Opioid Use Disorder
Conditions
Keywords
Alkermes, Buprenorphine, Naltrexone, Vivitrol, Opioid Use, Opiates, Dependence, Abuse, Heroin, Painkillers, Substance Abuse
Brief summary
This study will evaluate the safety, effectiveness and tolerance of low doses of oral naltrexone along with buprenorphine to treat opioid use disorder prior to the first injection of VIVITROL.
Interventions
DRUGNTX/BUP
Daily doses
DRUGNTX/PBO-B
Daily doses
DRUGPBO-N/PBO-B
Daily doses
Sponsors
Alkermes, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide informed consent * Willing and able to provide government-issued identification * Has a BMI of 18.0-40.0 kg/m\^2 * Has a physiologic dependence on opioids * Is voluntarily seeking treatment for opioid use disorder and willing to completely withdraw from his/her opioid use throughout the study with desire for or motivation for antagonist therapy * Wiling to abide by the contraception requirements for the duration of the study * Additional criteria may apply
Exclusion criteria
* Is pregnant, planning to become pregnant or breastfeeding during the study * Has used Buprenorphine within 7 days prior to randomization * Has used Methadone within 14 days prior to randomization * Has a history of VIVITROL use within 90 days prior to screening or has used oral naltrexone within 14 days prior to randomization * Has a history of seizures or has received anticonvulsant therapy within the past 5 years * Has a condition, disease state, or previous medical history that would preclude safe participation in the study or affect the ability to adhere to the protocol visit schedule, requirements, or assessments * Has a current diagnosis of schizoaffective disorder, bipolar disorder, or untreated and unstable major depressive disorder * Is currently physiologically dependent on any psychoactive substance (except opioids, caffeine, or nicotine) requiring medical intervention for detoxification * Has a history of hypersensitivity or adverse reaction to Buprenorphine, Naltrexone, or Naloxone * Has a history of more than 3 unsuccessful inpatient or medically assisted outpatient opioid detoxifications during his/her lifetime * Has significant suicidal ideation or behavior within the past year * Is currently participating, or has participated, in a clinical trial of an investigational drug, device, or biologics within 3 months prior to screening * Has a history of accidental opioid drug overdose in the past 3 years whether or not medical treatment was sought or received * Is court mandated to receive treatment for opioid use disorder * Additional criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Who Receive and Tolerate a VIVITROL Injection | 1 week | Toleration to the injection was demonstrated by mild opioid withdrawal symptoms (Clinical Opiate Withdrawal Scale \[COWS\] \</=12 or Subjective Opiate Withdrawal Scale \[SOWS\] \</=10) following VIVITROL administration. The COWS is a clinician-rated questionnaire designed to measure 11 common opioid withdrawal signs or symptoms. The summed score provides information about the level of physical dependence on opioids. The range of COWS scores is 0-4 (none to minimal); 5-12 (mild); 13-24 (moderate); 25-36 (moderately severe); and 37-48 (severe withdrawal. The SOWS is a 16-item self-report questionnaire designed to measure the severity of opioid withdrawal symptoms. The subject rates the intensity of symptoms using a 5-point scale. The range of SOWS scores is 1-10 (mild); 11-20 (moderate); and 21-30 (severe). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Peak COWS Score During Treatment Period Prior to VIVITROL Injection | 1 week | The Clinical Opiate Withdrawal Scale (COWS) is a clinician-rated questionnaire designed to measure 11 common opioid withdrawal signs or symptoms. The summed score provides information about the level of physical dependence on opioids. The range of COWS scores is 0-4 (none to minimal); 5-12 (mild); 13-24 (moderate); 25-36 (moderately severe); and 37-48 (severe withdrawal. |
| Area Under the Curve (AUC) COWS Score During the Treatment Period Prior to VIVITROL Injection | The COWS was administered 4-6 times per day during the Treatment Period (Days 1-7) | The Clinical Opiate Withdrawal Scale (COWS) is a clinician-rated questionnaire designed to measure 11 common opioid withdrawal signs or symptoms. The summed score provides information about the level of physical dependence on opioids. The range of COWS scores is 0-4 (none to minimal); 5-12 (mild); 13-24 (moderate); 25-36 (moderately severe); and 37-48 (severe withdrawal. To determine the daily AUC COWS score, a curve was generated by plotting the COWS scores against the time the test was taken. The area under this curve was calculated using the linear trapezoidal rule. For the total AUC COWS score, the AUCs calculated for each day during the treatment period were added together. To normalize for time, the total AUC COWS score was then divided by the number of days with daily AUC COWS score during the treatment period. The AUC COWS has a different range than the standard scale as it measures not the score itself, but the area under the curve of the score plotted against time. |
| Proportion of Days With COWS Peak Score of Less Than or Equal to 12 During the Treatment Period Prior to the VIVITROL Injection | 1 week | The Clinical Opiate Withdrawal Scale (COWS) is a clinician-rated questionnaire designed to measure 11 common opioid withdrawal signs or symptoms. The summed score provides information about the level of physical dependence on opioids. The range of COWS scores is 0-4 (none to minimal); 5-12 (mild); 13-24 (moderate); 25-36 (moderately severe); and 37-48 (severe withdrawal. |
