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

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02262728
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2
• Actual Duration (Months): 42.8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Sep 30, 2014
• Actual Primary Completion Date: Aug 13, 2015
• Actual Study Completion Date: Apr 25, 2018

Arms and Interventions

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 Names: TMC435 ; Drug: Daclatasvir; Daclatasvir 60 mg tablet orally once daily for 12 weeks; Other Names: BMS-790052 ; Drug: Sofosbuvir; Sofosbuvir 400 mg tablet orally once daily for 12 weeks; Other Names: 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 Names: TMC435 ; Drug: Daclatasvir; Daclatasvir 60 mg tablet orally once daily for 12 weeks; Other Names: BMS-790052 ; Drug: Sofosbuvir; Sofosbuvir 400 mg tablet orally once daily for 12 weeks; Other Names: GS-7977

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12) [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 [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) [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 [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) [Follow-up Week 24 (Week 36)]

5. Time to Reach Maximum Plasma Concentration (Tmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite) [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) [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) [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) [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) [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 [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		San Antonio	Texas	United States

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT02262728
• Other Study ID Numbers: CR105028; TMC435HPC2010
• First Posted: Oct 13, 2014
• Last Update Posted: May 8, 2019
• Last Verified: Apr 1, 2019

• 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: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Liver Diseases; Sofosbuvir; Simeprevir

Study Results

Participant Flow

Arm/Group Title	Panel 1 SMV 150mg/DCV 60mg/SOF 400mg	Panel 2 SMV 150mg/DCV 60mg/SOF 400mg
Arm/Group Description	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 millimeters of mercury [mm Hg]) received simeprevir (150 milligram [mg] capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (150 mg capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks.
Period Title: Treatment Period (12 Weeks)
STARTED	19	21
COMPLETED	19	21
NOT COMPLETED	0	0
Period Title: Treatment Period (12 Weeks)
STARTED	19	21
COMPLETED	15	18
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	Panel 1 SMV 150mg/DCV 60mg/SOF 400mg	Panel 2 SMV 150mg/DCV 60mg/SOF 400mg	Total
Arm/Group Description	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 millimeters of mercury [mm Hg]) received simeprevir (150 milligram [mg] capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (150 mg capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks.	Total of all reporting groups
Overall Participants	19	21	40
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56	61	58.5
Sex: Female, Male (Count of Participants)
Female	5 26.3%	10 47.6%	15 37.5%
Male	14 73.7%	11 52.4%	25 62.5%
Region of Enrollment (Count of Participants)
United States	19 100%	21 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Study Drug Treatment (SVR12)
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) analysis set included all enrolled participants who took at least 1 dose of study drug.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Number (95% Confidence Interval) [Percentage of Participants]	100 526.3%	100 476.2%

2. Secondary Outcome

Title	Percentage of Participants With On-Treatment Virologic Response
Description	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.
Time Frame	Week 1, 2, 4, 6, 8, 10, 12

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) analysis set included all enrolled participants who took at least 1 dose of study drug. Here, 'n' signifies number of participants evaluable for this outcome measure at specific time point.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Week 1 : >= 15 IU/mL	72.2 380%	76.2 362.9%
Week 1 : < 100 IU/mL	61.1 321.6%	38.1 181.4%
Week 1: < 15 IU/mL undetect/detectable	27.8 146.3%	23.8 113.3%
Week 1 : < 15 IU/mL detectable	11.1 58.4%	19.0 90.5%
Week 1 : < 15 IU/mL Undetectable	16.7 87.9%	4.8 22.9%
Week 2 : >= 15 IU/mL	10.5 55.3%	47.6 226.7%
Week 2 : < 100 IU/mL	94.7 498.4%	71.4 340%
Week 2: < 15 IU/mL undetect/detectable	89.5 471.1%	52.4 249.5%
Week 2 : < 15 IU/mL detectable	36.8 193.7%	19.0 90.5%
Week 2: < 15 IU/mL undetectable (vRVR)	52.6 276.8%	33.3 158.6%
Week 4 : >= 15 IU/mL	0 0%	9.5 45.2%
Week 4 : < 100 IU/mL	100.0 526.3%	100.0 476.2%
Week 4: < 15 IU/mL undetect/detectable	100.0 526.3%	90.5 431%
Week 4 : < 15 IU/mL detectable	5.6 29.5%	28.6 136.2%
Week 4 : < 15 IU/mL undetectable (RVR)	94.4 496.8%	61.9 294.8%
Week 6 : >= 15 IU/mL	0 0%	0 0%
Week 6 : < 100 IU/mL	100.0 526.3%	100.0 476.2%
Week 6: < 15 IU/mL undetect/detectable	100.0 526.3%	100.0 476.2%
Week 6 : < 15 IU/mL detectable	5.3 27.9%	20.0 95.2%
Week 6 : < 15 IU/mL undetectable	94.7 498.4%	80.0 381%
Week 8 : >= 15 IU/mL	0 0%	0 0%
Week 8 : < 100 IU/mL	100.0 526.3%	100.0 476.2%
Week 8: < 15 IU/mL undetect/detectable	100.0 526.3%	100.0 476.2%
Week 8 : < 15 IU/mL detectable	0 0%	4.8 22.9%
Week 8 : < 15 IU/mL undetectable	100.0 526.3%	95.2 453.3%
Week 10 : >= 15 IU/mL	0 0%	0 0%
Week 10 : < 100 IU/mL	100.0 526.3%	100.0 476.2%
Week 10: < 15 IU/mL undetect/detectable	100.0 526.3%	100.0 476.2%
Week 10 : < 15 IU/mL detectable	0 0%	0 0%
Week 10 : < 15 IU/mL undetectable	100.0 526.3%	100.0 476.2%
Week 12 : >= 15 IU/mL	0 0%	0 0%
Week 12 :< 100 IU/mL	100.0 526.3%	100.0 476.2%
Week 12: < 15 IU/mL undetect/detectable	100.0 526.3%	100.0 476.2%
Week 12 : < 15 IU/mL detectable	0 0%	0 0%
Week 12 : < 15 IU/mL undetectable	100.0 526.3%	100.0 476.2%

