Sulfasalazine for the Treatment of Primary Sclerosing Cholangitis

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, randomized, double-blinded placebo controlled trial to assess the benefit of sulfasalazine in the treatment of PSC. The specific objectives of this study are to determine if sulfasalazine treatment 1) results in reduced serum ALP and other biomarkers of liver injury in PSC; 2) improves PSC patient symptoms; and 3) is safe in patients with PSC. We are recruiting remotely throughout the United States so an individual anywhere in the US with PSC and IBD can be enrolled.

Detailed Description
-----------------
As there is a strong association between PSC and IBD, it is reasonable to hypothesize that a therapy of proven benefit for UC may prove to also be effective for PSC. Unfortunately, several therapies which are indicated for the treatment of UC have not been effective in PSC including anti-TNF therapies and other anti-inflammatory medications. Sulfasalazine and mesalamine, medications commonly used for the treatment of UC, may be exceptions to this trend. While this therapy has never been formally tested in PSC, some retrospective reports suggest a possible benefit. Our current understanding of the mechanism of action of these medications suggests there is reasonable to believe they may also be effective in PSC. We are recruiting remotely throughout the United States so an individual anywhere in the US with PSC and IBD can be enrolled.

Official Title
-----------------
A Randomized, Placebo-controlled Pilot Study of Sulfasalazine for the Treatment of Primary Sclerosing Cholangitis (PSC)

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

Intervention / Treatment
-----------------
* Drug: Sulfasalazine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 15-80 A diagnosis of PSC for at least 6 months based upon cholangiography (ERCP or MRCP) demonstrating intrahepatic and/or extrahepatic biliary strictures, beading or irregularity consistent with PSC. ALP > 1.67 times the upper limit of normal (ULN) at screening Inflammatory bowel disease Subject must either be on a stable dose of ursodeoxycholic acid for > 6 months prior to screening or have been discontinued > 4 weeks prior to screening (enrollment of patients who are on UDCA will be limited to 50% of all enrolled patients). We are recruiting remotely throughout the United States so an individual anywhere in the US with PSC and IBD can be enrolled. Exclusion Criteria: Anticipated need for liver transplant within one year as determined by Mayo PSC risk score treatment Evidence of decompensated liver disease such as variceal bleeding, ascites, or hepatic encephalopathy. Evidence of advanced liver disease including MELD score > 10, bilirubin > 3.0, platelet count < 100,000; or INR > 1.4 Concomitant chronic liver disease including alcohol related liver disease, chronic hepatitis B or C infection, haemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency, non-alcoholic steatohepatitis, autoimmune hepatitis, or primary biliary cholangitis Secondary causes of sclerosing cholangitis Known intolerance to sulfasalazine (including but not limited to allergy to sulfa or mesalamine) or folic acid History of cholangiocarcinoma or colon cancer within 5 years History of colectomy with > 1/3 bowel resected Treatment with any investigational agents, within two months or 5 half-lives of the investigational product, whichever is longer. Active illicit drug or alcohol abuse Current or past use of sulfasalazine within 6 months of enrollment. Need for chronic use of antibiotics Evidence of bacterial cholangitis within 6 months of enrollment In patients with Ulcerative Colitis, simple clinical colitis activity index of > 4 or, if Crohn's disease, a Harvey-Bradshaw index of > 5 Chronic kidney injury (eGFR < 59) Pregnancy or lactation

Ages Eligible for Study
-----------------
Minimum Age: 15 Years
Maximum Age: 80 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: Sequential Assignment
Interventional Model Description: There are two arms in this trial: active drug and placebo. We are recruiting remotely throughout the United States so an individual anywhere in the US with PSC and IBD can be enrolled.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Drug (Sulfasalazine)<br> | Drug: Sulfasalazine<br>* Patients will be initiated on a low dose of sulfasalazine (500 mg) twice daily (bid). Dosage will be increased throughout the study.<br>* Other names: Azulfidine;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Patients will be initiated on 1 placebo tablet twice daily (bid). Dosage will be increased throughout the study.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Mean Alkaline Phosphatase (ALP) | Proportion of patients with reduction of mean ALP < 1.5 x ULN at end of treatment | Baseline through the end of the Study at Week 22 | 
| Normalization of ALP below the upper limit of normal | Assessment in number of patients whose ALP normalizes | Baseline through the end of the Study at Week 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall changes in ALP levels | Proportion of patients with ALP > or < 1.5 x ULN at end of treatment | Baseline through the end of the Study at Week 22 | 
| Changes in blood tests | Change in mean Liver Function Tests (e.g. Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), total bilirubin) and C-reactive Protein | Baseline through the end of the Study at Week 22 | 
| Adverse Events | Unexpected and Serious Adverse Events will be examined | Baseline through the end of the Study at Week 22 | 
| Changes in Mayo PSC risk score | Number of patients with changes in Mayo PSC risk score | Baseline through the end of the Study at Week 22 | 
| Changes in Modified Fatigue Scale (MFS) | Number of patients with changes in MFS score | Baseline through the end of the Study at Week 22 | 
| Changes in pruritus visual analog scale (VAS) | Number of patients with changes in VAS score | Baseline through the end of the Study at Week 22 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sclerosing, Cholangitis