Does CERC-501 Attenuate Stress-precipitated Smoking Lapse?
Phase: PHASE2
Conditions: Smoking
Sponsor: Yale University

Study Protocol, including Statistical Analysis Plan 
 
Official Title: 
Does CERC-501 Attenuate Stress-precipitated Smoking Lapse? 
Brief Title: 
“Does CERC-501 Attenuate Stress-precipitated Smoking Lapse?” (Sherry McKee, 
PhD, PI) 
ClinicalTrials.gov ID: NCT02800928 
Protocol Date: Most recent IRB approval—5/4/18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol and Statistical Analysis Plan for 
“Does CERC-501 Attenuate Stress-precipitated Smoking Lapse?” 
(NCT02800928): Sherry McKee, PhD, PI (Yale University) 
Scientific Background 
There is a significant unmet medical need for treatments that reduce the abuse and 
dependence of addicting drugs, including tobacco, alcohol, cocaine and opiates.  In recent 
years, opiate antagonists such as naltrexone and nalmefene have been shown to be effective 
treatments for alcohol and opioid abuse.  The effects on tobacco users is equivocal, with well-
established effects in short-term laboratory studies of subjective effects, but lack of clear 
sustained effect on abstinence, perhaps due to the chronic negative effects of mu opioid 
receptor blockade. 
Accumulating evidence indicates that selective antagonism of kappa-opioid receptors (KORs) 
may provide therapeutic benefit in the treatment of depression.  A therapeutic role for KORs in 
major depressive disorder (MDD) is based upon an emerging scientific literature showing that 
KORs and the endogenous ligand dynorphin are highly expressed within the prefrontal cortico-
striatal loop, which mediates reward and affective states.1  KOR antagonists have been shown 
to block stress-induced potentiation of cocaine and conditioned place preference, an animal 
model of drug relapse. 
CERC-501 (previously known as LY2456302) is a high-affinity, selective KOR antagonist being 
developed for the treatment of substance abuse and MDD, by blocking aversive signaling 
cascades in the brain triggered by chronic psychological or physical stress.   
In a mouse model of precipitated nicotine withdrawal, CERC-501 decreased anxiety-like 
behavior, somatic signs of withdrawal and hyperalgesia.  However, the effects on anxiety and 
pain behavior had a U-shaped dose response curve, suggesting that doses that selectively block 
KOR will have the greatest overall effect on symptoms clinically. 
In three previous human trials, CERC-501 has been shown to be safe and well tolerated at single 
oral doses up to 60 mg.  At multiple daily doses of 10 mg or less, CERC-501 provides substantial 
blockade of KOR as assessed in positron emission tomography (PET) imaging studies with 
minimal effect on mu opiate receptors as assessed by fentanyl-induced miosis. 
The current study will evaluate the effect of CERC-501 on the latency to start smoking and the 
number of cigarettes smoked during the smoking self-administration period after a 18-hour 
period of abstinence.  Subjective measures of cravings, positive and negative mood, and 
withdrawal symptoms will also be assessed.   
 

Study Objective 
The primary objective of this study is to: 
To demonstrate that CERC-501 10 mg/day compared to placebo will increase the ability to 
resist smoking, and reduce subsequent ad-lib smoking following overnight nicotine deprivation 
and personalized stress imagery in subjects who are heavy smokers. 
 
