Will the Use of Baclofen Reduce Cocaine Use in Patients With Cocaine Dependence?

Condition(s) targeted: Cocaine Dependence

Intervention: Baclofen (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: Department of Veterans Affairs

Cocaine is a powerfully addictive stimulant. Cocaine dependence is a significant public health problem associated with serious medical, psychiatric, social and economic consequences. In 1997, an estimated 1. 5 million Americans were chronic cocaine users; in 1999, the Office of National Drug Control Policy estimated the number of chronic cocaine users in U. S. at 3. 6 million. However, despite intensive investment of resources and some promising data from a recent trial with Selegiline, no medications so far, have demonstrated clear evidence of efficacy for the treatment of cocaine dependence.

This study investigated a new drug, Baclofen, as a potential medication for cocaine dependency. Each subject was assigned either to the Baclofen group or a matched placebo (or dummy medication) group by chance, after a 2-week screening period. The treatment period was 8 weeks long, when the medication was administered orally, with follow-up assessments for 4 weeks after completion of the treatment period. The main objective of this study was to assess the suitability and safety of Baclofen to treat the craving of cocaine use among the heavy cocaine users.

Official title: CSP #1021 - Double-Blind, Placebo-Controlled Multi-Center Trial of Baclofen for the Treatment of Cocaine Dependence

Study design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Detailed description: Primary Hypothesis: Baclofen treatment, compared to placebo, will be associated with fewer days of cocaine use as assessed by self-report confirmed with urine assays for benzoylecgonine.

Intervention: The active treatment was baclofen at a dose escalating from 10 mg to 60 mg daily or matched placebo during week 1, 60 mg baclofen daily or matched placebo during weeks 2 to 7 with baclofen dose tapering off or matched placebo during week 8.

Primary Outcome: Weekly mean proportion of cocaine non-use days

Study Abstract:

STUDY OBJECTIVE: To assess the efficacy and safety of baclofen in reducing cocaine use in subjects with cocaine dependence. It was hypothesized that baclofen treatment, compared to placebo, would be associated with fewer days of cocaine use as assessed by self-report confirmed with urine assays for benzoylecgonine (BE).

STUDY DESIGN: This was a double-blind, placebo-controlled, parallel design study in which, after a 14-day screening period, subjects were randomly assigned to receive baclofen or matched placebo administered orally for 8 weeks with follow-up assessments for 4 weeks after treatment completion. Adaptive randomization was used to balance treatment groups based on clinical site and gender. All subjects received psychosocial therapy.

STUDY POPULATION: 160 subjects with Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for cocaine dependence determined by structured clinical interview (SCID) were randomized into one of two treatment groups (80 subjects per group). Subjects who were at least 18 years-of-age, with at least 3 BE-positive urine provided within 14 days of screening, with the ability to understand and provide written informed consent, that met all of the study inclusion and did not meet any of the exclusion criteria were randomized into the study.

TREATMENTS: During the 8 weeks of treatment, subjects received baclofen at a dose escalating from 10 mg to 60 mg daily or matched placebo during week 1, 60 mg baclofen daily or matched placebo during weeks 2 to 7 with baclofen dose tapering off or matched placebo during week 8. All subjects received weekly sessions of cognitive behavioral therapy (CBT)once a week during the 8 weeks of treatment. HIV counseling was performed as a component of CBT.

SAFETY ASSESSMENTS: All candidates for study enrollment had a physical examination, a 12-lead electrocardiogram (ECG) and clinical laboratory studies (blood chemistry, hematology, urinalysis, and pregnancy test, if female) completed during screening and week 8 or at the time of study discontinuation. Prior medication use was assessed at screening and on study day 1 before 1st dose of study drug was administered. A urine screen for other substances of abuse was assessed weekly during screening, baseline, treatment and follow-up periods. Vital signs were assessed at every clinic visit during screening (3 times a week) and once a week during treatment period. A pregnancy test, if female, was performed within 2 days prior to the first dose of investigational agent administration and at week 4 and week 8; subjects also had clinical laboratory studies (blood chemistry, hematology and urinalysis) at week 4. Adverse events (AEs) and concomitant medication use were assessed at each study visit and each follow-up visit and recorded weekly on a case report form (CRF).

EFFICACY ASSESSMENTS: The primary outcome variable was weekly proportion of cocaine non-use days assessed by self report confirmed with urine assay for BE. Secondary assessments evaluating treatment effects on cocaine use included overall increases in the proportion of cocaine non-use days, increases in the proportion of successful subjects, weekly proportion of non-use days according to subject's self-report of use (SUR) without regard to BE levels, weekly non-use days of other drugs of abuse and increases in the largest number of consecutive cocaine non-use days.

ANALYSIS: Each primary and secondary outcome variable was analyzed using appropriate statistical methods for the intent-to-treat population, evaluable population, and for study completers. It was hypothesized that baclofen treatment, compared to placebo, would be associated with a statistically significant change in cocaine use as assessed by weekly proportion of cocaine non-use days. Statistical tests were two-sided at a 5% Type I error rate. Confidence intervals were two-sided with a 95% confidence coefficient.

