E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
E.1.1.1 | Medical condition in easily understood language |
Nonalcoholic Steatohepatitis (NASH) |
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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 |
1. To evaluate the effect of each dose of MK-3655 versus placebo on the proportion of individuals with nonalcoholic steatohepatitis (NASH) resolution without worsening of fibrosis after 52 weeks. 2. To evaluate the safety and tolerability of MK-3655 compared with placebo. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of each dose of MK-3655 versus placebo on mean percent relative reduction from baseline in liver fat content (LFC) after 24 weeks. 2. To evaluate the effect of each dose of MK-3655 versus placebo on the proportion of individuals with ≥1 stage improvement in fibrosis without worsening of steatohepatitis after 52 weeks. 3. To evaluate the effect of each dose of MK-3655 versus placebo on the proportion of individuals with ≥2 point improvement in the Nonalcoholic Fatty Liver Disease Activity Score (NAS) without worsening of fibrosis after 52 weeks.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has histological confirmation of NASH based on a liver biopsy obtained ≤6 months before Visit 1/Screening. If no acceptable biopsy performed ≤6 months before Visit 1/Screening is available, a liver biopsy will be performed at Visit 3/Liver Biopsy. Histological criteria for study entry include: - NAS ≥4 with a score ≥1 point in each component (steatosis, ballooning, and lobular inflammation), AND - NASH CRN fibrosis score of Stage 2 or 3. 2. Has an MRI-PDFF ≥8% as assessed at Visit 2/MRI-PDFF. 3. Has a baseline MELD-Na score ≤12 at Visit 1/Screening. 4. Is a male or female aged 18 years to 80 years (in Japan and Taiwan, aged 20 to 80 years), at the time of signing the ICF. 5. Has a BMI ≥25 kg/m2 and ≤50 kg/m2 at the time of Visit 1/Screening. 6. Has stable weight (based on self-reporting) defined as ≤5% gain or loss of body weight for at least 3 months before Visit 1/Screening. 7. Meets one of the following criteria: - Has no history of T2DM. OR - Has a history of T2DM with an A1C ≤9.5% at Visit 1/Screening and controlled by diet or stable doses of AHAs. 8. Has a systolic blood pressure of ≤160 mm Hg and a diastolic blood pressure ≤90 mm Hg (after at least a 10-minute seated rest) based on the mean of 3 measurements at Visit 1/Screening OR blood pressure is considered likely to be below these limits by Visit 5/Randomization (Day 1) with initiation or adjustment of antihypertensive medication. 9. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests,and/or other study procedures. 10. Contraceptive use by male participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a WOCBP OR Is a WOCBP and: - Uses a contraceptive method that is highly effective. - Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. - Abstains from breastfeeding during the study intervention period and for at least 16 weeks after the last dose of study intervention. -Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy. 12. The participant (or legally acceptable representative, if applicable) has provided documented informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the main study without participating in FBR.
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E.4 | Principal exclusion criteria |
1. Has presence of cirrhosis on liver biopsy. 2. Has Type 1 diabetes. 3. Has a history of malignancy, unless cancer free ≥5 years, or is under evaluation for active or suspected malignancy before signing the ICF except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. 4. Has a history of bariatric surgery ≤5 years before Visit 1/Screening. 5. Has undergone a major surgical procedure ≤3 months before signing the ICF or has major surgery planned during the study. 6. Has a history or evidence of: - Chronic liver disease other than NASH - Hepatitis B as defined by the presence of HBsAg - Hepatitis C as defined by the presence of HCV RNA or positive Hepatitis C antibody (anti-HCV); participants with a history of HCV infection may be included if HCV PCR is negative ≥3 years - Drug-induced liver disease - Ongoing autoimmune liver disease - Decompensated liver disease - HIV - Primary biliary cirrhosis (cholangitis) - Primary sclerosing cholangitis - Reye Syndrome - Splenomegaly - Wilson’s disease - Documented Cushing disease, Cushing syndrome, or any condition associated with hypercortisolism - Hyperthyroidism, and is currently being treated. - Hypothyroidism, and is on thyroid hormone replacement therapy that has not been at a stable dose for at least 12 weeks prior to Visit 1/Screening. - Alpha-1-antitrypsin deficiency - Hemochromatosis or iron overload - Spontaneous bacterial peritonitis - Known bile duct obstruction - Hepatocellular carcinoma - Untreated obstructive sleep apnea - Hemostasis disorder - Hematological disorder 7. Has significant systemic or major illnesses other than liver disease, including recent events (≤6 months before Visit 1/Screening) of congestive heart failure, unstable coronary artery disease, arterial revascularization, pulmonary disease, renal failure, stroke, transient ischemic attack, or organ transplantation. 