Trial Outcomes & Findings for Drug Interaction Study With BI 201335 and Methadone or Buprenorphine/Naloxone (NCT NCT01637922)

NCT ID: NCT01637922

Last Updated: 2015-08-03

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 34 participants
• Primary outcome timeframe: 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
• Results posted on: 2015-08-03

Participant Flow

Participant milestones

Measure	Methadone Group patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): Oral dose of BI 201335(faldaprevir) 480 mg on day 2 and 240 mg twice daily for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): Oral dose of BI 201335(faldaprevir) 480 mg on day 2 and 240 mg twice daily for days 3 to 9.
Overall Study STARTED	15	19
Overall Study COMPLETED	13	14
Overall Study NOT COMPLETED	2	5

Reasons for withdrawal

Measure	Methadone Group patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): Oral dose of BI 201335(faldaprevir) 480 mg on day 2 and 240 mg twice daily for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): Oral dose of BI 201335(faldaprevir) 480 mg on day 2 and 240 mg twice daily for days 3 to 9.
Overall Study Adverse Event	0	1
Overall Study Protocol Violation	0	1
Overall Study Withdrawal by Subject	0	3
Overall Study Lost to Follow-up	2	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) n=19 Participants patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Total n=34 Participants Total of all reporting groups
Age, Continuous	35.4 years STANDARD_DEVIATION 11.0 • n=5 Participants	34.1 years STANDARD_DEVIATION 8.7 • n=7 Participants	34.6 years STANDARD_DEVIATION 9.7 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	16 Participants n=7 Participants	27 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

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.

Outcome measures

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
R-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. R-methadone with FDV (Day 9)	6990 [ng*h/mL] Geometric Coefficient of Variation 31.7	—
R-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. R-methadone alone (Day 1)	5920 [ng*h/mL] Geometric Coefficient of Variation 37.2	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state.

Outcome measures

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
R-methadone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. R-methadone with FDV (Day 9)	393 [ng/ml] Geometric Coefficient of Variation 29.8	—
R-methadone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. R-methadone alone (Day 1)	345 [ng/ml] Geometric Coefficient of Variation 33.3	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose

Outcome measures

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
R-methadone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. R-methadone with FDV (Day 9)	235 [ng/mL] Geometric Coefficient of Variation 36.8	—
R-methadone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. R-methadone alone (Day 1)	210 [ng/mL] Geometric Coefficient of Variation 39.4	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

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.

Outcome measures

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
S-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9 S-methadone with FDV (Day 9)	7610 [ng*h/ml] Geometric Coefficient of Variation 39.3	—
S-methadone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9 S-methadone alone (Day 1)	6470 [ng*h/ml] Geometric Coefficient of Variation 41.5	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state.

Outcome measures

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
S-methadone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9 S-methadone with FDV (Day 9)	474 [ng/mL] Geometric Coefficient of Variation 36.6	—
S-methadone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9 S-methadone alone (Day 1)	425 [ng/mL] Geometric Coefficient of Variation 34.9	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose

Outcome measures

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
S-methadone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9 S-methadone with FDV (Day 9)	231 [ng/mL] Geometric Coefficient of Variation 46.3	—
S-methadone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9 S-methadone alone (Day 1)	207 [ng/mL] Geometric Coefficient of Variation 48.8	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

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.

Outcome measures

Measure	Methadone Group n=13 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Buprenorphine: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. BUPRENORPHINE with FDV (Day 9)	58700 [pg*h/ml] Geometric Coefficient of Variation 73.1	—
Buprenorphine: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. BUPRENORPHINE alone (Day 1)	54000 [pg*h/ml] Geometric Coefficient of Variation 86.5	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state.

Outcome measures

Measure	Methadone Group n=13 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Buprenorphine: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. BUPRENORPHINE with FDV (Day 9)	7610 [pg/ml] Geometric Coefficient of Variation 74.5	—
Buprenorphine: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. BUPRENORPHINE alone (Day 1)	8240 [pg/ml] Geometric Coefficient of Variation 92.0	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose

Outcome measures

Measure	Methadone Group n=12 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Buprenorphine: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. BUPRENORPHINE with FDV (Day 9)	1110 [pg/mL] Geometric Coefficient of Variation 99.0	—
Buprenorphine: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. BUPRENORPHINE alone (Day 1)	904 [pg/mL] Geometric Coefficient of Variation 109	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

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.

