Clinical trial NCT01738503: Multiple Dose Pharmacokinetics Depot Buprenorphine in Opioid-Dependent Subjects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Opioid Related Disorder
Keywords: Opioid Dependence, Buprenorphine, Depot, SUBUTEX, RBP-6000
Lead sponsor: Indivior Inc.
Sponsor class: INDUSTRY
First posted: 2012-11-30
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: Inclusion Criteria:

* Male and female subjects
* Agree not to take any buprenorphine products other than those administered for the current study throughout participation in the study
* Body mass index (BMI) of \>18.0 to \< 33.0 kg/m

Exclusion Criteria:

* Participants with a current diagnosis requiring chronic opioid treatment
* Participants with a history of risk factors of Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) or an ECG demonstrating a Fridericia's corrected QT interval (QTcF) \>450 msec in males and QTcF \> 470 in females at screening
* Abuse of buprenorphine or use of buprenorphine within 14 days of informed consent

Primary outcomes:
measure: Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Days -14 to -1 (Subutex treatment), Days 1-316 (RBP-6000 treatment)
measure: Buprenorphine PK: % Fluctuation
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Buprenorphine PK: Area Under Plasma Concentration Time Curves (AUC)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Buprenorphine PK: Average Plasma Concentration (Cavg)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Buprenorphine PK: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Buprenorphine PK: Minimum Observed Plasma Concentration (Cmin)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Buprenorphine PK: Swing of Plasma Concentrations
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Buprenorphine PK: Time to Maximum Buprenorphine Plasma Concentration (Tmax)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Buprenorphine PK: Accumulation Index in Terms of Area Under the Curve (Rac(AUC))
timeFrame: Days 1-28, 85-113
measure: Buprenorphine PK: Accumulation Index in Terms of Maximum Observed Plasma Drug Concentration (Rac(Cmax))
timeFrame: Days 1-28, 85-113
measure: Buprenorphine PK: Apparent Clearance at Steady-State (CLss/F) Following Injections 4 and 6
timeFrame: Days 85-113, 141-169
measure: Buprenorphine PK: Area Under Plasma Concentration Time Curve From Time Zero Of Injection 4 (AUC0-∞)
timeFrame: Days 85-113
measure: Buprenorphine PK: Terminal Phase Half Life (t1/2) Calculated For Injection 4
timeFrame: Days 85-113
measure: Norbuprenorphine PK: % Fluctuation
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Norbuprenorphine PK: Area Under Plasma Concentration Time Curves (AUC)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Norbuprenorphine PK: Average Plasma Concentration (Cavg)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Norbuprenorphine PK: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Norbuprenorphine PK: Minimum Observed Plasma Concentration (Cmin)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Norbuprenorphine PK: Swing of Plasma Concentrations
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Norbuprenorphine PK: Time to Maximum Buprenorphine Plasma Concentration (Tmax)
timeFrame: Day -1, Days 1-29, 85-113, 141-197
measure: Norbuprenorphine PK: Accumulation Index in Terms of Area Under the Curve (Rac(AUC))
timeFrame: Days 1-28, 85-113
measure: Norbuprenorphine PK: Accumulation Index in Terms of Maximum Observed Plasma Drug Concentration (Rac(Cmax))
timeFrame: Days 1-28, 85-113
measure: Norbuprenorphine PK: Area Under Plasma Concentration Time Curve From Time Zero Of Injection 4 and 6 (AUC0-∞)
timeFrame: Days 85-113, 141-197
measure: Norbuprenorphine PK: Terminal Phase Half Life (t1/2) Calculated For Injection 4
timeFrame: Days 85-113, 141-197
Secondary outcomes:
measure: Change From Baseline in the Clinical Opiate Withdrawal Scale (COWS) Prior to Injections 1, 2, 3, 4 and 6
timeFrame: Baseline (screening to Day -13), Days -1, 1, 29, 57, 85 141
measure: Change From Baseline in the Subjective Opiate Withdrawal Scale (SOWS) Prior to Injections 1, 2, 3, 4 and 6
timeFrame: Baseline (screening to Day -13), Days -1, 1, 29, 57, 85 141
measure: Change From Baseline in the Clinical Opioid Craving Visual Analog Scale (VAS) Total Score Prior to Injections 1, 2, 3, 4 and 6
timeFrame: Baseline (screening to Day -13), Days -1, 1, 29, 57, 85 141
measure: Change From Baseline in the Clinical Global Impression Severity (CGI-S) Scale on Days 1, 7, 29, 57, 85 and 141
timeFrame: Baseline (screening Day -15), Days 1, 7, 29, 57, 85, 141
measure: Change From Baseline in the Clinical Global Impression Improvement (CGI-I) Scale on Days 7, 29, 57, 85 and 141
timeFrame: Baseline (Day 1), Days 7, 29, 57, 85, 141
measure: Columbia Suicide Severity Rating Scale (C-SSRS): Severity
timeFrame: Screening (summary of lifetime), Screening (last 6 months), Day 65, Day 113, End of Study (up to day 365)
measure: Percentage of Urine Drug Screen Samples Negative for Opioids
timeFrame: Day 1 to End of Study (up to day 365)
Other outcomes:
Locations:
city: Overland Park
country: United States
facility: Vince and Associates Clinical Research
state: Kansas
Study officials:
affiliation: Vince and Associates Clinical Research
name: Bradley D Vince, DO
role: PRINCIPAL_INVESTIGATOR
References: