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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

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ClinicalTrials.gov Identifier: NCT02262728
Recruitment Status : Completed
First Posted : October 13, 2014
Results First Posted : February 13, 2017
Last Update Posted : May 8, 2019
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Brief 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).

Condition or disease Intervention/treatment Phase
Hepatitis C, Chronic Drug: Simeprevir Drug: Daclatasvir Drug: Sofosbuvir Phase 2

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 30, 2014
Actual Primary Completion Date : August 13, 2015
Actual Study Completion Date : April 25, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Panel 1
Participants with Child-Pugh score <7 with evidence of portal hypertension (confirmed by presence of esophageal varices or hepatic venous pressure gradient [HVPG] greater than or equal to 10 millimeter of mercury [mm Hg]) will receive simeprevir (150 milligram [mg] capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks.
Drug: Simeprevir
Simeprevir 150 milligram (mg) capsule orally once daily for 12 weeks
Other Name: TMC435

Drug: Daclatasvir
Daclatasvir 60 mg tablet orally once daily for 12 weeks
Other Name: BMS-790052

Drug: Sofosbuvir
Sofosbuvir 400 mg tablet orally once daily for 12 weeks
Other Name: GS-7977

Experimental: Panel 2
Participants with Child-Pugh score 7 to 9 (extremes included) will receive simeprevir (150 mg capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks.
Drug: Simeprevir
Simeprevir 150 milligram (mg) capsule orally once daily for 12 weeks
Other Name: TMC435

Drug: Daclatasvir
Daclatasvir 60 mg tablet orally once daily for 12 weeks
Other Name: BMS-790052

Drug: Sofosbuvir
Sofosbuvir 400 mg tablet orally once daily for 12 weeks
Other Name: GS-7977




Primary Outcome Measures :
  1. Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12) [ Time Frame: Week 24 ]
    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.


Secondary Outcome Measures :
  1. Percentage of Participants With On-Treatment Virologic Response [ Time Frame: Week 1, 2, 4, 6, 8, 10, 12 ]
    On-treatment virologic response was determined by HCV RNA results satisfying a specified threshold. The following thresholds were considered at any time point: <LLOQ undetectable, <LLOQ detectable, and <LLOQ undetectable or detectable. The LLOQ value was 15 IU/mL. Very rapid virologic response (vRVR) is undetectable HCV RNA at Week 2 while on treatment and Rapid virologic response (RVR) is undetectable HCV RNA at Week 4 while on treatment.

  2. 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) [ Time Frame: Week 16 and Week 36 ]
    Participants were considered to have achieved SVR4 and SVR24 if the HCV RNA was <LLOQ detectable or undetectable at 4 weeks and 24 weeks respectively after the end of study drug treatment. The LLOQ value was 15 IU/mL.

  3. Percentage of Participants With HCV NS3/4A Sequence, NS5A and NS5B After End of Treatment in Participants Not Achieving SVR [ Time Frame: 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 ]
    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.

  4. Absolute Values of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Levels at Follow-up Week 24 (Week 36) [ Time Frame: Follow-up Week 24 (Week 36) ]
  5. Time to Reach Maximum Plasma Concentration (Tmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite) [ Time Frame: 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 ]
    Tmax is the time to reach maximum observed plasma concentration.

  6. 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) [ Time Frame: 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 ]
    The AUC(0-24) is area under the plasma concentration-time curve from time 0 to 24 hours after dosing.

  7. Maximum Plasma Concentration (Cmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite) [ Time Frame: 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 ]
    The Cmax is the maximum observed plasma concentration.

  8. Minimum Plasma Concentration (Cmin) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite) [ Time Frame: 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 ]
    The Cmin is the minimum observed plasma concentration.

  9. Pre-dose (Trough) Concentration (C0h) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite) [ Time Frame: 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 ]
    The C0h is the pre-dose plasma concentration.

  10. Percentage of Participants With On-treatment Failure [ Time Frame: Week 12 ]
    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.

  11. Percentage of Participants With Viral Relapse [ Time Frame: Week 16, 24 and 36 ]
    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.

  12. Percentage of Participants With SVR12 Who Maintained to Have HCV RNA <LLOQ Until the End of 3 Years Follow up [ Time Frame: Week 24 post treatment until the end of 3-year follow-up ]
    Percentage of participants with SVR12 who maintained to have HCV RNA <LLOQ (15 IU/mL) until the end of 3 years follow up were reported.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02262728


Locations
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United States, Texas
San Antonio, Texas, United States
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
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Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02262728    
Other Study ID Numbers: CR105028
TMC435HPC2010 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: October 13, 2014    Key Record Dates
Results First Posted: February 13, 2017
Last Update Posted: May 8, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Janssen Research & Development, LLC:
Hepatitis C, Chronic
Simeprevir
Daclatasvir
Sofosbuvir
Decompensated Liver Disease
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis C
Hepatitis C, Chronic
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Hepatitis, Chronic
Sofosbuvir
Simeprevir
Antiviral Agents
Anti-Infective Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action