Sustained Virological Response (SVR) to Antiviral Treatment of Liver Transplant Recipients With Recurrent Hepatitis C

Hepatitis C Clinical Trial

— SUSTAIN  

Official title:

A Multi-center, Randomized, Open Label, Controlled Study to Compare the Sustained Virological Response During Treatment With Neoral or Tacrolimus in Maintenance Liver Transplant Recipients Treated With Pegylated Interferon and Ribavirin for Recurrent Hepatitis C

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00938860
• Other study ID #: COLO400A2430
• Secondary ID: 2009-010806-12
• Status: Completed
• Phase: Phase 4
• First received: July 13, 2009
• Last updated: May 5, 2015
• Start date: September 2009
• Est. completion date: May 2013

Study information

• Verified date: May 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Ministry of HealthAustria: Federal Office for Safety in Health CareBelgium: Federal Agency for Medicinal Products and Health ProductsBrazil: Ministry of HealthCanada: Health CanadaColombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y AlimentosFrance: Ministry of HealthGermany: Ministry of HealthHungary: National Institute of PharmacyItaly: Ministry of HealthKorea: Food and Drug AdministrationRomania: Ministry of Public HealthRussia: Ministry of Health of the Russian FederationSpain: Ministry of HealthSwitzerland: SwissmedicUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

This study will assess the rates of Sustained Virological Response following anti-viral therapy with Peg-Interferon plus Ribavirin in patients that have been liver transplanted with recurrent Hepatitis C and treated with Neoral or tacrolimus.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 92
• Est. completion date: May 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion criteria:

• Liver transplantation performed at least 6 months and up to 5 years prior randomization and due to HCV cirrhosis, with or without pre-transplant hepatocellular carcinoma (HCC) within Milan or UCSF criteria

• Immunosuppresive regimen based on tacrolimus b.i.d.- (twice or once daily) for at least 6 months prior randomization

• Diagnosis of HCV genotypes 1 or 4 infection prior to transplantationconfirmed at screening

• Indication of treatment with Peg-IFN and ribavirin due to histological evidence of chronic HCV infection defined as a fibrosis stage equal or greater than 1 using the Ishak-Knodell scoring system (IK =1) in a liver biopsy performed at screening or up to 4 months prior to randomization.

Exclusion criteria:

• Serum creatinine >150 µmol/L (1.6 7 mg/dL) or eGFR < 50 ml/min (4-variable Modification of Diet in Renal Disease [MDRD Cockcroft-Gault formula])

• Multi-organ transplant recipients

• Recent episode of steroid-treated acute rejection (AR) within 3 months prior to randomization, or >1 episode of steroid-treated AR in the last 6 months, or any number of steroid-resistant AR episodes in the last 6 months including evidence of chronic rejection or ductopenia

• Evidence of conditions that could cause graft dysfunction other than HCV infection

• Patients with signs of decompensated liver disease, defined as presence of ascites, variceal bleeding, encephalopathy or deteriorated hepatic synthetic function (albumin <3.5g/dL or, total direct bilirubin >1.5mg/dL or, INR >1.5)

• Co-infection with HIV or Hepatitis B (defined as HBsAg-positive) at screening

• Use of mTOR inhibitors (everolimus or sirolimus) in the 6 months prior to screening

• Antiviral treatment for HCV administered at any time after liver transplantation

• Patients on daily doses of corticosteroids higher than 5 mg/day

• Patients with fibrosing cholestatic hepatitis

• Patients with current diagnosis of malignancies, including lymphoproliferative disorders

• Patients with platelet count <70,000/mm3 or neutrophiles <1,500/mm3

• History of HCC outside Milan criteria based on radiology or UCSF criteria based on analysis of the explant

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Liver Transplantation

Intervention

Drug:
• cyclosporin (Neoral)
Neoral capsules bid, Doses were to be adjusted as necessary to achieve and maintain recommended C0 (monitoring of trough levels) or C2 concentration 2 hours post dosing) target ranges
• tacrolimus (Prograf)
Tacrolimus capsules bid, doses were adjusted as necessary to achieve and maintain recommended C0 target ranges.

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Bruxelles
Brazil	Novartis Investigative Site	Fortaleza	CE
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Canada	Novartis Investigative Site	Winnipeg	Manitoba
Colombia	Novartis Investigative Site	Bogotá	Cundinamarca
Colombia	Novartis Investigative Site	Bogotá
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Lyon Cedex 04
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Toulouse Cedex 4
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Muenchen
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Udine	UD
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Valladolid	Castilla y Leon
Switzerland	Novartis Investigative Site	Zurich
United Kingdom	Novartis Investigative Site	Birmingham
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Gainesville	Florida
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Madison	Wisconsin
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Palo Alto	California
United States	Novartis Investigative Site	Phoenix	Arizona
United States	Novartis Investigative Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Canada,  Colombia,  France,  Germany,  Italy,  Korea, Republic of,  Russian Federation,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Sustained Virological Response (SVR) Following Treatment of Hepatitis C Virus (HCV) Infection With Peg-IFN and Ribavirin in Liver Transplanted Recipients on Maintenance Therapy With Neoral or Tacrolimus	The achievement of SVR, defined as HCV RNA below limit of detection at the end of AV treatment, 24 weeks after end of AV treatment (W24 post). A dichotomous variable (SVR achieved: Yes/No) was computed. A patient was classified as non-responder (SVR not achieved) if HCV RNA was detectable at the completion of antiviral treatment, at W24post, or at any time between W24 and completion of antiviral treatment. The HCV RNA detection limit was <15 IU/ml (<1.18 log IU/ml)	Week 24	No
Secondary	Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components	Efficacy failure (biopsy proven acute rejection (BPAR), graft loss, or death	Week 80	No
Secondary	Number of Participants With Fibrosis Progression (Increase in Ishak-Knodell (IK) Score by at Least One Point From the Baseline)	Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite, Participants showing an increase of Ishak Knodell fibrosis score by at least one level (increase of =1)	Week 80	No
Secondary	Number of Participants of Rapid Viral Response (RVR)	RVR defined as non-detectable HCV RNA 4 weeks after initiation of antiviral treatment. The HCV RNA detection limit was <15 IU/ml (<1.18 log IU/ml)	Week 4	No
Secondary	Number of Participants of Early Viral Response (EVR)	EVR defined as non-detectable HCV RNA or a =2 logs reduction of HCV RNA at 12 weeks after initiation of antiviral treatment. The HCV RNA detection limit was <15 IU/ml (<1.18 log IU/ml)	Week 12	No
Secondary	Number of Participants for the End of Treatment Response (ETR)	ETR defined as non-detectable HCV RNA at the completion of AV treatment. The HCV RNA detection limit was <15 IU/ml (<1.18 log IU/ml)	Week 80	No
Secondary	Number of Participants of True Non-responder Rate	Defined as failure to achieve at least a 2 log reduction of Hepatitis C virus (HCV) RNA. The HCV RNA detection limit was <15 IU/ml (<1.18 log IU/ml)	Week 80	No
Secondary	Number of Participants for Relapse Rate	Defined as reappearance of detectable Hepatitis C Virus (HCV) RNA at 24 weeks after completion of antiviral treatment when HCV RNA was undetectable at the end of treatment. The HCV RNA detection limit was <15 IU/ml (<1.18 log IU/ml)	Week 24	No
Secondary	Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason	Defined as number of patients with dose reduction or discontinuation of AV therapy due to poor tolerability	Week 80	No