Conditions: Primary Sclerosing Cholangitis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

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

Detailed description:
Investigators will assess the following:

1. Changes on serum alkaline phosphatase levels at 3 \& 6 months.
2. Changes in other liver biochemistries at 3 \& 6 months.
3. Changes in IL-17 \&IFNγ levels at 6 weeks and 6 months.

Arms:
arm 1: Daily dosing of VC over 6 months

Interventions: intervention 1: Vidofludimus calcium
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 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) 
 
 NCT03722576 
 
6/23/2020 


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)  
 
 
 
 
 
Lead Principle 
Investigator 
Dr. Keith Lindor 
College of Health Solutions 
Arizona State University 
550 North 3rd Street 
Phoenix, AZ  85004 
(602) 496-1237 
 
Regulatory Sponsor: 
Dr. Elizabeth Carey 
Division of Gastroenterology and Hepatology 
Mayo Clinic Arizona 
5777 E. Mayo Boulevard 
Phoenix, AZ  85054 
(480) 342-1094 
 
Study Product: 
 
Vidofludimus Calcium 
 
Version: 
 
Version 2.6 – Amendment 7 
June 23, 2020 
 
List of Changes Since Previous Version: 
• 
Revised language on contraception 
 
 
Previous Version(s) 
 
Version 1.0 – August 01, 2018 
Version 2.0 – November 29, 2018 
Version 2.1 – December 20, 2018 
Version 2.2 – March 12, 2019 
Version 2.3 – October 11, 2019 
Version 2.4 – December 18, 2019 
Version 2.5 – April 28, 2020 
 
 
 
 
 
 
 
 
Specific Aims  
 


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Primary sclerosing cholangitis (PSC) is an idiopathic disease of the liver with a prevalence of 
approximately 50,000 patients in the United States. To date, no medical therapies other than liver 
transplantation (LT) have been shown to modify the natural course of PSC. The median time from 
diagnosis of PSC to death or LT is only 8 years. The investigational product vidofludimus calcium (VC) is 
a novel compound that selectively inhibits dihydroorotate dehydrogenase (DHODH), the enzyme that 
catalyzes the rate-limiting step in pyrimidine synthesis. Through a unique dual mechanism, VC inhibits 
proliferating lymphocytes and reduces release of the proinflammatory cytokines IL-17 and IFNγ. 
 
Inflammatory bowel disease (IBD) is frequently seen in patients with PSC. Studies have indicated a 
central role for IL-17 and IL-17-producing lymphocytes in the pathogenesis of both diseases. Clinical data 
has also shown vidofludimus to be effective in the treatment of IBD while exhibiting a highly favorable 
safety profile. 
 
Given this train of evidence, we are proposing a small, exploratory clinical trial investigating the role of 
VC in PSC. The trial will be conducted by investigators with long careers dedicated to the study of PSC 
and other hepatobiliary disorders. The trial will be executed at two sites that are both tertiary referral 
centers for PSC. 
 
I. 
Goal: 
The overall goal of this study is to examine the safety, tolerability, and efficacy of daily 
dosing with vidofludimus calcium over a 6-month period on the clinical course and 
progression of primary sclerosing cholangitis. 
The results will help us: 
- 
Establish proof-of-concept that VC may show activity for the treatment of PSC 
- 
Gain insight into the effect of VC on profiles of the proinflammatory cytokines IL-17 and 
IFNγ 
- 
Establish data to design more comprehensive clinical studies 
 
II. 
Impact of Study: 
This open-label, single-arm pilot study will give us the opportunity to explore the potential of 
this novel drug to show activity in patients suffering from PSC, a rare but devastating disease 
with no known effective treatment. 
 
III. 
Expected Outcome: 
We hypothesize that in PSC, daily treatment with vidofludimus calcium will result in reduction of 
serum ALP, a surrogate marker that has been shown to strongly correlate with positive outcomes 
in PSC. Further, we hypothesize that treatment will result in a decrease in certain 
proinflammatory cytokines, particularly IL- 17 and IFNγ. We expect based on a wealth of 
preclinical and clinical evidence that treatment with vidofludimus calcium will be safe and well 
tolerated. 
 
IV. 
Specific Aims of the Study: 
1. Determine if VC reduces serum alkaline phosphatase (ALP) in adults with PSC. Levels of 
serum ALP after 3 and 6 months of VC treatment will be compared with baseline (month 
0). 
2. Assess other liver biochemistries (an indication of general liver health) at 3 and 6 
months of VC treatment and compare to baseline (month 0). 
3. Determine if changes in the proinflammatory cytokines IL-17 and IFNγ predict 


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response to VC. Cytokines will be measured at baseline, 4 weeks, and 6 months. 
 
If successful, this low-risk, high-reward study will lay the groundwork for larger, more 
comprehensive clinical studies investigating the efficacy of VC in PSC. This could ultimately lead to 
the development of a successful therapy for PSC and significantly improve patient outcome and 
quality of life. 
 
RESEARCH STRATEGY 
 
Significance 
Primary sclerosing cholangitis (PSC) is an idiopathic disease of the liver with incidence and prevalence 
rates ranging from 0-1.3 per 100,000 inhabitants/year and 0-16.2 per 100,000 inhabitants, 
respectively, although these rates appear to be trending upward1. Based on our experience and 
reported studies, we estimate a PSC prevalence of approximately 50,000 patients in the United States. 
PSC is characterized by ongoing inflammation of the intrahepatic and/or extrahepatic bile ducts, which 
can ultimately lead to cirrhosis and end- stage liver disease (ESLD). PSC also increases the risk for 
colorectal and hepatobiliary cancer2. The disease can affect both children and adults and is frequently 
associated with inflammatory bowel disease (IBD), namely ulcerative colitis (UC)3-7. PSC is an important 
risk factor for cholangiocarcinoma (CCA), a bile duct cancer that carries a grave prognosis, and for 
colorectal adenocarcinoma in patients with colitis2. 
 
To date, no medical therapies other than liver transplantation (LT) have been shown to modify the 
natural course of PSC. The median time from diagnosis of PSC to death or LT is only 8 years8 with the 
most recent modification of the Mayo PSC risk score being a helpful tool to predict prognosis9. An 
invasive and expensive procedure, LT is currently the only life-extending therapy for patients with ESLD 
secondary to PSC and patients with PSC complicated by CCA who meet specific criteria1,10,11. PSC is 
currently the fifth leading indication for LT in the United States, and is the leading indication for 
transplantation in some European countries.10,12 Nevertheless, even after LT, de novo IBD and CCA 
have both been reported13,14 and PSC recurrence rates as high as 20-40% have been seen.15,16 Taken 
together, these data highlight the considerable disease burden, cost to the healthcare system, and 
clinical impact of PSC. 
 
Only a handful of therapeutic agents for PSC have undergone clinical trials, possibly due to low 
disease prevalence. None of the agents studied have shown a beneficial effect on clinically important 
endpoints and survival in PSC.17 Ursodeoxycholic acid (UDCA) is the single most extensively studied 
agent in PSC. However, large randomized and controlled prospective clinical trials have failed to 
demonstrate that UDCA can positively affect patient outcome.18,19 Further, the safety of long term use 
of high-dose UDCA in PSC patients has been questioned, as it has been associated with increased rates 
of serious adverse events.19,20 The American Association for the Study of Liver Disease (AASLD) 
recommends against the use of UDCA in PSC patients.7 
 
Liver transplantation remains the sole treatment for end-stage PSC. There are several current avenues 
of research addressing treatment strategies for PSC. One target is the farnesoid X receptor, which plays 
a key role in bile acid homeostasis. Other evidence suggests a link with the intestinal microbiota, 21 
leading to the investigation of fecal transplantation and probiotics as therapeutic approaches. A very 
promising therapy is the use of oral vancomycin. In addition to its potential effects on microbiota, work 
by Abarbanel et al.22 suggests that its therapeutic properties in PSC are linked to immunomodulatory 
effects on regulatory T cells. 


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PSC is thought to arise from a combination of genetic and environmental factors, with increased 
prevalence among first-degree relatives indicating a strong genetic component.23 One of the more 
intriguing aspects of PSC is the striking frequency of comorbidity with IBD, particularly ulcerative 
colitis. PSC is frequently seen in patients with underlying IBD3,24 and is the most common hepatobiliary 
manifestation seen in those patients.25 Conversely, IBD is present in 70–80% of PSC patients, up to 
90% of that in the form of UC.26-29The link between PSC and IBD is not yet understood, but given the 
intimate relationship and shared antigen exposure between the gut and hepatobiliary systems (gut- 
liver crosstalk), it is not surprising to find PSC to be an extraintestinal manifestation of IBD. Recent 
genotyping studies suggest common genetic underpinnings, with three UC susceptibility loci also 
found to be associated with PSC.30 Beyond genetic linkage, two emerging theories, which are not 
mutually exclusive, have been proposed to contribute to this close association. In one hypothesis, 
lymphocytes activated in the inflamed gut of IBD patients are aberrantly recruited to the liver via 
enterohepatic circulation. The work of Adams and colleagues31-36 suggests that this is due to 
expression in the liver of adhesion molecules that are normally restricted to the gut. This aberrant 
homing results in the infiltration of the liver by T cells, including T helper 17 (Th17) cells, resulting in 
inflammation leading to PSC.37-38 In the other, the so-called “leaky gut” hypothesis, the increased 
permeability of the chronically inflamed bowel facilitates translocation of bacterial components to the 
liver and bile duct via the enterohepatic circulation, contributing to the pathogenesis of PSC. In 
support of this, intraportal injection of enteric bacteria in rabbits39 and intestinal leakage of bacteria in 
rats40 have both been shown to lead to PSC-like symptoms. 
 