3. Secondary Outcome

Title	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)
Description	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.
Time Frame	Week 16 and Week 36

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) analysis set included all enrolled participants who took at least 1 dose of study drug. Here , 'n' signifies number of participants evaluable for this outcome measure at specific time point.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
SVR 4	100 526.3%	100 476.2%
SVR 24	100 526.3%	100 476.2%

4. Secondary Outcome

Title	Percentage of Participants With HCV NS3/4A Sequence, NS5A and NS5B After End of Treatment in Participants Not Achieving SVR
Description	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.
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

Outcome Measure Data

Analysis Population Description

The ITT analysis set who failed achieving SVR. Since all participants achieved SVR, the number of participants for this endpoint analysis was zero.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	0	0

5. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) analysis set included all enrolled participants who took at least 1 dose of study drug. Here, 'n' signifies number of participants evaluable for this outcome measure at specific time point.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Baseline : ALT	137.8 (101.90)	60.9 (29.52)
Baseline : AST	119.1 (80.57)	83.5 (35.68)
Follow-Up Week 24 : ALT	34.8 (11.30)	32.3 (9.75)
Follow-Up Week 24 : AST	39.2 (21.86)	35.0 (10.31)

6. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)
Description	Tmax is the time to reach maximum observed plasma concentration.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set included all participants who received atleast 1 dose of study drug and had valid pharmacokinetic profile. Here 'n' signifies number of participants analyzed for this outcome measure at specific time point.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Simeprevir: Week 2	6.00	8.00
Simeprevir: Week 8	6.00	8.00
Daclatasvir: Week 2	3.00	4.00
Daclatasvir: Week 8	2.50	4.00
Sofosbuvir: Week 2	1.00	2.00
Sofosbuvir: Week 8	1.75	2.00
GS-331007: Week 2	4.00	4.00
GS-331007: Week 8	4.00	4.00

7. Secondary Outcome

Title	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)
Description	The AUC(0-24) is area under the plasma concentration-time curve from time 0 to 24 hours after dosing.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set included all participants who received atleast 1 dose of study drug and had valid pharmacokinetic profile. Here 'n' signifies number of participants analyzed for this outcome measure at specific time point.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Simeprevir : Week 2	113835 (91598)	142162 (80217)
Simeprevir : Week 8	98568 (80037)	207221 (162168)
Daclatasvir : Week 2	16487 (6323)	17858 (7726)
Daclatasvir : Week 8	15574 (5347)	20787 (10741)
Sofosbuvir : Week 2	2870 (978)	3915 (1258)
Sofosbuvir : Week 8	2746 (963)	3933 (1315)
GS-331007 : Week 2	17900 (6320)	21118 (11301)
GS-331007 : Week 8	18132 (7469)	22829 (15394)

8. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)
Description	The Cmax is the maximum observed plasma concentration.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set included all participants who received atleast 1 dose of study drug and had valid pharmacokinetic profile. Here 'n' signifies number of participants analyzed for this outcome measure at specific time point.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Simeprevir : Week 2 (reference)	6976 (4439)	7726 (3946)
Simeprevir : Week 8 (test)	6029 (3936)	10498 (7492)
Daclatasvir : Week 2	1187 (397)	1145 (440)
Daclatasvir : Week 8	1072 (313)	1210 (543)
Sofosbuvir : Week 2	1571 (738)	1615 (986)
Sofosbuvir : Week 8	1276 (856)	1527 (993)
GS-331007 : Week 2	1403 (369)	1561 (720)
GS-331007 : Week 8	1404 (361)	1594 (952)

