| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nonalcoholic Fatty Liver Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Nonalcoholic Fatty Liver Disease |
|
| 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 | 10082249 |
| E.1.2 | Term | Nonalcoholic fatty liver disease |
| 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 |
1. To evaluate the effect of efinopegdutide versus semaglutide on mean relative reduction from baseline in liver fat content (LFC) after 24 weeks.
2. To evaluate the safety and tolerability of efinopegdutide compared with semaglutide. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of efinopegdutide versus semaglutide on mean absolute reduction from baseline in LFC after 24 weeks.
2. To evaluate the effect of efinopegdutide versus semaglutide on mean percent change from baseline in body weight at 24 weeks.
3. To evaluate the effect of efinopegdutide versus semaglutide on change from baseline in fasting lipid levels over 24 weeks. |
|
| 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 |
|
| E.3 | Principal inclusion criteria |
1. Has an LFC ≥10% as assessed by MRI-PDFF at V2/MRI-PDFF
2. Has a BMI ≥25 kg/m2 and ≤50 kg/m2 at the time of V1/Screening
3. Has stable weight defined as ≤5% gain or loss of body weight for at least 3 months before V1/Screening
4. Meets 1 of the following criteria:
● Has no history of T2DM
OR
● Has a history of T2DM with an A1C ≤8.5% at V1/Screening AND controlled by diet or a stable dose of metformin for the 3 months before V1/Screening
5. Is male or female, from 18 years to 70 years of age (inclusive) (in Taiwan, from 20 years to 70 years of age [inclusive]; in South Korea, from 19 years to 70 years [inclusive]), at the time of signing the informed consent.
6. 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 using a contraceptive method that is highly effective, with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 5 weeks after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention
● A WOCBP must have 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
● The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
● Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
7. The participant (or legally acceptable representative) has provided documented informed consent for the study. The participant may also provide consent for FBR and/or the PK substudy. However, the participant may participate in the main study without participating in FBR and/or the PK substudy |
|
| E.4 | Principal exclusion criteria |
1. History of T1DM, diabetic ketoacidosis, or diabetes secondary to pancreatitis or pancreatectomy
2. History of obesity with a known secondary cause
3. Ongoing, inadequately controlled hypothyroidism or hyperthyroidism
4. History of glucagonoma
5. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasm type-2 syndrome
6. Calcitonin value of ≥50 pg/mL (≥50 ng/L) at V1/Screening
7. Symptomatic hyperglycemia that, in the investigator’s opinion, requires immediate initiation, adjustment, or addition of antihyperglycemic therapy
8. Significant systemic or major illnesses including recent events of congestive heart failure, unstable angina, myocardial infarction, arterial revascularization, stroke, or transient ischemic attack
9. History of pathologic, symptomatic, or sustained tachyarrhythmia
10. History of Wolff-Parkinson-White syndrome or congenital long QT syndrome
11. Average triplicate seated BP reading of SBP ≥160 mm Hg and/or DBP ≥100 mm Hg at V1/Screening
12. Average triplicate seated HR reading of <50 bpm or >100 bpm
13. History or evidence of chronic liver disease other than NAFLD or NASH
14. Known history of cirrhosis
15. History of acute or chronic pancreatitis
16. History of a bariatric surgical procedure or a known clinically significant gastric emptying abnormality
17. Previous or current history of a clinically significant eating disorder
18. History of severe psychiatric disorders, major depressive disorder, or any lifetime history of suicide attempt
19. History of malignancy ≤5 years before providing documented informed consent for the study except for squamous or basal cell carcinomas of the skin and carcinomas in situ of the cervix
20. Clinically active hematologic disorder and/or hemostasis disorder
21. HIV as assessed by medical history or current use of antiretroviral therapy
22. Undergone a major surgery within 3 mo before providing documented informed consent for the study, or has not fully recovered from surgery, or has major surgery planned during the participation of the current study
23. History of organ transplantation, except for corneal transplant