The proinflammatory cytokine interleukin 17 (IL-17) is a key mediator of a variety of immune related 
human diseases41 and Th17 lymphocytes, T helper cells defined by their production of IL-17, are found 
in chronically inflamed human tissues.42 In IBD, Th17 cells massively infiltrate the inflamed intestine43 
and UC patients demonstrate greatly increased expression of IL-17 in colonic mucosa.44 Perhaps not 
surprisingly, recent studies indicate a central role of IL-17 in the pathogenesis of PSC. Significant 
increases in IL-17-expressing lymphocytes are found in the livers of PSC patients compared to other 
types of liver inflammation. IL-17- expressing T cells aggregate around damaged bile ducts and in areas 
of neoductular proliferation.45 PBMCs from PSC patients manifested significantly increased frequencies 
of Th17 cells compared to both healthy and cholestatic controls in response to pathogen stimulation.46 
CARD9, one of the UC susceptibility loci that has also been associated with PSC, encodes a gene 
product that has been shown to be involved in the induction of Th17 responses to some pathogens.47 
These results are all consistent with the strong clinical linkage between UC and PSC, the key role of IL- 
17 as a target for potential therapeutic intervention, and speak to the strong possibility of an overlap in 
therapeutic approaches to the two diseases. 
 
The investigational product vidofludimus calcium (VC) is a novel compound that blocks the de novo 
synthesis of pyrimidines by selectively inhibiting human dihydroorotate dehydrogenase (DHODH), 
the enzyme that catalyzes the rate-limiting step in this synthesis pathway. Proliferating or activated 
lymphocytes require this de novo pathway to meet their needs for pyrimidines, an essential 
component of nucleic acids, with DHODH inhibition in these cells leading to cell cycle arrest and 
apoptosis. On the other hand, resting lymphocytes do not depend on de novo synthesis, instead 
satisfying their pyrimidine requirements through the DHODH-independent salvage pathway. Thus, VC 
selectively affects activated, rapidly proliferating lymphocytes. Metabolic stress following inhibition 
of pyrimidine synthesis induces upregulation of the transcriptional regulator HEXIM1 which acts by 
two independent mechanisms48 to modulate IL-17-mediated inflammation. By sequestering the pTEFb 
complex, it inhibits transcription of specific inflammatory signaling molecules, including IL-17. 


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Additionally, with prolonged pyrimidine depletion, HEXIM1 binds to and stabilizes apoptotic gene transcripts, 
leading to cell death in activated cells (e.g. Th17 lymphocytes). Through these two molecular mechanisms, 
DHODH leads to a reduction of proinflammatory cytokine release including IL- 17 and interferon-gamma (IFNγ). 
Preclinical studies confirm these effects of vidofludimus. In two different mouse models of colitis, oral 
vidofludimus not only evoked substantial improvements in clinical and histological colitis scores and reduced 
lymphocyte infiltration, but also effected a significant reduction of IL-17 and IFNγ in the colon.49 Similarly, in a rat 
model of colitis, vidofludimus improved inflammation and inhibited IL-17 production.50 
 
Vidofludimus calcium constitutes a novel chemical class with no structural similarity to other known 
pharmaceuticals and the calcium salt is a more readily absorbable form of vidofludimus free acid. Its 
blood half-life of approximately 30 hours makes it suitable for once daily oral treatment. Currently, VC 
is being developed as a treatment for patients with ulcerative colitis and Crohn’s disease (CD). Two 
Phase 2 clinical trials examining the safety and efficacy of vidofludimus in rheumatoid arthritis (RA) 
have previously been completed (see Table 1). Although the primary endpoint was not met, the trials 
demonstrated consistent numerical superiority of vidofludimus over placebo. More importantly, these 
large RA trials established the safety of this compound, with an adverse event profile no different 
from placebo. Most notable are the results from a Phase 2a study that explored the efficacy, safety, 
and tolerability of vidofludimus in steroid-dependent IBD (both UC and CD). Overall, 88.5% of subjects 
responded following 12 weeks of treatment: 54% achieved complete response (complete weaning 
from steroids) and a further 35% were able to reduce steroid usage.51 Further, favorable safety and 
tolerability profiles were demonstrated. Taken together, the safety data from these trials indicate that 
vidofludimus at therapeutic doses is safe and well tolerated in humans; a conclusion supported by a 
wealth of non-clinical pharmacology, pharmacokinetics, and toxicology data. These previous clinical 
studies have established a safe and effective dose of VC to be used in this proposed pilot study in 
patients with PSC as well as a more extensive Phase 2 trial in UC. 
 
Given the favorable safety data, the demonstrated reduction of tissue IL-17 levels and inhibition of Th17 
cells, the efficacy established in early clinical trials of patients with IBD, and the strong link between UC 
and PSC, vidofludimus calcium is a low risk, high reward candidate for therapeutic intervention in rare 
but devastating disease PSC. This pilot study is designed to show a first indication of activity of VC in 
patients with PSC using surrogate endpoints. If successful, this study will lay the groundwork for larger 
more comprehensive clinical studies investigating the efficacy of VC in PSC. Development of a successful 
therapy to reduce or halt the progress of this disease, for which there is currently no effective 
treatment, will significantly improve patient outcome and quality of life. Further, as PSC is one of the 
leading indications for liver transplantation in the US and Europe, it would significantly reduce the 
requirement for this expensive and risky procedure and lessen the burden on the transplant system, 
reducing wait times for others in need of LT. 


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Phase 
Study Description 
1 
SC12267-1-2003: Single dose escalating Phase 1 study in 57 male volunteers 
investigating single doses of vidofludimus up to 350 mg (complete) 
1 
SC12267-2-2004: Multiple dose escalating Phase 1 study in 32 male volunteers 
investigating multiple doses of vidofludimus up to 70 mg (complete) 
2a 
SC12267-3-2005: Phase 2a study in 116 RA patients evaluating efficacy and safety of 
vidofludimus (20 mg or 35 mg) monotherapy or placebo (complete) 
2a 
SC12267-4-2008: Phase 2a study in 34 IBD patients evaluating efficacy and safety of 
vidofludimus (35 mg) (“ENTRANCE”) (complete) 
2 
SC12267-5-2009: Phase 2 study in 241 RA patients evaluating efficacy and safety of 
vidofludimus (35 mg) or placebo on methotrexate background therapy 
(“COMPONENT”) (complete) 
1 
P1-IMU-838-SAD: Open-Label, Single Ascending Dose, Phase 1, Study to Assess the 
Safety, Tolerability and Pharmacokinetics of Single Oral Doses of IMU-838 in Healthy 
Male Subjects Including Assessment of a Possible Food Effect (complete) 
1 
P1-IMU-838-MAD: Double-blind, Placebo Controlled, Ascending Dose, Phase 1, 
Study to Assess the Safety, Tolerability and Pharmacokinetics of Multiple Oral Doses 
of IMU-838 in Healthy Male Subjects (ongoing) 
2 
P2-IMU-838-UC: A phase 2, multicenter, randomized, double-blind, placebo- 
controlled, dose-finding study to evaluate the efficacy and safety of IMU-838 for 
induction and maintenance therapy in moderate-to-severe ulcerative colitis 
(planned) 
Table 1. Completed, ongoing and planned clinical studies 
 
Innovation  
Vidofludimus calcium constitutes a novel chemical class and has no structural similarity to other 
known pharmaceuticals. Its chemical structure is considerably different from other DHODH 
inhibitors49,52 such as leflunomide (Arava®, approved for use in RA and psoriatic arthritis) and its active 
metabolite teriflunomide (Aubagio®, approved for use in multiple sclerosis). Compared to a number of 
existing IBD therapeutic agents that might be considered as candidates for treatment of PSC, data so far 
indicates that VC is likely to exhibit a superior safety and tolerance profile. Thiopurine analogues 
azathioprine and mercaptopurine are in common use for managing UC and CD, but at least one third of 
patients fail to respond to therapy and up to 28% of patients stop medication due to intolerable side 
effects.53 Methotrexate, the established second-line immunosuppression in CD, exhibits a clinically 
relevant toxicity profile.54,55 Approved TNFα blockers, such as infliximab and adalimumab, have 
demonstrated excellent clinical response in UC and CD, however, major infections have been linked to 
TNFα-inhibitor treatments.56 The DHODH inhibitor leflunomide has shown efficacy in CD, however its 
side effect of diarrhea is not acceptable in an IBD patient population.57 
 
Vidofludimus is a potent inhibitor of human DHODH, three times more effective than teriflunomide. A 
second important and distinguishing property of vidofludimus is its potent inhibition of IL-17 and IFNγ 
release from stimulated immune cells. Inhibition of IL-17 production was found to be independent of its 
effects on lymphocyte proliferation and it is believed that both these independent activities of 
vidofludimus contribute to its therapeutic effects in IBD.50,58 This dual mechanism of action confers a 
unique advantage over other DHODH inhibitors and makes vidofludimus a promising therapeutic option 
for both UC and PSC, diseases with frequent comorbidity and a common pattern of Th17 lymphocytic 
infiltration. With good clinical data for UC already in hand and a more comprehensive UC study in the 
works, a pilot trial for PSC is warranted. Success would result in a major step towards an effective 


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treatment for PSC where one does not currently exist. 
 
