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

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)

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.

Study Overview

• Status: Unknown
• Conditions: Non-Alcoholic Fatty Liver Disease; Non Insulin Dependent Diabetes; ALT
• Intervention / Treatment: Dietary supplement: Betaine (trimethyglycine)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Timothy R Morgan, MD; Phone Number: 562-826-5212; Email: timothy.morgan@va.gov
• Study Contact Backup: Name: Aliya Asghar, MPH; Phone Number: 562-826-5212; Email: aliya.asghar@va.gov

Study Locations

• United States
  • California
    • Long Beach, California, United States, 90822
      • Recruiting
      • VA Long Beach Healthcare System
      • Contact: Timothy R Morgan, MD; Phone Number: 562-826-5212; Email: timothy.morgan@va.gov
      • Contact: Aliya Asghar, MPH; Phone Number: 562-826-5212; Email: aliya.asghar@va.gov

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:

Inclusion Criteria for all patients:

1. Age 18-75 years
2. A clinical diagnosis of non-alcoholic fatty liver disease.
3. Alanine aminotransferase (ALT) levels ≥60 IU/mL

4. 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:

1. Evidence of liver disease other than non-alcoholic fatty liver disease or non-alcoholic steatohepatitis
2. 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
3. Active substance abuse within the past year
4. Prior or ongoing use of injectable insulin
5. Use of oral corticosteroids within the prior 30 days
6. Hospitalization within the past 14 days
7. Known HIV infection
8. HgA1c >10%
9. Known heart failure of New York Heart Association class 2, 3, or 4
10. Any condition, which in the opinion of the investigator, would impede compliance or hinder the completion of the study
11. History of allergic reactions attributed to compounds of similar chemical or biologic composition to betaine
12. Current use of betaine or S-adenosylmethionine supplements, or refusal to abstain from their use during the study
13. Known cystathionine beta-synthase (CBS) deficiency.
14. Pregnancy or refusal to use birth control measures or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: diabetic patients with NAFLD; 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); 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.
Active Comparator: non-diabetics with NAFLD; 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); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Southern California Institute for Research and Education
• Investigators: Principal Investigator: Timothy R Morgan, MD, VA Long Beach Healthcare System

Publications and helpful links

General Publications

• Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999 Jun;116(6):1413-9. doi: 10.1016/s0016-5085(99)70506-8.
• Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999 Mar;29(3):664-9. doi: 10.1002/hep.510290347.

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2013
• Primary Completion (Anticipated): December 30, 2021
• Study Completion (Anticipated): December 30, 2021

Study Registration Dates

• First Submitted: February 20, 2017
• First Submitted That Met QC Criteria: March 2, 2017
• First Posted (Actual): March 8, 2017

Study Record Updates

• Last Update Posted (Actual): March 17, 2020
• Last Update Submitted That Met QC Criteria: March 16, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Liver Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Non-alcoholic Fatty Liver Disease; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Gastrointestinal Agents; Hypolipidemic Agents; Lipid Regulating Agents; Lipotropic Agents; Betaine
• Other Study ID Numbers: Betaine 2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: IPD will not be shared with anyone outside authorized research personnel.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No