Outcome measures

Measure	Methadone Group n=12 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Norbuprenorphine: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. NORBUPRENORPHINE with FDV (Day 9)	59200 [pg*h/ml] Geometric Coefficient of Variation 93.5	—
Norbuprenorphine: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. NORBUPRENORPHINE alone (Day 1)	42900 [pg*h/ml] Geometric Coefficient of Variation 135	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state.

Outcome measures

Measure	Methadone Group n=12 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Norbuprenorphine: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. NORBUPRENORPHINE with FDV (Day 9)	3690 [pg/mL] Geometric Coefficient of Variation 91.9	—
Norbuprenorphine: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. NORBUPRENORPHINE alone (Day 1)	2770 [pg/mL] Geometric Coefficient of Variation 126	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose

Outcome measures

Measure	Methadone Group n=11 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Norbuprenorphine: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. NORBUPRENORPHINE with FDV (Day 9)	2080 [pg/mL] Geometric Coefficient of Variation 102	—
Norbuprenorphine: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. NORBUPRENORPHINE alone (Day 1)	2010 [pg/mL] Geometric Coefficient of Variation 113	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

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.

Outcome measures

Measure	Methadone Group n=13 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Naloxone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. NALOXONE with FDV (Day 9)	971 [pg*h/ml] Geometric Coefficient of Variation 69.8	—
Naloxone: Geometric Mean Steady-state AUC0-24 on Day 1 and on Day 9. NALOXONE alone (Day 1) N=12	1000 [pg*h/ml] Geometric Coefficient of Variation 87.9	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for the maximum measured concentration of faldaprevir in plasma at steady state.

Outcome measures

Measure	Methadone Group n=14 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Naloxone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. NALOXONE with FDV (Day 9)	284 [pg/mL] Geometric Coefficient of Variation 107	—
Naloxone: Geometric Mean Steady-state Cmax on Day 1 and on Day 9. NALOXONE alone (Day 1) N=13	357 [pg/mL] Geometric Coefficient of Variation 82.9	—

PRIMARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug and had evaluable data for at least one observation for at least one primary endpoint. Subjects considered to be not evaluable, if the subject had a protocol deviation relevant to relative bioavailability. Or experienced emesis and vomiting at or before two times median tmax.

These are the unadjusted summary statistics on the original scale for steady-state plasma concentration of faldaprevir 24 hours after the last dose

Outcome measures

Measure	Methadone Group n=1 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Naloxone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. NALOXONE with FDV (Day 9)	23.4 [pg/mL] Geometric Coefficient of Variation NA There was insufficient data to produce an estimate for dispersion. There was only 1 patients for this endpoint.	—
Naloxone: Geometric Mean Steady-state C24hr on Day 1 and on Day 9. NALOXONE alone (Day 1)	25.6 [pg/mL] Geometric Coefficient of Variation NA There was insufficient data to produce an estimate for dispersion. There was only 1 patient for this endpoint.	—

SECONDARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug.

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.

Outcome measures

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) n=19 Participants patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 2	0.0 units on a scale Interval -1.0 to 1.0	0.0 units on a scale Interval -2.0 to 1.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 3	0.0 units on a scale Interval -1.0 to 1.0	0.0 units on a scale Interval -2.0 to 1.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 4 (N=15,18)	0.0 units on a scale Interval -2.0 to 1.0	0.0 units on a scale Interval -3.0 to 1.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 5 (N=15,18)	0.0 units on a scale Interval -1.0 to 0.0	0.0 units on a scale Interval -3.0 to 1.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 6 (N=15,18)	0.0 units on a scale Interval -1.0 to 0.0	0.0 units on a scale Interval -3.0 to 2.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 7 (N=15,15)	0.0 units on a scale Interval -1.0 to 1.0	0.0 units on a scale Interval -2.0 to 1.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 8 (N=15,15)	0.0 units on a scale Interval -1.0 to 0.0	0.0 units on a scale Interval -3.0 to 1.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 9 (N=15,15)	0.0 units on a scale Interval -1.0 to 1.0	0.0 units on a scale Interval -2.0 to 2.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 10 (N=15,15)	0.0 units on a scale Interval -1.0 to 1.0	0.0 units on a scale Interval -2.0 to 1.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 11 (N=15,15)	0.0 units on a scale Interval -1.0 to 1.0	0.0 units on a scale Interval -3.0 to 0.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline Day 12 (N=15,15)	0.0 units on a scale Interval -1.0 to 1.0	0.0 units on a scale Interval -3.0 to 1.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Objective Opiate Withdrawal Scale (OOWS)-Change From Baseline End of Treatment (EOT) (N=14,16)	0.0 units on a scale Interval -1.0 to 2.0	0.0 units on a scale Interval -3.0 to 1.0

SECONDARY outcome

Timeframe: 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

Population: This set included all subjects who took at least one dose of study drug.

