S-adenosylmethionine (SAMe) in Patients With Primary Sclerosing Cholangitis (PSC)

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to investigate clinical effects (liver biochemistries, health-related quality of life, liver stiffness) and underlying mechanisms of hepatoprotection of S-adenosylmethionine in patients with primary sclerosing cholangitis. The study will be performed in a randomized and placebo-controlled fashion.

Detailed Description
-----------------
The study is designed as a randomised, double-blind, placebo-controlled trial. Eighty participants will be randomized in 1:1 ratio to one of two arms of the study: Intervention or Placebo. Participants in Intervention Group will be treated with S-adenosyl-L-methionine 1200 mg/daily in tablets in two divided doses (800mg in the morning and 400mg midday) over the period of 6 months. Patients in Placebo Group will receive a placebo of identical appearance, smell and taste, with the same schedule. Participants will be monitored in out-patient clinic at baseline, interim visits at weeks: 4, 12, end of treatment at 24 weeks and follow-up visit after 4-6 weeks wash-out period. Treatment adherence, adverse events, serum biochemistry and health related quality of life will be assessed at each visit. Liver fibrosis will be measured with transient elastography at baseline and at the end of treatment.

Official Title
-----------------
Clinical Effect and Molecular Mechanisms of Action of S-adenosylmethionine (SAMe) in Patients With Primary Sclerosing Cholangitis (PSC)

Conditions
-----------------
Primary Sclerosing Cholangitis (PSC)

Intervention / Treatment
-----------------
* Dietary Supplement: S-Adenosyl-L-methionine (SAMe)
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: primary sclerosing cholangitis fulfilling EASL criteria; age: 18 - 75 years; treatment with ursodeoxycholic acid (UDCA) in a dose of 13-15mg/kg b.w. for at least 6 months. Exclusion Criteria: inability to give informed consent; patients with other forms of chronic liver diseases; decompensated liver cirrhosis (Child-Pugh class B-C); patients with PSC who underwent stenting of their biliary tree within 6 months; other diseases or states that can affect quality of life and mood: decompensated diabetes mellitus, renal insufficiency requiring dialyses, malignancy, heart failure ≥ New York Heart Association (NYHA) II, organ transplantation, known HIV infection, rheumatoid arthritis, asthma, psychiatric disorders; treatment with: steroids, statins, rifampicin, antidepressants; pregnant or breastfeeding women; history of hypersensitivity reactions to S-adenosylmethionine; any other condition, which in the opinion of the investigators would impede the patient's participation or compliance in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S-adenosylmethionine (SAMe)<br>Participants randomized to SAMe Group will receive S-adenosyl-L-methionine 1200 mg/daily (as 2400mg SAMe disulfate tosylate) in tablets in two divided doses (800mg in the morning and 400mg midday) over the period of 6 months. In addition, patients will receive standard treatment with ursodeoxycholic acid (UDCA) at a dose of 13-15 mg/kg b.w. | Dietary Supplement: S-Adenosyl-L-methionine (SAMe)<br>* S-adenosyl-L-methionine 1200 mg/daily as 2400mg S-Adenosyl-L-methionine disulfate tosylate<br>* Other names: S-adenosylmethionine;|
| Placebo Comparator: Placebo<br>Patients in Placebo Group will receive a placebo of identical appearance, smell and taste, with the same schedule. In addition, patients will receive standard treatment with ursodeoxycholic acid (UDCA) at a dose of 13-15 mg/kg.In addition, patients will receive standard treatment with ursodeoxycholic acid (UDCA) at a dose of 13-15 mg/kg b.w. | Other: Placebo<br>* Placebo of identical appearance, smell and taste, with the same schedule.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in liver biochemistries | Change in levels of liver enzymes (Aspartate Transaminase, Alanine Transaminase, Gamma-glutamyltransferase, Alkaline Phosphatase) | 6 months | 
| Change in Health-related Quality of Life | Change in severity of chronic fatigue and other aspects of health-related quality of life assessed by questionnaire SF-36 (36-Item Short Form Survey). | 6 months | 
| Change in PSC-related Quality of Life | Change in severity of chronic fatigue and other aspects of health-related quality of life assessed by questionnaire PBC-40. | 6 months | 
| Change in Quality of Life | Change in severity of generalized anxiety disorder assessed by questionnaire GAD-7 (General Anxiety Disorder-7). | 6 months | 
| Change in pruritus severity | Change in pruritus severity on the Visual Analogue Scale (VAS) - 0 (no pruritus) to 10 (worst pruritus). | 6 months | 
| Change in liver stiffness | Change in liver stiffness on liver elastography (measured in kPa) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular assesment of hepatoprotective properties of SAMe | Assessment of changes in antioxidant defence system (assessed as plasma MDA, SOD2, FGF-19, TNF-α, IL6, IL10, TGFβ, INFγ, homocysteine concentrations). | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PSC