MRX-800: A Long-Term Safety Study of Maralixibat, an Apical Sodium Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Subjects Who Previously Participated in a Maralixibat Study
Phase: PHASE2
Conditions: Cholestatic Liver Disease
Sponsor: Mirum Pharmaceuticals, Inc.

 
PROTOCOL: MRX-800 
TITLE: 
MRX-800: A Long-Term Safety Study of Maralixibat, an Apical 
Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the 
Treatment of Cholestatic Liver Disease in Subjects Who Previously 
Participated in a Maralixibat Study 
SHORT TITLE: 
MERGE: Maralixibat Extension Safety Study PRovidinG Long-tErm 
Treatment to Subjects with Cholestatic Liver Disease 
DRUG: 
Maralixibat (formerly SHP625 or LUM001) 
IND: 
EudraCT: 
119916; 119917; 147617 
2019-002755-42 
Phase: 
SPONSOR: 
2 
Mirum Pharmaceuticals Inc. 
950 Tower Lane 
Foster City, CA 94404 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
 
CONTRACT 
RESEARCH 
ORGANIZATION:  
PROTOCOL:  
HISTORY: 
Premier Research 
One Park Drive, STE 150 
Box 13608 
Research Triangle Park, NC 27709 
Amendment 3 (Global), 12 Nov 2020 
Amendment 2 (Europe), 09 Dec 2019 
Amendment 1 (Europe), 18 Nov 2019 
Original Protocol, Version 1.0, 13 Sep 2019 
This study will be performed in compliance with ICH Good Clinical Practices and applicable regulatory 
requirements, including the archiving of essential documents.  
This document contains confidential and proprietary information of Mirum and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Mirum Pharmaceuticals Inc. 
   
 
 
 
 
   

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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ...........................................................................................2 
TABLE OF CONTENTS ...........................................................................................................3 
LIST OF TABLES .....................................................................................................................7 
LIST OF FIGURES ...................................................................................................................7 
PROTOCOL SYNOPSIS...........................................................................................................8 
ABBREVIATIONS .................................................................................................................19 
1 
INTRODUCTION .................................................................................................24 
1.1 
Indication and Current Treatment Options ......................................................24 
1.2 
Product Background and Clinical Information ................................................26 
1.3 
Summary of Potential Risks and Benefits .......................................................29 
2 
RATIONALE AND OBJECTIVES ......................................................................31 
2.1 
Rationale for the Study ....................................................................................31 
2.2 
Study Objectives ..............................................................................................32 
2.2.1 
Primary Objective ............................................................................................32 
2.2.2 
Secondary Objectives .......................................................................................32 
2.2.3 
Exploratory Objectives ....................................................................................33 
3 
STUDY DESIGN...................................................................................................33 
3.1 
Study Design and Flow Chart ..........................................................................33 
3.1.1 
Rationale for Treatment ...................................................................................35 
3.1.2 
Rationale for Primary Endpoint .......................................................................36 
3.1.3 
Rationale for Study Population ........................................................................36 
3.2 
Duration and Study Completion Definition .....................................................37 
3.3 
Sites and Regions .............................................................................................37 
4 
STUDY POPULATION ........................................................................................37 
4.1 
Inclusion Criteria .............................................................................................37 
4.2 
Exclusion Criteria ............................................................................................38 
4.3 
Reproductive Potential .....................................................................................38 
4.3.1 
Female Contraception ......................................................................................38 
4.3.2 
Male Contraception ..........................................................................................39 
4.4 
Fasting Requirements.......................................................................................39 
4.5 
Withdrawal/Discontinuation from Study .........................................................40 
4.5.1 
Reasons for Discontinuation from Study .........................................................41 
4.5.2 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ...........................41 
5 
TREATMENT .......................................................................................................42 
5.1 
Identity of Investigational Product ...................................................................42 

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5.2 
Administration of Study Medication ...............................................................42 
5.2.1 
Interactive Response Technology ....................................................................42 
5.2.2 
Allocation and Dispensing of Study Medication .............................................42 
5.2.3 
Dosing ..............................................................................................................43 
5.3 
Labeling, Packaging, Storage, and Handling ...................................................45 
5.3.1 
Labeling ...........................................................................................................45 
5.3.2 
Packaging .........................................................................................................45 
5.3.3 
Storage .............................................................................................................45 
5.4 
Drug Accountability.........................................................................................45 
5.5 
Subject Compliance .........................................................................................46 
5.6 
Prior and Concomitant Treatment ....................................................................47 
5.6.1 
Prior Treatment ................................................................................................47 
5.6.2 
Concomitant Treatment ...................................................................................47 
5.6.3 
Permitted Treatment .........................................................................................48 
6 
STUDY PROCEDURES .......................................................................................48 
6.1 
Study Schedule.................................................................................................48 
6.1.1 
Screening Visit 0/Day 0 ...................................................................................48 
6.1.2 
Treatment Period ..............................................................................................50 
6.1.3 
End of Treatment/End of Trial .........................................................................51 
6.1.4 
Safety Follow-Up (
) ....................................................51 
6.2 
Study Evaluations and Procedures ...................................................................52 
6.2.1 
Safety ...............................................................................................................52 
6.2.2 
Efficacy ............................................................................................................55 
6.2.3 
Medical History, Disease History, and Medication History ............................57 
6.2.4 
Demographics ..................................................................................................57 
6.2.5 
Others ...............................................................................................................58 
6.2.6 
Volume of Blood to be Drawn from Each Subject ..........................................58 
7 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ...................59 
7.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ..............................................................................................................59 
7.1.1 
Treatment-Emergent Adverse Event ................................................................60 
7.1.2 
Unexpected Adverse Event ..............................................................................60 
7.1.3 
Suspected Unexpected Serious Adverse Reaction ...........................................60 
7.1.4 
Severity Categorization ....................................................................................61 
7.1.5 
Relationship Categorization .............................................................................61 
7.1.6 
Outcome Categorization ..................................................................................62 
7.1.7 
Symptoms of the Disease Under Study ...........................................................62 

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7.1.8 
Clinical Laboratory and Other Safety Evaluations ..........................................62 
7.1.9 
Adverse Events of Special Interest ..................................................................63 
7.1.10 
Pregnancy .........................................................................................................63 
7.1.11 
Abuse, Misuse, Overdose, and Medication Error ............................................64 
7.2 
Serious Adverse Event Procedures ..................................................................64 
7.2.1 
Reference Safety Information ..........................................................................64 
7.2.2 
Reporting Procedures .......................................................................................64 
7.2.3 
Serious Adverse Event Definition ...................................................................65 
7.2.4 
Serious Adverse Event Collection Time Frame ...............................................66 
7.2.5 
Serious Adverse Event Onset and Resolution Dates .......................................66 
7.2.6 
Fatal Outcome ..................................................................................................66 
7.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting..........................................................................................................67 
7.3 
Safety Monitoring ............................................................................................67 
7.3.1 
General Guidelines ...........................................................................................67 
7.3.2 
Safety Monitoring Guidelines ..........................................................................68 
7.3.3 
ALGS and PFIC Liver Chemistry....................................................................68 
7.3.4 
Biliary Atresia Liver Chemistry.......................................................................70 
7.3.5 
Cholangitis Diagnostic Criteria (Biliary Atresia) ............................................72 
7.3.6 
Safety Monitoring for Triglycerides ................................................................73 
7.3.7 
Safety Monitoring for Fat Soluble Vitamins ...................................................73 
7.3.8 
Monitoring/Stopping Rules for Coagulation Panel Results .............................73 
7.4 
Adjustment of Dose .........................................................................................73 
7.5 
Data Monitoring Committee ............................................................................74 
8 
STATISTICS .........................................................................................................74 
8.1 
Statistical Analysis ...........................................................................................74 
8.2 
Sample Size Calculation ..................................................................................75 
8.3 
Analysis Populations ........................................................................................75 
8.4 
Subject Disposition, Demographics, and Baseline Characteristics .................75 
8.5 
Treatment Exposure and Medical History .......................................................75 
8.6 
Safety and Tolerability Analyses .....................................................................76 
8.6.1 
Safety Endpoints ..............................................................................................76 
8.6.2 
Adverse Events ................................................................................................76 
8.6.3 
Vital Signs ........................................................................................................77 
8.6.4 
Laboratory Assessments ..................................................................................77 
8.6.5 
Concomitant Treatments ..................................................................................77 
8.6.6 
Liver Ultrasound ..............................................................................................77 

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8.7 
Efficacy Analyses ............................................................................................78 
8.7.1 
Efficacy Endpoints ...........................................................................................78 
8.8 
Other Analyses .................................................................................................80 
 
 
 
 
 
 
8.8.4 
Additional Analyses .........................................................................................81 
9 
STUDY CONDUCT ..............................................................................................81 
9.1 
Sponsor’s and Investigator’s Responsibilities .................................................81 
9.1.1 
Sponsor Responsibilities ..................................................................................81 
9.1.2 
Good Clinical Practice Compliance .................................................................82 
9.1.3 
Indemnity/Liability and Insurance ...................................................................82 
9.1.4 
Public Posting of Study Information ................................................................82 
9.1.5 
Study Suspension, Termination, and Completion............................................82 
9.2 
Investigator’s Responsibilities .........................................................................83 
9.2.1 
Good Clinical Practice Compliance .................................................................83 
9.2.2 
Protocol Adherence and Investigator Agreement ............................................83 
9.2.3 
Documentation and Retention of Records .......................................................84 
9.3 
Clinical Data Management ..............................................................................85 
9.4 
Monitoring Procedures.....................................................................................85 
9.5 
Quality Assurance/Audit ..................................................................................86 
9.6 
Record Retention .............................................................................................86 
9.7 
Sample Retention .............................................................................................86 
9.8 
Ethical Considerations .....................................................................................87 
9.8.1 
Informed Consent/Assent ................................................................................87 
9.8.2 
Institutional Review Board or Ethics Committee ............................................87 
9.9 
Study Site Initiation .........................................................................................88 
9.10 
Study Site Closure............................................................................................88 
9.11 
Privacy and Confidentiality .............................................................................88 
10 
FINAL CLINICAL STUDY REPORT .................................................................89 
11 
PUBLICATION .....................................................................................................89 
12 
REFERENCES ......................................................................................................90 
13 
APPENDICES .......................................................................................................93 
Appendix 1 
Clinical Outcomes Assessments ..........................................................94 
Appendix 2 
Observer Itch-Reported Outcome Instrument ItchRO(Obs)™ ............95 
 
 

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Appendix 6 
Clinician Scratch Scale ......................................................................107 
 
 
Appendix 8 
Management of Clinical Study Procedures During Covid-19 Pandemic 
or Other Force Majeure ......................................................................109 
 
 
 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ...........................................................................21 
Table 2 
Sample Daily Exposure (mg/day) for Subjects - BIDa ..............................43 
Table 3 
Dosing Table for Study MRX-800 ............................................................44 
Table 4 
Prohibited Treatments and Time Restriction Prior to Visit 0/Day 0 .........48 
Table 5 
List of Laboratory Analytes .......................................................................54 
 
 
Table 7 
Enhanced Liver Injury Monitoring Criteria ...............................................71 
Table 8 
Treatment Interruption Criteria ..................................................................72 
 
LIST OF FIGURES 
Figure 1 
Study Design ..............................................................................................35 
 

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ABBREVIATIONS 
7αC4 
7α-hydroxy-4-cholesten-3-one 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALGS 
Alagille syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
APRI 
AST to platelet ratio index 
ASBT 
apical sodium-dependent bile acid transporter 
ASBTi 
apical sodium-dependent bile acid transporter inhibitor 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
β-hCG 
beta-human chorionic gonadotropin 
BID 
twice daily (dosing) 
CBC 
complete blood count 
CFMB 
change from maralixibat baseline 
CI 
confidence interval 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CSS 
Clinician Scratch Scale 
DMC 
data monitoring committee 
EOT 
end of treatment 
ET 
early termination 
FGF-19 
fibroblast growth factor-19 
FIB-4 
fibrosis-4 
GI 
gastrointestinal 
GGT 
gamma-glutamyl transferase 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
HPE 
hepatoportoenterostomy 
IB 
Investigator’s Brochure 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 

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ItchRO™ 
Itch-Reported Outcome 
ItchRO(Obs)™ 
Observer-reported Itch-Reported Outcome Instrument 
 
