A phase 2, open-label study to assess the safety and efficacy of Bemnifosbuvir (bem) and Ruzasvir (rzr) in subjects with chronic hepatitis c virus (hcv) infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 280
- 试验地点
- 8
- 主要终点
- - To evaluate the safety and tolerability of BEM + RZR
研究概览
简要总结
This is an open-label trial toevaluate 8 weeks of treatment with BEM + RZR in subjects with chronic HCVinfection. Approximately 280 treatment-naïve subjects with genotype (GT) 1, 2,3, 4, 5, 6 or 7, either without cirrhosis or with compensated cirrhosis, will beenrolled.
A lead-in group of 60 non-cirrhoticsubjects will initially be enrolled. At 4 weeks posttreatment, this lead-ingroup will be evaluated for safety, sustained virologic response at 4 weeksposttreatment (SVR4) and virologic relapse; enrollment will open to theremaining 220 subjects provided that ≤ 6 subjects in the lead-in group (fromthe per-protocol [PP] population) experience virologic failure and no studystopping rules are met.
Subjects will be screened for up to4 weeks, although this can be extended for up to 6 weeks for extenuatingcircumstances with Sponsor approval.
Eligible subjects will enter thetreatment period and receive BEM + RZR for 8 weeks. After Day 1, during thetreatment period, subjects may self-administer study drugs (ie, investigationalmedicinal product [IMP]) at home, with the exception of subjects who agree toadditional blood sampling as part of up to 2 substudies. These subjects will berequired to take their study drug in the clinic on certain days. Subjects willreturn to the clinic for evaluations at Weeks 1, 2, 4, 6 and 8 (End ofTreatment [EOT]) during the treatment period.
Following their last visit of thetreatment period (including subjects who prematurely discontinue treatment),subjects will enter the Follow-up period and return to the clinic forevaluations at Follow-up Weeks 4, 12, and 24. End-of-Study (EOS) is defined asthe visit at 24 weeks posttreatment.
Adverse events (AEs) andconcomitant medications will be reviewed during visits throughout the treatmentand follow-up periods. Subjects may also be contacted between visits to assesstheir compliance with the dosing regimen (during the treatment period) and todiscuss AEs and concomitant medications.
The primary endpoint is SVR12. Secondaryendpoints include virologic failure and SVR24. Exploratory endpoints areresistance to either study drug (BEM or RZR), SVR12 in subgroups defined bydemographics and/or baseline characteristics, HCV RNA changes from baseline andexposure-response relationships. Safety endpoints are the incidence of AEs,serious adverse events (SAEs), and AEs resulting in treatment discontinuation;clinical laboratory abnormalities; vital sign measurements; andelectrocardiogram (ECG) parameters.
There will be two substudies (PK only; PK-VK),each requiring separate consent; up to 50 subjects can consent to either orboth. Subjects who consent to the PK-only substudy will provide additionalblood samples at any planned treatment visit as early as Week 2 based on conveniencefor subject and investigator. Subjects who consent to the PK-VK substudy willprovide additional blood samples a) on Day 1; and b) on Days 2 and 3 (24 and 48hours after the first dose; ± 2 hours). Study drug will be administered at theclinic on these days
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 85.00 Year(s)（—）
- 性别
- All
入选标准
- •Willing and able to provide written informed consent.
- •Male or female subjects between ≥ 18 years of age (or the legal age of consent per local regulations) and ≤ 85 years of age.
- •Fridericia-corrected QT (QTcF) interval ≤ 440 ms for males and ≤ 460 ms for females at Screening Note: The mean of the triplicate readings should be used to assess the QTcF.
- •Female subjects of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or to the use of an acceptable effective contraception, as described in Section 5.
- •Females must have a negative pregnancy test at Screening and at Day 1 prior to dosing.
- •Subjects must be direct-acting antiviral (DAA)-treatment-naïve, defined as never exposed to an approved or experimental DAA for HCV Note: Prior exposure to (peg)interferon with or without ribavirin is acceptable, as long as it/they were not administered with a DAA. -Subjects must have HCV GT1, GT2, GT3, GT4, GT5, GT6, or GT7 (with no evidence of non-typeable or mixed GT), documented at Screening.
- •Documented medical history compatible with chronic HCV, including any one of the following:.
- •positive for anti-HCV antibody, HCV RNA, or an HCV GT at least 6 months prior to Day 1, or -positive for anti-HCV antibody at Screening with clinical or laboratory evidence of chronic HCV disease, such as the presence of fibrosis by biopsy or noninvasive tests.
