Clinical trial NCT01953432
Conditions: Cocaine Dependence
Keywords: Cocaine-Related Disorders Cocaine Doxazosin Cardiovascular Agents Antihypertensive Agents Adrenergic alpha-1 Receptor Antagonists Adrenergic alpha-Antagonists Adrenergic Antagonists Molecular Mechanisms of Pharmacological Action Neurotransmitter Agents Therapeutic Uses Pharmacologic Actions Substance-Related Disorders
Sponsor: VA Office of Research and Development
Start date: 2014-04-01; Completion date: 2017-10-01
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cocaine use disorders affect approximately 1.5 million Americans annually. Currently, there are no US Food and Drug Administration approved medications for treatment of cocaine dependence; however, both animal and human studies suggest that medications affecting the noradrenergic system can reduce cocaine craving and use. The investigators will study the effect of doxazosin, an alpha-1 adrenergic antagonist, in reducing cocaine use and anxiety symptoms among cocaine-dependent individuals. In addition, the investigators will identify genetic subpopulations of participants who preferentially respond to the medication.

Detailed description:
The noradrenergic system, especially the alpha 1-adrenergic receptor, may play an important role in cocaine addiction in humans. Doxazosin is a long-acting and selective alpha 1-adrenergic receptor blocker, which inhibits the binding of norepinephrine to alpha receptors in the autonomic nervous system. This study will evaluate the efficacy of doxazosin in reducing cocaine-using behavior in treatment seeking cocaine-dependent individuals, and will guide future pharmacotherapy trials using Doxazosin or related alpha 1 receptor antagonists for treatment of cocaine addiction.

This 12-week double-blind, placebo controlled clinical trial will provide treatment for cocaine-dependent patients and includes a 8-week maintenance medication trial (weeks 3-10). At the end of this period, subjects will have a 2-week study medication taper (weeks 11-12). Qualifying subjects will be randomized to receive Doxazosin up to 8 mg/day or placebo.

At the beginning of week 1, participants will receive Doxazosin, or placebo according to their randomized assignments, and are maintained on these agents through week 12. At the end of the study (weeks 11-12), participants will undergo discontinuation from active/inactive medication over a 2-week period. Subjects who wish to be transferred to an appropriate treatment program or research program will be referred to upon request, during the study weeks 11-12.

Arms: arm 1: Doxazosin is a long-acting and selective alpha 1-NE blocker, which inhibits the binding of norepinephrine to alpha receptors in the autonomic nervous system. arm 2: Matched placebo daily dosing.
Interventions: intervention 1: Doxazosin intervention 2: Placebo
Intervention descriptions: intervention 1: Doxazosin is initiated at 2 mg/wk, and titrated up to a maximum of 8 mg/day over approximately 4 weeks. Participants will be maintained on 8mg daily dosing until week 13. The subjects will undergo the discontinuation from the study medication during weeks 14 -15. intervention 2: Matched placebo daily dosing

Protocol documents:
Prot_SAP_000.pdf: 
Pharmacogenetic Trial of Noradrenergic Medication for Treatment of Cocaine Abuse 
 
