Multiple Dose Pharmacokinetics Depot Buprenorphine in Opioid-Dependent Subjects

Study Overview
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Brief Summary
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This is an open-label study in treatment seeking opioid-dependent subjects for safety, tolerability, pharmacokinetics (PK), efficacy markers, and opioid receptor availability of subcutaneous injections of depot buprenorphine after induction and stabilization of treatment seeking subjects onto Subutex. Subjects were planned to receive 4 subcutaneous (SC) injections of RBP-6000 separated by 28 days (Cohorts 1-5) or 6 SC injections of RBP-6000 separated by 28 days (Cohort 6) after a 13-day induction and dose stabilisation period on SUBUTEX Sublingual (SL) tablet at dose levels of 8-24 mg.

Detailed Description
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Open-label SUBUTEX Sublingual Tablet Induction and Stabilisation Period After completing the screening period, subjects entered an open-label SUBUTEX SL tablet induction and stabilisation period to achieve stable daily doses of 8 mg, 12 mg, 14 mg, 24 mg or 8 - 24 mg (variable) during a 13 day inpatient (Day -14 to Day -1) period. Open-label Treatment Phase On Day 1, eligible subjects discontinued use of SUBUTEX SL tablet and received a subcutaneous (SC) injection of RBP-6000. The dose of RBP-6000 received and the cohort to which a subject was assigned depended upon the SUBUTEX SL tablet dose on Day -1. Injection 1 (Day 1): 3 days inpatient post-dose (Day 1 to Day 3) and outpatient visits (Day 4 to Day 28); serial pharmacokinetic (PK) samples Injection 2 (Day 29): 60-hour inpatient pre-dose and post-dose (Day 28 to Day 31) and outpatient visits (Day 32 to Day 56); sparse PK samples Injection 3 (Day 57): 60-hour inpatient pre-dose and post-dose (Day 56 to Day 59) and outpatient visits (Day 60 to Day 84); sparse PK samples Injection 4 (Day 85): 60-hour inpatient pre-dose and post-dose (Day 84 to Day 87) and outpatient visits (Day 88 to Day 113 [or Day 112 for Cohort 6]); serial PK samples Cohort 6 ONLY: Injection 5 (Day 113): 60-hour inpatient pre-dose and post-dose (Day 112 to Day 115) and outpatient visits (Day 116 to Day 140); serial PK samples Cohort 6 ONLY: Injection 6 (Day 141): 60-hour inpatient pre- and post-dose (Day 140 to Day 143) and outpatient visits (Day 144 to Day 169); serial PK samples Safety Follow-up: weekly visits up to 60 days post-Injection 4 (PK Day 114 to Day 141) for subjects in Cohorts 1-5 who did not take part in the positron emission tomography (PET) imaging sub-study and up to 60 days post-Injection 6 (PK Day 169 to Day 197) for subjects in Cohort 6 The objective of the PET imaging sub-study was to evaluate the relationship between buprenorphine plasma levels and the ability of the 200 mg and 300 mg doses of RBP-6000 to reduce mu-opioid receptor availability measured with [11C]carfentanil and positron emission tomography (PET) scans. This objective was exploratory in nature and results are not reported as part of these summary results.