8. Has a known hypersensitivity to any of the ingredients or excipients of the IMP. 9. Has experienced any bone trauma, fracture, or bone surgery ≤2 months before Visit 1/Screening. 10. Has a history of osteoporosis or an indication that requires treatment with a bone-active pharmacological agent in the classes listed in exclusion criterion #18 at Visit 1/Screening. 11. Has current or history of significant alcohol consumption for a period of more than 3 consecutive months ≤24 months before Visit 1/Screening. 12. Has an inability to reliably quantify alcohol consumption. 13. Has a recent history of drug abuse (defined as ≤3 years) or is a current user of recreational or illicit drugs at the time of Visit 1/Screening. 14. Has a known psychiatric or any other cognitive disorder per the opinion of the investigator, that would interfere with the participant’s ability to cooperate with the requirements of the study. 15. Is at imminent risk of self-harm, based on clinical interview and responses on the C-SSRS, or of harm to others in the opinion of the investigator. 16. Has a total score >12 on the PHQ-9. 17. Is on treatment with or has been treated with the following agents: Within ≤12 months before Visit 1/Screening: -Thiazolidinediones (ie, pioglitazone, rosiglitazone) -Investigational agents as defined in the protocol Within ≤6 months before Visit 1/Screening: -L-ornithine L-aspartate -Investigational agents as defined in the protocol 18. Is on treatment with or has used bone-active agents in the classes listed in the protocol ≤24 months before Visit 1/Screening. 19. Is on treatment with or has used drugs associated with NAFLD ≤6 months before Visit 1/Screening 20. Is on treatment or likely to require treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids. 21. Is on treatment with anticoagulants. 22. Is on treatment with an AHA or other medications indicated in the protocol. 23. Is currently participating in or has participated in an interventional clinical study with an investigational compound or device ≤3 months before participating in this current study. 24. Has exclusionary laboratory values. 25. Has poor venous access that precludes routine peripheral blood sampling required for this study. 26. Has received blood products ≤2 months before Visit 1/Screening and/or donated blood products ≤1 month before Visit 1/Screening. 27. Has a clinically significant ECG abnormality that requires further diagnostic evaluation or intervention. 28. Has claustrophobia to a degree that prevents tolerance of MRI scanning procedure. 29. Has a metallic implant of any sort that prevents MRI examination, or any other contraindication to MRI examination. 30. In the opinion of the investigator, the participant has any other condition which would impede competence or compliance or possibly hinder completion of the study. 31. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Percentage of participants with NASH resolution without worsening fibrosis assessed with the NASH Clinical Research Network (CRN) scoring system (evaluated by blinded independent central review [BICR]) after 52 weeks 2. Percentage of participants with adverse events (AEs) up to 56 weeks 3. Percentage of participants discontinuing study intervention due to adverse events (AEs) up to 52 weeks
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. At 52 weeks 2. Up to 56 weeks 3. Up to 52 weeks
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E.5.2 | Secondary end point(s) |
1. Change from baseline in liver fat content (LFC) (%) measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF) (evaluated by BICR) after 24 weeks 2. Percentage of participants with ≥1 stage improvement in fibrosis without worsening of steatohepatitis assessed with the NASH CRN scoring system (evaluated by BICR) after 52 weeks 3. Percentage of participants with ≥2 point improvement (PI) in the Nonalcoholic Fatty Liver Disease Activity Score (NAS) with ≥1 PI in inflammation/ballooning without worsening fibrosis by NASH CRN scoring system (evaluated by BICR) after 52 weeks
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline and 24 Weeks 2. At 52 weeks 3. At 52 weeks
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | 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 | 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 | 2 |
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 |
Argentina |
Australia |
Canada |
Chile |
China |
Colombia |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
New Zealand |
Puerto Rico |
Taiwan |
United States |
France |
Sweden |
Spain |
Germany |
Greece |
Italy |
Russian Federation |
Turkey |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 9 |