Phase-II Clinical Trial Evaluating Guanfacine for Smoking Cessation
Phase: PHASE2
Conditions: Smoking Cessation
Sponsor: Yale University

STUDY PROTOCOL INCLUDING STATISTICAL ANALYSIS PLAN 
 
OFFICIAL TITLE: Guanfacine Clinical Trial for Smoking Cessation 
 
BRIEF TITLE: Guanfacine Clinical Trial for Smoking Cessation (Sherry McKee, PhD, PI) 
 
CLINICALTRIALS.GOV ID: NCT02051309 
 
PROTOCOL DATE: October 7, 2021 
 
 

Identifying effective medications for the treatment of tobacco dependence remains a high priority as the 
vast majority of smokers fail to maintain long-term abstinence even with FDA approved 
pharmacotherapies. One promising, yet relatively unexplored avenue for medication development for 
smoking cessation are medications which target stress-reactivity. Several lines of evidence suggest that 
stress is a primary mediator of smoking maintenance and relapse. Preclinical research demonstrates 
that noradrenergic pathways are involved in stress-induced reinstatement to nicotine, as well as 
nicotine-related reinforcement and withdrawal, and that their manipulation may be of potential 
therapeutic benefit for smoking cessation. 
Guanfacine is an alpha2a adrenergic receptor agonist known to attenuate stress-induced reinstatement 
to alcohol and other drugs of abuse in preclinical studies. Guanfacine rescues the prefrontal cortex from 
detrimental effects of stress and improves working memory, attention, and behavioral control. In a 
study evaluating 3mg/day guanfacine for smoking cessation, we demonstrated that guanfacine was well 
tolerated, attenuated the effects of stress on smoking, reduced smoking-related reinforcement, 
improved cognition, and significantly reduced smoking during a brief treatment phase. 
 
STUDY OBJECTIVE 
To conduct a Phase II clinical trial evaluating the efficacy of guanfacine for smoking cessation. Using a 
double-blind, placebo-controlled, parallel group design, we randomized adult daily smokers to 
guanfacine (6mg/day ER, or placebo) combined with brief behavioral support for an 8-week treatment 
period.  
 
STUDY DESIGN AND METHODS 
This Phase II, clinical trial is a double-blind, placebo-controlled, parallel group study. Adult daily smokers 
motivated to quit smoking were be randomized to guanfacine (6mg day ER) or placebo Sex will be a 
stratification variable (50% female). Following eligibility screening and randomization, participants were 
titrated to steady state medication levels over a 3-week period. Participants completed an 8-week 
treatment period combining medication with brief behavioral support and were followed 6 months 
post-treatment to assess the durability of medication effects. The primary outcome measure was rates 
of prolonged smoking abstinence at the end of the 8-week treatment phase.  
 
ELIGIBILTY 
Minimum Age: 18 Years   
Maximum Age: 65 Years   
Sex: 
All   
Gender Based:   
Accepts Healthy Volunteers: 
Yes   
Criteria: 

Inclusion Criteria: 
Age 18-65 
Able to read, write and comprehend English 
Smoker 
Able to take oral medications and willing to adhere to a medication regimen 
Provide evidence of a stable living residence in the last 2 months, have reasonable transportation to the 
study site, and have no plans to move within the next 3 months or unresolved legal problems 
Exclusion Criteria: 
Any significant current medical conditions that would contraindicate smoking 
Current Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) abuse or dependence of other 
substances, other than nicotine dependence or alcohol abuse 
Positive test results at intake appointment on urine drug screen for illicit drugs 
Past 30 days use of any psychoactive drugs including anxiolytics and antidepressants 
Women who are pregnant or nursing 
Suicidal, homicidal or evidence of current mental illness such as schizophrenia, bipolar disorder or major 
depression, or anxiety disorders 
Meeting DSM-IV criteria for current attention deficit hyperactivity disorder (ADHD) 
Individuals who are currently taking medications known to be effective for smoking cessation or are 
regular users of other tobacco products in the past 30 days 
Only one member per household can participate in the study 
Specific exclusions for administration of guanfacine not already specified include: 
EKG evidence at baseline screening for any clinically significant conduction abnormalities or arrhythmias 
Known intolerance for guanfacine or any alpha blocker 
History of fainting, syncopal attacks 
Heart failure or myocardial infarction 
Impaired liver (as indicated by aspartate aminotransferase (AST), alanine aminotransferase (ALT) >3x 
normal) 
Renal function (as indicated by estimated creatinine clearance <60cc/min) 
Treatment with any antihypertensive drug or any alpha-adrenergic blocker 
Use of any central nervous system depressant (e.g., phenothiazines, barbiturates, benzodiazepines) 

Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin), 
or consumption of grapefruit juice 
Subjects may not have donated blood in the past 8 weeks or have been involved in other investigational 
studies that involve substantial blood draws or medications unknown to us 
 
 
STATISTICIAL CONSIDERATIONS 
PRIMARY HYPOTHESIS: Guanfacine vs placebo will increase rates of prolonged abstinence during weeks 
3 to 8 of the 8-week treatment period. Logistic regression was used to evaluate medication effects on 
the abstinence outcome.