Study on GS300 on NAFLD

Study Overview
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Brief Summary
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To determine the efficacy of GS300 when administered for 24 weeks in patients with Nonalcoholic Fatty Liver Disease (NAFLD).

Detailed Description
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This is a multicenter, randomized, placebo-controlled, double-blinded, parallel-group study. Patients will be randomized 1:1 to receive either GS300 or placebo. The study includes an up to 6 weeks screening period, a 24-week treatment period, and a 1-week follow-up period. Approximately 250 patients (125 patients per arm) will be enrolled (at least 40% from each gender and at least 40% from US and 40% from Europe).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Assessing the Effect of GS300 on Nonalcoholic Fatty Liver Disease

Conditions
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Nonalcoholic Fatty Liver, Weight Loss

Intervention / Treatment
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* Device: GS300
* Device: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 22 years and ≤ 65 years Body Mass Index (BMI) ≥ 27 and ≤ 40 kilogram (kg)/meter2 (m2) Negative for Hepatitis B, C and Human Immunodeficiency Virus (HIV) within 6 months of screening [HbsAg negative and Hepatitis C Virus (HCV) RNA negative; subjects treated and cured of HCV must have completed treatment and tested negative for HCV at least 2 years prior to study enrollment] Fibroscan CAP score > 300 decibels (dB)/m Stable body weight defined as less than 5% change in body weight in the 3 months prior to screening (per patient report) Approximately 250 patients (approximately 125 patients per treatment arm) Prediabetes i) Untreated prediabetic patients with FPG ≥ 100 mg/ dL (≥ 5.6 mmol/L) and < 126 mg/dL (< 7.0 mmol/L) at both Screening Visits with HbA1c ≤ 6.4% (≤ 46 mmol/mol) - if only one value is within this range, the other value should not be ≥ 126 mg/dL (≥ 7.0 mmol/L) and HbA1c should be ≥ 5.7% (≥ 39 mmol/mol) and ≤ 6.4% (≤ 46 mmol/mol) ii) Drug-treated (metformin) prediabetic patients with FPG ≥ 70 mg/dL (≥ 3.9 mmol/L) and < 126 mg/dL (< 7.0 mmol/L) at both Screening Visits Type 2 Diabetes i) Untreated type 2 diabetic patients with FPG ≤ 200 mg/dL (≤ 11.2 mmol/L) at both Screening Visits and either FPG ≥ 126 mg/dL (≥ 7.0 mmol/L) at both Screening Visits or FPG < 126 mg/dL (< 7.0 mmol/L) at one or both Screening Visits with HbA1c ≥ 6.5% (≥ 48 mmol/mol) ii) Drug-treated [metformin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors, and/or insulin] type 2 diabetic patients with FPG ≥ 70 mg/dL (≥ 3.9 mmol/L) and ≤ 270 mg/dL (≤ 15.1 mmol/L) at both Screening Visits Note, approximately 10% to 20% of enrolled Type 2 diabetic patients will be on insulin therapy Normoglycemia (up to approximately 10% of patients) Normoglycemic patients with FPG ≥ 70 mg/dL (≥ 3.9 mmol/L) and < 100 mg/ dL (< 5.6 mmol/L) at both Screening Visits with HbA1c < 5.7% (< 39 mmol/mol) and HOMA-IR ≥ 3.0 MRI PDFF ≥ 10% Willing to sign the ICF prior to any study related procedures Exclusion Criteria: Self-reported alcohol intake > 20 gram (g)/day for women and > 30 g/day for men (on average per day) as per medical history Alcohol Use Disorders Identification Test (AUDIT) questionnaire: AUDIT-C score of ≥ 4 in men and ≥ 3 in women will be followed by a full AUDIT questionnaire by interview with patients excluded for score ≥ 8 Prior liver transplant Liver cirrhosis as evidenced by any of the following: Serum albumin < 3.5 g/dL (0.53 mmol/L) INR > 1.3 (unless due to anticoagulant therapy) AST/ALT ratio ≥ 2 Direct bilirubin > 0.3 mg/dL (5.13 micromol (micromol)/L) Platelet count < 150,000/microL History or evidence of other chronic liver diseases, including, but not limited to the following: Current active autoimmune hepatitis Primary biliary cholangitis (PBC) Primary sclerosing cholangitis Wilson's disease Alpha-1-antitrypsin (A1AT) deficiency Hemochromatosis Drug-induced liver disease, as defined on the basis of typical exposure and history Bile duct obstruction Suspected or proven liver cancer History of hepatic encephalopathy Portal hypertension (esophageal varices, ascites, splenomegaly) History of gastric surgery (up to 10% patients with history of gastric bypass or sleeve gastrectomy may be enrolled if the surgery occurred more than 6 months prior to enrollment and patients had a weight change < 5% during the 3 months prior to enrollment) Angina, coronary bypass, or myocardial infarction within 6 months prior to Screening Visit Inflammatory bowel disease, celiac disease, or other significant gastrointestinal disease - for example, a history of bowel obstruction without surgical correction (patients with irritable bowel syndrome may be enrolled) Pregnancy Absence of medically approved contraceptive methods in females of childbearing potential (e.g., hysterectomy, oral contraceptives, non-oral contraceptive medications or intrauterine device combined with a barrier method, two combined barrier methods such as diaphragm and condom or spermicide, or condom and spermicide; bilateral tubal ligation and vasectomy are not acceptable methods) Type 1 Diabetes HbA1c > 8.5% (> 69 mmol/mol) Serum LDL-C ≥ 160 mg/dL (≥ 4.15 mmol/L) Serum triglycerides ≥ 350 mg/dL (≥ 3.96 mmol/L) Use of any medications for the treatment of diabetes within 3 months prior to enrollment. Note, metformin, DPP-4 inhibitors, and insulin at a stable dose over the last 3 months are allowed. Insulin dose variance of 20% (decrease or increase) is allowed. Any change in standard of care or background therapy for liver disease or other ongoing chronic conditions within 3 months prior to enrollment, including changes in the following: Antidiabetic medications (metformin, DPP-4 inhibitors, insulin) Thyroid hormones Medications treating depression Medications treating dyslipidemia Medications treating hypertension Vitamin E Regular/daily use of any of the following within 3 months prior to enrollment or anticipated regular/daily use during the study period: High dose nonsteroidal anti-inflammatory drugs (NSAIDS) (equivalent of > 3,200 mg/day ibuprofen) Systemic corticosteroids, anabolic steroids Methotrexate, amiodarone, tamoxifen, tetracyclines, estrogens at doses greater than those used for hormone replacement, valproic acid Probiotic supplements (yogurt is allowed) Addictive, non-prescribed medications including amphetamines, barbiturates, cocaine, opiates, methadone and phencyclidine as per medical history or regular daily use of cannabinoids Use of any anti-obesity medications (including herbal preparations) within 2 months prior to enrollment or any anticipated use during the study period History of allergic reaction to carboxymethylcellulose (CMC), citric acid, sodium stearyl fumarate, raw cane sugar, gelatin, or titanium dioxide Currently enrolled in another investigational device or drug study, or less than 3 months since ending another investigational device or drug study(s), or receiving other investigational treatment(s) Any disease or condition that, in the opinion of the investigator or Sponsor, would interfere with study participation

