Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Subjects With Biliary Atresia After Hepatoportoenterostomy
Phase: PHASE2
Conditions: Biliary Atresia
Sponsor: Mirum Pharmaceuticals, Inc.

1 
 
 
 
PROTOCOL: 
MRX-701  
TITLE: 
Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to 
Evaluate the Efficacy and Safety of Maralixibat in the Treatment of 
Subjects with Biliary Atresia after Hepatoportoenterostomy  
SHORT TITLE: 
EMBARK: Evaluation of Maralixibat in Biliary Atresia Response 
post-Kasai 
DRUG: 
Maralixibat 
IND: 
147617 
EUDRACT: 
2020-000974-22 
SPONSOR 
Mirum Pharmaceuticals Inc. 
950 Tower Lane 
Foster City, CA 94404 
COORDINATING 
INVESTIGATOR: 
 
PROTOCOL 
HISTORY: 
Version 1, 26 June 2020 
Version 2, 24 August 2020 
Version 3, 3 February 2021 
Version 4, 6 May 2021 
Version 5, 25 March 2022 
Version 6, 25 April 2023 
This study will be performed in compliance with the International Council for Harmonisation 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. 
   
 
 
 
 
 
   
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
MRX-701 Protocol-v6  (Global)

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MRX-701 Protocol, Version 6 
 
 
Maralixibat 
 
 
 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ...........................................................................................2 
TABLE OF CONTENTS ...........................................................................................................3 
LIST OF TABLES .....................................................................................................................7 
LIST OF FIGURES ...................................................................................................................7 
STUDY SYNOPSIS ..................................................................................................................8 
ABBREVIATIONS .................................................................................................................22 
1 
BACKGROUND INFORMATION ......................................................................24 
1.1 
Indication and Current Treatment Options ......................................................24 
1.2 
Product Background and Clinical Information ................................................24 
2 
STUDY OBJECTIVES AND PURPOSE .............................................................27 
2.1 
Rationale for the Study ....................................................................................27 
2.2 
Study Objectives and Endpoints ......................................................................28 
2.2.1 
Primary Objective and Endpoint ......................................................................28 
2.2.2 
Secondary Objectives and Endpoints of the Double-Blind Period ..................29 
2.2.3 
Exploratory Objectives and Endpoints of the Double-Blind Period ................29 
2.2.4 
Open-Label Extension Objectives and Endpoints ...........................................31 
3 
STUDY DESIGN...................................................................................................31 
3.1 
Study Design and Flow Chart ..........................................................................31 
3.1.1 
Rationale for Treatment Dose ..........................................................................32 
3.1.1.1 
Clinical Efficacy ..............................................................................................33 
3.1.1.2 
Clinical Safety and Tolerability .......................................................................33 
3.1.1.3 
Nonclinical Safety Data Justify Dosing of Children <1 year of age ...............34 
3.1.2 
Rationale for Primary Endpoint .......................................................................34 
3.1.3 
Rationale for Study Population ........................................................................36 
3.2 
Duration and Study Completion Definition .....................................................36 
3.3 
Sites and Regions .............................................................................................37 
4 
STUDY POPULATION ........................................................................................37 
4.1 
Inclusion Criteria .............................................................................................37 
4.2 
Exclusion Criteria ............................................................................................37 
4.3 
Reproductive Potential .....................................................................................38 
4.4 
Withdrawal/Discontinuation from Study .........................................................39 
4.4.1 
Reasons for Discontinuation from Study .........................................................39 
4.4.2 
Participants “Lost to Follow-Up” Prior to Last Scheduled Visit .....................40 
5 
PRIOR AND CONCOMITANT TREATMENT ..................................................40 
5.1 
Prior Treatments...............................................................................................40 
5.2 
Concomitant Treatments ..................................................................................40 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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6 
STUDY MEDICATION ........................................................................................41 
6.1 
Investigational Product ....................................................................................41 
6.1.1 
Investigational Product Benefit-Risk Guidance...............................................41 
6.1.2 
Blinding the Treatment Assignment ................................................................42 
6.2 
Administration of Study Medication ...............................................................42 
6.2.1 
Interactive Response Technology for Study Medication Management ...........42 
6.2.2 
Allocation of Treatment to Participants and Unblinding .................................43 
6.2.3 
Dosing ..............................................................................................................43 
6.2.4 
Dose Escalation ................................................................................................44 
6.2.4.1 
Data Monitoring Committee Review of Dose Escalation................................47 
6.3 
Labeling, Packaging, Storage, and Handling ...................................................49 
6.4 
Drug Accountability.........................................................................................49 
6.5 
Participant Compliance ....................................................................................50 
7 
STUDY PROCEDURES .......................................................................................51 
7.1 
Study Schedule.................................................................................................51 
7.1.1 
Screening Period (Day –21 to -1) ....................................................................52 
7.1.2 
Baseline and Dose-Escalation Period:  Double-Blind Visits Baseline to 
Week 8 .......................................................................................................52 
7.1.3 
Stable-Dosing Period:  Double-Blind Visits from Week 10 to Week 26 ........53 
7.1.4 
Dose-Escalation Period:  OLE Visits from Week 26 to Week 34 ...................53 
7.1.5 
Stable-Dosing Period:  OLE Visits at Week 36+.............................................53 
7.1.6 
Early Termination/End of Treatment ...............................................................53 
7.1.7 
Follow-Up After Early Termination/End of Treatment ...................................54 
7.1.8 
 
