Effects of SAMe in Patients With Alcoholic Liver Disease

• Sponsor: University of California, Davis (Other)
• Overall Status: Completed
• CT.gov ID: NCT00573313
• Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA) (NIH), Abbott (Industry), Joint Clinical Research Center (Other), University of Colorado, Denver (Other), University of California, Los Angeles (Other)
• Enrollment: 94
• Location: 1
• Arms: 2
• Duration (Months): 48
• Patients Per Site Per Month: 2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Liver Disease, Alcoholic	Drug: S-adenosylmethionine; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 94 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effects of SAMe in Patients With Alcoholic Liver Disease
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: S-adenosylmethionine (SAMe) Alcoholic liver disease patients receiving S-adenosylmethionine (SAMe)at 400 mg capsule three times daily for 24 weeks	Drug: S-adenosylmethionine; Alcoholic liver disease patients received drug at dose of 400 mg three times daily for 24 weeks.
Placebo Comparator: Sugar pill ALD subjects receiving Placebo three times daily for 24 weeks.	Drug: Placebo; Alcoholic liver disease patients received identical size and shape sugar pill placebo three times daily for 24 weeks.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Davis Medical Center	Sacramento	California	United States	95817

Sponsors and Collaborators

• University of California, Davis
• National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Abbott
• Joint Clinical Research Center
• University of Colorado, Denver
• University of California, Los Angeles

Investigators

• Principal Investigator: Charles H Halsted, MD, University of California, Davis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, Davis
• ClinicalTrials.gov Identifier: NCT00573313
• Other Study ID Numbers: 200311168; R01AA014562; NIAAA_HAL-014562
• First Posted: Dec 14, 2007
• Last Update Posted: May 30, 2017
• Last Verified: May 1, 2017

• Keywords provided by University of California, Davis: Alcoholic Liver Disease (ALD); S-adenosylmethionine; SAMe
• Additional relevant MeSH terms: Liver Diseases; Liver Diseases, Alcoholic

Study Results

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 Detail	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.

Arm/Group Title	S-adenosylmethionine (SAMe)	Healthy	Sugar Pill	Lifestyle Counseling
Arm/Group Description	Alcoholic liver disease patients receiving S-adenosylmethionine (SAMe)at 400 mg capsule three times daily for 24 weeks.	Subjects were enrolled into this arm for baseline measurement only.	ALD subjects receiving Placebo three times daily for 24 weeks.	Subjects were enrolled into this arm for baseline measurements only.
Period Title: Overall Study
STARTED	18	28	19	26
COMPLETED	13	28	13	26
NOT COMPLETED	5	0	6	0

Baseline Characteristics

Arm/Group Title	S-adenosylmethionine (SAMe) Treatment	Healthy	Lifestyle Counseling	Sugar Pill Placebo	Total
Arm/Group Description	The treatment group received S-adenosylmethionine (SAM) 400 mg three times daily.	Healthy subjects without alcoholism or liver disease.	Active drinkers non liver disease subjects	The placebo group received a sugar pill identical in appearance that was taken three times daily.	Total of all reporting groups
Overall Participants	18	28	26	19	91
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	17 94.4%	28 100%	25 96.2%	19 100%	89 97.8%
>=65 years	1 5.6%	0 0%	1 3.8%	0 0%	2 2.2%
Sex: Female, Male (Count of Participants)
Female	6 33.3%	10 35.7%	4 15.4%	6 31.6%	26 28.6%
Male	12 66.7%	18 64.3%	22 84.6%	13 68.4%	65 71.4%
Region of Enrollment (participants) [Number]
United States	18 100%	28 100%	26 100%	19 100%	91 100%

Outcome Measures

1. Primary Outcome

Title	Changes in Serum AST Levels
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	S-adenosylmethionine (SAMe)	Sugar Pill
Arm/Group Description	Alcoholic liver disease patients receiving S-adenosylmethionine (SAMe)at 400 mg capsule three times daily for 24 weeks.	ALD subjects receiving Placebo three times daily for 24 weeks.
Measure Participants	13	13
Median (Full Range) [Units per liter (U/L)]	-13.5 (51.344)	-56 (18.243)

2. Secondary Outcome

Title	Changes in Serum SAM
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	S-adenosylmethionine (SAMe)	Sugar Pill
Arm/Group Description	Alcoholic liver disease patients receiving S-adenosylmethionine (SAMe)at 400 mg capsule three times daily for 24 weeks.	ALD subjects receiving placebo sugar pill three times daily for 24 weeks.
Measure Participants	13	13
Median (Full Range) [nmol/liter]	54 (92.535)	7 (150.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-adenosylmethionine (SAMe), Sugar Pill
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments	The data provided here are for changes in serum AST levels as representative of all clinical laboratory parameters measured.
	Method	ANCOVA
	Comments	Analysis of covariance controlled for baseline data, e.g. AST.
Method of Estimation	Estimation Parameter	Ratio of Geometric Means at 24 weeks.
	Estimated Value	0.1505
	Confidence Interval	(2-Sided) 95%; -0.1853 to 0.4863
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1615
	Estimation Comments	Obtained median values and ranges and log transformations of SD.

Adverse Events

Adverse Event Reporting Description	Adverse events were only measured in participants with alcoholic liver disease who were randomized to receive intervention.
Arm/Group Title	S-adenosylmethionine (SAMe) Treatment		Sugar Pill Placebo
Arm/Group Description	The treatment group received S-adenosylmethionine (SAM) 400 mg three times daily.		The placebo group received a sugar pill identical in appearance that was taken three times daily.
All Cause Mortality
	S-adenosylmethionine (SAMe) Treatment		Sugar Pill Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	S-adenosylmethionine (SAMe) Treatment		Sugar Pill Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	S-adenosylmethionine (SAMe) Treatment		Sugar Pill Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/18 (55.6%)		10/19 (52.6%)
Gastrointestinal disorders
Diarrhea	4/18 (22.2%)	4	4/19 (21.1%)	4
Abdominal bloating	3/18 (16.7%)	3	2/19 (10.5%)	2
Nausea	0/18 (0%)	0	2/19 (10.5%)	2
Abdominal pain	3/18 (16.7%)	3	2/19 (10.5%)	2
Nervous system disorders
Headache	2/18 (11.1%)	2	0/19 (0%)	0
Night sweats, hair loss, xerostomia	1/18 (5.6%)	1	0/19 (0%)	0

Limitations/Caveats

Relatively small numbers of subjects analyzed with 13 each completers in the treatment and placebo groups. Within each group, violation of protocal by resumption of alcohol intake accounted for dropouts.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.