24. Received blood products ≤2 mo before V1/Scr, and/or donated blood products ≤1 month before V1/Scr, and/or plans to donate blood products throughout the duration of the study
25. Active diabetic proliferative retinopathy or a history of maculopathy
26. Untreated obstructive sleep apnea
27. Known allergies, hypersensitivity, contraindication, or intolerance to the active ingredients and/or excipients of efinopegdutide or semaglutide
28. Treated with any GLP-1 receptor agonist or investigational GLP-1/GCGR co-agonist within the 6 mo before V1/Scr
29. Been treated with thiazolidinediones within the 6 mo before V1/Scr
30. Previous or current use of prescription weight-management medications, or over-the-counter weight-loss medications or therapies within the 3 mo before V1/Scr
31. Been treated with systemic corticosteroid medication within the 3 mo before V1/Scr or is likely to require treatment with systemic corticosteroid medication during the study treatment period
32. Been treated with any of the following medications within the 3 mo before V1/Scr or is likely to require treatment with the following medications during the study treatment period:
● Antipsychotic drugs
● Anticonvulsants
● Tricyclic antidepressants, lithium, levodopa, and dopamine receptor agonists
33. On treatment with selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors that is not a stable dose for at least 3 mo before V1/Scr
34. On treatment with an antihypertensive therapy that is not a stable dose for at least 3 mo before V1/Scr
35. On treatment with an antihyperlipidemic therapy that is not a stable dose for at least 1 mo before V1/Scr
36. Is currently on treatment with >100 IU/day of vitamin E AND the dose has not been stable for at least 3 months before V1/Screening.
37. On treatment with anticoagulants
38. On treatment with or has used drugs associated with NAFLD ≤6 mo before V1/Scr
39. Recent history of drug abuse or is a current user of recreational or illicit drugs at the time of V1/Scr
40. On treatment with or is likely to require treatment with a prohibited medication listed in the protocol
41. Is currently participating in or has participated in an interventional clinical study and received an investigational compound or used an investigational device ≤3 months
42. Clinically significant ECG abnormality that requires further diagnostic evaluation or intervention at V1/Scr
43. Inability to have an MRI-PDFF due to due to claustrophobia / metallic implant
44. Has poor venous access that precludes the routine peripheral blood sampling required for this study.
45. Exclusionary laboratory values as listed in the protocol
46. Routinely consumes ≥480 mg of caffeine in caffeinated beverages per day |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Mean Relative Reduction from Baseline in Liver Fat Content (LFC) Measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF), Evaluated by Blinded Independent Central Review (BICR) After 24 weeks
2. Number of Participants Who Experience an Adverse Event
3. Number of Participants Who Discontinue Study Intervention Due to an Adverse Event |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. At Baseline and 24 weeks
2. Up to Approximately 29 weeks
3. Up to Approximately 24 weeks
|
|
| E.5.2 | Secondary end point(s) |
1. Mean Absolute Reduction from Baseline in LFC Measured by MRI-PDFF (evaluated by BICR) After 24 Weeks
2. Mean Percent Change from Baseline in Body Weight After 24 weeks
3. Mean Change from Baseline in Total Cholesterol After 24 Weeks
4. Mean Change from Baseline in Non-High Density Lipoprotein-Cholesterol (non-HDL-C) After 24 Weeks
5. Mean Change from Baseline in High Density Lipoprotein-Cholesterol (HDL-C) After 24 Weeks
6. Mean Change from Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) After 24 weeks
7. Mean Change from Baseline in Triglycerides (TG) After 24 Weeks
8. Mean Change from Baseline in Apolipoprotein B (apoB) After 24 Weeks |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Baseline and 24 Weeks
2. At Baseline and 24 Weeks
3. At Baseline and 24 Weeks
4. At Baseline and 24 Weeks
5. At Baseline and 24 Weeks
6. At Baseline and 24 Weeks
7. At Baseline and 24 Weeks
8. At Baseline and 24 Weeks |
|
| 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 | 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Israel |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Taiwan |
| United States |
| France |
| Poland |
| Spain |
| Italy |
| Russian Federation |
| Turkey |
| Ukraine |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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