Clinical trial NCT01132313: Safety, Antiviral Effect and PK of BI 207127 + BI 201335 +/- RBV for 4 up to 40 Weeks in Patients With Chronic HCV Genotype 1 Infection
Official title: Safety, Antiviral Effect and Pharmacokinetics of BI 207127 in Combination With BI 201335 and With or Without Ribavirin for 4, 16, 24, 28 or 40 Weeks in Patients With Chronic HCV Genotype 1 Infection (Randomized Phase Ib/II)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C, Chronic
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2010-05-28
Enrollment: 488
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The substances BI 201335 and BI 207127 are being developed for the treatment of chronic hepatitis C virus infection. BI 201335 and BI 207127 work by preventing the virus from replicating.

The currently available medications pegylated interferon alfa and ribavirin for hepatitis C ca have considerable adverse events in patients and in many cases are not sufficiently effective. This is particularly the case in treatment of patients infected with genotype 1 of HCV.

A combination therapy of these new substances without pegylated interferon alfa may be associated with fewer adverse events that currently available (pegylated interferon-alfa-based) medication and may also provide a treatment option to the large number of patients with contraindications or intolerance to pegylated interferon alfa.

This clinical trial (1241.21) currently consists of 3 distinct studies: Part 1, Part 2 and Part 3.

Part 1 (SOUND-C1) is a 2 armed study as described in experimental arms 1 and 2 below (actual enrollment: 56 patients; randomized and treated: 32) Part 2 (SOUND-C2) is a 5 armed study as described in experimental arms 3 to 7 below (actual enrollment: 465; randomized and treated: 362) Part 3 (SOUND-C3) includes 3 arms as described in experimental arms 8 to 10 below (83 patients randomized and treated)


Eligibility criteria: Inclusion criteria:

* Chronic hepatitis C virus (HCV) infection of genotype (GT) 1
* Parts 1-3:Treatment naive to Interferon -alfa (IFN), Pegylated interferon -alfa (PegIFN), ribavirin (RBV), and any direct acting antiviral agent for chronic hepatitis C
* Part 4: Treatment experienced with confirmed prior virological failure to an approved dose of PegIFN/RBV (null-response)
* HCV RNA \>=10,000 IU/mL at screening
* Liver biopsy within two years or fibroscan within six months prior to baseline
* Liver biopsy within two years or fibroscan within 6 months prior to screening
* Age 18-75 years

Exclusion criteria:

* Hepatitis C virus (HCV) infection of mixed genotype
* Evidence of liver disease due to causes other than chronic HCV infection
* Positive ELISA for human immunodeficiency virus (HIV)
* Hepatitis B virus (HBV) infection
* Decompensated liver disease or history of decompensated liver disease
* Active or suspected malignancy within the last 5 years
* Ongoing or historical photosensitivity or recurrent rash
* History of alcohol or drug abuse (except cannabis) within the past 12 months
* Body mass index (BMI)I \<18 or \> 35 kg/m2
* Usage of any investigational drugs within 30 days prior to enrolment, or 5 half-lives, whichever is longer; o the planned usage of an investigational drug during the course of the current study
* Known hypersensitivity to any ingredient of the study drugs
* A condition that is defined as one which in the opinion of the investigator may interfere with the patient's capability for participation in the trial or may influence the results of the trial
* Alpha fetoprotein \>100ng/mL at screening; if \>20ng/mL and \<=100ng/mL, patients can be included if there is no evidence of liver cancer in an appropriate imaging study within 6 months prior to randomisation
* Total bilirubin \> 2 mg/dL with ratio of direct/indirect \> 1
* AST or ALT \>5xULN
* INR prolonged to \>1.7xULN
* Requirement for chronic systemic corticosteroids
* Received concomitant systemic antiviral, hematopoietic growth factor, or immunomodulatory treatment within 30 days prior to enrolment or 5 half-lives, whichever is longer
* Received silymarin or glycyrrhizin or Sho-saiko-to within 30 days prior to enrolment
* Contraindications pertaining to PegIFN or RBV

