported 
cocaine or alcohol associated serious adverse events, or significant changes in vital signs noted at 
study visits.  Thus, based on the data from the pilot trial, varenicline appears to be safe to study 
in cocaine dependent participants.  
 
Interactions between varenicline and cocaine 
There is experimental evidence that neither actylcholine agonists or antagonists interact in a 
clinically meaningful way with cocaine. 

 
 
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Conclusions:  Varenicline appears to be well-tolerated with a minimal side-effects profile as 
evidenced from adverse events reported in smoking cessation trials.  The selection of a dose of 1.0 
mg BID (2.0 mg per day) of varenicline is within the accepted dosing ranges recommended on the 
package insert. 
 
Consent Procedures:  All study procedures will be described in detail for the subjects by the 
research nurse, a physician, or other trained staff person in an individual consent session.  The 
consent form and session will include the following information:  Detailed information about the 
medication; that is, a description of the medication, rationale for why it is being studied, frequency 
of dosing and length of treatment, potential side effects, safeguards and emergency procedures.  
Information will also be provided about the psychosocial treatment, frequency of visits and length 
of treatment, safeguards and emergency procedures, etc.  Collection of lab specimens (number of 
venipunctures and urine specimens required) will be reviewed.  Eligibility will be reviewed.  The 
number and frequency of the research interviews and self-assessments will be reviewed. 
In addition, subjects will be assured that their participation is voluntary and that withdrawal from 
the study does not jeopardize current or future treatment.  Subjects will also be told that if at any 
time during the study the research team feels that the subject needs more intensive, standard 
treatment, the subject will be referred to one of the available inpatient or outpatient treatment 
programs near their place of residence. 
All subjects will be informed of potential risks and benefits involved in the study.  Potential 
medication side effects will be described to all subjects.  Subjects will be informed that their 
participation in the treatment trial may be discontinued at any time because of serious medication 
side effects, their noncompliance with treatment, missing appointments or if continued 
participation is considered an endangerment to their welfare. 
At the end of the consent session, a quiz is given.  Subjects scoring below 100% correct will receive 
additional instruction regarding the study and consent form.  Incorrect questions from the quiz will 
be administered again until all questions are answered correctly. 
 
Protection of Subjects:  Potential subjects will be screened for medical illnesses that would 
preclude the use of varenicline.  Subjects selected for the study will be monitored closely.  Subjects 
will be evaluated three times a week while receiving study medication.  Adverse events will be 
monitored by research staff at weekly visits, and the psychiatrist or nurse   will be available at 
other visits to assess the subject if needed.  At the conclusion of medications, an end of study 
physical will be completed and the baseline laboratory tests, including EKG, will be repeated.  
Subjects will be given a 24 hour emergency number they can call if necessary. Adverse events: If 
the subject is discontinued in treatment due to a serious adverse event, the subject will be followed 
clinically by medical staff until the adverse experience resolves itself and becomes stable. 
Subjects taking concomitant medications will be monitored closely for signs of toxicity. Subjects 
with a history of current severe psychiatric symptoms, use of any investigational medication within 
the last 30 days, AIDS or other serious illness which may require hospitalization during the study, 
impaired renal function or known liver disease, will be excluded from the study. Pregnant women 
or women who refuse to use acceptable forms of birth control will be excluded from the study.  
Urine pregnancy tests will be performed monthly. 
The dose of varenicline will be started at 0.5 mg BID and increased to 1.0 mg BID by the end of 
the first week of medication therapy. 
 

 
 
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Venipuncture will be carried out with good aseptic technique by a nurse or physician.  
Venipuncture sites will be monitored carefully for signs of infection. 
If a subject experiences an adverse event, appropriate evaluation and management will be 
undertaken.  This may include medical management, a reduction in study of medication, a 
temporary cessation of study drug, or early termination from the trial, if necessary 
Strict confidentiality will be maintained.  Clinical records will be stored in a restricted location 
and only the research team and clinical staff assigned to the care of the individual subjects will 
have access to the records.  An exception to this rule will be made for representatives of the FDA 
and the National Institute on Drug Abuse (NIDA) and contract monitors and or auditors.  The 
subject will be informed of these exceptions in the informed consent document. 
Because data regarding cocaine use is being obtained, a certificate of confidentiality was obtained 
for this study.  Subjects will be informed of this in the informed consent document. 
 
Potential Benefits:  Subjects will benefit from close medical and psychiatric attention over and 
above that which they will receive in an intensive outpatient treatment program. 
The potential benefits to society include decreased cocaine use with a resultant decrease in cocaine 
morbidity and mortality, as well as a reduction in the overall social cost of cocaine dependence. 
 
Risk Benefit Ratio:  The potential benefits of this study far outweigh the potential risks.  Cocaine 
dependence is a serious problem and treatment is difficult.  Even in the best programs, relapse 
rates are high.  Subjects accepted into the study will receive close medical and psychiatric 
monitoring, as well as treatment in an outpatient treatment program free of charge.  Varenicline 
has been shown to be safe and well tolerated at doses to be used in this study.  Subjects will be 
screened prior to admission into the study, and those at risk for adverse reactions will be excluded.  
Those selected for participation will be monitored closely for adverse effects. 
2 Study Objectives 
The proposed 5-year project will evaluate the efficacy of 2.0 mg/day of varenicline for the 
treatment of 200 treatment-seeking cocaine dependent outpatients in a double-blind, placebo-
controlled 13-week trial.  Study medications will be given by medical practitioners, trained to 
provide Medical Management (developed as part of NIAAA’s COMBINE study).  In addition, 
participants will receive weekly individual psychosocial treatment sessions utilizing Cognitive 
Behavioral Coping Skills Therapy (CBT), (CBT manual is part of NIAAA’s Project MATCH and 
has been adapted for this population through prior consultation with Dr. Kathleen Carroll). 
 
3 Study Design 
3.1 General Design 
This is a Phase II double-blind randomized controlled clinical trial.  The hypotheses in 
the proposed study will be tested with a 2-group design to assess the efficacy of varenicline as 
compared to placebo.  We will follow NIAAA’s COMBINE Medical Management (MM) 
manual in weekly dispensing medications, safety checks and medication adherence.  The 
psychosocial treatment will be Cognitive Behavioral Coping Skills Therapy (CBT).  Subjects 
will be 200 men and women with current DSM-IV diagnoses of cocaine dependence that will be 
randomized to receive either varenicline or placebo (100 subjects per group).  All subjects will 

 
 
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receive weekly sessions of CBT.  The study length for each subject is comprised of 1-4 weeks of 
screening (referred to as “week 1”) and a 12-week double-blind, placebo-controlled trial with 
CBT (medication phase). At the end of the study subjects will be referred to continuing care 
programs in the community. 
 
 
3.2 Primary Study Endpoints 
 
Primary Hypothesis: 
• Subjects receiving varenicline will have higher rates of cocaine abstinence than will those 
receiving placebo, as determined by urine assay for benzoylecgonine (BE), the primary 
metabolite of cocaine. 
3.3 Secondary Study Endpoints 
 
Secondary Hypotheses: 
• We further hypothesize that within the varenicline group, medication compliant 
participants (>80% of pills taken) will have higher rates of cocaine abstinence than those 
who are non-compliant (<80% of pills taken). 
 
• We expect that the varenicline group will report less craving for cocaine than will the 
placebo group, as measured by lower scores on the Cocaine Craving Questionnaire 
(Tiffany et al., 1993) and the Minnesota Cocaine Craving Scale (Halikas et al., 1991) 
during the medication treatment phase. 
 
• We expect that the varenicline group will show greater decreases in cigarette smoking than 
will the placebo group, as evidenced by CO and cotinine levels. 
 
 
• Primary Safety Endpoints 
A nurse or physician will assess for adverse events weekly.  Adverse events will be monitored by 
research staff at all other visits, and the psychiatrist or nurse will be available at other visits to 
assess the subject if needed.  At the conclusion of medications, an end of study physical will be 
completed and the baseline laboratory tests, including EKG, will be repeated.  If the subject is 
discontinued in treatment due to a serious adverse event, the subject will be followed clinically by 
medical staff until the adverse experience resolves itself and becomes stable. 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
1.  Males and females, 18 to 65 years old. 

 
 
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2. Meets DSM-IV criteria for Cocaine Dependence, as determined by the Structured Clinical 
Interview for DSM-IV (SCID). 
3.  Live within a commutable distance of the Treatment Research Center (TRC) at the Penn/VA 
Center for Studies of Addiction, University of Pennsylvania.  We define this to be a distance 
within the service area of Septa, within an hour drive, or a distance that both the 
participant and Principal Investigator (PI) find acceptable. 
4.  Understands and signs the informed consent. 
 
4.2 Exclusion Criteria: 
1. Current DSM-IV diagnosis of any psychoactive substance dependence other than cocaine, 
alcohol or nicotine dependence, as determined by the SCID. 
2. Subject is, in the investigator’s opinion, at risk of requiring medical detoxification for alcohol 
dependence during the study. 
3. Concomitant treatment with psychotropic medications. 
4. Current gambling problems. This will be assessed by the participant’s self-report. 
5. Participants mandated to treatment based upon a legal decision or as a condition of 
employment who will use participation in this study to fulfill their court mandated treatment 
requirement. 
This will be assessed by the participant’s self-report. 
6. Current severe psychiatric symptoms, e.g., psychosis, dementia, suicidal or homicidal ideation, 
mania or depression requiring antidepressant therapy in the opinion of the Principal 
Investigator (PI). 
7.  Use of any investigational medication within the past 30 days. 
8. Subject has serious heart, lung, kidney, immune system, GI tract (ulcerative colitis, 
regional enteritis, or gastrointestinal bleeding) disease. 
9.   Current use of naltrexone, disulfiram, modafinil, stimulants, haloperidol, benzodiazepines or 
anticonvulsants.  Anticonvulsants (e.g., gabapentin) prescribed for pain is not 
exclusionary. 
10.  Known hypersensitivity to varenicline. 
11. Participants with known AIDS or other serious illnesses that may require hospitalization 
during the study. 
12. Female subjects who are pregnant or lactating, or female subjects of child-bearing potential 
who are not using acceptable methods of birth control.  Acceptable methods of birth control 
include: 
a. barrier (diaphragm or condom) with spermicide 
b. intrauterine progesterone contraceptive system 
c. levonorgestrel implant 
d. medroxyprogesterone acetate contraceptive injection 
e. oral contraceptives 
f. tubal ligation. 
13. Participants with impaired renal function as indicated by corrected creatinine clearance below 
60 ml/min as determined by the modified Cockcroft equation. 
14. Clinical laboratory tests (CBC, blood chemistries, urinalysis) outside normal limits that are 
clinically unacceptable to the Medical Director.  EKG-1st degree heart block, sinus 

 
 
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tachycardia, left axis deviation, and nonspecific ST or T wave changes are allowed; liver 
function tests [LFTs] <5 x ULN are acceptable). 
 