 
LDL-C 
low density lipoprotein cholesterol 
 
 
 
 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
PEBD 
partial external biliary diversion  
 
 
PFIC 
progressive familial intrahepatic cholestasis 
PIS 
Patient Impression of Severity 
PK 
pharmacokinetics 
PT 
prothrombin time 
RBP 
retinol binding protein 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acids 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TJP2 
tight junction protein 2 gene 
TSB 
total serum bilirubin 
ULN 
upper limit of normal 
 

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1 
INTRODUCTION 
1.1 
Indication and Current Treatment Options  
Alagille syndrome (ALGS) is an inherited cholestatic liver disease in children. In patients with 
ALGS, impairment of the egress of bile acids from the liver leads to cholestasis, hepatocellular 
injury and damage, and progressive liver disease that may ultimately lead to the need for liver 
transplantation. Itch (pruritus) is the archetypal symptom of cholestasis, occurring at all stages of 
cholestatic liver disease, with or without jaundice. 
ALGS is an autosomal dominant multisystem genetic disorder with variable penetration. The 
clinical diagnosis is based on the presence of intrahepatic bile duct paucity on liver biopsy in 
association with at least 3 of the major clinical features: chronic cholestasis, cardiac disease, 
skeletal abnormalities, ocular abnormalities, and characteristic facial features. Fewer than 200 
patients with ALGS are born each year in the United States. The estimated prevalence in the 
United States is 3 per 100,000. Elevations of serum bilirubin up to 30 times normal and serum 
bile salts up to 100 times normal are common. Levels of markers of bile duct damage, including 
gamma-glutamyltransferase (GGTP or GGT) and alkaline phosphatase (ALP), usually are 
significantly elevated. Cholesterol levels may also be elevated. Multiple xanthomas are common 
sequelae of severe cholestasis. The pruritus seen in patients with this condition is among the 
most severe of any chronic liver disease, and it is present in most children by the third year of 
life. Although surgical interruption of the enterohepatic circulation has been successfully 
employed in the treatment of cholestasis and hypercholesterolemia in ALGS (Emerick and 
Whitington, 2002; Modi et al. 2007), the management of cholestasis in ALGS remains largely 
supportive at this time. As cholestasis tends to improve over the first 5 to 10 years, therapies that 
ameliorate the complications of cholestasis, without a commitment to liver transplantation, are 
highly desirable (Emerick et al. 1999). 
Progressive familial intrahepatic cholestasis (PFIC) is a rare autosomal recessive liver disorder 
characterized by intrahepatic cholestasis due to canalicular bile transport defects. There are more 
than 4 subtypes of PFIC classified based on different mutations. PFIC1, 2, and 3 result from 
mutations in the adenosine triphosphate (ATP) phospholipid transporting 8B1, ATP binding 
cassette subfamily B member 11, and ATP binding cassette subfamily B member 4 (ABCB4) 
genes, respectively, and all share the main clinical manifestations of cholestasis and pruritus. 
PFIC4 is based on mutations in the tight junction protein 2 gene (TJP2) and leads to failure of 
protein localization, disruption of tight-junction structure, and severe cholestatic liver disease 
(Sambrotta, 2014). In children, PFIC represents 10% to 15% of causes of cholestasis and 
10% to 15% of indications for liver transplantation (Davit-Spraul et al. 2009). PFIC2 is the most 
common subtype and is diagnosed in approximately 50% to 60% of patients with PFIC 
(Al Mehaidib and Al Shahrani, 2013) while PFIC1 (also known as Byler’s disease) and PFIC3 
account for approximately 10% to 20% (Alissa et al. 2008; Davit-Spraul et al. 2009) and 
30% to 40% of the PFIC population, respectively (Al Mehaidib and Al Shahrani, 2013).  

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Progressive familial intrahepatic cholestasis is associated with early mortality, morbidity, and 
devastating consequences on patients’ quality of life. In the absence of surgery, PFIC1 and 
PFIC2 are very aggressive diseases, with only 10% to 15% of PFIC1 and PFIC2 (depending on 
the variant) patients surviving through the age of 18 (Jericho, 2015). PFIC2 is associated with a 
continuous progressive course of symptoms (Al Mehaidib and Al Shahrani, 2013). While 
extrahepatic involvement, such as pancreatitis or diarrhea, can be a feature of PFIC1, the initial 
presentation and evolution of the disease in PFIC2 tends to be more severe than in PFIC1, with 
persistent jaundice occurring within the first months of life and rapid progression to cirrhosis and 
liver failure within the first years of life (Pawlikowska et al. 2010). Interruption of the entero-
hepatic circulation of bile acids through partial external biliary diversion (PEBD) surgery can 
lead to promising results with respect to pruritus, jaundice, and histology, both in patients with 
PFIC1 and PFIC2. Schukfeh (2012) reported a dramatic 1-year outcome in patients undergoing 
PEBD with 13/21 (62%) of patients normalizing serum bile acids (sBA) and liver function; 
however, other groups have reported overall failure rates of PEBD of up to 30%, with 30% to 
50% of patients requiring repeat surgery (Halaweish and Chwals 2010). Additionally, PEBD 
must be performed before liver fibrosis and cirrhosis are established for optimal benefit. For the 
vast majority of patients who do not undergo PEBD or do not respond, liver transplantation may 
be the only treatment option (Emerick et al. 2008; Yang et al. 2009; Arnell et al. 2010; 
Schukfeh et al. 2012).  
Biliary atresia is a rare, inflammatory condition of the biliary tree that presents in the first weeks 
of life and involves extrahepatic bile duct obstruction. This is associated with consequent liver 
injury, fibrosis, and cirrhosis that leads to portal hypertension and a decline in hepatic synthetic 
function. Infants with biliary atresia are often born at-term, have normal birth weight, and 
generally considered to be thriving well. The first symptoms appear in the first weeks of life with 
prolonged jaundice (beyond 2 weeks of life), acholic stools, and dark urine (Chardot 2006). The 
jaundice is accompanied by irritability and weight loss. 
The underlying disease mechanism in biliary atresia involves the mechanical obstruction of the 
extrahepatic biliary tree and impairment of bile flow, which leads to an ongoing cycle of liver 
injury due to the accumulation of toxic bile acids and rapidly progressing liver fibrosis, cirrhosis, 
and portal hypertension. This manifests with increased serum bilirubin and serum bile acids 
(sBA), as well as increased liver enzymes (Chen et al. 2008; Zhou et al. 2015). 
Untreated, the outcome of biliary atresia is uniformly fatal (Karrer et al. 1996). The etiology and 
pathogenesis of biliary atresia, however, remain largely unknown and are likely multi-factorial 
(Wehrman et al. 2019). That stated, genetic, infective, inflammatory/immunological, and 
toxicological factors have been implicated (Hartley et al. 2009; Verkade et al. 2016; Kilgore and 
Mack 2017). Biliary atresia is a recognized orphan disease. Recent biliary atresia estimates in 
Western countries show a prevalence between 0.5 and 0.8 per 10,000 live births, corresponding 
to 16,450 to 22,320 annual cases in the United States (Sanchez-Valle et al. 2017). 
The two most important improvements in the care of patients with biliary atresia to date have 
been the Kasai hepatoportoenterostomy (HPE or Kasai) and orthotopic liver transplantation. HPE 
remains the standard of care as first-line intervention, generally being performed within the first 
2 months of life. The procedure consists of surgically removing affected extra-hepatic bile ducts 

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and establishing bile flow by connecting a small bowel loop directly to the hepatic hilum, 
bypassing the obstructed bile ducts. HPE significantly improves long-term outcomes (native liver 
survival, mortality, morbidity), with approximately 40%–64% of patients experiencing clearance 
of jaundice (Chardot et al. 1999; McKiernan et al. 2000; Davenport et al. 2004; Wildhaber et al. 
2008; Pakarinen et al. 2018). However, although HPE frequently improves the signs and 
symptoms of biliary atresia, a substantial proportion of patients do not respond fully. 
Approximately 40%–50% of patients will require a liver transplant by 2 years of age despite 
undergoing HPE, making biliary atresia the leading cause of pediatric liver transplantation 
worldwide. This population, therefore, has a clear unmet medical need to improve outcomes and 
reduce the need for liver transplantation and long-term immunosuppressive therapy. At present, 
there are no approved pharmacological agents that have demonstrated efficacy in achieving this 
goal. 
Given the clinical outcomes associated with PFIC, ALGS, and biliary atresia, including the 
negative impact on patients’ and caregivers’ quality of life and the fact that there are currently no 
approved treatments, there is a high unmet medical need for a novel treatment for these diseases.  
1.2 
Product Background and Clinical Information 
Maralixibat chloride (formerly SHP625, LUM001) is a potent inhibitor (IC50=0.3 nM) of the 
apical sodium-dependent bile acid transporter/ileal bile acid transporter/solute carrier family 10 
(sodium/bile acid co-transporter family) member 2 (ASBT/IBAT/SLC10A2), a transmembrane 
protein localized on the luminal surface of ileal enterocytes (hereafter referred to as ASBT). 
Maralixibat was designed to be minimally absorbed, thereby maximizing the local exposure of 
the molecule to the receptor, minimizing systemic exposure of the drug, limiting drug-drug 
interactions, and systemic toxicity. These characteristics include a high molecular weight of 
710 Da and the presence of a positively charged quaternary amino moiety that can interact with 
the negatively charged surface of the enterocyte cell membrane and prevent absorption.  
The pharmacokinetics (PK), safety, and efficacy of maralixibat were assessed in a previous 
clinical development program that evaluated maralixibat as a potential lipid-lowering agent in 
patients with hypercholesterolemia. The hypercholesterolemia, primary sclerosing cholangitis 
(PSC), and primary biliary cholangitis (PBC) programs were terminated by the previous 
Sponsors for strategic and commercial reasons. Current development efforts are focused on rare 
pediatric cholestatic liver diseases, including ALGS, PFIC, and biliary atresia. 

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(mean [SD] time since original diagnosis was 93.97 months [75.361]). The study endpoint 
(Week 14/ET) was considered to be the last post-baseline value obtained before or within 7 days 
of the date of last dose. Analysis of the primary efficacy endpoint was based on the Wilcoxon 
signed rank test comparing serum bile acid levels at the study endpoint (Week 14/ET) with 
baseline. Significant reductions from baseline were observed at Week 6 and at study endpoint. 
However, the study was not powered for determination of statistical significance and further 
interpretation of these results is limited. The significant reduction in serum bile acid levels were 
not reflected in improvements in the secondary endpoints of liver function parameters. No 
significant reductions from baseline ALT, AST, ALP, or total bilirubin were found in paired 
difference test results; however, an increase in mean direct bilirubin values at study endpoint was 
noted. The sixth secondary endpoint, reduction in Adult ItchRO™ weekly sum score from 
baseline values to study endpoint, also was found to be nominally significantly improved from 
baseline using the paired difference test (p=0.0495). 
The majority of TEAEs were mild or moderate in severity (11/27 subjects [40.7%] and 
6/27 subjects [22.2%], respectively). Across treatment groups, the most frequently reported 
TEAEs occurred in the GI disorders SOC (22/27 subjects [81.5%]) and included TEAEs of 
diarrhea (14/27 subjects [51.9%]), nausea (9/27 subjects [33.3%]), abdominal pain (8/27 subjects 
[29.6%]), and abdominal distension (4/27 subjects [14.8%]). 
More than 119 subjects have been exposed to maralixibat, some for longer than 4 years, in the 
current pediatric cholestatic liver disease program, which includes completed and ongoing Phase 
2 and Phase 3 studies (studies in ALGS, PFIC, and biliary atresia). Consistent with the previous 
clinical program, the most commonly reported ADRs were abdominal cramping/pain and 
diarrhea/loose stools, the majority of which were mild or moderate in severity. Related SAEs 
included abdominal pain, abdominal pain upper, diarrhea, cholangitis, increased blood bilirubin, 
increased international normalized ratio (INR), pancreatitis, increased alanine aminotransferase 
(ALT), autoimmune hepatitis, hematochezia, and anemia. No deaths or important new or 
unexpected risks have been identified to date. A program-wide review of liver safety parameters, 
including an independent external expert adjudication of selected cases, indicated that 
maralixibat may cause ALT elevations in a certain percentage (2%–5% probably, 10%–20% 
probably or possibly related events) of subjects with ALGS, similar to the ALT elevations 
reported after PEBD surgery in this patient population. No predictors of this treatment response 
have been identified so far. None of the observed events were serious and none led to 
liver-related morbidity or mortality. There is no evidence to date that this effect is due to a direct 
hepatotoxic effect from the minimal amount of maralixibat that is systemically absorbed. The 
long-term consequences of the observed ALT elevations remain unclear. There is currently no 
evidence that maralixibat causes bilirubin elevations in patients with ALGS, and there is 
insufficient evidence of an association between bilirubin or liver enzyme elevations and 
maralixibat treatment in patients with PFIC. 
Clinical data from the Phase 2 study LUM001-304 demonstrated that treatment with 
400 μg/kg/day once daily (QD) of maralixibat was associated with a statistically significant 
improvement in both pruritus scores and reduction of sBA versus placebo at the end of a 
randomized drug-withdrawal period (Weeks 19 to 22) in which patients were switched to 
placebo or remained on maralixibat. The protocol-specified primary endpoint of the mean 