Primary outcomes:
measure: Part 1: Rapid Virological Response (RVR)
timeFrame: 4 weeks
measure: Part 2: Sustained Virological Response (SVR)
timeFrame: From drug administration until 12 weeks after end of treatment, up to 52 weeks
measure: Part 3 and 4: Sustained Virological Response (SVR)
timeFrame: From drug administration until 12 weeks after end of treatment, up to 36 weeks
Secondary outcomes:
measure: Part 1: Time to Virological Response
timeFrame: From drug administration until end of drug administration, up to 4 weeks
measure: Part 2: Time to Virological Response
timeFrame: From drug administration until end of drug administration, up to 40 weeks
measure: Part 1 and 2: Plasma HCV RNA Level Not Detectable at Week 4
timeFrame: 4 weeks
measure: Part 2: Sustained Virological Response at 4 and 24 Weeks After End of Treatment
timeFrame: 4 weeks and 24 weeks after the end of treatment, up to 64 weeks
measure: Part 3 and 4: Plasma HCV RNA Level <25 IU/mL at Week 4 and 12 of Treatment
timeFrame: Week 4 and 12
measure: Part 3 and 4: Sustained Virological Response (SVR) at 4 Weeks After End of Treatment
timeFrame: up to 28 weeks
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: 1241.21.0003 Boehringer Ingelheim Investigational Site
state: California
city: San Diego
country: United States
facility: 1241.21.0006 Boehringer Ingelheim Investigational Site
state: California
city: San Francisco
country: United States
facility: 1241.21.0004 Boehringer Ingelheim Investigational Site
state: California
city: Palm Harbor
country: United States
facility: 1241.21.0011 Boehringer Ingelheim Investigational Site
state: Florida
city: Valparaiso
country: United States
facility: 1241.21.0013 Boehringer Ingelheim Investigational Site
state: Indiana
city: Springfield
country: United States
facility: 1241.21.0008 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: Fayetteville
country: United States
facility: 1241.21.0019 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Arlington
country: United States
facility: 1241.21.0012 Boehringer Ingelheim Investigational Site
state: Texas
city: Austin
country: United States
facility: 1241.21.0005 Boehringer Ingelheim Investigational Site
state: Texas
city: Dallas
country: United States
facility: 1241.21.0007 Boehringer Ingelheim Investigational Site
state: Texas
city: Houston
country: United States
facility: 1241.21.0010 Boehringer Ingelheim Investigational Site
state: Texas
city: Seattle
country: United States
facility: 1241.21.0017 Boehringer Ingelheim Investigational Site
state: Washington
city: Heidelberg
country: Australia
facility: 1241.21.61002 Boehringer Ingelheim Investigational Site
state: Victoria
city: Melbourne
country: Australia
facility: 1241.21.61001 Boehringer Ingelheim Investigational Site
state: Victoria
city: Linz
country: Austria
facility: 1241.21.43003 Boehringer Ingelheim Investigational Site
city: Wien
country: Austria
facility: 1241.21.43001 Boehringer Ingelheim Investigational Site
city: Wien
country: Austria
facility: 1241.21.43002 Boehringer Ingelheim Investigational Site
city: Clichy
country: France
facility: 1241.21.33005 Boehringer Ingelheim Investigational Site
city: Grenoble cédex 9
country: France
facility: 1241.21.33007 Boehringer Ingelheim Investigational Site
city: Lyon
country: France
facility: 1241.21.33003 Boehringer Ingelheim Investigational Site
city: Marseille
country: France
facility: 1241.21.33001 Boehringer Ingelheim Investigational Site
city: Montpellier
country: France
facility: 1241.21.33002 Boehringer Ingelheim Investigational Site
city: Paris
country: France
facility: 1241.21.33004 Boehringer Ingelheim Investigational Site
city: Paris
country: France
facility: 1241.21.33008 Boehringer Ingelheim Investigational Site
city: Vandoeuvre Cedex
country: France
facility: 1241.21.33006 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1241.21.49002 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1241.21.49003 Boehringer Ingelheim Investigational Site
city: Düsseldorf
country: Germany
facility: 1241.21.49007 Boehringer Ingelheim Investigational Site
