Phase 2b study evaluating efficacy, safety and tolerability of study drug called NGM282 (Aldafermin) in Patients with Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis
- Conditions
- Compensated Cirrhosis Due to Nonalcoholic SteatohepatitisMedDRA version: 22.0Level: PTClassification code 10053219Term: Non-alcoholic steatohepatitisSystem Organ Class: 10019805 - Hepatobiliary disordersMedDRA version: 20.1Level: LLTClassification code 10064844Term: Compensated cirrhosisSystem Organ Class: 10019805 - Hepatobiliary disordersTherapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]
- Registration Number
- EUCTR2019-002341-38-FR
- Lead Sponsor
- GM Biopharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 150
1. Males and females from 18 to 75 years of age who are able to comprehend and willing to sign an Informed Consent Form (ICF).
2. Liver biopsy consistent with a diagnosis of NASH and Fibrosis Stage 4 (F4) Cirrhosis according to NASH CRN criteria and per the central pathologist evaluation.
a. A historical biopsy is acceptable if obtained within 6 months of the Screening Visit and tissue slides are available and acceptable for the central pathologist evaluation.
b. Liver biopsies must be consistent with a diagnosis of NASH as defined by: hepatocellular ballooning, steatosis, and lobular inflammation according to the NAS and determined by the central pathologist evaluation, minimum 1 point in each category.
c. NASH must be the etiology of cirrhosis (i.e., no other causes of cirrhosis)
3. Total liver fat content (LFC) = 8% as measured by MRI-PDFF.
4. Criterion deleted per Amendment 2.
5. AFP = 20 ng/mL at Screening.
6. Negative for hepatic lesions/nodules indicating HCC risk
a. MRI is the preferred imaging modality. There must be no nodules with a Liver Imaging and Reporting Data System (LI-RADS) score of = 2 by central radiologist evaluation.
b. If MRI is not available or not possible to be performed, a multi-phasic CT scan may be used to assess HCC risk. There must be no nodules with a LI-RADS score = 2 by central radiologist evaluation.
c. If MRI and CT are not available or not possible to be performed for screening a potential subject, then ultrasonography of the liver may be performed:
1) If no hepatic lesions or nodules (local radiologist evaluation) and AFP = 20 ng/mL, the potential subject may be considered further for enrollment.
2) For any findings of hepatic lesions or nodules (local radiologist evaluation) that are not clearly benign cysts and have not been shown clearly benign by prior CT or MRI, follow up MRI must be performed and meet criteria (no nodules with LI-RADS score of = 2 evaluated centrally) in order for the potential subject to be considered further for enrollment.
7. Subjects with Type 2 Diabetes (T2D) or insulin resistance are permitted as long as diabetic medications (oral, injectable, and long-acting insulin) are stable within 3 months prior to Screening, as outlined in Section 6.4.
8. Other concomitant medications/therapies used for the treatment of co-existing conditions (Section 6.4) are acceptable but require a stable regimen for at least 3 months prior to the Screening.
9. Statin use is acceptable based on the following criteria, as assessed by the investigator at Screening:
a. Statin-naïve is defined as no administration of statins within 3 months prior to Screening.
b. Statin-Experienced is defined as currently receiving = 50% of the maximal approved dose of statin therapy
i. Requires a stable statin dosing at least 3 months prior to Screening
10. The following additional laboratory parameters must be met at Screening:
a. Total bilirubin within ULN
i. If Gilbert’s Syndrome, direct bilirubin within ULN.
b. HbA1c = 9.5%.
c. Platelet count = 140,000/mm3.
d. Creatinine clearance = 60 mL/min as calculated by Cockcroft-Gault equation.
e. Serum alanine amino transferase (ALT) levels = 5X upper limit of normal (ULN).
f. Serum aspartate amino transferase (AST) levels = 5X ULN.
g. Alkaline phosphatase = 1.5X ULN.
h. Serum albumin =3.5 g/dL.
i. International normalized ratio (INR) =1.7.
11. Female subjects must be either of a) non-childbearing potential, defined as women who have ha
1. Other causes of liver disease that are primary, secondary, or otherwise causes of cirrhosis or which may confound the intended patient population according to the investigator, including but not limited to alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders, primary biliary cirrhosis, drug-induced hepatotoxicity, Wilson’s disease, hemochromatosis, and alpha-1-anti-trypsin deficiency based on medical history and/or centralized read of liver histology.