4.3 Subject Recruitment and Screening 
The proposed project will be conducted at the University of Pennsylvania’s Treatment 
Research Center (TRC).  The TRC is a community-based (non-veteran) outpatient addiction 
treatment-research program that is part of the University of Pennsylvania Center for the Study of 
Addictions (Dr. Henry Kranzler, Director). The TRC offers outpatient addiction treatment for 
individuals from the greater Philadelphia area who are seeking treatment for their addiction and 
who qualify for one of our grant-sponsored treatment studies on alcohol, cocaine, dual cocaine-
alcohol, marijuana, heroin or nicotine dependence.  Subject recruitment is ongoing and 
accomplished through community, professional, and self-referrals from the greater metropolitan 
Philadelphia area.  Most of the TRC callers seeking treatment who are approved for intake (via 
phone pre-screen) and give written consent (93%) are subsequently randomized (85%) into a 
treatment-research study.  All subjects enrolled at the TRC receive medical monitoring and high-
quality treatment—at no cost.  Female-focused recruitment strategies, including direct appeals to 
female-medical specialties such as OB-GYN offices, has increased our ability to recruit female 
cocaine and alcohol dependent subjects. 
Prior to participating in treatment-research studies at the TRC, all subjects undergo a 
medical and psychosocial intake to determine health and potential eligibility for treatment in one 
of the TRC’s research programs.  Routine measures obtained on the first day the subject arrives at 
the TRC are a psychosocial history, medical history, and the Beck Depression Inventory (BDI). 
Before study-specific eligibility criteria are assessed, subjects are asked for their consent.  
At the consent session, all assessments, lab procedures and information on study medications are 
fully explained.  Subjects are given information about confidentiality, study payments and under 
what circumstances they may be prematurely discontinued from treatment.  Subjects are told that 
a blood alcohol concentration (BAC) reading will be required at each TRC visit, and that the 
reading must be below 0.02, otherwise the visit will be rescheduled.  If their BAC reading is 0.08 
or higher, they will be detained until arrangements are made for them to be escorted home or the 
reading decreases to an acceptable level (e.g., 0.02).   At the end of the session, subjects take a 
consent “quiz” that can be re-taken until all of the questions are answered correctly.  Subjects then 
give written consent and are given phone numbers of key project staff and a 24-hour emergency 
number.  After signing informed consent, subjects continue with screening assessments to 
determine if they meet eligibility criteria. 
Subsequent screening procedures include blood chemistry, CBC, urinalysis, psychiatric 
interview, assessment of baseline drug and alcohol use using the Timeline Follow Back, Addiction 
Severity Index. 
4.3.1 Genetics of Addiction 
The TRC has a Genetics Research Bank to collect and store samples from individuals 
participating in research studies at the University of Pennsylvania Treatment Research Center 
(TRC). Individuals providing blood samples will have screened and/or participated in various 
research studies focused on an addictive disorder. These samples will be used to study various 
candidate genes and/or whole genomes and their relationship to clinical and demographic data 
collected as part of the other research studies that the individual has participated. The Genetics of 

 
 
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Addiction study stopped recruitment on 01/07/2015. Persons participating in the intake process 
for research studies at the TRC are no longer eligible to sign a separate consent for the Genetics 
of Addiction study. Persons reporting for intake have usually undergone a telephone or in-person 
screening to see if they are eligible for ongoing studies at the TRC. Participants who signed 
consent for the Genetics of Addiction study during the recruitment phase had two vials of blood 
drawn to analyze their genotype, as outlined in the Genetics of Addiction protocol.  
This study (Varenicline for Cocaine) does not have any genetic hypotheses.  As such, the 
information obtained from the genetics blood bank will not be shared with the Principal 
Investigator of this study by Dr. Oslin, the Principal Investigator of the Genetics of Addiction 
study. As such, the below language (taken from study consent) addresses the non-linkage 
between the two studies: 
 
“In addition to your participation in this trial, you may have also consented to a 
separate study of the Genetics of Addiction.  If you consented to the Genetics of 
Addiction study, those results are separate from this trial and will not be 
combined with the results from this trial.    If you have any concerns about your 
participation in the Genetics of Addiction study, please discuss with the research 
staff.” 
 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Clinical Trial Discontinuation Criteria:  All randomized subjects are included in the 
intent-to-treat analysis.  All subjects who prematurely discontinue treatment will be scheduled for 
a final evaluation, the end-of-trial visit.  Subjects will also be given appropriate treatment referrals.  
Subjects are not dropped from all study activity unless they request they not be contacted, or the 
subject cannot be located for assessment.  Subjects will be informed at the consent session that 
medications may be discontinued due to: 1) Intolerable side effects; or 2) Extreme lab values with 
a repeat test.  In these two cases, the subjects may continue with the CBT part of the treatment, as 
well as receive medical attention.  Subjects will be informed at the consent session that he or she 
may be discontinued from all treatment due to: 1) Development or exacerbation of significant 
psychiatric or medical symptoms that necessitate inpatient admission or a more aggressive 
therapeutic intervention than provided by the protocol; these subjects would not be invited back to 
take study medication but will be followed for data collection and may remain eligible for 
psychosocial treatment; 2) A return to significant cocaine use or emergence of another substance 
abuse problem which necessitates inpatient admission or a more aggressive treatment than 
provided by the protocol; subjects who are admitted for inpatient stabilization for cocaine use may 
return for data collection and psychosocial treatment after discharge to complete the 12 week trial, 
but study medication will not be restarted if they miss more than two weeks of study medication; 
3) Incarceration > 1 week; subjects may return for data collection and psychosocial treatment after 
discharge to complete the 12 week trial but study medication will not be restarted if they miss more 
than two weeks of study medication 4) subject’s behavior compromises subject’s safety.  The 
reason the subjects are discontinued from medication and/or the clinical trial and any referrals 
made are documented in a Note to File found in the subject’s source document binder or medical 
chart.  Study medications will not be restarted in subjects missing more than two weeks of study 
medications because this would necessitate restarting the dose titration schedule and may result in 

 
 
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a significant confound in the analysis of medication response.  Varenicline can be abruptly stopped 
in patients without significant adverse effects. 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Standard procedures developed here at TRC are used to help locate missing subjects.  These 
include the identification and verification of home and work phone numbers, emergency contacts 
and collateral contacts.  Subjects who have missed an appointment are re-contacted initially by 
phone, then by letter and finally by registered mail.  Emergency and other collateral contacts are 
used when subjects themselves cannot be contacted. Contacts are attempted daily for a minimum 
of one week then less frequently by mail.  Subjects are not considered lost to follow up until the 
entire study is completed and the database is ready to be closed. 
 
5 Study Drug 
5.1 Description 
Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral 
administration. Following administration of multiple oral doses of varenicline, steady-state 
conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits 
linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of 
varenicline was virtually complete after oral administration and systemic availability was high. 
Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein 
binding of varenicline is low (≤20%) and independent of both age and renal function. 
 
Metabolism/Elimination 
The elimination half-life of varenicline is approximately 24 hours. Varenicline undergoes 
minimal metabolism with 92% excreted unchanged in the urine. Renal elimination of varenicline 
is primarily through glomerular filtration along with active tubular secretion possibly via the 
organic cation transporter, OCT2. 
 
Study medication will be prepared by the Research Pharmacist at the Hospital of the 
University of Pennsylvania by over-encapsulating varenicline 0.5 and 1.0 mg capsules. 
 
5.2 Treatment Regimen 
Study medication will be initiated in Week 2.  The research physician or nurse will explain 
the dosing regimen and subjects will be randomized to receive either varenicline or placebo.  The 
statistician will randomize subjects to either varenicline or placebo using a computer-generated 
program of urn randomization, based on specified criteria that are described below. 
The dose of varenicline will begin at 0.5 mg daily, and will be titrated up to the target daily 
dose of 2.0 mg/day at the start of the second week of medication (see Table 1). If adverse events 
occur, the physician or nurse may keep the dose the same or reduce to fewer pills.  If the side 
effects subside, subjects can be re-challenged or kept at a lower number of pills. During the last 
week of the medication phase of the trial, varenicline will be reduced to 1.0 mg daily.  

 
 
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Pharmacotherapy will be completed by the end of the 13th week.  If tolerated, subjects will be 
taking the maximum daily dosage (2.0 mg of varenicline or identical appearing capsules) for 10 
weeks (Weeks 3-12). 
 
Table 1.  Dosing Schedule (taken from package insert) 
Wk. 
Daily Dose 
2 (days 1-3) 
0.5 mg 
2 (days 4-7) 
0.5 mg BID (1.0 mg daily) 
3 
1.0 mg BID (2.0 mg daily) 
4 
1.0 mg BID (2.0 mg daily) 
5 
1.0 mg BID (2.0 mg daily) 
6 
1.0 mg BID (2.0 mg daily) 
7 
1.0 mg BID (2.0 mg daily) 
8 
1.0 mg BID (2.0 mg daily) 
9 
1.0 mg BID (2.0 mg daily) 
10 
1.0 mg BID (2.0 mg daily) 
11 
1.0 mg BID (2.0 mg daily) 
12 
1.0 mg BID (2.0 mg daily) 
13 
0.5 mg BID (1.0 mg daily) 
 
There have been no severe interactions noted between varenicline and any other drugs. 
Nonetheless, in the proposed study, weekly monitoring by a nurse or physician provides a safety 
net. We will be monitoring adverse events via self-reports, BAC readings, and liver enzymes 
collected routinely during the trials.  Side effects can be treated by lowering the dose of study 
medications or discontinuing the study medications when necessary.  The subject will be 
discontinued from medications if he or she has experienced a medication associated serious 
adverse event (SAE), cannot tolerate minimum dosages of study medication, or becomes pregnant.  
Any subject who is discontinued from the study medications can still complete the CBT portion 
of the treatment. If the subject reports an SAE, the subject will be followed until the event is 
resolved.  Federal, sponsor, and institutional guidelines are followed for reporting SAEs. 
 