NCT01953432 
 
March 14, 2019 


Title 
Pharmacogenetic Trial Of Noradrenergic Medication for Treatment of 
Cocaine Dependence 
Protocol # 
H-32926, Baylor College of Medicine IRB
PI 
Daryl Shorter, MD
Grant # 
VA-funded CDA
 1 of 5 
Background and Objectives 
Cocaine use disorders are a significant cause of morbidity and mortality throughout the 
world. Cocaine has been shown to significantly worsen symptoms of hyperarousal among 
Vietnam combat veterans with post-traumatic stress disorder (PTSD), a disorder which 
affects approximately 14% of all previously deployed U.S. military personnel. Noradrenergic 
antagonism reduces cocaine use.  Noradrenergic treatment for cocaine use can also reduce 
anxiety (PTSD) symptoms.  
Original goals of proposed research were: (1) To investigate the intersection between 
cocaine dependence and anxiety disorders such as PTSD, given the common involvement 
of the noradrenergic system in the neuropathogenesis of these disorders; (2) To apply 
pharmacogenetics to identify subpopulations of cocaine dependent individuals that respond 
preferentially to pharmacologic treatments affecting the noradrenergic system.  
However, due to a reduced sample size from 150 to 43 individuals (see Data Analysis 
section), the final goal was reduced to only determining whether Doxazosin was an effective 
agent in reducing cocaine use. No further level of analysis was possible due to the reduced 
sample size.   
Data Analysis 
In our original proposal we anticipated randomizing N = 150 in a 1:1 ratio to two conditions 
(n = 75 per condition).  However, due to significant difficulties in recruitment in this 
population, total recruitment goal was reduced to 43 individuals with approximately equal 
distribution into active vs placebo arms for this study. Analysis will be made via a Bayesian 
analysis using a posterior predictive distribution.  
Rather than serving as the definitive trial of doxazosin for treatment of cocaine use disorder, 
the aim of this CDA was to examine whether or not the compound warrants further 
investigation in a larger scale, phase IIb/III trial.  Developing effective pharmacotherapy 
requires incremental investigation of biologically plausible treatments based on 
systematically accruing data.  Bayesian statistical inference provides a principled approach 
to answer this question.  Bayesian statistical reasoning lends itself particularly well to 
evaluating evidence in this context.  Indeed, addressing the so-called “Pipeline Problem” in 
developing clinical applications, the FDA has indicated that Bayesian statistics offers one 
avenue of improved methodological efficiency.i,ii,iii,iv,v,vi   Decision-making based on an initial 
trial of a compound for a new indication is assisted by estimates of the probability of an 
effect of some specified magnitude.  These statements, not part of the conventional, 
Frequentist statistical lexicon, are accessible via Bayesian approaches, even with small 
sample sizes.vii,viii
Strengths of the Bayesian analysis are as follows: 
1) Present the strengths of using a Bayesian approach to obtain probabilistic estimates of
the effect sizes that exist, given our current data.
2) Stipulate prior distributions for analysis of the current data (prior to examining the data).
These priors will include: a) weak, diffuse priors and b) empirically-based informative priors
derived from a sample drawn from the same general population.


Title 
Pharmacogenetic Trial Of Noradrenergic Medication for Treatment of 
Cocaine Dependence 
Protocol # 
H-32926, Baylor College of Medicine IRB 
PI 
Daryl Shorter, MD 
Grant # 
VA-funded CDA 
 
 
 2 of 5 
 
 
3) Stipulate a decision-rule that, prior to examining the data, will articulate the necessary 
threshold of evidence that will warrant further consideration of the current test compound in 
future trials. This decision-rule requires two parts: a) specification of an effect that would 
merit continued investigation, and b) specification of the posterior probability that this effect, 
or one larger, exists that would be sufficient to warrant future trials.  The decision rule we will 
initially propose to the DSMB is that if, after analysis with empirically-derived informative 
priors, the drug compound (doxazosin) demonstrates a posterior probability >0.66 (2 in 3 
chance) of a >15% increase in sustained 2-week abstinence at the end of treatment, then 
the drug warrants further investigation.   
 
Risk/Benefits Ratio 
The primary benefit of participation in this study is the potential for reduction of cocaine use 
through the study medication as well as through access to the guided cognitive behavioral 
therapy (CBT) option. If the treatment is found to be effective, other individuals with similar 
problems may benefit from the findings of this study. The psychological and laboratory 
assessments confer minimal risks and these are minimized through confidentiality 
procedures and the use of skilled personnel to administer the assessments. The medication 
treatment confers potential risk, but Doxazosin has been found to be safe in previous 
studies. Careful screening of physical health prior to study entry and close daily monitoring 
of patients during the study should reduce these risks. This proposed study may help to 
develop new and more effective treatments for stimulant dependence. Given that the risks 
are managed appropriately and the societal benefits are substantial, the ratio of this study 
appears greatly weighted towards benefit. 
 
