Strategic Transformation of the Market of HCV Treatments

Study Overview
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Brief Summary
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This is a Phase II/III, multicenter, multi-country, trial to assess the efficacy, safety, tolerance and pharmacokinetics of sofosbuvir plus ravidasvir for the treatment of HCV infection.

Detailed Description
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This is a Phase II/III, multicenter, multi-country trial to assess the efficacy, safety, tolerance and pharmacokinetics of SOF-RDV for the treatment of HCV infection, across genotypes 1,2,3,6, among non-cirrhotic and cirrhotic with CTP class A, interferon/ribavirin naïve or experienced, HCV mono-infected and HCV/HIV co-infected subjects. It will also study the pharmacokinetics of RDV and, in HCV/HIV co-infected subjects, possible drug-drug interactions with antiretrovirals. The treatment duration will be 12 weeks for subjects with no cirrhosis (Metavir F0 to F3) and 24 weeks for subjects with compensated cirrhosis (Metavir F4, CTP class A). The study is performed in 2 stages. Stage 1 has been completed. Efficacy and safety results from Stage 1 were reviewed and approved by the independent Data and Safety Monitoring Board (DSMB) which provided the recommendation to proceed with the study stage 2. On-going stage 2 aims to supplement Stage 1 results and provide additional information on the performance of SOF-RDV in the main genotypes found in Malaysia and Thailand.

Official Title
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Open Label Phase II/III, Multicenter, Trial to Assess the Efficacy, Safety, Tolerance, and Pharmacokinetics of Sofosbuvir Plus Ravidasvir in HCV (+/- HIV) Chronically Infected Adults With no or Compensated Cirrhosis in Thailand and Malaysia