7.2 
Study Evaluations and Procedures ...................................................................54 
7.2.1 
Efficacy ............................................................................................................54 
7.2.1.1 
Biomarkers .......................................................................................................54 
7.2.1.2 
Other Efficacy Assessments ............................................................................55 
7.2.2 
Safety ...............................................................................................................55 
7.2.2.1 
Physical Examination, Vital Signs, and Neurodevelopmental Examination ...55 
7.2.2.2 
Electrocardiograms ..........................................................................................56 
7.2.2.3 
Clinical Laboratory Evaluations ......................................................................57 
7.2.3 
Demographics, Medical History, Disease History, and Medication History ...58 
7.2.4 
Other Assessments ...........................................................................................58 
7.2.4.1 
Clinical Pharmacology Assessments ...............................................................58 
7.2.4.2 
Healthcare Resource Utilization ......................................................................58 
7.2.5 
Volume of Blood to Be Drawn from Each Participant ....................................59 
7.3 
Adverse Event Collection ................................................................................62 
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7.3.1 
Adverse Event Collection Period .....................................................................62 
7.3.2 
Follow-Up ........................................................................................................62 
7.3.3 
Expedited Safety Reporting .............................................................................62 
7.3.4 
Adverse Events of Special Interest ..................................................................62 
7.3.5 
Overdose and Special Reporting Situations .....................................................63 
7.3.6 
Disease Progression .........................................................................................64 
7.3.7 
Adverse Event Definition ................................................................................64 
7.3.8 
Serious Adverse Event Definition ...................................................................65 
7.3.9 
Recording and Follow-Up of AEs, AESIs, and SAEs .....................................66 
7.3.10 
Assessment of Severity ....................................................................................66 
7.3.11 
Assessment of Causality ..................................................................................67 
7.4 
Safety Monitoring Guidelines ..........................................................................68 
7.4.1 
Data Monitoring Committee ............................................................................68 
7.4.2 
Liver Parameters ..............................................................................................69 
7.4.2.1 
General Guidelines...........................................................................................69 
7.4.2.2 
Enhanced Monitoring Criteria for Liver Parameters .......................................70 
7.4.2.3 
Guidelines for Interruption of Study Medication for Specific Liver 
Parameters ..................................................................................................72 
7.4.3 
Cholangitis Diagnostic Criteria........................................................................74 
7.4.4 
Growth and Development ................................................................................75 
7.4.4.1 
Growth .............................................................................................................75 
7.4.4.2 
Nutrition ...........................................................................................................75 
7.4.4.3 
 
7.4.5 
Lipid-Soluble Vitamins ....................................................................................76 
7.4.5.1 
Rules for Study Medication Discontinuation Following LSV Deficiency ......78 
7.4.6 
Safety Monitoring for Coagulation Panel Results ...........................................79 
7.4.7 
Safety Monitoring for Propylene Glycol Toxicity ...........................................79 
7.4.8 
Study Medication Discontinuation Rules for Diarrhea ....................................79 
7.4.9 
Study Medication Discontinuation Rules for Grade 4 AEs .............................80 
8 
STATISTICAL ANALYSIS .................................................................................80 
8.1 
Sample Size Calculation and Power Considerations .......................................80 
8.2 
Analysis Populations ........................................................................................80 
8.3 
Participant Disposition and Demographic and Baseline Characteristics .........81 
8.4 
Efficacy Analyses ............................................................................................81 
8.4.1 
Primary Efficacy Endpoint ..............................................................................81 
8.4.1.1 
Primary Analysis for Primary Efficacy Endpoint ............................................81 
8.4.1.2 
 
