Clinical trial NCT00854802: A Study of Debio 025 (Alisporivir) Combined With Peg-IFNα2a and Ribavirin in Treatment naïve Chronic Hepatitis C Genotype 1 Patients
Official title: A Multicentre, Randomised, Double-blind, Placebo-controlled, Parallel-group Phase II Study on the Efficacy and Safety of Debio 025 Combined With Peg-IFNα2a and Ribavirin in Treatment naïve Chronic Hepatitis C Genotype 1 Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Hepatitis C
Keywords: Hepatitis
Hepatitis C
Lead sponsor: Debiopharm International SA
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2009-03-03
Enrollment: 290
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare several Debio 025 (alisporivir)/peg-IFNα2a/ribavirin triple therapies with the current standard of care (SOC) in treatment naïve chronic hepatitis C genotype 1 patients.

Detailed description: This is an international, multicentre, randomised, double-blind, placebo-controlled, 4-arm, parallel-group, multiple dose phase II study comparing 3 Debio 025 (alisporivir)/peg-IFNα2a/ribavirin regimens to SOC treatment in treatment naïve chronic HCV genotype 1 patients.

Patients are randomised into 1 of 4 arms receiving either Debio 025/peg-IFNα2a/ribavirin triple therapy for a fixed treatment duration of 48 weeks (Treatment A) or 24 weeks (Treatment B), Debio 025/peg-IFNα2a/ribavirin triple therapy for a response-based treatment duration of 24 or 48 weeks (Treatment C), or blinded SOC treatment for 48 weeks (Treatment D). Follow-up is 24 weeks in all treatment arms.

Eligibility criteria: Inclusion Criteria:

* Males or females aged ≥ 18 and ≤ 65 years.
* Body mass index (BMI) ≥ 18 and ≤ 32 kg/m\^2.
* Hepatitis B surface antigen (HbsAg) negative and HIV-1 negative.
* Serological diagnosis of chronic hepatitis C viral infection genotype 1 for \> 6 months.
* Chronic liver disease consistent with chronic hepatitis C infection on a biopsy or FibroScan® obtained within the past 24 months (36 months for patients with incomplete/transition to cirrhosis).
* Previously untreated for hepatitis C virus (HCV) infection (approved or investigational drug).
* Plasma HCV RNA level lower limit ≥ 100 IU/ml assessed by quantitative polymerase chain reaction (qPCR) or equivalent; no upper limit.
* Neutrophil count ≥ 1500/µL; hemoglobin (Hb) ≥ 12g/dL for females and ≥ 13g/dL for males; platelets ≥ 90,000/µL.
* Patients with incomplete/transition to cirrhosis on biopsy or an elasticity score between 9.5 and 14 kPa on FibroScan must have an abdominal ultrasound (US), computed tomographic (CT) scan, or magnetic resonance imaging (MRI) scan without evidence of hepatocellular carcinoma (within 2 months prior to randomisation) and a serum alpha-foetoprotein (AFP) \< 100 ng/mL.
* Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) \< 5 times the upper limit of normal.
* Normal or compensated liver function and absence of complicated portal hypertension as documented by the following:

  * No history of bleeding oesophageal varices;
  * Absence of ascites;
  * Absence of encephalopathy;
  * Albumin ≥ 35 g/L;
  * Total bilirubin ≤ 1.8 mg/dL (≤ 30 µmol/L);
  * Prothrombin (INR ≤ 1.5).
* Creatinine clearance \> 50 mL/min.
* Thyroid stimulating hormone (TSH) within normal range;
* All patients should be informed about Debio 025 and ribavirin foetotoxicity:

  * Females may participate if they are surgically sterile or post-menopausal. Pre-menopausal females may participate if they use 2 reliable contraceptive methods (oral contraceptive + barrier method). The contraceptive regimen must be maintained during the treatment period and for 4 months after the last Debio 025 or ribavirin dose.
  * Male patients must be surgically sterile or use 2 reliable contraceptive methods (oral contraceptive + barrier method). The contraceptive regimen must be maintained during the treatment period and for 7 months after the last Debio 025 or ribavirin dose.
* Signed informed consent before any study procedures.
* Negative pregnancy test within one week of first investigational product administration for female patients of child bearing potential.

