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Infectious Diseases clinical trial

A Phase 3, Global, Multicenter, Randomized, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir/GS-9857 Fixed-Dose Combination for 8 Weeks Compared to Sofosbuvir/Velpatasvir for 12 Weeks in Direct-Acting Antiviral-Naïve Subjects with Chronic HCV Infection

Summary:
Hepatitis C virus (HCV) infection is a global health challenge with an estimated 150 million individuals infected worldwide. HCV primarily affects the liver and can cause liver cirrhosis leading onto liver failure or liver cancer.

There are 7 major genotypes (genetic variations) of HCV; there is no current standard of care treatment for all
genotypes. A therapy that avoids the costs and delays of having to assess the HCV genotype would facilitate therapy and reduce treatment cost.

Recently, the development of oral direct-acting antivirals (DAAs) has provided a major advance in the treatment of HCV. However, there are a growing number of patients who do not respond to DAA-based therapies and this patient population currently has no retreatment options.

SOF/VEL/GS-9857 FDC (fixed dose combination) is a combined formulation in a single tablet for the treatment of chronic HCV infection. This combines three mechanisms of action:

• Sofosbuvir (SOF), an NS5B polymerase inhibitor, is currently approved in the US and other regions for the treatment of HCV infection as a component of combined treatment.
• Velpatasvir (VEL), an NS5A inhibitor that has in vitro anti-HCV activity across all genotypes, which is currently being evaluated in four Phase 3 studies as a combined tablet with SOF.
• GS-9857, a new NS3/4A protease inhibitor with potent in vitro antiviral activity against genotypes 1 to 6 HCV.

This study aims to enrol approximately 780 participants aged over 18 diagnosed with chronic HCV who have not
previously been treated with DAAs. The study will take place at approximately 120 centres in the US, Canada, New Zealand, Australia, France, Germany and the UK. This study will compare the effectiveness of treatment with SOF/VEL/GS-9857 FDC for 8 weeks with that of SOF/VEL FDC for 12 weeks in patients with chronic HCV of all genotypes.

Inclusion criteria:
Participants must meet all of the following inclusion criteria to be eligible for participation in this study:
1) Willing and able to provide written informed consent
2) Male or female, age ≥18 years
3) Body mass index (BMI) ≥ 18 kg/m2
4) HCV RNA ≥ 10 4 IU/mL at Screening
5) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy.
6) HCV treatment status of one of the following:
a. Treatment-naïve with no prior exposure to any IFN, RBV, or approved or experimental HCV-specific DAA
b. Treatment experienced with an IFN-based regimen and no prior exposure to an approved or experimental HCV-specific DAA
i. The most recent treatment must have been completed at least 8 weeks prior to Screening
ii. Participants must not have discontinued the most recent regimen due to either an adverse event or virologic failure due to noncompliance
c. The participant’s medical records must include sufficient detail of prior treatment(s) to confirm eligibility.
7) Cirrhosis Determination
a. Presence of cirrhosis is defined as any one of the following:
i. FibroTest® score > 0.75 and AST:platelet ratio index (APRI) > 2 during Screening
ii. Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5)
iii. Transient elastography (FibroScan®) with a result of > 12.5 kPa
b. Absence of cirrhosis is defined as any one of the following, unless the definition of cirrhosis has been met:
i. FibroTest® score ≤ 0.48 and APRI ≤ 1 performed during Screening
ii. Liver biopsy within 2 years of Screening showing absence of cirrhosis
iii. Transient elastography (FibroScan®) with a result of ≤ 12.5 kPa within 6 months of Day 1
8) Liver imaging within 6 months prior to Day 1 is required in cirrhotic participants to exclude hepatocellular carcinoma (HCC)
9) Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to enrolment
10) Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
11) Lactating females must agree to discontinue nursing before starting study medication.
12) Participant must be of generally good health, with the exception of chronic HCV infection, as determined by the investigator
13) Participant must be able to comply with the dosing instructions for study medication administration and able to complete the study schedule of assessments

Exclusion criteria:
Participants who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Current or prior history of any of the following:
a. Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with
participant treatment, assessment or compliance with the protocol; participants currently under evaluation for a
potentially clinically significant illness (other than HCV) are also excluded
b. Gastrointestinal disorder or post-operative condition that could interfere with the absorption of the study
medication
c. Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy
d. Hepatic decompensation (e.g., clinical ascites, encephalopathy, and/or variceal haemorrhage)
e. Solid organ transplantation
f. Significant cardiac disease
g. Unstable psychiatric condition including hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within 2 years prior to Screening
h. Malignancy within the 5 years prior to Screening, with the exception of specific cancers that have been cured by surgical resection (e.g., basal cell skin cancer, etc.). Participants under evaluation for possible malignancy are not eligible
i. Significant medication allergy (e.g., hepatotoxicity)
2) Screening ECG with clinically significant abnormalities
3) Participant has the following laboratory parameters at Screening:
a. ALT > 10 × the upper limit of normal (ULN)
b. AST > 10 × ULN
c. Direct bilirubin > 1.5 × ULN
d. Platelets < 50,000/μL e. HbA1c > 8.5%
f. Creatinine clearance (Crcl) < 50 mL/min as calculated by the Cockcroft-Gault equation g. Haemoglobin < 10 g/dL h. Albumin < 3 g/dL i. International Normalised Ratio of prothrombin time (INR) > 1.5 × ULN unless participant has known haemophilia or is stable on an anticoagulant regimen affecting INR
4) HCV genotype 3, as determined by the central laboratory, and the presence of cirrhosis.
5) Chronic liver disease of a non-HCV aetiology (e.g., haemochromatosis, Wilson’s disease, alfa-1 antitrypsin
deficiency, cholangitis)
6) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
7) Clinically-relevant alcohol or drug abuse within 12 months of Screening. A positive drug screen will exclude
participants unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the investigator
8) Use of any prohibited concomitant medications
9) Known hypersensitivity to the study medication, the metabolites, or formulation excipient.

Principal Investigator for this trial: Dr Stephen D Ryder

Research Ethics Committee Reference: 15/ES/0185

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076

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