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change from Weeks 18 to 22 of fasting sBA levels in patients who previously responded to 
maralixibat treatment (defined by a reduction in sBA ≥50% from Baseline to Week 12 or 
Week 18) showed a statistically significantly difference between the maralixibat group versus the 
placebo group (p=0.046). In addition, in a pre-specified analysis (referred to as the Week 48 
analysis), the change from Week 18 in pruritus as measured by the ItchRO™ weekly morning 
average scores at Week 22 demonstrated a nominal statistically significant difference between 
maralixibat vs placebo (p=0.0002), as well as a nominal statistically significant difference in the 
absolute Week 22 score at the end of the treatment withdrawal period (p=0.0002). Patients 
treated with placebo experienced a recurrence of their pruritus to near baseline levels, whereas 
those who continued on maralixibat mostly maintained their reduction in pruritus. A total of 
72.4% of subjects experienced an Itch-Reported Outcome Observer (ItchRO[Obs]™) reduction 
of ≥1.0 point by Week 48, considered to be the threshold for meaningful change. 
In the Phase 2 study in subjects with PFIC (LUM001-501), an open-label study of the efficacy 
and long-term safety of maralixibat in the treatment of cholestatic liver disease in pediatric 
patients with PFIC, data from the final and posthoc analyses demonstrated significant 
improvements in a subgroup of 6 out of 19 subjects with non-truncating PFIC2 (nt-PFIC2) at 
doses of up to 280 µg/kg once daily (QD). A subsequent dose increase to 280 µg/kg twice daily 
(BID) produced a similar improvement in 1 additional subject with nt-PFIC2 who did not 
respond to the previous dose regimen. These improvements consisted of normalization or ≥75% 
decrease in sBA levels, concomitant with an increase in 7α-hydroxy-4-cholesten-3-one (7αC4) 
levels, a disappearance or clinically meaningful improvement in pruritus, as well as an increase 
in quality of life scores. Liver-related parameters (aspartate aminotransferase [AST]/ALT and 
total serum bilirubin [TSB]) were also normalized in those subjects with abnormal baseline 
values. The treatment responders experienced a significant catch-up growth, as indicated by a 
positive height and weight z-score change from baseline compared to those subjects who did not 
respond to maralixibat treatment. The data from Study LUM001-501 demonstrate that all 
maralixibat participants who achieved the established NAPPED sBA response threshold (defined 
as sBA threshold of <102 µmol/L or a 75% reduction; van Wessel et al. 2020) remain transplant 
free, whereas most of those who did not achieve the sBA response criteria eventually received a 
liver transplantation. The difference between the groups was statistically significant (p=0.0006). 
Always refer to the latest version of the Maralixibat Chloride Investigator’s Brochure (IB) for the 
overall benefit-risk assessment and the most accurate and current information regarding drug 
metabolism, PK, efficacy, and safety of maralixibat.  
1.3 
Summary of Potential Risks and Benefits 
An important therapeutic advantage of maralixibat is its high selectivity for ASBT, the location 
of ASBT on the luminal surface of the enterocyte, and its limited systemic exposure. In 
single- and repeat-dose PK studies in rat, rabbit, and dog, the oral bioavailability of maralixibat 
was < 1% at all doses tested and PK values in clinical studies were at or below the lower level of 
quantification in the adult and pediatric populations. 
The nonclinical safety profile is supported by multiple PD and safety pharmacology, ADME, 
single-dose toxicity, repeat-dose toxicity, genotoxicity, reproductive toxicity, and juvenile 

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toxicity studies. Results from PD studies in rats, dogs, and monkeys indicate that selective 
inhibition of ASBT by maralixibat results in increased fecal bile acid excretion, inhibition of the 
postprandial rise in serum bile acids, and decrease in serum total cholesterol. No clinically 
significant changes were observed in rat neurobehavioral, dog cardiovascular, or guinea pig 
pulmonary function safety pharmacology studies following single oral or IV administration of 
maralixibat.  
The most commonly reported AEs across the previous clinical program of hypercholesterolemia, 
and the current program of cholestatic liver diseases are in the GI disorders SOC and include 
abdominal cramping/pain and diarrhea/loose stools. The majority of AEs were mild or moderate 
in severity. These GI-related AEs are believed to be mechanism-based, due to elevated bile acid 
concentrations in the colon and therefore are not unexpected. In the completed studies in the 
cholestatic liver disease clinical program, GI-related AEs have resulted in 3 of the 6 study 
discontinuations due to AEs to date. Preliminary data from the ongoing studies indicate that 
1 subject has discontinued due to a GI-related AE (hematochezia).  
To date, a total of 48 subjects across completed and ongoing studies have had an SAE. Related 
SAEs from the completed studies included abdominal pain and cholangitis. The only related 
SAEs from the ongoing studies have been blood bilirubin increased, which resulted in 
withdrawal of the investigational product. The study medication was restarted for the patient 
with the SAE of blood bilirubin increased. The possibly related SAEs of hematochezia, anemia, 
and the suspected unexpected serious adverse reaction (SUSAR) of autoimmune hepatitis 
(preferred term hepatobiliary disease) resulted in withdrawal of the investigational product and 
study discontinuation. No deaths have been reported.  
Results of the LUM001-304 48-week analysis showed a clinically meaningful reduction in 
pruritus in patients with ALGS. There was a consistent and clearly distinct behavior between the 
maralixibat and placebo groups, with an increase to near baseline levels in the placebo group 
when maralixibat was removed, and no material change in ItchRO(Obs)™ in subjects who 
continued on maralixibat during the randomized drug withdrawal period. Pruritus results 
corresponded with changes in PD markers such as sBA, 7αC4, and cholesterol. Preliminary data 
from the long-term extension study LUM001-303 show persistent treatment response over 
>3 years of treatment. 
Results of LUM001-501 final and posthoc analyses showed 6 patients with PFIC2 who 
demonstrated a resolution or significant reduction of pruritus (ItchRO™ ≥1.0 change from 
baseline) and serum bile acids (sBA ≥75% change from baseline). A seventh patient was 
declared a responder after starting BID dosing and doubling the total daily dose. In those 
responders, bilirubin and aminotransferase levels also normalized in those patients who had 
elevated values at baseline. 
The overall safety, tolerability, and preliminary efficacy of maralixibat in ongoing and completed 
studies indicate that there is a positive benefit-to-risk profile for the treatment of rare pediatric 
cholestatic liver diseases. 

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2 
RATIONALE AND OBJECTIVES 
2.1 
Rationale for the Study 
There is currently no approved treatment for PFIC, ALGS, or biliary atresia, and available 
medical approaches have limited efficacy. Maralixibat is currently being investigated in pediatric 
patients with ALGS, PFIC, and biliary atresia. 
Maralixibat has been studied for the treatment of pruritus in pediatric patients with ALGS, in 
which lower doses than the planned therapeutic dose of 400 μg/kg/day QD were investigated in 
13-week placebo-controlled studies LUM001-301 and LUM001-302. These studies showed 
trends towards improvement in pruritus and reduction in sBA, as well as an improvement in 
QoL. Subjects who completed these studies were offered the opportunity to enroll into long-term 
extension studies, LUM001-305 and LUM001-303, which are both ongoing for >4 years. In 
study LUM001-304, treatment of ALGS patients with 400 μg/kg/day once daily (QD) of 
maralixibat was associated with a statistically significant improvement in both pruritus scores 
and reduction of sBA vs placebo at the end of a randomized drug withdrawal period 
(Weeks 19 to 22) in which patients were switched to placebo or remained on maralixibat. This 
study is ongoing in an open-label extension for > 4 years.  
Maralixibat was generally safe and well tolerated throughout the clinical development program, 
including Study LUM001-304. Overall, the safety profile observed for the higher doses of 
maralixibat (at or above the planned commercial dose of 400 μg/kg/day) has been comparable to 
that observed at lower doses. Adverse events occurred more commonly in the first 12 months of 
treatment and reduced with increased duration of exposure over 4 years, which in part may be 
due to subjects who tolerated the drug and stayed in the study. 
Data from the final and post-hoc analyses from the Phase 2 study LUM001-501 in subjects with 
PFIC show that a subgroup of subjects with PFIC2 experienced clinically significant 
improvements after maralixibat treatment at 280 µg/kg/day as manifested by a large reduction or 
normalization of sBA, reduction in pruritus, and normalization of TSB and ALT for those with 
elevated baseline values. Also, BID dosing (560 µg/kg/day) led to a higher response rate 
compared with the previously used QD dosing.  
There is currently no approved pharmacological treatment for biliary atresia, and available 
medical approaches (e.g., steroids, immunoglobulins) have limited efficacy. The nonclinical and 
clinical data outlined above provide a strong scientific rationale for the use of maralixibat in 
biliary atresia, suggesting that a reduction in sBA levels in this patient population may lead to 
improvements in cholestatic liver disease and ultimately prolonged native liver survival, similar 
to the treatment benefits observed in other pediatric cholestatic indications. 
Clinical data from ongoing and completed Phase 2 studies in PFIC and ALGS indicate that 
maralixibat improves signs and symptoms of cholestasis and may improve markers of liver 
injury and long-term outcome. This includes reductions in sBA, as well as improvements in 
growth and other measures suggestive of disease modification, such as transplant- or biliary 
diversion-free survival. In disease states, bile acids have been shown to induce damage and 

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during the study, agree to use acceptable methods of contraception, as defined below, 
throughout the study period and for 
 following the last dose of study 
medication. If hormonal contraceptives are used, they should be administered 
according to the package insert.  
Acceptable methods of contraception are: 
• 
Intrauterine devices plus condoms 
• 
Double-barrier methods (e.g., condoms and diaphragms with spermicidal gel or foam) 
• 
Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for 
at least 
 prior to the Screening Visit 0/Day 0, plus condoms. Note: If subject 
becomes sexually active during the study, he or she should use one of the other 
acceptable methods noted above in addition to the hormonal contraceptive until it has 
been stabilized for 
. 
4.3.2 
Male Contraception 
Contraception is required for all sexually active male subjects and their partners. All male 
subjects must agree not to donate sperm, and to use 1 of the following approved methods of 
contraception until 
 following the last dose of study medication: 
• 
Male condom with spermicide 
• 
Intrauterine device with spermicide (use by female sexual partner) 
• 
Female condom with spermicide (use by female sexual partner) 
• 
Contraceptive sponge with spermicide (use by female sexual partner) 
• 
Intravaginal system (e.g., vaginal ring with spermicide, a diaphragm with spermicide, 
or a cervical cap with spermicide) (use by female sexual partner) 
• 
Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner). 
4.4 
Fasting Requirements 
On study visit days at which blood samples are collected for the lipid panel and/or cholestasis 
biomarkers, subjects are encouraged to fast for 
 (water intake is permitted if 
necessary but not recommended) before blood sample collection (see Table 1). On these visit 
days, study medication should be administered as usual, in the morning 30 minutes before the 
normal breakfast time. Only water should be consumed until the scheduled clinic visit. 