 Approach  
We are proposing to test the hypothesis that vidofludimus calcium, a novel drug product, will be an 
effective treatment strategy for the rare but devastating disease primary sclerosing cholangitis. The 
rationale for this is based on i) the strong linkage between ulcerative colitis and PSC; ii) the known 
involvement of Th17 lymphocytes and IL-17 in both disorders; iii) the demonstrated effect of 
vidofludimus on lymphocyte proliferation and IL-17 production; and iv) clinical evidence for the 
efficacy of vidofludimus in patients with UC. Our approach is to investigate this hypothesis using a 
small two- center pilot study employing serum alkaline phosphatase, a surrogate marker having a well-
established association with clinical outcome, as our primary endpoint. We further hypothesize that 
treatment with VC will affect profiles of proinflammatory cytokines and will assess IL-17 and IFNγ levels 
as a potential early indicator of improvements in ALP. 
 
The Specific Aims of the study are: 
1. Determine if VC reduces serum alkaline phosphatase (ALP) in adults with PSC. Levels of 
serum ALP after 3 and 6 months of VC treatment will be compared with baseline (month 
0). 
2. Assess other liver biochemistries (an indication of general liver health) at 3 and 6 
months of VC treatment and compare to baseline (month 0). 
3. Determine if changes in the proinflammatory cytokines IL-17 and IFNγ predict 
response to VC. Cytokines will be measured at baseline, 4 weeks, and 6 months. 
 
 These results will help us: 
- 
Establish feasibility of the hypothesis that VC will play a therapeutic role in treatment of 
PSC 
- 
Gain insight into the effect of VC on profiles of the proinflammatory cytokines IL-17 and 
IFNγ 
- 
Pave the way for more comprehensive clinical studies 
 
Study Design and Methodology  
This pilot study will be a 6-month, 30-subject clinical trial to assess the effects of VC on a surrogate 
biochemical endpoint known to have relevant association with clinical outcomes in PSC. All endpoint 
tests chosen are rapid, inexpensive, and minimally invasive. Due to the low prevalence of PSC, the 
study will be a single-arm, open-label study. The study will be undertaken at two sites, Mayo Clinic, 
Rochester, Minnesota (20 subjects) and Mayo Clinic, Phoenix, Arizona (10 subjects), both of which are 
tertiary referral centers for PSC. Immunic AG, a biotechnology company based in Munich, Germany, 
will supply the study agent in sufficient quantities for the study (see Letter of Support from Immunic 
AG). We have confirmed through consultation with NIH personnel that this is permissible under this 
funding opportunity. 
 
During the 6-month treatment period, subjects will receive 30 mg VC orally once daily, a dose 
determined to be both safe and therapeutically relevant based on previous clinical studies (see Table 
1). This will be preceded by a lead-in dosing period where subjects will receive 15 mg VC once daily for 
1 week. Lead-in dosing is used to minimize the risk of drug intolerance during the initial treatment 
period. While no clinically relevant adverse events have been noted at 30 mg once daily dosing, in rare 
instances potentially drug-related hematuria has been observed in the first few days of treatment at 
higher doses (≥70 mg/day). As a precaution, subjects will be monitored for two weeks after initial drug 


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exposure for elevated erythrocytes in the urine by a dipstick test. It is not anticipated that hematuria 
will be seen if it has not developed within the first two weeks of drug exposure. 
 
The following endpoints will be assessed at various times during the study and compared with 
baseline: 
i. 
Primary endpoint: 
a. Improvement of serum alkaline phosphatase (ALP) [baseline, 3 months, and 6 months] 
ii. Secondary endpoints: 
a. Bilirubin, Total and Direct [baseline, 3 months and 6months] 
b. AST and ALT (aspartate and alanine transaminases) [baseline, 3 months, and 6 months] 
c. Proinflammatory cytokine profile (IL-17 and IFNγ) [baseline, 4 weeks, and 6 months] 
 
The most extensively studied surrogate endpoint in PSC is serum alkaline phosphatase (ALP). Our 
group at Mayo Clinic and others have reported an association between serum ALP and clinical 
outcomes in PSC. Specifically, normalization of serum ALP appears to be associated with long-term 
survival free of CCA, liver transplantation, liver-related death, and colorectal cancer and persistent 
ALP elevation has been associated with worse outcomes in PSC.59-61 Therefore, we have chosen this 
simple, rapid, inexpensive, and minimally invasive test as our primary endpoint. AST, ALT, and 
bilirubin will be monitored to assess general liver health during the treatment. AST, ALT, or total 
bilirubin elevation can signal increased liver damage or liver cell necrosis, while elevated direct 
bilirubin may indicate bile duct obstruction. Further, it is hypothesized that treatment with VC will 
result in a reduction of IL-17 and IFNγ production. Levels of these cytokines will be measured at 4 
weeks and at 6 months (end of study) and compared to baseline. The early 4-week time point will be 
used to determine whether early changes in these cytokines may predict improvements in ALP. 
 
A 25% improvement in ALP with no more than a 33% worsening of AST after 6 months of treatment will 
be assessed as a positive outcome. While full normalization of ALP levels is unlikely over the short course 
of this pilot study, a 25% improvement would be deemed significant, indicating that VC has a positive 
effect on the progression of PSC. A less than 33% increase in AST levels concomitant with this ALP 
reduction would be acceptable, as it would be considered only a mild elevation. While a recent 
consensus statement from the International PSC Study Group indicates that transient elastography (TE), 
a new technique that allows non- invasive assessment of liver fibrosis, is one of the top three most 
promising surrogate endpoints for PSC (along with ALP and liver histology),62 it is unlikely that significant 
changes in TE would manifest in the 6-month course of this study. Thus, TE will not be included as an 
endpoint. Reduction of proinflammatory cytokines IL- 17 and IFNγ at the early 4-week time point 
concomitant with reduced ALP at the end of study would indicate a role for cytokine levels as an early 
predictor of improvements. 
 
At the end of the 6-month treatment, any subjects demonstrating benefit may optionally continue VC 
treatment under a single-patient IND. Subjects without benefit will return to standard of care for PSC 
patients. All subjects will receive a post-study follow-up assessment at 30 days to capture any 
remaining adverse events. 
 
 
 
 
 
 


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Timeline and Schedule  
For each subject, study participation will consist of a screening period of up to 1 month, a lead-in dosing 
period of 1 week, treatment period of 6 months, and a follow-up period of up to 1 month. A recruitment 
period of no more than 6 months is anticipated. Subjects will be seen in clinic at baseline and at the end 
of the treatment period, where safety, clinical and laboratory evaluations will be performed. Screening 
and Baseline Visits may be done on the same day. Any procedures done to meet inclusion/exclusion 
criteria at Screening do not need to be repeated for the Baseline values at the discretion of the 
investigator. Every other day during the first two weeks, urine dipstick testing for hematuria will be 
performed. Between the clinical visits, patients will have laboratory tests and be monitored by phone 
call every 4 weeks throughout the treatment period, and again at 1 month after completion of the 
treatment period for safety, adverse events, subject health, and adherence to the study protocol. Safety 
monitoring tests will include AST, ALT, ALP, TBIL, DBIL. Cytokines (IL-17 and IFN-ɣ) will be tested at 
Baseline, 4 weeks, and 6 months. Blood will be collected at Baseline, 4 weeks, 3 months, and 6 months 
and stored for potential future analysis. Images from the MRCP and results from the Fibroscan, both 
done as standard of care, will be recorded at Screening /Baseline and at 6 months. If images from the 
MRCP or results from the Fibroscan are not performed as standard of care or are not available from the 
medical record, they do not need to be performed for the study.  Women of childbearing capability will 
undergo monthly pregnancy tests. It will be required that both patient and partner use a barrier method 
as well as hormonal contraception while on study. If patient or partner has had onset of menopause, a 
hysterectomy, tubal ligation, or vasectomy, no other contraception is required. Those with a confirmed 
positive test will be removed from the study.  
 
