Randomized, Double-Blind, Placebo-Controlled Study of Simvastatin in Patients with Primary Sclerosing Cholangitis (PSC)

The primary objective of this study is to evaluate whether treatment with **simvastatin** prolongs survival free from bile duct cancer, variceal bleeding, and transplantation in patients with **primary sclerosing cholangitis (PSC)**. This is clinically relevant as PSC is a chronic liver disease that can lead to serious complications, including liver failure and cancer, thus improving survival without these events would significantly impact patient outcomes.

Secondary objectives include assessing the effect of simvastatin on surrogate markers for treatment effects in PSC, such as serum concentrations of alkaline phosphatase and bilirubin, and elastography. Additionally, the study aims to determine if simvastatin influences the progression of the disease, as measured by the MELD score, Child-Pugh score, and coloniographic progress on MR/MRCP, as well as the development of cirrhosis, PSC-related symptoms, ascites, and encephalopathy. Another secondary objective is to evaluate whether simvastatin prevents the development of colon cancer or dysplasia. These objectives are important for understanding the broader impact of simvastatin on disease progression and associated complications in PSC.

The clinical trial involves participants diagnosed with **primary sclerosing cholangitis (PSC)**, a chronic liver disease. The study population includes both male and female subjects aged between 18 and 75 years. Participants are required to have a cholangiographically verified PSC and/or liver biopsy, with or without inflammatory bowel disease (IBD). The trial population was selected based on specific inclusion criteria, including the requirement for written consent and recent medical imaging and procedures, such as MR/MRCP and coloscopy for those with known IBD. Female participants of childbearing potential must adhere to a highly efficient method of contraception during the study. The sponsor has not provided information regarding the total number of participants. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study aims to evaluate whether treatment with simvastatin can prolong survival free from bile duct cancer, variceal bleeding, and transplantation in individuals with PSC.

The clinical trial is designed to evaluate the efficacy of **simvastatin** in prolonging survival free from bile duct cancer, variceal bleeding, and transplantation in patients with **primary sclerosing cholangitis** (PSC). This study is a randomized, double-blind, placebo-controlled multicenter trial. Participants will be randomly assigned to receive either Simvastatin Sandoz 40 mg film-coated tablets or a placebo, administered orally. The trial is expected to run until September 30, 2030, with recruitment having commenced on June 28, 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-75 years), a cholangiographically verified PSC, and written consent. Women of childbearing potential must agree to use a highly efficient method of contraception during the study. Follow-up visits will be scheduled to monitor primary endpoints, including the number of days from randomization to death, liver transplantation listing, first variceal bleeding, and diagnosis of bile duct cancer. Secondary endpoints will assess serum concentrations of alkaline phosphatase and bilirubin, MELD and Child Pugh Scores, and symptoms related to PSC.

The expected length of participant involvement is up to 60 months, with conditions for early termination including withdrawal of consent or adverse events. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged. The trial is categorized as a Phase 4 therapeutic exploratory study, not classified as low intervention. Participants' safety and the integrity of the trial data are prioritized throughout the study duration.

The clinical trial involves the administration of **Simvastatin**, marketed as Simvastatin Sandoz 40 mg film-coated tablets. This experimental medication is formulated as a film-coated tablet and is intended for **oral use**. Each tablet contains 40 mg of the active substance, simvastatin, which is a chemical compound. The maximum daily dose is 40 mg, and the treatment period is limited to 60 days. Participants are required to take the medication once daily. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. Simvastatin is being investigated for its potential to prolong survival free from bile duct cancer, variceal bleeding, and transplantation in patients with primary sclerosing cholangitis.

The study also includes a **placebo** group, which will receive a placebo designed to match the Simvastatin Sandoz 40 mg tablets. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo does not contain any active pharmaceutical ingredients and is administered in the same manner as the experimental medication, with participants taking one tablet orally each day for the duration of the 60-day treatment period. The use of a placebo allows for a controlled comparison to assess the efficacy and safety of simvastatin in the treatment of primary sclerosing cholangitis.

The efficacy of simvastatin in the treatment of **primary sclerosing cholangitis (PSC)** will be assessed through a randomized, double-blind, placebo-controlled multicenter study. The primary endpoints for evaluating efficacy include the number of days from randomization to death, listing for liver transplantation, first variceal bleeding, and diagnosis of bile duct cancer, gall bladder cancer, or hepatocellular cancer. These endpoints will be measured from the time of randomization to the occurrence of each event.

Secondary endpoints will include serum concentrations of alkaline phosphatase and bilirubin, MELD Score, Child Pugh Score, progress of cholangiographic image with MR, elastography, symptoms related to PSC such as itching or bacterial cholangitis requiring treatment, ascites, encephalopathy, dysplasia in the biliary tract or gall bladder, and the development of colon cancer or dysplasia. These parameters will be collected and analyzed to provide a comprehensive assessment of the treatment's efficacy.