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Safety and Tolerability Study of Depot Buprenorphine in Treatment Seeking Subjects With Opioid Use Disorder

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ClinicalTrials.gov Identifier: NCT02510014
Recruitment Status : Completed
First Posted : July 28, 2015
Results First Posted : March 29, 2018
Last Update Posted : March 29, 2018
Sponsor:
Information provided by (Responsible Party):
Indivior Inc.

Brief Summary:
A multi-center, open-label, long-term safety study in which approximately 600 subjects diagnosed with opioid use disorder will be enrolled. Following a screening period, all subjects will receive run in SUBOXONE sublingual film followed by an initial injection of open-label high dose (300 mg) RBP-6000. The RBP-6000 monthly injection dose can be adjusted to low dose (100 mg), and back to high dose, based on the medical judgment of the Investigator. Subjects will participate in the study for either 6 or 12 months.

Condition or disease Intervention/treatment Phase
Opioid Use Disorder Opioid-related Disorders Drug: SUBOXONE sublingual film Drug: RBP-6000 Phase 3

Detailed Description:

Approximately 600 subjects diagnosed with opioid use disorder will be enrolled; approximately 300 subjects who completed the randomized,double-blind, placebo-controlled study NCT02357901 (RB-US-13-0001) ('roll-over' participants), and approximately 300 subjects who did not participate in study RB-US-13-0001 ('de novo' participants). Following informed consent and completion of screening procedures, all subjects will receive SUBOXONE sublingual film, titrated to response.

After 4-14 days of SUBOXONE sublingual film treatment, subjects will be evaluated for enrollment into the study. Eligible subjects will receive 300 mg RBP-6000 as an initial dose, followed by monthly injections of 100 mg or 300 mg RBP-6000, based on the medical judgment of the investigator.

Subjects who participated in study RB-US-13-0001 ('roll-over' participants) will receive monthly injections for up to 6 months. Subjects who did not participate in study RB-US-13-0001 ('de novo' participants) will receive monthly injections for up to12 months.

At all injection visits continuous electrocardiogram recordings and pulse oximetry will be collected prior to injection and at least 4 hours after injection. Subjects will return to the clinic every 1-4 weeks for laboratory tests, complete study questionnaires, adverse event and injection site assessments.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 775 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Long-Term Safety and Tolerability Study of Depot Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With Opioid Use Disorder
Actual Study Start Date : July 27, 2015
Actual Primary Completion Date : January 31, 2017
Actual Study Completion Date : January 31, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Roll-over Subjects
Subjects who completed RB-US-13-0001 received SUBOXONE sublingual film during the Run-In period, followed by an initial open-label injection of 300 mg RBP-6000. Participants continued with monthly injections of either 300 mg or 100 mg (based on judgement of the Investigator) for a total of 6 months in the Treatment period.
Drug: SUBOXONE sublingual film
SUBOXONE (buprenorphine sublingual film) is used for induction therapy on Days -14 to -12. Participants then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to starting the Treatment Period.
Other Names:
  • SUBOXONE
  • buprenorphine

Drug: RBP-6000
Injections administered subcutaneously every 28 days on alternate sides of participant's abdomen starting at 300 mg. Subsequent doses of RBP-6000 could be adjusted down to 100 mg with the possibility of adjusting back up to 300 mg based on the medical judgment of the investigator. De novo subjects receive up to 12 injections and roll-over subjects receive up to 6 injections.
Other Name: Atrigel buprenorphine

Experimental: De Novo Subjects
Subjects who did not participate in RB-US-13-0001 received SUBOXONE sublingual film during the Run-In period, followed by an initial open-label injection of 300 mg RBP-6000. Participants continued with monthly injections of either 300 mg or 100 mg (based on judgement of the Investigator) for a total of 12 months in the Treatment period.
Drug: SUBOXONE sublingual film
SUBOXONE (buprenorphine sublingual film) is used for induction therapy on Days -14 to -12. Participants then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to starting the Treatment Period.
Other Names:
  • SUBOXONE
  • buprenorphine

