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] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.1 |
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 |
To evaluate whether the combination of SEMA with CILO/FIR causes fibrosis improvement and NASH resolution in subjects with compensated cirrhosis due to NASH |
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E.2.2 | Secondary objectives of the trial |
- To confirm the contribution of SEMA to NASH resolution in subjects treated with the combination of SEMA and CILO/FIR by comparing with subjects treated with CILO/FIR alone - To confirm the contribution of CILO/FIR to fibrosis improvement in subjects treated with the combination of SEMA and CILO/FIR by comparing with subjects treated with SEMA alone |
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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 Genomic Sample Collection Additional samples will be obtained from subjects who agree to participate and provide their additional specific consent. These samples should be collected at the Day 1, Week 48, Week 72, and ET (if applicable) visits. The specimens collected for optional future genomic research may be used to advance the development of the drug and/or increase our knowledge and understanding of the biology of the disease under investigation or related diseases. These specimens may also be used to study the association of biomarkers with biological pathways, disease pathogenesis, progression, and/or treatment outcomes, including efficacy, AEs, and the processes of drug absorption and disposition. In addition, these specimens may be used to develop biomarker and/or diagnostic assays and establish the performance characteristics of these assays. |
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E.3 | Principal inclusion criteria |
1)Men and women between 18 and 80 years of age, inclusive, based on the date of the screening visit 2)Willing and able to give informed consent prior to any study-specific procedures being performed 3)Cirrhosis (F4) due to NASH as defined in the protocol 4)The following laboratory parameters at screening, as determined by the central laboratory: a)Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2, as calculated by the Modification of Diet in Renal Disease (MDRD) equation to estimate creatinine clearance (CLcr) b)HbA1c ≤ 10% (or serum fructosamine ≤ 400 umol/L if HbA1c is not quantifiable) c)Hemoglobin > 10.6 g/dL d)INR ≤ 1.4, unless due to therapeutic anticoagulation e)Total bilirubin ≤ 1.3 x ULN (unless due to an alternative etiology such as Gilbert’s syndrome or hemolytic anemia) f)Serum albumin ≥ 3.5 g/dL g)Serum ALP ≤ 2 x ULN h)Platelet count ≥ 125,000/uL i)Serum triglyceride level ≤ 250mg/dL. If initial screening value is >250 mg/dL, triglycerides may be retested during the screening period. Fasting serum triglycerides must be confirmed to be ≤ 250 mg/dL prior to Day 1. Management of hypertriglyceridemia may be initiated or modified at investigator discretion during the screening period (Section 7.7.4.1). j)ALT < 5 x ULN 5)BMI ≥ 23 kg/m2 at screening |
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E.4 | Principal exclusion criteria |
1)Any history of decompensated liver disease in the opinion of the investigator, including clinically relevant ascites, hepatic encephalopathy (HE), or variceal bleeding 2)Child-Pugh (CP) score > 6 at screening, unless due to an alternative etiology such as Gilbert’s syndrome or therapeutic anticoagulation 3)Model for End-stage Liver Disease (MELD) score >12 at screening, unless due to an alternative etiology such as therapeutic anticoagulation 4)Chronic HBV infection (HBsAg positive) 5)Chronic HCV infection (HCV antibody and HCV RNA positive). Subjects cured of HCV infection less than 2 years prior to the screening visit are not eligible. 6)Other causes of liver disease based on medical history and/or central pathologist review of liver histology, including but not limited to: alcoholic liver disease, autoimmune disorders (eg, PBC, PSC, autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency 7)History of liver transplantation 8)Current or prior history of HCC 9)HIV infection 10)Weight loss >10% within 180 days of screening, or >5% between the date of the biopsy used for eligibility and the date of screening 11)Any weight reduction surgery or procedure in the 2 years prior to screening or malabsorptive weight loss surgery (eg, Roux-en-Y or distal gastric bypass) at any time prior to screening 12)History of intestinal resection that could result in malabsorption of study drug 13)Planned coronary, carotid, or peripheral artery intervention or unstable cardiovascular disease in the opinion of the investigator 14)History of uncontrolled chronic pulmonary disease in the opinion of the investigator within 180 days prior to screening 15)Men who habitually drink greater than 21 units/week of alcohol or women who habitually drink greater than 14 units/week of alcohol 16)Positive urine drug screen for amphetamines, cocaine, or opiates at screening, unless due to a prescription medication 17)Use of any prohibited concomitant medication prior to enrollment 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 the date of screening and through the end of the study. Participation in a study of an investigational device may be approved by the medical monitor or designee. 19)History of malignancy within 5 years of screening with the following exceptions: a)Adequately treated carcinoma in situ of the cervix b)Adequately treated basal or squamous cell cancer or other localized nonmelanoma skin cancer 20)For subjects with type 2 diabetes diagnosed prior to the date of the screening visit OR based on screening visit results (HbA1c ≥ 6.5% or fasting plasma glucose ≥ 126 mg/dL, confirmed on repeat testing), subjects must have no evidence of uncontrolled and potentially unstable retinopathy or maculopathy as determined by a fundoscopic examination performed starting 90 days prior to screening visit date through Day 1. If there has been worsening of the subject’s visual function since a historical fundoscopic examination in the opinion of the investigator, then the fundoscopic examination must be repeated prior to Day 1 for eligibility. Pharmacological pupil dilation is a requirement unless using a digital fundus photography camera specified for nondilated examination. 21)Acute pancreatitis within 180 days prior to screening 22)History or presence of chronic pancreatitis 23)History of symptomatic gallbladder or biliary tract disease in the opinion of the investigator within 6 months prior to screening, unless a cholecystectomy has been performed 24)Presence or history of type 1 diabetes 25)Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullar thyroid carcinoma 26)Treatment with GLP-1 RAs (including SEMA) in the period from 90 days prior to the screening visit and from 90 days prior to the date of the historical qualifying liver biopsy (if applicable) 27)Female who is pregnant, breastfeeding, intends to become pregnant, or is of childbearing potential and not using an adequate contraceptive method 28)Men who engage in heterosexual intercourse not using an adequate method of contraception 29)Presence of any laboratory abnormality or condition that, in the opinion of the investigator, could interfere with or compromise a subject’s treatment, assessment, or compliance with the protocol and/or study procedures. This includes a history of substance abuse and/or psychiatric condition requiring hospitalization and/or emergency room visit within 2 years of screening 30)Known hypersensitivity to the study drug(s), metabolites, or formulation excipient(s) 31)For subjects who have not completed a series of an authorized COVID-19 vaccination regimen prior to screening, a positive result for COVID-19 on SARS-CoV-2 RT-PCR test |
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E.5 End points |
E.5.1 | Primary end point(s) |
The coprimary endpoints are as follows; - ≥ 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) at Week 72 in the SEMA+CILO/FIR versus placebo groups - NASH resolution (defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0) at Week 72 in the SEMA+CILO/FIR versus placebo groups |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline / Day 1 and week 72 |
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E.5.2 | Secondary end point(s) |
- NASH resolution at Week 72 in subjects treated with SEMA+CILO/FIR versus CILO/FIR alone - ≥1-stage improvement in fibrosis without worsening of NASH at Week 72 in subjects treated with SEMA+CILO/FIR versus SEMA alone |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline / Day 1 and week 72 |
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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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
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 | 4 |
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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Canada |
Japan |
United States |
France |
Spain |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 23 |