Effect of Simvastatin on the Prognosis of Primary Primary Sclerosing Cholangitis (PSC)

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, placebo controlled multicenter study. A total of 700 patients will be included. The study will include patients with primary sclerosing cholangitis (PSC) for daily intake of 40 mg simvastatin/placebo for 5 years. The aim is to study effect of prognosis of PSC by long term intake of simvastatin. Outcome measures are death, liver transplantation, cholangiocarcinoma or bleeding from esophageal varices. Subjects will be randomized (1:1) between Simvastatin and placebo.

Official Title
-----------------
Effect of Simvastatin on the Prognosis of Primary Sclerosing Cholangitis (PSC); A Randomized, Double-blind, Placebo Controlled Multicenter Study

Conditions
-----------------
Primary Sclerosing Cholangitis

Intervention / Treatment
-----------------
* Drug: Simvastatin 40mg
* Drug: Placebo oral tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: PSC verified by cholangiography or liver biopsy, with or without irritable bowel disease (IBD). Men and women between ≥18 years and ≤75 years. Written informed consent. A magnetic resonance imaging (MRI) or Magnetic resonance cholangiopancreatography (MRCP) performed within 4 months prior to randomization. Colonoscopy performed within 24 months prior to randomization, if known IBD. For women of childbearing potential efficient contraceptive. Exclusion Criteria: Subjects on waiting list for transplantation Transplanted subjects Previous variceal bleeding Previous hepatobiliary malignancy Subjects with secondary sclerosing cholangitis Intake of any type of statins within 3 months prior to randmization Known intolerance to simvastatin. Pregnancy or breastfeeding.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simvastatin<br>Simvastatin 40 mg administered orally daily for 5 years. | Drug: Simvastatin 40mg<br>* 40 mg orally daily for 5 years.<br>|
| Placebo Comparator: Placebo<br>Placebo for Simvastatin 40 mg administered orally daily for 5 years. | Drug: Placebo oral tablet<br>* 40 mg orally daily for 5 years.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival from time to randomization to death from any cause. | Time from the date of randomization to the date of death, assessed up to 5 years. | 
| Listing for liver transplantation | Date the subject is getting registered on the waiting list for liver transplantation. | Time from the date of randomization to the date of listing for liver transplantation, assessed up to 5 years. | 
| Time to first varices bleeding | Date of the subject's first varices bleeding according to hospital patient records. | Time from the date of randomization to the date of the first varices bleeding, assessed up to 5 years. | 
| Time to diagnosis of cholangiocarcinoma, gall bladder cancer, or hepatocellular cancer. | Diagnosis of cancer of bile duct cancer or gall bladder, or hepatocellular cancer according to hospital patient records. | Time from the date of randomization to cancer diagnosis, assessed up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on serum concentration of alkaline phosphatase (ALP). | Assessment of changes in the serum concentration of alkaline phosphatase. | Assessed yearly up to 5 years. | 
| Effect on serum concentration of bilirubin | Assessment of changes in the serum concentration of bilirubin. | Assessed yearly up to 5 years. | 
| Effect on the progress of PSC by liver failure measurement | Assessment of liver failure using Model for End Stage Liver Disease (MELD) Score (biochemical and clinical variables). | Assessed at every visit except the 3 months visit, up to 5 years. | 
| Effect on the progress of PSC by liver failure measurement. | Assessment of liver failure using Child Pugh Score | Assessed at every visit except the 3 months visit, up to 5 years. | 
| Effect on the progress of PSC assessed by cholangiography at MRI. | Progress assessed by cholangiography MRI | Assessed at inclusion and the 60 months visit. | 
| Effect on the progress of PSC assessed by elastography | Assessment of fibrosis stage using elastography. | Assessed yearly up to 5 years. | 
| Effect on the progress of PSC assessed by clinical symptoms | Assessment of symptoms including itching and bacterial cholangitis that requires treatment, ascites and encephalopathy. | Assessed yearly up to 5 years. | 
| Effect on the progress of PSC assessed by measurement of biliary dysplasia | Biliary dysplasia from brush samples taken at endoscopic retrograde cholangiopancreatography (ERCP). | Assessed upon clinical indication, up to 5 years. | 
| Effect on the development of colon cancer or colon dysplasia. | Development of colon cancer and/or colon dysplasia according to hospital patient records. | Assessed at 60 months. | 
| Effect on the progress of PSC assessed by serum fibrosis markers | Fib-4, ELF (if funded) | Assessed yearly up to 5 years |