Principal Investigator: Juan  Gallegos-Orozco
Keywords: Cirrhosis , Liver Disease , Compensated Cirrhosis , NASH Department: Gastroenterology
IRB Number: 00134974
Specialty: Gastroenterology, Gastroenterology, Gastroenterology, Gastroenterology, Gastroenterology
Sub Specialties: Liver Disease, Liver Biopsies, Endoscopy, Hepatology
Recruitment Status: Recruiting

Contact Information

Srinivas Mulamalla
srinivas.mulamalla@hsc.utah.edu
8015852283

Simple Summary

The study is being done to look at:•How well aldafermin works for the treatment of cirrhosis caused by NASH•If the use of aldafermin is safe•How safe and effective aldafermin is as compared to a placebo (looks like aldafermin, but doesn’t contain the active ingredient) •How safe and effective rosuvastatin is for the treatment of high cholesterol when taken with aldafermin

Inclusion Criteria

1. Males and females between 18 and 75 years of age, inclusive, 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 tissue slides are available within 12 months prior to Screening and are acceptable for the central pathologist evaluation.
b. Liver biopsies must be consistent cirrhosis according to the NASH CRN classification, as assessed by the central reader.
c. NASH must be the etiology of cirrhosis (i.e., no other causes of cirrhosis)
3. Criterion deleted per protocol Version 5.0.
4. Subjects must have Definitive NASH cirrhosis as defined in Noureddin 2020.
a.

 Current biopsy shows cirrhosis with steatohepatitis. There is no evidence for a competing etiology.

b.    Previous biopsy showed steatohepatitis, but now with cirrhosis either by clinical history or current features, imaging, noninvasive tests, or biopsy. If there is a current biopsy, it does not show evidence of steatosis or steatohepatitis, as these histological findings may have disappeared (burn-out). There is no evidence for a competing etiology. There is at least one coexisting or history of metabolic comorbidity to corroborate a diagnosis of NAFLD.

c.    Current biopsy shows cirrhosis with steatosis. There is no evidence for competing etiology. There are at least two coexisting or history of metabolic comorbidities, including obesity and/or T2DM to corroborate a diagnosis of NAFLD.

5. Have 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 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 coexisting conditions are acceptable (Section 6.4), if on a stable regimen for at least 3 months prior to the Screening, except for non-statin lipid lowering agents, which can be used until Day 1 of 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 dose at least 3 months prior to Screening.
Note: The following are the acceptable daily doses of approved statin therapies, and other lipid lowering agents. Also listed under Section 6.4:
a. Atorvastatin: ≤ 40 mg/day
b. Fluvastatin: ≤ 40 mg/day
c. Lovastatin: ≤ 40 mg/day (for both immediate and extended release)
d. Pitavastatin: ≤ 2 mg/day
e. Pravastatin: ≤ 40 mg/day
f. Simvastatin: ≤ 40 mg/day
g. Rosuvastatin: ≤ 20 mg/day
10. The following additional laboratory parameters must be met at Screening
a. Total bilirubin ≤1.3 mg/dL
i. if Gilbert’s Syndrome, with direct bilirubin within ULN.
b. HbA1c ≤ 9.5%
c. Platelet count ≥120,000/mm3
Subjects who meet the Baveno VI criteria with a platelet count >110,000/mm3 and <120,000/mm3 may be enrolled if they meet the expanded Baveno VI criteria. (Note: No more than 30% of the remaining population will be enrolled using the Baveno VI criteria.)
d. Creatinine clearance ≥ 60 mL/min as calculated by Cockcroft-Gault equation
e. Serum alanine amino transferase (ALT) levels ≤ 5 x ULN
f. Serum aspartate amino transferase (AST) levels ≤ 5 x ULN
g. Alkaline phosphatase ≤1.5 x 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 had a hysterectomy, bilateral oophorectomy, medically documented ovarian failure, documented postmenopausal, or a follicle stimulating hormone ≥ 40 mIU/mL, OR b) if of childbearing potential, defined as including women < 55 years of age with ≤ 2 years of amenorrhea (absence of menstruation and not due to any reversible medical cause or any current medication use), then have a negative serum pregnancy test at Screening and urine pregnancy test at the Day 1 visit prior to first dose of study drug, and must be non lactating and non-breastfeeding. Note: Females who do not meet this criterion can be included if they meet criterion 12 below.
12. Female subjects of childbearing potential and male subjects with a female partner of childbearing potential must agree to consistent and adequate birth control from Screening to EOS (Week 54):
-Recommended forms of contraception for males: condom, vasectomy, and sexual abstinence
i. Vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of the female subject of childbearing potential trial participant and that the vasectomized partner has received medical assessment of the surgical success.
ii. Condom use is not considered as a highly effective form of contraception alone and may be used effectively with a second method of contraception.
iii. Sexual abstinence is considered a highly effective method only if defined as abstaining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.
 Recommended forms of contraception for females: hormone containing- contraceptive
 medication, Intrauterine device with a failure rate < 1% per year, cervical cap or diaphragm with spermicidal agent, bilateral tubal occlusion (tubal sterilization), sexual abstinence
i. Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) associated with inhibition of ovulation
ii. Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation
iii. Cervical cap or diaphragm with spermicidal agent is not considered as a highly effective form of contraception alone and may be used effectively with a second method of contraception
Sexual abstinence is considered a highly effective method only if defined as abstaining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of the subject.
13. Able and willing to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments.

