Clinical Trial to Evaluation the Safety and Efficacy of GR-MD-02 for the Treatment of Liver Fibrosis and Resultant Portal Hypertension in Patients With Nash Cirrhosis (NASH-CX)

A Multicenter, Randomized, Placebo-controlled, Double-blind, Parallel-group, Phase 2 Clinical Trial to Evaluation the Safety and Efficacy of GR-MD-02 for the Treatment of Liver Fibrosis and Resultant Portal Hypertension in Patients With Nash Cirrhosis

Study GT 026 is a Phase 2, multicenter, parallel group, North American, randomized, placebo controlled, double blind study. This study will enroll subjects with portal hypertension (HVPG greater than or equal to 6 mm Hg) who also have a liver biopsy with cirrhosis (Ishak stage 5 or 6), presumably due to NASH, excluding subjects with medium and large varices and those with decompensated cirrhosis.

Subjects with portal hypertension and cirrhosis will be randomly assigned (1:1:1 ratio) to receive 1 of 3 treatment assignments including placebo, GR MD 02 in a dose of 2 mg/kg lean body mass, or GR MD 02 in a dose of 8 mg/kg lean body mass administered every other week over a 52 week period for a total of 26 intravenous infusions. The primary endpoint analysis is the baseline adjusted change in HVPG at 1 year (53 55 weeks) in subjects treated with placebo as compared to subjects treated with GR MD 02 (2 mg/kg/week or 8 mg/kg/week).

An esophagogastroduodenoscopy (EGD) with evaluation for varices, HVPG, and liver biopsy will be performed before the first infusion and after the final 26th dose of the investigational medicinal product (IMP). Additionally, subjects will undergo a FibroScan (if available) prior to the first infusion, at Infusion Visit 13, and 14 to 28 days following final 26th infusion, an methacetin breath test (MBT), will be performed if available at screening, at Infusion Visit 13, and 14 to 28 days after the final infusion, and blood will be collected for assessment of biomarkers.

All subjects are to attend 2 postdose visits: the first will occur 14 to 28 days after the final dose administration and a second will occur 14 days following the first postdose visit.

Subjects will be offered enrollment into a subsequent separate study, an open label extension study, if there is adequate tolerability and no safety issues or signs of clinical progression that would recommend discontinuation.

Subjects who do not enroll in the open label extension study will be contacted via telephone every 6 months for 2 years and annually thereafter for a total of 4 years.

Study Overview

• Status: Completed
• Conditions: Hypertension, Portal
• Intervention / Treatment: Drug: GR-MD-02; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 162
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Diego, California, United States, 92103
      • University of California San Diego Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Digestive Health Specialist
    • Miami, Florida, United States, 33136
      • University of Miami
    • Palmetto Bay, Florida, United States, 33157
      • IMIC
    • Tampa, Florida, United States, 33606
      • Tampa General Medical Group
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Feinberg School of Medicine, Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
    • Bethesda, Maryland, United States, 20889-5600
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Saint Paul, Minnesota, United States, 55114
      • Minnesota Gastroenterology PA
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • Kansas City VA Medical Center
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27103
      • Digestive Health Specialists
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • University Gastroenterology
  • South Carolina
    • Charleston, South Carolina, United States, 29403
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37212-1610
      • Vanderbilt University Medical Center
  • Texas
    • Arlington, Texas, United States, 76012
      • Texas Clinical Research Institute LLC
    • Dallas, Texas, United States, 75246
      • Texas Digestive Research Center
    • Fort Sam Houston, Texas, United States, 78234
      • San Antonio Military Medical Center
    • Houston, Texas, United States, 77030
      • St Luke's Episcopal Hospital
    • Live Oak, Texas, United States, 78233
      • Pinnacle Clinical Research, PLLC
    • San Antonio, Texas, United States, 78215
      • Texas Liver Institute
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Mary Immaculate Hospital
    • Norfolk, Virginia, United States, 23502
      • Digestive and Liver Disease Specialists
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Richmond, Virginia, United States, 23249
      • McGuire Veterans Affairs Medical Center
    • Richmond, Virginia, United States, 23226
      • Bon Secours St. Mary's Hospital of Richmond
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center
    • Seattle, Washington, United States, 98104
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Has a HVPG measurement ≥6 mm Hg.

