A Prospective, Randomized, Open Label Trial of Two Doses of Oral Betaine

Study Overview
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Brief Summary
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Betaine (trimethyglycine) is a food supplement that is approved for sale in the United States without a prescription. In this study, betaine will be provided to patients as a powder that can be mixed with aqueous solutions and consumed orally.

Detailed Description
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This is a prospective, unblinded, randomized study of oral betaine in diabetic and non-diabetic patients who have a clinical diagnosis of NAFLD and an ALT≥ 50 IU/mL. A clinical diagnosis of NAFLD is based on the presence of risk factors for NAFLD (such as overweight and insulin resistance) and the exclusion of other causes of liver disease, such as alcohol or viral hepatitis. Two cohorts of patients will be studied: Cohort 1 (diabetic) will consist of patients with a clinical diagnosis of non-insulin dependent type II diabetes mellitus; Cohort 2 (non-diabetics) will consist of patients without a clinical diagnosis of type 2 diabetes mellitus. 24 patients will be enrolled in each cohort (total of 48 patients enrolled in the study) with an anticipated drop out of 4 subjects per cohort. Patients will be given dietary instructions and advice on exercise appropriate for the management of NAFLD (NIDDK and liverfoundation.org handouts). Patients will be prescribed 4 grams of betaine/day (2 grams PO BID) for the first 4 weeks of the study. After 4 weeks, patients in each cohort (NIDDM and non-diabetic) will be randomized (1:1) to continue receiving betaine 4 grams per day or increase to 8 grams per day for an additional 8 weeks. All patients will be seen in clinic on a monthly basis during treatment, and again 4 and 12 weeks after completion of betaine treatment. The total duration of the study is 24 weeks (12 weeks of betaine treatment and 12 weeks of follow-up). The primary outcome is change in ALT during 12 weeks of betaine treatment (i.e., ALT at week 12 compared with ALT at baseline (entry). Secondary outcomes include safety, efficacy of betaine in each cohort, and are changes in laboratory tests related to NAFLD.

Official Title
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A Prospective, Randomized, Open Label Trial of Two Doses of Oral Betaine in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) and Elevated Alanine Aminotransferase (ALT)

Conditions
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ALT, Non-Alcoholic Fatty Liver Disease, Non Insulin Dependent Diabetes

Intervention / Treatment
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* Dietary Supplement: Betaine (trimethyglycine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria for all patients: Age 18-75 years A clinical diagnosis of non-alcoholic fatty liver disease. Alanine aminotransferase (ALT) levels ≥60 IU/mL Laboratory tests as defined below: Platelets > 100,000/dL Total bilirubin < 2 mg/dL Creatinine < 1.6 mg/dL Inclusion Criteria for Group 1: diabetic patients 1. At least one of the following: Fasting blood sugar ≥ 126mg/dL Hemoglobin A1c (HgA1c) of > 6.5% 2-hour plasma glucose level of > 200mg/dL during a glucose tolerance test Receiving treatment with insulin sensitizing drugs (metformin) or sulfonylureas (glipizide, etc.) 3. Inclusion Criteria for Group 2: Non-diabetic patients with insulin resistance (must have both) Fasting blood glucose of 100-125 mg/dL and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score >3.0 Exclusion Criteria: Evidence of liver disease other than non-alcoholic fatty liver disease or non-alcoholic steatohepatitis Alcohol consumption of more than 12g/d (1 drink) for females or more than 24g/day (2 drinks) for males, for 3 months during the past year Active substance abuse within the past year Prior or ongoing use of injectable insulin Use of oral corticosteroids within the prior 30 days Hospitalization within the past 14 days Known HIV infection HgA1c >10% Known heart failure of New York Heart Association class 2, 3, or 4 Any condition, which in the opinion of the investigator, would impede compliance or hinder the completion of the study History of allergic reactions attributed to compounds of similar chemical or biologic composition to betaine Current use of betaine or S-adenosylmethionine supplements, or refusal to abstain from their use during the study Known cystathionine beta-synthase (CBS) deficiency. Pregnancy or refusal to use birth control measures or breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Two cohorts of patients will be studied: Cohort 1 (diabetic) will consist of patients with a clinical diagnosis of non-insulin dependent type II diabetes mellitus; Cohort 2 (non-diabetics) will consist of patients without a clinical diagnosis of type 2 diabetes mellitus. 24 patients will be enrolled in each cohort (total of 48 patients enrolled in the study) with an anticipated drop out of 4 subjects per cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: diabetic patients with NAFLD<br>Patients will be prescribed 4 grams of betaine/day (2 grams PO BID) for the first 4 weeks of the study. After 4 weeks, patients in each cohort will be randomized (1:1) to continue receiving betaine 4 grams per day or increase to 8 grams per day for an additional 8 weeks. | Dietary Supplement: Betaine (trimethyglycine)<br>* Betaine (trimethyglycine) is a food supplement that is approved for sale in the United States without a prescription. In this study, betaine will be provided to patients as a powder that can be mixed with aqueous solutions and consumed orally.<br>|
| Active Comparator: non-diabetics with NAFLD<br>Patients will be prescribed 4 grams of betaine/day (2 grams PO BID) for the first 4 weeks of the study. After 4 weeks, patients in each cohort will be randomized (1:1) to continue receiving betaine 4 grams per day or increase to 8 grams per day for an additional 8 weeks. | Dietary Supplement: Betaine (trimethyglycine)<br>* Betaine (trimethyglycine) is a food supplement that is approved for sale in the United States without a prescription. In this study, betaine will be provided to patients as a powder that can be mixed with aqueous solutions and consumed orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in alanine aminotransferase (ALT) level in all study participants | Compare the week 12 ALT levels with the baseline ALT in study patients. Comparison will be performed using a paired t-test. | after 12 weeks of Betaine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare changes in alanine aminotransferase (ALT) level in both cohorts | A Paired T test analysis will compare changes in ALT levels between Patients with NIDDM (cohort 1) and Patients without NIDDM (cohort 2) | after 12 weeks of Betaine |