Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support. FDA label
Also known as RBP-6000, Subcutaneous buprenorphine, SUBOXONE, Sublingual Film, SUBOXONE sublingual film, Subutex, naloxone
Buprenorphine · 8 trials · 5 indications
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 or surgical intervention to prevent one of the outcomes listed in this definition.
Vital signs include: * systolic blood pressure (mmHg) * diastolic blood pressure (mmHg) * respiratory rate (breaths/minute) * pulse oximetry (%) * pulse rate (beats/min) * temperature (C)
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. The number of participants with TEAEs specific to laboratory tests are summarized.
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 primary 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. Missing urine drug screen(s) (UDS) samples and/or self-reports were considered as non-negative.
The study's primary objective was to determine if the opioid blocking effect for the first injection of buprenorphine 300 mg (RBP-6000) on Day 1 was not inferior to placebo when challenged by hydromorphone. Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme liking of the drug 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone administration on the challenge days listed in the time frame field. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.
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
% 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
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
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
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
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
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
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
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).
Accumulation index in terms of Cmax calculated as ratio of Cmax Injection 4/ Cmax Injection 1.
Apparent clearance at steady-state (CLss/F) = Dose / AUCtau (tau was 28 days).
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.
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.
% 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
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
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
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
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
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
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
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).
Accumulation index in terms of Cmax calculated as ratio of Cmax Injection 4/ Cmax Injection 1.
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.
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.
Safety and tolerability were evaluated during the 12-week Treatment Phase by oral cavity examination and assessment. Oral mucosa was graded as follows: Grade 0: Normal mucosa Grade 1: Localized mucosal erythema and/or irritation without ulceration Grade 2: Erythema and/or irritation and induration without ulceration Grade 3: Ulceration, with or without any other combination of signs
Safety and tolerability were evaluated during the 12-week Treatment Phase by oral cavity examination and assessment.
Relative bioavailability will be assessed using AUC0-28days.
Relative bioavailability will also be assessed using Cmax
Safety will be assessed by AEs, ECGs, laboratory measurements, local injection site tolerability and vital signs
Individual plasma concentrations will be collected to compute PK parameters. The individual concentrations will be summarized using descriptive statistics.
Safety to be assessed by AEs, ECGs, laboratory measurements, local injection site tolerability and vital signs
The frequency of all adverse events (AE) and serious adverse events (SAE) deemed to be related to treatment.
| Arm | Type | Description |
|---|---|---|
| RBP-6000 (100/300 mg Flex) | EXPERIMENTAL | On Day 1 of the study all eligible subjects received a single subcutaneous (SC) injection of RBP-6000. Participants returned to the site for monthly injection visits every 28 days (-2/+7 days) for a total of up to 6 injections. Participants were not required to complete all 6 injections and could choose to terminate from the study at any time. For each injection, participants could receive either a dose of 100 mg RBP-6000 or 300 mg RBP-6000, based on the medical judgement of the investigator. |
| RBP-6000 300mg/100mg | EXPERIMENTAL | During the Run-In Period, participants are inducted onto SUBOXONE sublingual film (SL) followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. Participants are then randomized. As of protocol Amendment 2 (21 August 2015) SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. Participants in this treatment arm are given RBP-6000 300 mg injections on Days 1 and 29. Injections 3-6 are separated by 28 days (Day 57-Day 141) and contain RBP-6000 100 mg. In addition, participants received individual drug counseling (IDC) at least once a week. |
| RBP-6000 300mg/300mg | EXPERIMENTAL | During the Run-In Period, participants are inducted onto SUBOXONE sublingual film (SL) followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. Participants are then randomized. As of protocol Amendment 2 (21 August 2015) SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. Participants in this treatment arm are given six RBP-6000 300 mg injections on Days 1 to 141 with injections separated by 28 days. In addition, participants received individual drug counseling (IDC) at least once a week. |
| Placebo Matching 300 mg/100 mg RBP-6000 | PLACEBO_COMPARATOR | During the Run-In Period, participants are inducted onto SUBOXONE sublingual film (SL) followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. Participants are then randomized. As of protocol Amendment 2 (21 August 2015) SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. Participants in this treatment arm are given placebo injections on Days 1 and 29 (matching the RBP-6000 300 mg dose volume). Injections 3-6 are separated by 28 days (Day 57-Day 141) and also contain placebo (matching the RBP-6000 100 mg volume). In addition, participants received individual drug counseling (IDC) at least once a week. |
| Placebo Matching 300 mg RBP-6000 | PLACEBO_COMPARATOR | During the Run-In Period, participants are inducted onto SUBOXONE sublingual film (SL) followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. Participants are then randomized. As of protocol Amendment 2 (21 August 2015) SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. Participants in this treatment arm are given six placebo injections (volume-matched to RBP-6000 300 mg dose) on Days 1 to 141 with injections separated by 28 days. In addition, participants received individual drug counseling (IDC) at least once a week. |
