E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonalcoholic Steatohepatitis (NASH) |
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E.1.1.1 | Medical condition in easily understood language |
Inflammation of the liver |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
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 |
The primary objective of this study is: To evaluate whether SEL can cause fibrosis regression and reduce associated complications in subjects with cirrhosis due to NASH. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is: To assess the safety and tolerability of SEL in subjects with NASH and cirrhosis |
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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 PK Substudy
Subjects may choose to participate in an optional PK substudy. Approximately 45 subjects will participate in the PK optional substudy in the Randomized Phase only. For subjects who agree to participate and provide their consent, one set of PK sampling will be performed between Week 4 and Week 48 (inclusive).
Optional Genomic Testing
Subjects may choose to participate in genomic testing. From subjects who agree to participate and provide consent, optional blood samples will be collected at the Day 1 visit and at Weeks 48, 96, 144, 192 and 240 for genomic testing, including DNA methylation. |
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E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this
study.
1) Willing and able to give informed consent prior to any study specific procedures being performed.
2) Liver biopsy consistent with NASH (defined as the presence of at least grade 1 steatosis, hepatocellular ballooning, and lobular inflammation according to the NAFLD Activity Score [NAS]) and cirrhosis (F4 fibrosis) according to the NASH CRN classification, in the opinion of the central reader.
3) Subject has the laboratory parameters at the Screening visit, as determined by the central laboratory.
4) Body Mass Index (BMI) ≥ 18 kg/m2 at Screening.
5) Males and non-pregnant, non-lactating females between 18-70 years of age; inclusive based on the date of the Screening visit.
6) Females of childbearing potential must have a negative pregnancy test at Screening and Day 1.
7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Prior history of decompensated liver disease, including clinical ascites, HE, or variceal bleeding
2) CP score > 7, as determined at Screening, unless due to therapeutic anti-coagulation.
3) MELD score > 12, as determined at Screening, unless due to therapeutic anti-coagulation.
4) Chronic HBV infection (HBsAg positive),
5) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection less than 5 years prior to the Screening visit are not eligible.
6) Other causes of liver disease including, but not limited to, alcoholic liver disease, hepatitis-B, hepatitis C, autoimmune disorders (e.g., primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, iron overload, and alpha-1-antitryspin deficiency, based on medical history and/or centralized review of liver histology.
7) History of liver transplantation.
8) Current or history of HCC.
9) Any weight reduction surgery in the 2 years prior to Screening or planned during the study (weight reduction surgery is disallowed during the study), and malabsorptive weight loss surgery (e.g., Roux-en-Y or distal gastric bypass) at any time prior to Screening.
10) Weight loss > 10% within 6 months of Screening.
11) HIV infection (HIV Ab and HIV ribonucleic acid [HIV RNA] positive).
12) Current alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 1 oz/30 mL measure of 40 proof alcohol).
13) Positive urine drug screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at
Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening may be included in the study. Subjects with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator.
14) Unstable cardiovascular disease.
15) Use of any prohibited concomitant medication as described in Section 5.4. Subjects on Vitamin E must be on a stable dose for at least 6 months prior to the diagnostic liver biopsy and subjects on antidiabetic medications must be on a stable dose for at least 3 months prior to diagnostic liver biopsy.
16) History of a malignancy within 5 years of Screening.
17) Unable to safely undergo a liver biopsy.
18) Participation in another investigational study of a drug or device within 30 days or within 5 half-lives of the prior investigational agent (whichever is longer) prior to Screening.
19) Concurrent participation in another therapeutic clinical study.
20) Known hypersensitivity to SEL, the metabolites, or formulation excipient.
21) Any laboratory abnormality or condition that, in the investigator’s opinion, could adversely affect the safety of the subject or impair the assessment of study results.
22) Presence of any condition that could, in the opinion of the investigator, compromise the subject’s ability to participate in the study, including a history of substance abuse or a psychiatric condition requiring hospitalization or emergency room visit within 2 years of Screening.
23) Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
The primary efficacy endpoint at Week 48 includes the proportion of subjects who achieve a ≥ 1-stage improvement in fibrosis (according to the NASH CRN classification) without worsening of NASH (defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation).
Clinical Efficacy Endpoint
The clinical efficacy endpoint at Week 240 is EFS. EFS will be assessed by time to the first clinical event including liver decompensation events, liver transplantation, or all cause mortality. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After the Screening period and a randomization visit at Day 1, study visits will occur on Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 and every 12 weeks thereafter until Week 240 with a Follow-Up visit and a Telephone Follow-Up visit. At minimum, review of AEs and concomitant medications and safety laboratory tests will be performed at every visit. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are as follows:
a) Proportion of subjects who have a ≥ 1-stage improvement in fibrosis without worsening of NASH at Week 240;
b) Proportion of subjects who have a ≥ 1-stage improvement in fibrosis at Week 48 and Week 240;
c) Proportion of subjects who have NASH resolution at Week 48 and Week 240. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After the Screening period and a randomization visit at Day 1, study visits will occur on Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 and every 12 weeks thereafter until Week 240 with a Follow-Up visit and a Telephone Follow-Up visit. At minimum, review of AEs and concomitant medications and safety laboratory tests will be performed at every visit. |
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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 | No |
E.6.11 | Pharmacogenomic | Yes |
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 | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 |
Australia |
Austria |
Belgium |
Canada |
France |
Germany |
Hong Kong |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
New Zealand |
Poland |
Singapore |
Spain |
Switzerland |
Taiwan |
Turkey |
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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last subject's last observation (or visit). |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 8 |