A Study of Debio 025 (Alisporivir) Combined With Peg-IFNα2a and Ribavirin in Treatment naïve Chronic Hepatitis C Genotype 1 Patients

Chronic Hepatitis C Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00854802
• Other study ID #: Debio 025-HCV-205
• Secondary ID: 2008-004605-34CD
• Status: Completed
• Phase: N/A
• First received: March 2, 2009
• Last updated: February 12, 2016
• Start date: January 2009
• Est. completion date: September 2010

Study information

• Verified date: February 2016
• Source: Debiopharm International SA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health ProductsFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesItaly: The Italian Medicines AgencyPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsRomania: National Medicines AgencySpain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 290
• Est. completion date: September 2010
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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-IFNa2a 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis C
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Debio 025
Debio 025 supplied in soft gel capsules
• Peg-IFNa2a
Peg-IFNa2a supplied in pre-filled syringes
• Ribavirin
Ribavirin supplied in tablets
• Debio 025 placebo
Debio 025 placebo supplied in soft gel capsules

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	UZ Gent	Gent
France	C.H.U - Hôpital Henri-Mondor	Creteil
France	C.H.U de Lyon Hôpital de l'Hôtel Dieu	Lyon
France	Hôpital de l'Archet 2	Nice
France	C.H.U Hôpital Cochin	Paris
France	C.H.U - Hôpital Saint Antoine	Paris - Saint Antoine
France	Hôpital du Haut-Levêque - C.H.U de Bordeaux	Pessac
France	C.H.U de Nancy-Hôpital Brabois	Vandoeuvre-les-Nancy
Germany	Charité - Universitatsmedizin Berlin	Berlin
Germany	Center for HIV and Hepatogastroenterology	Düsseldorf
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Universitätsklinikum Essen	Essen
Germany	J.W. Goethe University Hospital	Frankfurt am Main
Germany	Albert-Ludwigs-Universität Freiburg, Universitätsk	Freiburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Medizinische Universitätsklinik	Heidelberg
Germany	Johannes Gutenberg-Universitaet Mainz	Mainz
Italy	Policlinico S.Orsola Malpighi	Bologna
Italy	Mangiagalli e Regina Elena di Milano	Milano
Italy	Seconda Università di Napoli- Secondo Policlinico	Napoli
Italy	"Policlinico ""Paolo Giaccone"" dell'Università di	Palermo
Italy	Az. Osp. Universitaria S. Giovanni Battista	Torino
Poland	Wojewódzki Szpital Specjalistyczny im. K. Dluskieg	Bialystok
Poland	Wojewódzki Szpital Obserwacyjno-Zakazny im. Tadeus	Bydgoszcz
Poland	Szpital Specjalistyczny w Chorzowie	Chorzów
Poland	Wojewódzki Szpital Zespolony w Kielcach	Kielce
Poland	Krakowski Szpital Specjalistyczny im. Jana Pawla I	Krakow
Poland	Wojewódzki Szpital Specjalstyczny im. Wl. Biegansk	Lódz
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Woj	Warszawa
Romania	Centrul de Diagnostic si Tratament Dr. Victor Babe	Bucharest
Romania	Institutul Clinic Fundeni	Bucharest
Romania	Spitalul Clinic Colentina	Bucharest
Romania	"Spitalul Clinic de Urgenta ""Prof. dr. Octavian F	Cluj Napoca
Romania	Institutul de Gastroenterologie si Hepatologie	Iasi
Spain	Hospital Universitari Germans Trias i Pujol	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona
Spain	Hospital Universitario de La Princesa	Madrid
Spain	Hospital Universitario Puerta de Hierro	Madrid
Spain	Hospital Universitario Nuestra Señora de Valme	Sevilla

Sponsors (2)

Lead Sponsor	Collaborator
Debiopharm International SA	Parexel

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Italy,  Poland,  Romania,  Spain, 

References & Publications (12)

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. Review. — View Citation

Flisiak R, Horban A, Gallay P, Bobardt M, Selvarajah S, Wiercinska-Drapalo A, Siwak E, Cielniak I, Higersberger J, Kierkus J, Aeschlimann C, Grosgurin P, Nicolas-Métral V, Dumont JM, Porchet H, Crabbé R, Scalfaro P. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology. 2008 Mar;47(3):817-26. doi: 10.1002/hep.22131. — View 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. — View 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. — View 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. — View Citation

Pawlotsky JM. Treatment of hepatitis C: don't put all your eggs in one basket! Gastroenterology. 2007 Apr;132(4):1611-5. — View Citation

Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J, McNair L, Purdy S, Kauffman R, Alam J, Jansen PL. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006 Oct;131(4):997-1002. — View Citation

Rice CM, You S. Treating hepatitis C: can you teach old dogs new tricks? Hepatology. 2005 Dec;42(6):1455-8. — View 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. — View 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. — View 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. — View 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. Epub 2005 Nov 7. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of participants achieving sustained viral response (SVR) 72 weeks after treatment start	SVR is defined as hepatitis C virus (HCV) RNA < 10 IU/mL (undetectable).	72 weeks after treatment start	No
Secondary	Percentage of participants achieving a rapid viral response (RVR) after 4 weeks of treatment	RVR is defined as HCV RNA level < 10 IU/mL after 4 weeks of treatment.	4 weeks after treatment start	No
Secondary	Percentage of participants achieving a complete early viral response (cEVR) after 12 weeks of treatment	cEVR is defined as HCV RNA level < 10 IU/mL after 12 weeks of treatment.	12 weeks after treatment start	No
Secondary	Percentage of participants achieving an early viral response (EVR) after 12 weeks of treatment	EVR is defined as a decrease from baseline of the HCV RNA level by > 2 log10 or undetectable (< 10 UI/mL) after 12 weeks of treatment.	12 weeks after treatment start	No
Secondary	Percentage of participants achieving an end-of-treatment response (ETR) at treatment end	ETR is defined as HCV RNA level < 10 IU/mL at the end of treatment (Week 24 or Week 48).	at end of treatment (Week 28 or Week 52)	No
Secondary	Percentage of participants achieving a sustained viral response 12 weeks after the end of treatment (SVR 12)	SVR 12 is defined as HCV RNA level < 10 IU/mL 12 weeks after the end of treatment (Week 40 or Week 64).	12 weeks after end of treatment (Week 40 or Week 64)	No
Secondary	Percentage of participants with sustained viral response 24 weeks after the end of treatment (SVR 24)	SVR 24 is defined as HCV RNA level < 10 IU/mL 24 weeks after the end of treatment (Week 52 or Week 76).	24 weeks after end of treatment (Week 52 or Week 76	No

External Links

•   Study sponsor