Pharmacokinetic Sample 
Those patients who experience a Serious Adverse Event (SAE) suspected of being related to the study 
drug during the treatment period will be asked to provide a single pharmacokinetic (PK) blood sample at 
discretion of the clinician. Ideally this should be drawn before the drug is taken that day. The sample 
may still be taken if the patient has taken their study drug within 1.5 hours of the PK blood draw. If it has 
been longer than 1.5 hours since the study medication was taken, the PK draw should be postponed 
until the next morning; however, if a draw the next day is not possible, then the blood sample may be 
collected and timing noted on the accompanying paperwork to the lab. All samples will be processed by 
a central laboratory. 
 
Risk Mitigation and Alternative Strategies  
We have structured the study to minimize risk to the subjects and have included ways to assess, track, 
and mitigate these potential risks. We will use a dosing scheme that has been shown convincingly to be 
safe and well tolerated. We will include a lead-in dosing period with testing for drug-induced hematuria 
during the early part of the study despite the fact that this adverse event has only been demonstrated 
to occur at higher doses. During clinical trials, the one serious adverse event reported was in a subject 
with Gilbert syndrome, a genetic disease characterized by a drastic reduction in the activity of UGT1A1. 
As VC is known to be a moderate inhibitor of UGT1A1, patients with Gilbert syndrome are excluded 
from this study. 
 
We have included liver function testing to monitor general liver health and to indicate potential 
hepatobiliary issues. Frequent assessments of general health will be performed and subjects will be 
instructed to alert the study coordinator of any potentially drug-related complications, particularly 
abdominal pain. Standard drug discontinuation criteria will be included in the protocol based on the 
investigators' knowledge of PSC and PSC- related clinical trials, information derived from previous 
vidofludimus clinical trials, and the extensive data contained within the drug manufacturer's 


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Investigator's Brochure. 
 
Due to the relatively low prevalence, it is possible that 30 subjects meeting inclusion criteria cannot 
be recruited within the planned 6-month recruitment period or that they are not split roughly 
equally between the two sites. In that case, we will extend the recruitment period and if required, 
we will execute the study with as few as 20 subjects, regardless of the distribution between sites. 
After the study is complete, further research may reveal other potentially interesting biomarkers 
that should be examined and thus we have included storage of extra blood draws during the study. 
Given the pilot nature of this study, it is possible that benefits are seen even though results are not 
conclusive. Study data may be examined more carefully to determine if benefits occur in a distinct 
subpopulation of subjects (e.g. in PSC patients with UC versus those without). 
 
Overall, considering the known safety data, the implemented risk minimization measures, the 
expected benefits in the target population, and the unmet medical need for treatment in PSC, the 
risk-benefit evaluation is considered favorable. 
 
PROTECTION OF HUMAN SUBJECTS 
This Human Subjects Research meets the definition of a clinical trial. 
 
I. 
Risks to Human Subjects 
 
a) Human Subjects Involvement, Characteristics, and Design: A total of 30 adults (age range 18-75 
years) who meet the criteria for diagnosis of primary sclerosing cholangitis (PSC), as defined by the 
American Association for the Study of Liver Diseases (AASLD) published guidelines, will be enrolled 
into this study from two centers. PSC patients with and without inflammatory bowel disease (IBD) 
will be included. Other inclusion and exclusion criteria are detailed below: 
 
 
Inclusion Criteria 
a. Male or female subject age 18-75 years 
b. 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). 
c. Indirect bilirubin <1.2 times the ULN 
d. An ultrasound (or equivalent imaging modality) that excludes biliary obstruction and malignancy 
within 6 months of study enrollment 
e. PSC with or without inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease 
f. Must agree to comply with the study protocol and provide informed consent 
 
Exclusion Criteria 
a. Pregnancy, attempting to become pregnant, or breastfeeding 
b. Active hepatitis A or B infection 
c. 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 
d. HIV/AIDS (per medical record or  HIVAb/HIV antigen) , tuberculosis, or positive interferon-gamma 
assay (IGRAs) for Mycobacterium tuberculosis 
e. Other cholestatic liver disease such as primary biliary cholangitis and cholestatic diseases of 
pregnancy 
f. History of metabolic liver diseases such as Wilson’s disease, Gilbert’s syndrome or hemochromatosis 


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g. Serum uric acid levels at Screening >1.2 ULN 
h. Inherited diseases of the liver such as α-1 antitrypsin deficiency 
i. 
Immunoglobulin G4-related cholangitis 
j. 
PSC with concomitant autoimmune hepatitis (AIH) and/or primary biliary cholangitis 
k. Secondary sclerosing cholangitis (SSC) 
l. 
Active acute ascending cholangitis requiring antibiotics 
m. CCA (malignant biliary stricture, neoplasm, and cytology/histopathology or positive fluorescence in 
situ hybridization (FISH) consistent with adenocarcinoma of the bile duct) 
n. 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. 
o. Presence of complications of advanced PSC such as hepatic encephalopathy, portal hypertension, 
hepato-renal syndrome, and hepato-pulmonary syndrome 
p. 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 
q. Ongoing alcohol abuse (>4 drinks per day for men, and >2 drinks per day for women) 
r. Moderate-to-severe renal impairment with a calculated creatinine clearance of <60mL/min 
s. 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 
t. Evidence of, or treatment for, C. difficile infection within 30 days before the 
initiation of the study drug 
u. Evidence of active C. difficile infection during the screening phase confirmed 
by a positive C. difficile toxin B 
v. Subjects who have been treated for intestinal pathogens other than C. difficile 
infection within 30 days prior to study drug initiation 
w. Received or plan to receive live vaccine within 30 days prior to, and through the end of the study 
x. Use of methotrexate at dose ≥17.5mg/week 
y. Rosuvastatin exceeding 10 mg daily. 
 
PSC is a rare idiopathic liver disease associated with significant morbidity and mortality. There is no 
cure for PSC. Recent clinical evidence suggests that vidofludimus calcium (VC) might be of therapeutic 
benefit in ulcerative colitis (UC). The strong linkage between UC and PSC, commonalities in the 
underlying immunological characteristics of the two diseases, and the known methods of action of VC 
combine to make a compelling case for the first ever clinical trial of VC as a therapeutic agent for PSC. 
The excellent safety profile of VC, derived from clinical and non-clinical studies, further validate this 
case. This study will help us determine whether VC demonstrates feasibility for use as treatment for 
PSC. 
 
Study subjects will be recruited and enrolled into the clinical trial from the following research sites: 
 
Study Site 
Investigator 
Number of 
Enrollees 
Arizona State University (ASU) 
Dr. Keith Lindor (Principal Investigator) 
Not Applicable 
Mayo Clinic Rochester (MCR) 
Dr. John Eaton (Co-Investigator) 
20 
Mayo Clinic Arizona (MCA) 
Dr. Elizabeth Carey (Co-Investigator) 
10 
Total 
30 
Table 2. Study sites, recruitment and enrollment 
 


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These sites have been selected because of their interest, experience, and engagement with substantial 
populations of PSC patients. Overall recruitment for the study will be 30 patients, but number of 
enrollees at each site may be adjusted at discretion of the investigators to facilitate recruitment. 
 
Each site (except ASU) will be responsible for: 
 Recruiting and screening subjects 
 Enrolling subjects into the clinical trial 
 Administering the study agent 
 Safety monitoring, clinical and laboratory assessments at the defined study time points 
 Reporting progress of study, side effects, and adverse events to the local Institutional Review 
Board (IRB) /clinical trial monitor 
 
We anticipate a recruitment period will be no longer than 6 months and a screening period of one 
month. Before beginning treatment of subjects with full dose of the drug, a lead-in dosing period 
where subjects will receive 15 mg VC once daily (half the treatment dose) for one week. Lead-in dosing 
is used to minimize the risk of drug intolerance during the initial treatment period. During the 6-month 
treatment period, subjects will be treated with 30 mg VC orally once daily, a dose determined to be 
both safe and therapeutically relevant based on results from previous clinical studies. Throughout the 
clinical trial, study subjects will undergo safety monitoring, clinical and laboratory evaluations. These 
will include: 
- 
Primary endpoint testing (serum alkaline phosphatase, ALP) at baseline, 3 and 6 months 
- 
Secondary endpoint testing (AST/ALT and bilirubin, total and direct) at baseline, 3 and 6 months 
- 
Cytokine level testing (IL-17 and IFNγ) at baseline, 4 weeks, and 6 months 
- 
Extra blood draws, to be stored for potential future studies, will be obtained at baseline, 4 weeks, 3 
months, and 6 months 
- 
Subjects will be seen in clinic at enrollment and at the end of study 
- 
Phone monitoring will be conducted every 4 weeks during the study, beginning at the end of the lead-
in dosing period. We will assess subject health and general well-being, including PSC-related 
symptoms and IBD-related complications, safety, adverse events, and adherence to the study 
protocol, 
- 
Subjects will be contacted by phone one month after the end of the study as a follow-up to assess 
health and well-being and to capture any additional adverse events 
 
At the end of the 6-month treatment, any subjects demonstrating benefit may optionally continue VC 
treatment under a single-patient IND. Subjects without benefit will return to standard of care for PSC 
patients. All subjects will receive a post-study follow-up assessment at 30 days to capture any remaining 
adverse events (see Figure 1 for an overview of the clinical trial design). 


