Opioid Related DisorderPhase 2NCT01738503
Multiple Dose Pharmacokinetics Depot Buprenorphine in Opioid-Dependent Subjects
A Phase 2 study testing RBP-6000 and Subutex in people with Opioid Related Disorder, run by Indivior Inc. at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Opioid Related Disorder
- What is being tested?
- RBP-6000 and Subutex
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 124 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2012to May 2014
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Vince and Associates Clinical Research
Overland Park, Kansas, 66212
About this study
Official title: 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
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.
Read the detailed description
- 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.
- Conditions
- Opioid Related Disorder
- Being tested
- RBP-6000, Subutex
- Keywords
- Opioid Dependence, Buprenorphine, Depot, SUBUTEX, RBP-6000
- Medical subject headings
- Opioid-Related Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RBP-6000Drug
Also called buprenorphine
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.
SubutexDrug
Also called buprenorphine
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.
| Study group | Role | What they receive |
|---|---|---|
| (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. Receives: Drug: RBP-6000; Drug: Subutex |
| (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 Receives: Drug: RBP-6000; Drug: Subutex |
| (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. Receives: Drug: RBP-6000; Drug: Subutex |
| (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. Receives: Drug: RBP-6000; Drug: Subutex |
| (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. Receives: Drug: RBP-6000; Drug: Subutex |
| (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. Receives: Drug: RBP-6000; Drug: Subutex |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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).
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Days 85-113, 141-197
Secondary outcomes (7)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 1 to End of Study (up to day 365)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Nov 2012 (estimated)
- Study startOct 2012
- Primary completionMay 2014
- Study completionMay 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Opioid Related DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 124 participants (actual)
Sponsor and investigators
- Lead sponsor
- Indivior Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Bradley D Vince, DO, Principal investigator, Vince and Associates Clinical Research
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01738503
- Sponsor's protocol ID
- RB-US-12-0005
- Status last verified
- Jan 2018
- First submitted
- 28 Nov 2012
- Last updated
- 23 Feb 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT01738503
- Acronym / sponsor ID
- RB-US-12-0005
- Conditions
- Opioid Related Disorder
- Keywords
- Opioid Dependence, Buprenorphine, Depot, SUBUTEX, RBP-6000
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 124 participants (actual)
- Lead sponsor
- Indivior Inc.Industry (pharma, biotech, devices)
- Study start
- Oct 2012 (actual)
- Primary completion
- May 2014 (actual)
- Study completion
- May 2014 (actual)
- First posted
- 30 Nov 2012 (estimated)
- Results
- Posted 23 Jan 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| (8 mg) RBP-6000: 50 mg | Experimental | Drug: RBP-6000, Drug: SubutexParticipants 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 | Drug: RBP-6000, Drug: SubutexParticipants 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 | Drug: RBP-6000, Drug: SubutexParticipants 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 | Drug: RBP-6000, Drug: SubutexParticipants 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 | Drug: RBP-6000, Drug: SubutexParticipants 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 | Drug: RBP-6000, Drug: SubutexParticipants 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (3 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RBP-6000Also: buprenorphine18% 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. | Drug | (12 mg) RBP-6000: 100 mg, (14 mg) RBP-6000: 200 mg, (24 mg) RBP-6000: 200 mg, (8 mg) RBP-6000: 100 mg, (8 mg) RBP-6000: 50 mg, (8-24 mg) RBP-6000: 300 mg |
| SubutexAlso: buprenorphineParticipants 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. | Drug | (12 mg) RBP-6000: 100 mg, (14 mg) RBP-6000: 200 mg, (24 mg) RBP-6000: 200 mg, (8 mg) RBP-6000: 100 mg, (8 mg) RBP-6000: 50 mg, (8-24 mg) RBP-6000: 300 mg |
Primary outcome
Participants With Treatment-Emergent Adverse Events (TEAEs)
Time frame: Days -14 to -1 (Subutex treatment), Days 1-316 (RBP-6000 treatment)
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
Buprenorphine PK: % Fluctuation
Time frame: Day -1, Days 1-29, 85-113, 141-197
% 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
Buprenorphine PK: Area Under Plasma Concentration Time Curves (AUC)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Buprenorphine PK: Average Plasma Concentration (Cavg)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Buprenorphine PK: Maximum Observed Plasma Concentration (Cmax)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Buprenorphine PK: Minimum Observed Plasma Concentration (Cmin)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Buprenorphine PK: Swing of Plasma Concentrations
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Buprenorphine PK: Time to Maximum Buprenorphine Plasma Concentration (Tmax)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Buprenorphine PK: Accumulation Index in Terms of Area Under the Curve (Rac(AUC))
Time frame: Days 1-28, 85-113
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).
