SUBLOCADE Rapid Initiation Study

Study Overview
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Brief Summary
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This study is to evaluate the safety and tolerability of initiating SUBLOCADE™ treatment following a shorter period of transmucosal (TM) buprenorphine treatment.

Detailed Description
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Currently patients who are appropriate candidates for SUBLOCADE™ injection for subcutaneous (SC) use must initiate treatment with TM buprenorphine for a minimum of 7 days before receiving their first injection. This study is to evaluate the safety and tolerability of starting SUBLOCADE treatment following a shorter period. Adults with moderate to severe opioid use disorder (OUD) not currently receiving medication assisted treatment will be recruited to participate. Prior to receiving TM buprenorphine, subjects will report their last opioid use and be experiencing at least mild withdrawal. Subjects will receive at least one dose of TM buprenorphine to ensure tolerability and that they show no evidence of precipitated withdrawal. If no evidence of intolerability or no precipitated withdrawal occurs, subjects will receive a single injection of SUBLOCADE and remain in the clinic for approximately 48 hours after the injection to assess for safety and tolerability.

Official Title
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An Open-label, Rapid Initiation Study for Extended-Release Buprenorphine Subcutaneous Injection (SUBLOCADE)

Conditions
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Opioid-use Disorder

Intervention / Treatment
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* Drug: TM buprenorphine
* Drug: SUBLOCADE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed the informed consent form (ICF) and have the ability to comply with the requirements and restrictions listed therein. Documented history of moderate or severe opioid use disorder (OUD) as defined by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Seeking buprenorphine-assisted treatment for OUD and is an appropriate candidate in the opinion of the Investigator or medically qualified sub-Investigator. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin test), is not lactating and, if of childbearing potential, agrees not to become pregnant while on the study and use medically acceptable means of contraception while on the study. Exclusion Criteria: Current diagnosis, other than OUD, requiring chronic opioid treatment. Meet DSM-5 criteria for severe alcohol-use disorder. Has received any medication assisted treatment within 2 weeks. Concurrent or prior treatment with any long-acting depot form of buprenorphine containing products. Concurrent treatment with another investigational agent or enrolment in another clinical study (except for an observational study) or treatment with another investigational agent within 30 days prior to screening. Concurrent treatment with medications contraindicated for use with buprenorphine as per local prescribing information, including benzodiazepines or any other central nervous system depressants. Significant traumatic injury, major surgical procedure (as defined by the Investigator) within 30 days prior to Day 1 or still recovering from prior surgery. Any other active medical condition, organ disease or concurrent medication or treatment that may either compromise subject safety or interfere with study endpoints. Congenital long QT syndrome, history of prolonged QT in the 3 months prior to screening, or a corrected QT interval (Fridericia's - QTcF) >450 msec (male) or >470 msec (female), or history of risk factors for Torsades de Pointes. Known personal and/or family history of congenital QT prolongation, or taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone) or other mediations that prolong the QT interval. Known family history of sudden unexplained death. Total bilirubin ≥1.5*upper limit of normal (ULN), alanine aminotransferase (ALT) ≥3*ULN, aspartate aminotransferase (AST) ≥5*ULN, serum creatinine >2*ULN at screening. Abdominal area unsuitable for SC injections. Uncontrolled intercurrent illness including, but not limited to, a medical or psychiatric illness/social situation that would limit compliance with study requirements or compromise the ability of the subject to provide written informed consent. Known allergy or hypersensitivity to buprenorphine, ATRIGEL or their excipients. Subject to court order requiring treatment for OUD. Subjects who are unable, in the opinion of the Investigator or Indivior, to comply fully with the study requirements including those who are currently incarcerated or pending incarceration/legal action. Clinic staff and/or subjects who have a financial interest in the study or who have an immediate family member of either the clinic staff and/or Indivior employees directly involved in the study.