Evaluation of Long-term Buprenorphine Plasma Exposure

Study Overview
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Brief Summary
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The study objective is to characterise the long-term plasma exposure to buprenorphine after stopping SUBLOCADE treatment. There are no interventions planned. This multicentre investigation will enroll participants from Study RB-US-13-0003 (NCT02510014) or both Studies RB-US-13-0003 and INDV-6000-301 (NCT02896296) and who received at least 2 subcutaneous (SC) injections of SUBLOCADE. There are two parts to the study: Part A consists of a single visit during which urine samples are collected to measure free buprenorphine and free norbuprenorphine concentrations; qualitative urine drug samples (UDS) for opioids, including buprenorphine; quantitative UDS for buprenorphine, norbuprenorphine and naloxone; and determination of creatinine concentration. Blood samples are collected for the determination of buprenorphine and norbuprenorphine plasma concentrations. Results on the quantitative UDS performed in Part A determine enrollment in Part B: participants who provide a quantifiable (i.e., positive) result for buprenorphine and/or norbuprenorphine and a non-quantifiable (i.e., negative) result for naloxone meet continuation criteria to move on to Part B if Part B is still open to enrolment. Part B consists of two visits 30 days apart in which the same tests are run as were done in Part A.

Detailed Description
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Data indicate that after discontinuing SUBLOCADE patients may have detectable concentrations of buprenorphine in plasma and urine for 12 months or longer. Previous Phase II/III studies did not evaluate the pharmacokinetics (PK) of buprenorphine beyond 2 months after the last injection; this study will characterize the long-term plasma exposure starting at least 12 months after the last injection. The study will also assess relationships between plasma drug concentrations, free drug concentrations in urine and urine drug screen (UDS) results in order to provide refined guidance to patients and physicians with respect to long-term exposure to buprenorphine after stopping SUBLOCADE treatment.

Official Title
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Evaluation of Long-term Buprenorphine Plasma Exposure in Subjects Who Received at Least 2 Subcutaneous (SC) Injections of Extended-release Buprenorphine (SUBLOCADE™) in Phase III Studies

Conditions
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Opioid-use Disorder

Intervention / Treatment
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* Diagnostic Test: Blood sample collection
* Diagnostic Test: Urine sample collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participated in Study RB-US-13-0003 or both Studies RB-US-13-0003 and INDV-6000-301 and received at least 2 subcutaneous (SC) injections of SUBLOCADE Within 12 to 36 months post his or her last SUBLOCADE injection at the time of the Screening Visit Female individuals of childbearing potential must agree to have a pregnancy test administered prior to enrollment and throughout the study. Pregnancy does not prohibit participation Willing to adhere to study procedures and provide written informed consent prior to the start of any study procedures. Exclusion Criteria: Received SUBLOCADE or any other long-acting buprenorphine product at any time after ending their participation in Study RB-US-13-0003 or Study INDV-6000-301 Taken any buprenorphine (prescribed or illicit) within 3 weeks prior to the Screening visit (study Part A, Visit 1)
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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Part A Cohort<br>Representative data set of participants from study RB-US-13-0003 or both studies RB-US-13-0003 and INDV-6000-301 who received at least 2 doses of SUBLOCADE 12-36 months prior. Part A consists of a single visit (Visit 1) for both screening and collection of blood and urine samples. | Diagnostic Test: Blood sample collection<br>* Determination of buprenorphine and norbuprenorphine plasma concentrations<br>Diagnostic Test: Urine sample collection<br>* Urine sample for determination of free buprenorphine and free norbuprenorphine concentrations, qualitative UDS for opioids, quantitative UDS for buprenorphine, norbuprenorphine and naloxone, and determination of creatinine concentration<br>|
| Part B Cohort<br>Part A participants with a quantifiable (i.e. positive) result for buprenorphine and/or norbuprenorphine and a non-quantifiable (i.e. negative) result for naloxone continue in the study for two additional visits (Visits 2 and 3) which are conducted approximately 30 days apart during which blood and urine samples are collected. | Diagnostic Test: Blood sample collection<br>* Determination of buprenorphine and norbuprenorphine plasma concentrations<br>Diagnostic Test: Urine sample collection<br>* Urine sample for determination of free buprenorphine and free norbuprenorphine concentrations, qualitative UDS for opioids, quantitative UDS for buprenorphine, norbuprenorphine and naloxone, and determination of creatinine concentration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Qualitative Urinary Drug Screen (UDS) for Buprenorphine in Parts A + B | The qualitative UDS (immunoassay) is the primary test used for the initial screening for opioids in patients in clinical practice. It provides only a qualitative assessment of buprenorphine exposure (i.e., positive or negative) with a low limit of quantification (LLOQ) of 5 ng/mL. The qualitative UDS is reported for Part A Cohort (Visit 1) and Part B Cohort (Visits 1, 2 and 3). Participants' last subcutaneous injections of extended release buprenorphine (SUBLOCADE™) was 22 - 38 months prior during previous phase III studies. | Days 1, 30, 60 | 
| Quantitative Urine Drug Screen (UDS) for Buprenorphine and Norbuprenorphine in Parts A + B | The quantitative UDS measures both buprenorphine and its glucuronide, or both norbuprenorphine and its glucuronide, with an LLOQ of 2 ng/mL. It is typically used by physicians for the confirmation of a positive result on the qualitative UDS. Data are reported for Part A Cohort (Visit 1) and Part B Cohort (Visits 1, 2 and 3). For Bup+Nor (abbreviation for Buprenorphine + Norbuprenorphine), the result is negative if results for both are negative, the result is positive if either result is positive. If both are missing/not available, or one is negative and the other is missing/not evaluable, the result is Not Available Participants' last subcutaneous injections of extended release buprenorphine (SUBLOCADE™) was 22 - 38 months prior during previous phase III studies. | Days 1, 30, 60 | 
| Urine Free Drug Test for Buprenorphine and Norbuprenorphine in Parts A + B | The urine free drug test only measures the free buprenorphine and free norbuprenorphine (without their glucuronides) with an LLOQ of 0.02 ng/mL. Data are reported for Part A Cohort (Visit 1) and Part B Cohort (Visits 1, 2 and 3). For Bup+Nor (abbreviation for Buprenorphine + Norbuprenorphine), the result is negative if results for both are negative, the result is positive if either result is positive. If both are missing/not available, or one is negative and the other is missing/not evaluable, the result is Not Available Participants' last subcutaneous injections of extended release buprenorphine (SUBLOCADE™) was 22 - 38 months prior during previous phase III studies. | Days 1, 30, 60 | 
| Plasma Drug Test for Buprenorphine and Norbuprenorphine in Parts A + B | A sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was used to assess the plasma exposure to buprenorphine and norbuprenorphine, its major metabolite. The LLOQ was 0.02 ng/mL for both analytes, which is much lower than the LLOQ of plasma/serum assays conducted by diagnostic laboratories. Data are reported for Part A Cohort (Visit 1) and Part B Cohort (Visits 1, 2 and 3). For Bup+Nor (abbreviation for Buprenorphine + Norbuprenorphine), the result is negative if results for both are negative, the result is positive if either result is positive. If both are missing/not available, or one is negative and the other is missing/not evaluable, the result is Not Available Participants' last subcutaneous injections of extended release buprenorphine (SUBLOCADE™) was 22 - 38 months prior during previous phase III studies. | Days 1, 30, 60 |