Clinical Deterioration and/or Suicide Risk Management:  All of the investigators have 
had experience managing and referring subjects under these conditions. We follow the TRC’s 
standing emergency policy when managing clinical deterioration related to addiction or psychiatric 
symptomatology for all of our subjects.  At the weekly visit, subjects are evaluated for the presence 
or persistence of any symptoms indicative of clinical deterioration due to a rapidly increasing 
problem with cocaine use, drinking, and/or psychiatric symptoms, including suicidality. Between 
visits, subjects are instructed to contact their treating physician or an authorized research staff 
member in the event that disturbing symptoms become evident. In all cases, these subjects are 
immediately evaluated, and if deemed appropriate, are referred to clinical treatment.  If possible, 
they will be maintained in the trial as long as all it is deemed safe to do so.  Also, any additional 
treatment is recorded for data analysis purposes.  At any time, subjects who are severely suicidal 
or at high risk of medical or physical harm will be immediately discontinued from the trial.  All 
subjects who are discontinued from the trial are still encouraged to attend the end of treatment 
visit. 
 

 
 
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5.3 Method for Assigning Subjects to Treatment Groups 
 
Urn Randomization: We will use urn randomization to stratify subjects across the two 
experimental conditions.  In the randomization scheme, we will stratify subjects on 2 baseline 
variables: 1. Gender; 2. Cigarette smoking status. We have no reason to suspect gender differences 
to mediate outcomes; however, it certainly is possible, given our sparse knowledge about female 
alcohol and drug abusers.  Also, because we estimate that fewer than 30% of our final sample will 
be females, based on TRC census data over the past 5 years, it is imperative that we use gender as 
one of the urn variables in randomizing.   
5.4 Preparation and Administration of Study Drug 
Study medication will be prepared, stored and dispensed by the Research Pharmacist at the 
Hospital of the University of Pennsylvania.   Ken Rockwell can be contacted at 215-349-8817. 
5.5 Subject Compliance Monitoring 
 
Medication Adherence:  Medication adherence will be monitored via observed dosing at 
each study visit and by pill counts upon the weekly return of the blister card.  These will also serve 
as the basis for actively enhancing medication adherence done as part of Combine’s Medical 
Management procedures. Blister cards can be organized by row and column and clearly marked 
per daily dose.  The design of the HUP blister cards makes it easy to titrate the dosage up at the 
initiation of the trial.  Blister packs provide the subjects with easy access for viewing the number 
of pills missing vs. remaining for each day since each pill is individually packaged and daily 
dosages are clearly marked.  Subjects will be given one blister card each week and are asked to 
bring it with them at each study visit and to return it the following week.  Each blister card contains 
the dose per day for each of the seven days of the week.  Doses for a given day are designated in 
a single row, with rows numbered consecutively to represent the days of the week. 
We purposely chose not to use the Medication Event Monitoring system (MEMs) cap 
bottles to dispense medications in this study due to their prohibitive costs.  We chose not to use a 
riboflavin marker to measure adherence because riboflavin has been shown to be an unreliable 
indicator of compliance due to difficulty in determining visual thresholds for the presence/absence 
of riboflavin.  Therefore, we will use pill counts in the presence of a returned blister pack to 
secondarily assess medication adherence.  We reimburse the participant $5 for each blister card 
returned, empty or not.  We have been doing this for over 5 years, with our IRB’s approval.  This 
procedure has netted us 80-90% return of blister cards by our research participants. 
Subjects who are significantly noncompliant with treatment medication (indicated by less 
than 50% of doses taken) will be counseled by the nurse assigned to MM therapy.  If that does not 
result in improved medication compliance, these subjects will meet with the PI of the study for 
further counseling. 
5.6 Prior and Concomitant Therapy 
Concomitant medications will be recorded for 30 days prior to consent throughout the end of 
treatment phase.  Medications that will not be allowed during screening week and the 
randomization phase include antidepressants, antianxiety medications, antipsychotic medications, 

 
 
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naltrexone, disulfiram, modafinil, stimulants, anticonvulsants, benzodiazepines, haloperidol. 
Anticonvulsants (e.g., gabapentin) prescribed for pain will not be exclusionary.  
Additional psychosocial therapies, including self-help groups, will be allowed during the 
randomized medication phase, but will be measured using the Treatment Services Review (TSR). 
Subjects admitted to inpatient detoxification during the trial may be invited back to continue 
psychosocial treatment and medications as outlined in section 1.1.2 above. 
5.7 Packaging 
Study drug will be dispensed weekly. It will be dispensed in blister packs with each daily dose 
clearly marked. Blister packs will be labeled with the name and address of the research Pharmacy, 
the name and 24 hour phone number of the PI, subject initials, randomization number, name of the 
study drug, study week, and # of capsules and instructions.  Each row on the blister pack represents 
a day’s dose, with the two daily doses clearly identified. 
5.8 Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
Study drug is to be supplied by Pfizer or purchased and will be over-encapsulated by the 
Research Pharmacy at the Hospital of the University of Pennsylvania. The matching placebo will 
be produced and over-encapsulated by the Research Pharmacy at the Hospital of the University.  
All study medication will be stored and dispensed by the Research Pharmacy at the Hospital of the 
University of Pennsylvania. 
5.8.2 Storage 
Study medication will be stored at the Research Pharmacy at the Hospital of the University 
of Pennsylvania.  A portion of the packaged medication will be stored on-site in a locked cabinet 
in order to be available for participants in the treatment phase of the study. Per FDA guidelines, 
all study medication both on-site and at the pharmacy will be stored at 25°C (77°F) with excursions 
permitted to 15-30°C (59-86°F). 
5.8.3 Dispensing of Study Drug 
. 
After randomization, study drug will be dispensed to each subject according to his or her 
randomization number.  Medication will be dispensed by blister pack each week.  A pill count log 
will be maintained in each subject’s CRF indicating how many capsules were dispensed and how 
many collected at the end of the week.  A dispensing log will also be maintained at the Research 
Pharmacy. 
Regular study drug reconciliation will be performed to document drug assigned, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug reconciliation form, 
and signed and dated by the study team. 
5.8.4 Return or Destruction of Study Drug 
All unused study drug will be returned to the Research Pharmacy.  At the completion of the study, 
there will be a final reconciliation of drug obtained from the Research Pharmacy, drug consumed, 
and drug returned.  This reconciliation will be logged on the drug reconciliation form, signed and 

 
 
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dated.  Any discrepancies noted will be investigated, resolved, and documented prior to return or 
destruction of unused study drug.  Drug destroyed on site will be documented in the study files. 
 
6 Study Procedures 
 
DESCRIPTION OF INSTRUMENTS (in alphabetical order) 
 
1. 
Addiction Severity Index (ASI) (McLellan et al., 1992).  The ASI is a 45-minute interview 
which yields composite scores, ranging from 0 to 1, of problem severity over the past 30 days 
in 7 areas: medical, employment, drug use, alcohol use, legal, family/social, and psychiatric.  
Studies have shown moderate to excellent interrater and test-retest reliability.  The ASI will be 
used to characterize baseline demographic and drug use variables for each subject.  The 
composite scores will be used as secondary outcome measures. The ASI is administered 
research staff at Baseline, at Week 7 and at medication completion (Visit 40). 
2. 
Adverse Events (AE) Adverse events will be collected at every visit and recorded in the CRF.  
Severity, expectedness, relatedness to study drug, action taken, and outcome will all be 
recorded (Visits 1-40). 
3. 
Brief Substance Craving Scale (BSCS) (Somoza et al 1995).  This instrument is to be used 
to assess craving once weekly.  The instrument was designed by the Craving Subcommittee of 
the NIDA Medications Development Research Units (MDRU).  It is an expansion of the 
Cincinnati Craving Scale.  Reliability data for the intensity and frequency questions has been 
collected at the Cincinnati MDRU.  The questions regarding Length, Number and Time were 
added by the Subcommittee.  The BSCS will be administered weekly and at the end of the 
randomized medication phase (Visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40) 
4. 
Clinical Global Impression Scale (CGI) (Guy, 1976).  The CGI is a brief clinical rating of 
severity of illness (at time of interview) and global improvement (from admission) using a 7-
point Likert scale. The CGI is done by an observer (CGIO) and the subject (CGIS) to assess 
clinical progress, global improvement and to assess the severity of the subject’s illness at 
regular contacts over the course of the study.  The CGI is done once during baseline by the 
observer and subject, weekly during the medication phase of the trial by the observer and 
subject and  once at the end of randomized medication phase by the nurse or physician and 
subject, (Visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40). 
5. 
Clinical Institutes Withdrawal Assessment for Alcohol, Revised (CIWA-AR) (Sullivan and 
Sellers 1989).  The CIWA-AR is a valid and reliable measure of alcohol withdrawal symptom 
severity.  It will be used to verify the need for alcohol detoxification prior to randomization 
and to measure alcohol withdrawal symptom severity among subjects who relapse to alcohol 
use during the trial.  The CIWA-AR will be administered at least once during the baseline. 
6. 
Cocaine Craving Questionnaire (CCQ) (Tiffany et al. 1993) This instrument will be 
administered once weekly, and at the end of randomized medication phase, to specifically 
assess cocaine craving (Visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40). 
7. 
Cocaine Selective Severity Assessment (CSSA) (Kampman et al., 1998).  The CSSA is a 10-
minute, 18-item study personnel-administered cocaine withdrawal scale developed at the TRC.  
The scale measures items that commonly occur after abrupt cessation of cocaine use, including: 
cocaine craving, depressed mood, appetite changes, sleep disturbances, lethargy, and 
bradycardia.  Individual items are scored on a 0-7 scale and a total score is derived from a sum 

 
 