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TM buprenorphine followed by SUBLOCADE 300 mg<br>Participants with a diagnosis of OUD stopped use of their current opioid prior to coming to the clinic to be assessed for withdrawal symptoms. If confirmed to be in withdrawal, participants were administered 4 mg transmucosal (TM) buprenorphine. If tolerated without sensitivity, clinical signs of sedation, or precipitated withdrawal, 300 mg SUBLOCADE was administered. Following SUBLOCADE administration, participants remained in the clinic for approximately 48 hours and were assessed for safety and tolerability, as well as for any signs of precipitated withdrawal. Participants returned to the clinic weekly, until the end-of-treatment (EOT) visit (28 days after SUBLOCADE administration). | Drug: TM buprenorphine<br>* 4mg TM buprenorphine, investigator choice as to brand<br>* Other names: generic buprenorphine;Drug: SUBLOCADE<br>* 300mg subcutaneous injection<br>* Other names: extended release buprenorphine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Who Experienced Any Precipitated Withdrawal Within One Hour After SUBLOCADE Administration | Clinical Opiate Withdrawal Scale (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. Precipitated withdrawal was defined as in increase in Clinical Opioid Withdrawal Scale (COWS) score by ≥6 from the pre-SUBLOCADE value within 1 hour SUBLOCADE injection. | Day 1: Pre-SUBLOCADE evaluation taken after TM buprenorphine treatment and prior to injection: SUBLOCADE evaluation taken within one hour of SUBLOCADE injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Treatment-Emergent Adverse Events (TEAE) | A TEAE was an AE that started after the administration of TM buprenorphine for induction on Day 1. 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 as 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 AE, 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 or surgical intervention to prevent one of the outcomes listed in this definition. AEs of special interest include SUBOCADE depot removal, occurrences of alanine aminotransferase (ALT) >3*upper limit of normal (ULN) and bilirubin >2*ULN. | Day 1 to Day 28 | 
| Participants With Treatment-Emergent Adverse Events (TEAE) Within 48 Hours Post-SUBLOCADE Injection | A TEAE was an AE that started after the administration of TM buprenorphine for induction on Day 1. 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 as 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 AE, 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 or surgical intervention to prevent one of the outcomes listed in this definition. AEs of special interest include SUBOCADE depot removal, occurrences of alanine aminotransferase (ALT) >3*upper limit of normal (ULN) and bilirubin >2*ULN. | Day 1 SUBLOCADE injection up to 48 hours later | 
| Cumulative Number of Participants Who Experienced a >=6 Point Clinical Opiate Withdrawal Scale (COWS) Total Score Increase After SUBLOCADE Administration From the Pre-SUBLOCADE Value at Key Timepoints | 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. Cumulative number of participants in key timepoints who had a COWS total score increase of ≥6 points from the pre-SUBLOCADE value. | Day 1: Pre-SUBLOCADE evaluation taken after TM buprenorphine treatment and prior to injection: SUBLOCADE evaluations taken 1, 6, 12, 24 and 48 hours after SUBLOCADE injection. | 
| COWS Total Score Normalized Area Under the Curve (AUC) Through Key Timepoints Post SUBLOCADE Injection | The area under the curve (AUC) for COWS total score from the pre-SUBLOCADE value to a later time point were calculated using the linear trapezoidal method. For each analysis time interval (AUC0-1hr, AUC0-6hrs, AUC0-12hrs, AUC0-24hrs, AUC0-48hrs) the AUC value was normalized across participants for the actual duration (in hours) of the time interval. The normalized AUC for COWS can be interpreted as the averaged AUC per hour or the averaged COWS over a time interval, as if the COWS was measured hourly during that time interval. Participants were included in a given interval if they had a pre-SUBLOCADE COWS assessment and a COWS assessment at the terminal timepoint for the interval. | SUBLOCADE injection on Day 1 through 1, 6, 12, 24 and 48 hours after SUBLOCADE injection | 
| Total Score on COWS At Timepoints During the Treatment Period | Clinical Opiate Withdrawal Scale (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. | Day 1 to Day 29 | 
| Total Score on Opioid Craving Visual Analogue Scale (OC-VAS) At Timepoints During the Treatment Period | Participants indicated their level of craving for opioids by marking a 100mm visual analogue scale where 0 = no craving and 100 = maximal craving. | Day 1 to Day 29 |