Buprenorphine PK: Accumulation Index in Terms of Maximum Observed Plasma Drug Concentration (Rac(Cmax))
Time frame: Days 1-28, 85-113
Accumulation index in terms of Cmax calculated as ratio of Cmax Injection 4/ Cmax Injection 1.
Buprenorphine PK: Apparent Clearance at Steady-State (CLss/F) Following Injections 4 and 6
Time frame: Days 85-113, 141-169
Apparent clearance at steady-state (CLss/F) = Dose / AUCtau (tau was 28 days).
Buprenorphine PK: Area Under Plasma Concentration Time Curve From Time Zero Of Injection 4 (AUC0-∞)
Time frame: Days 85-113
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.
Buprenorphine PK: Terminal Phase Half Life (t1/2) Calculated For Injection 4
Time frame: Days 85-113
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.
Norbuprenorphine PK: % Fluctuation
Time frame: Day -1, Days 1-29, 85-113, 141-197
% 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
Norbuprenorphine PK: Area Under Plasma Concentration Time Curves (AUC)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Norbuprenorphine PK: Average Plasma Concentration (Cavg)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Norbuprenorphine PK: Maximum Observed Plasma Concentration (Cmax)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Norbuprenorphine PK: Minimum Observed Plasma Concentration (Cmin)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Norbuprenorphine PK: Swing of Plasma Concentrations
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Norbuprenorphine PK: Time to Maximum Buprenorphine Plasma Concentration (Tmax)
Time frame: Day -1, Days 1-29, 85-113, 141-197
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
Norbuprenorphine PK: Accumulation Index in Terms of Area Under the Curve (Rac(AUC))
Time frame: Days 1-28, 85-113
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).
Norbuprenorphine PK: Accumulation Index in Terms of Maximum Observed Plasma Drug Concentration (Rac(Cmax))
Time frame: Days 1-28, 85-113
Accumulation index in terms of Cmax calculated as ratio of Cmax Injection 4/ Cmax Injection 1.
Norbuprenorphine PK: Area Under Plasma Concentration Time Curve From Time Zero Of Injection 4 and 6 (AUC0-∞)
Time frame: Days 85-113, 141-197
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.
Norbuprenorphine PK: Terminal Phase Half Life (t1/2) Calculated For Injection 4
Time frame: Days 85-113, 141-197
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.
7 secondary outcomes
Change From Baseline in the Clinical Opiate Withdrawal Scale (COWS) Prior to Injections 1, 2, 3, 4 and 6
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline (Day 1), Days 7, 29, 57, 85, 141
Columbia Suicide Severity Rating Scale (C-SSRS): Severity
Time frame: 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
Time frame: Day 1 to End of Study (up to day 365)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Feb 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bradley D Vince, DO principal investigator
Vince and Associates Clinical Research
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing RBP-6000 and Subutex in people with Opioid Related Disorder, run by Indivior Inc. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jan 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Participants With Treatment-Emergent Adverse Events (TEAEs) (time frame: Days -14 to -1 (Subutex treatment), Days 1-316 (RBP-6000 treatment)). The study lists 24 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2018.