HIV, AIDS, Opioid Dependence, Drug Dependence
Conditions
Brief summary
Specific Aim: To conduct a randomized, placebo-controlled trial of extended release-naltrexone (XR-NTX) among Human Immunodeficiency Virus (HIV) infected prisoners meeting Diagnostic Statistical Manual IV (DSM-IV) criteria for opioid dependence who are transitioning from the structure of a correctional setting to the community. Hypotheses: i. XR-NTX will result in improved HIV clinical outcomes, including lower changes in HIV-1 RNA levels, higher CD4 counts and higher rates of retention in care. ii. XR-NTX will result in improved opioid treatment outcomes, including longer time to opioid relapse, lower addiction severity and lower craving for opioid. iii. XR-NTX will result in reduced drug- and sex-related HIV risk behaviors compared to the control group. iv. XR-NTX will result in decreased rates of reincarceration after 12 months of release to the community.
Detailed description
The specific aim for this study is to conduct a placebo-controlled trail (RCT) of XR-NTX among HIV+ persons in jails and prisons meeting DSM-IV criteria for opioid dependence who are transitioning to the community. HIV treatment outcomes (HIV-1 RNA levels, CD4 count, Highly Active Antiretroviral Therapy (HAART) adherence, retention in care), substance abuse (time to relapse to opioid use, % opioid negative urines, opioid craving), adverse side effects and HIV risk behavior (sexual and drug-related risks) outcomes will be compared in 150 recruited prisoners and jail detainees in Connecticut (CT) and Massachusetts (MA) who will be randomized 2:1 to either XR-NTX or placebo. The primary outcome of interest will be the proportion with a HIV-RNA \<400 copies/mL at 6 months. Secondary outcomes include mean CD4 count, antiretroviral adherence, retention on HAART and in HIV care, HIV risk behaviors, time-to-relapse to opioid use, percent opioid negative urines, retention on d-NTX and HIV quality of life. Primary and secondary outcomes will be assessed for an additional 6 months after completion of the intervention. If this placebo-controlled trial of XR-NTX among released HIV+ criminal justice system (CJS) persons with opioid dependence demonstrates efficacy and safety, it is likely to become an evidence-based intervention to intervene with this extremely marginalized population in a way that will meet Healthy People 2010's goals to increase the quality and years of life, decrease health disparities particularly among minorities, break the cycle of addiction, reduce the numbers of people within the CJS and launch a number of new and innovative trials and second generation questions for future research. As such, the individual, our health care system and society have a high likelihood to benefit. This will not only be true for strategies here in the U.S., but may have even greater application for geographic areas where the interface between opioid disorders and HIV is even greater.
Interventions
Extended-Release Naltrexone (Vivitrol), once a month by IM injection, for a total of 6 months. Dosage is 380mg
Sponsors
Baystate Medical Center
National Institute on Drug Abuse (NIDA)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Meets DSM-IV criteria for opioid dependence 2. Age \> 18 years 3. Confirmed HIV infection, either through positive HIV antibody or detectable HIV-1 RNA level. 4. Within the Connecticut Department of Corrections (CTDOC) or Hampden County Correctional Center (HCCC) and within 30 days of being released to the greater New Haven, Hartford or Springfield areas or within 30 days after release from CTDOC or HCCC. 5. No participation in pharmacotherapy trial in the previous 30 days 6. Not pregnant
Exclusion criteria
