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

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Drug: midazolam; Drug: BI 201335; Drug: caffeine; Drug: tolbutamide; Drug: pegylated interferon; Drug: BI 207127; Drug: ribavirin; Drug: tenofovir

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
      • 1241.27.0200 Boehringer Ingelheim Investigational Site
    • Vancouver, British Columbia, Canada
      • 1241.27.0600 Boehringer Ingelheim Investigational Site
    • Vancouver, British Columbia, Canada
      • 1241.27.0700 Boehringer Ingelheim Investigational Site
    • Victoria, British Columbia, Canada
      • 1241.27.0400 Boehringer Ingelheim Investigational Site
  • Ontario
    • London, Ontario, Canada
      • 1241.27.0100 Boehringer Ingelheim Investigational Site
    • Ottawa, Ontario, Canada
      • 1241.27.0300 Boehringer Ingelheim Investigational Site
  • Quebec
    • Montreal, Quebec, Canada
      • 1241.27.0500 Boehringer Ingelheim Investigational Site
• Germany
  • Frankfurt am Main, Germany
    • 1241.27.4901 Boehringer Ingelheim Investigational Site
  • Köln, Germany
    • 1241.27.4907 Boehringer Ingelheim Investigational Site
  • Leipzig, Germany
    • 1241.27.4903 Boehringer Ingelheim Investigational Site
  • Mainz, Germany
    • 1241.27.4906 Boehringer Ingelheim Investigational Site
• United States
  • California
    • La Mesa, California, United States
      • 1241.27.0006 Boehringer Ingelheim Investigational Site
  • Maryland
    • Rockville, Maryland, United States
      • 1241.27.0005 Boehringer Ingelheim Investigational Site
  • New Jersey
    • Marlton, New Jersey, United States
      • 1241.27.0004 Boehringer Ingelheim Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • 1241.27.0003 Boehringer Ingelheim Investigational Site
  • Utah
    • Salt Lake City, Utah, United States
      • 1241.27.0001 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Chronic hepatitis C genotype 1 infection, diagnosed at least 6 months prior to screening
2. Treatment naive or confirmed prior treatment relapse or partial response following treatment with interferon and ribavirin
3. Age 18 to 70 years
4. HCV RNA (Hepatitis C Virus RiboNucleic Acid) = 1,000 IU/mL at screening
5. Liver biopsy or fibroscan to exclude cirrhosis

Exclusion criteria:

1. Hepatitis C Virus (HCV) infection of mixed genotype; Hepatitis B Virus (HBV) or Human Immunodeficiency Virus (HIV) co-infection
2. Evidence of acute or chronic liver disease due to causes other than chronic HCV infection,
3. Decompensated liver disease, or history of decompensated liver disease,
4. Body weight < 40 or > 125 kg,
5. Clinical evidence of significant or unstable cardiovascular disease, chronic pulmonary disease, history or evidence of retinopathy or clinically significant ophthalmological disorder
6. Pre-existing psychiatric condition that could interfere with the subject's participation in and completion of the study
7. Laboratory parameters disorders (thalassemia major, sickle cell anemia or glucose 6 phosphate dehydrogenase deficit)
8. Hemoglobin < 12 g/dL for women and < 13 g/dL for men
9. 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: February 1, 2012
• First Submitted That Met QC Criteria: February 1, 2012
• First Posted (Estimate): February 3, 2012

Study Record Updates

• Last Update Posted (Estimate): June 10, 2016
• Last Update Submitted That Met QC Criteria: May 4, 2016
• Last Verified: May 1, 2016

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; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Purinergic Antagonists; Purinergic Agents; Antimetabolites; Antineoplastic Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Tenofovir; Interferons; Midazolam; Ribavirin; Caffeine; Tolbutamide
• Other Study ID Numbers: 1241.27; 2012-004102-10 (EudraCT Number: EudraCT)