Exclusion Criteria:

* Treatment with any investigational drug within 6 months prior to the first dose of investigational product.
* HCV genotype different from genotype 1.
* Any previous HCV treatment (approved or investigational).
* Histologic evidence of complete hepatic cirrhosis (including compensated cirrhosis) based on a previous liver biopsy (if available).
* Ongoing or recent use of any other medication (including over the counter medication and herbal products) within 2 weeks before study start or within 5 drug half-lives of that medication (whichever is longer) that are known inhibitors/inducers of cytochrome P450 (CYP450) 3A, substrates of P-glycoprotein 1 (P-gP), or substrates/inhibitors of organic anion-transporting polypeptides (OATP), multidrug resistance-associated protein 2 (MRP2), or bile salt export pump (BSEP) and are mentioned in the list of unauthorised medications;
* Any medical contraindications to peg-IFNα2a and/or ribavirin treatment;
* Any other cause of relevant liver disease other than HCV including but not limited to hepatitis B virus (HBV), drug- or alcohol-related cirrhosis, autoimmune hepatitis, haemochromatosis, Wilson's disease, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).
* Any other condition which, in the opinion of the Investigator, would make the patient unsuitable for enrollment or could interfere with the patient participating in and completing the study. Patients with risk factors (hypertension or diabetes) need to have an ophthalmologic investigation (including fundoscopy).
* History of moderate, severe, or uncontrolled psychiatric disease, especially depression, including a history of hospitalisation or prior suicidal attempt.
* Uncontrolled arterial hypertension, ie, patients with systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg.
* History of pancreatitis, uncontrolled diabetes mellitus, or retinopathy.
* Anti-nuclear antibody (ANA) titre \> 1:640 at screening and/or evidence of autoimmune hepatitis on liver biopsy.
* Alcohol consumption \> 20 g/day for females and \> 30 g/day for males.
* History of major organ transplantation with an existing functional graft.
* Pregnancy or lactation.
* Haemoglobinopathies (thalassaemia major, sickle cell anaemia or drepanocytosis).
* Familial history of severe neonatal cholestasis or pregnancy cholestasis.
* Evidence of an active or suspected cancer, or a history of malignancy where the risk of recurrence is ≥ 20% within 2 years.

