Efficacy and Safety of BI 201335 (Faldaprevir) in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-naïve Genotype 1 Hepatitis C Infected Patients (STARTverso 1)

A Phase III, Randomised, Double-blind and Placebo-controlled Study of Once Daily BI 201335 120 mg for 12 or 24 Weeks or BI 201335 240 mg for 12 Weeks in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-naïve Patients With Genotype 1 Chronic Hepatitis C Infection

The objective of this trial is to evaluate the efficacy and safety of two different treatment regimens with BI 201335, both in combination with PegIFN/RBV) as compared to standard of care (SOC) with PegIFN/RBV alone.

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: Placebo; Drug: PegIFN/RBV; Drug: BI 201335; Drug: BI 201335

• Study Type: Interventional
• Enrollment (Actual): 656
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria
    • 1220.30.4303 Boehringer Ingelheim Investigational Site
  • Wien, Austria
    • 1220.30.4301 Boehringer Ingelheim Investigational Site
  • Wien, Austria
    • 1220.30.4302 Boehringer Ingelheim Investigational Site
  • Wien, Austria
    • 1220.30.4304 Boehringer Ingelheim Investigational Site
• Belgium
  • Bruxelles, Belgium
    • 1220.30.3201 Boehringer Ingelheim Investigational Site
  • Bruxelles, Belgium
    • 1220.30.3207 Boehringer Ingelheim Investigational Site
  • Edegem, Belgium
    • 1220.30.3204 Boehringer Ingelheim Investigational Site
  • Gent, Belgium
    • 1220.30.3205 Boehringer Ingelheim Investigational Site
  • Leuven, Belgium
    • 1220.30.3202 Boehringer Ingelheim Investigational Site
  • Liège, Belgium
    • 1220.30.3203 Boehringer Ingelheim Investigational Site
• France
  • Clermont-Ferrand, France
    • 1220.30.3314 Boehringer Ingelheim Investigational Site
  • Clichy, France
    • 1220.30.3301 Boehringer Ingelheim Investigational Site
  • Lille, France
    • 1220.30.3311 Boehringer Ingelheim Investigational Site
  • Marseille, France
    • 1220.30.3303 Boehringer Ingelheim Investigational Site
  • Montpellier, France
    • 1220.30.3304 Boehringer Ingelheim Investigational Site
  • Nice Cedex 3, France
    • 1220.30.3305 Boehringer Ingelheim Investigational Site
  • Paris, France
    • 1220.30.3302 Boehringer Ingelheim Investigational Site
  • Paris Cedex 20, France
    • 1220.30.3309 Boehringer Ingelheim Investigational Site
  • Pessac Cedex, France
    • 1220.30.3316 Boehringer Ingelheim Investigational Site
  • Rennes Cedex 09, France
    • 1220.30.3315 Boehringer Ingelheim Investigational Site
  • Saint Laurent du Var, France
    • 1220.30.3312 Boehringer Ingelheim Investigational Site
  • Toulouse, France
    • 1220.30.3313 Boehringer Ingelheim Investigational Site
• Germany
  • Aachen, Germany
    • 1220.30.4917 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1220.30.4902 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1220.30.4904 Boehringer Ingelheim Investigational Site
  • Bonn, Germany
    • 1220.30.4916 Boehringer Ingelheim Investigational Site
  • Dortmund, Germany
    • 1220.30.4913 Boehringer Ingelheim Investigational Site
  • Düsseldorf, Germany
    • 1220.30.4906 Boehringer Ingelheim Investigational Site
  • Düsseldorf, Germany
    • 1220.30.4909 Boehringer Ingelheim Investigational Site
  • Erlangen, Germany
    • 1220.30.4912 Boehringer Ingelheim Investigational Site
  • Frankfurt am Main, Germany
    • 1220.30.4901 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1220.30.4908 Boehringer Ingelheim Investigational Site
  • Herne, Germany
    • 1220.30.4907 Boehringer Ingelheim Investigational Site
  • Kiel, Germany
    • 1220.30.4914 Boehringer Ingelheim Investigational Site
  • Leipzig, Germany
    • 1220.30.4903 Boehringer Ingelheim Investigational Site
  • Mainz, Germany
    • 1220.30.4911 Boehringer Ingelheim Investigational Site
  • München, Germany
    • 1220.30.4905 Boehringer Ingelheim Investigational Site
  • Ulm, Germany
    • 1220.30.4915 Boehringer Ingelheim Investigational Site
• Japan
  • Chiba, Chiba, Japan
    • 1220.30.8106 Boehringer Ingelheim Investigational Site
  • Gifu, Gifu, Japan
    • 1220.30.8111 Boehringer Ingelheim Investigational Site
  • Itabashi-ku, Tokyo, Japan
    • 1220.30.8107 Boehringer Ingelheim Investigational Site
  • Izunokuni, Shizuoka, Japan
    • 1220.30.8112 Boehringer Ingelheim Investigational Site
  • Kamakura, Kanagawa, Japan
    • 1220.30.8108 Boehringer Ingelheim Investigational Site
  • Kita-gun, Kagawa, Japan
    • 1220.30.8117 Boehringer Ingelheim Investigational Site
  • Kofu, Yamanashi, Japan
    • 1220.30.8109 Boehringer Ingelheim Investigational Site
  • Kurashiki, Okayama, Japan
    • 1220.30.8116 Boehringer Ingelheim Investigational Site