| Incidence of Adverse Effects | Up to 92 days | The number of subjects who experienced treatment-emergent Adverse Events. |
| Area Under the Curve SOWS Score During the Treatment Period Prior to the VIVITROL Injection | The SOWS was administered 4-6 times per day during the Treatment Period | The Subjective Opiate Withdrawal Scale (SOWS) is a 16-item self-report questionnaire designed to measure the severity of opioid withdrawal symptoms. The subject rates the intensity of symptoms using a 5-point scale. The range of SOWS scores is 1-10 (mild); 11-20 (moderate); and 21-30 (severe). To determine the daily AUC SOWS score, a curve was generated by plotting the SOWS scores against the time the test was taken. The area under this curve was calculated using the linear trapezoidal rule. For the total AUC SOWS score, the AUCs calculated for each day during the treatment period were added together. To normalize for time, the total AUC SOWS score was then divided by the number of days with daily AUC SOWS score during the treatment period. The AUC SOWS has a different range than the standard scale as it measures not the score itself, but the area under the curve of the score plotted against time. |
| Mean Score for Desire of Opioids During Treatment Period Prior to VIVITROL Injection | 1 week | The Desire for Opioids Visual Analog Scale (VAS) uses a 100-mm, horizontal linear scale, with 0 anchored on the left representing no desire for opioids and 100 anchored on the right representing strongest imaginable desire for opioids. Subjects placed a vertical line on the scale to indicate their desire for opioids at that particular time. |
Countries
United States
Participant flow
Recruitment details
Adults with opioid use disorder who were voluntarily seeking treatment were eligible to enroll.
Pre-assignment details
Two subjects were randomized, but did not receive study drug. Four subjects attempted enrollment at multiple sites. The data collected on these subjects during their second enrollment was excluded from the efficacy analyses.
Participants by arm
| Arm | Count |
|---|---|
| NTX/BUP Oral naltrexone + sublingual buprenorphine
NTX/BUP: Daily doses | 126 |
| NTX/PBO-B Oral naltrexone + sublingual placebo
NTX/PBO-B: Daily doses | 126 |
| PBO-N/PBO-B Oral placebo naltrexone + sublingual placebo buprenorphine
PBO-N/PBO-B: Daily doses | 126 |
| Total | 378 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 | 2 |
| Overall Study | Duplicate Patient | 1 | 0 | 0 |
| Overall Study | Failed Naloxone Challenge | 0 | 1 | 0 |
| Overall Study | Incarceration | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 14 | 16 | 15 |
| Overall Study | Lost to Follow-up | 40 | 51 | 55 |
| Overall Study | Noncompliance with Protocol | 0 | 0 | 1 |
| Overall Study | Noncompliance with study drug | 0 | 1 | 1 |
| Overall Study | Patient not Stable | 0 | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 0 |
| Overall Study | Protocol Violation | 4 | 2 | 3 |
| Overall Study | Subject did not want last Vivitrol Injec | 0 | 0 | 1 |
| Overall Study | Transportation Issues | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 37 | 27 | 29 |
Baseline characteristics
| Characteristic | NTX/BUP | Total | PBO-N/PBO-B | NTX/PBO-B |
|---|---|---|---|---|
| Age, Continuous | 40 years STANDARD_DEVIATION 10.68 | 38.0 years STANDARD_DEVIATION 10.19 | 36.5 years STANDARD_DEVIATION 10.38 | 37.5 years STANDARD_DEVIATION 9.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 47 Participants | 16 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 106 Participants | 331 Participants | 110 Participants | 115 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 4 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 27 Participants | 76 Participants | 24 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 14 Participants | 7 Participants | 5 Participants |
| Race (NIH/OMB) White | 95 Participants | 279 Participants | 93 Participants | 91 Participants |
| Region of Enrollment United States | 126 participants | 378 participants | 126 participants | 126 participants |
| Sex: Female, Male Female | 40 Participants | 129 Participants | 42 Participants | 47 Participants |
| Sex: Female, Male Male | 86 Participants | 249 Participants | 84 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 126 | 0 / 126 | 0 / 126 |
| other Total, other adverse events | 18 / 126 | 12 / 126 | 19 / 126 |
| serious Total, serious adverse events | 2 / 126 | 1 / 126 | 2 / 126 |
Outcome results
Primary
Proportion of Subjects Who Receive and Tolerate a VIVITROL Injection
Toleration to the injection was demonstrated by mild opioid withdrawal symptoms (Clinical Opiate Withdrawal Scale \[COWS\] \</=12 or Subjective Opiate Withdrawal Scale \[SOWS\] \</=10) following VIVITROL administration. The COWS is a clinician-rated questionnaire designed to measure 11 common opioid withdrawal signs or symptoms. The summed score provides information about the level of physical dependence on opioids. The range of COWS scores is 0-4 (none to minimal); 5-12 (mild); 13-24 (moderate); 25-36 (moderately severe); and 37-48 (severe withdrawal. The SOWS is a 16-item self-report questionnaire designed to measure the severity of opioid withdrawal symptoms. The subject rates the intensity of symptoms using a 5-point scale. The range of SOWS scores is 1-10 (mild); 11-20 (moderate); and 21-30 (severe).