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Figure 1. Clinical trial design 
 
 
 
 
Screening 
(up to 1 month) 


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A dosage of 30 mg vidofludimus calcium has been chosen based on data from previous clinical trials. 
Vidofludimus has been investigated in two Phase 1 trials. A single dose study (escalating 17.5 - 350 
mg) and a multiple dose study (35 and 70 mg once daily over 14 consecutive days) were performed in 
nearly 90 healthy male volunteers. In these studies, vidofludimus demonstrated robust 
pharmacokinetics with a tmax at 4 hours, a half-life of about 36 hours, and a reasonable dose linearity, 
which justifies once daily dosing. At a dose of 35 mg vidofludimus, plasma trough levels between 4.4 
and 5.8 μg/ml were achieved, so that throughout the dosing interval plasma levels of vidofludimus 
were constantly above the IC50 values for inhibitory effects on stimulated human peripheral blood 
lymphocytes in vitro and for DHODH inhibition. In a Phase 2a study, vidofludimus (35 mg) 
demonstrated efficacy in patients with Crohn’s disease and ulcerative colitis, with 88.5% of subjects 
responding to treatment. 
 
Serum alkaline phosphatase (ALP) is one of the most extensively studied surrogate endpoint in PSC. 
Our group at Mayo Clinic and others have reported an association between serum ALP and clinical 
outcomes in PSC. Normalization of serum ALP appears to be associated with long-term survival free of 
cholangiocarcinoma, liver transplantation, liver-related death, and colorectal cancer, whereas 
persistent ALP elevation has been associated with worse outcomes in PSC. Therefore, we have chosen 
this simple, rapid, inexpensive, and minimally invasive test as the primary endpoint. Aspartate 
transaminase (AST), alanine transaminase (ALT), and bilirubin will be monitored to assess general liver 
health during the treatment. AST, ALT, or total bilirubin elevation can signal increased liver damage or 
liver cell necrosis, while elevated direct bilirubin may indicate bile duct obstruction. Part of the 
hypothesis being tested is that treatment with VC will result in a reduction of IL-17 and IFNγ 
production. Levels of these cytokines will be measured at 4 weeks and at 6 months and compared to 
baseline to determine whether early changes in these proinflammatory cytokines may predict 
improvements in ALP. 
 
A 25% improvement in ALP with no more than a 33% worsening of AST after 6 months of treatment 
will be assessed as a positive outcome. While full normalization of ALP levels is unlikely over the short 
course of this pilot study, a 25% improvement would be deemed significant, indicating that VC has a 
positive effect on the progression of PSC. A less than 33% increase in AST levels would be considered 
only a mild elevation and as such would be tolerable when accompanied by a concomitant reduction 
of ALP. While a recent consensus statement from the International PSC Study Group indicates that 
transient elastography (TE), a new technique that allows non-invasive assessment of liver fibrosis, is 
one of the top three most promising surrogate endpoints for PSC (along with ALP and liver histology), 
it is unlikely that significant changes in TE would manifest in the 6 month course of this study. Thus, TE 
will not be included as an endpoint. 
 
Vidofludimus calcium will be supplied by Immunic AG, Munich, Germany throughout the full course of 
the clinical trial. It has been confirmed through consultation with NIDDK personnel that this is 
permissible under this funding opportunity and does not constitute undue involvement by a foreign 
component. As this is a single- arm pilot trial, no placebo will be used. All study medication will be 
manufactured, tested, and released according to current Good Manufacturing Practice guidelines and 
local requirements. The active ingredient is vidofludimus calcium. Inactive ingredients are 
microcrystalline cellulose EP, polyvidon K25, crospovidone EP type A, talc, and magnesium stearate. 
The tablet formulation consists of a specific polymorph of vidofludimus calcium. Tablets are white, 
uncoated, biconvex tablets with a diameter of 8 mm. The dosage strength will be 15 mg VC per tablet. 
Subjects will take one tablet once daily during lead-in dosing period and two tablets, once daily during 
the treatment period. A licensed pharmacist (designated by the co-investigator) at each research site’s 


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pharmacy will be responsible for dispensing study medication. All study drugs will be labeled with 
"Caution: New Drug--Limited by Federal (or United States) law to investigational use" per 21 CFR 312.6.  
 
b) Sources of Materials: Please refer to Table 3 for details on the data that will be collected from 
study subjects. Each study subject will be assigned a study identification number. No protected 
health information (PHI) will be collected. Blood samples, collected and stored at the respective 
research sites, will be labeled using the subject’s unique study identification numbers. Study 
documents and generated data will be stored securely in a password-protected database and in 
locked cabinets in locked offices. Only research team members authorized by the principal 
investigator will have access to study subject’s data. 


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Table 3 – Data Collection Schedule 
Enrollment/ 
Baselinea 
Lead-in 
Dosing 
Period 
Treatment Period 
Follow-up 
Period 
Screeninga 
Procedures 
Up to 
Month -1 
Day 0 
Week 1 
± 1d 
W2 
(D14) 
±3d 
W4 
± 7d 
W8 
± 7d 
W12 
[M3] 
± 7d 
W16 
± 7d 
W20 
± 7d 
W24 
[M6] 
± 7d 
W28 
± 7d 
Informed Consent 
x 
CLINICAL 
Demographics 
x 
Medical History, initial 
x 
Review inclusion and 
exclusion criteria 
x 
x 
Clinic Visit 
x 
x 
Physical Examination 
x 
x 
Vital signs 
x 
x 
MRCP (images from medical record)b 
 
X 
 
 
 
 
 
 
 
X 
 
Transient elastography (from medical 
record)b 
 
X 
 
 
 
 
 
 
 
X 
 
Telephone evaluations 
x 
x 
X 
x 
x 
X 
x 
x 
Review any concurrent 
medications 
x 
x 
x 
X 
x 
x 
X 
x 
x 
x 
Assess for PSC-related 
complications 
x 
x 
x 
X 
x 
x 
X 
x 
x 
x 
Assess for IBD-related 
symptoms or complications 
x 
x 
x 
X 
x 
x 
X 
x 
x 
x 
Adherence to study protocol 
x 
X 
x 
x 
X 
x 
x 
x 
Adverse events evaluation 
x 
X 
x 
x 
X 
x 
x 
x 
Dispense Study Medication 
xc 
 
 
 
 
 
 
 
 
LABORATORY 
Hematuria testing by urine dipstick 
(patient self- administered every 
other day during lead-in period and 
during first week of Treatment 
x 
x 
HepBsAg, , Anti-HCV (from medical 
record) 
Xd 
 
 
 
 
 
 
 
 
HepBcAb, Anti-HAVIgM, (only if 
available from medical record) 
X 
 
 
 
 
 
 
 
 
Screening for HIV and TB  
x 
 
 
 
 
 
 
 
 
Creatinine with Estimated GFR (from 
medical record) 
X 
 
 
 
 
 
 
 
 
Uric acid 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testing (Monthly 
during treatment period for women 
of child-bearing potential) 
x 
x 
 
X 
x 
x 
X 
x 
x 
Pharmacokinetics, if possible for 
those experiencing SAE 
X 
 
ALP 
 
x 
 
X 
X 
X 
x 
X 
X 
x 
X 
Bilirubin, Total and 
Direct/Indirect 
x 
X 
X 
X 
x 
X 
X 
x 
X 
AST/ALT 
x 
X 
X 
X 
x 
X 
X 
x 
X 
Blood sample collection for 
potential future analysis 
frozen at -70°c 
x 
x 
 
x 
x 
Cytokine testing (IL-17 and IFN-ɣ) 
x 
x 
 
x 
a Screening and Baseline Visits may be done on the same day. Any procedures done to meet inclusion/exclusion criteria at Screening do not need to be 
repeated for the Baseline values at the discretion of the investigator.b If not available from medical record, does not need to be performed for the study. c 
Study may be mailed to participant after Baseline Visit once all test results available. d Will be tested at screening if unavailable from medical record  


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c) Potential Risks: 
 
1. Risks related to the study drug (VC)  
Risks associated with the use of VC include hematuria early in the course of treatment. Although no 
clinically related adverse events were observed at doses of vidofludimus >70 mg, at higher doses 
potential drug-related increases in urine red blood cells (RBCs) and hematuria were observed. The 
underlying mechanism leading to increased red blood cells in urine appears to be increased uric acid 
elimination during the initial days after drug administration. Inhibition of the urate transport system 
URAT1 by VC may decrease the tubular re-uptake of uric acid in kidneys, leading to increased uric 
acid in the urine. This may in turn result in microcrystallization of uric acid in acidic urine and may 
lead to the occurrence of red blood cells in urine. Although this may not normally lead to clinically 
relevant adverse events at therapeutic doses, it may be important for patients with a risk factor of 
increased serum uric acid. 
 