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of the individual item scores.  The CSSA has been found to be a reliable and valid measure of 
cocaine withdrawal symptoms. The CSSA will be administered by research staff at each visit 
during baseline, weekly during the medication phase of the trial and at the end of randomized 
medication phase (Visits 1, 2, 3, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40). 
8. 
Concomitant Medications (CONMEDS) Concomitant medications will be recorded starting 
from 30 days prior to consent to the end of the randomized medication phase.  They will be 
recorded weekly by the study nurse or physician, once at the end of randomized medication 
phase, and once at end of treatment (Visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40). 
9. 
Delay Discounting Questionnaire (Kirby & Marakovic, 1996) This questionnaire asks 
participants to repeatedly choose between two hypothetical monetary rewards: immediately 
available (smaller sooner rewards) and temporally delayed for time period between 10 and 75 
days (larger later).  The questionnaire allows for calculation of an indifference point, which is 
the value at which a participant switches from preferring the smaller sooner to the larger later 
reward.  This indifference point is a measure of impulsivity, and can be tracked through 
repeated administration of the Delay Discounting questionnaire to assess changes in 
impulsivity over time (Visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40). 
10. Fagerstrom Nicotine Tolerance Questionnaire (FNTQ 25) is a 5-minute, 8-item, self-report 
designed to measure physical dependence to nicotine.  The validity and reliability of this scale 
have been supported in numerous studies.  Scores range from 0 (no dependence) to 11 (high 
dependence).  A score of 8 or more is considered to be indication of high dependence and 4-7 
moderate dependence.  This questionnaire will be administered once in the screening weeks 
(Visit 1). 
11. Medical history & Physical exam (PE)  A complete medical history and physical exam will 
be conducted by the nurse or physician at Visit 1.  The physical exam will be repeated at visit 
40. 
12. Minnesota Cocaine Craving Scale (MCCS) (Halikas et al., 1991).  The MCCS is a valid and 
reliable measure of cocaine craving.  Craving is assessed over three dimensions, intensity, 
duration, and frequency and subjects are asked to evaluate their craving for the prior week.  
The MCCS will be administered at baseline, weekly throughout the medication phase of the 
trial, once at the end of randomized medication phase (Visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 
31, 34, 37, 40). 
13. Multiple Choice Procedure (MCP) (Griffiths, Troisi II, Silverman & Mumford, 1993)  This 
adaptation of the MCP asks participants to choose between a hypothetical static amount of 
cocaine and hypothetical variable amounts of money.  Repeated administrations of the MCP 
allow for assessment of changes in the relative reinforcing effects of cocaine over time, 
evidenced by shifts in how much participants are willing to “pay” for a static amount of 
cocaine   (visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40). 
14. Pill Count The number of capsules of study medication dispensed and the number returned 
each week will be recorded in the CRF (visit 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40). 
15. Structured Clinical Interview for DSM-IV (SCID) (First et al., 1996), Mini-International 
Neuropsychiatric Interview (MINI) (Sheehan et al., 2002), The substance abuse module 
(Module E) of the SCID-IV will be used to diagnose substance abuse problems. The major 
depressive episode modules (Modules A and B) of the MINI Plus will be used to diagnosis 
current and past episodes of major depression and current episodes of major depression with 
melancholic features.  Other lifetime DSM-IV Axis I and II diagnoses will be obtained from 
the MINI.  The SCID/MINI/MINI Plus will be done once during baseline to confirm diagnoses 

 
 
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of cocaine and alcohol dependence and determine if Axis I, Axis II or other substance disorder 
diagnoses are present.  Time of administration will be 45 minutes. The SCID/MINI/MINI Plus 
will be administered by a clinically-trained Diagnostic Interviewer. 
16. Timeline Follow Back Interview (TLFB) (Sobell and Sobell, 1995).  The TLFB is a 15-30 
minute, semi-structured interview adapted by our laboratory to collect information about daily 
cocaine, alcohol, and nicotine use.  Critical life events are reviewed retrospectively to prompt 
recall of cocaine use measured in days used and dollars worth of cocaine used. Nicotine use is 
measured by number of cigarettes (or other forms of tobacco) per day.  Cocaine, and nicotine 
use are recorded on a personalized calendar.  Other drugs and any days spent in a controlled 
environment are also recorded on the calendar.  The TLFB will be given by trained research 
staff at baseline to cover 3 months immediately preceding treatment entry and will be updated 
at each research visit to determine any time spent in a controlled environment and cocaine, 
nicotine, and other drug use during the period since the last visit.  The composite of these 
assessments will be additive over the course of the study so that we will have continuous data 
on cocaine and nicotine use (Visit 1 through 40). 
17. Treatment Group Prediction Form Integrity of the study blind will be evaluated by having 
the nurse or physician, therapist, research staff and subject predict which medication group 
assignment (active or placebo).  (Week 7 and Visit 40). 
18. Treatment Services Review  (TSR) (McLellan et al., 1992).  The TSR is a 5-minute interview 
given by the research staff to record the subject’s use of services received in 7 areas covered 
in the ASI since the last visit.  Test-retest reliabilities are high (McLellan et al., 1992a).  The 
measure is given during baseline week, weekly throughout the medication phase, at the end of 
randomized medication phase and at the end of treatment visit so that there is a continuous 
record of non-study treatment services throughout the trial (Visits 1,4,7,10,13,16,19,22,25,28, 
31, 34, 37, 40).  These data will be used to compare utilization of ancillary treatments during 
the trial in the varenicline and placebo groups. 
19. The Symptom Checklist 90 Revised  (SCL-90-R) (Derogatis, 1977) is a ninety item self 
report measure that measures psychiatric symptom severity on a 4 point scale from 0 “not at 
all” to 4 “extremely.”  Nine factor scores are generated including depression, anxiety, phobic 
anxiety, somatization, interpersonal sensitivity, paranoia, psychoticism, obsessive-
compulsive, and hostility.  This scale is a standard measure used clinically at the Treatment 
Research Center.  It has been shown to correlate well with clinician rated improvement and 
provides a measure of self-perceived symptom reduction. It will be administered at baseline 
and the end of the randomized medication phase (Visits 1 and 40). 
20. Risk Assessment Battery  (RAB) (Snider et al., 1994) is a 38 item self report questionnaire 
which assesses high risk behavior for exposure to the HIV virus.  The RAB yields drug, sex 
and total risk scores.  It will be administered at baseline and the end of the randomized 
medication phase (Visits 1 and 40). 
21. Hamilton Anxiety Rating Scale (Ham A)  This instrument will be administered during 
baseline and at the end of the randomized medication phase ( Visits 1 and 40) to assess changes 
in anxiety symptoms that occur during the trial. 
22. Hamilton Depression Rating Scale (Ham D) (Nordgren 1995, Hamilton 1967).  This 
instrument will be administered during baseline and again at the end of treatment to assess 
changes in depressive symptoms.  This version of the Hamilton Depression Scale is based on 
the Hamilton Rating Scale for Depression (HRSD-24).  Items 25 through 28 (Increased 
Appetite, Weight Gain, Hypersomnia, Social Withdrawal) have been added by the NIDA 

 
 
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Medications Development Division from various other scales believed to be pertinent to MDD 
research.  These have not been validated.  The additional items will be analyzed separately.  
This instrument will be administered at baseline and at the end of the randomized medication 
phase (Visits 1 and 40). 
23. Short Form-36 Health Status Questionnaire (SF-36) (Jenkinson, 1994).  The SF-36 is a 
10-minute, 36-item self-report of the subject’s quality of life.  Eight health concepts are 
assessed: 1) limitations in physical activities; 2) limitations in social activities due to physical 
or emotional problems; 3) limitations in activities due to physical problems; 4) bodily pain; 
5) general mental health; 6) limitations in activities due to emotional problems; 7) vitality; 
and 8) general health perceptions.  The SF-36 will be given once at baseline, at end of 
treatment (week 14). 
24. Weight and Vital Signs Body weight, temperature, pulse and blood pressure will be monitored 
weekly, and at the end of randomized medication phase (Visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 
28, 31, 34, 37, 40). 
 
Laboratory Measurements 
1. Breathalyzer  (BAL) Blood alcohol levels will be estimated at each study visit (1-40) by 
breathalyzer. 
2. Carbon Monoxide (CO) Expired carbon monoxide, a biomarker for very recent cigarette 
smoking will be assessed at each visit (1-40) by Bedfont CO monitor. 
3. Urine cotinine will be measured at each study visit (1-40) using NicCheck urinary cotinine 
dipstick testing.  Cotinine captures cigarette smoking within the past 48 hours. 
4. Electrocardiogram is a standard 12-lead ECG recorded once during baseline and one time 
at the end of randomized medication phase by the nurse or physician.  Any abnormal results 
are brought to the attention of the principal investigator or study physician (Visits 1, 40). 
5. Complete Blood Count and Blood Chemistry will be collected once at baseline and once 
at the end of the randomized medication phase by the nurse or physician and sent to an off-
site laboratory for examination.  The tests include glucose, uric acid, BUN, creatinine, glom 
filt rate, BUN/creatinine ratio, sodium, potassium, osmolality, albumin, bilirubin, alkaline 
phosphatase, LDH, AST (SGOT), ALT (SGPT), GGT, cholesterol, triglycerides, HDL 
cholesterol, VLDL cholesterol, LDL cholesterol, T. cholesterol/HDL ratio, Estimated CHD 
risk, WBC, RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, RDW and platelets.  Any 
abnormal results are brought to the attention of the principal investigator or study physician 
(Visits 1 and 40). 
6. Urinalysis will be collected once at baseline and once at the end of randomized medication 
phase by the nurse or physician and sent to an off-site laboratory for examination.  The test 
includes color, appearance, specific gravity, pH, protein, glucose, occult blood, ketones, 
leukocyte esterase, nitrite, bilirubin urobilinogen, and microscopic examination of urine 
sediment. Any abnormal results are brought to the attention of the principal investigator or 
study physician (Visits 1 and 40). 
7. Qualitative Benzoylecgonine Screens (UBT):  Qualitative urine benzoylecgonine levels 
will be obtained at each study visit using One Step Drug Screen Test Cards (Cliawaived) 
or tested at the Main Toxicology Laboratory at the Philadelphia VA Medical Center. 
8. Qualitative Urine Drug Screens (UDS): Qualitative (emit) urine toxicology of 
benzodiazepines, barbiturates, amphetamines, and opiates will be done weekly during the 
baseline phase, the medication phase of the trial and once at the end of randomized 

 
 
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medication phase (Visits 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40) at the Main 
Toxicology Laboratory at the Philadelphia VA Medical Center. 
9. Urine Pregnancy Test  (UPT): A specimen will be collected once at baseline, every four 
weeks during the randomized medication phase, and once at the end of randomized 
medication.  Samples will be tested at the Main Toxicology Laboratory of the Philadelphia 
VA Medical Center (Visits 1, 19, 40). 
 
Screening: Subject will have three screening visits.  The visits must be completed within a 
minimum of one week and a maximum of four weeks.  The screening period is referred to as 
“Week 1”. 
 
Regular Evaluation Visits:  Subjects will be in contact with the research staff three times 
weekly throughout the medication Phase of the study (weeks 2-13), preferably every Monday, 
Wednesday, and Friday (M,W,F).  A few basic measures will be taken at each visit, UDS for BE, 
breathalyzer, TLFB, and adverse event recording.  At the first evaluation visit each week, the 
following additional measures will be accomplished by research staff: Urine drug screen for 
benzodiazepines, barbiturates, opiates, marijuana, methadone, amphetamine, CSSA, Subject 
(CGIS), Treatment Services Review (TSR), Minnesota Cocaine Craving Scale (MCCS), and 
Cocaine Craving Questionnaire (CCQ). This will take about 45 minutes. At the first visit of week 
7 and week 13, research staff will administer the Addiction Severity Index (ASI) (about 20 
minutes) and obtain the Treatment Group prediction Form.  Each subject will meet weekly with a 
nurse or physician for MM sessions to assess clinical status, monitor vital signs and weight, 
dispense study medications, pill count, monitor concomitant medications, monitor adverse events 
and provide Clinical Global Impressions (CGI) ratings. This will take about 15-30 minutes.  The 
nurse or physician will also complete a Treatment Group Prediction Form at week 7 and visit 40. 
The subject’s individual therapist will complete the CGI weekly weeks 2-13 and complete 
the Treatment Group Prediction Form at week 7 and visit 40(about 3 minutes). 
 