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4.5 
Withdrawal/Discontinuation from Study 
This is a long-term study, and a subject’s participation will continue until the end of the study or 
at the Sponsor’s discretion. Early termination is defined as the discontinuing of any subject’s 
study participation before the end of the study or due to the Sponsor’s decision to stop the study. 
A subject may withdraw from the study at any time for any reason without prejudice to his or her 
future medical care by the physician or at the institution. Should a subject decide to withdraw 
from the study, the Investigator will make every effort to schedule and complete the EOT/ET 
Visit (Table 1 and Section 6.1.3). 
The Investigator or Sponsor may discontinue the subject from the study at any time in case of 
possibly related or related SAE(s) and may consider discontinuation for poor compliance, AE(s), 
or other reasons (refer to Section 4.5.1). The Investigator is encouraged to discuss 
discontinuation of a subject with the Medical Monitor when possible (see Section 7.3.3.2).  
Adverse events that in the Investigator’s opinion would compromise the subject’s ability to 
safely continue in the study would warrant the subject’s discontinuation from the study. The 
reason for discontinuation must be recorded in the subject’s source documents and case report 
form (CRF). If a subject is discontinued for more than 1 reason, each reason should be 
documented in the source, and the primary reason for discontinuation should be captured in the 
CRF. 
Subjects who discontinue from the study for safety reasons will be followed-up until resolution 
of the event or until a final outcome according to the Investigator’s discretion. 
If subjects discontinue from the study due to disease progression and require PEBD or liver 
transplant surgery or listing for liver transplant, both the reason for discontinuation and outcome 
(i.e., PEBD, cholecystostomy tube, ileal exclusion, liver transplant, or listed for liver transplant 
or other) should be recorded in the subject’s source document. If known, the date of the future 
scheduled procedure should also be recorded. The information regarding PEBD, liver transplant 
or listing for transplant or other procedure will be collected in the CRF at the time the subject 
completes/early terminates from the study (EOT/ET) until the completion of their follow-up 
period. Any dose increase of concomitant medications or introduction of new medication for the 
treatment of pruritus and/or cholestatic liver disease will also be collected. 
The reason for termination and the date of stopping study medication must be recorded in source 
documents and CRF. The evaluations listed for the EOT/ET Visit are to be performed as 
completely as possible for any subject who discontinues (See Table 1 and Section 6.1.3). 
Subjects, their caregivers, and/or their family doctor/primary care physician will be contacted by 
the Investigator and/or designee to obtain information on how the subject’s disease has 
progressed and whether the subject has had PEBD surgery or has been listed for, or had a liver 
transplant or any other procedure relevant to the management of the subject’s cholestatic liver 
disease (i.e., PEBD, cholecystostomy tube, ileal exclusion, liver transplant, or listed for liver 

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5 
TREATMENT  
5.1 
Identity of Investigational Product 
The investigational product (IP) is maralixibat chloride (formerly SHP625, LUM001), which 
will be provided as a fixed, oral solution (i.e., 
) along with either 0.5-, 
1.0-, or 3.0-mL sized oral dosing dispensers. The study medication, maralixibat, is presented in 
30 mL volumes packaged in 30 mL size amber colored PET bottles and requires refrigerated 
storage condition (2°C–8°C). 
One of the excipients in the maralixibat oral solution is propylene glycol (PG). To limit subject 
exposure to PG, a specific strength and volume of oral solution will be prescribed to a given 
subject based on his or her body weight and target dose. The dosing plan will limit PG exposure 
to 
 and, at the same time, will provide appropriate dosing volumes to ensure 
accurate dosing.  
Additional information on maralixibat dosing and PG exposure is provided in the Maralixibat 
Chloride IB and the pharmacy manual. 
5.2 
Administration of Study Medication 
Details on handling and management of the study medication will be described in the pharmacy 
manual. 
 
5.2.1 
Interactive Response Technology 
An interactive response technology (IRT) will be used for screening subjects, management of 
study visits, and ordering of study medication. The appropriately delegated site personnel will 
receive training on the use of the IRT system.  
The IRT manual, which contains details on applicable modules corresponding to study visits, 
assessment and/or procedures (see Table 1), including study medication management, will be 
provided to the site. 
5.2.2 
Allocation and Dispensing of Study Medication 
Eligible subjects will receive study medication at the Screening Visit 0/Day 0 and at subsequent 
visits (
) thereafter. If necessary, 
study medication may be dispensed at an unscheduled clinic visit or via direct from 
site-to-patient shipment in between visits. 

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luminal bile acid release associated with meals. Study medication should be administered 
approximately at the same time each day throughout the study.  
5.3 
Labeling, Packaging, Storage, and Handling 
5.3.1 
Labeling  
All study medication is labeled according to country-specific requirements. Additional labels 
may, on a case-by-case basis, be applied to the study medication to satisfy local or institutional 
requirements, but must not: 
• 
Contradict the clinical study label 
• 
Obscure the clinical study label 
• 
Identify the study subject by name 
Additional labels may not be added without the Sponsor’s prior full agreement. 
5.3.2 
Packaging  
Study medication is packaged in the following labeled containers: 
 
 
 
 
 
 
• 
Ready-to-use oral solution of maralixibat 
 
The Sponsor or designee will provide 0.5, 1.0, and 3.0 mL sized oral dosing dispensers. Changes 
to Sponsor-supplied packaging may not occur without full agreement in advance by the Sponsor. 
5.3.3 
Storage 
The Investigator has overall responsibility for ensuring that study medication is stored in a 
secure, limited-access location at refrigerated storage conditions (2°C–8°C). Temperature 
monitoring is required at the storage location to ensure that the study medication is maintained 
within an established temperature range. The Sponsor must be notified immediately upon 
discovery of any excursion from the established range, or if there are any changes to the storage 
area of the study medication that could affect the integrity of the study medication. 
5.4 
Drug Accountability 
Investigators will be provided with sufficient amounts of the study medication to carry out this 
protocol for the agreed number of subjects. The Investigator or designee will acknowledge 
receipt of the study medication, documenting shipment content and condition. Accurate records 
of all study medication dispensed, used, returned, and/or destroyed must be maintained. 

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whom the 
 is expired may be considered for entry into MRX-800 after discussion 
with the medical monitor. 
Subjects who meet eligibility criteria will be dispensed enough study medication to last until 
their next expected clinic visit. Assessments and procedures will be performed as outlined in 
Table 1. 
Evaluations and procedures completed for 
 will serve as the 
evaluations for the MRX-800 Screening Visit 0/Day 0. Therefore, data and assessment results 
will be pulled by data management from 
 to the MRX-800 
Screening Visit 0/Day 0 CRF accordingly, including physical examination and vital signs 
(including height and weight), and laboratory assessments listed in Table 5. Note that laboratory 
assessments have to be performed if the laboratory samples in 
 were collected 
 prior to the scheduled MRX-800 Screening Visit 0/Day 0. 
For females of childbearing potential, the 
 serum β-hCG pregnancy test 
results will be used, if available. Otherwise, a urine pregnancy test will be performed (see 
Section 6.2.1.5). A positive urine pregnancy test result requires a subject to undergo a serum 
β-hCG pregnancy test. Results of the pregnancy test must be reviewed prior to dispensing study 
medication. 
AEs ongoing at the time of the subject’s 
 should be entered by 
the site into the MRX-800 Adverse Event CRF.  
New AEs for the MRX-800 will only be collected from the time informed consent (and/or assent 
when appropriate) is signed (see Section 7.1). 
The following data (not an exhaustive list) from the previous study will be pulled by data 
management to the current study: Race and Medical/Disease History.  
The following are expected to be entered by the site in the MRX-800 CRF: Date of Birth, Age, 
Sex, ongoing Concomitant Medication(s). Local, country-specific guidelines should be followed 
where there is regional variation for collection of demographic information. 
If the subject does not meet eligibility criteria following completion of screening assessments, 
the subject will be considered as a screen failure. A screen failure is a subject who has given 
informed consent (and/or assent when appropriate) and failed to meet the inclusion and/or met at 
least 1 of the exclusion criteria and has not been dispensed or administered study medication. 
The Investigator or designee will register the subject as a screen failure in the IRT system. 
In exceptional cases, subjects who initially fail to meet eligibility criteria may be re-screened. All 
re-screenings should be discussed with the Medical Monitor. 

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Height will be measured by trained site staff in children who can stand on their own (generally 
≥ 2 years) using a calibrated stadiometer or headboard, respectively, via 2 independent 
measurements, recorded to the nearest 0.1 cm (and a third measurement if values differ by 
> 0.5 cm). The same stadiometer should be used for all study visit measurements.  
Weight will be assessed, recorded to the nearest 0.1 kg, using a calibrated balance or electronic 
scale (children who can stand on their own, generally ≥2 years of age).  
Standardized instructions based on regulatory guidance for height and weight measurements will 
be provided in the study manual. 
6.2.1.4 
Clinical Laboratory Evaluations 
All clinical laboratory evaluations will be performed according to the central laboratory manual. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The Investigator 
or Sub-Investigator must assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are clinically significant or not. Abnormal clinical laboratory values, 
which are unexpected or not explained by the subject’s clinical condition, may, at the discretion 
of the Investigator or Sponsor, be repeated as soon as possible until confirmed, explained, or 
resolved. 
Clinical laboratory assessments will be performed as listed in Table 5.  
Unscheduled safety laboratory sampling should be conducted throughout the study as required in 
case of any clinical safety concerns. The local laboratory values are not required to be collected 
in the CRF, except for those that are directly relevant to the monitoring of an AE/SAE; collection 
of other values may be requested by the Sponsor. 
 
 

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Table 5 
List of Laboratory Analytes 
β-hCG 
Serum or urine (if indicated) 
 
CBC with Differential 
Hematocrit 
Hemoglobin 
MCV, MCH, MCHC 
Red blood cells 
Platelets 
White blood cells 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Coagulation 
aPTT (sec) 
INR 
PT (sec) 
Clinical Chemistry 
Albumin 
ALP 
Amylase 
ALT (SGPT) 
AST (SGOT) 
Bilirubin, direct 
(conjugated) 
Total serum 
Bilirubin (TSB) 
Blood urea nitrogen 
(BUN) 
Calcium 
Chloride 
Creatinine 
GGT  
Glucose 
Lipase 
Phosphate 
Potassium 
Sodium 
Total protein 
Uric Acid 
Measured serum 
Osmolality 
Total Lipids 
 
Lipid Panela 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Triglycerides (TG) 
 
Cholestasis Biomarkersa 
Total serum bile acids (sBA) 
Serum bile acid subspecies 
7α-hydroxy-4-cholesten-3-
one 
FGF-19 
Autotaxin 
 
 
Lipid Soluble Vitaminsa 
25-hydroxy vitamin D 
Retinol 
Retinol binding protein 
(RBP) 
α-Tocopherol 
Urinalysis 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Occult blood and cells 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic examinationb 
Oxalatec,d 
Creatinined 
 
Marker of hepatocellular 
carcinoma 
α-fetoprotein 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; 
APRI=AST to platelet ratio index; AST=aspartate aminotransferase; β-hCG=beta human chorionic gonadotropin; 
FGF-19=fibroblast growth factor 19; FIB-4=fibrosis-4; GGT=gamma-glutamyl transferase; HDL-C=high density 
lipoprotein cholesterol; INR=international normalized ratio; LDL-C=low density lipoprotein cholesterol; 
MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean 
corpuscular volume; PT=prothrombin time; RBP=Retinol binding protein: SGOT=serum glutamic-oxaloacetic 
transaminase; SGPT=serum glutamic-pyruvic transaminase; WBC=white blood cell 
a Blood samples for the analysis of lipid panel and lipid soluble vitamins should be drawn prior to administration of 
vitamin supplementation. Blood samples for the analysis of cholestasis biomarkers and lipid panel should be 
drawn as much as possible approximately 
 after food or formula (water intake is permitted if necessary but 
not recommended). Other biomarkers [e.g., lysophosphatidic acid (LPA)] may be measured. At the discretion of 
the Sponsor, samples will be collected and appropriately stored for subsequent analysis, as needed. 
b Will be performed on abnormal findings unless otherwise specified. 
c Oxalate will be assessed at 
. 
d Spot tests on creatinine and oxalate levels will be done to monitor for signs of nephrolithiasis.  
  
 
A serum storage sample will be collected for the analysis of cholestasis biomarkers as 
determined by the Sponsor. 