Time frame: 1 week
Population: The Full Analysis Set (FAS) includes all subjects in the Safety Population (randomized subjects who received at least 1 dose of study drug), excluding the second enrollment of duplicate subjects (those subjects who enrolled multiple times in the same study).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NTX/BUP | Proportion of Subjects Who Receive and Tolerate a VIVITROL Injection | 57 Participants |
| NTX/PBO-B | Proportion of Subjects Who Receive and Tolerate a VIVITROL Injection | 51 Participants |
| PBO-N/PBO-B | Proportion of Subjects Who Receive and Tolerate a VIVITROL Injection | 57 Participants |
p-value: 0.9495% CI: [0.61, 1.7]Regression, Logistic
p-value: 0.38395% CI: [0.48, 1.33]Regression, Logistic
Secondary
Area Under the Curve (AUC) COWS Score During the Treatment Period Prior to VIVITROL Injection
The Clinical Opiate Withdrawal Scale (COWS) is a clinician-rated questionnaire designed to measure 11 common opioid withdrawal signs or symptoms. The summed score provides information about the level of physical dependence on opioids. The range of COWS scores is 0-4 (none to minimal); 5-12 (mild); 13-24 (moderate); 25-36 (moderately severe); and 37-48 (severe withdrawal. To determine the daily AUC COWS score, a curve was generated by plotting the COWS scores against the time the test was taken. The area under this curve was calculated using the linear trapezoidal rule. For the total AUC COWS score, the AUCs calculated for each day during the treatment period were added together. To normalize for time, the total AUC COWS score was then divided by the number of days with daily AUC COWS score during the treatment period. The AUC COWS has a different range than the standard scale as it measures not the score itself, but the area under the curve of the score plotted against time.
Time frame: The COWS was administered 4-6 times per day during the Treatment Period (Days 1-7)
Population: All randomized subjects who received at least 1 dose of study drug and had 1 post-baseline COWS measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NTX/BUP | Area Under the Curve (AUC) COWS Score During the Treatment Period Prior to VIVITROL Injection | 955.7 Score on a scale | Standard Deviation 535.38 |
| NTX/PBO-B | Area Under the Curve (AUC) COWS Score During the Treatment Period Prior to VIVITROL Injection | 1004.8 Score on a scale | Standard Deviation 524.01 |
| PBO-N/PBO-B | Area Under the Curve (AUC) COWS Score During the Treatment Period Prior to VIVITROL Injection | 800.6 Score on a scale | Standard Deviation 403.01 |
Secondary
Area Under the Curve SOWS Score During the Treatment Period Prior to the VIVITROL Injection
The Subjective Opiate Withdrawal Scale (SOWS) is a 16-item self-report questionnaire designed to measure the severity of opioid withdrawal symptoms. The subject rates the intensity of symptoms using a 5-point scale. The range of SOWS scores is 1-10 (mild); 11-20 (moderate); and 21-30 (severe). To determine the daily AUC SOWS score, a curve was generated by plotting the SOWS scores against the time the test was taken. The area under this curve was calculated using the linear trapezoidal rule. For the total AUC SOWS score, the AUCs calculated for each day during the treatment period were added together. To normalize for time, the total AUC SOWS score was then divided by the number of days with daily AUC SOWS score during the treatment period. The AUC SOWS has a different range than the standard scale as it measures not the score itself, but the area under the curve of the score plotted against time.