2. Evidence of drug induced steatohepatitis secondary to amiodarone, corticosteroids, estrogens, methotrexate, tetracycline, or other medications known to cause hepatic steatosis.
3. History of hepatic decompensation, including: variceal bleeding, ascites, or hepatic encephalopathy.
4. Prior or pending liver transplantation.
5. Child Pugh class B and C status.
6. Model of end stage liver disease (MELD) score > 12.
7. Evidence of worsening liver disease (defined below) between screening visits (i.e. Day -56 and Day -42) including measures of AST, ALT, alkaline phosphatase (ALP) or total bilirubin (TBL):
8. History of porto-systemic shunt procedure.
9. Based on screening endoscopy (EGD), has any evidence of varices regardless of size.
10. Clinically significant cardiovascular or cerebrovascular event or new diagnosis within 6 months of Screening, including but not limited to congestive heart failure, myocardial infarction, acute coronary syndrome, revascularization, stroke (hemorrhagic or ischemic), transient ischemic attack (TIA), or implanted defibrillator or pacemaker (for uncomplicated elective, non-biventricular pacemaker procedure, 3 months post procedure will be allowed).
11. Gastric bypass or bariatric surgery in the past 5 years or planned procedure during the study period.
12. History of clinically significant unstable or untreated illness or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol.
13. Documented significant weight change (± 5%) < 3 months prior to Screening.
14. Screening ECG with clinically significant abnormalities that in the investigator's opinion, require evaluation and possible treatment.
15. Positive for HBsAg, antiHIV Ab, or antiHCV Ab plus HCV-RNA. Subjects who are antiHCV Ab- positive but HCV-RNA negative (secondary to treatment or viral clearance) are eligible with at least a 1-year period since documented sustained viral response at Week 12 post-treatment.
16. History of malignancy diagnosed or treated within 2 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ or breast ductular carcinoma in situ is allowed if appropriately treated within 2 years prior to Screening); subjects under evaluation for malignancy are not eligible. History of hepatocellular carcinoma at any point regardless of treatment or treatment success will be excluded.
17. A positive drug screen (e.g., morphine, heroin, cocaine) will exclude subjects unless it can be clearly explained by a prescribed medication. The diagnosis and prescription must be approved by the Investigator and the Medical Monitor.
18. Significant alcohol intake as measured by a phosphatidylethanol (PEth) level = 200 ng/mL AND significant alcohol use, as determined by the Alcohol Use Disorders Identification Test (AUDIT-C) alcohol consumption questionnaire (Appendix 3).
19. Criterion deleted per Amendment 2.
20. Consumption of = 21 uni
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Primary end point(s): 1. The primary efficacy endpoint is the histologic response defined as a subject achieving an improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) after 48 weeks of treatment with aldafermin or matched placebo.<br>2. The primary safety endpoint is frequency, severity and timing of adverse events (AEs) and serious adverse events (SAEs).;Timepoint(s) of evaluation of this end point: end point 1: after 48 weeks of treatment with aldafermin or matched placebo<br>end point 2: throughout the study;Main Objective: The primary objective of this study is to evaluate the efficacy and safety of aldafermin compared to placebo.;Secondary Objective: The secondary efficacy objectives of this study are to evaluate the effect of aldafermin on pharmacokinetics and on biomarkers of target engagement, fibrogenesis and imaging.
- Secondary Outcome Measures
Name Time Method Secondary end point(s): 1. Aldafermin concentrations pre-dose at all treatment visits and 4-hours post-dose at Day 1, Week 24, and Week 48 in all subjects. In a subset of subjects participating in an optional PK study, full PK profiles up to 24 hours will be assessed at Day 1 and steady state at end of treatment (EOT, Week 48).<br>2. Changes from baseline over time in C4 and serum bile acids and compared to placebo.<br>3. Changes from baseline over time in Pro-C3 and Enhanced Liver Fibrosis (ELF) and compared to placebo.<br>4. Changes from baseline over time in alanine transaminase (ALT) and aspartate transaminase (AST) and compared to placebo in subjects with elevated transaminases at baseline.<br>5. Changes from baseline over time in liver stiffness measure (LSM by FibroScan®) and compared to placebo.;Timepoint(s) of evaluation of this end point: 1.pre-dose at all treatment visits and 4-hours post-dose at Day 1, Week 24, and Week 48 in all subjects<br>2. at week 48<br>3. EOT<br>4. EOT<br>5. at week 48