E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Liver fibrosis in Subjects with Nonalcoholic Steatohepatitis |
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E.1.1.1 | Medical condition in easily understood language |
Fatty Liver where the cells in the liver have abnormal fat built-up and built-up of scar tissue in the liver. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objective (Part 1):
•Demonstrate the superiority of CVC compared to placebo on liver histology at Month 12 relative to the Screening biopsy, in adult
subjects with a liver biopsy diagnosis of NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system) as confirmed by an independent central
pathologist
Primary Objective (Part 2):
•Demonstrate the superiority of CVC compared to placebo on the composite endpoint of histopathologic progression to cirrhosis, (defined
by NASH CRN Fibrosis Stage 4) liver-related clinical outcomes, and all-cause mortality, as measured by the time to first occurrence of any of the listed adjudicated events (clinical outcomes composite endpoint) – (all subjects)
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E.2.2 | Secondary objectives of the trial |
Part 1:
Evaluate the effect of CVC compared to placebo on liver histology at Month 12 relative to the screening biopsy for the proportion of subjects with improvement in fibrosis of at least 2 stages (NASH CRN system) AND no worsening of steatohepatitis
Part 1 and 2:Evaluate the effect of CVC compared to placebo on liver histology relative to the Screening biopsy for the proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN system), regardless of effect on steatohepatitis.
Part 1 and 2:Evaluate the safety and tolerability of CVC for the treatment of liver fibrosis in adult subjects with NASH.
Part 2:Evaluate the effect of CVC compared to placebo on liver histology relative to the Screening biopsy for the proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN system), AND no worsening of steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning grade). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Pharmacogenetic testing
The goal of this research is to find variations in DNA that will help identify persons with Liver Fibrosis with Nonalcoholic Steatohepatitis that will have the best response with CVC or to identify persons who will have fewer side effects in order to maximize their benefit from CVC. |
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E.3 | Principal inclusion criteria |
1. Male and female subjects aged between 18-75 years
2. Ability to understand and sign a written informed consent form (ICF)
3. Histological evidence of NASH based on central reading of the liver biopsy slides
4. 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 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.
5. 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. |
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E.4 | Principal exclusion criteria |
1. Inability to undergo a liver biopsy safety
2. Hepatitis B surface antigen (HBsAg) positive
3. Hepatitis C antibody (HCVAb) positive
4. Human immunodeficiency virus (HIV)-1 or HIV-2 infection
5. Prior or planned liver transplantation
6. Other known causes of chronic liver disease
7. History or presence of cirrhosis (NASH CRN Fibrosis Stage 4) and/or hepatic decompensation
including ascites, hepatic encephalopathy or variceal bleeding
8. Alcohol consumption greater than 21 units/week for males or 14
units/week for females
9. AST > 5 × upper limit of normal (ULN) at Screening
10. ALT > 5 × ULN at Screening
11. HbA1c > 9% at Screening
12. Serum albumin < 3.5 g/dL
13. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 at Screening
according to the Modification of Diet in Renal Disease (MDRD) equation
14. Platelet count < 100,000/mm3 at Screening
15. Total bilirubin > 1.3 mg/dL (subjects with hyperbilirubinemia
associated with documented Gilbert's syndrome may be eligible upon
review by the medical monitor) at Screening
16. International normalized ratio (INR) > 1.3 at Screening
17. Model of end stage liver disease (MELD) score > 12
18. 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)
19. Known history of hepatocellular carcinoma (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 (included but no limited to Oncotype DX
12 gene recurrence score <30 for stage II or lower colon cancer; earlystage,
estrogen-receptor-positive, HER2-negative breast cancers that
have not spread to the lymph nodes; Oncotype DX 21 gene recurrence
score <18 for earlystage invasive breast cancer; or Oncotype DX ductal
carcinoma in situ [DCIS] 12 gene recurrence score <39 for noninvasive
breast cancer)
20. Active, serious infections that require parenteral therapy (antibiotic or
antifungal) within 30 days prior to Screening Visit
21. Clinically significant cardiovascular or cerebrovascular disease within
the past 3 months
22. Females who are pregnant or breastfeeding
chemotherapeutic agents and immunomodulating agents (such as
systemic corticosteroids, interleukins, interferons)
23. Current or anticipated treatment with radiation therapy, cytotoxic
chemotherapeutic agents and immune-modulating agents (such as
systemic corticosteroids, interleukins and interferons)
24. 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 of stable therapy prior to the liver biopsy at 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).
25. Receiving ongoing therapy with any disallowed medication during the conduct of the study. Disallowed medication in use prior to enrollment will be required 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, except for medications listed in exclusion criterion 24.)
26. Allergy to the study drug or its components
27. Receiving any investigational products within 30 days prior to
Screening or anticipated use during the study
28. 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 study)
29. Participation in any other clinical study at Screening without approval
from the sponsor
30. 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1): Proportion of subjects with improvement in fibrosis by 2 stages
(NASH CRN system) AND no
worsening of steatohepatitis (no worsening of lobular inflammation or
hepatocellular ballooning grade)
(Part 2): Time to first occurrence of any of the following adjudicated
events:
Death (all cause), Histopathologic progression to cirrhosis (defined by
NASH CRN Fibrosis Stage 4),
Hepatocellular carcinoma, Liver transplant, MELD score ≥15, Ascites
(requiring intervention, ie, large volume paracentesis ≥ 1L or initiation
of a diuretic), Hospitalization (as defined by a stay of ≥ 24 hours) for
onset of: variceal bleed, hepatic encephalopathy (defined by a West
Haven Stage of ≥2), spontaneous bacterial peritonitis (confirmed by
diagnostic paracentesis with positive ascitic fluid bacterial culture) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: Month 12
Part 2: Duration of study |
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E.5.2 | Secondary end point(s) |
Parts 1 and 2:
Proportion of subjects with improvement in fibrosis by at least 2 stages(NASH CRN system) AND no worsening of steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning grade) on liver
histology at Month 12 relative to the screening biopsy.
Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN system), regardless of effect on steatohepatitis, relative to the Screening biopsy.
Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN system), regardless of effect on steatohepatitis, at Month 12 relative to the screening biopsy.
Part 2: Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN system) AND no worsening of steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning grade) on liver biopsy relative to the Screening biopsy |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 155 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
France |
Germany |
Greece |
Hong Kong |
Hungary |
India |
Israel |
Italy |
Mauritius |
Mexico |
New Zealand |
Norway |
Peru |
Poland |
Portugal |
Puerto Rico |
Romania |
Russian Federation |
Singapore |
Slovenia |
Spain |
Switzerland |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The primary analysis of Part 1 will occur when approximately 1200 randomized subjects have been followed for at least 12 months. The primary analysis for Part 2 will occur when adjudicated events have been accrued in approximately 367 unique subjects across Part 1 and Part 2.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |