A Study to Evaluate the Pharmacokinetic Effect of SCH 503034 (Boceprevir) on Methadone or Buprenorphine/Naloxone Plasma Concentrations (P08123)

An Open-Label, One-Period Study in Patients Receiving Methadone or Buprenorphine/Naloxone Maintenance Therapy to Evaluate the Effect of SCH 503034 (Boceprevir) on Either Methadone or Buprenorphine/Naloxone Plasma Concentrations (Protocol No. P08123)

In this study, participants on methadone or buprenorphine/naloxone maintenance therapy will be given boceprevir. Blood samples will be taken at specified intervals to find out whether boceprevir affects the pharmacokinetics of methadone, buprenorphine, or naloxone.

Study Overview

• Status: Completed
• Conditions: Hepatitis C Virus
• Intervention / Treatment: Drug: boceprevir; Drug: methadone; Drug: buprenorphine/naloxone

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body Mass Index (BMI) between 18 and 36, inclusive
• Reliable participation in a methadone maintenance or buprenorphine maintenance or buprenorphine/naloxone maintenance program for at least two (2) months prior to Day 1.
• Is receiving once daily oral dose of methadone therapy at a stable

individualized dose for at least 4 weeks, receiving once

daily buprenorphine dose at a stable individualized dose for at 4 weeks with, if on buprenorphine only therapy, naloxone added for at least 2 weeks prior to Day 1.

• 12-lead electrocardiogram (ECG) conduction intervals within gender-specific normal range
• Vital signs within normal range
• Clinical laboratory tests within normal range
• Women who are postmenopausal, surgically sterilized, or premenopausal and use a medically-accepted method of contraception.

Exclusion Criteria:

• Pregnancy, breast feeding, or intention to become pregnant or father a child while on study or within 3 months after end of trial
• History or presence of inflammatory bowel disease, ulcers, or gastrointestinal or rectal bleeding
• History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection
• History of pancreatic injury or pancreatitis
• History or presence of liver disease or liver injury
• History or presence of impaired renal function
• History of urinary obstruction or difficulty in voiding
• History of any infectious disease within 4 weeks prior to drug administration that in the opinion of the investigator, affects the subject's ability to participate in the trial
• Positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV)
• Positive screen for drugs with a high potential for abuse such as cocaine, amphetamines, methylenedioxymethamphetamine (MDMA), barbiturates, benzodiazepines, or opiates/opioids

• Excessive use of alcohol in the 2 weeks prior to Day -1, defined as greater than 3 glasses of alcoholic beverages (1 is approximately equivalent to: beer [284 mL/10 oz], wine

  [125 mL/4 oz], or distilled spirits [25 mL/1 oz]) per day.

• Blood donation in the past 60 days
• Previous administration of SCH 503034 (boceprevir)
• Current participation in another clinical study or participation in a clinical study (e.g., laboratory or clinical evaluation) within 30 days of baseline
• Study staff personnel or family members of the study staff personnel
• Demonstrated allergic reactions (eg, food, drug, atopic reactions or asthmatic episodes) that, in the opinion of the investigator and sponsor, interfere with their ability to participate in the trial
• History of malignancy within 5 years from Screening
• Consumption of excessive amounts (equivalent to > 6 cups of brewed coffee/day) of coffee, tea, cola or other caffeinated beverages
• Receipt of any of the following more recently than the washout period prior to Baseline: inhibitors or inducers of cytochrome (CYP) P450, CYP2B6, CYP3A4, and CYP2D6; or oral contraceptives containing drospirenone

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methadone + boceprevir; Participants receive standard methadone maintenance therapy (20-150 mg tablets, liquid, or disket, orally, once per day) on Days 1 through 8 + boceprevir (800 mg [4 x 200 mg capsules], orally, every 8 hours) on Days 2 through 7)	Drug: boceprevir; boceprevir 800 mg (4 x 200 mg capsules), orally, every 8 hours, Day 2 through Day 7; Other Names: SCH 503034, Victrelis™; Drug: methadone; methadone, 20-150 mg tablets, liquid, or disket, orally, once per day, Day 1 through Day 8
Experimental: Buprenorphine/naloxone + boceprevir; Participants receive standard buprenorphine/naloxone maintenance therapy (8/2-24/6 mg, tablets, sublingual, once per day) on Days 1 through 8 + boceprevir (800 mg [4 x 200 mg capsules], orally, every 8 hours) on Days 2 through 7	Drug: boceprevir; boceprevir 800 mg (4 x 200 mg capsules), orally, every 8 hours, Day 2 through Day 7; Other Names: SCH 503034, Victrelis™; Drug: buprenorphine/naloxone; buprenorphine/naloxone 8/2-24/6 mg, tablets, sublingual, once per day, Day 1 through Day 8

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration Versus Time Curve (AUC) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir	AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for methadone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for methadone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for methadone + boceprevir.	Methadone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and methadone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Maximum Concentration (Cmax) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir	Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for methadone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for methadone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for methadone + boceprevir.	Methadone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and methadone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
AUC of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir	AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir.	Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Cmax of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir	Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir.	Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir	AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir.	Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Cmax of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir	Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir.	Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Hulskotte EG, Bruce RD, Feng HP, Webster LR, Xuan F, Lin WH, O'Mara E, Wagner JA, Butterton JR. Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy. Eur J Clin Pharmacol. 2015 Mar;71(3):303-11. doi: 10.1007/s00228-014-1789-4. Epub 2015 Feb 11.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: June 28, 2011
• First Submitted That Met QC Criteria: July 14, 2011
• First Posted (Estimate): July 18, 2011

Study Record Updates

• Last Update Posted (Actual): April 7, 2017
• Last Update Submitted That Met QC Criteria: March 9, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Hepatitis C; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Respiratory System Agents; Antitussive Agents; Buprenorphine; Naloxone; Buprenorphine, Naloxone Drug Combination; Methadone
• Other Study ID Numbers: P08123

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf

http://engagezone.msd.com/ds_documentation.php