Vidofludimus Calcium for Primary Sclerosing Cholangitis

Study Overview
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Brief Summary
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To examine the safety, tolerability, and efficacy of daily dosing with vidofludimus calcium over a 6-month period.

Detailed Description
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Investigators will assess the following: Changes on serum alkaline phosphatase levels at 3 & 6 months. Changes in other liver biochemistries at 3 & 6 months. Changes in IL-17 &IFNγ levels at 6 weeks and 6 months.

Official Title
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Investigation of the Activity of Vidofludimus Calcium, a Novel, Orally Available, Small Molecule Inhibitor of Dihydroorotate Dehydrogenase, as a Treatment for Primary Sclerosing Cholangitis (PSC)

Conditions
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Primary Sclerosing Cholangitis

Intervention / Treatment
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* Drug: Vidofludimus calcium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject age 18-75 years Diagnosis of PSC consistent with the guidelines published by the AASLD. All subjects must have an elevated serum ALP of at least 1.5 times upper limit of normal (ULN) at baseline plus cholangiographic evidence of PSC (MRI, endoscopic retrograde cholangiography, or direct cholangiography). Indirect bilirubin <1.2 times the ULN An ultrasound (or equivalent imaging modality) that excludes biliary obstruction and malignancy within 6 months of study enrollment PSC with or without inflammatory bowel disease, such as ulcerative colitis or Crohn's disease Must agree to comply with the study protocol and provide informed consent Exclusion Criteria: Pregnancy, attempting to become pregnant, or breastfeeding Active hepatitis A or B infection Active hepatitis C infection (antibody positive); patients with a history of hepatitis C infection will be eligible for this study if they have undetectable levels of HCV RNA HIV/AIDS (per medical record or HIVAb/HIA antigen), tuberculosis, or positive interferon-gamma assay (IGRAs) for Mycobacterium tuberculosis Other cholestatic liver disease such as primary biliary cholangitis and cholestatic diseases of pregnancy Metabolic liver diseases such as Wilson's disease, Gilbert's syndrome or hemochromatosis Serum uric acid levels at screening >1.2 ULN Inherited diseases of the liver such as α-1 antitrypsin deficiency Immunoglobulin G4-related cholangitis PSC with concomitant autoimmune hepatitis (AIH) and/or primary biliary cholangitis Secondary sclerosing cholangitis (SSC) Active acute ascending cholangitis requiring antibiotics CCA (malignant biliary stricture, neoplasm, and cytology/histopathology or positive fluorescence in situ hybridization (FISH) consistent with adenocarcinoma of the bile duct) A liver biopsy, if one has been previously obtained, which showed non-alcoholic steatohepatitis (NASH). Patients with suspected fatty liver by imaging will not be excluded. Presence of complications of advanced PSC such as hepatic encephalopathy, portal hypertension, hepato-renal syndrome, and hepato-pulmonary syndrome History of liver transplantation, anticipated need for liver transplantation within 12 months from randomization, a Model of End-stage Liver Disease (MELD) score of ≥15, or a Child Pugh score >6 Ongoing alcohol abuse (>4 drinks per day for men, and >2 drinks per day for women) Moderate-to-severe renal impairment with a calculated creatinine clearance of <60mL/min Any other conditions or abnormalities that, in the opinion of the investigator, may compromise the safety of the subject or interfere with the subject participating in or completing the study Evidence of, or treatment for, C. difficile infection within 30 days before the initiation of the study drug Evidence of active C. difficile infection during the screening phase confirmed by a positive C. difficile toxin B Subjects who have been treated for intestinal pathogens other than C. difficile infection within 30 days prior to study drug initiation Received or plan to receive live vaccine within 30 days prior to, and through the end of the study Use of methotrexate at dose ≥17.5mg/week Rosuvastatin exceeding 10 mg daily

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vidofludimus Calcium (VC)<br>Daily dosing of VC over 6 months | Drug: Vidofludimus calcium<br>* During the 6-month treatment period, subjects will receive 30 mg VC orally once daily. This will be preceded by a lead-in dosing period where subjects will receive 15 mg VC once daily for 1 week.<br>* Other names: IMU-838;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects Who Experience a Positive Outcome as Measured by Combination of Serum Alkaline Phosphatase (ALP) and Aspartate Aminotransferase (AST) Levels. | The number of subjects who have both an ALP reduction from baseline to week 24 that is greater or equal to 25% and their AST increase from baseline is less than or equal to 33% at week 24. ALP measured as international units per liter (IU/L). AST measured as international units per liter (IU/L). | Baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abnormal Aspartate Aminotransferase (AST) | Number of subjects with abnormal (not within normal range) AST levels. AST is an enzyme found in high amounts in liver, heart, and muscle cells. This test is mainly done along with other tests such as alkaline phosphatase and bilirubin to diagnose and monitor liver disease. This test evaluates hepatocyte integrity, as serum levels of this enzyme rise in response to a variety of forms of injury to hepatic cells. The normal range is 5 to 40 U/L . Units: U/L | Baseline to 24 weeks | 
| Abnormal Alanine Aminotransferase (ALT) | Number of subjects with abnormal (not within normal range) ALT levels. An enzyme normally present in liver and heart cells that is released into the bloodstream when the liver or heart is damaged. The blood ALT levels are elevated with liver damage (for example, from viral hepatitis) or with an insult to the heart (for example, from a heart attack). The normal range is 7 to 56 U/L. Units: U/L | 24 weeks | 
| Abnormal Total Bilirubin | Number of subjects with abnormal (not within normal range) Total Bilirubin levels. Bilirubin is a yellowish pigment found in bile, a fluid made by the liver. A small amount of older red blood cells are replaced by new blood cells every day. Bilirubin is left after these older blood cells are removed. The liver helps break down bilirubin so that it can be removed from the body in the stool. The normal range for total bilirubin is 0.3 to 1.2 mg/dL Units: mg/dL | 24 weeks | 
| Abnormal Direct Bilirubin | Number of subjects with abnormal (not within normal range) direct bilirubin levels. In the liver, bilirubin is changed into a form that your body can get rid of. This is called conjugated bilirubin or direct bilirubin. This bilirubin travels from the liver into the small intestine. A very small amount passes into your kidneys and is excreted in your urine. Normal range for direct bilirubin is 0.3 and 1.2 milligrams per deciliter (mg/dL). Units: mg/dL | 24 weeks |