Efficacy and Safety Study of Simeprevir in Combination With Sofosbuvir in Participants With Genotype 1 Chronic Hepatitis C Virus Infection and Cirrhosis

Study Overview
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Brief Summary
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The purpose of the study is to investigate the efficacy and safety of 12 weeks of simeprevir (150 mg qd) in combination with sofosbuvir (400 mg qd) in chronic hepatitis C virus (HCV) genotype 1 infected men and women with cirrhosis who are HCV treatment-naïve or treatment-experienced.

Detailed Description
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This is a open-label (all people know the identity of the intervention), single arm, multicenter study. The study will consist of a screening phase up to 4 weeks, open-label treatment phase of 12 weeks, and post-treatment follow up phase up to 24 weeks after end of treatment. Approximately 100 participants will receive 150 mg simeprevir in combination with 400 mg sofosbuvir once dailyfor 12 weeks. Safety evaluations will include assessment of adverse events, clinical laboratory tests, vital signs, and physical examination. The maximum study duration for each participant will be approximately 40 weeks.

Official Title
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A Phase 3, Multicenter, Open-Label, Single-Arm Study to Investigate the Efficacy and Safety of a 12-Week Regimen of Simeprevir in Combination With Sofosbuvir in Treatment-Naïve or -Experienced Subjects With Chronic Genotype 1 Hepatitis C Virus Infection and Cirrhosis

Conditions
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Hepatitis C Virus Infection

Intervention / Treatment
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* Drug: Simeprevir
* Drug: Sofosbuvir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hepatitis C virus (HCV) genotype 1 infection (confirmed at screening). HCV ribonucleic acid (RNA) greater than 10,000 IU/mL at screening Treatment-experienced participants must have at least 1 documented previous course of interferon-based regimen with or without ribavirin Participants must have an hepatic imaging procedure (ultrasound, computerized tomography scan or magnetic resonance imaging scan) within 6 months prior to the screening visit (or between screening and Day 1) with no findings suspicious for hepatocellular carcinoma Participant must be willing and able to comply with the protocol requirements Participants with liver cirrhosis Exclusion Criteria: Evidence of clinical hepatic decompensation (history or current evidence of ascites, bleeding varices or hepatic encephalopathy) Infection/co-infection with HCV non-genotype 1 Co-infection with human immunodeficiency virus (HIV) type 1 or type 2 (HIV-1 or HIV-2) (positive HIV-1 or HIV-2 antibodies test at screening) Co-infection with hepatitis B virus (hepatitis B-surface-antigen positive) Previously been treated with any direct acting anti-HCV agent (approved or investigational) for chronic HCV infection