city: Esslingen
country: Germany
facility: 1241.21.49005 Boehringer Ingelheim Investigational Site
city: Frankfurt am Main
country: Germany
facility: 1241.21.49001 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1241.21.49006 Boehringer Ingelheim Investigational Site
city: Hannover
country: Germany
facility: 1241.21.49009 Boehringer Ingelheim Investigational Site
city: Leipzig
country: Germany
facility: 1241.21.49004 Boehringer Ingelheim Investigational Site
city: Mainz
country: Germany
facility: 1241.21.49008 Boehringer Ingelheim Investigational Site
city: Auckland NZ
country: New Zealand
facility: 1241.21.64001 Boehringer Ingelheim Investigational Site
city: Aveiro
country: Portugal
facility: 1241.21.35103 Boehringer Ingelheim Investigational Site
city: Coimbra
country: Portugal
facility: 1241.21.35104 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 1241.21.35101 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 1241.21.35105 Boehringer Ingelheim Investigational Site
city: Porto
country: Portugal
facility: 1241.21.35102 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 1241.21.40001 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 1241.21.40002 Boehringer Ingelheim Investigational Site
city: Bucharest
country: Romania
facility: 1241.21.40003 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1241.21.34002 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1241.21.34005 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1241.21.34003 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1241.21.34004 Boehringer Ingelheim Investigational Site
city: Majadahonda-Madrid
country: Spain
facility: 1241.21.34001 Boehringer Ingelheim Investigational Site
city: Valencia
country: Spain
facility: 1241.21.34006 Boehringer Ingelheim Investigational Site
city: Basel
country: Switzerland
facility: 1241.21.41003 Boehringer Ingelheim Investigational Site
city: Bern
country: Switzerland
facility: 1241.21.41006 Boehringer Ingelheim Investigational Site
city: St. Gallen
country: Switzerland
facility: 1241.21.41001 Boehringer Ingelheim Investigational Site
city: Zürich
country: Switzerland
facility: 1241.21.41002 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Zeuzem S, Mantry P, Soriano V, Buynak RJ, Dufour JF, Pockros PJ, Wright D, Angus P, Buti M, Stern JO, Kadus W, Vinisko R, Bocher W, Mensa FJ. Short article: Faldaprevir, deleobuvir and ribavirin in IL28B non-CC patients with HCV genotype-1a infection included in the SOUND-C3 phase 2b study. Eur J Gastroenterol Hepatol. 2016 Aug;28(8):923-6. doi: 10.1097/MEG.0000000000000649.
citation: Asselah T, Zeuzem S, Soriano V, Bronowicki JP, Lohse AW, Mullhaupt B, Schuchmann M, Bourliere M, Buti M, Roberts SK, Gane EJ, Stern JO, Voss F, Baum P, Gallivan JP, Bocher WO, Mensa FJ. ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection. PLoS One. 2015 Dec 9;10(12):e0144004. doi: 10.1371/journal.pone.0144004. eCollection 2015.
citation: Zeuzem S, Soriano V, Asselah T, Gane EJ, Bronowicki JP, Angus P, Lohse AW, Stickel F, Mullhaupt B, Roberts S, Schuchmann M, Manns M, Bourliere M, Buti M, Stern JO, Gallivan JP, Voss F, Sabo JP, Bocher W, Mensa FJ; SOUND-C2 Study Group. Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis. Antimicrob Agents Chemother. 2015 Feb;59(2):1282-91. doi: 10.1128/AAC.04383-14. Epub 2014 Dec 15.
citation: Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse AW, Mullhaupt B, Schuchmann M, Bourliere M, Buti M, Roberts SK, Gane EJ, Stern JO, Vinisko R, Kukolj G, Gallivan JP, Bocher WO, Mensa FJ. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013 Aug 15;369(7):630-9. doi: 10.1056/NEJMoa1213557.
citation: Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Mullhaupt B, Gane E, Schuchmann M, Lohse AW, Pol S, Bronowicki JP, Roberts S, Arasteh K, Zoulim F, Heim M, Stern JO, Nehmiz G, Kukolj G, Bocher WO, Mensa FJ. Faldaprevir (BI 201335), deleobuvir (BI 207127) and ribavirin oral therapy for treatment-naive HCV genotype 1: SOUND-C1 final results. Antivir Ther. 2013;18(8):1015-9. doi: 10.3851/IMP2567. Epub 2013 Apr 4.