Exclusion Criteria

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): 
a. For subjects with TBL, AST, ALT, or ALP baseline levels >ULN, the second assessment should not exceed an increase of 35% over the first assessment.
Note: An unscheduled visit may be necessary to confirm eligibility if the difference exceeds the allowable percent difference. If performed, unscheduled visit results will be compared to the average of Day -56 and Day -42 results to determine eligibility. If liver function tests are repeated to verify eligibility criteria have been met, there must be a minimum of 14 days (2 weeks) between the Day -42 visit and any unscheduled visit.
8. History of porto-systemic shunt procedure.
9. No evidence of gastroesophageal varices as documented by one of the following assessments: 
a. A historical and locally evaluated EGD obtained within 365 days of screening or
b. A locally evaluated EGD conducted during the screening period
* If no EGD is available, the latest EGD assessment guidelines during a global pandemic† for patients with compensated cirrhosis (i.e., the expanded Baveno VI criteria, Petta 2018) as follows can be used as a replacement for the EGD to determine eligibility:
a. Platelet count >110,000/m3, and a FibroScan® <30 kPa on a M probe or <25 kPa on a XL probe Note: No more than 30% of the remaining population will be enrolled with the expanded Baveno VI criteria.
† EGD waived in patients with compensated cirrhosis during a global pandemic per AASLD/ASGE guidelines.
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 HCVRNA-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 protocol Version 3.0.
20. Consumption of ≥ 21 units of alcohol per week in males and ≥ 14 units of alcohol per week in females for two years prior to Screening, where a “unit” of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1-ounce shot of hard liquor.
21. Use of any prohibited concomitant medications as described in Section 6.4 within 3 months prior to screening;
a. Weight loss medications.
b. Any medication that is contraindicated according to the rosuvastatin package insert (Appendix 5) or if subject has a known hypersensitivity to rosuvastatin product components (Section 6.1.3).
c. Hepatotoxic medications (Appendix 6); allopurinol allowed.
d. Anabolic steroids.
22. History of statin intolerance, as defined by presence of significant side effects while on statins and/or inability to take or use statins for treatment.
23. Prior participation in a clinical trial of aldafermin, unless previously enrolled into a placebo arm of the trial.
24. History of severe allergic or anaphylactic reactions to recombinant therapeutic proteins, fusion proteins, or chimeric, human, or humanized antibodies.
25. Participation in a study of another investigational agent within 28 days or five half-lives of the drug (whichever is longer) prior to Screening.
26. Any acute or chronic condition that, in the opinion of the Investigator, would limit the subject’s ability to participate, complete, and/or would confound data interpretation in this clinical study.

Participant Reimbursement

Yes