End of Medication Phase Evaluations:  These will be done after the completion of Week 
13, or at the completion of the trial in participants who are discontinued from the trial prematurely. 
At this time, a nurse or physician will conduct the following procedures: vital signs and 
weight, physical exam, electrocardiogram, concomitant medications, adverse events, obtain blood 
samples for chemistry including liver function tests and CO2, CBC, obtain a urinalysis, CGI, pill 
count, and Treatment Group Prediction Form. 
Research staff will conduct the following procedures: breathalyzer, CO, cotinine, ASI, TSR, 
CSSA, CCQ, SCL-90-R, RAB, BSCS, CGI, MCCS, TLFB, UDS, UBT, UPT, and Treatment 
Group Prediction Form. A clinically trained diagnostician will conduct the Ham A and Ham D. 
This entire visit will take about 120 minutes. 
 
 
Psychosocial Treatment:  Subjects will receive weekly psychotherapy from week 2 through 
week 13.  This results in 12 individual, cognitive behavioral therapy (CBT) sessions, each lasting 
50 minutes, for each subject. 
CBT is based on general principles of social learning theory, which assume that disordered 
individuals have coping skill deficits that prevent them from managing high-risk situations.  CBT 
utilizes direct practice, role playing and fine-tuning of new coping skills to achieve treatment goals.  

 
 
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The CBT we will use is based on relapse prevention principles. We are currently using, as part of 
another study, Project MATCH’s CBT manual that Dr. Kathy Carroll has adapted for use in 
treating both cocaine and alcohol dependence (Kadden et al., 1992, Carroll et al., 1991, 1994).  We 
will follow this manual in all procedures.  We have had much experience with this manualized 
therapy as we have used it to treat over 300 cocaine and alcohol dependent subjects in two previous 
clinical trials. 
CBT will be provided by a clinician who will receive training and day-to-day supervision 
from Margo Hendrickson, the TRC’s Clinical Director.  All CBT visits will be audiotaped and a 
minimum of two treatment sessions (an early and later session) will be rated for clinician adherence 
to the respective treatment principles and therapeutic alliance.  Ms. Hendrickson is trained in CBT 
principles and is familiar with Dr. Carroll's manual.  She will provide the adherence ratings for the 
audiotapes.  We will use Dr. Carroll’s adherence checklists, which are written based on general 
principles of CBT and can be used in both core and elective sessions.  These tapes will also assist 
in the supervision provided to the clinician and reduce drift. 
Subjects will also receive once weekly Medical Management (MM)—an intervention 
developed as part of NIAAA’s COMBINE that provides advice and support from medical 
practitioners concomitantly with dispensing medications and checking safety and compliance. The 
main goal of the intervention is to increase medication compliance.  All subjects will receive 
regularly scheduled manualized adherence enhancement therapy for cocaine dependence.  The 
initial MM session is an hour; follow-up sessions last no more than 15-30 minutes. 
After the initial MM visit, subjects will meet with their nurse for 15-30 minutes for a total of 
12 visits, primarily to dispense varenicline and assess varenicline safety (adverse events), 
treatment adherence (pill counts and visit attendance), and drinking / cocaine use status.  The 
content of each visit is fully outlined in the MM manual (see appendix) and is briefly outlined in 
the following tables. 
 
Table 2. Medical Management (MM): Content of Initial Visit 
 
• Review with participant their biopsychosocial status, using the Clinician Report from the MM 
manual. 
• Discuss with participant the role of the MM clinician: Safety, Education, Support 
• Educate participant about his/her cocaine disorder and about the medication, i.e., varenicline 
• Record baseline safety information 
• Discuss importance of medication adherence --develop a plan for medication adherence 
• Encourage attendance at CBT therapy visits, MM visits and self-help support groups 
 
Table 3. Medical Management (MM): Content of Follow-up Visits 
• Brief check on medical functioning 
• Determine participant status re: using cocaine?  Medication taking? 
• Give support and advice based on participant status 
 
Nurse Recruitment and Training:  The Nurse will be responsible for interacting clinically 
with the subjects.  Training and supervision will focus on the clinical skills and pharmacological 
knowledge needed to manage individual cases within the parameters of MM.  The training will 
also aim to impart a high level of personal responsibility for the welfare of study subjects. 

 
 
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6.1 Visit 1 (screening) 
All screening procedures are to be completed prior to randomization (visits 1, 2, or 3).  They 
may not necessarily be completed at the exact visit noted below. 
Nurse or physician: 
1. Informed consent and consent quiz 
2. Medical history 
3. Physical Exam (PE) 
4. Vital signs weight (VITALS) 
5. Electrocardiogram (EKG) 
6. Concomitant medications (CONMEDS) 
7. Adverse Events (AE) 
8. CBC and blood chemistry including liver function tests (LFT) and CO2. 
9. Urinalysis (UA) 
10. Clinical Global Impression Scale, Observer (CGIO) 
11. Supplemental questions 
12. Clinical Institutes Withdrawal Scale for Alcohol Revised (CIWA AR) 
 
Research staff 
1. Breathalyzer (BAL) 
2. CO 
3. Cocaine Selective Severity Assessment (CSSA) 
4. Treatment Services Review (TSR) 
5. Minnesota Cocaine Craving Scale (MCCS) 
6. Cocaine Craving Questionnaire (CCQ) 
7. Fargerstrom Nicotine Tolerance Questionnaire (FNTQ) 
8. Brief Substance Craving Scale (BSCS) 
9. Multiple Choice Procedure (MCP) 
10. Delay Discounting Questionnaire (DD) 
11. Risk Assessment Battery (RAB) 
12. Symptom Checklist-90-Revised (SCL-90-R) 
13. Timeline Follow Back (TLFB) 
14. Urine drug screen other than cocaine (UDS) 
15. Urinary BE level (qualitative) 
16. Cotinine 
17. Clinical Global Impression Scale, Subject (CGIS) 
18. Urine pregnancy test (UPT)(females) 
19. Short Form Health Survey (SF-36) 
6.2 Visit 2 (screening) 
 
Research Staff 
1. CSSA 
2. BAL 
3. TLFB 

 
 
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4. UBT 
5. AE 
6. CO 
7. Cotinine 
 
Diagnostician 
1. Structured Clinical Interview for DSM-IV (SCID) / Mini International 
Neuropsychiatric Interview (MINI) 
2. Hamilton Anxiety Rating Scale (HAM A) 
3. Hamilton Depression Rating Scale (HAM D) 
6.3 Visit 3 (screening) 
 
Research Staff 
1. CSSA 
2. BAL 
3. UBT 
4. TLFB 
5. Addiction Severity Index (ASI) 
6. AE 
7. CO 
8. Cotinine 
 
6.4 First visit of each study week during randomized medication phase:  Visits 4, 
7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37 
 
All assessments may not be collected at the exact visits specified.  Assessments completed 
weekly will be collected on either the first, second, or third visit of the week.  Assessments not 
completed weekly must be completed within half of the time frame that exists before the next 
scheduled collection of the assessment. 
 
Nurse or physician 
1. Dispense study medications 
2. Medical Management session (MM) 
3. VITALS 
4. CONMEDS 
5. AE 
6. CGIO 
7. Pill count 
8. Treatment Group Prediction Form visit 19 
 
Research Staff 
1. CCQ 
2. CSSA 
3. CGIS 
4. TSR 

 
 
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5. MCCS 
6. BSCS 
7. MCP 
8. DD 
9. UDS 
10. CO 
11. Cotinine 
12. UBT 
13. BAL 
14. TLFB 
15. AE 
16. ASI at visit 19 
17. Treatment Group Prediction Form visit 19 
18. UPT at visit 19 (females) 
19. Any earned fishbowl draws completed and voucher earnings delivered 
 
6.5 Second visit of each study week during randomized medication phase:  Visit 5, 
8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38 
 
CBT Therapist 
1. CBT Psychotherapy 
2. CGIO 
3. Treatment Group Prediction Form at visit 20 
 
Research Staff 
1. UBT 
2. BAL 
3. TLFB 
4. AE 
5. CO 
6. Cotinine 
7. Any earned fishbowl draws completed and voucher earnings delivered 
 
6.6 Third visit of each study week during randomized medication phase: Visit 6, 9, 
12, 15, 18, 21, 24, 27, 30, 33, 36, 39 
 
Research Staff 
1. UBT 
2. CO 
3. Cotinine 
4. BAL 
5. TLFB 
6. AE 
7. Any earned fishbowl draws completed and voucher earnings delivered 
 

 
 
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6.7 End of Randomized Medication Phase:  Visit 40 
 
Nurse or physician 
1. PE 
2. VITALS 
3. EKG 
4. CONMEDS 
5. AE 
6. CBC and blood chemistry including liver function tests (LFT) and CO2. 
7. UA 
8. CGIO 
9. Pill count 
10. Treatment Group Prediction Form 
 
Research Staff 
1. CCQ 
2. CSSA 
3. CGIS 
4. TSR 
5. MCCS 
6. BSCS 
7. MCP 
8. DD 
9. RAB 
10. SCL-90-R 
11. UDS 
12. UBT 
13. BAL 
14. TLFB 
15. ASI 
16. Treatment Group Prediction Form (research technician and subject) 
17. UPT(females) 
18. Short Form Health Survey (SF-36) 
19. CO 
20. Cotinine 
 
CBT Therapist 
1. Treatment Group Prediction Form 
2. CGIO 
 
Diagnostician 
1. HAM A 
2. HAM D 

 
 
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7 Statistical Plan 
7.1 Sample Size Determination 
Power Analysis 
Based on the results of our pilot trial (Plebani et al., 2011), we use the method described 
by Diggle et al. (1994) to estimate power, assuming a compound symmetry covariance structure.  
We assume a Type-I error level (Alpha level) of 0.05. 
7.2 Statistical Methods 
Data Analyses: The data analyses will be performed by Dr. Kevin Lynch, the CSA 
Statistician, and his staff.  Prior to performing analyses, standard data screening/cleaning 
procedures will be applied (Tabachnik and Fidell, 2000).  These procedures will (1) screen the 
data for data-entry errors, (2) check for outliers, (3) assess the extent and pattern of missing data, 
and (4) check that appropriate assumptions of Normality are met whenever necessary.  Because of 
the size of the sample, it is unlikely that the randomization will result in significant imbalance of 
the distributions of demographic or other variables across the treatment groups. However, some 
additional covariates will be considered for inclusion in the analyses, to improve the precision of 
estimation for the treatment effects (Hauk et al., 1998).  In particular, we will consider covariates 
describing levels of alcohol and cocaine use prior to the study.  In all analyses, the assumptions 
underlying the application of all the statistical methods that are used will be examined, principally 
through the use of standardized residuals, influence diagnostics, and graphical displays. 
 