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.

Outcome measures

Measure	Methadone Group n=15 Participants patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) n=19 Participants patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 2	0.0 units on a scale Interval -4.0 to 2.0	-1.0 units on a scale Interval -11.0 to 2.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 3	0.0 units on a scale Interval -1.0 to 2.0	0.0 units on a scale Interval -16.0 to 9.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 4 (N=15,18)	0.0 units on a scale Interval -2.0 to 1.0	0.0 units on a scale Interval -17.0 to 3.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 5 (N=15,18)	0.0 units on a scale Interval -4.0 to 1.0	-0.5 units on a scale Interval -21.0 to 3.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 6 (N=15,18)	0.0 units on a scale Interval -3.0 to 1.0	-0.5 units on a scale Interval -23.0 to 2.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 7 (N=15,15)	0.0 units on a scale Interval -2.0 to 1.0	-1.0 units on a scale Interval -22.0 to 4.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 8 (N=15,15)	0.0 units on a scale Interval -3.0 to 1.0	-1.0 units on a scale Interval -24.0 to 3.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 9 (N=15,15)	0.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -21.0 to 13.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 10 (N=15,15)	0.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -19.0 to 4.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 11 (N=15,15)	0.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -23.0 to 4.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline Day 12 (N=15,15)	0.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -27.0 to 4.0
Pharmacodynamic Assessment of Withdrawal From Either Methadone or Buprenorphine/Naloxone Using the Subjective Opiate Withdrawal Scale (SOWS)-Change From Baseline End of Treatment (EOT) (N=14,16)	0.0 units on a scale Interval -4.0 to 1.0	-1.0 units on a scale Interval -20.0 to 3.0

Adverse Events

Methadone Group

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Buprenorphine/Naloxone (Suboxone)

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Methadone Group n=15 participants at risk patients on stable methadone therapy (at least 30 days) up to a maximum of 180mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.	Buprenorphine/Naloxone (Suboxone) n=19 participants at risk patients on stable buprenorphine/naloxone therapy (at least 30 days) up to a maximum dose of 24mg/6mg per day. Days 1-13. BI 201335(faldaprevir): BI 201335(faldaprevir) for days 3 to 9.
Blood and lymphatic system disorders Thrombocytosis	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Eye disorders Conjunctivitis	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Eye disorders Dry eye	6.7% 1/15 • 30 days	0.00% 0/19 • 30 days
Gastrointestinal disorders Abdominal discomfort	6.7% 1/15 • 30 days	5.3% 1/19 • 30 days
Gastrointestinal disorders Abdominal pain	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Gastrointestinal disorders Abdominal pain upper	6.7% 1/15 • 30 days	5.3% 1/19 • 30 days
Gastrointestinal disorders Constipation	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Gastrointestinal disorders Dyspepsia	13.3% 2/15 • 30 days	0.00% 0/19 • 30 days
Gastrointestinal disorders Nausea	46.7% 7/15 • 30 days	52.6% 10/19 • 30 days
Gastrointestinal disorders Vomiting	33.3% 5/15 • 30 days	26.3% 5/19 • 30 days
General disorders Fatigue	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Hepatobiliary disorders Drug-induced liver injury	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Hepatobiliary disorders Jaundice	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Investigations Blood bilirubin increased	20.0% 3/15 • 30 days	36.8% 7/19 • 30 days
Investigations Blood creatine phosphokinase increased	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Metabolism and nutrition disorders Decreased appetite	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Nervous system disorders Dizziness	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Nervous system disorders Headache	13.3% 2/15 • 30 days	10.5% 2/19 • 30 days
Skin and subcutaneous tissue disorders Dry skin	6.7% 1/15 • 30 days	0.00% 0/19 • 30 days
Skin and subcutaneous tissue disorders Erythema	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/15 • 30 days	5.3% 1/19 • 30 days
Skin and subcutaneous tissue disorders Pruritus generalised	6.7% 1/15 • 30 days	0.00% 0/19 • 30 days

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights..
• Publication restrictions are in place

Restriction type: OTHER