  • Kurume, Fukuoka, Japan
    • 1220.30.8118 Boehringer Ingelheim Investigational Site
  • Matsumoto, Nagano, Japan
    • 1220.30.8110 Boehringer Ingelheim Investigational Site
  • Nagoya, Aichi, Japan
    • 1220.30.8113 Boehringer Ingelheim Investigational Site
  • Namegata, Ibaraki, Japan
    • 1220.30.8105 Boehringer Ingelheim Investigational Site
  • Nishinomiya, Hyogo, Japan
    • 1220.30.8114 Boehringer Ingelheim Investigational Site
  • Omura, Nagasaki, Japan
    • 1220.30.8119 Boehringer Ingelheim Investigational Site
  • Omuta, Fukuoka, Japan
    • 1220.30.8122 Boehringer Ingelheim Investigational Site
  • Osaka, Osaka, Japan
    • 1220.30.8121 Boehringer Ingelheim Investigational Site
  • Sapporo, Hokkaido, Japan
    • 1220.30.8101 Boehringer Ingelheim Investigational Site
  • Sendai, Miyagi, Japan
    • 1220.30.8102 Boehringer Ingelheim Investigational Site
  • Tanabe, Wakayama, Japan
    • 1220.30.8115 Boehringer Ingelheim Investigational Site
  • Tsuchiura, Ibaraki, Japan
    • 1220.30.8104 Boehringer Ingelheim Investigational Site
• Portugal
  • Aveiro, Portugal
    • 1220.30.3503 Boehringer Ingelheim Investigational Site
  • Barreiro, Portugal
    • 1220.30.3509 Boehringer Ingelheim Investigational Site
  • Coimbra, Portugal
    • 1220.30.3506 Boehringer Ingelheim Investigational Site
  • Lisboa, Portugal
    • 1220.30.3501 Boehringer Ingelheim Investigational Site
  • Lisboa, Portugal
    • 1220.30.3505 Boehringer Ingelheim Investigational Site
  • Lisboa, Portugal
    • 1220.30.3507 Boehringer Ingelheim Investigational Site
  • Porto, Portugal
    • 1220.30.3502 Boehringer Ingelheim Investigational Site
  • Vila Real, Portugal
    • 1220.30.3504 Boehringer Ingelheim Investigational Site
• Romania
  • Bucharest, Romania
    • 1220.30.4001 Boehringer Ingelheim Investigational Site
  • Bucharest, Romania
    • 1220.30.4002 Boehringer Ingelheim Investigational Site
  • Bucharest, Romania
    • 1220.30.4003 Boehringer Ingelheim Investigational Site
  • Bucharest, Romania
    • 1220.30.4004 Boehringer Ingelheim Investigational Site
• Russian Federation
  • Chelyabinsk, Russian Federation
    • 1220.30.7002 Boehringer Ingelheim Investigational Site
  • Moscow, Russian Federation
    • 1220.30.7001 Boehringer Ingelheim Investigational Site
  • Moscow, Russian Federation
    • 1220.30.7004 Boehringer Ingelheim Investigational Site
  • Moscow, Russian Federation
    • 1220.30.7005 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 1220.30.7006 Boehringer Ingelheim Investigational Site
  • St. Petersburg, Russian Federation
    • 1220.30.7007 Boehringer Ingelheim Investigational Site
• Spain
  • A Coruña, Spain
    • 1220.30.3406 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1220.30.3402 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1220.30.3404 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1220.30.3405 Boehringer Ingelheim Investigational Site
  • Santander, Spain
    • 1220.30.3408 Boehringer Ingelheim Investigational Site
  • Sevilla, Spain
    • 1220.30.3403 Boehringer Ingelheim Investigational Site
  • Valencia, Spain
    • 1220.30.3401 Boehringer Ingelheim Investigational Site
  • Vigo (Pontevedra), Spain
    • 1220.30.3407 Boehringer Ingelheim Investigational Site
• Switzerland
  • Bern, Switzerland
    • 1220.30.4106 Boehringer Ingelheim Investigational Site
  • La Chaux-de-Fonds, Switzerland
    • 1220.30.4103 Boehringer Ingelheim Investigational Site
  • Lugano, Switzerland
    • 1220.30.4107 Boehringer Ingelheim Investigational Site
  • St. Gallen, Switzerland
    • 1220.30.4108 Boehringer Ingelheim Investigational Site
  • Zürich, Switzerland
    • 1220.30.4101 Boehringer Ingelheim Investigational Site
• United Kingdom
  • Bristol, United Kingdom
    • 1220.30.4405 Boehringer Ingelheim Investigational Site
  • London, United Kingdom
    • 1220.30.4404 Boehringer Ingelheim Investigational Site
  • London, United Kingdom
    • 1220.30.4409 Boehringer Ingelheim Investigational Site
  • London, United Kingdom
    • 1220.30.4410 Boehringer Ingelheim Investigational Site
  • Manchester, United Kingdom
    • 1220.30.4401 Boehringer Ingelheim Investigational Site
  • Nottingham, United Kingdom
    • 1220.30.4408 Boehringer Ingelheim Investigational Site
  • Oxford, United Kingdom
    • 1220.30.4407 Boehringer Ingelheim Investigational Site
  • Southampton, United Kingdom
    • 1220.30.4403 Boehringer Ingelheim Investigational Site
  • Whitechapel, London, United Kingdom
    • 1220.30.4406 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 infection, diagnosed by positive anti-HCV antibodies and detected HCV RNA at screening in addition to:

   1. positive anti-HCV antibodies or detected HCV RNA at least 6 months prior to screening; or,
   2. liver biopsy consistent with chronic HCV infection.
2. HCV genotype 1 infection confirmed by genotypic testing at screening.
3. Therapy-naïve to interferon, pegylated interferon, ribavirin or any antiviral / immunomodulatory drug for acute or chronic HCV infection.
4. HCV RNA = 1,000 IU/mL at screening

5. Documentation of a liver biopsy within 3 years or fibroscan within 6 months prior to randomization.

   Note: If cirrhosis has been previously demonstrated on a biopsy, then biopsies obtained more than 3 years before randomization need not be repeated. Biopsies may be waived for patients who would be placed at risk from the procedure. Inability to do a liver biopsy in patients at risk for the procedure should not exclude such patients from a trial.

6. Age 18 to 70 years

7. Female patients:

   1. with documented hysterectomy,
   2. who have had both ovaries removed,
   3. with documented tubal ligation,
   4. who are post-menopausal with last menstrual period at least 12 months prior to screening, or
   5. of childbearing potential with a negative serum pregnancy test at screening and Day 1, that, if sexually active, agree to use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of ribavirin in addition to the consistent and correct use of a condom. Patients must agree not to breast-feed at any time from the date of screening until 7 months after the last dose of ribavirin.

   Medically accepted methods of contraception for females in this trial are ethinyl estradiol containing contraceptives, diaphragm with spermicide substance and intra-uterine device.