RESULTS: For this trial, the primary outcome measure and all the secondary outcome measures were analyzed for three pre-defined groups: the intent-to-treat (ITT) population (N = 160), the evaluable population (N = 132), and the study completers (N = 115). The primary outcome of interest was the increase in the number of cocaine non-use days in the 8-week outpatient trial for subjects with severe cocaine addiction. The repeated measure analysis of the primary outcome for all the three populations indicated Baclofen's inability to increase the number of cocaine non-use days significantly compared to Placebo. A series of secondary outcomes were also analyzed to measure reduction in cocaine use and to measure reduction in severity of cocaine dependence and craving for cocaine use. Again, Baclofen failed to reduce both the severity of cocaine dependence and the craving for cocaine compared to Placebo.

Main Manuscript - (record authors, title, journal, year, volume, page nos.):

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

INCLUSION CRITERIA:

1. Be at least 18 years-of-age.

2. Have a DSM-IV diagnosis of cocaine dependence as determined by SCID.

3. Be seeking treatment for cocaine dependence.

4. Have provided at least 4 urine samples during the 14-day screening period, of which 3 or more are BE-positive (>300 ng/mL).

5. Be able to verbalize understanding of consent form, able to provide written informed consent, and verbalize willingness to complete study procedures.

6. If female and of child bearing potential, agree to use of one of the following methods of birth control or be surgically sterile: oral contraceptives, patch, barrier (diaphragm or condom, intrauterine contraceptive system, levonorgestrel implant, medroxyprogesterone acetate contraceptive injection, complete abstinence from sexual intercourse, hormonal vaginal contraceptive ring

7. Have completed all other psychological assessments (ASI- Lite, HRBS, CGI-S, CGI-O, BSCS, CSSA, HAM-D) during the 14- day screening period.

EXCLUSION CRITERIA:

1. Have current dependence, defined by DSM-IV criteria, on any psychoactive substance other than cocaine, alcohol, nicotine, or marijuana or physiological dependence on alcohol requiring medical detoxification.

2. Be mandated by the court to obtain treatment for cocaine- dependence.

3. Be anyone who in the opinion of the investigator would not be expected to complete the study protocol; for example, due to probable incarceration, vacation, or relocation from the clinic area.

4. Have a psychiatric disorder, as assessed by the SCID, or a neurological disorder including but not limited to epilepsy and absence seizures, brain disease, dementia or any disorder that, in the opinion of the study physician requires ongoing treatment that would make study participation unsafe or which would make treatment compliance difficult.

5. Have had electroconvulsive therapy within the past 3 months preceding screening.

6. Have current suicidal ideation or plan (within the past 30 days) as assessed by the SCID.

7. Be pregnant or lactating.

8. Have serious medical illnesses including, but not limited to: uncontrolled hypertension, significant heart disease (including myocardial infarction within one year of enrollment), or any clinically significant cardiovascular abnormality (ECG), hepatic, renal or gastrointestinal disorders that could result in a clinically significant alteration of metabolism or excretion of the study agent, potentially life-threatening or progressive medical illness other than addiction that may compromise subject safety or study conduct

9. Have clinically significant abnormal laboratory

10. Have AIDS according to the current CDC criteria for AIDS ? MMWR 1999; 48 (No. RR-13: 29-31).

11. Have active syphilis that has not been treated or refuse treatment for syphilis (see note below).

12. Have active tuberculosis (positive tuberculin test and confirmatory diagnostic chest x-ray).

13. Have a diagnosis of adult onset asthma (i. e., 21 years or older), or chronic obstructive pulmonary disease (COPD), including those with a history of acute asthma within the past two years, and those with current or recent (past 3 months) treatment with inhaled or oral beta-agonist or steroid therapy (because of potential serious adverse interactions with cocaine).

14. Be actively using albuterol or other beta agonist medications, regardless of formal diagnosis of asthma. A subject without respiratory disease who will consent to discontinue beta-agonist use, may be considered for inclusion.

15. Have received medication that could interact adversely with baclofen, with the time of administration of study agent and other medications based on the longest time interval of

A, B, or C, below:

A) Five half lives of other medication or active metabolite(s), whichever is longer; or B) Two weeks; or C) Interval recommended by other medication?s product labeling. Medications that fall into this category include: Muscle relaxants (including tricyclic antidepressants), Antiseizure medication, CNS depressants (tranquilizers, sleeping pills), and MAO inhibitors.

16. Have participated in any behavioral and/or pharmacological intervention study within 2 months preceding the beginning of screening.

17. Have known or suspected hypersensitivity to baclofen.

18. Be taking baclofen for any reason currently or during the past year.

19. Have tested positive twice for benzodiazepines during the 14-day screening period.

San Francisco General Hospital, San Francisco, California 94110, United States

UCLA Torrance Clinic, Torrance, California 90502, United States

VA Medical Center, Denver, Colorado 80220, United States

VA Maryland Health Care System, Baltimore, Maryland 21201, United States

PENN-VA Addiction Treatment Research Center, Philadelphia, Pennsylvania 19104-6178, United States

South Texas Veterans Healthcare System, San Antonio, Texas 78284, United States

VA Medical Center, Salt Lake City, Utah 84148, United States

Inova Center of Addictive Treatment Services, Falls Church, Virginia 22042, United States

Starting date: October 2003
Ending date: September 2005
Last updated: February 7, 2007