Pharmacogenetic Trial of Doxazosin for Treatment of Cocaine Abuse

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT01953432
• Collaborator: Baylor College of Medicine (Other)
• Enrollment: 43
• Location: 1
• Arms: 2
• Actual Duration (Months): 42
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cocaine Dependence	Drug: Doxazosin; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pharmacogenetic Trial of Noradrenergic Medication for Treatment of Cocaine Abuse
• Actual Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Sep 1, 2017
• Actual Study Completion Date: Oct 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doxazosin 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.	Drug: Doxazosin; 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.; Other Names: Cardura (Doxazosin Mesylate)
Placebo Comparator: Placebo Matched placebo daily dosing.	Drug: Placebo; Matched placebo daily dosing; Other Names: Sugar pills (capsule)

Outcome Measures

Primary Outcome Measures

1. Percentage of Cocaine-positive Urines [Up to 12 weeks, or for the duration of the participant's involvement in the study]

   Over period of 12 weeks with 43 participants total (Doxazosin group = 22; Placebo group = 21), the overall percentage of cocaine positive urines per treatment group

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion 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. 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.

7. 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:

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 contraindicate 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas	United States	77030

Sponsors and Collaborators

• VA Office of Research and Development
• Baylor College of Medicine

Investigators

• Principal Investigator: Daryl I Shorter, MD, Michael E. DeBakey VA Medical Center, Houston, TX

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 14, 2019

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01953432
• Other Study ID Numbers: CLIN-014-12F; 1IK2CX000946-01
• First Posted: Oct 1, 2013
• Last Update Posted: Feb 20, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by VA Office of Research and Development: 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
• Additional relevant MeSH terms: Cocaine-Related Disorders; Doxazosin

Study Results

Participant Flow

Arm/Group Title	Doxazosin	Placebo
Arm/Group Description	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. Doxazosin (target 8mg/day) Induction - Week 1: 1mg once daily over days 1--3; 2mg once daily over days 4-7; Week 2: 4mg once daily over days 8-10; 8mg once daily over days 11-14; Week 3: 8mg once daily over days 15-end of week 10 Doxazosin tapered over weeks 11-12 -- Week 11: 4mg on Monday, Tuesday, Wednesday, and Thursday and 1mg for the duration of week 11. During week 12, subjects will receive 1mg on Monday, Tuesday, and Wednesday only. No further medication will be given for the remainder of week 12.	Matched placebo daily dosing. Placebo: Matched placebo daily dosing
Period Title: Overall Study
STARTED	22	21
COMPLETED	8	6
NOT COMPLETED	14	15

Baseline Characteristics

Arm/Group Title	Doxazosin	Placebo	Total
Arm/Group Description	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. Doxazosin (target 8mg/day) Induction - Week 1: 1mg once daily over days 1--3; 2mg once daily over days 4-7; Week 2: 4mg once daily over days 8-10; 8mg once daily over days 11-14; Week 3: 8mg once daily over days 15-end of week 10 Doxazosin tapered over weeks 11-12 -- Week 11: 4mg on Monday, Tuesday, Wednesday, and Thursday and 1mg for the duration of week 11. During week 12, subjects will receive 1mg on Monday, Tuesday, and Wednesday only. No further medication will be given for the remainder of week 12.	Matched placebo daily dosing. Placebo: Matched placebo daily dosing	Total of all reporting groups
Overall Participants	22	21	43
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	22 100%	21 100%	43 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	53.4	54.9	54.2
Sex: Female, Male (Count of Participants)
Female	2 9.1%	0 0%	2 4.7%
Male	20 90.9%	21 100%	41 95.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 4.8%	1 2.3%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	19 86.4%	17 81%	36 83.7%
White	3 13.6%	3 14.3%	6 14%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	22 100%	21 100%	43 100%
Lifetime cocaine years (years) [Mean (Full Range) ]
Mean (Full Range) [years]	24.5	24.1	24.3

Outcome Measures

1. Primary Outcome

Title	Percentage of Cocaine-positive Urines
Description	Over period of 12 weeks with 43 participants total (Doxazosin group = 22; Placebo group = 21), the overall percentage of cocaine positive urines per treatment group
Time Frame	Up to 12 weeks, or for the duration of the participant's involvement in the study

Outcome Measure Data

Analysis Population Description

Study population was comprised of 43 cocaine-dependent individuals who met inclusion criteria for this study.

Arm/Group Title	Doxazosin	Placebo
Arm/Group Description	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. Doxazosin (target 8mg/day) Induction - Week 1: 1mg once daily over days 1--3; 2mg once daily over days 4-7; Week 2: 4mg once daily over days 8-10; 8mg once daily over days 11-14; Week 3: 8mg once daily over days 15-end of week 10 Doxazosin tapered over weeks 11-12 -- Week 11: 4mg on Monday, Tuesday, Wednesday, and Thursday and 1mg for the duration of week 11. During week 12, subjects will receive 1mg on Monday, Tuesday, and Wednesday only. No further medication will be given for the remainder of week 12.	Matched placebo daily dosing. Placebo: Matched placebo daily dosing
Measure Participants	22	21
Number [percentage of cocaine-positive urines]	67.6	69

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doxazosin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Probability of 0.75 that the OR exceeded 1.00 (OR = 1.01, 95% CI = 0.98-1.05)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Probability of 0.96 that the odds ratio exceeded 1.00 (OR = 1.03, 95% CI = 1.00-1.07)

Adverse Events

Time Frame	Adverse events were assessed at each visit (Monday, Wednesday, Friday) during the active (medication) portion of the study for each participant (12 weeks).
Arm/Group Title	Doxazosin		Placebo
Arm/Group Description	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. Doxazosin: 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.		Matched placebo daily dosing. Placebo: Matched placebo daily dosing
All Cause Mortality
	Doxazosin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/21 (0%)
Serious Adverse Events
	Doxazosin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Doxazosin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/22 (36.4%)		5/21 (23.8%)
Gastrointestinal disorders
Nausea	2/22 (9.1%)	2	1/21 (4.8%)	1
Diarrhea	0/22 (0%)	0	2/21 (9.5%)	2
Stomach Pain/Indigestion	1/22 (4.5%)	1	1/21 (4.8%)	1
Constipation	1/22 (4.5%)	1	0/21 (0%)	0
General disorders
Dry mouth	1/22 (4.5%)	1	1/21 (4.8%)	1
Lightheadedness	1/22 (4.5%)	1	1/21 (4.8%)	1
Dizziness	1/22 (4.5%)	1	0/21 (0%)	0
Muscle twitching	0/22 (0%)	0	1/21 (4.8%)	1
Immune system disorders
Swelling	0/22 (0%)	0	1/21 (4.8%)	1
Allergies	1/22 (4.5%)	1	0/21 (0%)	0
Infections and infestations
Cold/Viral Illness	1/22 (4.5%)	1	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Back Pain	0/22 (0%)	0	1/21 (4.8%)	1
Nervous system disorders
Numbness	1/22 (4.5%)	1	0/21 (0%)	0
Psychiatric disorders
Increased Drug Craving	0/22 (0%)	0	1/21 (4.8%)	1
Reproductive system and breast disorders
Erectile Dysfunction	0/22 (0%)	0	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Bronchitis	0/22 (0%)	0	1/21 (4.8%)	1

Limitations/Caveats

There was a protocol amendment and the primary outcome measure was changed. The planned analysis was revised to a Bayesian approach to ensure more robust analysis of data given smaller sample size.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.