8.4.1.3 
 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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8.4.1.4 
 
 
 
 
 
8.4.2 
Secondary Efficacy Endpoints .........................................................................85 
8.4.3 
Adjustment for Multiplicity .............................................................................85 
8.4.4 
Exploratory Efficacy Endpoints .......................................................................86 
8.4.5 
Open-Label Efficacy Endpoints .......................................................................86 
8.5 
Safety and Tolerability Analyses .....................................................................86 
8.5.1 
Safety and Tolerability Endpoints ...................................................................86 
8.6 
Pharmacokinetic Analyses ...............................................................................87 
8.7 
Other Analyses .................................................................................................87 
8.8 
Primary Analysis ..............................................................................................87 
9 
STUDY CONDUCT ..............................................................................................87 
9.1 
Sponsor and Investigator Responsibilities .......................................................87 
9.1.1 
Sponsor Responsibilities ..................................................................................87 
9.1.2 
Good Clinical Practice Compliance .................................................................87 
9.1.3 
Indemnity/Liability and Insurance ...................................................................88 
9.1.4 
Public Posting of Study Information................................................................88 
9.1.5 
Study Suspension, Termination, and Completion............................................88 
9.2 
Investigator Responsibilities ............................................................................89 
9.2.1 
Good Clinical Practice Compliance .................................................................89 
9.2.2 
Protocol Adherence and Investigator Agreement ............................................89 
9.2.3 
Documentation and Retention of Records .......................................................89 
9.2.3.1 
Data Collection and Case Report Forms ..........................................................89 
9.2.3.2 
Recording, Access, and Retention of Source Data and Study Documents ......90 
9.2.3.3 
Financial Disclosure.........................................................................................91 
9.3 
Clinical Data Management ..............................................................................91 
9.4 
Monitoring Procedures.....................................................................................91 
9.5 
Quality Assurance/Audit ..................................................................................91 
9.6 
Record Retention .............................................................................................92 
9.7 
Sample Retention .............................................................................................92 
9.8 
Ethical Considerations .....................................................................................92 
9.8.1 
Informed Consent.............................................................................................92 
9.8.2 
Institutional Review Board or Ethics Committee ............................................93 
9.9 
Study Site Initiation .........................................................................................93 
9.10 
Study Site Closure............................................................................................93 
9.11 
Privacy and Confidentiality .............................................................................94 
10 
FINAL CLINICAL STUDY REPORT .................................................................95 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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STUDY SYNOPSIS  
Protocol Number:  MRX-701 
Drug:  Maralixibat (SHP625, LUM001) 
Title of the Study:  Randomized, Double-blind, Placebo-Controlled Phase 2 Study to Evaluate the 
Efficacy and Safety of Maralixibat in the Treatment of Subjects with Biliary Atresia after 
Hepatoportoenterostomy  
Short Title:  EMBARK: Evaluation of Maralixibat in Biliary Atresia Response post-Kasai  
Number of Participants (total and for each treatment arm):  Approximately 72 participants 
will be enrolled (36 per treatment group).  Participants will be randomized 1:1 to maralixibat 
600 μg/kg twice daily (BID) or placebo BID. 
Investigators:  International, multicenter study 
Sites and Regions:  The study will be conducted at multiple sites in North America, Europe, and 
Asia.  Other regions may be added, if necessary. 
Clinical Phase:  2 
Background 
Biliary atresia (BA) 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.   
The two most important improvements in the care of patients with BA 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 extrahepatic bile ducts 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.  However, although 
HPE frequently improves the signs and symptoms of BA, 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 BA 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. 
