Liver Disease, Alcoholic
Conditions
Keywords
Alcoholic Liver Disease (ALD), S-adenosylmethionine, SAMe
Brief summary
Prior studies in animal models have established that the pathogenesis of alcoholic liver disease (ALD) is regulated in part by the effects of chronic alcohol abuse on hepatic methionine metabolism. The hypothesis of the clinical study was that provision of the methionine metabolite S-adenosylmethionine (SAM) would correct abnormal hepatic methionine metabolism thereby effectively treating ALD. The two goals of the clinical research were a)to determine the clinical relationship of aberrant hepatic methionine metabolism to ALD by comparisons of patterns of serum methionine metabolites in groups of ALD patients, alcoholics without liver disease, and normal healthy subjects, and b) to determine the treatment effects of SAM on patterns of serum methionine metabolites and on the histopathology and biochemical features of liver injury in ALD patients.
Detailed description
We assessed a total of 297 potential ALD candidates, from whom 40 were enrolled in the study. In addition, we enrolled 26 gender matched active alcohol drinkers without liver disease (AD) and 28 age and gender matched healthy control subjects (HS). Of the original 40 ALD subjects who provided initial enrollment data, 3 declined to proceed with the trial. Therefore, 37 ALD patients were randomized to receive SAM at a dose of 400 mg or placebo three times daily for 24 weeks. However 11 of these dropped out after initial evaluation, leaving 26 ALD patients, 13 in each arm, who completed the 24 week trial.
Interventions
Alcoholic liver disease patients received drug at dose of 400 mg three times daily for 24 weeks.
DRUGPlacebo
Alcoholic liver disease patients received identical size and shape sugar pill placebo three times daily for 24 weeks.
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Abbott
Joint Clinical Research Center
University of Colorado, Denver
University of California, Los Angeles
University of California, Davis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* ALD) a history of chronic alcoholism according to established AUDIT and WHO criteria with the presence of clinical and laboratory features of established liver disease. Also, willingness to undergo liver biopsies at start and completion of the study, and to comply with study medication or placebo and required clinic visits and blood sampling. * a history of chronic alcoholism without evidence of liver disease; * healthy subjects without history of alcoholism or presence of liver disease.
Exclusion criteria
* viral Hepatitis B or C * hemochromatosis * Wilson Disease * sclerosing cholangitis * primary biliary cirrhosis * other chronic disease * renal insufficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Serum AST Levels | Week 0 to week 24 | Biochemical values for liver function tests and histopathology scores were obtained at week 0 and 24 of the treatment trial, and changes in each were recorded. Here are reported changes in aspartate transaminase (AST) as representative of all changes. Since only baseline values were obtained in the Healthy and Lifestyle counseling groups, there are no recorded changes in these two groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Serum SAM | September 2005- June 2009 | We compared serum levels of SAM at time 0 and week 24 of the study in the alcoholic liver disease groups only, since these parameters were measured in the healthy and lifestyle coaching groups only at baseline. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited between July 1, 2005 and June 30, 2009 through the emergency room and clinics of the University of California Davis Health System.
Pre-assignment details
Three (3) participants with alcoholic liver disease dropped out before randomization. Participants (128) excluded because did not meet recruitment criteria, (105) because had not telephone or other means of contact, or (24) declined to participate.
Participants by arm
| Arm | Count |
|---|---|
| S-adenosylmethionine (SAMe) Treatment The treatment group received S-adenosylmethionine (SAM) 400 mg three times daily. | 18 |
| Healthy Healthy subjects without alcoholism or liver disease. | 28 |
| Lifestyle Counseling Active drinkers non liver disease subjects | 26 |
| Sugar Pill Placebo The placebo group received a sugar pill identical in appearance that was taken three times daily. | 19 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 5 | 0 | 6 | 0 |
Baseline characteristics
| Characteristic | S-adenosylmethionine (SAMe) Treatment | Healthy | Lifestyle Counseling | Sugar Pill Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 28 Participants | 25 Participants | 19 Participants | 89 Participants |
| Region of Enrollment United States | 18 participants | 28 participants | 26 participants | 19 participants | 91 participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 4 Participants | 6 Participants | 26 Participants |
| Sex: Female, Male Male | 12 Participants | 18 Participants | 22 Participants | 13 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 18 | 10 / 19 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 |
Outcome results
Primary
Changes in Serum AST Levels
Biochemical values for liver function tests and histopathology scores were obtained at week 0 and 24 of the treatment trial, and changes in each were recorded. Here are reported changes in aspartate transaminase (AST) as representative of all changes. Since only baseline values were obtained in the Healthy and Lifestyle counseling groups, there are no recorded changes in these two groups.
Time frame: Week 0 to week 24
Population: Analysis of AST values was based on numbers of participants in each group who completed the study. Analysis is pre-specified to apply only to subjects with alcoholic liver disease.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| S-adenosylmethionine (SAMe) | Changes in Serum AST Levels | -13.5 Units per liter (U/L) | Full Range 51.344 |
| Sugar Pill | Changes in Serum AST Levels | -56 Units per liter (U/L) | Full Range 18.243 |
Secondary
Changes in Serum SAM
We compared serum levels of SAM at time 0 and week 24 of the study in the alcoholic liver disease groups only, since these parameters were measured in the healthy and lifestyle coaching groups only at baseline.
Time frame: September 2005- June 2009
Population: Whereas 37 subjects started the protocol, due to protocol violation, there remained 26 subjects, 13 in each group, for final analyses. Here are reported changes in AST values to represent all variables.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| S-adenosylmethionine (SAMe) | Changes in Serum SAM | 54 nmol/liter | Full Range 92.535 |
| Sugar Pill | Changes in Serum SAM | 7 nmol/liter | Full Range 150.5 |
Comparison: Power calculation indicated that a sample size of 20 subjects per treatment arm would detect differences between groups of 0.9 within-subject standard deviations or higher at 80% power and 5% level of significance.p-value: 0.3695% CI: [-0.1853, 0.4863]ANCOVA