During clinical trials using vidofludimus, one serious adverse event of hepatitis was reported in a 
subject with Gilbert syndrome. Gilbert syndrome, which is associated with elevated blood levels 
of unconjugated bilirubin, is a genetic disease characterized by an up to 70–80% reduction in 
the glucuronidation activity of UGT1A1. The fact that VC is a moderate inhibitor of UGT1A1 may 
have contributed to this adverse event. Thus, patients with known or suspected Gilbert 
syndrome or with elevation of indirect (unconjugated) bilirubin above 1.2 time upper limit of 
normal (ULN) will be excluded from this clinical study. 
 
Biliary hyperplasia, or increased cell proliferation in bile ducts, was seen when VC was tested in 
dog and rat models. In humans, there is no clinical means to test for this effect. When VC was 
stopped in either animal the bile duct cell proliferation stopped. This side-effect, which was only 
visible under the microscope, was only seen when the blood levels of VC were significantly 
higher than what we anticipate in human subjects who enter this clinical trial. 
 
2. Risks related to the disease to be studied (PSC either in the absence or the presence of IBD) 
Potential problems that may occur during the clinical trial as part of the natural course of PSC 
and/or PSC- associated IBD include problems related to PSC biliary strictures. Most PSC patients 
have strictures in the biliary tree. Dominant strictures can induce stagnation of bile, resulting in 
bacterial colonization and secondary bacterial cholangitis. This biliary infection, acute ascending 
cholangitis, is a gastrointestinal emergency with high mortality rates if left untreated. The 
management is directed at treating the infection with broad-spectrum antibiotics and biliary 
drainage (endoscopic, percutaneous, or surgical). 
 
Cholangiocarcinoma is a feared complication of PSC. Annual cross-sectional imaging of the liver is 
currently recommended as standard of care for all PSC patients to screen for cholangiocarcinoma. 
We recommend liver ultrasound every 6-12 months in all PSC patients. Magnetic resonance 
imaging of liver (liver MRI) is permissible, but not required. 
 
PSC is often associated with inflammatory bowel diseases, namely ulcerative colitis. Study subjects 
will undergo clinical assessment for IBD at clinic visits. Study subjects will be instructed to call the 
study coordinators/investigators to report any new symptoms that may be due to flare up of IBD. 
Common symptoms that suggest IBD flare up are abdominal pain, fever, bloody stools, and an 
increase in frequency of bowel movements. In addition, phone monitoring will be performed 
periodically throughout the study to specifically inquire about the presence of any of these 


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symptoms. If symptoms are reported, the clinical site investigator may request further diagnostic 
testing and a clinical evaluation will be required. As symptoms of Clostridium difficile colitis may 
resemble those of an IBD flare-up, Clostridium difficile infection needs to be ruled out. 
 
Clostridium difficile colitis has been reported in IBD patients. If a study subject develops symptoms 
of Clostridium difficile colitis, C. difficile infection will be confirmed. The IBD status of the patient 
should be considered when weighing treatment options as recommended treatments may differ 
between the two patient populations. 
 
Colon cancer is an important endpoint in IBD, particularly in patients with PSC and UC. 
Currently, screening colonoscopy is recommended annually in patients with PSC and IBD. 
 
3. Risks related to the confidentiality of medical records  
We take very seriously the issue of patient confidentiality and potential problems related to data 
management and Electronic Medical Records (EMR). Nonetheless, breach of data or EMR by 
unauthorized personnel is a potential problem. Data will be stored in a locked cabinet and in a 
password secured internet database. Only personnel authorized by the Principal Investigator will 
be allowed to access study subject’s data. 
 
II. 
Adequacy of Protection against Risks 
 
a) Recruitment and Informed Consent  
Institutional Review Board (IRB) review and approval of the study protocol, informed consent form, 
recruitment material, and all study subjects’ materials will be obtained prior to initiation of the 
study. Any amendments to the study protocol will require review and approval by the IRB before 
changes are implemented to the study. All changes to the informed consent form will be IRB 
reviewed and approved; a determination will be made regarding whether previously consented 
study subjects need to be reconsented. 
 
Subjects will be recruited at the participating clinical research centers. Potential subjects will be 
identified and contacted by the individual site investigator and/or study coordinator. If the patient 
agrees, consent for participation will be obtained. The site investigator will be responsible for 
explaining the purpose of the study, goals, risks, benefits, study procedures, expectations from 
study subjects, and expected outcomes and/or results. The site investigator will also answer any 
questions that may arise. Study subjects will have the opportunity to carefully review the consent 
and study materials and ask questions prior to signing. The study subjects will have the opportunity 
to discuss the study with their family members, friends, caregiver, and healthcare providers and/or 
think about the study prior to agreeing to participate. The study subject will sign the informed 
consent prior to any procedures being done specifically for the study. The informed consent will be 
stored as part of the subject’s medical records for future reference, and a copy of the informed 
consent will be given to the study subjects for their records. Study subjects will be able to withdraw 
from the study at any time, and their lack of participation will have no effect on the care they 
receive. The rights and welfare of the subjects will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
 
 
 
 


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b) Protections Against Risk 
 
1. Protections against risks related to the study drug (VC)  
Risks associated with the use of VC include hematuria early in the course of treatment, believed to 
be due to microcrystallization of excess uric acid in the urine. As a precaution against this risk, 
patients with serum uric acid levels >1.2 ULN will be excluded from the study. Additionally, study 
subjects will be advised to drink sufficient fluids during the study to ensure adequate urine flow. 
Further, the trial will include a one week lead-in period where subjects receive half the treatment 
dose to minimize the risk of drug intolerance during the initial treatment period. Subjects will be 
monitored for two weeks after initial drug exposure for elevated RBCs in the urine by a urine 
dipstick test. It is not anticipated that hematuria will be seen if it has not developed within the first 
two weeks of drug exposure. Positive results will be immediately reported to the study coordinator 
and standard medical care will be provided. Three consecutive positive readings will require 
microscopic assessment of urine for sediment. All findings of RBCs in the urine will be listed as 
urinalysis abnormalities but will only be recorded as an adverse event when deemed by the 
investigator to be clinically significant. The investigator will assess whether there are more probable 
alternatives to explain this finding (e.g. evidence of contamination, evidence of infection not 
considered secondary to a drug induced damage, other benign causes such as menstruation, 
vigorous exercise, viral illness, trauma, or infection). If moderate or severe hematuria (see Table 4) 
cannot be remedied, the subject will discontinue VC treatment. 
 
Due to an occurrence of a potentially drug-related adverse event of hepatitis in a subject with 
Gilbert syndrome, patients with known or suspected Gilbert syndrome or with elevation of 
indirect (unconjugated) bilirubin above 1.2 ULN will be excluded from this clinical study 
 
To protect pregnant women, fetuses, and breastfeeding children, women who are pregnant, 
attempting to become pregnant, or breastfeeding will be excluded from the study. For female 
subjects of childbearing age, some form of contraception will be required during the study. A urine 
pregnancy test will be performed during each clinic visit and once a month during the entire 
treatment period. Subjects with a positive pregnancy test will discontinue the study immediately. 
 
Classification 
Symptoms 
Mild 
Asymptomatic hematuria: 
clinical or diagnostic observations only 
Moderate 
Symptomatic hematuria: 
with moderate flank pain (and including short-term [treatment for <24 hours], 
standard dose therapy with oral nonsteroidal anti-inflammatory drugs, oral 
acetaminophen or oral aspirin), interfering with but not limiting activities of daily 
living 
Severe 
Gross or macrohematuria; 
Any hematuria in connection with severe flank pain limiting activities of daily living. 
Any hematuria requiring additional treatment (e.g. oral anti-emetics or muscle 
relaxants, around the clock narcotic analgesics, use of narcotics or any intravenous 
treatment) or procedures for maintaining adequate urinary flow (e.g. urinary catheter 
or bladder irrigation). 
Table 4. Classification of symptoms of hematuria 
 
 


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To date, no clear indication for drug-induced hepatic effects has been identified in clinical trials 
with vidofludimus. Nevertheless, liver function monitoring (ALP, AST, ALT and bilirubin) will be 
included as part of this clinical trial. Further liver function testing will be initiated in the event of 
any of the following: 
 
a. Elevated ALP ≥3 x baseline 
b. Elevated AST and/or ALT ≥ 3x baseline 
c. Elevated total bilirubin ≥ 2x baseline 
d. Any elevation of bilirubin of 0.3mg/dl or more, regardless of ALT or AST levels, and 
in the presence of indicators of immunological reaction (e.g. rash or >5% 
eosinophilia), or appearance of nausea, vomiting, and right upper quadrant pain 
(symptoms consistent with clinical hepatitis) 
e. other suspected drug-induced liver injury(DILI) 
 
 Testing of all liver parameters (ALP, ALT, AST, total and indirect bilirubin) will be repeated within 48 to 72 
hours. If repeat testing still shows an elevated liver function test, the patient will be placed under close 
observation, as defined in the DILI guidance, until the liver enzymes return to within 10% of baseline. This 
includes, but is not limited to, repeating liver function tests 2 or 3 times weekly, detailed evaluation of 
medical history and concomitant drug use, ruling out other causes of liver enzyme increases, and further 
liver function tests as considered appropriate by the investigator. 
 