Maralixibat is a minimally absorbed inhibitor of the ileal bile acid transporter (IBAT; also known as 
the apical sodium-dependent bile acid transporter or solute carrier family 10 member 2).  By virtue of 
its ability to inhibit bile acid absorption and lower circulating bile acid levels, maralixibat is being 
developed by Mirum Pharmaceuticals, Inc. (Mirum), as a potential therapeutic agent for the treatment 
of BA. 
Rationale 
Clinical data from other forms of pediatric cholestatic diseases, including ongoing and completed 
Phase 2 studies in progressive familial intrahepatic cholestasis and Alagille syndrome, indicate that 
maralixibat improves signs and symptoms of cholestasis and may improve markers of liver injury as 
well as long-term liver-related outcomes.  This includes reductions in serum bile acid (sBA), as well 
as improvements in growth and other measures suggestive of disease modification, including 
transplant and biliary diversion event-free survival.  Maralixibat has demonstrated an acceptable 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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safety profile in more than 1600 exposed participants overall, including more than 119 children 
≥12 months of age with cholestatic liver disease. 
Elevated sBA levels are associated with increased morbidity and mortality in several cholestatic 
diseases.  High bile acid levels are understood to be an important driver of liver disease in patients 
with BA after HPE.  A consistent body of literature has demonstrated that biliary drainage, as 
measured by bilirubin levels at 3 and 6 months after HPE, is a prognostic indicator for long-term 
transplant-free survival in BA. 
Given the above, a reduction in the levels of serum and hepatic bile acids in patients with BA is 
hypothesized to slow or prevent liver injury, and therefore improve long-term transplant-free survival.  
Based on the understanding of maralixibat’s mechanism of action and its ability to durably reduce 
sBA in pediatric cholestasis for >6 years, maralixibat has the potential to reduce the long-term liver 
sequelae of BA. 
Objectives and Endpoints 
Objectives 
Primary Objective: 
• 
To evaluate the efficacy of maralixibat on biliary drainage after HPE in participants with BA 
Secondary Objectives: 
• 
To evaluate the rate of clinically relevant reductions in cholestatic biomarkers with 
maralixibat treatment 
• 
To evaluate the rate of liver-related clinical events  
• 
To evaluate the safety, tolerability, and pharmacokinetics of maralixibat 
Exploratory Objectives: 
• 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Open-Label Extension Objectives: 
• 
All of the above primary and secondary objectives analyzed over the full study duration, 
including the open-label extension (OLE) period  
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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2. History of surgical disruption of the enterohepatic circulation other than HPE 
3. Has had any of the following:  HPE performed by laparoscopy, undergone a second HPE, or 
has undergone an exploratory bile duct procedure 
4. Participant not tolerating enteral feeds at screening or during the screening period 
5. Evidence of another pathology involving the intrahepatic bile ducts (e.g., paucity, sclerosing 
cholangitis) 
6. Diagnosis of polysplenia syndrome, including evidence of BA splenic malformation 
syndrome, or major malformation of another organ system 
7. Diagnosis of cystic BA (based on clinician judgment, including but not limited to 
ultrasonography and cholangiography results) 
8. Decompensated cirrhosis (international normalized ratio >1.5 after correction of possible 
vitamin K deficiency, history or presence of clinically significant ascites, known varices, 
variceal hemorrhage, and/or encephalopathy) 
9. Previous or imminent need for liver transplantation 
10. Known hypersensitivity to maralixibat or any of its excipients 
11. Previous use of an IBAT inhibitor, N-acetyl cysteine, immunoglobulins, or traditional or 
herbal medicine remedies that are used to treat liver diseases or with a safety profile known to 
impact liver parameters. 
12. Receipt of investigational drug, biologic, or medical device within 30 days or 5 half-lives 
(whichever is longer) prior to screening 
13. Treatment with other medications containing propylene glycol (PG) or alcohol or any 
substrate for alcohol dehydrogenase (e.g., ethanol).  For participants <1 month of age only. 
14. Known caregiver history of unreliability, mental instability, or cognitive impairment that, in 
the opinion of the investigator or sponsor medical monitor, could compromise the validity of 
informed consent, compromise the safety of the participant, or lead to nonadherence with the 
study protocol or inability to conduct the study procedures 
15. Presence of other significant liver disease or any other conditions or abnormalities which, in 
the opinion of the investigator or sponsor medical monitor, may compromise the safety of the 
participant or interfere with participation in or completion of the study (prior or current 
cytomegalovirus infection is allowed) 
16. History or presence of any other disease or condition known to interfere with the absorption, 
distribution, metabolism or excretion of drugs, including bile salt metabolism in the intestine 
(e.g., inflammatory bowel disease), per investigator discretion 
 
