| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BIOPSY-CONFIRMED NONALCOHOLIC STEATOHEPATITIS WITH FIBROSIS STAGE 2 OR 3 |
|
| E.1.1.1 | Medical condition in easily understood language |
| NONALCOHOLIC STEATOHEPATITIS (NASH) |
|
| 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 | 27.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019668 |
| E.1.2 | Term | Hepatic fibrosis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| 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 the effect of a range of DGAT2i doses administered alone, and coadministration of DGAT2i + ACCi, compared to placebo, and the coadministration of DGAT2i + ACCi relative to DGAT2i alone, in participants with biopsy confirmed NASH and fibrosis, on resolution of NASH without worsening of fibrosis or improvement in fibrosis by ≥1 stage without worsening of NASH, or both |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of a range of DGAT2i doses administered alone, and coadministration of DGAT2i + ACCi, compared to placebo, and the coadministration of DGAT2i + ACCi relative to DGAT2i alone, on liver fat.
2. To evaluate the effect of a range of DGAT2i doses administered alone, and coadministration of DGAT2i + ACCi, compared to placebo, and the coadministration of DGAT2i + ACCi relative to DGAT2i alone, in participants achieving improvement in different responder definitions.
3. To assess the safety and tolerability with a range of DGAT2i doses administered alone, and coadministration of DGAT2i + ACCi, compared to placebo, and the coadministration of DGAT2i + ACCi relative to DGAT2i alone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female participants between the ages of 18 (or the minimum country-specific age of consent if >18) and 75 years, inclusive, at PreQ (Prequalification visit) and SCR1 (Screen 1 / Visit 1);
2. At PreQ and SCR1, meet ≥ 2 of the following criteria [for laboratory parameters, results must be as assessed by the sponsor-identified central laboratory, with a single repeat permitted to assess eligibility, at each of these 2 visits, if needed] –
- FPG ≥ 100 mg/dL (5.6 mmol/L), or on pharmacological agents with explicit purpose of improving glycemic control;
- Fasting serum HDL-C <40 mg/dL (1 mmol/L) for males and <50 mg/dL (1.3 mmol/L) for females, or on pharmacological agents with explicit purpose to increase HDL-C;
- Fasting serum TG ≥150 mg/dL (1.7 mmol/L), or on pharmacological agents with explicit purpose to decrease TG;
- Seated BP ≥130 / 85 mm Hg, or on pharmacological agents with explicit purpose for BP control;
- Waist circumference ≥40 inches (102 cm) for males and ≥35 inches (89 cm) for females.
3.Meet the following criteria, based on an evaluable FibroScan® as defined in Section 8.1.2.1 (±AST as assessed by sponsor-identified defined in Section 8.1.2.1 (±AST as assessed by sponsor-identified central laboratory); with a single repeat assessment permitted to assess eligibility, if needed, at each of these 2 visits;
•At PreQ and SCR1, FASTTM score =0.30, derived using sponsor-provided NASH tool
OR
•At PreQ and SCR1, meet a combination of –
•CAPTM =280 dB/m plus
•VCTETM between 8.0 and 20.0 kPa, inclusive;
•Eligibility using this non-invasive assessment must occur prior to conduct of screening/baseline liver biopsy at SCR2.
4.At SCR2, ultrasound-guided (and in limited cases, other imaging technique(s) as outlined in Section 8.1.1), percutaneous, liver biopsy meeting the NASH CRN definition14 as determined by sponsor identified central pathologist(s) as follows –
•A total NAS score of =4 (and up to total score of 8) comprising of steatosis grade =1, plus inflammation grade of =1, plus ballooning grade =1
•Along with fibrosis of F2 or F3;
NOTE: A historical biopsy may be accepted if performed =12 weeks prior to SCR2 and tissue slides are accessible to the sponsor- identified central pathologists(s) for determination of eligibility (and to serve as a baseline): in such cases,
•Eligibility based on inclusion criterion 3 at PreQ and SCR1 is not required;
•SCR2 date reflects date of shipment of historical tissue sample to sponsor-identified central laboratory after confirmation of eligibility based on assessments performed at PreQ and SCR1 visits;
•In all cases, date of procedure of the liver biopsy used to determine
eligibility (and serve as baseline) must be =24 weeks prior to Day 1
5. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures
- Including following completion of screening/baseline liver biopsy, participants must confirm willingness to undergo the 2nd biopsy, while in study.