   Male patients:

   1. who are documented to be sterile, or
   2. who are without pregnant female partner(s) and consistently and correctly use a condom while their female partner(s) (if of child-bearing potential) use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of ribavirin. It is in the responsibility of the male patient to ensure that his partner(s) is not pregnant prior to screening into the study or becomes pregnant during the treatment and the observation phase. Female partners of childbearing potential should perform monthly pregnancy tests from the date of screening until 7 months after the last dose of ribavirin (tests will be provided by the sponsor).
8. Signed informed consent form prior to trial participation

Exclusion criteria:

1. HCV infection of mixed genotype (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening
2. Evidence of acute or chronic liver disease due to causes other than chronic HCV infection. Incidental steatosis diagnosed by biopsy is not an exclusion criterion.
3. HIV co-infection
4. Hepatitis B virus (HBV) infection based on presence of HBs-Ag
5. Active malignancy, or history of malignancy within the last 5 years prior to screening (with an exception of appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the uterine cervix)
6. Active or, history of alcohol or illicit drug abuse other than cannabis within the past 12 months
7. A condition that is defined as one which in the opinion of investigator may put the patient at risk because of participation in this study, may influence the results of this study, or limit the patients ability to participate in this study
8. Usage of any investigational drugs within 30 days prior to screening, or planned usage of an investigational drug during the course of this study.
9. Received concomitant systemic antiviral, hematopoietic growth factor, or immunomodulatory treatment within 30 days prior to randomization. Patients being treated with oral antivirals such as acyclovir, famciclovir or valacyclovir for recurrent herpes simplex infection; or with oseltamivir or zanamivir for influenza A infection, may be screened.
10. Received silymarin (milk thistle), glycyrrhizin, or Sho-saiko-to (SST) within 28 days prior to randomization and throughout the treatment phase of this trial.
11. Known hypersensitivity to any ingredient of the study drugs.
12. Alpha fetoprotein value > 100 ng/mL at screening; if > 20 ng/mL and = 100 ng/mL, patients may be included if there is no evidence of liver cancer in an appropriate imaging study (e.g., ultrasound, CT scan, or MRI) within last 6 months prior to randomization (Visit 2).