Investigational Product, Dose, and Mode of Administration 
Maralixibat will be provided in the form of an oral solution (i.e., 
 mg/mL) along with 
either 0.5-, 1.0-, or 3.0- mL sized dosing dispensers, vials for formulation dilution, and bottle adapters 
(if required) to clinical sites.  The reference/comparator product is a placebo, which will also be 
provided as an oral solution along with dosing dispensers of the same size (either 0.5 mL, 1.0 mL, or 
3.0 mL). 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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ABBREVIATIONS 
Abbreviation 
Definition 
 
 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALGS 
Alagille syndrome 
ALP 
alkaline phosphatase 
 
 
AUC 
area under the concentration-time curve 
BA 
biliary atresia 
BID 
twice daily (dosing) 
CRA 
clinical research associate 
CRF 
case report form 
CRP 
C-reactive protein 
CRO 
contract research organization 
CSR 
clinical study report 
CSS 
Clinician Scratch Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
data monitoring committee 
DILI 
drug-induced liver injury 
EMA 
European Medicines Agency 
EOT 
end-of-treatment 
ET 
early termination 
fBA 
fecal bile acid 
FDA 
US Food and Drug Administration 
GI 
gastrointestinal 
GCP 
Good Clinical Practice 
GGT 
γ-glutamlytransferase 
GLP 
Good Laboratory Practice 
HCV 
hepatitis C virus 
HPE 
hepatoportoenterostomy 
IBAT 
ileal bile acid transporter 
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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Abbreviation 
Definition 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat (population) 
IV 
intravenous 
 
 
LSV 
lipid-soluble vitamin 
 
 
 
 
 
 
 
 
OLE 
open-label extension 
 
 
 