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned to one of two groups in parallel for the duration of the study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active<br>GS300: Three (3) GS300 capsules [approximately 0.65 grams (g)] two (2) times per day ingested 10 minutes (min) before meals (i.e., lunch and dinner) - total of 3.9 g per day | Device: GS300<br>* Gelesis300 hydrogel in gelatin capsules<br>|
| Placebo Comparator: Placebo<br>Placebo: Three (3) placebo capsules two (2) times per day 10 min before meals (i.e., lunch and dinner) | Device: Placebo<br>* Placebo capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight loss ≥ 5% | Proportion of patients with weight loss ≥ 5% at Week 24. | 24 Weeks | 
| Placebo-adjusted percent change in weight from Baseline to Week 24 | Placebo-adjusted percent change in weight from Baseline to Week 24. | 24 Weeks | 
| Relative reduction in liver fat | Relative reduction in liver fat from Baseline to Week 24, as measured by hepatic Magnetic Resonance Imaging Proton Density Fat Fraction (MRI PDFF). | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight loss ≥ 7.5% | To assess reduction in weight (≥ 7.5%) in patients with NAFLD treated with GS300 or placebo. | 24 Weeks | 
| Weight loss ≥ 10% | To assess reduction in weight (≥ 10%) in patients with NAFLD treated with GS300 or placebo. | 24 Weeks | 
| To evaluate the percentage of patients with ≥ 30% relative reduction in liver fat | To evaluate the percentage of patients with ≥ 30% relative reduction in liver fat in patients treated with GS300 or placebo. | 24 Weeks | 
| To assess placebo-adjusted waist circumference reduction | To assess placebo-adjusted waist circumference reduction after 24 weeks of treatment with GS300 or placebo. | 24 Weeks | 
| To assess the impact of GS300 on glycemic control in patients with NAFLD | To assess the impact of GS300 on glycemic control in patients with NAFLD treated with GS300 or placebo. | 24 Weeks | 
| To assess the impact of GS300 on liver enzymes in patients with NAFLD | To assess the impact of GS300 on liver enzymes in patients with NAFLD treated with GS300 or placebo. | 24 Weeks |