Primary Hypotheses: 
Hypothesis 1:   The outcome of interest is cocaine use, measured with three-times-weekly 
urine benzoylecgonine (BE) levels and self-reports of use from the Time Line Follow Back, 
combined to yield daily use/no-use indicators for each study day.  We will be examining both point 
prevalence and continuous cocaine abstinence.  A generalized estimating equations (GEE) model 
will be used to model the effects of group and time on the log-odds of use across the treatment 
period. 
The explanatory variables in these models will be a factor for group, and terms for time 
effects, and group by time interactions.  In these models, we are interested in weekly rates of use, 
so time will be coded as weekly units, with up to seven daily indicators providing replications 
within a week.  These models will provide valid estimates of the regression parameters (i.e. group 
and time effects) without requiring that the correlation between a subjects repeated urine drug 
screens is known.  It is usually enough to specify a simple “working” correlation matrix, which 
need not agree with the true correlation matrix underlying the repeated measures.  This provides a 
“robust” approach, but usually at the cost of larger sample sizes, and the lack of simple methods 
for comparing different models.  Based on the work of Lipsitz,(Lipsitz et al., 1994), the sample 
size in this study will be more than adequate for the method to be valid.  We will follow the 
recommendations of Pan and Connett (Pan and Connett, 2002) in selecting the working correlation 
matrix, and the recommendations of Pan (Pan, 2001a) in using an adjusted AIC statistic (his QIC 
statistic) to compare models. These analyses will be performed using PROC GENMOD in SAS. 
 
Secondary Hypotheses: 
Hypothesis 2 (effects of compliance with medication): The main analyses will be 
performed using an intent-to-treat (ITT) approach, so subjects will be analyzed according to their 

 
 
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assigned treatment, without reference to the level of treatment they actually receive.  It is likely 
that some subjects will not comply with their assigned treatment, and that this non-compliance will 
be related to subject characteristics, and/or to unmeasured factors related to outcome.  This non-
compliance can diminish the extent to which the treatment groups are comparable with respect to 
measured and unmeasured variables.  In this study, the placebo group will be unable to obtain 
varenicline, so non-compliance will probably result in underestimated treatment effects. We will 
gather information on compliance, and use it in further analyses to assess the sensitivity of the ITT 
analyses to the presence of non-compliance.  The information will be obtained from weekly pill 
counts, on the basis of self-report and examination of blister packs. 
Initially, we will use these sources to determine whether each subject has complied with 
their assigned medication for at least 80% of the trial. We will then include a binary variable 
indicating “80%” compliance in the analyses described above for Hypothesis 1, both as a main 
effect and as an interaction effect with varenicline group. 
We will also use the sources described above to define variables representing 
compliance/non-compliance over each the 12 weeks of the treatment period.  For the primary 
outcomes, we will perform extensions of instrumental variable regression analyses presented by 
Nagelkerke et al. (Nagelkerke et al., 2000).  Here the instrumental variable is randomization and, 
under certain assumptions, will control for unmeasured bias when estimating the effect of 
varenicline relative to placebo in those who comply with their assigned treatment.  These analyses 
will permit a more complete examination of the time-varying effects of compliance across the 
treatment period. 
 
Hypothesis 3: The CCQ and MCC scales will provide weekly measures of cocaine 
craving.  The scales provide a seven and a six-category Likert response, respectively, and it is 
likely that we will collapse some adjacent categories prior to the analyses, and regard the responses 
as ordinal.  The analyses for these hypotheses will be perfectly analogous to those for Hypothesis 
1, except that mixed-effects models for ordinal responses will be used (Hedeker and Mermelstein, 
2000).  These analyses will be performed using PROC NLMIXED in SAS. 
Hypothesis 4:  The CO and cotinine measures will be used to analyze dynamic changes in 
cigarette smoking, both in isolation and as they relate to cocaine use. 
Other Analytic Issues: 
 
Missing Data:  For the longitudinal analyses described above, drop out from treatment and 
occasional missing daily use indicators will lead to incomplete data. The mixed effects and GEE 
models described above can make use of all available data provided by subjects, but the inferences 
drawn from them will be unaffected by the missing data only if the missing data can be regarded 
as ignorable, in the sense of Laird (Laird, 1988).  In the current setting, this is implausible, and 
further analyses of the sensitivity of the mixed-effects and GEE models to the presence of missing 
data will be required.  For the urine toxicology data, a simple approach, of frequent use in the 
current setting, is to assume that any missing urines are positive.  While this is a reasonable starting 
point for analyses, it almost certainly overestimates the rates of use, and underestimates the 
variability about those rates, and further investigation through more formal analyses is required. 
We will use selection models to examine the effects of missing data (Kenward, 1998, Rotnitzky et 
al., 1998).  We will explicitly model the probability of drop out at a time point as a function of 
baseline characteristics and responses at previous time points, using a logistic regression model, 
and incorporate the predicted probabilities into the main analysis.  Any attempt to model the drop 

 
 
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out process requires us to make modeling assumptions about it, none of which can be tested on the 
observed data.  While this was originally seen as a controversial aspect of the approach (Diggle 
and Kenward, 1994), it has become standard practice to perform the analyses under a range of 
different assumptions, and to assess the sensitivity of the results to them (Rotnitzky et al., 1998). 
 
Additional Analyses:  We will also collect and analyze some additional measures, of 
withdrawal severity, general clinical improvement (CGI), and external treatment (TSR).  These 
variables are intended to provide a description of change in these areas across the course of the 
study.  They will be used in analyses addressing possible mechanisms of treatment process, and 
will be included as time-varying covariates in the longitudinal analyses described above.  Because 
we have no a priori hypotheses on their likely influence, and because there are selection issues 
regarding the interpretation of post-randomization change, we regard these analyses as exploratory 
and as hypothesis-generating for future studies. 
7.3 Subject Population(s) for Analysis 
• All-treated population:  Any subject randomized into the study that received at least one 
dose of study drug 
8 Safety and Adverse Events 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should be 
regarded as adverse events.  Abnormal results of diagnostic procedures are considered to be 
adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is: 
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, drug overdose 

 
 
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or abuse, a seizure that did not result in in-patient hospitalization, or intensive treatment of 
bronchospasm in an emergency department would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events. 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the 
period from the initiation of any study procedures to the end of the study treatment visit.   
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that meet 
the definition of an adverse event must also be recorded and documented as an adverse event. 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) that 
the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor of any death or adverse 
event occurring at any time after a subject has discontinued or terminated study participation that 
may reasonably be related to this study.  The sponsor should also be notified if the investigator 
should become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study. 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of 
the following conditions is met: 
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• 
The abnormality suggests a disease and/or organ toxicity 
• 
The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in this 
protocol.  Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported 
as an adverse event in the following circumstances: 

 
 
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• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study. 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study personnel must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the appropriate adverse 
event electronic form.  All clearly related signs, symptoms, and abnormal diagnostic procedures 
results should be recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course 
of each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation should be recorded and reported immediately. 
8.3 
Reporting of Serious Adverse Events 
8.3.1 Study Sponsor Notification by Investigator 
A serious adverse event must be reported to the study sponsor within 24 hours of the event.  
The investigator will keep a copy of an SAE report form on file at the study site.  Report serious 
adverse events by phone and/or facsimile to: 
 
Kyle M. Kampman, M.D. (Principal Investigator / Medical Director) 
215 746 2764 
 
 
At the time of the initial report, the following information should be provided: 
• Study identifier 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether 
study 
treatment 
was 
discontinued 
• The reason why the event is classified as 
serious 
• Investigator 
assessment 
of 
the 
association between the event and 
study treatment 
 
As information regarding the SAE becomes available, the investigator must provide further 
information on the serious adverse event in the form of a written narrative.  This should include a 
copy of the completed Serious Adverse Event form, and any other diagnostic information that will 

 
 
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assist the understanding of the event.  Significant new information on ongoing serious adverse 
events should be provided promptly to the study sponsor. 
8.3.2 IRB Notification by Investigator 
Reports of adverse events that are both unexpected and study drug related must be 
submitted to the IRB in real-time (weekly). These AEs will be recorded on the subject’s AE Log 
and documentation of IRB notification will be kept in the regulatory binder. Reports of all serious 
adverse events (including follow-up information) that are unexpected and study drug related must 
be submitted to the IRB within 10 working days.  Copies of each report and documentation of IRB 
notification and receipt will be kept in the regulatory binder.  
8.3.3 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of the drug as soon as 
possible but no later than 7 calendar days from the sponsor’s original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found to fit the 
criteria for reporting, the study sponsor will submit the adverse event in a written report to the 
FDA as soon as possible, but no later than 15 calendar days from the time the determination is 
made. 
8.4 
Unblinding Procedures 
 
Integrity of the Blind:  All research staff will be blind to the medication status until the 
end of the study.  A statistician will work with the research pharmacist at HUP in setting up the 
urn randomization sequences, and will ensure that the codes linking subject’s ID numbers to 
treatments are secured in an opaque envelope that will be maintained in a locked drawer in the 
research pharmacy.  If a subject is prematurely discontinued from the trial, all attempts will be 
made to not break the blind.  If an emergency necessitates that the blind be broken, only the 
pharmacist will have access to the blind to do so.  He will be given the name of the staff who have 
authority to request that the blind be broken (Dr. Kampman or the TRC Doctor-On-Call ).  The 
HUP pharmacist can be reached 24 hours a day by beeper and can access a subject’s code rapidly.  
If the study blind is broken for any subject this will be documented in the subject’s medical chart. 
8.5 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will 
include a regular assessment of the number and type of serious adverse events. 

