Study to Assess Efficacy, Safety, Tolerability and Pharmacokinetics of Simeprevir, Daclatasvir and Sofosbuvir in Treatment-naive Participants With Chronic Hepatitis C Virus Genotype 1 Infection

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy of 6 or 8 weeks of treatment regimen containing simeprevir (SMV), daclatasvir (DCV) and sofosbuvir (SOF) in treatment-naive (not having received treatment with any approved or investigational drug) participants with chronic hepatitis (inflammation of the liver) C virus (HCV) genotype 1 infection with early stages of liver fibrosis or with cirrhosis.

Detailed Description
-----------------
This is an open-label (participants and researchers are aware about the treatment participants are receiving), and multicenter (when more than 1 hospital or medical school team work on a medical research) study. The study will consist of a Screening Phase (6 weeks); an Open-label Treatment Phase (6 weeks for Arm A and 8 weeks for Arm B); and a Post-treatment Follow-up Phase (until 24 weeks after end of study treatment). Using a staggered approach, all eligible participants will be assigned to 1 of the 2 arms, according to their level of fibrosis. Arm A (consists of chronic HCV genotype 1 infected participants with early stages of liver fibrosis): participants will receive a combination therapy of SMV 150 milligram (mg), DCV 60 mg and SOF 400 mg once daily for 6 weeks. Arm B (consists of chronic HCV genotype 1 infected participants with cirrhosis): participants will receive a combination therapy of SMV 150 mg, DCV 60 mg and SOF 400 mg once daily for 8 weeks. A sub-study will be performed at a selected study site, where only participants who will be eligible to participate in both the main study and the sub-study will be enrolled. Intra-hepatic and plasma HCV ribonucleic acid (RNA) levels; intra-hepatic, peripheral innate and adaptive immune responses during the treatment, will be assessed in the sub-study. Participants' safety will be monitored throughout the study.

Official Title
-----------------
A Phase 2, Randomized, Open-label Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of 6 or 8 Weeks of Treatment With Simeprevir, Daclatasvir and Sofosbuvir in Treatment-naive Subjects With Chronic Hepatitis C Virus Genotype 1 Infection

Conditions
-----------------
Hepatitis C Virus

Intervention / Treatment
-----------------
* Drug: Simeprevir 150 mg
* Drug: Daclatasvir 60 mg
* Drug: Sofosbuvir 400 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HCV genotype 1 infection and HCV RNA plasma level greater than (>) 10,000 international units per milliliter (IU/mL), both determined at Screening Participants of Arm A should have evidence of early stages of liver fibrosis, defined by a FibroSURE score less than or equal to (<=) 0.48 and aspartate aminotransferase to platelet ratio index (APRI) score <=1 Participants of Arm B should have evidence of cirrhosis, defined by a FibroSURE score >0.75 and APRI score >2, OR a previous (historical) biopsy documenting a METAVIR score F4. In addition, participants should have absence of esophageal varices or presence of small (grade 1) esophageal varices determined by upper gastrointestinal endoscopy, and absence of findings indicative of hepatocellular carcinoma in an ultrasonography HCV treatment-naive, defined as not having received treatment with any approved or investigational drug for chronic HCV infection Pegylated interferon (PegIFN) and ribavirin (RBV) eligible, defined as not having any contraindication to the use of PegIFN and RBV, in line with the prescribing information for each compound Exclusion Criteria: A. Main Study: Co-infection with HCV of another genotype than genotype 1 and/or human immunodeficiency virus (HIV) type 1 or 2 (positive HIV-1 or HIV 2 antibody test at Screening) Any evidence of liver disease of non-HCV etiology. This includes, but is not limited to, acute hepatitis A infection, hepatitis B infection (hepatitis B surface antigen positive), 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 Evidence of clinical hepatic decompensation or presence of grade 2/3 esophageal varices Any of the protocol defined laboratory abnormalities B. Sub-study: Presence of coagulopathy (hemophilia) or hemoglobinopathy (including sickle cell disease, thalassemia) Use of any anti-coagulant (for example, warfarin, heparin) or anti-platelet medications within 1 week of the Screening visit Any of the protocol defined laboratory abnormalities

