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

Primary Purpose

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

Status

Unknown status

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Betaine (trimethyglycine)

About this trial

This is an interventional treatment trial for Non-Alcoholic Fatty Liver Disease

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

VA Long Beach Healthcare SystemRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

diabetic patients with NAFLD

non-diabetics with NAFLD

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)

Full Information

NCT ID

NCT03073343

First Posted

February 20, 2017

Last Updated

March 16, 2020

Sponsor

Southern California Institute for Research and Education

1. Study Identification

Unique Protocol Identification Number

NCT03073343

Brief Title

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

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

March 2020

Overall Recruitment Status

Unknown status

Study Start Date

November 12, 2013 (Actual)

Primary Completion Date

December 30, 2021 (Anticipated)

Study Completion Date

December 30, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Southern California Institute for Research and Education

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

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)

Allocation

Randomized

Enrollment

48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

diabetic patients with NAFLD

Arm Type

Active Comparator

Arm Description

Arm Title

non-diabetics with NAFLD

Arm Type

Active Comparator

Arm Description

Intervention Type

Dietary Supplement

Intervention Name(s)

Betaine (trimethyglycine)

Intervention Description

Primary Outcome Measure Information:

Title

Change in alanine aminotransferase (ALT) level in all study participants

Description

Compare the week 12 ALT levels with the baseline ALT in study patients. Comparison will be performed using a paired t-test.

Time Frame

after 12 weeks of Betaine

Secondary Outcome Measure Information:

Title

Compare changes in alanine aminotransferase (ALT) level in both cohorts

Description

A Paired T test analysis will compare changes in ALT levels between Patients with NIDDM (cohort 1) and Patients without NIDDM (cohort 2)

Time Frame

after 12 weeks of Betaine

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Timothy R Morgan, MD

Phone

562-826-5212

timothy.morgan@va.gov

First Name & Middle Initial & Last Name or Official Title & Degree

Aliya Asghar, MPH

Phone

562-826-5212

aliya.asghar@va.gov

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Timothy R Morgan, MD

Organizational Affiliation

VA Long Beach Healthcare System

Official's Role

Principal Investigator

Facility Information:

Facility Name

VA Long Beach Healthcare System

City

Long Beach

State/Province

California

ZIP/Postal Code

90822

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Aliya Asghar, MPH

Phone

562-826-5212

aliya.asghar@va.gov

First Name & Middle Initial & Last Name & Degree

Timothy R Morgan, MD

Phone

562-826-5212

timothy.morgan@va.gov

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

IPD will not be shared with anyone outside authorized research personnel.

Citations:

PubMed Identifier

10348825

Citation

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.

Results Reference

background

PubMed Identifier

10051466

Citation

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.

Results Reference

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

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