| depot buprenorphine | EXPERIMENTAL | Participants were treated with RBP-6000 300-mg in a single subcutaneous injection on Days 1 and 29 following a prior 14 day stabilization period (day -14 to day -1) of buprenorphine and naloxone (SUBOXONE) . Challenges consist of participants receiving on three consecutive days intramuscular (IM) injections of hydromorphone 0 mg (placebo), 6 mg and 18 mg doses during weeks 1-12 in randomized sequential order. |
| (8 mg) RBP-6000: 50 mg | EXPERIMENTAL | 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. |
| (12 mg) RBP-6000: 100 mg | EXPERIMENTAL | 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 |
| (24 mg) RBP-6000: 200 mg | EXPERIMENTAL | 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. |
| (8 mg) RBP-6000: 100 mg | EXPERIMENTAL | 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. |
| (14 mg) RBP-6000: 200 mg | EXPERIMENTAL | 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. |
| (8-24 mg) RBP-6000: 300 mg | EXPERIMENTAL | 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. |
| Sublingual administration | EXPERIMENTAL | Buprenorphine/naloxone film strip administered sublingually |
| Buccal administration | EXPERIMENTAL | Buprenorphine/naloxone film strip administered buccally |
| RBP-6000 - Light MW | EXPERIMENTAL | Single subcutaneous injection of RBP-6000 (buprenorphine) 300 mg, formulated with a light molecular weight (MW) polymer. |
| RBP-6000 - Heavy MW | EXPERIMENTAL | Single subcutaneous injection of RBP-6000 (buprenorphine) 300 mg, formulated with a heavy molecular weight (MW) polymer. |
| RBP-6000 - Intermediate MW | ACTIVE_COMPARATOR | Single subcutaneous injection of RBP-6000 (buprenorphine) 300 mg, formulated with an intermediate molecular weight (MW) polymer (reference). |
| Cohort 1 | EXPERIMENTAL | Subjects to receive low dose of RBP-6000 subcutaneously as a single injection |
| Cohort 2 | EXPERIMENTAL | Subjects to receive medium dose of RBP-6000 subcutaneously as a single injection |
| Cohort 3 | EXPERIMENTAL | Subjects to receive high dose of RBP-6000 subcutaneously as a single injection |
| Cohort 4 | EXPERIMENTAL | Subjects would receive medium dose RBP-6000 as a single injection after up to 12 mg daily dosing of sublingual (SL) suboxone tablets for 7 days |
| RBP-6000 | EXPERIMENTAL | A single dose of RBP-6000 will be administered on Study Day 1 |
| Name | Type | Description |
|---|---|---|
| RBP-6000 | DRUG | Monthly injections subcutaneously on alternate sides of participant's abdomen. Dose could be adjusted from 100 mg to 300 mg (or the reverse) based on the medical judgment of the investigator. |
| SUBOXONE | DRUG | SUBOXONE (buprenorphine sublingual film) is used for induction therapy. Participants take sublingual film for 3 days according to the sublingual film prescribing information; they then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to randomization. Following randomization, SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. |
| Placebo | DRUG | Six injections of placebo administered subcutaneously every 28 days on alternate sides of participant's abdomen at volumes matching the experimental drug. |
| Buprenorphine | DRUG | A subcutaneous depot injection of buprenorphine 300 mg was delivered using the ATRIGEL® Delivery System on study days 1 and 29. As the depot degrades, buprenorphine is released into systemic circulation over an extended period of time. |
| buprenorphine and naloxone | DRUG | Buprenorphine and naloxone (SUBOXONE® sublingual film) is given to participants on days -14 to day -1 (the SUBOXONE sublingual film stabilization period) or as soon as they start to experience withdrawal symptoms. SUBOXONE sublingual film may be initially administered several times daily until a stable dose between 8 mg and 24 mg daily is established. |
| hydromorphone | DRUG | Hydromorphone IM challenges are administered during the screening period (days -17 to -15), on days -3 to -1 during the buprenorphine and naloxone (SUBOXONE sublingual film) stabilization period, and weekly during the 12-week treatment period after administration of RBP-6000. Each challenge consists of 3 days during which participants are randomly administered 0 mg (placebo), 6 mg and 18 mg hydromorphone via intramuscular (IM) injection daily in varying blinded sequences. Additionally, hydromorphone can also be earned during the afternoon Reinforcing effects tasks sessions up to the same randomized dose received in the hydromorphone challenge that morning (or money can be chosen). |
| Subutex | DRUG | 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. |
| Buprenorphine/naloxone Film Strip | DRUG | Buprenorphine/naloxone dosed between 4/1 mg to 32/8 mg once a day for 12 weeks by sublingual route |
| SUBOXONE Sublingual Film | DRUG | Subjects will be dose-stabilized on SUBOXONE sublingual film prior to administration of RBP-6000. SUBOXONE sublingual film will be administered beginning after the subject is experiencing signs and symptoms of withdrawal on Day -8 and continue until Day -1. |
Inclusion Criteria: 1. Provide written consent to participate in this study. 2. Completed the End of Study Visit for the RB-US-13-0003 study (NCT02510014). 3. Be considered eligible in the medical judgment of the Investigator. 4. Females: Women of childbearing potential (defined as all women who ar...
Buprenorphine is used for the treatment of opioid use disorder and other opioid-related disorders. It is a small molecule being developed by Indivior Pharmaceuticals, Inc. for these psychiatric indications. Clinical development has focused on blocking opioid effects and on safety and tolerability in adults with opioid use disorder.
Buprenorphine targets OPRK1 and OPRM1, the kappa and mu opioid receptors, and acts as an agonist at these receptors. This receptor activity underlies its use in opioid use disorder, where it is studied for blockade of opioid effects in participants with opioid disorder.
Buprenorphine is developed by Indivior Pharmaceuticals, Inc., which trades under the ticker INDV. The company has sponsored Phase 2 studies of the drug, including a multiple dose study of blockade of opioid effects and a safety and tolerability study of buprenorphine/naloxone film strips.
Buprenorphine is in Phase 2 clinical development for opioid use disorder and opioid-related disorders. It is investigational and has not been approved for these uses based on the development information available. The completed Phase 2 program includes one study with 382 participants and another with 39 participants.
Buprenorphine has been studied in two completed Phase 2 trials. NCT02044094 evaluated multiple dose blockade of opioid effects by injections of buprenorphine in participants with opioid disorder, enrolling 39 adults in the United States. NCT00640835 assessed the safety and tolerability of buprenorphine/naloxone film strips, enrolling 382 adults in the United States.