Drug Interaction Study With BI 201335 and Methadone or Buprenorphine/Naloxone

Study Overview
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Brief Summary
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Otherwise healthy subjects who are currently bein maintained on either methadone or buprenorphine/naloxone for opioid maintenance therapy who have been on a stable dose for at least 30 days will be administered BI 201335 daily to determine if a drug interaction occurs between BI 201335 and either methadone or buprenorphine/naloxone.

Official Title
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Effect of Multiple Dosing With BI 201335 on the Safety, Pharmacokinetics and Pharmacodynamics of Steady-state Methadone and Buprenorphine/Naloxone in Subjects on Stable Addiction Management Therapy

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: BI 201335
* Drug: BI 201335


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: stable dose of either methadone or buprenorphine/naloxone for 30 days for opioid maintenance therapy. Male and female volunteers with a body mass index (BMI) = 18.5 and < 32 with a minimum weight of 50kg. Exclusion criteria: any other significant medical illness of clinical significance. history of rash or photosensitivity chronic or acute infections including HIV, hepatitis B and hepatitis C. history of allergy considered significant for this study intake of any other medications except for methadone or buprenorphine/naloxone. QTc on electrocardiogram (ECG) > 470. use of any other investigational drug within 30 days of the study. drug or alcohol abuse (other than the defined opioid maintenance therapy with either methadone or buprenorphine/naloxone) blood donation of more than 100mL within four weeks of the trial. excessive physical activities one week prior to and during the trial. any clinically relevant laboratory value. concomitant use of any food product known to alter P450 or P-gp activity such as grapefruit juice, seville oranges and St. John's Wort. inadequate venous access For women of childbearing potential: pregnancy or planning to become pregnant within 3 months of the trial positive pregnancy test at screening visit no proof of sterilization or unwilling or unable to use a double barrier method of birth control during the study and up to 3 months after the study. lactation with active breastfeeding from screening up to 30 days after last study visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methadone group<br>patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day | Drug: BI 201335<br>* BI 201335 for 9 days<br>|
| Active Comparator: Buprenorphine<br>patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. | Drug: BI 201335<br>* BI 201335 for 9 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for area under the concentration time curve (AUC) of faldaprevir in plasma over a uniform dosing interval from 0 to 24 hours. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| R-methadone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| R-methadone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| S-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9 | These are the unadjusted summary statistics on the original scale for area under the concentration time curve (AUC) of faldaprevir in plasma over a uniform dosing interval from 0 to 24 hours. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| S-methadone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9 | These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| S-methadone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9 | These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Buprenorphine: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for area under the concentration time curve (AUC) of faldaprevir in plasma over a uniform dosing interval from 0 to 24 hours. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Buprenorphine: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Buprenorphine: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Norbuprenorphine: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for area under the concentration time curve (AUC) of faldaprevir in plasma over a uniform dosing interval from 0 to 24 hours. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Norbuprenorphine: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Norbuprenorphine: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Naloxone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for area under the concentration time curve (AUC) of faldaprevir in plasma over a uniform dosing interval from 0 to 24 hours. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Naloxone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state. | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 
| Naloxone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. | These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose | 0 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours on Day 1 and Day 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline | The OOWS is conducted by a trained independent examiner for either the presence or absence of the following symptoms during a 10 minute observation period at designated times during the trial. The minimum possible OOWS score is 0 and the maximum possible score is 13. Objective criteria: Yawning, Rhinorrhoea, Piloerection, perspiration, lacrimation, mydriasis, hot and cold flushes, restlessness, vomiting, tremors, anxiety, muscle twitches, abdominal cramps. Higher score indicates increasing severity of opiate withdrawal syndrome. | Baseline, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12 and End of treatment | 
| Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline | The SOWS is a subjective scale self-evaluated by the subject. The SOWS shows items reflecting the common motor, autonomic, gastrointestinal, musculo-skeletal, and psychic symptoms of opiate withdrawal. Subjects are instructed to rate each symptom on a scale of 0 to 4 (0=not at all, 1=a little, 2=moderately, 3=quite a bit, 4=extremely) at designated times [c.f. Section 3.1]. The minimum possible SOWS score is 0, the maximum 64. The following subjective criteria are answered by the subject using the scale below: 1) I feel anxious, 2) I feel like yawning 3) I am perspiring, 4) My eyes are watering, 5) My nose is running, 6) I have goose flesh, 7) I am shaking 8) I have hot flushes, 9) I have cold flushes, 10) My bones and muscles ache, 11) I feel restless, 12) I feel nauseous, 13) I feel like vomiting, 14) My muscles twitch, 15) I have cramps in my stomach, 16) I feel like shooting up now. Higher score indicates increasing severity of opiate withdrawal syndrome. | Baseline, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12 and End of treatment |