 
Table 5 – Algorithm for monitoring and interrupting study drug for Hepatocellular DILI signals in clinical 
trials evaluating drugs for patients with PBC and PSC without advance cirrhosisa and Normal Baseline ALT 
Values (Palmer et al 2019) 
Treatment 
emergent ALT 
Bilirubin 
Symptomsb 
Action 
ALT ≥ 5x ULN 
Normal 
Gilbert’s syndrome or haemolysis: No 
change in baseline total bilirubin 
None 
Blood tests should be repeated 2-5 daysc 
Follow-up for symptoms 
ALT ≥ 8x ULN 
Normal or elevated 
None or 
present 
Interrupt study drug 
Blood tests houdl be repeated within 2-5 
days c 
Initiate close monitoring and workup for 
competing aetiologies 
Study drug can be restarted only if 
another aetiology is identified and liver 
enzymes return to baseline. Drug cannot 
be restarted if hepatic decompensation 
occurred.d 
ALT ≥ 3x ULN 
Total bilirubin ≥ 2x baseline 
Gilbert’s syndrome or haemolysis: direct 
bilirubin > 2x baseline if baseline > 0.5 
mg/dL 
None or 
present 
Interrupt study drug 
Blood tests should be repeated within 2-5 
daysc 
Initiate close monitoring and workup for 
competing aetiologies. 
Study drug can be restarted only if 
another aetiology is identified and 
abnormalities return to baseline. Drug 
cannot be restarted if hepatic 
decompensation occursd. 
ALT ≥ 5x ULN 
Normal or elevated 
Present 
Interrupt study drug 


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Repeat blood tests in 2-5 daysc 
Initiate close monitoring and workup for 
competing aetiologies. 
Study drug can be restarted only if 
another aetiology is identified and 
abnormalities return to baseline. 
Drug cannot be restarted if hepatic 
decompensation occursd. 
aAdvanced Cirrhosis indicated Child Pugh B and C 
bLiver-related symptoms (eg, severe fatigue, nausea, new onset of or worsenting or pruritus, right upper quandant pain); 
Immunologic reaction (eg, rash, >5% eosinophilia); New onset of or increase of pruritus; or hepatic decompensation 
cThe specific interval between tests should also be determined based on the patient’s clinical condition. 
dThe study subject will require close follow-up monitoring to exclude recurrence of liver injury after restarting the study drug. 
 
 
Consider re- starting study medication only if a definitive alternative etiology is identified 
and liver tests return to within 10% of baseline. Discontinue the drug if total bilirubin, ALP, 
ALT, or AST elevation recurs following re-challenge. 
 
Overall, the safety profile at the dosage level to be used in this trial is quite positive. An in-
depth analysis of the entire clinical database demonstrates that vidofludimus at daily doses 
below 70 mg is not associated with an increased rate of clinically relevant adverse reactions, 
including hematuria, relative to placebo. These studies include 233 subjects with 
rheumatoid arthritis, Crohn’s disease, or ulcerative colitis who received daily doses of 
vidofludimus 20 mg (~3000 treatment days) or vidofludimus 35 mg (~16,500 treatment 
days) in 3 clinical trials with individual treatment durations of 12-13 weeks. 
 
The investigator will open an IND for the proposed clinical trial. Immunic AG, the drug 
supplier, will allow the investigator to reference Immunic’s IND for vidofludimus calcium (see 
Letter of Support from Immunic). 
 
2. Protections against risks related to the disease to be studied (PSC either in the absence 
or the presence of IBD): Acute ascending cholangitis, an acute biliary infection with high 
mortality rates, is a risk in patients with PSC. Study subjects will be asked about 
symptoms/signs of ascending cholangitis during clinic visits and phone calls, and subjects 
will be provided with a list of symptoms and instructed to report the symptoms to the 
study coordinator immediately if they arise. Symptoms suggestive of acute ascending 
cholangitis or biliary tree stricture include new onset jaundice, abdominal pain, dark 
urine, and light- colored stools. Study subjects will be advised to come to the clinic for 
evaluation or visit the nearest emergency room for consultation with an emergency 
room physician. If clinical suspicion for acute ascending cholangitis is high, the course of 
action may include aggressive antibiotic therapy and relief of biliary obstruction (via 
percutaneous, endoscopic, or surgical intervention), with or without a hospital stay. The 
Tokyo guidelines are commonly used for the diagnosis of acute ascending cholangitis. 
 
 
The Tokyo criteria are: 
i. 
Two of three (fever, right upper quadrant pain, and jaundice), plus 
ii. 
Systemic inflammation (elevated white blood count and/or C-reactive protein),plus 
iii. 
Abnormal liver function tests, plus 


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iv. 
Imaging detection of biliary dilatation and etiology (stone, stricture, stent, neoplasm) 
 
Cholangiocarcinoma (CCA) is one of the most serious complications of PSC. Screening for CCA is 
currently recommended every 6-12 months (by liver ultrasound or MRI) as part of standard of 
care for PSC patients. Patients with CCA at screening will be excluded. If during the course of the 
study CCA is suspected, subjects will undergo the necessary evaluations (which is part of 
standard of care) to exclude CCA. 
 
As PSC is frequently associated with IBD, study subjects will undergo clinical assessment for IBD 
at clinic visits and by phone between these visits. Study subjects should report any new 
symptoms of an IBD flare to the study coordinator. These symptoms include abdominal pain, 
fever, bloody stools, and an increase in frequency of bowel movements. 
 
In subjects with UC, we will use the Ulcerative Colitis Clinical Score to assess the disease 
activity/severity. This score, a modification of the well-known Mayo Score, consists of 4 items: 
stool frequency, rectal bleeding, subject’s functional assessment, and physician’s global 
assessment (PGA). Scores range from 0 to 12 points, with higher scores meaning more active 
disease. The Short inflammatory Bowel Disease Questionnaire (SIBDQ) is a health-related quality 
of life HRQoL tool measuring physical, social, and emotional status in IBD patients. The SIBDQ 
contains 10 items with 4 dimensions: bowel symptoms (3 items); systemic symptoms (2 items); 
emotional function (3 items); and social function (2 items). The total score ranges from 10 (worst 
health) to 70 (best). The SIBDQ can be administered and scored quickly and easily. 
 
In cases of confirmed Clostridium difficile colitis, any antibiotics the patient is already taking 
that are not specifically directed at Clostridium difficile will be reduced or stopped. Antibiotics 
such as vancomycin or other appropriate antibiotics specifically directed at Clostridium difficile 
will be administered. The use of immunosuppressive drugs should be minimized, but if 
required, patient will be closely monitored. 
 
IBD, particularly ulcerative colitis, is an important risk factor for colorectal cancer. 
Currently, screening colonoscopy is recommended annually in patients with PSC and 
IBD. 
 
3. Protections against risks related to the confidentiality of medical records: Study subject 
confidentiality is strictly held in trust by the investigators and their staff. This confidentiality is 
extended to cover testing of biological samples in addition to the clinical information relevant to 
the study subjects. 
 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the generated data will be 
released to any unauthorized third party a without prior written approval by the appropriate 
authorities. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
may inspect all study documents, generated data, and records required to be maintained by the 
investigators, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records related to the subjects involved in this study. The research study site will permit 
access to such records. 


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The study subject’s contact information will be securely stored at each research site for internal 
used during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the IRB and/or the institutional regulations. Study 
subject’s research data, which is for the purpose of statistical analysis and scientific reporting, will 
be transmitted to and stored at the Data Collection Center at Mayo Clinic Rochester. This will not 
include the study subject’s contact or identifying information. Rather, individual study subjects and 
their research data will be identified by a unique study identification number. Throughout this 
study, blood samples will be collected from study subjects and stored at the study sites for 
potential future analysis. These will also be labeled using only unique study identification 
numbers. 
 
Names and identifiers of study subjects will be coded, and the principal study documents will be 
kept secured in a password-protected database and in locked cabinets in locked offices. The 
information obtained from this study may be published in scientific journals or presented at 
scientific meetings; however, a subject’s identity will be kept strictly confidential. 
 