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AEs that were ongoing at the time of the subject’s previous lead-in study should be entered by 
the site into the MRX-800 CRF for further follow-up. 
Where possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has 
not been made, then each symptom should be listed individually, and a diagnosis should be 
provided when the underlying cause is clear. All AEs should be captured on the appropriate AE 
pages in the CRF and in source documents. 
All AEs must be followed to closure, regardless of whether the subject is still participating in the 
study. Closure indicates that an outcome is reached, stabilization achieved (the Investigator does 
not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented. 
7.1.1 
Treatment-Emergent Adverse Event 
A treatment-emergent AE (TEAE) is defined as any event emerging or manifesting at or after the 
initiation of treatment with an IP or medicinal product or any existing event that worsens in 
either intensity or frequency following exposure to the IP or medicinal product.  
In this study, all AEs will be considered TEAEs. 
7.1.2 
Unexpected Adverse Event 
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not consistent with 
the medical terms, severity, representation, or description used in the Reference Safety 
Information (RSI). “Unexpected” also refers to the AEs that are mentioned in the IB as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the product but are 
not specifically mentioned as occurring with the particular product under investigation.  
The expectedness of AEs will be determined by the Sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated from the pharmacological properties of a product. 
7.1.3 
Suspected Unexpected Serious Adverse Reaction 
A SUSAR is defined as any suspected adverse reaction to study treatment (i.e., including active 
comparators) that is both serious and unexpected.  
The event(s) must meet all of the following: 
• 
Suspected adverse reaction 
• 
Serious 
• 
Unexpected 

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• 
Assessed as related to study treatment 
7.1.4 
Severity Categorization 
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of study medication, must be recorded 
as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to dosing of 
study medication, but the dyspepsia becomes severe and more frequent after first dose of study 
medication has been administered, a new AE of worsening dyspepsia [with the appropriate date 
of onset] is recorded on the appropriate CRF). 
The investigator will make an assessment of the maximum intensity for each AE and SAE 
according to the NCI CTCAE, version 5.0. Should a subject experience any AE not listed in the 
CTCAE, the following grading system should be used to assess severity: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
• 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
NOTES: An event is defined as “serious” when it meets at least one of the predefined outcomes 
as described in the definition of an SAE. In the absence of meeting any of the seriousness 
criteria, a severe event does not qualify as being serious. A semicolon indicates “or” within the 
description of the grade, not “and.” 
7.1.5 
Relationship Categorization 
A physician/Investigator must make the assessment of relationship to study medication for each 
AE. The Investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the study medication. If there is no 
valid reason for suggesting a relationship, then the AE should be classified as “not related.” 
Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting a 
possible cause-and-effect relationship between the study medication and the occurrence of the 
AE, then the AE should be considered “related.” The causality assessment must be documented 
in the source document. 

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The following additional guidance may be used to determine the relationship: 
Term 
Relationship Definition 
Related 
The temporal relationship between the event and the administration of the study medication 
is compelling and/or follows a known or suspected response pattern to that product, and the 
event cannot be explained by the subject’s medical condition, other therapies, or accident. 
Not 
Related 
The event can be readily explained by other factors such as the subject’s underlying medical 
condition, concomitant therapy, or accident and no plausible temporal or biologic 
relationship exists between the study medication and the event. 
7.1.6 
Outcome Categorization 
The outcome of AEs must be recorded on the CRF. Outcomes are as follows: 
• 
Fatal 
• 
Not recovered/Not Resolved 
• 
Recovered/Resolved 
• 
Recovered/Resolved with Sequelae  
• 
Recovering/Resolving 
• 
Unknown 
Action taken (i.e., dose increased, dose not changed, dose reduced, drug interrupted, drug 
withdrawn, not applicable, or unknown) will also be recorded on the AE CRF. 
7.1.7 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, disease progression resulting in study discontinuation 
should be recorded as an AE.  
7.1.8 
Clinical Laboratory and Other Safety Evaluations 
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during treatment with the study medication, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value. When evaluating such changes, the extent of deviation from the reference range, 
the duration until return to the reference range, either while continuing treatment or after the 
EOT with the study medication, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration. 

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Laboratory abnormalities should not be classified as AEs as long as they are within the normal 
day-to-day fluctuation or expected progression of the disease and are part of the efficacy data to 
be collected in the study; however, significant worsening of laboratory parameters should be 
recorded as an AE. Laboratory abnormalities related to disease progression that result in 
interruption of study medication should be captured as AEs. 
If, at the end of the treatment phase, there are abnormal clinical laboratory or vital sign which 
were not present at the Screening Visit 0/Day 0), further investigations should be performed until 
the values return to within the reference range or until a plausible explanation (e.g., concomitant 
disease) is found for the abnormal values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE. 
7.1.9 
Adverse Events of Special Interest 
The following events are adverse events of special interest (AESIs) for subjects in this study and 
must be reported to the sponsor within 24 hours after awareness, irrespective of regulatory 
seriousness criteria or causality: 
• Lipid soluble vitamin deficiency requiring study drug discontinuation 
• Liver parameter disruption requiring study drug interruption and/or dose modification  
7.1.10 
Pregnancy 
All pregnancies are to be reported from the time informed consent (and/or assent when 
appropriate) is signed until the defined follow-up period stated in Section 6.1.4. 
Any report of pregnancy for any female study subject or the partner of a male subject must be 
reported within 24 hours to the Sponsor or designated Medical Monitor using the pregnancy 
report form.  
The pregnant female study subject must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the Investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post-partum. 
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion due to a 
congenital abnormality, or a complication or pregnancy or a congenital abnormality diagnosed 
any time during the pregnancy or post-partum are considered SAEs and must be reported per 
Section 7.2.2 Reporting Procedures. An elective abortion of a normal pregnancy without 
complications is not considered an SAE. 

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In addition to the above, if the Investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE, using the Pregnancy Report Form. 
7.1.11 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the Medical 
Monitor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 7.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE.  
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• 
Abuse – Persistent or sporadic intentional intake of study medication when used for a 
non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society 
• 
Misuse – Intentional use of study medication other than as directed or indicated at 
any dose (Note: this includes a situation where the study medication is not used as 
directed at the dose prescribed by the protocol) 
• 
Overdose – Intentional or unintentional intake of a dose of study medication 
exceeding the protocol-prescribed daily dose 
• 
Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of a study medication. For studies, medication errors are reportable to the Sponsor 
only as defined below. 
Cases of subjects missing doses of study medication are not considered reportable as medication 
errors. The administration and/or use of the unassigned or expired study medication is/are always 
reportable as a medication error. 
7.2 
Serious Adverse Event Procedures 
7.2.1 
Reference Safety Information 
The RSI for this study is Section 6.8 of the maralixibat chloride IB that the Sponsor has provided 
under separate cover to all Investigators. 
7.2.2 
Reporting Procedures 
All SAE/AESIs must be reported by the Investigator within 24 hours of becoming aware of the 
event using the electronic data capture system; the Safety Report Form may be used in instances 
when the system is not available. Note: The 24-hour reporting requirement for SAE/AESIs does 
not apply to reports of abuse, misuse, overdose, or medication errors (see Section 7.1.11) unless 
they result in an SAE/AESI. 

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SAE/AESI Reporting:  
SAE/AESIs that meet the criteria defined in the study protocol must be reported within 24 hours 
of awareness via the electronic data capture system. The Safety Report Form may be used and 
sent via email (Safety@catalystcr.com) in instances when the electronic data capture system is 
unavailable. In situations where internet or email is unavailable, contact the local Clinical 
Research Associate for further assistance. 
Safety Report Form and associated documents and communications should be filed in the study 
binder. 
The Safety Report Form could be used for reporting other event types such as medication error, 
overdose, etc. Pregnancy information should be reported on the Pregnancy Report Form. 
For all urgent protocol- or safety-related issues during and outside of business hours, the 
Investigator must contact the Premier Research Medical Monitor: 
North America (US and Canada) sites: Central phone number: +1 512 686 1256 (US) 
European and ROW sites: Central phone number: +44 118 936 4096 (United Kingdom) 
The Investigator or designee must complete, sign, and date the serious AE form, verify the 
accuracy of the information recorded on the form with the corresponding source documents 
(Note: Source documents are not to be sent unless requested), and submit the form following the 
instructions in the study manual. Follow-up information should be reported as soon as available.  
7.2.3 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence (whether considered to be related to study 
medication or not) that at any dose: 
• 
Results in death 
• 
Is life-threatening. Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it was 
more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should 
not be classified as SAEs. For example, an admission for a previously scheduled 
ventral hernia repair would not be classified as an SAE; however, complication(s) 
resulting from a hospitalization for an elective or previously scheduled surgery that 
meet(s) serious criteria must be reported as SAE(s). 
• 
Results in persistent or significant disability/incapacity 

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• 
Is a congenital abnormality/birth defect 
• 
Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization; or the development of drug 
dependency or drug abuse.  
7.2.4 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to study drug) are collected from the time the subject signs 
the informed consent (and/or assent when appropriate) until the defined follow-up period stated 
in Section 6.1.4 and must be reported within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the study medication and discovered by the 
Investigator at any interval after the study has completed must be reported within 24 hours of the 
first awareness of the event. 
7.2.5 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form (and/or assent when appropriate) or leading up to the onset date of the SAE, or following 
the resolution date of the SAE, must be recorded as an AE, if appropriate. 
7.2.6 
Fatal Outcome 
Death in itself is not an SAE but an outcome arising from a SAE. Any SAE that results in the 
subject’s death (e.g., the SAE was noted as the primary cause of death) must be recorded on the 
CRF with an outcome of “fatal” and the date of death recorded as the resolution date. For all 
other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be recorded as “not resolved,” without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another study medication action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the study medication should be recorded as “dose not 
changed” or “not applicable” (if the subject never received study medication). The study 
medication action taken of “withdrawn” should not be selected solely as a result of the subject’s 
death. 

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7.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor is responsible for notifying the relevant regulatory authorities (US central IRBs/EU 
central ECs and EU competent authorities) of related, unexpected SAEs. 
In addition, the Sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the maralixibat program.  
The Investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur, as required by local law. 
During the course of the study, the sponsor shall inform the regulatory authorities of any 
SUSARs occurring with maralixibat that occur globally as follows (local reporting requirements 
may vary): 
(a) if it is neither fatal nor life threatening, within 15 days after becoming aware of the 
information; and 
(b) if it is fatal or life threatening, within 7 days after becoming aware of the information. 
For fatal and life-threatening events, the sponsor shall, within 8 days after having informed the 
regulatory authorities, submit a complete report including an assessment of the importance and 
implication of any findings made. 
7.3 
Safety Monitoring 
7.3.1 
General Guidelines 
In the evaluation of AEs and the potential relationship to study medication it is important to note 
that due to their liver disease many patients with ALGS have abnormal liver enzyme levels 
(e.g., ALT, ALP) and total bilirubin at baseline. If an individual subject exhibits a CTCAE 
Grade 3 treatment-emergent laboratory abnormality, with the exception of the specific rules 
outlined below (Section 7.3.2), dosing can be suspended or continued as per the Investigator’s 
judgment and following discussion with the medical monitor. If suspended the Investigator and 
medical monitor will evaluate the subject’s safety data and make a decision to either restart 
dosing at the same level, restart dosing at a lower dose level, or discontinue dosing. 
To ensure subject safety, if 6 or more subjects at a dose level lower suspend or stop study 
medication or exhibit treatment-emergent toxicity of CTCAE Grade 3 or greater in the same 
SOC, with the exception of the specific rules outlined in the following sections, further dosing of 
subjects at that dose level and any higher dose levels will be halted until a safety assessment is 
completed.  
Study visits and completion of ItchRO™ (ALGS and PFIC), for all subjects, will continue during 
the 
 Repeating Treatment Cycle. After review, a decision will be made whether to restart 
dosing at the same dose level, restart dosing at a lower dose level, or discontinue the subjects 

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If, at any time in the study, an ALT or total bilirubin result meets the criteria shown in the table 
that follows in relation to the subject’s baseline level, the initial measurement(s) should be 
confirmed within 48 to 72 hours of notification of the laboratory result (Confirmation Guidance 
as per Section 7.3.2). 
Baseline ALT 
ALT 
< ULN 
> 5 x ULN 
> ULN 
> 3 x baseline and > 5 x ULN 
 
Baseline Total Bilirubin 
Total Bilirubin 
Total Bilirubin ≤ 10 mg/dL 
3 mg increases 
Total Bilirubin > 10 mg/dL 
5 mg increases 
 
Frequency of Repeat Measurements: Subjects with a confirmed ALT or total bilirubin level that 
is continuing to rise should have their liver chemistry tests (ALT, ALP, INR, and total bilirubin) 
retested as clinically indicated, until levels stabilize or begin to recover. 
Further Investigation into Liver Chemistry Elevations: Based on the inclusion criteria for this 
study, the population to be enrolled will have pre-existing baseline liver disease and will be 
monitored closely by the Investigators with experience in the management of pediatric hepatic 
diseases. For subjects with a confirmed elevation in ALT or total bilirubin level as described 
above, the following evaluations should be performed as clinically indicated: 
• Close and frequent monitoring of liver enzyme and serum bilirubin tests as clinically 
indicated. Frequency of retesting can decrease if abnormalities stabilize or the study 
medication has been discontinued and the subject is asymptomatic. If the appropriate 
frequency of monitoring is not feasible study medication administration will be 
suspended. 
• Obtain a detailed history of symptoms and prior and concurrent diseases. 
• Obtain comprehensive history for concomitant drug use (including nonprescription 
medications, herbal, and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets. 
• Obtain a history for exposure to environmental chemical agents and travel. 