1. Unable to provide informed consent 2. Verbally or physically threatening to research staff 3. Unable to communicate in either English or Spanish 4. Pending trials for a felony 5. Liver failure (Childs-Pugh Class B or C Cirrhosis) 6. Grade IV Hepatitis (liver function tests \> 10X normal) 7. Receiving opioid prescription narcotics or has pain syndrome necessitating future use of opioid prescription narcotics. 8. Receiving active methadone or buprenorphine/naloxone for the treatment of opioid dependency 9. Active opioid withdrawal (within 3-5 days since last opioid ingestion) 10. Pregnancy or unwilling to take contraceptives measures 11. Breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants Who Had Undetectable HIV-1 RNA Levels at Less Than 400 Copies/mL at Six Month | 6 months | Baseline labs will be drawn while subject is in prison, one to three months prior to release. Additionally, labs will be drawn every 3 months for 1 year to monitor changes in HIV-1 RNA levels. Treatment time period was the first 6 months where the primary outcome data will be based on. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CD4 Cell Count (Cells/mL) | Baseline and 6 months | Baseline labs will be drawn while subject is in prison, one to three months prior to release. Additional labs will be drawn every 3 months for 1 year to monitor changes in CD4 levels. |
| Time to Opioid Relapse or End of Intervention | 6 months | Measuring days to first relapse based on self reported opioids (heroin) use within the 6 month (180 days) intervention period. If participants had no follow-up visits, and thus no self reported opiate use, they were treated as missing. Those who did not relapse within the 6 month intervention period were treated as having 180 days until relapse. |
| Addiction Severity | baseline, and 6 months | The Addiction Severity Index (ASI) questionnaire will be used to assess addiction severity. The ASI composite scoreprovides reliable and valid measure of patient status in a particular module of interest which can then be usecompared at the beginning of treatment to the evaluation endpoint to note the improvement or lack thereof. In this assessment the drug composite score was calculated using algorithm by Treatment Research Institute. If the score increases then it shows increase in severity where as if it decreases then it shows decrease in severity for that measured module. The scale ranges from 0 to 1. The mean composite scores for drug use from baseline to 6 months were compared using Nonparametric test. |
| Craving for Opioids | 6 months | Craving at baseline compared to 6 month. This is assessed through a self report scale rated 0 to 10; 0 meaning not craving and 10 meaning highest craving. Change in craving score was categorized as 1)no change between baseline and 6 month; 2)increased craving - baseline craving was reported lower than at 6 month; 3)decreased craving - baseline craving was reported higher than 6 month craving. |
| Particpants Who Had Undetectable HIV-1 RNA Levels at Less Than 50 Copies/mL | 6 months | Baseline labs will be drawn while subject is in prison, one to three months prior to release. Additionally, labs will be drawn every 3 months for 1 year to monitor changes in HIV-1 RNA levels. Treatment time period was the first 6 months where the primary outcome data will be based on. |
| Participants With Opiate Abstinence Via By Doing Urine Toxicology Test | 6 month | Percent of subjects with no opiate use at 6 month. Missing data was treated as failure (opiate positive). |
| Opioid Abstinence at 6 Months for Those With More Than 4 Injections | 6 months | Based on self reported opioids (heroin) use. All participants receiving Placebo as well as participants who received 3 or less XR-NTX injections were compared to those who receive 4 or more XR-NTX injection. |
| ART Adherence for 4 or More Injections XR-NTX Versus Placebo and 3 or Less Injections of XR-NTX | 6 months | The arm/group number of the participants vary from the primary outcome because this is a treatment effect analysis. All client with missing data at 6 months were considered as failure - meaning - they had less than 100% ART adherence. |
| Antiretroviral Therapy (ART) Adherence 100% | 6 months | Number of subjects with 100% adherence at 6 months measured using Visual Analogue Scale: 0% to 100% |
Countries
United States
Participant flow
Recruitment details
151 subjects consented, 58 lost before randomization
Participants by arm
| Arm | Count |
|---|---|
| Extended-Release Naltrexone Participants will receive intramuscular (IM) injections of Naltrexone once monthly for 6 months, the first injection being prior release
Extended-Release Naltrexone: Extended-Release Naltrexone (Vivitrol), once a month by IM injection, for a total of 6 months. Dosage is 380mg | 66 |
| Placebo Participants will receive IM injections of Placebo once monthly for 6 months, the first injection being prior release
