Addiction Treatment in Russia: Oral vs. Naltrexone Implant

Study Overview
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Brief Summary
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Heroin addiction is a growing problem in Russia; individuals who enter heroin addiction treatment often relapse. Therefore, effective heroin addiction treatments are necessary to prevent relapse. The purpose of this study is to compare oral naltrexone with a naltrexone implant that provides opioid blockade for two months in preventing relapse to heroin addiction in St. Petersburg, Russia.

Detailed Description
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The usual treatment of heroin addiction in Russia involves detoxification and 2-4 weeks of rehabilitation with referral to outpatient follow-up. Though most patients complete inpatient treatment, few keep follow-up appointments and relapse rates are high. More effective therapies are needed, especially in view of the epidemic of heroin addiction that has resulted in the spread of HIV and other infectious diseases. A recently-completed study of 52 patients randomized to oral naltrexone (ON) or oral naltrexone placebo (ONP) has shown efficacy in preventing relapse and reducing HIV risk but dropout was a problem with only 44% of ON patients proven to have not relapsed by 6 months (as compared to 16% of ONP patients). A larger study of 280 patients randomized to ON or ONP replicated these results and found some indication that adding an selective serotonin reuptake inhibitor (SSRI) to naltrexone may improve its efficacy in women, probably because they tend to have higher levels of psychiatric symptoms than men. We think that retention and outcome can be improved by using a longer acting naltrexone preparation, and in this study we propose to compare ON with a depot naltrexone implant (DNI) that is manufactured and approved for use in Russia, and provides opioid blockade for 8-10 weeks. We will use a placebo-controlled, double-blind/double-dummy design since a placebo-controlled trial is required by the Russian equivalent of our FDA as a condition for testing a pharmacotherapy. Participants will be male and female heroin addicts who have been detoxified in addiction treatment hospitals or outpatient settings in St. Petersburg and have a family member willing and able to supervise medication adherence and facilitate follow-up. After giving informed consent and confirming the absence of physiologic dependence, 306 patients will be randomly assigned to a 6-month treatment in one of three groups of 102 each: oral naltrexone (ON) + depot naltrexone implant placebo (DNIP); oral naltrexone placebo (ONP) + depot naltrexone implant (DNI); or ONP + DNIP. All patients will receive biweekly clinical management/adherence enhancement counseling. Assessments will be done at baseline, at each biweekly appointment during the 6-months of medication treatment, and at 3 and 6 months following the end of study medication. Primary outcome will be the relapse free proportion at months 1-6; secondary outcomes will be time to dropout, opioid positive urines, HIV risk, use of alcohol and other drugs, psychiatric symptoms, and other measures of overall adjustment. We hypothesize that outcomes will be better with DNI than ON, and that each will be more effective than placebo.

Official Title
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Addiction Treatment in Russia: Oral and Depot Naltrexone

Conditions
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Heroin Dependence, Opioid-Related Disorders

Intervention / Treatment
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* Drug: naltrexone implant
* Drug: oral naltrexone
* Drug: oral placebo naltrexone
* Drug: placebo implant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current opioid dependence Recently completed opioid detoxification Exclusion Criteria: Serious medical or psychiatric condition requiring immediate hospitalization or that would make participation in the study hazardous Planning to leave the study area within the 12 months following study entry Imminent incarceration Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ONP + DNI<br>Oral naltrexone placebo (ONP) + Depot Naltrexone Implant (DNI) 1000 mg | Drug: naltrexone implant<br>* naltrexone implant is 1000 mg naltrexone<br>* Other names: DNI;Drug: oral placebo naltrexone<br>* oral placebo naltrexone resembles active medication<br>* Other names: ONP;|
| Active Comparator: ON + DNIP<br>Oral naltrexone (ON) 50 mg + Depot Naltrexone placebo Implant (DNIP) | Drug: oral naltrexone<br>* oral naltrexone 50 mg/day<br>* Other names: ON;Drug: placebo implant<br>* placebo implant resembles active medication<br>* Other names: DNIP;|
| Placebo Comparator: ONP + DNIP<br>Oral placebo naltrexone + placebo naltrexone implant | Drug: oral placebo naltrexone<br>* oral placebo naltrexone resembles active medication<br>* Other names: ONP;Drug: placebo implant<br>* placebo implant resembles active medication<br>* Other names: DNIP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retention Without Relapse to Heroin Addiction (Measured at Month 6) | Survival analysis (Kaplan-Meier survival functions with log-rank Cox-Mantel criteria for group comparison was used to determine the primary outcome of retention, defined as not missing 2 consecutive counseling sessions and not having a relapse. Because this outcome combined patients who failed to keep appointments with those who kept appointments but relapsed, the proportion of non-survivors attributable to proven relapse. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Dropped Out of Treatment | Kaplan-Meier survival curves for the event of subjects who dropped out of treatment | 6 months | 
| Positive Opioid Urine Test | missed urine tests were imputed to be positive for opiates | 6 months | 
| Use of Alcohol | use of alcohol grams per day | 6 months | 
| Composite Score of Psychiatric Problems | composite score is a decimal score; with 0 = no problems, 1 = the most problems based on the Addiction Severity Index composite score of 11 indexed questions. | 6 months | 
| HIV Risk (Baseline) | The Risk Assessment Behavior (RAB), is an HIV risk Scale. The Total Score is scored by adding the values that correspond to the responses selected by the subject for the items asked. This highest total score is 40 (highest risk), and the lowest score = 0 (no risk). This assessment has 2 Subsections: 1) Drug Risk = 8 questions (lowest Drug Risk score = 0 (no risk), and highest drug risk score = 22 =(greatest risk), 2) 10 Sex Risk questions: scores are 0 = no risk, and 18 = highest risk). Total RAB Score = Drug Risk Total + Sex Risk Total (0 = no risk, 40 = highest). See: Risk Assessment Battery (RAB) Scoring System, https://www.med.upenn.edu/hiv/assets/user-content/.../RABScoringv2.112.21.95.doc | baseline | 
| Global Assessment Form (GAF) | Assessment of overall psychiatric function comprises Axis V in the DSM-IV (DSM-IV, 1994). GAF scores range from 0 to 100. A reasonably well-functioning person will score above 70; serious impairment is below 50. | baseline | 
| Amphetamine Drug Use | Number of subjects who used Amphetamine in the past 90 days at baseline as measured by the TimeLine Follow-back Form (TLFB) . The TLFB is an instrument that assesses substance use over a specified period of time (Sobel & Sobel, 1992). | baseline | 
| Cocaine Drug Use | Number of subjects with cocaine drug use in the past 90 days at baseline as measured by the TimeLine Follow-back Form (TLFB) . The TLFB is an instrument that assesses substance use over a specified period of time (Sobel & Sobel, 1992). | baseline | 
| Marijuana Drug Use | Number of subjects with Marijuana use in the past 90 days at baseline as measured by the TimeLine Follow-back Form (TLFB) . The TLFB is an instrument that assesses substance use over a specified period of time (Sobel & Sobel, 1992). | baseline | 
| Benzodiazepine Drug Use | Number of subjects with benzodiazepine drug use in the past 90 days at baseline as measured by the TimeLine Follow-back Form (TLFB) . The TLFB is an instrument that assesses substance use over a specified period of time (Sobel & Sobel, 1992). | baseline |