9. Secondary Outcome

Title	Minimum Plasma Concentration (Cmin) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)
Description	The Cmin is the minimum observed plasma concentration.
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

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants who received atleast 1 dose of study drug and had valid pharmacokinetic profile. Here 'n' signifies number of participants analyzed for this outcome measure at specific time point.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Simeprevir : Week 2	3133 (3410)	4363 (3081)
Simeprevir : Week 8	2639 (2725)	6955 (6035)
Daclatasvir : Week 2	414 (230)	519 (275)
Daclatasvir : Week 8	442 (192)	660 (416)
Sofosbuvir : Week 2	NA (NA)	NA (NA)
Sofosbuvir : Week 8	NA (NA)	NA (NA)
GS-331007 : Week 2	419 (198)	441 (254)
GS-331007 : Week 8	443 (213)	523 (392)

10. Secondary Outcome

Title	Pre-dose (Trough) Concentration (C0h) of Simeprevir, Daclatasvir, Sofosbuvir and GS-331007 (Sofosbuvir Metabolite)
Description	The C0h is the pre-dose plasma concentration.
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

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants who received atleast 1 dose of study drug and had valid pharmacokinetic profile. Here 'n' signifies number of participants analyzed for this outcome measure at specific time point.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Simeprevir : Week 2	3577 (3685)	5218 (3461)
Simeprevir : Week 8	3160 (3725)	8577 (7398)
Daclatasvir : Week 2	494 (279)	646 (384)
Daclatasvir : Week 8	492 (232)	824 (476)
Sofosbuvir : Week 2	NA (NA)	NA (NA)
Sofosbuvir : Week 8	NA (NA)	NA (NA)
GS-331007 : Week 2	484 (236)	490 (282)
GS-331007 : Week 8	478 (262)	572 (450)

11. Secondary Outcome

Title	Percentage of Participants With On-treatment Failure
Description	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.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) analysis set included all enrolled participants who took at least 1 dose of study drug. Here "N" (Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Number [Percentage of Participants]	0 0%	0 0%

12. Secondary Outcome

Title	Percentage of Participants With Viral Relapse
Description	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.
Time Frame	Week 16, 24 and 36

Outcome Measure Data

Analysis Population Description

The ITT analysis set who failed achieving SVR. Since all participants achieved SVR, the number of participants for this endpoint (viral relapse) analysis was zero.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	0	0

13. Secondary Outcome

Title	Percentage of Participants With SVR12 Who Maintained to Have HCV RNA <LLOQ Until the End of 3 Years Follow up
Description	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.
Time Frame	Week 24 post treatment until the end of 3-year follow-up

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) analysis set included all enrolled participants who took at least 1 dose of study drug.

Arm/Group Title	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh A	SMV 150mg/DCV 60mg/SOF 400mg - Child-Pugh B
Arm/Group Description	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]) received simeprevir (SMV) (150 milligram [mg] capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.	Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (SMV) (150 mg capsule), daclatasvir (DCV) (60 mg tablet) and sofosbuvir (SOF) (400 mg tablet) orally once daily for 12 weeks.
Measure Participants	19	21
Number [Percentage of participants]	78.9 415.3%	85.7 408.1%