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• 
Serology for viral hepatitis (HAV IgM, HbsAg, hepatitis C virus (HCV) antibody, CMV 
IgM, and EBV antibody panel) 
• Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
• AST, creatine phosphokinase (CPK), and lactate dehydrogenase (LDH) 
• CBC with differential blood count (eosinophils) 
• Reticulocyte count, PT/INR 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT, or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Medical Monitor. 
 
7.3.3.2 
Stopping Rules for Liver Chemistry Evaluations 
In the event of confirmed laboratory results exceeding the following criteria, and the event is 
without an alternative explanation as discussed with the Medical Monitor, discontinuation 
of dosing of a subject with study medication will be considered if (see also Stopping Rules 
Guidance in Section 7.3.2): 
 
Baseline Tests 
Change Observed 
ALT (any level) 
ALT ≥ 20 x ULN 
Total Bilirubin ≤ 10 mg/dL 
5 mg increase and a 2 x increase over baseline level 
Total Bilirubin > 10 mg/dL 
2 x increase over baseline level 
 
7.3.4 
Biliary Atresia Liver Chemistry 
7.3.4.1 
Enhanced Monitoring Criteria for Liver Parameters (Biliary Atresia) 
For subjects with biliary atresia, causes of liver injury other than drug-induced liver injury 
should also be considered; specifically, a differential diagnosis of cholangitis should be 
investigated if clinically indicated, according to the criteria listed in this protocol and based on 
clinician judgement.  
Table 7 provides the criteria for enhanced monitoring of liver parameters in the absence of a 
plausible alternative explanation for the observed abnormalities. If an alternative explanation has 
been identified, medical treatment and monitoring should be guided by that diagnosis. 

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Table 7 
Enhanced Liver Injury Monitoring Criteria 
Parameter 
Enhanced Monitoring Criteria 
ALT 
> (2× baseline value AND >50 U/L) OR 
>500 U/L 
Total serum bilirubin 
>2× baseline value OR 
> (baseline value + 2 mg/dL) 
INRa 
INR ≥1.5 
INR=international normalized ratio. 
Note: Diagnosis of infective cholangitis, as well as other potential 
causes, should be ruled out (based on the specified cholangitis diagnostic 
criteria alongside clinician judgement) before judgment regarding liver 
injury is confirmed.  
a 
INR value despite adequate vitamin K supplementation. 
 
Additional investigations of liver parameters, including gastroenterology/hepatology 
consultations, and/or hepatic imaging, may be requested at the discretion of the investigator, in 
consultation with the medical monitor. The diagnosis of ascending cholangitis should be 
investigated, if clinically indicated (see Section 7.3.5). 
7.3.4.2 
Guidelines for Interruption of Study Medication for Specific Liver Parameters 
(Biliary Atresia) 
If the confirmed laboratory results meet any of the criteria below and the event is without an 
alternative explanation (i.e., intercurrent illness, disease progression, natural history of the 
disease, cholangitis), interruption of study medication should be considered (see Table 8). If an 
alternative explanation has been identified, study medication may continue if deemed appropriate 
by the PI and medical monitor; medical treatment and monitoring should be guided by that 
diagnosis. 

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Table 8 
Treatment Interruption Criteria 
Parameter 
Treatment Interruption Criteria 
ALT 
> (3× baseline value AND >100 U/L) OR 
>600 U/L  
Total serum 
bilirubin 
>3× baseline value OR 
> (baseline value + 3 mg/dL) 
INRa 
> baseline value +0.5 
INR=international normalized ratio. 
Note: Diagnosis of infective cholangitis, as well as other potential 
causes, should be ruled out (based on the specified cholangitis 
diagnostic criteria alongside clinician judgement) before judgment 
regarding liver injury is confirmed.  
a INR value despite adequate vitamin K supplementation. 
 
7.3.5 
Cholangitis Diagnostic Criteria (Biliary Atresia) 
Cholangitis must be considered as a differential diagnosis in subjects showing abnormalities of 
liver parameters during the treatment period. Investigation for cholangitis should be considered if 
a subject exceeds bilirubin enhanced liver injury monitoring criteria (Table 7) and must be 
performed if a subject fulfills bilirubin treatment interruption criteria (Table 8). Suggested 
diagnostic criteria are: 
• Fever >38°C or elevated inflammatory markers (white cell count, CRP, procalcitonin) in 
a child with no other obvious source of infection 
• Evidence of cholestasis 
o Elevation of direct bilirubin by 25% or at least >1.0 mg/dL above previous baseline 
levels,  
AND 
o Abnormal liver function tests:  Increase in 2 or more of AST, ALT, ALP, or GGT to 
1.5× ULN or >25% above baseline values if previously elevated 
 
These criteria are based on the Tokyo guidelines and have been modified for this patient setting 
(Kiriyama et al. 2018). Other signs (e.g., decreased stool pigmentation in a child who previously 
had stool pigmentation, identified dominant biliary stricture) should also be considered. Cases of 
cholangitis with positive bacterial culture of blood or ascites should be categorized as being 
“culture-proven cholangitis,” whereas, culture-negative cholangitis cases should be categorized 
as being “culture-unproven cholangitis.” 
The diagnosis of cholangitis will be captured as a safety endpoint. Further, for subjects with a 
positive diagnosis of cholangitis, the Enhanced Monitoring and Treatment Interruption criteria 
during cholangitis episodes will apply (Table 7 and Table 8). This includes the temporary 

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interruption of study medication until investigator judgment (with potential discussion with the 
medical monitor) deems the episode has stabilized or resolved. Once the cholangitis episode has 
improved, use of the Enhanced Monitoring and Treatment Interruption criteria (Table 7 and 
Table 8) will revert to the standard aforementioned guidelines for monitoring.  
7.3.6 
Safety Monitoring for Triglycerides 
In the event of a confirmed laboratory result for fasting total triglyceride >500 mg/dL, the 
Investigator and the Medical Monitor may consider a temporary interruption of study 
medication. Dosing may resume when the triglyceride level returns to <300 mg/dL or to the 
subject’s baseline level. 
7.3.7 
Safety Monitoring for Fat Soluble Vitamins  
Vitamin status will be assessed per the Schedule of Assessments (See Table 1), and blood 
samples will be obtained at the study visits before the daily dose of vitamins is administered. In 
the event of a confirmed laboratory result that falls either below or above the normal range for a 
vitamin (25-hydroxy vitamin D, retinol, retinol binding protein, tocopherol [α]), or for an 
elevated INR (as a proxy for vitamin K status), the Investigator should make the appropriate 
modification to the subject’s vitamin supplementation regimen. 
The response to the change in regimen will be assessed by relevant follow-up blood work 
1 month later. Changes will continue to be made until the levels are in the desired range. 
Adjustments may be discontinued outside of the desired range if there is agreement between the 
Investigator and Medical Monitor that vitamin sufficiency cannot be reasonably expected.  
7.3.8 
Monitoring/Stopping Rules for Coagulation Panel Results 
In the event of a confirmed laboratory result for INR > 1.5 that is unresponsive to vitamin K 
therapy, the Investigator and the Medical Monitor may consider a temporary interruption of 
study medication. Dosing may resume when the INR falls below 1.5 or returns to the subject’s 
baseline level. 
7.4 
Adjustment of Dose 
Gastrointestinal intolerance, as evidenced by diarrhea/loose stools, abdominal pain/cramping and 
nausea, is expected to be the most frequent manifestation of a lack of tolerability to study 
medication. If an individual subject exhibits a treatment emergent CTCAE Grade 2 or greater 
drug-related GI toxicity, study medication dose may be lowered to a previously well tolerated 
dose; later attempts to escalate the dose are permitted. If the subject is on a BID dosing regimen, 
dose lowering should first be attempted with the afternoon dose. Dose reduction and escalation 
decisions should be made in consultation with the Medical Monitor. A requirement for 
intravenous fluids as treatment for diarrhea will lead to temporary discontinuation of study 
medication. Re-challenge of treatment with study medication in such patients will be done at the 
discretion of the Investigator. 

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8.6.3 
Vital Signs 
Vital signs (temperature, systolic and diastolic blood pressure, heart rate, and respiratory rate) 
will be summarized descriptively by study visit and disease as observed and change from 
baseline values. Potentially clinically important (PCI) values for select vital signs results will be 
defined in the SAP. The number and proportion of subjects with PCI values will be presented by 
disease group. 
8.6.4 
Laboratory Assessments 
Safety laboratory test results will be summarized descriptively by study visit and disease group 
as observed and change from baseline values. The number and proportion of subjects with 
clinical laboratory values below, within, or above the normal range by time point and in relation 
to baseline will be tabulated for each safety laboratory analyte by treatment group in a shift table. 
Potentially clinically important (PCI) laboratory ranges will be defined in the SAP for select 
laboratory tests. The number and proportion of subjects with PCI laboratory values will be 
presented by treatment group.  
Efficacy laboratory tests (i.e., total sBA, sBA subspecies, ALT, total and conjugated bilirubin, 
7αC4, FGF-19, autotaxin, FIB-4, and APRI) will not be included in safety summaries. 
Assessments of serum α-fetoprotein will be listed for individual subjects and summarized using 
descriptive statistics by study visit. 
8.6.5 
Concomitant Treatments 
Prior and concomitant treatments will be summarized descriptively by disease group using the 
number and proportion of subjects. 
Prior medications will be presented separately from concomitant treatments. Medications that 
started prior to the first dose of maralixibat in MRX-800 will be considered prior medications 
whether or not they were stopped prior to the first dose of maralixibat in MRX-800. Any 
medications continuing or starting after the first dose of maralixibat in MRX-800 will be 
considered to be concomitant. If a medication starts prior to the first dose of maralixibat in 
MRX-800 and continues after the first dose of maralixibat in MRX-800, it will be considered 
both prior and concomitant. 
Medications will be coded using the World Health Organization Drug Dictionary.  
8.6.6 
Liver Ultrasound 
Liver ultrasound (or MRI) results will be summarized descriptively and presented in listings. 

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The Sponsor reserves the right to withdraw a subject from the study, to terminate participation of 
a study site at any time, and/or to discontinue the study. 
The Sponsor agrees to provide the Investigator with sufficient material and support to permit the 
Investigator to conduct the study according to the study protocol.  
9.1.2 
Good Clinical Practice Compliance 
The Sponsor and any third party to whom aspects of the study management or monitoring have 
been delegated will undertake their assigned roles for this study in compliance with all applicable 
industry regulations, ICH GCP Guideline E6 (1996) and E6 R2 (2017), EU Directive 
2001/20/EC, as well as all applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of the study Sponsor and/or the company 
organizing/managing the research on behalf of the Sponsor to inspect study data, subjects’ 
medical records and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The Sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The Sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of study 
medication for shipment to the site. 
9.1.3 
Indemnity/Liability and Insurance 
The Sponsor ensures that suitable clinical study insurance coverage is in place prior to the start 
of the study.  
If appropriate, a copy of the indemnity document is supplied to the Investigator before study 
initiation, per local country guidelines. 
9.1.4 
Public Posting of Study Information 
The Sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating Investigators’ names 
and contact information.  
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements. 
9.1.5 
Study Suspension, Termination, and Completion 
This is a long-term study expected to continue until the end of study or until the Sponsor decides 
otherwise. The Sponsor may suspend or terminate the study, or part of the study, at any time for 
any reason.  

