Drug Drug Interaction Study Between BI 201335 and BI 207127 in Chronic Hepatitis C Infected Patients

Study Overview
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Brief Summary
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To evaluate the drug-drug interactions between BI 201335 and BI 207127 as well as their combined effect on CYP probe drug substrates and on tenofovir and raltegravir in treatment naive or prior treatment relapse patients with chronic hepatitis C infection.

Official Title
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A Multi-centre, Open Label, Parallel Group Trial to Evaluate the Pharmacokinetic Interactions Between BI 207127 (600 mg t.i.d. or 600 mg b.i.d.) and BI 201335 (120 mg q.d.) Given in Combination With Ribavirin for 24 Weeks, and Their Combined Effect on the Pharmacokinetics of Tenofovir, Raltegravir, Caffeine (the Probe Drug Substrate for CYP1A2), Tolbutamide (the Probe Drug Substrate for CYP2C9) and Midazolam (the Probe Drug Substrate for CYP3A4) in Treatment naïve Patients and Prior Treatment Relapse or Partial Responder Patients With Genotype 1 Chronic Hepatitis C Infection

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: midazolam
* Drug: BI 201335
* Drug: tenofovir
* Drug: caffeine
* Drug: tolbutamide
* Drug: tolbutamide
* Drug: midazolam
* Drug: caffeine
* Drug: pegylated interferon
* Drug: BI 201335
* Drug: BI 201335
* Drug: BI 207127
* Drug: BI 207127
* Drug: BI 201335
* Drug: BI 207127
* Drug: ribavirin
* Drug: ribavirin
* Drug: ribavirin
* Drug: pegylated interferon
* Drug: ribavirin
* Drug: caffeine
* Drug: tolbutamide
* Drug: BI 207127
* Drug: midazolam
* Drug: BI 201335
* Drug: BI 207127
* Drug: ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Chronic hepatitis C genotype 1 infection, diagnosed at least 6 months prior to screening Treatment naive or confirmed prior treatment relapse or partial response following treatment with interferon and ribavirin Age 18 to 70 years HCV RNA (Hepatitis C Virus RiboNucleic Acid) = 1,000 IU/mL at screening Liver biopsy or fibroscan to exclude cirrhosis Exclusion criteria: Hepatitis C Virus (HCV) infection of mixed genotype; Hepatitis B Virus (HBV) or Human Immunodeficiency Virus (HIV) co-infection Evidence of acute or chronic liver disease due to causes other than chronic HCV infection, Decompensated liver disease, or history of decompensated liver disease, Body weight < 40 or > 125 kg, Clinical evidence of significant or unstable cardiovascular disease, chronic pulmonary disease, history or evidence of retinopathy or clinically significant ophthalmological disorder Pre-existing psychiatric condition that could interfere with the subject's participation in and completion of the study Laboratory parameters disorders (thalassemia major, sickle cell anemia or glucose 6 phosphate dehydrogenase deficit) Hemoglobin < 12 g/dL for women and < 13 g/dL for men Patients who have been previously treated with at least one dose of any antiviral or immunomodulatory drug other than interferon alfa or ribavirin for acute or chronic HCV infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Effect of BI 207127 on BI 201335, the effect of BI 201335 and dual oral direct acting antiviral (DAAs) on caffeine, tolbutamide and midazolam | Drug: tolbutamide<br>* CYP2C9 probe drug<br>Drug: midazolam<br>* CYP3A probe drug<br>Drug: caffeine<br>* CYP1A2 probe drug<br>Drug: BI 201335<br>* HCV protease inhibitor<br>Drug: pegylated interferon<br>* HCV treatment<br>Drug: BI 207127<br>* HCV polymerase inhibitor<br>Drug: ribavirin<br>* HCV treatment<br>|
| Experimental: Group B<br>Effect of BI 201335 on BI 207127, the effect of BI 207127 and metabolites and dual oral DAAs on caffeine, tolbutamide and midazolam | Drug: BI 201335<br>* HCV protease inhibitor<br>Drug: caffeine<br>* CYP1A2 probe drug<br>Drug: tolbutamide<br>* CYP2C9 probe drug<br>Drug: pegylated interferon<br>* HCV treatment<br>Drug: BI 207127<br>* HCV polymerase inhibitor<br>Drug: ribavirin<br>* HCV treatment<br>Drug: midazolam<br>* CYP3A probe drug<br>|
| Experimental: Group C<br>Effect of Dual oral DAAs on tenofovir | Drug: tenofovir<br>* nucleoside analogue<br>Drug: BI 207127<br>* HCV polymerase inhibitor<br>Drug: ribavirin<br>* HCV treatment<br>Drug: BI 201335<br>* HCV protease inhibitor<br>|
| Experimental: Group D<br>Effect of BI 201335 and BI 207127 at 600 mg b.i.d. on caffeine, tolbutamide and midazolam | Drug: midazolam<br>* CYP3A probe drug<br>Drug: BI 201335<br>* HCV protease inhibitor<br>Drug: BI 207127<br>* HCV polymerase inhibitor<br>Drug: ribavirin<br>* HCV treatment<br>Drug: caffeine<br>* CYP1A2 probe drug<br>Drug: tolbutamide<br>* CYP2C9 probe drug<br>|