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (Simeprevir/Sofosbuvir)<br>100 participants will receive 1 capsule of 150 mg simeprevir and 1 tablet of 400 mg sofosbuvir orally (by mouth) once daily for 12 weeks. | Drug: Simeprevir<br>* 100 participants will receive 1 capsule of 150 mg orally once daily for 12 weeks.<br>Drug: Sofosbuvir<br>* 100 participants will receive 1 tablet of 400 mg sofosbuvir orally once daily for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Sustained Virologic Response (SVR) 12 Weeks After the Actual End of Treatment (EOT) | Participants with hepatitis C virus (HCV) ribonucleic acid (RNA) less than (<) 25 international unit per milliliter (IU/mL) (detectable or undetectable) at 12 weeks after the actual end of treatment. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Sustained Virologic Response (SVR) 4 Weeks After the Actual End of Treatment (EOT) | Participants with hepatitis C virus (HCV) ribonucleic acid (RNA) less than (<) 25 international unit per milliliter (IU/mL) (detectable or undetectable) at 4 weeks after the actual end of treatment. | Week 16 | 
| Percentage of Participants With a Sustained Virologic Response (SVR) 24 Weeks After the Actual End of Treatment (EOT) | Participants with hepatitis C virus (HCV) ribonucleic acid (RNA) less than (<) 25 international unit per milliliter (IU/mL) (detectable or undetectable) at 24 weeks after the actual end of treatment. | Week 36 | 
| Percentage of Participants With On-treatment Virologic Response | On-treatment virologic response was determined by HCV RNA results satisfying a specified threshold. <LLOQ undetectable was considered as threshold at any time point. The LLOQ value is 25 IU/mL. EOT=End of Treatment. | Week 2, 4 and End of Treatment (Week 12) | 
| 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 | 
| Percentage of Participants With Viral Breakthrough | Viral breakthrough was defined as confirmed greater than (>) 1 log10 increase in HCV RNA from nadir or confirmed HCV RNA >100 IU/mL in participants who had previously achieved HCV RNA < LLOQ (25 IU/mL). | Up to End of Treatment (Week 12) | 
| Percentage of Participants With Viral Relapse | Viral relapse was defined as participants who did not achieve SVR12 and had HCV RNA < LLOQ (25 IU/mL) undetectable at EOT and had HCV RNA >= LLOQ (25 IU/mL) during the follow-up period. | During the Follow-up (Week 24) | 
| Change From Baseline in Hepatitis C Symptom and Impact Questionnaire Version 4 (HCV-SIQv4) Overall Body System Score (OBSS) up to Follow-up Week 12 | The HCV-SIQv4 OBSS was a self-administered questionnaire that contained 33 items: 29 questions developed to assess severity or frequency of symptoms associated with HCV or its treatment, 3 questions regarding the impact of symptoms on work/school attendance, and 1 question regarding the impact of symptoms on daily activities. A symptom severity score (the mean of responses to the 29 symptom items); each symptom score was transformed to have a range from 0 to 100 (most severe). Higher HCV SIQv4 scores indicates worse symptom severity, more time missed from work/school, and more impairment in daily activities, respectively. | Baseline, Week 4, Week 12 and Follow-Up Week 12 | 
| Change From Baseline in Fatigue Severity Score (FSS) up to Follow-up Week 24 | The FSS was a self-administered questionnaire with 9 items developed to assess disabling fatigue that has been used extensively in studies of chronic HCV infection. Item responses were measured on a 7-point Likert scale ranging from strongly disagree (1 point) to strongly agree (7 points). The 9 items were averaged to produce a total score; a lower total score indicates less severe fatigue. FSS scores have a range from 1 to 7 where higher scores indicate more severe fatigue. | Baseline, Week 12, Follow-up Week 12 and 24 | 
| Percentage of Participants With Depression by Using Center for Epidemiologic Studies Depression Scale (CES-D) | The CES-D Scale assessed how often during the past week participants experienced 20 symptoms commonly associated with major depression. The CES-D scores range from 0 (no symptoms) to 60 (all 20 symptoms most or all of the time during the past 5 to 7 days). The CES-D scores between 16 and 23 points indicate mild to moderate depressive illness while CES-D scores >=23 indicate probable major depressive illness. | Baseline, Week 12, Follow-up Week 12 and 24 | 
| Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D) up to Follow-up Week 24 | The EQ-5D questionnaire was a brief, generic health-related quality of life (HRQOL) assessment that could also be used to incorporate participant preferences into health economic evaluations. The EQ-5D questionnaire assessed HRQOL in terms of degree of limitation on 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and as overall health using a thermometer visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health). | Baseline, Follow-up Week 12 and 24 | 
| Number of Participants Not Achieving SVR Showing Emerging Mutation at Time of Failure in HCV NS3/4A Sequence and NS5B up to Follow-up Week 24 | Sequencing of the HCV nonstructural protein 3/4A (NS3/4A) 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. Sequencing data is available for 16 participants. | Baseline, Day 3, Week 1, 2, 3, 4, 8, 12, Follow-up Week 4, 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C Virus Infection, Simeprevir, Sofosbuvir, HCV, Cirrhosis