Extended-Release Naltrexone: Extended-Release Naltrexone (Vivitrol), once a month by IM injection, for a total of 6 months. Dosage is 380mg | 27 |
| Total | 93 |
Baseline characteristics
| Characteristic | Total | Placebo | Extended-Release Naltrexone |
|---|---|---|---|
| Age, Continuous | 45.8 years STANDARD_DEVIATION 8.2 | 43.9 years STANDARD_DEVIATION 7.8 | 46.6 years STANDARD_DEVIATION 8.3 |
| Alcohol Use Severity (AUDIT score) Abstinent or Low-Risk Drinking | 65 Participants | 23 Participants | 42 Participants |
| Alcohol Use Severity (AUDIT score) Harmful Drinking | 2 Participants | 0 Participants | 2 Participants |
| Alcohol Use Severity (AUDIT score) Hazardous Drinking | 13 Participants | 2 Participants | 11 Participants |
| Alcohol Use Severity (AUDIT score) Missing | 1 Participants | 0 Participants | 1 Participants |
| Alcohol Use Severity (AUDIT score) Possible Dependence | 12 Participants | 2 Participants | 10 Participants |
| Currently prescribed ART | 82 Participants | 24 Participants | 58 Participants |
| Housing status Homeless | 36 Participants | 12 Participants | 24 Participants |
| Housing status Stable | 34 Participants | 11 Participants | 23 Participants |
| Housing status Unstable | 23 Participants | 4 Participants | 19 Participants |
| Opioid craving | 3.3 units on a scale STANDARD_DEVIATION 3.6 | 3.5 units on a scale STANDARD_DEVIATION 3.8 | 3.2 units on a scale STANDARD_DEVIATION 3.6 |
| Sex: Female, Male Female | 17 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Male | 76 Participants | 21 Participants | 55 Participants |
| Years Reported use of substances Alcohol | 12.2 years STANDARD_DEVIATION 14.3 | 9.2 years STANDARD_DEVIATION 11.6 | 13.5 years STANDARD_DEVIATION 15.2 |
| Years Reported use of substances Cannabis | 13.6 years STANDARD_DEVIATION 13.7 | 12.8 years STANDARD_DEVIATION 12.5 | 14 years STANDARD_DEVIATION 14.3 |
| Years Reported use of substances Cocaine | 17.9 years STANDARD_DEVIATION 10.6 | 18.7 years STANDARD_DEVIATION 8.6 | 17.5 years STANDARD_DEVIATION 11.4 |
| Years Reported use of substances Heroin | 19.6 years STANDARD_DEVIATION 10.9 | 18.4 years STANDARD_DEVIATION 10.2 | 20.1 years STANDARD_DEVIATION 11.2 |
| Years Reported use of substances Other Opioids | 2.9 years STANDARD_DEVIATION 6.7 | 3.2 years STANDARD_DEVIATION 5.4 | 2.8 years STANDARD_DEVIATION 7.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 66 | 4 / 27 |
| serious Total, serious adverse events | 0 / 66 | 0 / 27 |
Outcome results
Primary
Participants Who Had Undetectable HIV-1 RNA Levels at Less Than 400 Copies/mL at Six Month
Baseline labs will be drawn while subject is in prison, one to three months prior to release. Additionally, labs will be drawn every 3 months for 1 year to monitor changes in HIV-1 RNA levels. Treatment time period was the first 6 months where the primary outcome data will be based on.
Time frame: 6 months
Population: A total of 80 participants had viral load data at 6 months (56 in XR-NTX group and 24 in Placebo group). The remaining 13 participants (10 in XR-NTX group and 3 in Placebo group) with missing viral load data at 6 months were considered as failure - meaning - having a viral load of 400 or more. Thus included into the final analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended-Release Naltrexone | Participants Who Had Undetectable HIV-1 RNA Levels at Less Than 400 Copies/mL at Six Month | 45 Participants |
| Placebo | Participants Who Had Undetectable HIV-1 RNA Levels at Less Than 400 Copies/mL at Six Month | 16 Participants |
p-value: 0.431Welch's T Test
Secondary
Addiction Severity
The Addiction Severity Index (ASI) questionnaire will be used to assess addiction severity. The ASI composite scoreprovides reliable and valid measure of patient status in a particular module of interest which can then be usecompared at the beginning of treatment to the evaluation endpoint to note the improvement or lack thereof. In this assessment the drug composite score was calculated using algorithm by Treatment Research Institute. If the score increases then it shows increase in severity where as if it decreases then it shows decrease in severity for that measured module. The scale ranges from 0 to 1. The mean composite scores for drug use from baseline to 6 months were compared using Nonparametric test.