2. Has a liver biopsy with cirrhosis (Ishak stage 5 or 6) presumably due to NASH. A liver biopsy diagnosis of cirrhosis presumably due to NASH will include the following 3 categories:

   • Cirrhosis with a definitive pathological diagnosis of NASH (presence of fat, ballooning degeneration, and inflammation);
   • Cirrhosis wherein the biopsy contains either fat (>5%) or ballooning hepatocytes with no evidence of viral hepatitis or other liver disease; or
   • Cirrhosis with no evidence of viral hepatitis or other liver disease in a subject with at least a 5 year history of obesity (BMI ≥30) or at least a 5 year history of diabetes mellitus (as defined by diagnosis by a physician and treatment with at least 1 antidiabetic medication).
3. Is ≥18 years of age and ≤75 years of age at the time of screening.
4. Absence of hepatocellular carcinoma by valid imaging (liver ultrasound, triple phase computed tomography of liver or magnetic resonance imaging of liver) within 6 months prior to randomization. If there is not such test available, then it should be performed as part of standard of care.
5. Is willing and able to provide written informed consent prior to the initiation of any study specific procedures.
6. Is not pregnant and must have a negative serum pregnancy test result prior to randomization.

7. If a fertile man or woman participating in heterosexual relations, agrees to use effective means of contraception (ie, 2 effective methods of contraception, one of which must be a physical barrier method).

   • Effective forms of contraception include condom, hormonal methods (birth control pills, injections or implants), diaphragm, cervical cap, or intrauterine device throughout his/her participation in this study and for 90 days after discontinuation of study treatment. 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 vasectomy, hysterectomy, bilateral salpingo oophorectomy, or bilateral tubal ligation. Postmenopausal women who have been amenorrheic for at least 2 years at the time of screening will be considered sterile.

8. 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.
9. 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 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.
10. Prior to randomization, any subject on statins, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, or β 1 selective adrenergic receptor inhibitors should have been on a stable dose for at least 2 months and all attempts should be made to continue the subject on the same dose of the medication for the duration of study participation.

Exclusion Criteria:

1. Has a history of hepatic decompensation including any episode of variceal bleeding, ascites not controlled by medication, or overt hepatic encephalopathy (defined by the clinical judgment of the principal investigator but shall include the presence of lethargy, disorientation, inappropriate behavior, and the presence of asterixis).

2. Has a presence of medium or large varices or varices with red signs regardless of size based on endoscopy.

   • Small varices are defined by veins that occupy <25% of the distal one third of the esophageal lumen when insufflated. Veins that completely flatten upon insufflation of the esophagus are not conserved varices. Any varices larger than that are medium (up to 50%) or large (>50%).
   • Red signs include red wale markings (dilated venules oriented longitudinally on the variceal surface), cherry red spots (small, red, spotty dilated venules usually approximately 2 mm in diameter on the variceal surface) or hematocystic spots (large, round, crimson red projection >3 mm that look like a blood blister on the variceal surface).
3. Has had a prior transjugular porto systemic shunt procedure.
4. Has evidence of other forms of chronic liver disease including viral hepatitis B or C, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alpha 1 antitrypsin deficiency, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis.

5. Has any of the following laboratory values:

   • Serum alanine aminotransferase levels >10 × the upper limits of normal
   • Serum aspartate aminotransferase levels >10 × the upper limits of normal

   • Platelet count <60 000/mm3

     *. Serum albumin ≤2.8 g/dL

   • International normalized ratio (INR) ≥1.7
   • Direct bilirubin ≥2.0 mg/dL
   • Alpha fetoprotein >200 ng/mL
6. Has a Model End-Stage Liver Disease (MELD) score ≥15 or Child Turcotte Pugh Class B or C.

7. Has an estimated creatinine clearance of <50 mL/minute. Glomerular filtration rate will be estimated using the Cockcroft-Gault equation (Cockcroft 1976):

   • Males: CrCl (mL/min) = ([140 - age] × weight) / (SCr × 72)
   • Females: CrCl (mL/min) = ([140 - age]) × weight) / (SCr × 72)] × 0.85
   • Where CrCl is creatinine clearance, age is in years, weight is in kg, and SCr is serum creatinine in mg/dL
8. Is unwilling or unable to safely undergo HVPG or liver biopsy.
9. Has known positivity for human immunodeficiency virus (HIV) infection or a positive HIV test result at screening.
10. Has had major surgery within 8 weeks of randomization, significant traumatic injury within 6 months, or anticipation of need for major surgical procedure during the course of the study.
11. Has a history of a solid organ transplant requiring current immunosuppression therapy.
12. Has used nonselective β adrenergic inhibitors within 6 weeks prior to randomization.
13. Has planned or anticipated variceal ligation therapy during the study.
14. Has had weight reduction surgery within the past 3 years or plans to undergo weight reduction surgery during the study.

15. Has current, significant alcohol consumption or a history of significant alcohol consumption for a period of more than 3 consecutive months any time within 1 year prior to screening.

    • 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).

    A score of ≥8 on the Alcohol Use Disorders Identification Test (AUDIT) (Babor 2000) will result in exclusion.

16. Has a positive urine screen result for amphetamines, cocaine, or nonprescription opiates (heroin, morphine) at screening.
17. Has clinically significant and uncontrolled cardiovascular disease (eg, uncontrolled hypertension, myocardial infarction within 6 months prior to randomization, unstable angina), New York Heart Association Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring devise/ablation or Grade II or greater peripheral vascular disease within 12 months prior to randomization.
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 concurrent infection including diagnoses of fever of unknown origin at the time of randomization.
20. Has a history of malignancy, except for the following: adequately treated nonmetastatic basal cell skin cancer; any other type of skin cancer, except melanoma, that has been adequately treated and has not recurred for at least 1 year prior to enrollment; and adequately treated in situ cervical cancer that has not recurred for at least 1 year prior to screening.
21. Participates in an investigational new drug study within 30 days prior to randomization (including follow up visits) or at any time during the current study.
22. Has a clinically significant medical or psychiatric condition considered high risk for participation in an investigational study.
23. Fails to give informed consent.
24. Has known allergies to the IMP or any of its excipients.
25. Has previously received GR-MD-02 within 6 months of randomization.
26. Is an employee or family member of the investigator or study center personnel.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 2 mg/kg GR MD 02; GR MD 02 in a dose of 2 mg/kg lean body mass administered every other week over a 52 week period for a total of 26 infusions	Drug: GR-MD-02; GR MD 02 (galactoarabino rhamnogalacturonate), a complex carbohydrate drug that binds to galectin 3; Other Names: galactoarabino rhamnogalacturonate
Active Comparator: 8 mg/kg GR MD 02; GR MD 02 in a dose of 8 mg/kg lean body mass administered every other week over a 52 week period for a total of 26 infusions	Drug: GR-MD-02; GR MD 02 (galactoarabino rhamnogalacturonate), a complex carbohydrate drug that binds to galectin 3; Other Names: galactoarabino rhamnogalacturonate
Placebo Comparator: Placebo; Phosphate buffered saline solution administered every other week over a 52 week period for a total of 26 infusions	Drug: Placebo; Placebo for GR-MD-02