Other exclusion criteria related to pegylated interferon and/or ribavirin restrictions are not listed here.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PegIFN/RBV; PegIFN/RBV for 48 weeks	Drug: PegIFN/RBV; PegIFN/RBV for 48 weeks
Experimental: BI 201335 for 12 or 24 weeks; BI 201335 once daily low dose for 12 or 24 weeks in combination with PegIFN/RBV for 24 or 48 weeks	Drug: PegIFN/RBV; PegIFN/RBV for 48 weeks; Drug: BI 201335; BI 201335 once daily high dose; Drug: BI 201335; BI 201335 once daily low dose
Active Comparator: Placebo and PegIFN/RBV; Placebo (oral) once daily plus PegIFN/RBV (subcutaneous injection/oral) for 24 weeks, followed by PegIFN/RBV alone up to Week 48.	Drug: Placebo; Drug: PegIFN/RBV; PegIFN/RBV for 48 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained Virological Response 12 Weeks Post-treatment (SVR12)	Sustained Virological Response 12 weeks post-treatment (SVR12), defined as plasma Hepatitis C virus (HCV) Ribonucleic acid (RNA) level < 25 IU/mL (undetected) 12 weeks after the originally planned treatment duration.	12 weeks post treatment, up to 60 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained Virological Response 24 Weeks Post-treatment (SVR24)	Sustained Virological Response 24 weeks post-treatment (SVR24), defined as plasma HCV RNA level < 25 IU/mL (undetected) 24 weeks after the originally planned treatment duration.	24 weeks post treatment, up to 72 weeks
Early Treatment Success (ETS)	Early treatment success (ETS), defined as a plasma HCV RNA level <25 IU/mL (detected or undetected) at week 4 and HCV RNA <25 IU/mL (undetected) at week 8.	week 4 and week 8
Alanine Aminotransferase (ALT) Normalisation: ALT in Normal Range at End of Treatment (EoT) When SVR12=YES	This will be presented as the number of patients. SVR12 means Sustained virological response 12 weeks post-treatment. BL = Baseline	12 weeks post treatment, up to 60 weeks
Alanine Aminotransferase (ALT) Normalisation: ALT in Normal Range at End of Treatment (EoT) When SVR12= NO	This will be presented as the number of patients. SVR12 means Sustained virological response 12 weeks post-treatment. BL = Baseline	12 weeks post treatment, up to 60 weeks
Alanine Aminotransferase (ALT) Normalisation: ALT in Normal Range at Sustained Virological Response 12 Weeks Post-treatment (SVR12) Visit, When SVR12=YES	This will be presented as the number of patients. BL = Baseline	12 weeks post treatment, up to 60 weeks
Alanine Aminotransferase (ALT) Normalisation: ALT in Normal Range at Sustained Virological Response 12 Weeks Post-treatment (SVR12) Visit, When SVR12=NO	This will be presented as the number of patients. BL = Baseline	12 weeks post treatment, up to 60 weeks
Aspartate Aminotransferase (AST) Normalisation: AST in Normal Range at End of Treatment (EoT) When SVR12=YES	This will be presented as the number of patients. SVR12 means Sustained virological response 12 weeks post-treatment. BL = Baseline	12 weeks post treatment, up to 60 weeks
Aspartate Aminotransferase (AST) Normalisation: AST in Normal Range at End of Treatment (EoT) When SVR12=NO	This will be presented as the number of patients. SVR12 means Sustained virological response 12 weeks post-treatment. BL = Baseline	12 weeks post treatment, up to 60 weeks
Aspartate Aminotransferase (AST) Normalisation: AST in Normal Range at Sustained Virological Response 12 Weeks Post-treatment (SVR12) Visit, When SVR12=YES	This will be presented as the number of patients. BL = Baseline	12 weeks post treatment, up to 60 weeks
Aspartate Aminotransferase (AST) Normalisation: AST in Normal Range at Sustained Virological Response 12 Weeks Post-treatment (SVR12) Visit, When SVR12=NO	This will be presented as the number of patients. BL = Baseline	12 weeks post treatment, up to 60 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Dieterich D, Nelson M, Soriano V, Arasteh K, Guardiola JM, Rockstroh JK, Bhagani S, Laguno M, Tural C, Ingiliz P, Jain MK, Stern JO, Manero M, Vinisko R, Kort J; STARTVerso4 study group. Faldaprevir and pegylated interferon alpha-2a/ribavirin in individuals co-infected with hepatitis C virus genotype-1 and HIV. AIDS. 2015 Mar 13;29(5):571-81. doi: 10.1097/QAD.0000000000000579.
• Jensen DM, Asselah T, Dieterich D, Foster GR, Sulkowski MS, Zeuzem S, Mantry P, Yoshida EM, Moreno C, Ouzan D, Wright M, Morano LE, Buynak R, Bourliere M, Hassanein T, Nishiguchi S, Kao JH, Omata M, Paik SW, Wong DK, Tam E, Kaita K, Feinman SV, Stern JO, Scherer J, Quinson AM, Voss F, Gallivan JP, Bocher WO, Ferenci P. Faldaprevir, pegylated interferon, and ribavirin for treatment-naive HCV genotype-1: pooled analysis of two phase 3 trials. Ann Hepatol. 2016 May-Jun;15(3):333-49. doi: 10.5604/16652681.1198803.
• Ferenci P, Asselah T, Foster GR, Zeuzem S, Sarrazin C, Moreno C, Ouzan D, Maevskaya M, Calinas F, Morano LE, Crespo J, Dufour JF, Bourliere M, Agarwal K, Forton D, Schuchmann M, Zehnter E, Nishiguchi S, Omata M, Kukolj G, Datsenko Y, Garcia M, Scherer J, Quinson AM, Stern JO; STARTVerso1 Study Group. STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection. J Hepatol. 2015 Jun;62(6):1246-55. doi: 10.1016/j.jhep.2014.12.024. Epub 2015 Jan 2.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: April 20, 2011
• First Submitted That Met QC Criteria: April 27, 2011
• First Posted (Estimate): April 28, 2011

Study Record Updates

• Last Update Posted (Estimate): September 18, 2015
• Last Update Submitted That Met QC Criteria: August 18, 2015
• Last Verified: August 1, 2015

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; Hepatitis A; Hepatitis C
• Other Study ID Numbers: 1220.30; 2010-021716-42 (EudraCT Number: EudraCT)