Time frame: baseline, and 6 months
Population: An additional subject's data from the experimental group was not collected at baseline. For the 6 months data, the total number of participants with completed assessment used for the analysis was 46 (31 in XR-NTX group and 15 in Placebo group).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Extended-Release Naltrexone | Addiction Severity | baseline | 0.37 units on a scale | Standard Deviation 0.16 |
| Extended-Release Naltrexone | Addiction Severity | 6 month | 0.12 units on a scale | Standard Deviation 0.13 |
| Placebo | Addiction Severity | baseline | 0.42 units on a scale | Standard Deviation 0.14 |
| Placebo | Addiction Severity | 6 month | 0.16 units on a scale | Standard Deviation 0.16 |
Secondary
Antiretroviral Therapy (ART) Adherence 100%
Number of subjects with 100% adherence at 6 months measured using Visual Analogue Scale: 0% to 100%
Time frame: 6 months
Population: 56 participants with missing data were considered as failure - meaning - with adherence less than 100%, and included into the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended-Release Naltrexone | Antiretroviral Therapy (ART) Adherence 100% | 25 Participants |
| Placebo | Antiretroviral Therapy (ART) Adherence 100% | 12 Participants |
Secondary
ART Adherence for 4 or More Injections XR-NTX Versus Placebo and 3 or Less Injections of XR-NTX
The arm/group number of the participants vary from the primary outcome because this is a treatment effect analysis. All client with missing data at 6 months were considered as failure - meaning - they had less than 100% ART adherence.
Time frame: 6 months
Population: All client with missing data at 6 months were considered as failure - meaning - they had less than 100% ART adherence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended-Release Naltrexone | ART Adherence for 4 or More Injections XR-NTX Versus Placebo and 3 or Less Injections of XR-NTX | 23 Participants |
| Placebo | ART Adherence for 4 or More Injections XR-NTX Versus Placebo and 3 or Less Injections of XR-NTX | 14 Participants |
Secondary
CD4 Cell Count (Cells/mL)
Baseline labs will be drawn while subject is in prison, one to three months prior to release. Additional labs will be drawn every 3 months for 1 year to monitor changes in CD4 levels.
Time frame: Baseline and 6 months
Population: Data was collected via labs. At month 6, due to attrition, data was only available for a total of 46 subjects. These include, 14 in Placebo and 32 in Extended-Release Naltrexone. The mean and STD are presented below.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Extended-Release Naltrexone | CD4 Cell Count (Cells/mL) | Baseline mean CD4 count | 465.2 cells/ml | Standard Deviation 273.8 |
| Extended-Release Naltrexone | CD4 Cell Count (Cells/mL) | Month 6 mean CD4 count | 462 cells/ml | Standard Deviation 306.6 |
| Placebo | CD4 Cell Count (Cells/mL) | Baseline mean CD4 count | 580.8 cells/ml | Standard Deviation 336.8 |
| Placebo | CD4 Cell Count (Cells/mL) | Month 6 mean CD4 count | 485.6 cells/ml | Standard Deviation 257.3 |
Secondary
Craving for Opioids
Craving at baseline compared to 6 month. This is assessed through a self report scale rated 0 to 10; 0 meaning not craving and 10 meaning highest craving. Change in craving score was categorized as 1)no change between baseline and 6 month; 2)increased craving - baseline craving was reported lower than at 6 month; 3)decreased craving - baseline craving was reported higher than 6 month craving.