Time frame: The SOWS was administered 4-6 times per day during the Treatment Period
Population: All randomized subjects who received at least 1 dose of study drug and had at least 1 post-baseline SOWS measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NTX/BUP | Area Under the Curve SOWS Score During the Treatment Period Prior to the VIVITROL Injection | 9038.5 Score on a scale | Standard Deviation 6800.6 |
| NTX/PBO-B | Area Under the Curve SOWS Score During the Treatment Period Prior to the VIVITROL Injection | 10,262.5 Score on a scale | Standard Deviation 7294.1 |
| PBO-N/PBO-B | Area Under the Curve SOWS Score During the Treatment Period Prior to the VIVITROL Injection | 9160.3 Score on a scale | Standard Deviation 6873.56 |
Secondary
Incidence of Adverse Effects
The number of subjects who experienced treatment-emergent Adverse Events.
Time frame: Up to 92 days
Population: The Safety Analysis Set was used to analyze this measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NTX/BUP | Incidence of Adverse Effects | 44 Participants |
| NTX/PBO-B | Incidence of Adverse Effects | 31 Participants |
| PBO-N/PBO-B | Incidence of Adverse Effects | 48 Participants |
Secondary
Mean Peak COWS Score During Treatment Period Prior to VIVITROL Injection
The Clinical Opiate Withdrawal Scale (COWS) is a clinician-rated questionnaire designed to measure 11 common opioid withdrawal signs or symptoms. The summed score provides information about the level of physical dependence on opioids. The range of COWS scores is 0-4 (none to minimal); 5-12 (mild); 13-24 (moderate); 25-36 (moderately severe); and 37-48 (severe withdrawal.
Time frame: 1 week
Population: The Full Analysis Set (FAS) included all subjects in the Safety Population (randomized subjects who received at least 1 dose of study drug), excluding the second enrollment of duplicate subjects (those subjects who enrolled multiple times in the same study).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NTX/BUP | Mean Peak COWS Score During Treatment Period Prior to VIVITROL Injection | 7.39 score on a scale | Standard Deviation 3.726 |
| NTX/PBO-B | Mean Peak COWS Score During Treatment Period Prior to VIVITROL Injection | 7.78 score on a scale | Standard Deviation 3.981 |
| PBO-N/PBO-B | Mean Peak COWS Score During Treatment Period Prior to VIVITROL Injection | 6.11 score on a scale | Standard Deviation 3.044 |
Secondary
Mean Score for Desire of Opioids During Treatment Period Prior to VIVITROL Injection
The Desire for Opioids Visual Analog Scale (VAS) uses a 100-mm, horizontal linear scale, with 0 anchored on the left representing no desire for opioids and 100 anchored on the right representing strongest imaginable desire for opioids. Subjects placed a vertical line on the scale to indicate their desire for opioids at that particular time.
Time frame: 1 week
Population: All randomized subjects who received at least 1 dose of study drug and provided at least 1 post-baseline measureable VAS assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NTX/BUP | Mean Score for Desire of Opioids During Treatment Period Prior to VIVITROL Injection | 48.1 score on a scale | Standard Deviation 27.61 |
| NTX/PBO-B | Mean Score for Desire of Opioids During Treatment Period Prior to VIVITROL Injection | 52.0 score on a scale | Standard Deviation 27.29 |
| PBO-N/PBO-B | Mean Score for Desire of Opioids During Treatment Period Prior to VIVITROL Injection | 45.8 score on a scale | Standard Deviation 26.03 |
Secondary
Proportion of Days With COWS Peak Score of Less Than or Equal to 12 During the Treatment Period Prior to the VIVITROL Injection
The Clinical Opiate Withdrawal Scale (COWS) is a clinician-rated questionnaire designed to measure 11 common opioid withdrawal signs or symptoms. The summed score provides information about the level of physical dependence on opioids. The range of COWS scores is 0-4 (none to minimal); 5-12 (mild); 13-24 (moderate); 25-36 (moderately severe); and 37-48 (severe withdrawal.
Time frame: 1 week
Population: The Full Analysis Set (FAS) included all subjects in the Safety Population (randomized subjects who received at least 1 dose of study drug), excluding the second enrollment of duplicate subjects (those subjects who enrolled multiple times in the same study).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NTX/BUP | Proportion of Days With COWS Peak Score of Less Than or Equal to 12 During the Treatment Period Prior to the VIVITROL Injection | 5.0 Number of days | Standard Deviation 2.23 |
| NTX/PBO-B | Proportion of Days With COWS Peak Score of Less Than or Equal to 12 During the Treatment Period Prior to the VIVITROL Injection | 4.5 Number of days | Standard Deviation 2.5 |
| PBO-N/PBO-B | Proportion of Days With COWS Peak Score of Less Than or Equal to 12 During the Treatment Period Prior to the VIVITROL Injection | 5.4 Number of days | Standard Deviation 2.02 |