 
 
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9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
 
The most significant risks to the subjects are those that would follow any breaches in 
confidentiality and the disclosure of clinical information.  While we recognize the potential 
severity of these risks we also do not want to overstate this risk.  Currently there are no known 
uses for information that may be obtained from this study.  
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data 
are contained in source documents.  Examples of these original documents and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
9.3 Case Report Forms 
The research data for this project will be gathered using the CSA's direct-entry data system, and 
will be stored on the DMU network. Interview data and self-report data are entered directly onto 
computers at the research sites, by research staff and study subjects respectively. Field validation 
(e.g. no out of range or otherwise invalid responses will be accepted) and form validation (e.g. 
logically impossible responses to different questions will not be accepted) are built into this entry 
process. 
Research Staff will be present with the subject through the entire assessment, and will review each 
instrument as it is completed. On completion of this review, research staff will transmit the data 
(in 128-bit encrypted form) over the Internet to the DMU data servers. After a series of online 
reviews, the data is archived on the servers. No identifying information is stored on the DMU 
servers. Only certain members of the DMU staff have permission to modify the archived data. 
Audit logs record any modification to the original entry. Various levels of password protection 

 
 
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allow different members of the research team appropriate levels of access to the data. The various 
levels of access are decided by the PI, in consultation with Mr. Petro, DMU Director, prior to the 
initiation of the study.  Mr. Petro will be responsible for working with the project staff to ensure 
the integrity of the data entry process, throughout the course of the study. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal of clinical development of the investigational product.  These documents should be retained 
for a longer period if required by an agreement with the sponsor.  In such an instance, it is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained. 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Purpose 
The investigator will allocate adequate time for monitoring this study.  The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. The 
monitoring of a clinical trial is necessary to ensure the protection of the subject’s rights, the 
safety of subjects enrolled in the trial and the integrity and quality of the resulting data.  This 
monitoring section details the Case Report Form (CRF) and source data verification of efficacy 
and safety parameters, the frequency of monitoring visits, regulatory document review, drug 
accountability and compliance review.  Monitoring will be conducted according to the 
University of Pennsylvania Sponsor-Investigator Standard Operating Procedures.   
 
10.1.a Trial Management  
  
 Projected Timetable: 
 
Each participant will be enrolled in the trial for 13 weeks.  With an N of 200 participants, and 
projected enrollment of 4 participants per month, we expect to complete the study within 5 years (60 
months). Below is the proposed timeline for the study: 
 
Study months 1-3: (Hire and train personnel, submit regulatory documents, prepare for 
study initiation; 
Study months 4-52: Recruit participants, collect data; 
Study months 52-54: Data collection for last enrolled participant; 
Study months 55-60: Data analysis and manuscript preparation. 
Recruitment rate: 4-6 participants per month will be recruited, with a recruitment target of 
60 subjects per year (36 subjects for Year 1). 
 
 
 

 
 
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TARGETED/PLANNED ENROLLMENT: Number of Subjects  
Ethnic Category  
Females  
Males  
Total 
Hispanic or Latino  
 
10 
30 
40 
Not Hispanic or Latino 
40  
120 
160 
Ethnic Category: Total of All Subjects 
50 
150 
200 
Racial Categories 
 
 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
38 
113 
151 
White 
12 
37 
49 
Racial Categories: Total of All Subjects 
50 
150 
200 
 
10.1.b Data Management and Analysis  
 
Data Acquisition 
 
Data will be collected by trained study staff with standardized forms using only a study 
number and initials to identify the participant.  A code that links the participant to the study will 
be kept confidential by the study team in a password protected secure database.  The clinical 
research coordinator and fellow staff members will be responsible for collecting and checking all 
clinical data.  This includes ensuring that all fields are completed appropriately, that the clinical 
database is complete and accurate and all corrections are done according to GCPs.  Any 
inconsistencies/deviations will be documented and reviewed by the PI.   
All data collection is HIPAA compliant. The TRC supports the appropriate privacy of all 
clinical and research data collected as part of any study. We follow Penn’s policy in the use and 
disclosure of protected health information in research in a manner that respects the patient’s 
privacy in accordance with the “Privacy Rule” promulgated under the Health Insurance 
Portability and Accountability Act (HIPAA) and other applicable laws.  All staff receive 
appropriate HIPAA training.  All participants sign a HIPAA-authorization form, receive a copy 
of this form, and receive a notice of Penn’s privacy practice.  HIPAA signed forms are retained 
in locked file cabinets with participants’ source documents.  
Data analysis will be conducted by the Center statistician, Dr. Kevin G. Lynch, with 
assistance from the PI. 
 
Data entry methods 
 
A computerized data entry and management system will be developed during the initial 
project months by the Center’s data management unit (DMU).  All data will be entered into this 
web-based entry system by the research staff.   
 
A closed and password protected data entry system has been designed so that only the 
responsible data entry person and the DMU supervisor can enter and/or edit data and this can be 
done only be using the programs and/or utilities available on the menu system.  Data and user 
stamping are used to create an audit trail. Range checks, review screens, and various error 
trapping routines are built into the system as quality control procedures.  All possible relevant 

 
 
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information on the forms is pre-coded and field-validated.  All specific instructions and choices 
are provided for all data forms. All errors on source documents must be initialed and dated.  The 
DMU director will be responsible for working with the project staff to ensure the integrity of the 
data entry process. The investigator or study research staff can request the data at any point 
during the study so that audits of the study’s current data input can be conducted and the data’s 
integrity assessed.  
 
After entry of all data in the Case Report Forms, these source documents will be kept on 
location until study closeout at which point they may be moved to a secure long-term storage 
facility.  
 
Mechanisms of Action: 
 
In our pilot study, we found significant differences between the longitudinal time course of 
the vareniclinine and placebo groups on the MCP. In addition to the analyses on the CCQ and 
MCC scale described above, we will also test for longitudinal differences on the Cocaine 
Selective Severity Assessment (CSSA), and also on alcohol craving as measured by the Penn 
Alcohol Craving (PACS) (intensity, frequency and duration subscales). To examine whether 
change in any of these measures is related to change in cocaine use, we will run further analyses 
where these scales are included as time varying covariates in models for cocaine use. We will 
also perform cross-sectional and longitudinal mediation analyses (MacKinnon, 2008), using 
these scales as possible mediators. 
10.1.c Quality Assurance Plan 
 
Procedures in place to ensure the validity and integrity of the data 
 
A closed and password protected data entry system has been designed so that only the 
responsible data entry person and the DMU supervisor can enter and/or edit data and this can 
be done only be using the programs and/or utilities available on the menu system.  Data and 
user stamping are used to create an audit trail.  
 
Procedures to guarantee the accuracy and completeness of the data collected 
 
The clinical research coordinator and fellow staff members will be responsible for 
collecting and checking all clinical data.  This includes ensuring that all fields are completed 
appropriately, that the clinical database is complete and accurate and all corrections are done 
according to GCPs. Range checks, review screens, and various error trapping routines are 
built into the system as quality control procedures.  All possible relevant information on the 
forms is pre-coded and field-validated.  All specific instructions and choices are provided for 
all data forms. All errors on source documents must be initialed and dated after correction. 
 
10.1.d Study Monitoring Plan 
 
 Monitor Selection and Training 
One primary monitor will be assigned for this trial and will be responsible to complete 
the monitoring process.  The monitor will be a Research Coordinator who is independent 

 
 
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from the trial and the study team.  A CV for the monitor will be obtained and updated 
annually.  The CV will be kept on file in the Sponsor section of the Regulatory Binder to 
document the qualifications of the monitor. To train the independent Monitor, the Principal 
Investigator and the Research Coordinator actively overseeing this trial will schedule a 
monitoring training session to discuss the protocol, case report forms, the informed 
consent, and the monitoring plan. In addition a monitoring manual will be created, which 
includes the complete protocol with the approved informed consent form, approved CRF, 
and this monitoring plan. 
 
Study Initiation  
 
The Principal Investigator will be responsible for assuring through personal contact 
between the co-investigators, the monitor and the clinical staff that each clearly understands 
and accepts the obligations incurred in the undertaking of this clinical trial.  The Principal 
Investigator will ensure that the clinical staff fully understand the nature of the protocol and 
the requirements for an adequate and well-controlled study; the obligation to conduct the 
clinical investigation in accordance with the applicable federal regulations; the obligation to 
obtain informed consent in accordance with 21 CFR Part 50; the obligation to obtain IRB 
review and approval of a clinical investigation before the investigation may be initiated; and 
will ensure a continuing review of the study by the IRB in accordance with 21 CFR Part 56. 
A check list containing the elements of study initiation as described in the CFR and ICH 
GCPs will be completed by the study staff prior to the first the monitoring visit and placed in 
the Sponsor section of the Regulatory Binder.   
 
Monitoring Visits 
 
Monitoring Flow Diagram 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
1st 
Monitoring 
Visit 
Subsequent 
Monitoring 
Visits 
5th 
Monitoring 
Visit and 
Study 
Closeout 
→→→
→→→
▪ When first two 
subjects enrolled 
have completed 
▪ 2nd occurs when 
approximately 
25% of total 
enrollment is 
reached 
▪ 3rd occurs when 
approximately 
50% of total 
enrollment is 
reached 
▪ 4th occurs when 
approximately 
75% of total 
enrollment is 
reached 
 
 
▪ 5th occurs 
when 100% of 
enrollment is 
reached 
▪ Visit to be 
conducted 
within 3 months 
after the last 
subject has 
completed the 
study.  Will also 
serve as the 
Closeout Visit. 

 
 
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Frequency 
 
Enrollment will be complete when 200 subjects are enrolled into the trial.  Enrollment for 
this study means when a participant is found to be eligible and is started on the study 
medication. Approximately 4 subjects will be enrolled per month.  After the study 
initiation visit, further monitoring visits will be conducted periodically throughout the 
study as described below.  (Note: The specific data to be reviewed at each visit is 
indicated in section 7.3.2) 
 
• The first independent monitoring visit will occur when the first two subjects have 
completed the study. 
 
• The second independent monitoring visit will occur when 25% of the subjects have 
been enrolled.   
 
• A third independent monitoring visit will be conducted when approximately 50% 
of the subjects have been enrolled.   
 
• A fourth independent monitoring visit will be conducted after 100% of the subjects 
have been enrolled.  This visit may be conducted after the subjects have completed 
the study and can also serve as the close-out monitoring visit (as required by GCPs 
and described in section 7.6). 
Data Review for Moderate Risk Study 
 
The monitor will complete: 
▪ The Compliance Assessment Checklist, developed by the University of 
Pennsylvania Office of Human Resources, will be used for monitoring the Regulatory 
Binders.  
▪ The monitor will also ensure that the CRFs are being completed and finalized in the 
DMU in a timely manner. 
 
All CRFs for the first 2 subjects will be 100% source data verified.  
 