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: sofosbuvir + ravidasvir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of chronic HCV infection, defined as: Positive anti-HCV antibody or detectable HCV RNA or HCV genotype at least 6 months before screening and HCV viral load ≥10^4 IU/mL at the time of screening / In subjects without documented HCV test results 6 months before screening, chronic hepatitis C infection can be assumed if risk exposures occurred > 6 months prior to screening and HCV viral load ≥10^4 IU/mL at the time of screening. Willing and able to provide written informed consent. Men and women age ≥ 18 years and < 70 years. Body Mass Index (BMI) of 18 to 35 kg/m2. Intention to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments. Women with a negative pregnancy test at screening and baseline. Women of child bearing potential who accept a highly effective contraceptive method from at least 2 weeks prior to study day 1 until 1-month post-treatment. A woman is of non-child bearing potential if she (a) reached natural menopause determined retrospectively after 12 months of amenorrhea without any other obvious medical cause or (b) had procedures like bilateral tubal ligation or hysterectomy or bilateral oophorectomy. Subjects who are compliant in an opioid substitution maintenance program (e.g. with methadone or buprenorphine) may be included as long as there is no concern about study medications adherence and interaction or compliance to study schedules. Inclusion criteria related to HIV/HCV co-infected patients: HIV/HCV co-infected patients receiving cART fulfilling the below criteria are eligible for the study: Antiretroviral therapy (ART) should have been initiated at least 6 months prior to screening / Patient has to have been on the same protocol-approved ARV regimen for ≥ 8 weeks prior to screening and is expected to continue the current ARV regimen through the end of study / HIV ARVs: agents allowed in this study should be administered per the prescribing information in the package insert / Screening HIV RNA < 50 copies/mL / Screening CD4 cell count ≥ 100 cells/uL HIV/HCV co-infected patients not receiving cART: Screening CD4 cell count must be ≥ 500 cells/uL Exclusion Criteria: Decompensated cirrhosis defined as: Evidence of advanced stage liver cirrhosis and Child-Turcotte-Pugh (CTP) Class B or C or CTP score >6) or current/past history of decompensation including ascites, variceal bleeding, spontaneous bacterial peritonitis, or hepatic encephalopathy. Hepatocellular carcinoma: for all patients with cirrhosis, hepatocellular carcinoma (HCC), should be excluded by liver imaging within 6 months prior to screening, and this must continue periodically as in routine HCC surveillance. Laboratory exclusion criteria: cirrhotic subjects with albumin < 2.8 g/dL direct bilirubin > 3xULN AST, ALT > 10xULN Low neutrophil count (≤599 cells/mm3), hemoglobin (<9.0 g/dL for male, <8.5 g/dL for female), platelets (<50000 cells/mm3 ) classified as ≥ Grade 3 Patients with serum creatinine > 1.5 ULN or end stage renal disease Hepatitis B co-infection (HBsAg positive) Pregnancy, as documented by positive pregnancy tests at screening or baseline Breastfeeding Subjects currently receiving or unable to stop the use for at least 1 week prior to receiving the first dose of study drug any medications or herbal supplements known to be potent inhibitors or moderate inducers of cytochrome P450 (CYP) 3A4 or potent inducers of P-glycoprotein. This includes subjects who are on amiodarone or other contraindicated/excluded drugs. Participation in other clinical trials within 3 months. Any clinically significant findings or unstable condition during the screening, medical history or physical examination that, in the investigator's opinion, would compromise participation in this study as per standard guidelines and local practice. This could include patients with poorly controlled hypertension, asthma, diabetes, or other life-threatening conditions. Current or history of use within the preceding 6 months of immunosuppressive or immune-modulating agents. Corticosteroid used to treat any medical condition are allowed if systemic for not more than 2 weeks or if topical. History of solid organ or bone marrow transplantation. Any prior NS5A inhibitors therapy. Patients with significant cardiovascular conditions including: myocardial infarction within the previous 6 months or heart failure NYHA class III or IV history of Torsade de pointes Third degree heart block QTcF (Fridericia) value ≥ 450 milliseconds at Baseline Severe sinus bradycardia with a rate of under 50 beats per minute A sinus bradycardia with third degree atrioventricular block or with Mobitz II AV block Use of medications associated with QT prolongation concurrently or within the 30 days prior to Screening Visit, including: macrolides, antiarrhythmic agents, azoles, fluoroquinolones, and tricyclic anti-depressants. Commonly used and essential medications for this study population like methadone and/or efavirenz is allowed as long as the QTcF value at baseline is < 450 milliseconds. Self-reporting active injection drug use at screening (only for stage 2). Exclusion criteria related to HIV/HCV co-infected patients: HIV/HCV co-infected patients not yet on stable antiretroviral therapy or for whom ART treatment initiation maybe scheduled during the study period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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: sofosbuvir + ravidasvir<br>12 weeks for non-cirrhotic patients, 24 weeks for cirrhotic patients | Drug: sofosbuvir + ravidasvir<br>* combination of sofosbuvir + ravidasvir<br>* Other names: ravisdasvir: PPI-668;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virological Response at 12 weeks post treatment completion (SVR12), as evidenced by HCV RNA level less than the lower limit of quantification | Related objective: to assess the efficacy of sofosbuvir-ravidasvir (SOF-RDV) at 12 weeks after the end of study treatment | 12 weeks after the end of the study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained virologic response at 4 and 24 weeks post treatment completion (SVR4 and SVR24), as evidenced by HCV RNA level less than the lower limit of quantification | Related objective: to assess the efficacy of SOF-RDV at 4 and 24 weeks after the end of study treatment | 4 and 24 weeks after the end of the study treatment | 
| Occurrence of on-treatment virologic failure among subjects not achieving SVR12 | Defined as HCV RNA ≥ LLOQ at the end of the treatment period. Related objective: to assess the efficacy of SOF-RDV 12 weeks after the end of study treatment. | 12 weeks after the end of the study treatment | 
| Occurrence of virologic breakthrough among subjects not achieving SVR12 | Defined as either confirmed ≥ 1 log10 IU/mL increase in HCV RNA from nadir while on treatment or confirmed HCV RNA ≥ LLOQ if HCV RNA previously declined to < LLOQ while on treatment. Related objective: to assess the efficacy of SOF-RDV 12 weeks after the end of study treatment. | 12 weeks after the end of the study treatment | 
| Occurrence of virologic relapse among subjects not achieving SVR12 | Defined as HCV RNA < LLOQ at the end of the treatment period but HCV RNA ≥ LLOQ during the post-treatment period. Related objective: to assess the efficacy of SOF-RDV 12 weeks after the end of study treatment. | 12 weeks after the end of the study treatment | 
| Occurrence of non-virologic failure among subjects not achieving SVR12 | Defined as any failure that does not meet the virologic failure criteria (e.g. adverse event, lost to follow-up). Related objective: to assess the efficacy of SOF-RDV 12 weeks after the end of study treatment. | 12 weeks after the end of the study treatment | 
| Occurrence of premature treatment discontinuation and occurrence of premature study discontinuation (overall and by reason for premature discontinuation) | Related objective: to assess the safety of SOF-RDV | Through study completion (up to 36 weeks for non-cirrhotic patients and up to 48 weeks for cirrhotic patients) | 
| Time to premature treatment discontinuation and time to premature study discontinuation | Related objective: to assess the safety of SOF-RDV | Through study completion (up to 36 weeks for non-cirrhotic patients and up to 48 weeks for cirrhotic patients) | 
| Occurrence of the following events: TEAE, TEAE considered to be at least possibly related to at least one of the study drugs, TEAE leading to premature treatment discontinuation, TE laboratory abnormality, grade 3/4 TEAE, TESAE and death | Related objective: to assess the safety of SOF-RDV. TEAE: Treatment Emergent Adverse Event TESAE: Treatment Emergent Serious Adverse Event | Through study completion (up to 36 weeks for non-cirrhotic patients and up to 48 weeks for cirrhotic patients) | 
| Time to first TEAE, time to first grade 3/4 TEAE and time to first TESAE | Related objective: to assess the safety of SOF-RDV. TEAE: Treatment Emergent Adverse Event TESAE: Treatment Emergent Serious Adverse Event | Through study completion (up to 36 weeks for non-cirrhotic patients and up to 48 weeks for cirrhotic patients) | 
| Maximum plasma concentration (Cmax) of ravidasvir (and sofosbuvir if needed) | Related objective: to study the pharmacokinetics (PK) of SOF and RDV and to evaluate potential drug-drug interactions with antiretrovirals and, as needed, interactions with concomitant prescribed or non-prescribed drugs. | Intensive PK (stage 1 only): 4 weeks after treatment initiation; Sparse PK: 4, 8 and 12 weeks after treatment initiation | 
| Baseline factors associated with SVR12 outcome | Related objective: to describe the subjects' demographic, clinical and biological characteristics and their relationship with SVR12. | Baseline and 12 weeks after the end of the study treatment | 
| Change in the PROQOL-HCV domain scores from treatment initiation to 12 weeks after treatment completion | Related objective: to assess the subjects' quality of life before and after therapy. PROQOL-HCV: Patient Reported Outcome Quality of Life survey for HCV, questionnaire that evaluates 7 domains, each domain scores range 0 to 100, where 100 corresponds to the best quality of life. | 12 weeks after the end of the study treatment | 
| Changes in HCV NS5A sequences from treatment initiation in subjects not achieving SVR12 | Related objective: to evaluate the presence of viral resistance-associated variants (RAVs) to SOF-RDV in patients with virological failure 12 weeks after treatment completion | 12 weeks after the end of the study treatment |