Procedures 
Recruitment will be by word-of-mouth and fliers posted in VA clinics. Interested candidates 
will be scheduled for a phone screen with a qualified investigative staff member and receive 
an explanation of the study purpose and requirements in lay language. The study 
procedures will select individuals more likely to comply with study requirements by requiring 
subjects to attend clinic visits and submit a minimum number of urine samples during the 
screening period. During the initial interview, the interviewer will not ask questions in a 
manner that reveals the eligibility criteria for study entry. If still interested in participating 
after receiving an explanation of the study, candidates will be given an opportunity to review, 
inquire about, and sign and date the study informed consent form (ICF). Any candidate who 
has difficulty understanding the information contained in the ICF will reread the 
misunderstood portion(s) of the consent and discuss it with a trained and qualified research 
staff member until s/he shows complete understanding of the information discussed in the 
consent form, and may thus give full consent. Any candidate who is unable to demonstrate 
understanding of the information contained in the ICF will be excluded from study 
participation. Candidates who are excluded, or who decline participation, will be given 
referrals to substance abuse treatment programs such as the VA. 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
Subject inclusion/selection criteria: 1) Signed informed consent form and HIPAA 
authorization form 2) Subject is cooperative, understands the risks and benefits, and is 
willing and able to adhere to study requirements. 3) Any race or ethnic origin 4) Diagnosis of 
cocaine-dependence according to DSM-IV criteria 5) Between the ages of 18 and 64 6) 


Title 
Pharmacogenetic Trial Of Noradrenergic Medication for Treatment of 
Cocaine Dependence 
Protocol # 
H-32926, Baylor College of Medicine IRB 
PI 
Daryl Shorter, MD 
Grant # 
VA-funded CDA 
 
 
 3 of 5 
 
Must be current users of cocaine with self-reported use of cocaine within the last 90 days, or 
at least one cocaine-positive urine during screening. Women of childbearing age are eligible 
to be included in the study if they have a negative pregnancy test at screening, agree to 
adequate contraception to prevent pregnancy, to have monthly pregnancy tests, and they 
understand the risk of fetal toxicity due to medication. 8) Must be in good general health as 
determined by self-report and/or CPRS-based medical history, general clinical examination 
conducted by a study physician, and lab tests. HIV testing will be recommended but is not 
required for participation in this study. 9) Motivated to discontinue or reduce cocaine use 
during the period of the study, as evidenced both by the judgment of the Investigator or 
designee and by the subject’s compliance level with the requirement for attendance at clinic 
visits, such that weekly urine sample requirements for inclusion criteria are fully met. 
 
Exclusion Criteria: 
Subject Exclusion Criteria: 1) Current diagnosis of other drug dependence, especially 
alcohol or benzodiazepine dependence, or abuse (other than cocaine, tobacco, or 
cannabis). 2) Significant medical conditions (e.g., major cardiovascular, renal, endocrine, 
hepatic disorders) such as abnormal liver function (with laboratory findings of SGOT or 
SGPT greater than three times normal), hypotension, a current cardiac condition that in the 
opinion of the investigator would contraindicate Doxasozin treatment, and those having a 
high risk of cardiovascular disease, seizure disorders, or another significant underlying 
medical condition which would ontraindicate Doxazosin treatment. 3) Lifetime schizophrenia, 
bipolar disorder, or other psychotic disorders (excluding substance-induced psychotic 
disorders). 4) Actively considering plans of suicidality or homicidality 5) Women planning to 
become pregnant or breastfeed during the study, refusal to use a reliable form of birth 
control, or refusal of monthly pregnancy testing. 6) Subjects who are prescribed certain anti-
hypertension drugs (i.e. doxasozin) will be excluded because these medications may 
interact with Doxazosin’s brain effects in reducing cocaine abuse.7)Subject has participated 
in another clinical trial or received any other investigational compound within 7 days prior to 
being randomized into this study These criteria will be assessed through a comprehensive 
evaluation, including complete physical, neurological, and clinical psychiatric examinations. 
Routine laboratory studies will include CBC, BUN/creatinine, serum glucose, electrolytes, 
liver function tests, pregnancy test, urine toxicologies, and ECG. Based on the ECG general 
medical history and physical exam, those having a high risk of cardiovascular disease will 
be excluded from participation. A physician will examine each subject and review the 
laboratory data and ECG. Results of the evaluation will be made available to the subject or 
subject's personal physician upon request. If any results are positive, subjects will be 
referred to their personal physician or to a local clinic of their choice. 
 
Cost/Payment 
Delineate clinical procedures from research procedures. Will subject's insurance (or subject) 
be responsible for research related costs? If so state for which items subject's insurance (or 
subject) will be responsible (surgery, device, drugs, etc). If appropriate, discuss the 
availability of financial counseling.  
 
There is no cost to the participants in this study. 
 