Weight:
6. BMI =25.0 kg/m2 (for sites in Africa, Europe, North/South America) or =22.5 kg/m2 (for sites in Asia) with upper limit of 45 kg/m2 (including rounding to a maximum of 45.1 kg/m2, calculated using sponsor provided NASH tool) at PreQ and SCR1 with a single repeat assessment of f body weight and/or BMI permitted on a different day to assess eligibility, if needed, at each of these 2 visits;
•In all cases, eligibility must conform to ability to ascertain evaluable FibroScan® (Section 8.1.2.1) and conduct of percutaneous liver biopsy (Section 8.1.1).
7. Body weight must be stable (ie, not vary by ≥5% for at least 12 weeks before SCR1).
8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICDs and in this protocol at PreQ and SCR1;
- For participants who qualify based on PreQ procedures, at SCR1, evidence of a separate personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the main study, is required;
-Plus, an additional provision/flexibility for those participating in Imaging substudy to offer dedicated consent for this procedure closer (but prior) to Baseline MRI-PDFF or at the time of consent obtained at SCR1.
|
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria
apply:
Medical Conditions:
1. Current significant alcohol consumption at either PreQ and SCR1 defined as any one of these parameters – with a single repeat assessment of laboratory-related parameters permitted using sponsor-identified central laboratory, to assess eligibility, if needed, at each of these 2 visits:
•>14 drinks/week (men) and >7 drinks/week (women) where 1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor
•%CDT≥1.5x ULN
•Total score of ≥8 on the AUDIT questionnaire
2. Evidence of other causes of liver disease at either PreQ and SCR1
3. History of pancreatitis, at PreQ
4. Any condition possibly affecting drug absorption at PreQ
•Participants who have undergone cholecystectomy and/or appendectomy are eligible for this study so long as the surgery occurred >6 months prior to PreQ
5. Diagnosis of T2DM which requires management with >3 medications within 12 weeks prior to SCR1 or management with excluded agents for glycemic control
6. Dyslipidemia which requires management with >3 lipid-modifying agents within 12 weeks prior to SCR1 or use of excluded agents for lipid management –
•Specific restrictions need to be satisfied at SCR1 in order to progress
•Those on gemfibrozil or lovastatin will need to agree to be switched to another agent once deemed eligible and for duration of study;
•Those on statins will be permitted based on review of the total daily dose
7. At PreQ or SCR1, those with severe hypertension defined as seated systolic BP≥180 mmHg and diastolic BP ≥105 mm Hg, or both, with a single repeat permitted, if needed, to assess eligibility at each of these 2 visits; and/or managed with >3 agents to control BP within 12 weeks prior to SCR1
•BP must be assessed using a blood pressure cuff size available at individual sites and compatible with the arm circumference of the participant
•Participants with seated BP ≥160/100 mmHg at PreQ or SCR1 must use the Run-In period to revise/adjust medications to improve BP control with BP-related randomization criteria met before dosing on Day 1/Visit 5
8. Cardiovascular event within 12 months prior to PreQ
9. Recent systemically administered treatments for malignancy including the use of chemotherapy, radiotherapy, or immunotherapy;
•Or any other active malignancy, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
10. Other medical or psychiatric condition including recent or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of participants achieving resolution of NASH without worsening of fibrosis or improvement in fibrosis by ≥1 stage without worsening of NASH or both, based on assessment by sponsor-identified central pathologist(s), |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Percent change in liver fat (assessed via MRI-PDFF in substudy population)
2. Proportion of participants achieving improvement in different responder definitions based on assessment by sponsor-identified central pathologist(s) at Week 48 –
- Resolution of NASH, without worsening of fibrosis
- Improvement in fibrosis by ≥1 stage, without worsening of NASH
- Improvement in fibrosis by ≥2 stages, without worsening of NASH
- Improvement of ≥2 points in Total NAS
3. Assessment of TEAEs, safety related clinical laboratory tests, vital signs, and 12-lead ECGs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,2. at Week 48
3. over time up to Week 48 |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 7 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Hong Kong |
| Puerto Rico |
| Taiwan |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| United States |
| Bulgaria |
| Poland |
| Slovakia |
|
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 17 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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