Official Title
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Open-Label, Multicenter, Multiple Dose Study of Safety, Tolerability, Pharmacokinetics, Efficacy Markers, and Opioid Receptor Availability of Subcutaneous Injections of Depot Buprenorphine in Treatment Seeking Opioid-Dependent Subjects

Conditions
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Opioid Related Disorder

Intervention / Treatment
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* Drug: RBP-6000
* Drug: Subutex


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects Agree not to take any buprenorphine products other than those administered for the current study throughout participation in the study Body mass index (BMI) of >18.0 to < 33.0 kg/m Exclusion Criteria: Participants with a current diagnosis requiring chronic opioid treatment Participants with a history of risk factors of Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) or an ECG demonstrating a Fridericia's corrected QT interval (QTcF) >450 msec in males and QTcF > 470 in females at screening Abuse of buprenorphine or use of buprenorphine within 14 days of informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (8 mg) RBP-6000: 50 mg<br>Participants are stabilized by day -5 on Subutex 8 mg. During the study, four subcutaneous (SC) injections containing RBP-6000 50 mg are given at 28 day intervals. | Drug: RBP-6000<br>* 18% Buprenorphine Sterile Solution for subcutaneous (SC) injection using the ATRIGEL® Delivery System. Each injection of RBP-6000 is separated by a minimum of 28 days and given on alternate sides of the participant's abdomen.<br>* Other names: buprenorphine;Drug: Subutex<br>* Participants were inducted and stabilized over a 14-day period (study days -14 to -1) on SUBUTEX sublingual tablets. Tablets are placed under the tongue until dissolved.<br>* Other names: buprenorphine;|
| Experimental: (12 mg) RBP-6000: 100 mg<br>Participants are stabilized by day -5 on Subutex 12 mg. During the study, four subcutaneous (SC) injections containing RBP-6000 100 mg are given at 28 day intervals | Drug: RBP-6000<br>* 18% Buprenorphine Sterile Solution for subcutaneous (SC) injection using the ATRIGEL® Delivery System. Each injection of RBP-6000 is separated by a minimum of 28 days and given on alternate sides of the participant's abdomen.<br>* Other names: buprenorphine;Drug: Subutex<br>* Participants were inducted and stabilized over a 14-day period (study days -14 to -1) on SUBUTEX sublingual tablets. Tablets are placed under the tongue until dissolved.<br>* Other names: buprenorphine;|
| Experimental: (24 mg) RBP-6000: 200 mg<br>Participants are stabilized by day -5 on Subutex 24 mg. During the study, four subcutaneous (SC) injections containing RBP-6000 200 mg are given at 28 day intervals. Participants who receive RBP-6000 containing 200 mg buprenorphine and reach Day 112 (and have received all 4 planned SC injections) have the option to participate in the Positron Emission Tomography (PET) Pilot substudy. In the PET Pilot sub-study participants remain on 200 mg SC injections at 28 day intervals for an additional 6-9 intervals until they complete an magnetic resonance imaging (MRI) and a PET scan and pharmacokinetic samples at week 1 and week 4 post injection. | Drug: RBP-6000<br>* 18% Buprenorphine Sterile Solution for subcutaneous (SC) injection using the ATRIGEL® Delivery System. Each injection of RBP-6000 is separated by a minimum of 28 days and given on alternate sides of the participant's abdomen.<br>* Other names: buprenorphine;Drug: Subutex<br>* Participants were inducted and stabilized over a 14-day period (study days -14 to -1) on SUBUTEX sublingual tablets. Tablets are placed under the tongue until dissolved.<br>* Other names: buprenorphine;|
| Experimental: (8 mg) RBP-6000: 100 mg<br>Participants are stabilized by day -5 on Subutex 8 mg. During the study, four subcutaneous (SC) injections containing RBP-6000 100 mg are given at 28 day intervals. | Drug: RBP-6000<br>* 18% Buprenorphine Sterile Solution for subcutaneous (SC) injection using the ATRIGEL® Delivery System. Each injection of RBP-6000 is separated by a minimum of 28 days and given on alternate sides of the participant's abdomen.<br>* Other names: buprenorphine;Drug: Subutex<br>* Participants were inducted and stabilized over a 14-day period (study days -14 to -1) on SUBUTEX sublingual tablets. Tablets are placed under the tongue until dissolved.<br>* Other names: buprenorphine;|
| Experimental: (14 mg) RBP-6000: 200 mg<br>Participants are stabilized by day -5 on Subutex 14 mg. During the study, four subcutaneous (SC) injections containing RBP-6000 200 mg are given at 28 day intervals. Participants who receive RBP-6000 containing 200 mg buprenorphine and reach Day 112 (and have received all 4 planned SC injections) have the option to participate in the Positron Emission Tomography (PET) Pilot substudy. In the PET Pilot sub-study participants remain on 200 mg SC injections at 28 day intervals for an additional 6-9 intervals until they complete an magnetic resonance imaging (MRI) and a PET scan and pharmacokinetic samples at week 1 and week 4 post injection. | Drug: RBP-6000<br>* 18% Buprenorphine Sterile Solution for subcutaneous (SC) injection using the ATRIGEL® Delivery System. Each injection of RBP-6000 is separated by a minimum of 28 days and given on alternate sides of the participant's abdomen.<br>* Other names: buprenorphine;Drug: Subutex<br>* Participants were inducted and stabilized over a 14-day period (study days -14 to -1) on SUBUTEX sublingual tablets. Tablets are placed under the tongue until dissolved.<br>* Other names: buprenorphine;|