Time frame: 6 months
Population: Data available at 6 month determined who was included into the analysis. In this case a total of 47 data points (those with both baseline and 6 month data points) were included into the analysis (32 Extended-Release Naltrexone and 15 Placebo).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Extended-Release Naltrexone | Craving for Opioids | No change | 12 Participants |
| Extended-Release Naltrexone | Craving for Opioids | Increased craving at 6 mo | 6 Participants |
| Extended-Release Naltrexone | Craving for Opioids | Decreased craving at 6 mo | 14 Participants |
| Placebo | Craving for Opioids | No change | 7 Participants |
| Placebo | Craving for Opioids | Increased craving at 6 mo | 3 Participants |
| Placebo | Craving for Opioids | Decreased craving at 6 mo | 5 Participants |
Secondary
Opioid Abstinence at 6 Months for Those With More Than 4 Injections
Based on self reported opioids (heroin) use. All participants receiving Placebo as well as participants who received 3 or less XR-NTX injections were compared to those who receive 4 or more XR-NTX injection.
Time frame: 6 months
Population: Collected via Time Line Fall Back (TLFB). Total N analyzed is 74. 12 of the clients had initial or some TLFB data indicating relapse but were counted as lost at 6 months for outcome 4. 19 Clients did not have TLFB data or if they did within 6 month it did not indicate any relapse. These were treated as missing and not included in analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended-Release Naltrexone | Opioid Abstinence at 6 Months for Those With More Than 4 Injections | 18 Participants |
| Placebo | Opioid Abstinence at 6 Months for Those With More Than 4 Injections | 13 Participants |
p-value: 0.03962Chi-squared
Secondary
Participants With Opiate Abstinence Via By Doing Urine Toxicology Test
Percent of subjects with no opiate use at 6 month. Missing data was treated as failure (opiate positive).
Time frame: 6 month
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Extended-Release Naltrexone | Participants With Opiate Abstinence Via By Doing Urine Toxicology Test | NEG Opi at Day of Release | 44 Participants |
| Extended-Release Naltrexone | Participants With Opiate Abstinence Via By Doing Urine Toxicology Test | NEG Opi at 6 month | 13 Participants |
| Placebo | Participants With Opiate Abstinence Via By Doing Urine Toxicology Test | NEG Opi at Day of Release | 17 Participants |
| Placebo | Participants With Opiate Abstinence Via By Doing Urine Toxicology Test | NEG Opi at 6 month | 5 Participants |
Secondary
Particpants Who Had Undetectable HIV-1 RNA Levels at Less Than 50 Copies/mL
Baseline labs will be drawn while subject is in prison, one to three months prior to release. Additionally, labs will be drawn every 3 months for 1 year to monitor changes in HIV-1 RNA levels. Treatment time period was the first 6 months where the primary outcome data will be based on.
Time frame: 6 months
Population: A total of 80 participants had viral load data at 6 months (56 in XR-NTX group and 24 in Placebo group). The remaining 13 participants (10 in XR-NTX group and 3 in Placebo group) with missing viral load data at 6 months were considered as failure - meaning - having a viral load of 400 or more. Thus included into the final analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Extended-Release Naltrexone | Particpants Who Had Undetectable HIV-1 RNA Levels at Less Than 50 Copies/mL | 40 Participants |
| Placebo | Particpants Who Had Undetectable HIV-1 RNA Levels at Less Than 50 Copies/mL | 11 Participants |
p-value: 0.087Welch's T Test
Secondary
Time to Opioid Relapse or End of Intervention
Measuring days to first relapse based on self reported opioids (heroin) use within the 6 month (180 days) intervention period. If participants had no follow-up visits, and thus no self reported opiate use, they were treated as missing. Those who did not relapse within the 6 month intervention period were treated as having 180 days until relapse.
Time frame: 6 months
Population: Data collected via Time Line Fall Back (TLFB). 15 in XR-NTX group and 4 in Placebo did not have data because of attrition - treated as missing. An additional 19 people in the treatment arm and 9 in placebo filled out the TLFB at 9 or 12 months, and this data was used to fill in missing information.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Extended-Release Naltrexone | Time to Opioid Relapse or End of Intervention | 137 days |
| Placebo | Time to Opioid Relapse or End of Intervention | 29 days |
p-value: 0.03Wilcoxon (Mann-Whitney)