- •HCV RNA ≥ 1,000 IU/mL at Screening.
- •Liver disease staging assessment as follows: -Absence of cirrhosis (F0 to F3) defined as any one of the following: − Liver biopsy within 24 months of Day 1 showing absence of cirrhosis − Fibroscan® within 12 months of Day 1 with a result of ≤ 12.5 kPa − Fibrosure® (Fibrotest®) performed during screening with a score of ≤ 0.48 and an aspartate aminotransferase (AST)-to-platelet ratio index (APRI) of ≤ 1 -Compensated cirrhosis (F4) defined as any one of the following: − Liver biopsy performed prior to Day 1 showing cirrhosis (Metavir stage 4 or equivalent) − Fibroscan® within 12 months of Day 1 showing cirrhosis with result > 12.5 kPa − Fibrosure® (Fibrotest®) performed during screening with a score of > 0.75 and an APRI of > 2 APRI formula: AST ÷ lab upper limit of normal (ULN) for AST × 100 ÷ (platelet count ÷ 100). NOTE: In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy or Fibroscan® is required. Liver biopsy results supersede the results obtained by Fibroscan® or Fibrosure®.
- •Subject is, in the opinion of the investigator, willing and able to comply with the study drug regimen and all other study requirements.
排除标准
- •Female subject is pregnant or breastfeeding -Co-infected with hepatitis B virus (HBV; positive for hepatitis B surface antigen [HBsAg]) and/or human immunodeficiency virus (HIV) -Abuse of alcohol and/or illicit drug use that could interfere with adherence to study requirements as judged by the investigator -Prior exposure to any HCV DAA -Requirement of any prohibited medications, as described in Section 5.8 -Use of other investigational drugs within 30 days of dosing or plans to enroll in another clinical trial of an investigational agent while participating in the present study -Subject with known allergy to the study medications or any of their components -History or signs of decompensated liver disease: ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, or other clinical signs of portal hypertension or hepatic insufficiency.
- •Cirrhotic and has a Child-Pugh score >6, corresponding to a Child-Pugh Class B or C Note: To calculate the Child-Pugh score, refer to the following website: https://www.mdcalc.com/calc/340/child-pugh-score-cirrhosis-mortality -History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC -Active clinically significant diseases including: -Evidence of history of chronic hepatitis not caused by HCV, including drug-induced hepatitis, hemochromatosis, Wilson’s disease, alpha-1-antitrypsin deficiency, alcoholic liver disease, and autoimmune hepatitis -Cardiac abnormalities/dysfunction that may interfere with subject treatment, assessment, or compliance with the protocol, including unstable angina, unstable congestive heart failure, and unstable arrhythmia -Malignant disease or suspicion or history of malignant disease within previous 5 years (except for adequately treated basal or basosquamous cell carcinoma) -Any medical condition requiring chronic use of systemic corticosteroids or other immunosuppressive drugs (e.g., for organ transplantation or autoimmune conditions). Note: Topical or inhaled corticosteroids are permitted. -Subject with intestinal malabsorption (e.g., structural defects, digestive failure, or enzyme deficiencies, with the exception of lactose intolerance) -Any other clinically significant medical condition that, in the opinion of the investigator, would jeopardize the safety of the subject or impact the validity of the study results.
- •Clinically significant abnormal ECG at Screening, as determined by the investigator.
- •Any of the following laboratory parameters at Screening: -Alanine aminotransferase (ALT) or AST > 10 x ULN -Total bilirubin > 3 mg/dL (> 51.3 μmol/L) -Albumin < 2.8 g/dL (< 28 g/L) -International Normalized Ratio (INR) > 2.2 unless subject has a stable INR on an anticoagulant -Hemoglobin < 10 g/dL -Hemoglobin A1c (HbA1c) > 8.5% -Platelet count < 50 x 109/L -Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 as estimated by the Modification of Diet in Renal Disease (MDRD) formula Note: Retests of Screening laboratory parameters or assessments may be permitted once in certain scenarios with medical monitor approval. Such scenarios may include lab processing error, results inconsistent with subject’s historical values/medical history, or other extenuating circumstances such as a recent or intercurrent illness potentially affecting Screening laboratory results.
结局指标
主要结局
- To evaluate the safety and tolerability of BEM + RZR
时间窗: The primary efficacy endpoint is SVR12.
-To evaluate the efficacy of BEM + RZR as assessed by the proportion of subjects achieving SVR12
时间窗: The primary efficacy endpoint is SVR12.
次要结局
- NA(NA)