Study Evaluating the Efficacy and Safety of Belapectin for the Prevention of Esophageal Varices in NASH Cirrhosis

This seamless, adaptive, two-stage, Phase 2b/3, randomized, double-blind, multicenter, parallel-groups, placebo-controlled study will assess the efficacy, safety, and tolerability of belapectin compared with placebo in patients with nonalcoholic steatohepatitis (NASH) cirrhosis and clinical signs of portal hypertension but without esophageal varices at baseline.


Eligibility Criteria:
Inclusion Criteria:

Each subject must meet all of the following criteria to be enrolled in this study:

1. Is male or female, ≥ 18 and ≤ 75 years of age at the time of Screening.
2. Is willing and able to provide written informed consent prior to the initiation of any study-specific procedures.
3. Has evidence of portal hypertension, with either one of the following:

   1. platelet count \<150,000/mm3

      OR
   2. documented hepatic venous pressure gradient (HVPG) measurement \>6 mmHg

      OR
   3. at least two of the following:

      * spleen size ≥14 cm (documented by ultrasound, MRI, or CT scan)
      * abdominal collateral circulation (documented by ultrasound, MRI, or CT scan or physical examination, ie, caput medusae)
      * documented liver transient elastography (eg, FibroScan) ≥20 kilopascals (kPa).
      * aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \>1.
4. Has a history confirming nonalcoholic steatohepatitis (NASH) cirrhosis, with at least one of the following:

   * There is a historical liver biopsy showing cirrhosis with steatohepatitis. There is no evidence for a competing etiology for the cirrhosis.
   * There is a historical liver biopsy showing steatohepatitis, and there is evidence of cirrhosis from clinical or imaging data or a second liver biopsy showing cirrhosis without all features of NASH (as the histological NASH lesions may have burnt out). There is no evidence for a competing etiology. There is at least 1 co-existing metabolic comorbidity at Screening: obesity (with either body mass index \[BMI\] ≥30 kg/m2 or waist circumference ≥102 cm \[40 in, men\] or ≥88 cm \[35 in, women\], or by ethnically appropriate cutpoints); hypertension (either on anti hypertensive drug therapy for at least 1 year or systolic/diastolic blood pressure (BP) \>140/80 mm Hg); Type 2 diabetes (glycated hemoglobin \[HbA1c\] ≥6.5%, or on anti-diabetic medication for at least 1 year); or dyslipidemia (triglycerides ≥150 mg/dL or on drug therapy for hypertriglyceridemia for at least 6 months; high-density lipoprotein cholesterol ≤40 mg/dL \[men\] or ≤50 mg/dL \[women\]) to corroborate a diagnosis of nonalcoholic fatty liver disease (NAFLD).
   * There is a historical liver biopsy showing cirrhosis with steatosis but not steatohepatitis. There is no evidence for a competing etiology. There are at least 2 co-existing (or history of) metabolic comorbidities (with obesity or diabetes being one of them) to corroborate a diagnosis of NAFLD.
   * There is a historical liver biopsy showing steatosis but now with cirrhosis either by clinical examination, imaging, or biopsy. If there is a current biopsy, it does not show evidence of steatosis or steatohepatitis as histological lesions may have burned out. There is no evidence for a competing etiology. There are at least 2 co existing (or history of) metabolic comorbidities (with obesity or diabetes being one of them) to corroborate a diagnosis of NAFLD.
   * Patient with cirrhosis with current or previous imaging showing steatosis. There is no liver histology available. There is no evidence for a competing etiology. There are at least two co-existing or history of metabolic comorbidities with obesity or diabetes being one of them to corroborate a diagnosis of NAFLD.
   * For patients not meeting the above mentioned criteria, a screening liver biopsy is necessary.