| Experimental: (8-24 mg) RBP-6000: 300 mg<br>Participants are stabilized by day -5 on a Subutex between 8-24 mg. During the study, four subcutaneous (SC) injections containing RBP-6000 300 mg are given at 28 day intervals. | Drug: RBP-6000<br>* 18% Buprenorphine Sterile Solution for subcutaneous (SC) injection using the ATRIGEL® Delivery System. Each injection of RBP-6000 is separated by a minimum of 28 days and given on alternate sides of the participant's abdomen.<br>* Other names: buprenorphine;Drug: Subutex<br>* Participants were inducted and stabilized over a 14-day period (study days -14 to -1) on SUBUTEX sublingual tablets. Tablets are placed under the tongue until dissolved.<br>* Other names: buprenorphine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Treatment-Emergent Adverse Events (TEAEs) | 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. A serious AE (SAE) is defined as any AE occurring at any dose that results in any of the following outcomes: death; lifethreatening AE; hospitalization or prolongation of existing hospitalization; a persistent or significant disability/incapacit | Days -14 to -1 (Subutex treatment), Days 1-316 (RBP-6000 treatment) | 
| Buprenorphine PK: % Fluctuation | % Fluctuation was defined as the degree of fluctuation of buprenorphine plasma concentrations calculated as (Cmax-Cmin)/Cavg*100, expressed as a percentage. Cmax=maximum plasma concentration Cmin=minimum plasma concentration Cavg = average plasma concentration Results are reported across three timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading. Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Buprenorphine PK: Area Under Plasma Concentration Time Curves (AUC) | AUC calculated using the linear trapezoidal rule and requiring a minimum of 5 data points for each time range. Results are reported across four timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24. Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48 Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672 Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) at hours 0-24, hours 0-672 The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Buprenorphine PK: Average Plasma Concentration (Cavg) | Cavg was defined as the AUC (timeframe)/timeframe. For example, the sublingual steady-state Cavg reading on Day -1 = AUC0-24/ 24 hours Results are reported across three timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading. Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Buprenorphine PK: Maximum Observed Plasma Concentration (Cmax) | Maximum observed plasma concentration, determined directly from individual concentration time data. Results are reported across four timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24. Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48 Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672 Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Buprenorphine PK: Minimum Observed Plasma Concentration (Cmin) | Minimum observed plasma concentration, determined directly from individual concentration time data. Results are reported across three timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24. Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672 Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Buprenorphine PK: Swing of Plasma Concentrations | The swing of buprenorphine plasma concentrations calculated as (Cmax-Cmin)/Cmin within the dosing interval. Cmax=maximum plasma concentration Cmin=minimum plasma concentration Results are reported across three timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading. Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Buprenorphine PK: Time to Maximum Buprenorphine Plasma Concentration (Tmax) | Results are reported across four timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24. Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48 Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672 Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) at hours 0-24, hours 0-672 The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Buprenorphine PK: Accumulation Index in Terms of Area Under the Curve (Rac(AUC)) | Accumulation index in terms of AUC calculated as ratio of AUCtau Injection 4/ AUCtau Injection 1. AUCtau = area under plasma concentration time curve over the dosing interval tau (for SC RBP-6000, tau=28 days). | Days 1-28, 85-113 | 
| Buprenorphine PK: Accumulation Index in Terms of Maximum Observed Plasma Drug Concentration (Rac(Cmax)) | Accumulation index in terms of Cmax calculated as ratio of Cmax Injection 4/ Cmax Injection 1. | Days 1-28, 85-113 | 
| Buprenorphine PK: Apparent Clearance at Steady-State (CLss/F) Following Injections 4 and 6 | Apparent clearance at steady-state (CLss/F) = Dose / AUCtau (tau was 28 days). | Days 85-113, 141-169 | 