Drug: RBP-6000
Injections administered subcutaneously every 28 days on alternate sides of participant's abdomen starting at 300 mg. Subsequent doses of RBP-6000 could be adjusted down to 100 mg with the possibility of adjusting back up to 300 mg based on the medical judgment of the investigator. De novo subjects receive up to 12 injections and roll-over subjects receive up to 6 injections.
Other Name: Atrigel buprenorphine




Primary Outcome Measures :
  1. Participants With Treatment-Emergent Adverse Events (TEAE) During the Treatment Period [ Time Frame: Day 1 to Week 49 (De novo arm); Day 1 to Week 25 (Roll-over arm) ]
    TEAE=any untoward medical occurrence that develops or worsens in severity after dispensation of the study drug and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= a marked limitation in activity. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent one of the outcomes listed in this definition.

  2. Percentage Change From Baseline to End of Study (Weeks 25 and 49) in Vital Signs [ Time Frame: Baseline (Day 1 predose) End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) ]

    Vital signs include

    • systolic blood pressure (mmHg)
    • diastolic blood pressure (mmHg)
    • respiratory rate (breaths/minute)
    • weight (kg)
    • body mass index (kg/m^2)
    • waist-to-hip ratio

    Baseline is defined as the last non-missing value prior to subcutaneous injection of RBP-6000 on Day 1.


  3. Shifts in Suicidality Using the Columbia Suicide Severity Rating Scale (C-SSRS) From Baseline to Most Severe Assessment During the Treatment Period [ Time Frame: Baseline (Screening visit, days -21 to -15), End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) ]

    The C-SSRS asks questions of study participants regarding whether they had suicidal ideation and/or suicidal behavior since the last visit using the electronic version of the scale. Only the most severe assessment is reported in this summary. Participants who experienced suicidal ideation and suicidal behavior are only summarized in the suicidal behavior since behavior is more severe than ideation.

    C-SSRS baseline version was completed during the screening visit. C-SSRS 'since-last-visit' version was completed weekly for the first month and at least every month until the end of the study.

    Shift table category titles are structured as: baseline category/treatment category. The category 'No Suicidal Ideation or Behaviour' has been abbreviated as 'No Suicidal I or B'.


  4. Worst Local Injection Site Pain From Injections as Measured by Participant-Reported Visual Analog Scale (VAS) [ Time Frame: De Novo Subjects: Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281 and 309 Roll-over Subjects: Days 1, 29, 57, 85, 113, 141 ]

    Injection site pain as measured by participant-reported VAS. The participant-reported VAS for injection site pain was measured on a 100 mm scale with 'no pain' at 0 mm and 'strongest pain ever' at 100 mm (total scale of 0-100). Participants marked where along the scale reflected their localized injection pain.

    The injection site pain VAS scores were obtained (after the completion of the injection) within 1 minute and at 5, 10, 15, 30 and 60 minutes (+- 5 minutes). The timing of the injection site pain VAS should have been measured from the end of the injection.

    Data represents the worst pain recorded for each participant across all injections and all VAS records. The mean value is presented.

    De Novo subjects were given injections on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281 and 309.

    Roll-over subjects were given injections on Days 1, 29, 57, 85, 113, 141.



Secondary Outcome Measures :
  1. Change From Baseline in the Clinical Opiate Withdrawal Scale (COWS) at End of Study (Weeks 25 and 49) [ Time Frame: Baseline (Day 1 predose), End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) ]

    COWS is an 11-item instrument used to assess signs and symptoms of opioid withdrawal. The score is the sum of the responses for a total range of 0-48. The COWS is commonly used by clinicians treating patients with buprenorphine to monitor the severity of withdrawal. COWS scores below 5 are considered not indicative of withdrawal. Scores from 5 to 12 are considered mild withdrawal; from 13 to 24 moderate withdrawal; 25 to 36 moderately severe withdrawal, and 37-48 severe withdrawal. Negative change from baseline values indicate a lessening of withdrawal symptoms.

    Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. Baseline value is reported as an observed actual value. Weeks 25 and 49 represent change from baseline values.