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When the study is terminated, the Sponsor will notify all Investigators to schedule EOT/ET visits 
for subjects who at that time are still receiving treatment with maralixibat. 
When the study is suspended or terminated, the Sponsor will ensure that applicable sites, 
regulatory agencies, and IRBs/ECs are notified as appropriate.  
Should the study be temporarily suspended due to safety concerns, re-initiation will follow local 
laws and regulations (see Section 7.5).  
The discontinuation of a registered clinical study which has been posted to a designated public 
website will be updated accordingly. 
9.2 
Investigator’s Responsibilities 
9.2.1 
Good Clinical Practice Compliance 
The Investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements and 
guidelines.  
It is the Investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
Investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks, and shall, upon request of the Sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for Investigators and Sub-Investigators are provided to the study 
Sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the Investigator should, with the 
subject’s consent (and/or assent when appropriate), inform them of the subject’s participation in 
the study. 
9.2.2 
Protocol Adherence and Investigator Agreement 
The Investigator and any Sub-Investigators must adhere to the protocol as detailed in this 
document. The Investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an Investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the Investigator suspends or terminates the study at their site, the Investigator will promptly 
inform the Sponsor and the IRB/EC and provide them with a detailed written explanation. Upon 
study completion, the Investigator will provide the Sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations. 

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To ensure compliance with the protocol and with guidelines, the study may be audited by an 
independent person. The Investigator agrees, by written consent to this protocol, to cooperate 
fully with compliance checks by allowing access to all study documentation by authorized 
individuals. 
9.2.3 
Documentation and Retention of Records 
9.2.3.1 
Data Collection and Case Report Forms 
The Investigators’ authorized site personnel must enter the information required by the study 
CRF Completion Guidelines for all data requiring transcription of the source. A study monitor 
will visit each site in accordance with the monitoring plan and review the CRF data against the 
source data for completeness and accuracy. Discrepancies between source data and data entered 
on the CRF will be addressed by qualified site personnel. When a data discrepancy warrants 
correction, the correction will be made by authorized site personnel. Data collection procedures 
will be discussed with the site at the site initiation visit and/or at the Investigator’s meeting. 
Unscheduled assessments (e.g., local labs) are not required to be collected in the CRF except for 
those that are directly relevant to the monitoring of an AE/SAE; collection of other values may 
be requested by the Sponsor. 
Electronic CRFs should be handled in accordance with instructions from the Sponsor.  
The Investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. CRFs must be completed by 
the Investigator or designee as stated in the site delegation log. 
All data submitted in the electronic CRF must be reviewed, approved and signed for by the 
Investigator. All data, except data entered directly into another platform (e.g., electronic), will 
have separate source documentation. 
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. 
9.2.3.2 
Recording, Access, and Retention of Source Data and Study Documents 
Information recorded in the CRF should be supported by corresponding source documentation. 
Source data to be reviewed during this study will include, but are not limited to subject’s medical 
file, daily dosing records and clinical laboratory reports. 
 
The consent form includes a statement by which the subject agrees to the monitor/auditor from 
the Sponsor or its representatives, national or local regulatory authorities, or the IRB/EC, having 
access to source data. Non-study site personnel will not disclose any personal information or 
personal medical information. 

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The study subject’s contact information will be securely stored at each site for internal use 
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 dictated by the reviewing IRB, institutional policies, or Sponsor 
requirements. 
Records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the Sponsor.  
9.2.3.3 
Financial Disclosure 
The Investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the Investigator received from the Sponsor. The 
following information is collected: any significant payments from the Sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in IP; any significant equity interest 
in the Sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
9.3 
Clinical Data Management 
A clinical database will be designed to collect data as specified in the data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
9.4 
Monitoring Procedures 
The Sponsor and/or designee will conduct site visits to monitor the study and ensure compliance 
with the protocol, GCP, and applicable regulations and guidelines. The assigned CRA/study 
monitor will visit the Investigator and site at periodic intervals, maintain periodic communication 
and review the CRF data against the source data for completeness and accuracy as defined in the 
monitoring plan. 
The Investigator agrees to allow the CRAs and other authorized personnel access. By signing the 
Investigator’s Acknowledgement, the Investigator agrees to meet with the CRA(s) during study 
visits; to ensure that study staff are available to the CRA(s) as needed, to provide the CRA(s) 
access to all study documentation, to the clinical supplies dispensing and storage area; and to 
assist the monitors in their activities, if requested. 

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9.5 
Quality Assurance/Audit 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the Sponsor or its representatives, and the 
IRB/EC for each site. The Investigator must permit these abovementioned parties to inspect 
facilities and to have direct access to original source records relevant to this study, regardless of 
media. 
9.6 
Record Retention 
Records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP, applicable requirements and 
may not be destroyed without written permission from the Sponsor. The Sponsor must retain all 
records for 25 years. 
9.7 
Sample Retention 
Samples may be used to purposes related to this research. The samples will be stored in a central 
archive until the Sponsor has determined that specimens are no longer needed, and the decision 
has been made that none of the samples needs to be reanalyzed and will eventually be destroyed. 
Only the Sponsor, the CRO/laboratory and other authorized designee will have access to the 
stored samples. 
As new biomarkers related to the disease and/or safety, efficacy, or mechanism of action of 
maralixibat may evolve during the conduct of the trial, the analyses of the stored specimens may 
also include biomarkers that are unknown at present or have not been included in the scientific 
hypotheses at initiation of the trial. 
The samples could be used to further liver disease research, its complications and other 
conditions for which individuals with liver disease are at increased risk and to improve 
treatment.  
Data collected for this study will be analyzed and stored centrally. The blinding of the identity of 
the subjects will be maintained. After the study is completed, the de-identified, archived data will 
be transmitted to and stored at a central repository. Data may be used by other researchers, 
including those outside of the study. Permission for any data transmission and other pertinent 
details will be included in the informed consent.  
Identifiable samples can be destroyed at any time at the request of the subject. During the 
conduct of the study, a subject can choose to withdraw consent to have specimens stored for 
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after the study is completed. Subjects may at any time contact the Investigator if they wish to be 
informed about results derived from stored specimens.  
9.8 
Ethical Considerations 
9.8.1 
Informed Consent/Assent 
It is the responsibility of the Investigator to obtain written informed consent (and/or assent when 
appropriate) from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and ICH GCP requirements. Each subject or the subject’s legally authorized 
representative, as applicable, is requested to sign and date the subject informed consent form 
(and/or assent when appropriate) or a certified translation if applicable, after the subject has 
received and read (or been read) the written subject information and received an explanation of 
what the study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities. A copy of the informed consent and 
assent documentation (i.e., a complete set of subject information sheets and fully executed 
signature pages) must be given to the subject or the subject’s legally authorized representative, as 
applicable. The informed consent form (and/or assent when appropriate) also includes a 
statement by which the subject agrees to the monitor/auditor from the Sponsor or its 
representatives, national or local regulatory authorities, or the IRB/EC, to access applicable 
source data. Signed consent and assent forms must remain in each subject’s study file and must 
be available for verification at any time.  
The PI provides the Sponsor with a copy of the consent form (or assent as applicable) that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the Sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., Sponsor or coordinating PI) is 
responsible for this action. 
9.8.2 
Institutional Review Board or Ethics Committee 
This protocol, the informed consent document (approved by the Sponsor or their designee), 
relevant supporting information and all types of subject recruitment information will be 
submitted to the IRB/EC for review, and all must be approved prior to site initiation. Study 
medication supplies will not be released until written IRB/EC approval has been received.  
The protocol cannot be altered or changed except through a protocol amendment. Prior to 
implementing changes in the study, the Sponsor and the IRB/EC must approve any amendments 
to the protocol and revisions of all informed consent documents, unless there is a subject safety 
issue. Protocol amendments will be filed with the appropriate regulatory agency(s) having 
jurisdiction over the conduct of the study. 
The IRB/EC will be kept apprised of the progress of the study and of any changes made to the 
protocol. The IRB/EC will also be informed of any serious and significant AEs. 

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9.9 
Study Site Initiation 
The Investigator and any site personnel may not screen or enroll subjects into the study until 
receiving notification from the Sponsor or its designee that the study can be initiated at the study 
site. The study site will not be authorized for study initiation until: 
1. The study site has received appropriate approvals (health/competent authorities, 
IRB/IEC) for the protocol and the appropriate ICF. 
2. All regulatory, GCP, and other appropriate documents have been submitted to and 
approved by the Sponsor or its designee. 
3. The study site has a Clinical Trial Agreement in place. 
9.10 
Study Site Closure 
At the end of the study, all study sites will be closed. The Sponsor may terminate participation of 
a study site at any time. Examples of conditions that may require premature termination of a 
study site include, but are not limited to, noncompliance with the protocol and/or applicable 
regulations and guidelines.  
9.11 
Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact. 
The confidentiality of subject records in EU countries will be protected in accordance to the 
General Data Protection Regulation guideline. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented (and/or assent when appropriate) to take part in the study, the 
Sponsor and/or its representatives may review medical records and data collected during the 
study. These records and data may, in addition, be reviewed by others including the following: 
independent auditors who validate the data on behalf of the Sponsor; third parties with whom the 
Sponsor may develop, register, or market maralixibat; national or local regulatory authorities; 
and the IRBs/ECs which gave approval for the study to proceed. The Sponsor and/or its 
representatives accessing the records and data will take all reasonable precautions in accordance 
with applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities.  
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected, if permitted under local laws governing privacy.  

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The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth, where allowed per local law, may be pulled to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
The study monitor, other authorized representative of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying the study medication may inspect all 
documents and records required to be maintained by the Investigator, including, but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this 
study. The site will permit access to such records. 
Non-study site personnel will not disclose any personal information or personal medical 
information. 
10 
FINAL CLINICAL STUDY REPORT 
A final clinical study report (CSR) will be written upon completion of the study. The CSR will 
include a summary of the study results based on statistical evaluation and clinical assessment of 
the protocol-defined endpoints.  
The Sponsor will endeavor to publish the results of all qualifying, applicable, and covered 
studies according to external guidelines in a timely manner regardless of whether the outcomes 
are perceived as positive, neutral, or negative. 
The final CSR may be submitted to the regulatory authorities. 
11 
PUBLICATION 
All publications relating to Sponsor products or projects must undergo appropriate technical and 
intellectual property review, with Sponsor agreement to publish prior to release of information.  
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral, or 
other form. 

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12 
REFERENCES 
Al Mehaidib A, Al Shahrani A. 1381 Progressive familial intrahepatic cholestasis in Arabs. 
J Hepatol. 2013;58:S555-S556. 
Alissa FT, Jaffe R, Shneider BL. Update on progressive familial intrahepatic cholestasis. J 
Pediatr Gastroenterol Nutr. 2008;46:241-52. 
Arnell H, Papadogiannakis N, Zemack H, et al. Follow-up in children with progressive familial 
intrahepatic cholestasis after partial external biliary diversion. J Pediatr Gastroenterol Nutr. 
2010;51:494-9. 
Chardot C. Biliary atresia. Orphanet J Rare Dis. 2006;1:28. 
Chardot C, Carton M, Spire-Bendelac N, et al. Prognosis of biliary atresia in the era of liver 
transplantation: French national study from 1986 to 1996. Hepatology. 1999;30:606–11. 
Chen HL, Liu YJ, Chen HL, et al. Expression of hepatocyte transporters and nuclear receptors in 
children with early and late-stage biliary atresia. Pediatr Res. 2008;63(6):667-73. 
Davenport M, De Ville De Goyet J, Stinger MD, et al. Seamless management of biliary atresia in 
England and Wales (1999-2002). Lancet. 2004;1354–7. 
Davit-Spraul A, Gonzales E, Baussan C, et al. Progressive familial intrahepatic cholestasis. 
Orphanet J Rare Dis. 2009;4:1. 
Emerick KM, Elias MS, Melin-Aldana H, et al. Bile composition in Alagille Syndrome and PFIC 
patients having partial external biliary diversion. BMC Gastroenterol. 2008;8:47. 
Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: 
frequency and relation to prognosis. Hepatology. 1999;29:822-9. 
Emerick KM, Whitington PF. Partial external biliary diversion for intractable pruritus and 
xanthomas in Alagille syndrome. Hepatology. 2002;35:1501-6. 
Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric 
Population. 2008. Accessed at: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/ethical_considerations_en.pdf 
European Medicines Agency. 2010. Guideline on Missing Data in Confirmatory Clinical Trials. 
Available online at https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
missing-data-confirmatory-clinical-trials_en.pdf. 
European Medicines Agency. 2020. Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic. Version 3, 28 April 2020. Available online at 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. 