Primary outcomes:
measure: Percentage of participants achieving sustained viral response (SVR) 72 weeks after treatment start
timeFrame: 72 weeks after treatment start
Secondary outcomes:
measure: Percentage of participants achieving a rapid viral response (RVR) after 4 weeks of treatment
timeFrame: 4 weeks after treatment start
measure: Percentage of participants achieving a complete early viral response (cEVR) after 12 weeks of treatment
timeFrame: 12 weeks after treatment start
measure: Percentage of participants achieving an early viral response (EVR) after 12 weeks of treatment
timeFrame: 12 weeks after treatment start
measure: Percentage of participants achieving an end-of-treatment response (ETR) at treatment end
timeFrame: at end of treatment (Week 28 or Week 52)
measure: Percentage of participants achieving a sustained viral response 12 weeks after the end of treatment (SVR 12)
timeFrame: 12 weeks after end of treatment (Week 40 or Week 64)
measure: Percentage of participants with sustained viral response 24 weeks after the end of treatment (SVR 24)
timeFrame: 24 weeks after end of treatment (Week 52 or Week 76
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Gent
country: Belgium
facility: UZ Gent
city: Creteil
country: France
facility: C.H.U - Hôpital Henri-Mondor
city: Lyon
country: France
facility: C.H.U de Lyon Hôpital de l'Hôtel Dieu
city: Nice
country: France
facility: Hôpital de l'Archet 2
city: Paris - Saint Antoine
country: France
facility: C.H.U - Hôpital Saint Antoine
city: Paris
country: France
facility: C.H.U Hôpital Cochin
city: Pessac
country: France
facility: Hôpital du Haut-Levêque - C.H.U de Bordeaux
city: Vandoeuvre-les-Nancy
country: France
facility: C.H.U de Nancy-Hôpital Brabois
city: Berlin
country: Germany
facility: Charité - Universitatsmedizin Berlin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Düsseldorf
country: Germany
facility: Center for HIV and Hepatogastroenterology
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt am Main
country: Germany
facility: J.W. Goethe University Hospital
city: Freiburg
country: Germany
facility: Albert-Ludwigs-Universität Freiburg, Universitätsk
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Medizinische Universitätsklinik
city: Mainz
country: Germany
facility: Johannes Gutenberg-Universitaet Mainz
city: Bologna
country: Italy
facility: Policlinico S.Orsola Malpighi
city: Milano
country: Italy
facility: Mangiagalli e Regina Elena di Milano
city: Napoli
country: Italy
facility: Seconda Università di Napoli- Secondo Policlinico
city: Palermo
country: Italy
facility: "Policlinico ""Paolo Giaccone"" dell'Università di
city: Torino
country: Italy
facility: Az. Osp. Universitaria S. Giovanni Battista
city: Bialystok
country: Poland
facility: Wojewódzki Szpital Specjalistyczny im. K. Dluskieg
city: Bydgoszcz
country: Poland
facility: Wojewódzki Szpital Obserwacyjno-Zakazny im. Tadeus
city: Chorzów
country: Poland
facility: Szpital Specjalistyczny w Chorzowie
city: Kielce
country: Poland
facility: Wojewódzki Szpital Zespolony w Kielcach
city: Krakow
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawla I
city: Lódz
country: Poland
facility: Wojewódzki Szpital Specjalstyczny im. Wl. Biegansk
city: Warszawa
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Woj
city: Bucharest
country: Romania
facility: Spitalul Clinic Colentina
city: Bucharest
country: Romania
facility: Institutul Clinic Fundeni
city: Bucharest
country: Romania
facility: Centrul de Diagnostic si Tratament Dr. Victor Babe
city: Cluj Napoca
country: Romania
facility: "Spitalul Clinic de Urgenta ""Prof. dr. Octavian F
city: Iasi
country: Romania
facility: Institutul de Gastroenterologie si Hepatologie
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Sevilla
country: Spain
facility: Hospital Universitario Nuestra Señora de Valme
Study officials:
affiliation: Debiopharm International SA
name: Rafael Crabbé, MD
role: STUDY_DIRECTOR
References:
citation: Paeshuyse J, Kaul A, De Clercq E, Rosenwirth B, Dumont JM, Scalfaro P, Bartenschlager R, Neyts J. The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology. 2006 Apr;43(4):761-70. doi: 10.1002/hep.21102.
citation: Inoue K, Umehara T, Ruegg UT, Yasui F, Watanabe T, Yasuda H, Dumont JM, Scalfaro P, Yoshiba M, Kohara M. Evaluation of a cyclophilin inhibitor in hepatitis C virus-infected chimeric mice in vivo. Hepatology. 2007 Apr;45(4):921-8. doi: 10.1002/hep.21587.
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citation: Pawlotsky JM. Treatment of hepatitis C: don't put all your eggs in one basket! Gastroenterology. 2007 Apr;132(4):1611-5. doi: 10.1053/j.gastro.2007.03.014. No abstract available.
citation: Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology. 2006 Jan;130(1):231-64; quiz 214-7. doi: 10.1053/j.gastro.2005.11.010. No abstract available.
citation: Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, Ibranyi E, Weiland O, Noviello S, Brass C, Albrecht J. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol. 2006 Jan;44(1):97-103. doi: 10.1016/j.jhep.2005.10.003. Epub 2005 Nov 7.
citation: Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology. 2003 Nov;38(5):1282-8. doi: 10.1053/jhep.2003.50449.
citation: Watashi K, Ishii N, Hijikata M, Inoue D, Murata T, Miyanari Y, Shimotohno K. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell. 2005 Jul 1;19(1):111-22. doi: 10.1016/j.molcel.2005.05.014.
citation: Rice CM, You S. Treating hepatitis C: can you teach old dogs new tricks? Hepatology. 2005 Dec;42(6):1455-8. doi: 10.1002/hep.20975.
citation: Ishii N, Watashi K, Hishiki T, Goto K, Inoue D, Hijikata M, Wakita T, Kato N, Shimotohno K. Diverse effects of cyclosporine on hepatitis C virus strain replication. J Virol. 2006 May;80(9):4510-20. doi: 10.1128/JVI.80.9.4510-4520.2006.
citation: Yang F, Robotham JM, Nelson HB, Irsigler A, Kenworthy R, Tang H. Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J Virol. 2008 Jun;82(11):5269-78. doi: 10.1128/JVI.02614-07. Epub 2008 Apr 2.