| Buprenorphine PK: Area Under Plasma Concentration Time Curve From Time Zero Of Injection 4 (AUC0-∞) | Area under plasma concentration time curve from time zero of Injection 4 extrapolated to infinity; calculated for Injection 4 (last injection) in subjects not participating in PET imaging sub-study only as: (AUC0-∞ was reported if the coefficient of determination R2 was at least 0.8 and the extrapolated area is less than 25%). A minimum of 5 data points was required. AUC up to the last measurable concentration (AUClast) was calculated by using the linear trapezoidal rule. | Days 85-113 | 
| Buprenorphine PK: Terminal Phase Half Life (t1/2) Calculated For Injection 4 | The terminal phase half life calculated for Injection 4 in subjects not participating in PET imaging sub-study. The t1/2 was reported only if the coefficient of determination R2 was at least 0.8. | Days 85-113 | 
| Norbuprenorphine PK: % Fluctuation | % Fluctuation was defined as the degree of fluctuation of norbuprenorphine plasma concentrations calculated as (Cmax-Cmin)/Cavg*100, expressed as a percentage. Cmax=maximum plasma concentration Cmin=minimum plasma concentration Cavg = average plasma concentration Results are reported across three timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading. Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Norbuprenorphine PK: Area Under Plasma Concentration Time Curves (AUC) | AUC calculated using the linear trapezoidal rule and requiring a minimum of 5 data points for each time range. Results are reported across four timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24. Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48 Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672 Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) at hours 0-24, hours 0-672 The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Norbuprenorphine PK: Average Plasma Concentration (Cavg) | Cavg was defined as the AUC (timeframe)/timeframe. For example, the sublingual steady-state Cavg reading on Day -1 = AUC0-24/ 24 hours Results are reported across three timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading. Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Norbuprenorphine PK: Maximum Observed Plasma Concentration (Cmax) | Maximum observed plasma concentration, determined directly from individual concentration time data. Results are reported across four timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24. Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48 Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672 Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Norbuprenorphine PK: Minimum Observed Plasma Concentration (Cmin) | Minimum observed plasma concentration, determined directly from individual concentration time data. Results are reported across three timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24. Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672 Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Norbuprenorphine PK: Swing of Plasma Concentrations | The swing of norbuprenorphine plasma concentrations calculated as (Cmax-Cmin)/Cmin within the dosing interval. Cmax=maximum plasma concentration Cmin=minimum plasma concentration Results are reported across three timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading. Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Norbuprenorphine PK: Time to Maximum Buprenorphine Plasma Concentration (Tmax) | Results are reported across four timeframes: Sublingual Period (Day -1 dose of SUBUTEX): a steady-state reading at hours 0-24. Initial Burst Parameters (Days 1-2 relative to RBP-6000 injections 1, 4 and 6) at hours 0-48 Plateau Parameters (Days 3-29 relative to RBP-6000 injections 1, 4 and 6) at hours 48-672 Overall Parameters (Days 1-29 relative to RBP-6000 injections 1, 4 and 6) at hours 0-24, hours 0-672 The PK sampling schedule was hour 0 (predose) on days -7 to -1, hours 0.5, 1,2,4,6, 8,12, 24 post-dose on Day -1 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672 post injections 1 and 4 hours 0 (pre-dose) 1, 2, 4, 6, 8, 12, 20, 24, 25, 26, 28, 30, 32, 36, 44, 48, 144, 192, 240, 312, 384, 456, 528, 600, 672, 846, 1008, 1200, 1344 post injection 6 | Day -1, Days 1-29, 85-113, 141-197 | 
| Norbuprenorphine PK: Accumulation Index in Terms of Area Under the Curve (Rac(AUC)) | Accumulation index in terms of AUC calculated as ratio of AUCtau Injection 4/ AUCtau Injection 1. AUCtau = area under plasma concentration time curve over the dosing interval tau (for SC RBP-6000, tau=28 days). | Days 1-28, 85-113 | 
| Norbuprenorphine PK: Accumulation Index in Terms of Maximum Observed Plasma Drug Concentration (Rac(Cmax)) | Accumulation index in terms of Cmax calculated as ratio of Cmax Injection 4/ Cmax Injection 1. | Days 1-28, 85-113 | 
| Norbuprenorphine PK: Area Under Plasma Concentration Time Curve From Time Zero Of Injection 4 and 6 (AUC0-∞) | Area under plasma concentration time curve from time zero of Injection 4 extrapolated to infinity; calculated for Injection 4 and 6 (last injection) in subjects not participating in PET imaging sub-study only as: (AUC0-∞ was reported if the coefficient of determination R2 was at least 0.8 and the extrapolated area is less than 25%). A minimum of 5 data points was required. AUC up to the last measurable concentration (AUClast) was calculated by using the linear trapezoidal rule. | Days 85-113, 141-197 | 