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13 
APPENDICES 

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Appendix 2 
Observer Itch-Reported Outcome Instrument ItchRO(Obs)™ 
ItchRO(Obs): Morning Diary 
Based on observations or what your child told you about his/her itching, how severe were your 
child’s itch-related symptoms (rubbing, scratching, skin damage, sleep disturbances or irritability) 
from when he/she went to bed last night until he/she woke up this morning? 
Select one response below. 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 
 I don’t know 
 
Below, please select all that contributed to your answer. 
 Child reported itching 
 Observed difficulty falling asleep or staying asleep (sleep disturbance) 
 Observed rubbing or scratching 
 Observed new or worsening marks on the skin due to rubbing or scratching 
 Observed fussiness or irritability 
 
 
 

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While you were observing your child from when he/she went to bed last night until he/she woke 
up this morning, how much of the time was your child rubbing or scratching?  
Select one response below. 
 None 
 A little bit of the time 
 Some of the time 
 Most of the time 
 Almost all of the time/constantly 
 I don’t know 
 

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ItchRO(Obs): Evening Diary 
Based on observations or what your child told you about his/her itching, how severe were your 
child’s itch-related symptoms (rubbing, scratching, skin damage, sleep disturbances or irritability) 
from the time he/she woke up this morning until he/she went to bed? 
Select one response below. 
 None  
 Mild 
 Moderate 
 Severe 
 Very severe 
 I don’t know 
 
Below, please select all that contributed to your answer. 
 Child reported itching 
 Observed difficulty falling asleep or staying asleep (sleep disturbance) 
 Observed rubbing or scratching 
 Observed new or worsening marks on the skin due to rubbing or scratching 
 Observed fussiness or irritability 
 
 
 

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While you were observing your child from the time he/she woke up this morning until he/she went 
to bed, how much of the time was your child rubbing or scratching?  
Select one response below. 
 None  
 A little bit of the time 
 Some of the time 
 Most of the time 
 Almost all of the time/constantly 
 I don’t know 
 

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Appendix 6 
Clinician Scratch Scale 
This scoring scale was originally developed to assess pruritus before and after surgical intervention 
in children with ALGS and PFIC (Whitington and Whitington, 1988).  
The clinician will rate the subject’s pruritus, as evidenced by scratching, according to the following 
scale: 
Score 
Description 
0 
None 
1 
Rubbing or mild scratching when undistracted 
2 
Active scratching without evident skin abrasions 
3 
Abrasion evident 
4 
Cutaneous mutilation, haemorrhage, and scarring evident 
 
 
 

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Appendix 8 
Management of Clinical Study Procedures During Covid-19 Pandemic or 
Other Force Majeure  
This appendix provides guidance for subject safety and ongoing access to medical care and 
investigational product during the global novel coronavirus 2019-nCoV (COVID-19) pandemic. 
During this global public health crisis, pragmatic and harmonized actions are required to ensure 
the necessary flexibility and procedural simplifications that are needed to maintain the integrity 
of the clinical studies and to ensure the rights, safety, and wellbeing of study subjects and the 
safety of clinical study staff. 
The measures detailed here will be implemented across Mirum studies on a temporary basis until 
the pandemic is considered resolved by governmental and public health organizations, as 
applicable. 
Regardless of the guidance provided below, consideration should be given to public health 
advice at the study locations and individual benefit/risk in treatment decisions for subjects at the 
study site during the pandemic (EMA 2020; FDA 2020). Logistical requirements should also be 
considered, such as the ability of subjects to travel to the study site, accessibility of public 
transportation, site restrictions on clinical trials, etc. 
The safety of the study subjects is of primary importance, and risks of involvement in the study, 
in particular with added challenges due to COVID-19, will be weighed against anticipated 
benefit for the trial subjects and society. 
Study Participation 
New Subject Enrollment  
Study sites may continue to recruit new subjects into ongoing studies, if deemed appropriate on 
benefit/risk assessment as described and provided that ALL of the following activities to 
preserve study integrity can be met: 
Upon discussion with the site monitor, the study site has confirmed the ability to enroll and 
manage new subjects effectively and in compliance with the protocol and this appendix. 
Upon discussion with the medical monitor, the study site has confirmed that appropriate safety 
monitoring can take place, in compliance with the protocol and this appendix. 
Data will continue to be entered into the Case Report Form (CRF) and queries resolved in a 
timely manner. 
The site monitor is able to access the study site to perform on-site monitoring or is able to 
perform remote monitoring of data. 
Conduct of Telephone/Virtual or Alternative Visits 
Due to the current pandemic, it is conceivable that not all subject visit commitments can be 
fulfilled. If a subject or caregiver is unable or unwilling to attend a study visit or a study site is 
unable to permit on-site visits by subjects and caregivers, adaptation of the on-site visit to a 
telephone visit, virtual visit, or use of an alternative location for assessment (including but not 
limited to local laboratories, family physician, home visit) is recommended to ensure continuity 

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of subject care during the study (as an interim measure). Priority should be given to maintaining 
ongoing safety follow-up. Study sites should speak with their site monitor before performing a 
telephone or virtual visit so he or she may provide guidance regarding logistics that may need 
consideration. Study sites should contact the medical monitor if the subject must miss more than 
one on-site visit in succession, because multiple incomplete visits may have the potential to 
impact evaluation of study endpoints as well the subject’s safety. For all remote visits, medical 
monitor and Mirum medical approval is required. The decision to accept protocol deviations for 
missed assessments is based on the risk to the subject of discontinuing study participation versus 
missed assessments, such as safety laboratory assessments. Where possible, a home visit should 
be organized to avoid missing visits or assessments. 
Alternative Blood Sample Collection: 
It is preferred that this alternative blood sample collection be performed in a manner to support 
delivery of samples to the central laboratory, but the analysis of samples may be performed at 
local laboratories, if necessary. If the analyses are performed at the local laboratories, the site 
will follow up with the subject to obtain the results and local laboratory reference ranges for data 
entry into EDC as soon as they are available. 
Safety Reporting and Maralixibat Treatment Recommendations for COVID-19 
The sponsor recognizes that COVID-19 presents an increased risk for all subjects. Due to the 
potential impact of COVID-19 on multiple organ systems, the sponsor recommends the 
following dose modification and management plan for subjects with confirmed or suspected 
COVID-19 while receiving treatment with maralixibat. 
The following safety reporting guidelines are required:  
All confirmed or suspected COVID-19–related adverse events (AEs) must be recorded in the 
CRF and the Serious Adverse Event (SAE) Report Form if the event meets the seriousness 
criteria. SAEs are reportable to the sponsor within 24 hours of awareness. All study drug 
interruptions or modifications must be recorded on the AE and drug administration CRFs. 
If an event is suspected to be COVID-19 infection, continuation of study drug, and any dose 
modifications should be assessed on a case-by-case basis, depending on the subject’s health 
status, and discussed with the medical monitor if needed. The COVID-19 infection should be 
managed as per local treatment guidance and Investigator’s clinical judgment. 
Drug-Drug Interaction Guidance Regarding Medication Used to Treat COVID-19: 
The study protocol and Investigator’s Brochure should be referenced for drug-drug interaction 
information. For further information the medical monitor can be contacted. 

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Documenting Alternative Contacts with Subjects: 
If an on-site visit is replaced by a telephone or virtual study visit, the following are guidelines for 
data capture: 
• If the visit is listed as on-site but is performed remotely, data should be captured as per a 
normal visit (i.e., document the remote visit in the source documents and complete the 
relevant CRF pages to capture the visit date, and any possible assessment that can be 
obtained, such as AEs, study drug administration, and/or concomitant medications and any 
additional safety or efficacy information). All assessments that cannot be performed should 
be marked as not done in the CRF. Any protocol deviations related to COVID-19 should be 
recorded in the clinic notes, prefixed COVID-19.  
• Visits that require procedures that cannot be performed remotely should be discussed with 
the site monitor because this may impact efficacy or safety analyses and should be 
documented as a protocol deviation due to COVID-19. 
 
Site-to-Subject Drug Shipment Instructions during Pandemic Containment 
If a subject is unable to go to the study site because of pandemic containment, the study site may 
ship the study drug to the home of the subject (or other agreed location) following approval by 
the sponsor.  
For such shipment, the following conditions must be met: 
• The sponsor is responsible for delivery of the study drug to the study site. Organization of 
shipments from the site to the subject will be the responsibility of the study site. 
• The subject or caregiver is informed about the shipment method, confirms the address for 
receipt of the drug, and agrees that his or her personal information (i.e., name and address) 
may be given to a professional carrier. 
• The investigator or designee (e.g., pharmacy) securely packages the drug for shipment.  
• A professional carrier is used by the investigator or designee to ship the drug securely and 
maintain chain of custody, with evidence provided. Maralixibat should be stored and shipped 
under refrigerated conditions (2°C–8°C) using ice packs. Shipments that are expected to be 

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completed within 48 hours from pickup to delivery do not generally require any specific 
temperature monitoring.  
• To respect subject confidentiality, the carrier should be given only the name and address of 
the recipient. The sponsor should not receive any personal information about the subject. 
• A procedure is defined with the carrier to immediately upon delivery confirm the receipt of 
the drug by the recipient and that it is received in good condition. 
• The site contacts the recipient to confirm the receipt of the drug and to confirm it is delivered 
in the expected conditions (e.g., not leaking, not broken) and gives instructions about the 
drug administration and storage. If the drug is delivered and is not within the expected 
conditions, the site will give instructions to the subject about the next steps. 
• The investigator or designee completes the drug accountability forms with each shipment 
made directly to a subject. 
• All documentation (originals/copies, as applicable) related to the site-to-subject drug 
shipment should be filed in the investigator site file, including the list of the medication being 
delivered, the quantity involved, and documentation of receipt by the trial subject.  
• Subjects should retain unused study drug and containers and return them to the investigator 
the next time they visit the investigator site  
COVID-19–Specific Remote Source Data Verification 
The source documents/source data considered for remote source data verification (rSDV) are 
those related to the primary endpoint, AEs/SAEs, important medical events, or the reasons for 
exclusion of a subject from the study. 
Remote access to source documents/source data for monitoring purposes may only take place in 
justified exceptional cases and only to the extent strictly necessary (i.e., only when direct access 
to study source data is not available due to COVID-19 pandemic restrictions).  
The following three options for source data reconciliation without the study monitor being 
physically present at the study site may be used, based on the site-specific source 
documentation/source data: 
The study site will provide the study monitor, under the responsibility of the investigator, with 
copies of the source documents/source data in which personal identifying information of the 
study subjects and information pertaining to their privacy has been obscured or redacted. 
Under the responsibility of the investigator, the study site will grant the study monitor direct, 
controlled, remote access to the systems with which the source documents/source data are 
managed. 

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The study site will grant the study monitor, under the responsibility of the investigator, passive 
access to the source documents/source data via live image transmission (e.g., sharing of the 
screen or image/sound transmission). 
 
Depending on the option selected for rSDV, the full process to be followed and requirements 
needed to be met are described in the specific rSDV section of the clinical monitoring plan as 
well as in a corresponding guideline for the investigators. 
In the case of live image transmission, this will take place exclusively via secured 
systems/environments and systems/servers within European Economic Area/European Union. 
In all cases, rSDV will be conducted exclusively by the authorized persons in accordance with 
the written informed consent of the study subjects and the written agreement of the Principal 
Investigator (PI)/PIs institution. 
Remote source data verification will take place in a protected environment (i.e., providing 
protection from unauthorized access in any form, including the use of privacy screens to prevent 
unauthorized viewing of source documents/source data), the source documents/source data 
reviewed by the study monitor will not be permanently stored by the study monitor, and if 
necessary, temporarily saved files (including ones automatically generated by the system) are 
permanently deleted at short notice. 
The study monitor will securely destroy any copy of obscured/redacted documents, whether 
paper or electronic, as soon as they have been used for source data verification.  
Appropriate corrective measures will be implemented in the event of technical difficulties or if 
the security of the transmission is no longer guaranteed. 
The information and communication technology used by the sponsor and the study site for rSDV 
is designed in such a way that secure and General Data Protection Regulation–compliant 
transmission is guaranteed. 
 

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