Study Design and Methods 
This is a double-blind, placebo-controlled, two-period, cross-over design examining 10 mg/day 
CERC-501 compared to placebo in subjects who are cigarette smokers currently not seeking 
treatment for tobacco use disorder, who currently smoke at least 10 cigarettes per day.  Half of 
the subjects in each group will receive CERC-501 10 mg first in Period 1 and the other half will 
receive placebo first in Period 1.  Each subject will “crossover” to the opposite treatment during 
Period 2.  The crossover design (within-subject analysis) allows the subject to be their own 
control.  Efficacy for CERC-501 on smoking behavior will be assessed in two ways:  1) crossover 
comparison of CERC-501 10 mg versus placebo; 2) parallel comparison of CERC-501 10 mg 
versus placebo in Period 1.  Gender will be a stratification variable and approximately 50% of 
the sample will be female. 
Sequence 1: CERC-501 10 mg for Period 1 and placebo for Period 2 
Sequence 2: Placebo for Period 1 and CERC-501 10 mg for Period 2 
After the screening period, subjects will be randomized in a 1:1 manner to one of two 
sequences (CERC-501 [10 mg] followed by placebo or placebo followed by CERC-501 [10 mg]).  
Subjects will return to the clinic daily Monday through Friday for supervised study drug 
administration.  On Saturday, Sunday, and holidays the subject will self-administer the study 
drug. All efforts will be made to have subjects come in for daily medication visits, but if a 
subject is unable to return for supervised study drug administration, they will be allowed to 
self-administer the drug. Each period of the crossover treatment consists of a 7-day out-patient 
treatment period followed by a single in-patient testing day on Day 8.  Subjects will participate 
in a laboratory session following the McKee Smoking Lapse Test2 and be discharged from the 
Hospital Research Unit (HRU) to undergo approximately 7 (+3)-day washout period followed by 
the second period of the crossover design and approximately 7-day follow up visit. 
Each laboratory session will consist of an overnight nicotine deprivation period, followed by 
personalized imagery (stress).  After the imagery procedure, subjects will have the option of 
initiating a tobacco self-administration session or delaying initiation by 5-minute increments for 
up to 50 minutes in exchange for monetary compensation.  Subsequently, the tobacco self-
administration session entails a 1-hour period in which subjects can choose to smoke using a 
smoking topography system.  Primary outcomes measures include the time to the first cigarette 

(i.e., ability to resist smoking) and the number of cigarettes smoked.  Subjects complete a 
follow-up appointment (approximately 7 +3 days from the second lab session) to evaluate the 
durability of effects.  
 
Eligibility Criteria 
Inclusion Criteria 
1. 
Provides written informed consent and agrees to complete required clinic visits 
2. 
Male or female 21 to 60 years of age inclusive 
3. 
Body mass index (BMI) 18.5 to 40 kg/m2 inclusive 
4. 
Smokes at least 10 cigarettes per day on average for the past 6 months  
5. 
Fagerstrom score ≥3 at screening  
6. 
Currently not seeking smoking cessation therapy  
7. 
Urine dip test for cotinine concentration >150 ng/mL 
8. 
In otherwise good general health without any unstable medical conditions (as 
determined by medical history, medication history, physical examination, 10- or 12 lead 
ECG, vital signs, and clinical laboratory testing)  
9. 
Able to read, write, and speak English 
10. 
Females must be either:  
a. 
Post-menopausal (amenorrhea for at least 12 consecutive months), surgically 
sterile -or- 
b. 
Women of childbearing potential (WOCBP) must meet the criteria below: 
i. 
Uses an acceptable double-barrier method of contraception as 
determined by the Investigator -and-  
ii. 
Is not lactating, has a negative serum beta human chorionic gonadotropin 
pregnancy test at screening and a negative urine pregnancy test prior to 
dosing on Days 1 and 8 of each treatment period.   
11. 
Male subjects must agree to use a condom if partner is of childbearing 
potential 
 
Exclusion Criteria 
1. 
Have used tobacco or other nicotine containing products other than cigarettes (e.g., 
nicotine patches, pipe, cigars, snuff, chewing tobacco or e-cigarettes) within the past 30 
days 
2. 
Any substance use disorder other than nicotine or caffeine as assessed by the 
Structured Clinical Interview-IV Axis I Disorders (SCID) for Diagnostic3 and Statistical 
Manual of Mental Disorders (DSM)4  
3. 
Current neurological conditions that interfere with study conduct, assessment or 
treatment in any significant fashion 
4. 
Any lifetime history of bipolar I, II; schizophrenia or any other psychotic disorders; 
personality disorders, impulse control disorders as assessed by the SCID-IV 

