An Efficacy, Safety and Pharmacokinetics Study of Simeprevir, Daclatasvir and Sofosbuvir in Participants With Chronic Hepatitis C Virus Genotype 1 or 4 Infection and Decompensated Liver Disease

Hepatitis C, Chronic Clinical Trial

Official title:

A Phase 2 Open-label Study to Investigate the Efficacy, Safety and Pharmacokinetics of 12 Weeks of Treatment With Simeprevir, Daclatasvir and Sofosbuvir, Followed by a 5-Year Post-treatment Long-term Follow-up, in Treatment-naïve and Treatment-experienced Subjects With Chronic Hepatitis C Virus Genotype 1 or 4 Infection and Decompensated Liver Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02262728
• Other study ID #: CR105028
• Secondary ID: TMC435HPC2010
• Status: Completed
• Phase: Phase 2
• Start date: September 30, 2014
• Est. completion date: April 25, 2018

Study information

• Verified date: April 2019
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the efficacy of a 12-week regimen containing simeprevir, daclatasvir and sofosbuvir in participants with decompensated liver disease (the liver function is insufficient) due to genotype 1 or 4 Hepatitis (inflammation of the liver) C virus (HCV) infection by assessing sustained virologic response 12-weeks after the end of study drug treatment (SVR12).

Description:

This is an open-label (all people know which treatment the participants receive) Phase 2 study to investigate the efficacy, safety and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir in treatment-naive (participants have never received HCV treatment with any approved or investigational agent) and treatment - experienced (participants have failed at least one previous course of [Pegylated] interferon [(Peg)IFN], with or without Ribavirin) participants. Participants will be assigned to 1 of 2 panels: Panel 1 (n=20): Child-Pugh score less than (<) 7 with evidence of portal hypertension (confirmed by presence of esophageal varices or HVPG greater than or equal to [>=] 10 mm Hg); Panel 2 (n=20): Child-Pugh score 7 to 9 (extremes included). The total study duration for each participant will be approximately 276 weeks. The study will consist of 3 parts: Screening Phase (approximately 4 weeks) and open-label treatment Phase (from Week 4 to 16) and follow-up Phase (until 5 years after the actual end of study drug treatment). Participants will receive simeprevir (150 milligram [mg] capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks. Efficacy will be primarily evaluated by percentage of participants with SVR12. Participants' safety will be monitored throughout the study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: April 25, 2018
• Est. primary completion date: August 13, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Documented chronic Hepatitis C virus (HCV) infection: diagnosis of HCV more than (>) 6 months before the Screening visit, either by detectable HCV ribonucleic acid (RNA), a HCV positive antibody or the presence of histological changes consistent with chronic hepatitis

• HCV genotype 1 or 4 infection and HCV RNA plasma level >10,000 international unit per milliliter (IU/mL) (both determined at screening)

• Presence of cirrhosis, which is defined as a FibroScan with a result of >14.5 kilopascals (kPa) at Screening

• HCV treatment-naive participants: participant has not received treatment with any approved or investigational drug for the treatment of HCV infection and HCV treatment-experienced participants: participant has had at least 1 documented previous course of a non-direct-acting antiviral agent (DAA), interferon (IFN)-based HCV therapy (with or without Ribavirin [RBV]). Last dose in this previous course should have occurred at least 2 months prior to Screening

• Decompensated liver disease: Panel 1: Child Pugh A (mild hepatic impairment) with evidence of portal hypertension [confirmed by the presence of esophageal varices on gastroscopy or hepatic venous pressure gradient (HVPG) greater than or equal to (>=) 10 millimeter of mercury (mm Hg)], Panel 2: Child-Pugh B (moderate hepatic impairment) 7 to 9 (extremes included)

Exclusion Criteria:

• Co-infection with any HCV genotype

• Co-infection with human immunodeficiency virus (HIV)-1 or -2 (positive HIV-1 or HIV-2 antibodies test at Screening)

• Co-infection with hepatitis B virus (hepatitis B surface antigen [HBsAg] positive)

• Any evidence of liver disease of non-HCV etiology. This includes, but is not limited to, acute hepatitis A infection, drug- or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis, or any other non-HCV liver disease considered clinically significant by the Investigator

• Use of any disallowed therapies before the planned first dose of study drugs

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic
• Liver Diseases

Intervention

Drug:
• Simeprevir
Simeprevir 150 milligram (mg) capsule orally once daily for 12 weeks
• Daclatasvir
Daclatasvir 60 mg tablet orally once daily for 12 weeks
• Sofosbuvir
Sofosbuvir 400 mg tablet orally once daily for 12 weeks

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12)	Participants were considered to have achieved SVR12 if the hepatitis C virus ribonucleic acid (HCV RNA) was less than (<) lower limit of quantification (LLOQ; 15 international unit per milliliter [IU/mL]) detectable or undetectable at 12 weeks after the end of study drug treatment.	Week 24
Secondary	Percentage of Participants With On-Treatment Virologic Response	On-treatment virologic response was determined by HCV RNA results satisfying a specified threshold. The following thresholds were considered at any time point:	Week 1, 2, 4, 6, 8, 10, 12
Secondary	Percentage of Participants With SVR 4 Weeks After End of Study Drug Treatment (SVR4) and SVR 24 Weeks After End of Study Drug Treatment (SVR24)	Participants were considered to have achieved SVR4 and SVR24 if the HCV RNA was	Week 16 and Week 36
Secondary	Percentage of Participants With HCV NS3/4A Sequence, NS5A and NS5B After End of Treatment in Participants Not Achieving SVR	Sequencing of the HCV nonstructural protein 3/4A (NS3/4A), nonstructural protein 5A (NS5A) and nonstructural protein 5B (NS5B) genes was done to identify pre-existing sequence polymorphisms and characterize emerging HCV viral variants in participants not achieving SVR. All participants in this study achieved SVR12. Therefore, reasons for not achieving SVR12 are not applicable.	Baseline, Day 3, Week 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, and Year 1, 1.5, 2, 2.5, 3 after end of treatment
Secondary	Absolute Values of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels at Follow-up Week 24 (Week 36)		Follow-up Week 24 (Week 36)
Secondary	Time to Reach Maximum Plasma Concentration (Tmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)	Tmax is the time to reach maximum observed plasma concentration.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours post-dose on Weeks 2 and 8
Secondary	Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours After Dosing (AUC[0-24]) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)	The AUC(0-24) is area under the plasma concentration-time curve from time 0 to 24 hours after dosing.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours post-dose on Weeks 2 and 8
Secondary	Maximum Plasma Concentration (Cmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)	The Cmax is the maximum observed plasma concentration.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours post-dose on Weeks 2 and 8
Secondary	Minimum Plasma Concentration (Cmin) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)	The Cmin is the minimum observed plasma concentration.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours post-dose on Weeks 2 and 8
Secondary	Pre-dose (Trough) Concentration (C0h) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)	The C0h is the pre-dose plasma concentration.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours post-dose on Weeks 2 and 8
Secondary	Percentage of Participants With On-treatment Failure	On-treatment failure is defined as participants who do not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of study drug treatment.	Week 12
Secondary	Percentage of Participants With Viral Relapse	Viral relapse is defined as participants who do not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (>=) LLOQ (15 IU/mL) at Week 16, 24 or 36.	Week 16, 24 and 36
Secondary	Percentage of Participants With SVR12 Who Maintained to Have HCV RNA <LLOQ Until the End of 3 Years Follow up	Percentage of participants with SVR12 who maintained to have HCV RNA	Week 24 post treatment until the end of 3-year follow-up