   Note: All liver biopsy blocks and/or slides for eligibility assessments (including those from historical biopsies) will be reviewed by the central study pathologist while the subject is in Screening. Results from the central study pathologist must be available before the subject is randomized.
5. Absence of hepatocellular carcinoma (HCC) by valid imaging (eg, ultrasound, CT scan, or MRI) within 6 months prior to randomization. If no such imaging result is available, then ultrasound imaging should be performed as part of standard of care.
6. Patients with diabetes mellitus can be enrolled, if they are adequately controlled on a stable dose or doses of antidiabetic medication(s) for at least 3 months before Screening, and their screening HbA1c is ≤9.5%.
7. Patients on vitamin E or pioglitazone can be enrolled if they are on a stable dose and regimen for at least 3 months before screening, and the dose is expected to be held constant during the trial.
8. Patients on a statin can be enrolled if they are on a stable regimen for at least 3 months before Screening, and expected to be held stable during the trial.
9. Is not pregnant and must have a negative serum pregnancy test result prior to randomization.
10. Is of non-childbearing potential or if a fertile man or woman participating in heterosexual relations, agrees to use two acceptable means of contraception (ie, 2 effective methods of contraception, one of which must be a physical barrier method \[eg, male or female condom, diaphragm\] when combined with a highly effective method of contraception \[ie, a method with a failure rate of \<1% per year when used consistently and correctly\]) throughout his/her participation in this study and for 90 days after discontinuation of study treatment.

    Highly effective forms of contraception include:
    * combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (such as oral, intravaginal, transdermal) methods
    * progestogen-only hormonal contraception associated with inhibition of ovulation (such as oral, injectable, implantable)
    * hormone-releasing intrauterine system (IUS)
    * intrauterine device (IUD)
    * bilateral tubal occlusion
    * a vasectomized partner, provided that partner is the sole sexual partner of the women of childbearing potential trial participant and that the vasectomized partner has received medical assessment of the surgical success
    * sexual abstinence (ie, a refraining from heterosexual intercourse during the entire period of the clinical trial, if it is the preferred and usual lifestyle of the subject).

    Surgically sterile males and females are not required to use contraception provided they have been considered surgically sterile for at least 6 months. Surgical sterility includes history of surgically successful vasectomy, hysterectomy, or bilateral salpingo-oophorectomy. Postmenopausal women who have been amenorrheic for at least 2 years at the time of Screening will be considered sterile.
11. If a lactating woman, agrees to discontinue nursing before the start of study treatment and refrain from nursing until 90 days after the last dose of study treatment.
12. If a man, agrees to refrain from sperm donation throughout the study period and for a period of 90 days following the last dose of investigational medicinal product (IMP). Female subjects may not begin a cycle of ova donation or harvest throughout the study period and for a period of 90 days following the last dose of IMP.

Exclusion Criteria:

Subjects meeting any of the following criteria will be excluded from the study:

1. Presence of esophageal, gastroesophageal, or isolated gastric varices, based on an upper gastrointestinal (GI) esophagogastroduodenoscopy (EGD) exam conducted during Screening. Patients with portal hypertensive gastropathy could be enrolled.
2. History of hepatic cirrhosis decompensation including any episode of variceal bleeding, ascites not controlled by medication, spontaneous bacterial peritonitis or overt hepatic encephalopathy (West Haven grade ≥2 as assessed by the principal investigator), OR develops signs of hepatic cirrhosis decompensation during Screening.
3. Known or suspected abuse of alcohol (\>20 g/day for women or \>30 g/day for men \[on average per day\]), as per medical history. Significant alcohol consumption is defined as more than 20 grams per day in females and more than 30 grams per day in males. On average, a standard drink in the United States is considered to be 14 grams of alcohol, equivalent to 12 fluid ounces of regular beer (5% alcohol), 5 fluid ounces of table wine (12% alcohol), or 1.5 fluid ounces of 80 proof spirits (40% alcohol).
4. Alcohol dependence (ie, a score \>8 on the Alcohol Use Disorders Identification Test)
5. Narcotics or any other drug abuse or dependence in the last 5 years
6. Prior trans-jugular intrahepatic portal-systemic (TIPS) shunt procedure
7. Documented causes of liver disease other than NASH, including but not restricted to:

   * Viral hepatitis, unless eradicated at least 3 years prior to Screening

     * acute hepatitis A infection (presence of hepatitis A immunoglobulin M \[IgM\] at Screening)
     * positive hepatitis B surface antigen
     * positive hepatitis C virus (HCV) ribonucleic acid (to be performed prior to randomization in case of positive HCV antibody)
   * Documented drug-induced liver disease
   * Alcoholic liver disease
   * Autoimmune hepatitis
   * Wilson's disease
   * Hemochromatosis
   * Primary biliary cholangitis
   * Primary sclerosing cholangitis
   * Genetic hemochromatosis
   * History or planned liver transplantation
   * Alpha-1 antitrypsin deficiency
8. History of human immunodeficiency virus (HIV), or positive HIV test at Screening
9. Any of the following test or score:

   * serum alanine aminotransferase (ALT) \> 5 × upper limit of normal (ULN)\*
   * serum aspartate aminotransferase (AST) \> 5 × ULN\*

     \*Screening values will be obtained at Screening Visit 1 (SV1) and Screening Visit 2(SV2) (which will be separated by 2 to 4 weeks). A second screening value that is \>50% higher than the first value should prompt re-evaluation of the severity of the underlying liver disease and eligibility for this trial. If a transaminase level at SV2 is \>33% different from the level at SV1, then additional measurements should be performed at Screening Visit 3 (SV3). In such cases, the baseline transaminase levels will be established for subjects using the mean value of 4 evaluations \[ie, at SV1, SV2, SV3, and Baseline (ie, pre-dose during Visit 1)\].
   * serum alkaline phosphatase (ALP) \> 2 × ULN
   * mean platelet count \< 50,000/mm3
   * total bilirubin ≥ 2.0 mg/dL (subjects with a documented history of Gilbert's syndrome can be enrolled if the direct bilirubin is within normal reference range)
   * model for end-stage liver disease (MELD) score ≥12
   * Child-Turcotte-Pugh (CTP) Score ≥7 Note: Following Phase 2b, subjects with CTP scores ≥7 may be enrolled if recommended\* by the Data Safety Monitoring Board (DSMB) and approved by the Trial Steering Committee (TSC), based on the planned interim analysis (IA). \[\*based on DSMB review of preliminary results from a separate hepatic impairment clinical trial (Study GT-032) which is assessing belapectin safety and pharmacokinetic (PK) in cirrhotic subjects with CTP scores ≥7.
   * estimated glomerular filtration rate \< 45 mL/min\* \*Note: per Modification of Diet in Renal Disease algorithm
10. Taking an angiotensin converting enzyme inhibitor, angiotensin II receptor blocker, or β-1 selective adrenergic receptor inhibitor, unless on a stable regimen for at least 3 months prior to Screening and no changes in the regimen are anticipated during the study. Subjects taking a non-selective beta blocker are not eligible to be enrolled (Investigators are encouraged to substitute another medication, if clinically warranted).
11. History of major surgery during Screening.
12. History of a solid organ transplant requiring immunosuppressive therapy.
13. History of bariatric surgery within 1 year of randomization, or plan to undergo bariatric surgery during the study.
14. Has positive screening test for illicit drugs of abuse at Screening.
15. Has participated in an investigational new drug study within 30 days or 5 half-lives whichever is longer, prior to randomization.
16. Has a history of malignancy within 5 years of randomization, except for basal cell carcinoma, squamous cell carcinoma, and adequately treated in situ uterine cervical cancer.
17. Has clinically significant cardiovascular disease (eg, uncontrolled hypertension, myocardial infarction, unstable angina), New York Heart Association Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring intervention (eg, pacemaker/ablation) or Grade II or greater peripheral vascular disease.
18. Has a history of clinically significant hematologic, renal, hepatic, pulmonary, neurological, psychiatric, gastrointestinal, systemic inflammatory, metabolic or endocrine disorder or any other condition that, in the opinion of the Investigator, renders the subject a poor candidate for inclusion into the study.
19. Has known allergies to the IMP or any of its excipients.
20. Has previously received belapectin within 6 months of randomization.
21. Is an employee or family member of the Investigator or study center personnel.