  2. Change From Baseline in the Subjective Opiate Withdrawal Scale (SOWS) at End of Study (Weeks 25 and 49) [ Time Frame: Baseline (Day 1 predose), End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) ]

    The Subjective Opiate Withdrawal Scale (SOWS) contains 16 symptoms whose intensity the participant rates on a scale of 0 (not at all) to 4 (extremely) for a full scale of 0 (no withdrawal symptoms) to 64 (extreme withdrawal symptoms). Negative change from baseline values indicate a lessening of withdrawal symptoms.

    Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. Baseline value is reported as an observed actual value. Weeks 25 and 49 represent change from baseline values.


  3. Change From Baseline in the Opioid Craving Visual Analog Scale (VAS) at End of Study (Weeks 25 and 49) [ Time Frame: Baseline (Day 1 predose), End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) ]

    The opioid craving scale was a 100 mm scale with 'no craving' indicated by 0 mm and 'strongest craving ever' indicated by 100 mm. Participants marked where along the scale reflected their craving for opioids.

    Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. Baseline value is reported as an observed actual value. Weeks 25 and 49 represent change from baseline values.


  4. Cumulative Distribution Function (CDF) of the Percentage Abstinence Collected From Week 1 Through End of Study (Weeks 25 and 49) [ Time Frame: Weekly during Month 1, Every other week from Month 2-6, Monthly from Month 7-12. De novo arm stopped at Week 49. Roll-over arm stopped at Week 25 ]

    Participants' self-reported illicit opioid drug use from the timeline followback (TLFB) interview and results from the urine drug screens (UDS) for opioids were combined into a single endpoint. Opioids assessed included codeine, hydrocodone, hydromorphone, methadone, morphine, opiates, oxycodone, and oxymorphone (by UDS) and amphetamine/methadone, buprenorphine, methadone, and opioids in the TLFB.

    Data represent the count of participants at various percentage abstinence levels. Abstinence was defined as urine samples being negative for opioids AND negative self-reports (obtained from Timeline Followback (TLFB) interviews) for illicit opioid use. The endpoint was based on visits in which paired urine samples and self-reports were expected for each subject as specified in the schedule of events. All missing reports for opioids were considered nonnegative.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

De novo subjects:

  • Seeking treatment for opioid use disorder (OUD) and for the previous 3 months meet the Diagnostic and Statistical Manual 5 (DSM-5) criteria for moderate or severe OUD
  • Appropriate candidate for opioid partial-agonist treatment
  • BMI between 18 and 35, inclusive

Roll-over subjects:

  • Completed RB-US-13-0001

Exclusion Criteria:

De novo subjects:

  • Current diagnosis, other than OUD, requiring chronic opioid treatment
  • Current substance use disorder with regard to substances other than opioids, cocaine, cannabis, tobacco or alcohol
  • Received medication-assisted treatment for OUD in the 90 days prior to informed consent
  • Use (within past 30 days prior to informed consent) or positive urine drug screen (UDS) at screening for barbiturates, benzodiazepines,methadone or buprenorphine
  • Treatment for OUD required by court order
  • History of recent suicidal ideation or attempt

Roll over subjects:

  • Experienced major protocol deviations or adverse events in RB-US-13-0001 which could potentially compromise subject safety
  • Discontinued early from study RB-US-13-0001

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02510014


  Show 42 Study Locations
Sponsors and Collaborators
Indivior Inc.
Investigators
Study Director: Global Director Clinical Development Indivior Inc.
  Study Documents (Full-Text)

Documents provided by Indivior Inc.:
Study Protocol: Original  [PDF] April 14, 2015
Study Protocol: Amendment 1  [PDF] August 19, 2015
Study Protocol: Amendment 2  [PDF] September 11, 2015
Study Protocol: Amendment 3  [PDF] March 25, 2016
Statistical Analysis Plan  [PDF] April 10, 2017
Study Protocol: Amendment 4  [PDF] August 4, 2016


Responsible Party: Indivior Inc.
ClinicalTrials.gov Identifier: NCT02510014     History of Changes
Other Study ID Numbers: RB-US-13-0003
First Posted: July 28, 2015    Key Record Dates
Results First Posted: March 29, 2018
Last Update Posted: March 29, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Disease
Opioid-Related Disorders
Pathologic Processes
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Buprenorphine
Buprenorphine, Naloxone Drug Combination
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Narcotic Antagonists