Adverse Events

Arm/Group Title	Panel 1 SMV 150mg/DCV 60mg/SOF 400mg		Panel 2 SMV 150mg/DCV 60mg/SOF 400mg
Arm/Group Description	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 millimeters of mercury [mm Hg]) received simeprevir (150 milligram [mg] capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks.		Participants with Child-Pugh score 7 to 9 (extremes included) received simeprevir (150 mg capsule), daclatasvir (60 mg tablet) and sofosbuvir (400 mg tablet) orally once daily for 12 weeks.
All Cause Mortality
	Panel 1 SMV 150mg/DCV 60mg/SOF 400mg		Panel 2 SMV 150mg/DCV 60mg/SOF 400mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Panel 1 SMV 150mg/DCV 60mg/SOF 400mg		Panel 2 SMV 150mg/DCV 60mg/SOF 400mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/19 (21.1%)		10/21 (47.6%)
Cardiac disorders
Sinus Node Dysfunction	0/19 (0%)		1/21 (4.8%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/19 (0%)		1/21 (4.8%)
Abdominal Pain	0/19 (0%)		2/21 (9.5%)
Ascites	0/19 (0%)		1/21 (4.8%)
Gastrointestinal Haemorrhage	0/19 (0%)		2/21 (9.5%)
Oesophageal Varices Haemorrhage	0/19 (0%)		1/21 (4.8%)
General disorders
Death	0/19 (0%)		1/21 (4.8%)
Hepatobiliary disorders
Biliary Dyskinesia	0/19 (0%)		1/21 (4.8%)
Hepatic Lesion	1/19 (5.3%)		1/21 (4.8%)
Infections and infestations
Appendicitis	0/19 (0%)		1/21 (4.8%)
Diverticulitis	1/19 (5.3%)		0/21 (0%)
Injury, poisoning and procedural complications
Overdose	0/19 (0%)		1/21 (4.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastrointestinal Stromal Tumour	1/19 (5.3%)		0/21 (0%)
Hepatocellular Carcinoma	0/19 (0%)		4/21 (19%)
Nervous system disorders
Cerebrovascular Accident	1/19 (5.3%)		0/21 (0%)
Encephalopathy	0/19 (0%)		1/21 (4.8%)
Hepatic Encephalopathy	0/19 (0%)		1/21 (4.8%)
Skin and subcutaneous tissue disorders
Skin Ulcer	1/19 (5.3%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Panel 1 SMV 150mg/DCV 60mg/SOF 400mg		Panel 2 SMV 150mg/DCV 60mg/SOF 400mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/19 (63.2%)		15/21 (71.4%)
Blood and lymphatic system disorders
Anaemia	2/19 (10.5%)		0/21 (0%)
Anaemia	3/19 (15.8%)		1/21 (4.8%)
Gastrointestinal disorders
Gingival bleeding	1/19 (5.3%)		0/21 (0%)
Nausea	1/19 (5.3%)		2/21 (9.5%)
Umbilical hernia	1/19 (5.3%)		0/21 (0%)
Gastrooesophageal Reflux Disease	1/19 (5.3%)		1/21 (4.8%)
Gingival Bleeding	1/19 (5.3%)		0/21 (0%)
Nausea	1/19 (5.3%)		2/21 (9.5%)
Stomatitis	1/19 (5.3%)		0/21 (0%)
Umbilical Hernia	1/19 (5.3%)		0/21 (0%)
General disorders
Influenza Like Illness	1/19 (5.3%)		1/21 (4.8%)
Oedema Peripheral	0/19 (0%)		2/21 (9.5%)
Infections and infestations
Staphylococcal infection	1/19 (5.3%)		0/21 (0%)
Tooth infection	1/19 (5.3%)		0/21 (0%)
Urinary tract infection	1/19 (5.3%)		2/21 (9.5%)
Diverticulitis	1/19 (5.3%)		0/21 (0%)
Pneumonia	1/19 (5.3%)		1/21 (4.8%)
Sepsis	1/19 (5.3%)		0/21 (0%)
Sinusitis	1/19 (5.3%)		0/21 (0%)
Staphylococcal Infection	1/19 (5.3%)		0/21 (0%)
Tooth Infection	1/19 (5.3%)		0/21 (0%)
Urinary Tract Infection	2/19 (10.5%)		3/21 (14.3%)
Injury, poisoning and procedural complications
Foot fracture	1/19 (5.3%)		0/21 (0%)
Patella fracture	1/19 (5.3%)		0/21 (0%)
Foot Fracture	1/19 (5.3%)		0/21 (0%)
Patella Fracture	1/19 (5.3%)		0/21 (0%)
Investigations
Blood bilirubin increased	0/19 (0%)		2/21 (9.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/19 (5.3%)		0/21 (0%)
Back pain	1/19 (5.3%)		0/21 (0%)
Pain in extremity	1/19 (5.3%)		0/21 (0%)
Arthralgia	1/19 (5.3%)		0/21 (0%)
Back Pain	1/19 (5.3%)		0/21 (0%)
Pain in Extremity	1/19 (5.3%)		0/21 (0%)
Nervous system disorders
Headache	1/19 (5.3%)		0/21 (0%)
Hepatic encephalopathy	0/19 (0%)		2/21 (9.5%)
Headache	2/19 (10.5%)		0/21 (0%)
Hepatic Encephalopathy	1/19 (5.3%)		4/21 (19%)
Restless Legs Syndrome	1/19 (5.3%)		0/21 (0%)
Psychiatric disorders
Insomnia	0/19 (0%)		2/21 (9.5%)
Irritability	1/19 (5.3%)		1/21 (4.8%)
Insomnia	0/19 (0%)		2/21 (9.5%)
Irritability	1/19 (5.3%)		1/21 (4.8%)
Skin and subcutaneous tissue disorders
Photosensitivity reaction	2/19 (10.5%)		1/21 (4.8%)
Pruritus	1/19 (5.3%)		2/21 (9.5%)
Skin mass	1/19 (5.3%)		0/21 (0%)
Photosensitivity Reaction	2/19 (10.5%)		0/21 (0%)
Pruritus	1/19 (5.3%)		2/21 (9.5%)
Skin Mass	1/19 (5.3%)		0/21 (0%)
Skin Ulcer	1/19 (5.3%)		0/21 (0%)
Vascular disorders
Hypertension	1/19 (5.3%)		1/21 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.