5. 
Current psychiatric conditions that interfere with study conduct, assessment, or 
treatment in any significant fashion, such as major depressive disorder (MDD), eating 
disorders, post-traumatic stress disorder, etc. We will screen for worsening of 
symptoms of depression and/or suicidality at each medication appointment and lab 
sessions by having participants complete the Beck Depression Inventory (BDI) and the 
Columbia-Suicide Severity Rating Scale (C-SSRS)5. If there is a worsening of symptoms of 
depression and/or suicidality, the participants will speak a licensed psychologist for 
evaluation. 
6. 
Recent active or past history of gastric disease such as peptic ulcer disease, gastritis, 
upper gastrointestinal bleeding, or any gastrointestinal malignancy or precancerous 
condition  
7. 
Active, comorbid disease that might limit the ability of the subject to participate in the 
study as determined by the Study MD (i.e., poorly controlled diabetes mellitus, 
congestive heart failure, etc.) 
8. 
Clinically significant clinical laboratory test taken during screening  
9. 
Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2 times 
the upper limit of normal (ULN)  
10. 
Human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C positive as determined 
by serology testing at Screening 
11. 
Positive ethanol breath test at screening or prior to dosing on Days 1 and 8 of each 
treatment period   
12. 
Positive urine drug test at screening or and/or prior to dosing on Days 1 and 8 of each 
treatment period except for cannabis 
13. 
History of severe allergies or multiple adverse drug reactions  
14. 
Known hypersensitivity to CERC-501  
15. 
Current use of a proton pump inhibitor or histamine 2 blocker 
16. 
Use of any investigational medication within 2 months prior to the start of this study or 
scheduled to receive an investigational drug other than the study drug during the course 
of this study  
17. 
Current use of any psychoactive medications including: antipsychotics, benzodiazepines, 
mood stabilizers, selective serotonin reuptake inhibitor/serotonin norepinephrine 
reuptake inhibitor (SSRI/SNRI) or other antidepressants mood stabilizers 
 
Statistical Considerations 
PRIMARY AIM 1. Using a double-blind, placebo-controlled parallel-group design, this Phase II 
study will randomize 20 daily smokers to either 10 mg/day CERC-501 or placebo (n=10 per 
group). Following titration to steady state levels, we will evaluate medication effects on stress-
induced changes in smoking behavior in the laboratory.  Primary Hypothesis 1. During the 
laboratory component, 10 mg/day CERC-501 compared to placebo will increase the ability to 
resist smoking, and reduce subsequent ad-lib smoking following overnight nicotine deprivation 
and personalized stress imagery. Linear mixed models with medication condition (10mg/day or 

0mg/day) as a within subject factor will be used to evaluate, in turn, time to smoking, and 
amount smoked collected in the laboratory. 
 
References 
1. 
Carlezon WA, Jr., Beguin C, DiNieri JA, et al. Depressive-like effects of the kappa-opioid 
receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp 
Ther. 2006;316(1):440-447. 
2. 
McKee SA, Weinberger AH, Shi J, Tetrault J, Coppola S. Developing and validating a 
human laboratory model to screen medications for smoking cessation. Nicotine Tob Res. 
2012;14(11):1362-1371. 
3. 
First MB, Spitzer, R.L., Gibbon, M., & Williams, J.B.W. Structured Clinical Interview for 
DSM-IV Axis I Disorders. Washington, D.C.: American Psychiatric Press; 1997. 
4. 
Association AP. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
(DSM-IV). Washington DC. 1994. 
5. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents 
and adults. Am J Psychiatry. 2011;168(12):1266-1277. 
6. 
Dunnett CW. A multiple comparisons procedure for comparing several treatments with 
a control. J. Am. Stat. Assoc. 1955;50:1096-1121.