Ensayos clínicos

Inclusion Criteria:

• Male and female subjects aged between 18 to 75 years.
• Ability to understand and sign a written informed consent form (ICF).
• Histological evidence of NASH based on central reading of the Screening biopsy slides.
  • Historical biopsy may be substituted for Screening period biopsy to determine eligibility if the following are met:
    • Historical biopsy was obtained no more than 6 months prior to the first day of screening;
    • Hepatic tissue is available for central histologic evaluation;
    • No new therapeutic intervention for NASH was made during the 6-month period (eg, obeticholic acid, vitamin E > 400 IU/day, pioglitazone, liraglutide, loss of ≥ 7% of body weight, bariatric surgery including gastric banding, investigational NASH agents);
    • Subjects must have been metabolically stable since the biopsy (no significant weight loss [≥ 7% of body weight], no major deterioration of glycemic control, and no introduction of new or investigational drugs for the treatment of T2DM).
• Subjects included in Part1 must have histopathological evidence of Stage 2 or 3 liver fibrosis per the NASH CRN System based on central reading of the Screening biopsy slides. Subjects newly randomized in Part 2 must have histological evidence of Stage 3 liver fibrosis per the NASH CRN System, based on central reading of the Screening period biopsy slides. Historical biopsy can be used, provided the criteria listed on Item 3a above are fulfilled.
• Females of childbearing potential and males participating in the study must agree to use at least 2 approved methods of contraception throughout the duration of the study and for 30 days after stopping study drug. Females who are  postmenopausal must have documentation of cessation of menses for ≥ 12 months without an alternative medical cause. Follicle-stimulating hormone (FSH) level in the postmenopausal range (≥ 30 mU/mL at Screening) may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
  • Females on HRT and whose menopausal status is in doubt will be required to use the contraception methods in Appendix 20.3 if they wish to continue their HRT during the study. Otherwise, they must temporarily discontinue HRT to enable confirmation of postmenopausal status before study enrollment.

Exclusion Criteria:

A subject will not be eligible for participation in Part 1 and/or Part 2 of this study if any of the following criteria apply:

• Inability to undergo a liver biopsy.
• Hepatitis B surface antigen (HBsAg) positive.
• Hepatitis C antibody (HCVAb) positive with the following 2 exceptions:
  • Subjects previously treated for viral hepatitis C with at least a 3-year period since documented sustained virologic response at Week 12 (post-treatment) may be eligible if all other eligibility criteria are met;
  • Subjects with presence of hepatitis C antibody but negative hepatitis C virus (HCV) ribonucleic acid (RNA) without treatment (i.e., spontaneous clearance) may be eligible if all other eligibility criteria are met.
• Human immunodeficiency virus (HIV)-1 or HIV-2 infection.
• Prior or planned liver transplantation.
• Other known causes of chronic liver disease, such as the following:
  • Alcoholic liver disease;
  • Primary biliary cholangitis;
  • Primary sclerosing cholangitis;
  • Autoimmune hepatitis;
  • Wilson's disease, hemochromatosis, or iron overload;
  • Alpha-1-antitrypsin (A1AT) deficiency.
• History or presence of cirrhosis (NASH CRN Fibrosis Stage 4) and/or hepatic decompensation including ascites, hepatic encephalopathy, or variceal bleeding.
• Alcohol consumption greater than 21 units/week for males or 14 units/week for females (one unit of alcohol is half pint of beer [285 mL; 9.64 oz], 1 glass of spirits [25 mL; 0.85 oz] or 1 glass of wine [125 mL; 4.23 oz]).
• AST > 5 × ULN at Screening.
• ALT > 5 × ULN at Screening.
• HbA1c > 9% at Screening.
• Serum albumin < 3.5 g/dL at Screening.
• Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m^2 according to the Modification of Diet in Renal Disease (MDRD) equation at Screening.
• Platelet count < 100,000/mm^3 at Screening.
• Total bilirubin > 1.3 mg/dL at Screening (subjects with hyperbilirubinemia associated with documented Gilbert’s syndrome may be eligible upon review by the medical monitor)
• International normalized ratio (INR) > 1.3 at Screening.
• Model of end stage liver disease (MELD) score > 12.
• Weight reduction, defined as ≥ 7% of body weight, through bariatric surgery in the past 5 years or bariatric surgery planned during the conduct of the study (including gastric banding and sleeve surgery).
• Known history of HCC at any time, history of malignancy within the past 5 years or ongoing malignancy other than: basal cell carcinoma, resected noninvasive cutaneous squamous cell carcinoma, or treated stage II or lower colorectal or breast cancer in remission for ≥ 2 years and with documented low risk of recurrence (including but not limited to Oncotype DX 12 gene recurrence score < 30 for stage II or lower colon cancer; early-stage, estrogen-receptor-positive, HER2-negative breast cancers that have not spread to the lymph nodes; Oncotype DX 21 gene recurrence score < 18 for early-stage invasive breast cancer; or Oncotype DX ductal carcinoma in situ [DCIS] 12 gene recurrence score < 39 for noninvasive breast cancer).
• Active, serious infections that require parenteral therapy (antibiotic or antifungal) within 30 days prior to Screening visit.
• Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, including but not limited to myocardial infarct, acute coronary syndrome, revascularization (percutaneous coronary intervention or coronary artery bypass
• grafting), ischemic stroke, or implanted defibrillator or pacemaker.
• Females who are pregnant or breastfeeding.
• Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and immunomodulating agents (eg, interleukins, interferons, cyclosporine, tacrolimus) except for vaccines or short-term corticosteroids.
• Receiving a glucagon-like peptide 1 (GLP-1) receptor agonist, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a sodium–glucose cotransporter 2 (SGLT2) and/or SGLT1 inhibitor, or a thiazolidinedione (TZD) for less than 6 months prior to the Screening period liver biopsy. Subjects on a stable therapy with a GLP-1 receptor agonist, DPP-4 inhibitor, SGLT1 and/or SGLT2 inhibitor, or a TZD for at least 6 months prior to the Screening liver biopsy may be considered eligible.
  • Important Note: if a historical biopsy is to be used, subjects need to be on stable therapy for at least 6 months prior to the day historical liver biopsy was performed.
• Receiving ongoing therapy with any disallowed medication during the conduct of the study. Disallowed medication in use prior to enrollment will require to be discontinued. For medications that are disallowed due to significant drug interactions with CVC, a washout period of 14 days or 5 half-lives, whichever is longer, must be observed prior to Baseline. For medications that are disallowed due to potential confounding effect on efficacy, a washout period of at least 6 months must be observed prior to the Screening liver biopsy.
  • Note: subjects receiving allowed concomitant medications need to be on stable therapy for at least 30 days prior to the Baseline visit.
• Allergy to the study drug or its components.
• Receiving any investigational products within 30 days prior to Screening or anticipated use during the trial.
• Receiving any investigational product being evaluated for the treatment of liver fibrosis or NASH in the 6 months prior to the Screening liver biopsy (subjects documented to be assigned to placebo in such trials may be eligible immediately following completion of their participation in the previous trial).
• Participation in any other clinical trial at Screening without approval from the sponsor.
• Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the dosing and protocol requirements.