In addition, the CRF for one in every cohort of 5 subjects will be 100% source data 
verified.   
 
If a greater than 10% error rate is noted during the data review, the monitor will source 
data verify 100% of the data on a larger sample at the following two monitoring visits. 
 
Additional subjects/events to be reviewed: 
a. All subjects who are discontinued from the protocol due to adverse events will 
be reviewed for key safety and efficacy data.  
b. All subjects who are discontinued because they are “lost to follow-up” or for 
“other” reasons, their data will be reviewed for 100% source data verification. 

 
 
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The following variables will be 100% source data verified for all subjects enrolled in the 
study. 
• Screening Consent (if applicable) 
• Informed Consent 
• Inclusion/Exclusion Criteria 
• Drug Accountability 
• Serious and Non-Serious Adverse Events 
• Prohibited concomitant medications  
 
Regulatory Documents Reviewed 
 
The Regulatory Documents will be maintained in the Regulatory Binder.  The Regulatory 
Binder will be reviewed by the monitor in an ongoing manner at the time of each 
monitoring visit.  The monitor will review the regulatory binder for completeness and 
will assure that the CRFs are being completed in a timely manner.      
Documentation of the Monitoring Visit 
 
 
 
 
 

 
 
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Monitoring Log 
 
The monitor is required to sign and date the monitoring log documenting the dates of the 
monitoring visit.  The Monitoring Log will be filed in the Regulatory Binder. 
 
Monitoring Report 
 
All monitoring visits will be documented on the Monitor’s Report and Visit Checklist.    
The original report for each visit will be filed in the Sponsor section of the Regulatory 
Binder. 
Close Out Visit 
 
The monitor will conduct the Close Out Visit at the time of the third monitoring visit and 
within 3 months after the last patient has completed the study. 
 
The following activities will be completed by the monitor to close out the study: 
• Ensure all data has been reviewed and collected; 
• Ensure all outstanding queries are answered; 
• Confirm all Serious Adverse Events, MedWatch Reports and IND Safety Reports, if 
applicable, have been reported to the IRB(s), NIDA, DSMB and FDA (if applicable); 
• Review the Regulatory documentation and Subject Files for completeness and 
compliance with GCP and all applicable federal regulations; 
• Ensure initial and revised 1572 forms were submitted to the IRB (if applicable); 
• Ensure all protocol violations were submitted to the IRB; 
• Ensure that all continuing review reports were submitted to the IRB;  
• Perform drug accountability and destroy any unused drug and 
• Review requirements for record retention with the investigator and the clinical staff. 
 
Compliance Monitoring Review 
 
Good Clinical Practice oversight monitoring is conducted for randomly selected studies 
by the Office of Human Research (such as Informed Consent Monitoring or Monitoring 
Plan implementation). In addition, studies may be randomly selected and reviewed by 
other designated offices in the School of Medicine for compliance aspects.   
 
Medical Monitoring  
 
Patient safety will be monitored continuously by the Principal Investigator or the 
designated, qualified Medical Monitor.  Additionally, the DSMB, as noted below, will 
provide guidance and input on an annual or as-needed basis.  The Principal Investigator 
has the front-line responsibility for identifying potential adverse events experienced by 
study participants, adjusting the intervention accordingly and reporting the experience.  
The Sponsor/Investigator is responsible for tracking these reports and relaying them as 
required to the FDA, IRBs and other investigators. 

 
 
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The potential risks of this study include adverse reactions to varenicline, potential 
adverse interactions between varenicline and cocaine and the small risk incurred by 
venipuncture.   In prior research with varenicline for cocaine dependence conducted here and 
elsewhere there have been no reported SAEs from varenicline, and the side effects have not 
required withdrawal of therapy; thus, preliminary data suggest minimal potential risk of 
varenicline treatment for cocaine dependent subjects. Subjects are asked about AEs at each study 
visit.  Any reported AEs are assessed by the Nurse Practitioner or Study Doctor and followed 
until resolution.  
 
Data Safety Monitoring Board (DSMB) 
 
Members and Affiliation 
 
A safety monitoring board has been established at the Center for the Studies of Addiction with 
the following purpose (according to NIDA guidelines): to assure that the safety of study subjects 
is protected while the scientific goals of the ongoing studies are being met. Specifically, the 
DSMB is charged with monitoring the safety of participants and the quality of the data, as well 
as the appropriate termination of studies either when significant benefits or risks have been 
uncovered or when it appears that a clinical trial cannot be concluded successfully. The DSMB 
consists of:  
 
• David Oslin, M.D., chair, a faculty member within the Department of Psychiatry at the 
University of Pennsylvania.  
• Kevin Lynch, Ph.D. (senior statistician),  
• David Metzger, Ph.D. and  
• Daniel Weintraub, M.D., who are faculty members of the University of Pennsylvania 
School of Medicine, Department of Psychiatry,  
• Deb Dunbar, MSN, CRNP and  
• Cynthia Clark, PhD, MSN, CRNP, who are medical professionals for the University of 
Pennsylvania Center for Studies of Addiction.  
 
Frequency of the DSMB  
 
This study will be reviewed by the DSMB on an annual basis (unless more frequent 
meetings are deemed necessary). Safety data will be reviewed annually by the Data 
Safety Monitoring Board. A Data Safety Monitoring Board report will be issued to the 
NIDA project officer with the annual progress report.  
 
Conflicts of Interest 
 
All board members meet NIDA requirements regarding background and experience, and 
none will have ethical conflicts, including financial interest related to study outcome.  
Individuals invited to serve on the board disclose any potential conflicts in writing.   
 
 
 
 
 

 
 
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Protection of confidentiality 
 
The DSMB is changed with the same confidentiality requirements as all other personnel 
involved in the study conduct. 
 
Monitoring activities (initial and ongoing study review) 
 
The DSMB reviews the study prior to study start, and again annually at DSMB meetings. 
 
Content of the DSMB Report 
 
An annual data safety monitoring report will be submitted to the NIDA project officer 
and will include, but may not be limited to, a synopsis of the trial, socio-demographic 
characteristics of subjects accrued, retention and disposition of subjects, quality assurance 
issues regulatory issues, and reports of AEs/SAEs.   
 
When the current study is reviewed, the meeting will open with a report on the trial 
status, followed by a closed session under the direction of Dr. Oslin. Issues related to 
recruitment, subject safety and efficacy, whether the primary study question is being 
answered, conflict of interest, confidentiality, and ongoing study review (including AEs, 
SAEs, and regulatory issues) are assessed.  Following each DSMB meeting, Dr. Oslin 
will make recommendations, and a final report (edited by all Board members) will be 
prepared and submitted to the NIDA PO, the Penn IRB, and (if required) the FDA 
according to each bodies reporting requirements.  
 
Drug Accountability 
 
Study drug for this trial consists of 2.0 mg of varenicline and matching placebo.  
Study drug will be supplied by Pfizer or purchased and will be stored at the University of 
Pennsylvania’s Investigational Drug Services located at 3600 Spruce Street, ground floor 
of the Maloney Building, Philadelphia Pa 19104.  The study drug needed for patient visits 
will be picked up on a weekly basis from the IDS.  All used and unused blister packs will 
be returned to the IDS upon completion of the study.  Once the monitoring of final drug 
accountability has taken place, all unused medication will returned to Pfizer or destroyed. 
The monitor will perform 100% drug accountability in an ongoing manner at the time of 
each monitoring visit.  The monitor will confirm the receipt, use and return of drug. 
 
Trial Efficacy  
 
Efficacy analyses will be conducted at the trial end.  There are no plans for interim analyses. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the 
EC/IRB, the sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory documents, 

 
 
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data collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study 
conduct.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the investigator and a copy of this decision will be provided to the sponsor before commencement 
of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  See Attachment 1 for a copy of the Subject Informed Consent Form.  
This consent form will be submitted with the protocol for review and approval by the IRB for the 
study.  The formal consent of a subject, using the IRB-approved consent form, must be obtained 
before that subject is submitted to any study procedure.  This consent form must be signed by the 
subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent. 
12 Study Finances 
12.1 Funding Source 
The National Institute on Drug Abuse is funding this protocol. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor 
prior to participation in this study.  All University of Pennsylvania investigators will follow the 
University conflict of interest policy. 
12.3 Subject Stipends or Payments 
Subjects will be financially compensated for travel and completing assessments. They will receive 
$5 for each visit for visits 1-3 ($15 total), a maximum of 438 voucher draws for attendance for 
visits 4-39 and $25.00 for visit 28. In addition, they will receive $5.00 for each medication pack 
they return. Maximum total compensation available for study participation is $900: $60 for 

 
 
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compliance, $15 for visits 1-3, $25 for final visit, and a maximum of $800 for attendance, prorated 
if the subject discontinues treatment or the study ends earlier than planned. Because compensation 
is based on fishbowl draws, the average payment earned will be closer to $300. Subjects will 
receive a maximum of $162 for travel in payments of $2 (last visit) or $4. 
 
The schedule of voucher draws for attendance is shown in Table 2 below. 
 
 
 
 
 
 
 
 
 
 
 
Table2  
 
 
 
 
 
 
 
 
 
Attendance 
Voucher 
Draw 
Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
 
 
7 
 
 
Visit 
1 
2 3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 
21 
Draws  
 
 
5 
5 
5 
6 
6 
6 
7 
7 
7 
8 
8 
8 
9 
9 
9 
10 10 
10 
Bonus  
 
 
 
 
5 
 
 
5 
 
 
5 
 
 
5 
 
 
5 
 
 
5 
Total 
Draws 
 
 
 
5 
5 
10 6 
6 
11 7 
7 
12 8 
8 
13 9 
9 
14 10 10 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 8 
 
 
9 
 
 
10  
 
11  
 
12  
 
13  
 
14  
 
Visit 
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40  
 
Draws 11 11 11 12 12 12 13 13 13 14 14 14 15 15 15 16 16 16  
 
 
Bonus  
 
5 
 
 
5 
 
 
5 
 
 
5 
 
 
5 
 
 
5 
 
 
 
Total 
Draws 
11 11 16 12 12 17 13 13 18 14 14 19 15 15 20 16 16 21  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Draws:  438 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The fishbowl will be filled with the following tokens as shown in Table 3 below: 
 
 
Number of tokens 
Value 
1 
$50 
2 
$25 
30 
$5 
267 
$1 
200 
“Good job” 
 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, 
nor any of the information provided by the sponsor for the purposes of performing the study, will 
be published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study. 
 
 
 

 
 
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15 Attachments 
 
1. Consent Form 
2. Monitoring Plan 
3. Study Procedures Flowchart/Table 
4. Varenicline prescribing information