| Norbuprenorphine PK: Terminal Phase Half Life (t1/2) Calculated For Injection 4 | The terminal phase half life calculated for Injection 4 in subjects not participating in PET imaging sub-study. The t1/2 was reported only if the coefficient of determination R2 was at least 0.8. | Days 85-113, 141-197 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Clinical Opiate Withdrawal Scale (COWS) Prior to Injections 1, 2, 3, 4 and 6 | COWS is an 11-item instrument used to assess symptoms of opioid withdrawal (Wesson et al., 1999). 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 moderate/severe withdrawal, and 37-48 severe withdrawal. Each participant was to be assessed by the same qualified and trained individuals throughout the course of the study as much as possible. Baseline was defined as the peak (maximum) value from screening to study Day -13 pre-SUBUTEX dose. The baseline score is reported as the mean of observed values. Other measurements were taken prior to dosing and reported as change from baseline values. Negative change from baseline values indicate a lessening of withdrawal symptoms. | Baseline (screening to Day -13), Days -1, 1, 29, 57, 85 141 | 
| Change From Baseline in the Subjective Opiate Withdrawal Scale (SOWS) Prior to Injections 1, 2, 3, 4 and 6 | 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). Baseline was defined as the peak (maximum) value from screening to study Day -13 pre-SUBUTEX dose. The baseline score is reported as the mean of observed values. Other measurements were taken prior to dosing and reported as change from baseline values. Negative change from baseline values indicate a lessening of withdrawal symptoms. | Baseline (screening to Day -13), Days -1, 1, 29, 57, 85 141 | 
| Change From Baseline in the Clinical Opioid Craving Visual Analog Scale (VAS) Total Score Prior to Injections 1, 2, 3, 4 and 6 | The Total Score was the sum of 10 questions regarding cravings each ranging from 0 (no craving) - 10 (extreme craving) for a total range from 0 (no cravings) to 100 (most intense craving I have ever had). Baseline was defined as the peak (maximum) value from screening to study Day -13 pre-SUBUTEX dose. The baseline score is reported as the mean of observed values. Other measurements were taken prior to dosing and reported as change from baseline values. Negative change from baseline values indicate a lessening of craving symptoms. | Baseline (screening to Day -13), Days -1, 1, 29, 57, 85 141 | 
| Change From Baseline in the Clinical Global Impression Severity (CGI-S) Scale on Days 1, 7, 29, 57, 85 and 141 | The CGI-S is a 7-item scale completed by the clinician used to rate the severity of symptoms. The total range is 1 (normal, not at all ill) to 7 (most extremely ill). Baseline was defined as value from screening (Day -13). The baseline score is reported as the mean of observed values. Other measurements were taken prior to dosing (not applicable for Day 7) and reported as change from baseline values. Negative change from baseline values indicate a lessening of the severity of symptoms. | Baseline (screening Day -15), Days 1, 7, 29, 57, 85, 141 | 
| Change From Baseline in the Clinical Global Impression Improvement (CGI-I) Scale on Days 7, 29, 57, 85 and 141 | The CGI-I is a 7-item scale completed by the clinician used to rate their impression of how much the participant has improved over a baseline state. The total range is 1 (very much improved) to 7 (very much worse). Baseline was defined as value from Day 1. The baseline score is reported as the mean of observed values. Other measurements were taken prior to dosing (not applicable for Day 7) and reported as change from baseline values. Negative change from baseline values indicate an improvement. | Baseline (Day 1), Days 7, 29, 57, 85, 141 | 
| Columbia Suicide Severity Rating Scale (C-SSRS): Severity | The scale used in the C-SSRS is a continuous variable ranging from 0 (no suicidal ideation present) to 5 (active ideation with specific plan and intent). Only participants with suicidal ideation (scale of 1-5) are reported. 1=desire to be dead to 5=active ideation with specific plan and intent. | Screening (summary of lifetime), Screening (last 6 months), Day 65, Day 113, End of Study (up to day 365) | 
| Percentage of Urine Drug Screen Samples Negative for Opioids | Urine samples were screened for the following drugs: opiates cocaine amphetamines methadone cannabinoids barbiturates buprenorphine. Buprenorphine was only included in the urine drug screen at screening and Day -14 to determine if the subject had used any buprenorphine-containing products prior to the start of SUBUTEX SL tablet dosing. benzodiazepines methamphetamine phencyclidine Urine drug screens were run every day when the participant was an inpatient; every 2-3 days when the participant was an outpatient. Drug screens were run less often for those participants in the PET substudy. | Day 1 to End of Study (up to day 365) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opioid Dependence, Buprenorphine, Depot, SUBUTEX, RBP-6000