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Portal Pressure at Year 1 (Change in HVPG From Baseline and 1 Year)	Change in Portal Pressure at Year 1 from Baseline	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Baseline-adjusted Mean Change in the Collagen Proportional Area (%), CPA	The baseline-adjusted mean change in the CPA at 1 year as determined by digital morphometric analysis of liver biopsies. Collagen proportionate area (CPA) measurement is a technique that quantifies fibrous tissue in liver biopsies by measuring the amount of collagen deposition as a proportion of the total biopsy area. CPA predicts clinical outcomes in patients with liver disease and can sub-classify cirrhosis.	1 year
The Number (Percentage) of Subjects Who Have at Least a One Stage Change in Ishak Assessment From Liver Biology Histopathology. Histopathological Staging of Fibrosis	The number (percentage) of subjects who have at least a one stage change in Ishak histopathological staging of fibrosis at 1 year as assessed on liver biopsy. Liver biopsy is the accepted standard for histologic assessment of liver disease activity and fibrosis. Ishak assessments on liver biopsy range from 0=no fibrosis to 6=cirrhosis.	1 year
The Baseline-adjusted Mean Change in Liver Stiffness	The baseline-adjusted mean change in liver stiffness as determined by FibroScan score 14 to 28 days after final infusion. FibroScan is a device that measures scarring by measuring the stiffness of your liver.The fibrosis result is measured in kilopascals (kPa) It's normally between 2 and 6 kPa. The highest possible result is 75 kPa. Many people with liver disease(s) have a result that's higher than the normal range.	14 to 28 days after final infusion
The Baseline-adjusted Mean Change in Methacetin Breath Test (MBT), Measured in Percentage	The baseline-adjusted mean change in the metabolic capacity of the liver as determined the methacetin breath test (MBT) at 14 to 28 days after final infusion. The results obtained from the MBT medical device are expressed as delta over baseline (DOB), which expresses the change in 13CO2/12CO2 ratio in comparison to the baseline measurement. It can be transformed into the percentage of 13C dose recovered over time (PDR) after the ingestion of Methacetin, and the cumulative PDR (CPDR), the rate at which 13C substrate is metabolized, derived from the breath 13C/12C ratio.	14 to 28 days after final infusion
The Number (Percentage) of Subjects Who Have at Least a One Stage Change in Brunt-Kleiner Assessment on Liver Biopsy Histopathological Staging of Fibrosis	The number (percentage) of subjects who have at least a one stage change in Brunt-Kleiner histopathological staging of fibrosis at 1 year as assessed on liver biopsy. Liver biopsy is the accepted standard for histologic assessment of liver disease activity and fibrosis. Brunt-Kleiner assessments on liver biopsy range from 0 (absent) to 4 (cirrhosis).	1 year
The Number (Percentage) of Subjects That Develop a Clinical Complication of Cirrhosis	The number (percentage) of subjects with progression of cirrhosis at 1 year, defined as the development of any of the following clinical complications: esophageal variceal hemorrhage or portal hypertensive gastropathy hemorrhage (confirmed by endoscopy or interventional radiology); clinically apparent ascites; spontaneous bacterial peritonitis; overt hepatic encephalopathy; an increase in Child-Turcotte-Pugh score ≥2 points; newly diagnosed varices in a subject without prior varices; progression from small to medium or large varices; qualification for liver transplant defined as a Model for End-Stage Liver Disease (MELD) score ≥15; listing for a liver transplant or the performance of a liver transplant; liver-related mortality	1 year

Collaborators and Investigators

• Sponsor: Galectin Therapeutics Inc.
• Collaborators: Dr. Naga Chalasani, MD, Indiana University; Dr. Stephen A. Harrison, MD, Brooke Army Medical Center

Publications and helpful links

General Publications

• Chalasani N, Abdelmalek MF, Garcia-Tsao G, Vuppalanchi R, Alkhouri N, Rinella M, Noureddin M, Pyko M, Shiffman M, Sanyal A, Allgood A, Shlevin H, Horton R, Zomer E, Irish W, Goodman Z, Harrison SA, Traber PG; Belapectin (GR-MD-02) Study Investigators. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension. Gastroenterology. 2020 Apr;158(5):1334-1345.e5. doi: 10.1053/j.gastro.2019.11.296. Epub 2019 Dec 5.
• Are VS, Vuppalanchi R, Vilar-Gomez E, Chalasani N. Enhanced Liver Fibrosis Score Can Be Used to Predict Liver-Related Events in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis. Clin Gastroenterol Hepatol. 2021 Jun;19(6):1292-1293.e3. doi: 10.1016/j.cgh.2020.06.070. Epub 2020 Jul 3.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: June 2, 2015
• First Submitted That Met QC Criteria: June 3, 2015
• First Posted (Estimate): June 4, 2015

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Liver Cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Fibrosis; Hypertension; Liver Cirrhosis; Hypertension, Portal
• Other Study ID Numbers: GT-026