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Chronic hepatitis C virus (HCV) genotype 1 infected participants with early stages of liver fibrosis, will receive Simeprevir (SMV) 150 milligram (mg), Daclatasvir (DCV) 60 mg and Sofosbuvir (SOF) 400 mg once daily for 6 weeks. | Drug: Simeprevir 150 mg<br>* Simeprevir 150 mg capsule orally once daily.<br>Drug: Daclatasvir 60 mg<br>* Daclatasvir 60 mg tablet orally once daily.<br>Drug: Sofosbuvir 400 mg<br>* Sofosbuvir 400 mg tablet orally once daily.<br>|
| Experimental: Arm B<br>Chronic HCV genotype 1 infected participants with cirrhosis, will receive SMV 150 mg, DCV 60 mg and SOF 400 mg once daily for 8 weeks. | Drug: Simeprevir 150 mg<br>* Simeprevir 150 mg capsule orally once daily.<br>Drug: Daclatasvir 60 mg<br>* Daclatasvir 60 mg tablet orally once daily.<br>Drug: Sofosbuvir 400 mg<br>* Sofosbuvir 400 mg tablet orally once daily.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response (SVR) at 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. | 12 weeks after end of study drug treatment (week 18 for Arm A and week 20 for Arm B) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With On-treatment Virologic Response | On-treatment virologic response was determined by hepatitis C virus (HCV) ribonucleic acid (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. | Day 2, Day 3, Week 1, 2, 3, 4, 6 (for Arm A) and 8 (for Arm B only) | 
| Percentage of Participants With Sustained Virologic Response at 4 Weeks (SVR4) and 24 Weeks (SVR24) After End of Study Drug Treatment | 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. | 4 weeks after end of study drug treatment (week 10 for Arm A and 12 for Arm B); 24 weeks after end of study drug treatment (week 30 for Arm A and 32 for Arm B) | 
| Percentage of Participants With On-Treatment Failure | Participants who did not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of treatment. Includes participants with: 1) viral breakthrough, defined as a confirmed increase of greater than (>)1 log10 in HCV RNA from nadir, or confirmed HCV RNA 2) confirmed detectable HCV RNA at the actual end of treatment (example, completed treatment, discontinued due to adverse events, withdrawal of consent) of >100 IU/mL in participants whose HCV RNA had previously been <LLOQ while on treatment. | Baseline up to End of Treatment (Week 6 for Arm A and Week 8 for Arm B) | 
| Number of Participants With Viral Relapse | Viral Relapse: Participants who did 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 during followup. | From Week 6 to Week 18 (for Arm A) and From Week 8 to Week 20 (for Arm B) | 
| Number of Participants With Late Viral Relapse | Late Viral Relapse: Participant who achieved SVR12 and the post treatment HCV RNA measurement fulfilled 1 the following conditions: a) at least 2 consecutive measurements not lesser than (<)15 IU/mL undetectable, of which at least the second measurement was >=15 IU/mL quantifiable or b) the last available measurement was >=15 IU/mL quantifiable. | From Week 18 to Week 30 (for Arm A), From Week 20 to Week 32 (for Arm B) | 
| Number of Participants With HCV Nonstructural Protein 3/4A (NS3/4A), NS5A and NS5B Sequence 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 preexisting sequence polymorphisms and characterize emerging HCV viral variants in participants not achieving SVR. | Up to Week 30 for Arm A and up to Week 32 for Arm B | 
| Percentage of Participants With or Without an NS3 Q80K Polymorphism at Baseline Achieving SVR | The Q80K polymorphism, associated with low level SMV in vitro resistance. Percentage of participants who achieved SVR with or without an NS3 Q80K polymorphism at baseline were reported. | up to Week 30 for Arm A and Week 32 for Arm B | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatitis C virus, Hepatitis C virus genotype 1, Chronic Hepatitis C Virus Genotype 1 Infection, Liver fibrosis, Cirrhosis, Simeprevir, Daclatasvir, Sofosbuvir