| Experimental: Group E<br>Effect of BI 201335 and BI 207127 on raltegravir | Drug: BI 201335<br>* HCV protease inhibitor<br>Drug: ribavirin<br>* HCV treatment<br>Drug: BI 207127<br>* HCV polymerase inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Faldaprevir (BI 201335) | Maximum concentration of an analyte in plasma | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| C24hr of Faldaprevir (BI 201335) | Concentration of an analyte in plasma at 24 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| Area Under the Concentration-time Curve (AUC) of Faldaprevir (BI 201335) From 0 to 24 Hours | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| Cmax of Deleobuvir (BI 207127) | Maximum concentration of an analyte in plasma | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| C6hr of Deleobuvir (BI 207127) | Concentration of an analyte in plasma at 6 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| AUC 0-6hr of Deleobuvir (BI 207127) | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| Cmax of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) | Maximum concentration of an analyte in plasma | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| C6hr of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) | Concentration of an analyte in plasma at 6 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| AUC 0-6hr of Deleobuvir Metabolite Acyl-glucuronide (BI 208333) | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| Cmax of Deleobuvir Reduction Metabolite CD 6168 | Maximum concentration of an analyte in plasma | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| C6hr of Deleobuvir Reduction Metabolite CD 6168 | Concentration of an analyte in plasma at 6 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| AUC 0-6hr of Deleobuvir Reduction Metabolite CD 6168 | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| Cmax of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) | Maximum concentration of an analyte in plasma | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| C6hr of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) | Concentration of an analyte in plasma at 6 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| AUC 0-6hr of Deleobuvir Metabolite CD 6168 ag (Acylglucuronide) | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 6 hours | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9, 17 and 66. | 
| Cmax of Caffeine | Maximum concentration of an analyte in plasma | 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66. | 
| AUC 0-infinity of Caffeine | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. | 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66. | 
| Cmax of Tolbutamide | Maximum concentration of an analyte in plasma | 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66. | 
| AUC 0-infinity of Tolbutamide | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. | 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66. | 
| Cmax of Midazolam | Maximum concentration of an analyte in plasma | 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66. | 
| AUC 0-infinity of Midazolam | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. | 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66. | 
| Cmax of 1-OH-Midazolam (1-hydroxy-midazolam) | Maximum concentration of an analyte in plasma | 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66. | 
| AUC 0-infinity of 1-OH-Midazolam (1-hydroxy-midazolam) | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity. | 5 min before and 1 hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 11:55h, 15h, 23:55h, 26h, 28h, 29:55h, 32h after first drug administration on day 1 also 5 min before, 1h, 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after drug on days 9, 17 and 66. | 
| Cmax of Tenofovir | Maximum concentration of an analyte in plasma. | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17 | 
| C24hr of Tenofovir | Concentration of an analyte in plasma at 24 hours. | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17 | 
| AUC 0-24hr of Tenofovir | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours. | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17 | 
| Cmax of Raltegravir | Maximum concentration of an analyte in plasma. | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17 | 
| C12hr of Raltegravir | Concentration of an analyte in plasma at 12 hours. | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17 | 
| AUC 0-12hr of Raltegravir | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 12 hours. | PK plasma samples were taken at: 5 minutes before drug administration and 1 hour (h), 2h, 3h, 4h, 5h, 5:55h, 8h, 10h, 11:55h, 15h, 23:55h after first drug administration on days 9 and 17 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Sustained Virological Response (SVR12) | Sustained virologic response (SVR12): Plasma Hepatitis C virus Ribonucleic acid (HCV RNA) level <25 IU/mL(international units per millilitre) undetectable at 12 weeks after the end of treatment. SVR12 was analyzed in a descriptive manner using frequency of participants who achieved SVR12. | 12 weeks post treatment |