III. 
Potential Benefits of the Proposed Research to Human Subjects and Others  
 
PSC is currently an untreatable condition. The only known effective therapeutic intervention is liver 
transplantation, a risky and expensive procedure. This study will be extremely valuable as a means to 
test the feasibility of VC as a safe and effective therapeutic agent for PSC. Any efficacy demonstrated will 
not only benefit those subjects, but will help pave the way for more comprehensive studies of VC and 
PSC and move towards a potential new and effective therapy for this disease. Considering the known 
safety data, the implemented risk minimization measures, the expected benefits in the target 
population, and the medical need for effective therapies for PSC, the risk-benefit evaluation is 
considered favorable 
 
IV. 
Importance of the Knowledge to be Gained  
 
This impact of VC on the progression of PSC is unknown. This small pilot study will help determine 
whether VC is likely to be used as a treatment option for PSC and whether more comprehensive 
clinical studies are warranted. Further, it will provide evidence for whether the proinflammatory 
cytokines IL-17 and IFNγ may be used as early markers of improvements in serum ALP in patients with 
PSC. This will be the first clinical trial to investigate this novel chemical entity as a treatment for PSC. 
 
 
 
 
 
 
DATA AND SAFETY MONITORING PLAN  
 
This Human Subjects Research meets the definition of a clinical trial. It involves intervention with a 
drug in individuals with an established diagnosis of PSC. The study will require data and safety 
monitoring. 
 
A Data and Safety Monitoring Board (DSMB) will include independent clinicians and a statistician 
will be established to review study data, safety, and study design according to the DSMB Charter.  


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The Principal Investigator (PI) will periodically assess study progress including; subject accrual and 
retention; compliance with inclusion/exclusion criteria; status of all enrolled subjects; and subject 
protocol adherence. 
 
The PI and other study staff will periodically review study forms to monitor for data quality and 
integrity. The PI and the study coordinators will ensure IRB compliance throughout the duration of the 
project. 
 
Annual reports will be provided to the IRB and the sponsor. These reports include; a summary of 
recruitment and retention and reasons for dropouts; a list and summary of AEs; whether AEs are 
consistent with pre-study assumptions; and whether the study is on track to be completed and 
accomplish the stated aims. 
 
The protections against risks related to subject confidentiality are outlined in the Protection of Human 
Subjects section. Briefly, the study protocol, documentation, data, and all other information generated 
will be held in strict confidence, with only authorized personnel permitted access. Study data and 
records will be stored securely in a password-protected database or in locked cabinets in locked 
offices. Study subjects, their samples, and their data will be labeled using only unique study 
identification numbers. Names and identifiers of study subjects will be coded and if data from the 
study are published or presented publicly, a subject’s identity will be kept strictly confidential. 
 
To ensure the safety of the participants and the validity and the integrity of the data, the clinical trial 
will be monitored by an independent DSMB with experience in clinical trials in liver diseases, 
including cholestatic liver diseases. They will act as the designated safety officers for the trial, 
reviewing clinical trial reports every 6 months and addressing all reports of AEs. Acting independently 
of the PI, they will monitor study progress, protocol adherence, IRB compliance, and adherence to 
the proposed protections against risks related to subject confidentiality. 
 
A safety monitoring system will be used to ensure appropriate identification, tracking and reporting of 
adverse events (AEs). We will use the Common Terminology Criteria for Adverse Events (CTCAE) 
grading system to monitor the clinical trial’s potential AEs and to grade the severity of any AEs that 
may occur. The CTCAE is a descriptive terminology that can be utilized for adverse event reporting. A 
grading scale based on severity is provided for each AE term. The CTCAE displays grades 1 through 5 
with unique clinical descriptions of severity for each AE based on the general guideline shown in Table 
6. 
 
 
 
 
 
 
Grade 
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention 
not indicated. 


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2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age - appropriate 
instrumental activities of daily living (ADL). 
3 
Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization is indicated; disabling; limiting self-care ADL. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
Table 6. CTCAE grading system developed by the National Cancer Institute 
 
 
 
The expected AEs related to this study and strategies to track, minimize, and manage these AEs 
have been discussed in detail in the Protection of Human Subjects section, but are summarized in 
Table 7 below. 


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Expected Adverse Event 
Risk Mitigation and Monitoring Strategies 
Hematuria 
* Exclude patients with elevated uric acid levels 
* Advise subjects to drink sufficient liquids during trial 
* Lead-in dosing 
* Monitor hematuria by urine dipstick testing 
Complications of Gilbert Syndrome * Exclude patients with Gilbert syndrome 
* Exclude patients with elevated unconjugated bilirubin 
Acute Ascending Cholangitis 
* Monitor for symptoms during clinic visits and phone calls 
* Instruct patients to report any symptoms of acute 
ascending cholangitis or biliary tree stricture 
immediately 
Cholangiocarcinoma 
* Standard of care screening by liver ultrasound or MRI 
every 6-12 months 
IBD Flare 
* Monitor for symptoms during clinic visits and phone calls 
* Instruct patients to report any symptoms of IBD flare 
Clostridium difficile Colitis 
* Monitor for symptoms during clinic visits and phone calls 
* Instruct patients to report any symptoms of Clostridium 
difficile colitis 
Colon Cancer 
* Standard of care screening by colonoscopy 
annually 
Table 7. Expected adverse events 
 
The occurrence of an AE, serious AE (SAE), or unanticipated problem may come to the attention of 
study personnel during study visits, interviews of a study subject presenting for medical care unrelated 
to this study, telephone calls, laboratory test review, and/or upon review of study reports by the study 
monitor. An SAE is defined by the FDA as “an adverse event that, in view of the investigator, study 
coordinator, or the sponsor, results in any of the following: death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect”. All AEs will be captured and documented. Information collected about the AEs 
will include time of onset, nature, severity, relationship to the study drug, related to the natural history 
of PSC/IBD, subject hospitalized or not, intervention(s), time of resolution of resolution/stabilization, 
and outcomes. 
 
Safety-related information (of any level) will be entered into the clinical database and reviewed 
routinely. All AEs, SAEs, and unanticipated problems will be managed in a manner consistent with local 
IRB guidelines. We will use the following strategy when reporting all AEs (regardless of severity and 
relationship to study drug or natural course of PSC/IBD): 
1. If the AE(s) meet the criteria for study termination the clinical trial will be stopped 
immediately until further discussion with the sponsor. 
2. For all other AEs and unanticipated problems, reports will be made within 72 hours to the 
clinical trial monitor and/or local IRB. The clinical trial monitor/IRB will assume the 
responsibility for reviewing the clinical trial data for safety concerns and reporting to any 
appropriate regulatory bodies including the sponsor. 
 
 
 


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The trial shall be stopped until further discussion with the sponsor if any of the following occur: 
• 
3 subjects develop the same grade 3 CTCAE 
• 
2 subjects develop any grade 4 CTCAE 
• 
1 subject develops a grade 5 CTCAE 
 
Participation of individual study subjects shall be terminated if any of the following occur: 
• 
Elevated ALP ≥ 3 x baseline that does not return to within 10% of baseline within two weeks 
• 
Elevated AST and/or ALT ≥ 3 x baseline that does not return to within 10% of baseline 
within two weeks 
• 
Elevated total bilirubin ≥ 2 x baseline that does not return to within 10% of baseline within two 
weeks 
• 
Serious allergic reaction 
• 
Pregnancy or breastfeeding 
 
Non-adherence to the study protocol by a study subject may, at the discretion of the principal 
investigator, be grounds for termination. 
 
Statistical Analysis Plan: The proportion of patients with normalization of serum ALP at 3 months 
and 6 months and their corresponding confidence intervals will be estimated using exact binomial 
method.  The primary endpoint is ALP normalization(within the normal limits of the laboratory test) 
rate at 6 months. We will define success as a 95% CI that dose not overlap 0 at 6 months. Further, we 
will further investigate if the absolute ALP decreases over time using mixed model with repeated 
measures to account for within patient correlation over time.  
 
All the liver biochemistries and proinflammatory cytokine profile over time will be analyzed using 
mixed model with repeated measures to investigate how VC treatment plays a role over the 6 
months duration. The liver biochemistries and proinflammatory cytokine will be dichotomized into 
abnormal and normal groups if possible and further the abnormal proportions at different time 
points will be estimated to see the trend over time.  
 
The incidence, type and relatedness of serious adverse events and adverse events will be monitored 
and reported for all the subjects. 
 
Adherence to Regulatory Standards: The investigators will ensure that this study is conducted in full 
conformity with Regulations for the Protection of Human Subjects of Research codified in 45 CFR Part 
46, 21 CFR Part 50, 21 CFR part 56, and the ICH; Good Clinical Practice E6. 
 
ClinicalTrials.gov Requirements: The principal investigator will ensure that this clinical trial is properly 
registered at www.clinicatrials.gov, per the Public Law 110-85 (also known as the FDA Amendments Act 
(FDAAA) of 2007), no later than 21 days after the first subject is enrolled. The principal investigator will 
also ensure that the results (including adverse events) of this clinical trial are reported no later than 1 
year after completion of the clinical trial. 
 
Inclusion of Women and Minorities: Women and minorities will be included in this study although the 
disease is primarily one of males and has been largely described in Caucasian populations to date, 
usually in patients who originate from northern Europe, northern North America, or New Zealand. It is 
expected that the study population will roughly reflect the natural distribution among PSC patients in 
the United States with respect to gender and race/ethnicity.