Dollar Amount: 
$ 820 
 
Distribution Plan: 
Pmnt Schedule  


Title 
Pharmacogenetic Trial Of Noradrenergic Medication for Treatment of 
Cocaine Dependence 
Protocol # 
H-32926, Baylor College of Medicine IRB 
PI 
Daryl Shorter, MD 
Grant # 
VA-funded CDA 
 
 
 4 of 5 
 
• Screen: up to $40• Study required weekly visits x 3 visits per week: $15 paid at end of 
each visit, bonus $20 at the end of visit 3 for each week for no missed visits and bottle 
return ($65/wk). Total compensation over the course of this 12-wk study, including screening 
is $820. All payments are made via direct deposit and distributed at the end of each 
scheduled visit. 
 
Sample Collection 
Sample: Blood 
• 
Blood chemistries:  
Chem 19, CBC as well as an EKG and general physical examination will be performed at 
screening. Blood drawings will occur at screening, and end of the study. These bloods 
include laboratory evaluation, liver function tests at screening and end of the study. 
 
• 
For blood draws, specify the amount drawn, in teaspoons, at each visit and across the 
course of the subjects entire participation time.   
12 ml (2.5 teaspoons ) of blood will be collected at screening and at the end of ths study for 
a total of 24ml or 5 teaspoons. 
 
SAMPLE: Urine 
• 
What is the purpose of the sample collection? 
Urine toxicology monitoring Urine samples will be monitored thrice weekly regardless of 
treatment group (typically, Monday, Wednesday, Friday) for opioids, cocaine metabolite 
(benzoylecgonine) and other drugs of abuse (e.g. benzodiazepines, barbiturates). Urines 
are rated negative if the quantity of drug or metabolite is <300 ng/ml (benzoylecgonine or 
benzodiazepine metabolites) or <200 ng/ml (opioids). Most opioids, benzoylecgonine, and 
benzodiazepines appear to be detectable after use for about 3 days. Thus, this frequency of 
urine monitoring will allow us to detect most drug use, including any regular cocaine use. 
Pregnancy tests will be conducted at screening, and weeks 4, 8, 12, and 15. 
 
Section R: Advertisements 
A PROGRAM FOR COCAINE USERS 
You may be eligible to participate in a 3-month research study to test a medication for 
cocaine abuse. This study is being conducted by the Michael E. DeBakey VA Medical 
Center and Baylor College of Medicine. We are currently seeking volunteers who will be 
compensated for study participation. 
 
877-807-3072 
 
All calls are CONFIDENTIAL. 
 
BCM Baylor College of Medicine Michael E. DeBakey VA Medical Center 
 
                                                             
References 
i FDA. Inovation/Stagnation: Challenge and Opportunity on the Critiical Path to New Medical 
Products.  March 2004. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html. 
ii FDA. (March, 2006) Innovation or Stagnation: Critical Path Opportunities List.  


Title 
Pharmacogenetic Trial Of Noradrenergic Medication for Treatment of 
Cocaine Dependence 
Protocol # 
H-32926, Baylor College of Medicine IRB 
PI 
Daryl Shorter, MD 
Grant # 
VA-funded CDA 
 
 
 5 of 5 
 
                                                                                                                                                                                                    
iii O’Neill, R.T.  FDA’s Critical Path Initiative:  A Perspective on the Contribution of Biostatistics.  
Biometrical Journal.  48(4):  559-564.  2006. 
iv Woodcock, J.  FDA introductory comments:  clinical studies design and evaluation issues.  
Clinical Trials.  2: 273-275. 
v Temple, R.  How the FDA currently makes decisions on clinical studies.  Clinical Trials.  2: 
276-281. 
vi Irony, T.  Bayesian Medical Device Clinical Trials in the Regulatory Setting.  Bayesian 
Biostatistics Conference.  University of Texas M.D. Anderson Cancer Center. Houston, Tx.  
2008. 
 
vii Spiegelhalter DJ, Myles JP, Jones DR, Abrams, KR. An introduction to Bayesian methods in 
health technology assessment. BMJ 1999;319(7208):508-512.  
 
viiiLilford RJ, Thornton JG, Braunholtz D. Clinical trials and rare diseases: a way out of a 
conundrum. BMJ 1995;311(7020):1621-1625.