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

Lead sponsor: Drugs for Neglected Diseases

Collaborator: Ministry of Health, Malaysia
Ministry of Health, Thailand

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.

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.

• Hepatitis C

Intervention type: Drug

Intervention name: sofosbuvir + ravidasvir

Description: combination of sofosbuvir + ravidasvir

Arm group label: sofosbuvir + ravidasvir

Other name: ravisdasvir: PPI-668

Criteria:

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 effective contraception from 2 weeks prior to study day 1 until 1 month post-treatment (Double contraceptive method including at least one barrier method). 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. In stage 1, active injection drug users could also be enrolled, as a pre-stratified subpopulation, however their data did not contribute to the primary analysis.

- 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 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 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. 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.

- 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

- 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.

- HIV/HCV co-infected patients not yet on stable antiretroviral therapy or for whom ART treatment initiation maybe scheduled during the study period.

Gender: All

Minimum age: 18 Years

Maximum age: 70 Years

Healthy volunteers: No

Last name: Isabelle Andrieux-Meyer, MD

Phone: +41 79 127 17 99

Email: [email protected]

Malaysia

Thailand

January 2020

Responsible party type: Sponsor

• Hepatitis C

Arm group label: sofosbuvir + ravidasvir

Arm group type: Experimental

Description: 12 weeks for non-cirrhotic patients, 24 weeks for cirrhotic patients

Allocation: N/A

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)