 
PFIC 
progressive familial intrahepatic cholestasis 
PG 
propylene glycol 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PND 
postnatal day 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acids 
TEAE 
treatment-emergent adverse events 
TK 
toxicokinetic 
UDCA 
ursodeoxycholic acid 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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1 
BACKGROUND INFORMATION 
1.1 
Indication and Current Treatment Options  
Biliary atresia (BA) 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 BA 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. 
Untreated, the outcome of BA is uniformly fatal (Karrer et al. 1996).  The etiology and 
pathogenesis of BA, however, remain largely unknown and are likely multifactorial 
(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).  BA is a recognized orphan disease.  Recent BA 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 BA 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 extrahepatic 
bile ducts 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 BA, 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 BA 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. 
1.2 
Product Background and Clinical Information 
Maralixibat chloride (hereafter referred to as maralixibat) is an inhibitor of the ileal bile acid 
transporter (IBAT; also known as the apical sodium-dependent bile acid transporter or solute 
carrier family 10 member 2).  The doses described in this document are of maralixibat 
chloride but are presented as “maralixibat.”  For example, 600 µg/kg maralixibat chloride is 
equivalent to 570 µg/kg maralixibat free base but will be referred to as 600 µg/kg maralixibat 
throughout this document. 
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In a healthy individual, bile acids promote activation of digestive enzymes and micellization 
of fats and lipid-soluble vitamins (LSV), permitting their intestinal absorption.  The IBAT is 
present in the terminal small intestine on the luminal surface of ileal enterocytes, where it 
mediates the uptake of conjugated bile acids across the brush border membrane of the 
enterocyte.  It facilitates the recycling of 95% of bile acids that enter the gut lumen back into 
the bloodstream in a system known as enterohepatic recirculation.  
The majority of bile acids (~95%) are absorbed by active transport in the terminal ileum, 
mediated by the IBAT.  Pharmacological inhibition of bile acid uptake through inhibition of 
the IBAT has the potential for clinical benefit by reducing hepatic accumulation of toxic bile 
acids, which play an essential role in BA liver damage and disease burden.  Due to its key 
role in bile acid re-uptake, IBAT is an ideal target for pharmacological interruption of bile 
acid transport.  Given its location, IBAT is accessible by compounds that are restricted to the 
lumen of the gut and do not require systemic exposure for inhibition of bile acid 
reabsorption.  As such, inhibiting the reuptake of bile acids via inhibition of IBAT may 
represent an ideal treatment for cholestatic disease in general and more specifically for BA 
(Neimark et al. 2004).  
Maralixibat is a potent, highly selective inhibitor (IC50=0.3 nM) of the IBAT.  This 
transmembrane protein transporter, localized on the luminal surface of ileal enterocytes, is 
present in the terminal 25% of the small intestine and mediates uptake of conjugated bile 
acids across the brush border membrane of the enterocyte.  Maralixibat is minimally 
absorbed due to its large molecular weight (710 Da) and the presence of a positively charged 
quaternary nitrogen atom, therefore maximizing the local exposure of the molecule to the 
receptor and minimizing unnecessary systemic exposure.   
Maralixibat-mediated blockade of intestinal reabsorption of bile acids by IBAT interrupts the 
enterohepatic circulation, thereby increasing fecal bile acid (fBA) excretion and lowering 
serum bile acid (sBA) levels.  Since reductions in sBA concentrations after surgical 
interruption of the enterohepatic circulation have been shown to be associated with 
improvements in cholestasis and outcomes in several pediatric cholestatic liver diseases 
(Emerick and Whitington 2002; Mehl et al. 2016; Bull et al. 2018; van Wessel et al. 2020), 
pharmacological interruption of the enterohepatic circulation by IBAT inhibition may be a 
nonsurgical and reversible alternative to achieve a similar reduction in sBA and thus improve 
disease outcomes. 
The ability of maralixibat to reduce sBA and prevent liver injury has been demonstrated in a 
rodent model of BA, the rat partial bile duct ligation model of cholestasis.  This animal 
model is relevant for BA because it replicates many details of the pathology and etiology as 
well as signs and symptoms of the disease.  In this model, the atresia of bile ducts is 
mimicked by surgically induced partial ligation.  Within 34 days following surgery, the 
animals develop increased levels of sBA, alkaline phosphatase (ALP), AST, ALT, 
γ-glutamyltransferase (GGT), and total bilirubin (Heinrich et al. 2011). 
Three nonclinical studies support the rationale for efficacy (see the Maralixibat Chloride 
Investigator’s Brochure [IB] for further details).  In the first study, 0.3-mg/kg and 10-mg/kg 
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doses of maralixibat were compared with vehicle and sham surgery.  After 14 days of 
treatment in the maralixibat-treated groups, sBA and liver enzymes were significantly 
improved compared with the vehicle groups.  Consistent with improvements in functional 
liver biochemistry, histopathologic analysis of liver tissue showed a reduction in necrosis, 
inflammatory cell infiltration and the number of proliferating cholangiocytes 14 days after 
liver injury.  Similar results were observed in a second study with 3 treatment arms (1 mg/kg 
and 10 mg/kg maralixibat, vehicle; Gedulin et al. 2013).  In a final study, it was demonstrated 
that treatment with maralixibat (1 mg/kg) significantly improved outcome in terms of sBA, 
liver enzymes, and total bilirubin as well as showed numerical superiority over treatment 
with ursodeoxycholic acid (UDCA; 1 mg/kg). 
Several safety and pharmacokinetic (PK) studies have also been performed.  In a 13-week 
adult rat Good Laboratory Practice (GLP) daily oral toxicity study (SA4947; M3000008), 
maralixibat was administered at dose levels up to 150 mg/kg/day in male rats and up to 
500 mg/kg/day in female rats; however, the bioavailability was <0.1% at these doses.  The 
maximum serum concentration (Cmax) and area under the concentration-time curve from 0 to 
24 hours (AUC0-24h) values generally increased with increasing dose.  Because there were no 
maralixibat-related findings in this study that were considered to be adverse, the no observed 
adverse effect level (NOAEL) was the highest doses administered, which were 
150 mg/kg/day for males and 500 mg/kg/day for females. 
In a separate rodent study, no significant changes were observed in safety pharmacology 
studies following single oral or intravenous (IV) administration.  No evidence of mutagenic 
or clastogenic activity was seen.  In a GLP juvenile toxicity study (postnatal day [PND] 7 to 
21) conducted in rats, no adverse effects were observed with oral doses of maralixibat that 
were 50 times greater than the current Phase 3 clinical dose of 1200 µg/kg/day (for an 
average 20-kg child). 
A definitive GLP juvenile toxicity study was conducted in which maralixibat was 
administered to rat pups from PND 7 through 21 (Study 2939-001 [MRXNC-001]).  
Maralixibat doses of 50, 100, and 250 mg/kg/day were given to both sexes:  the study 
included 20 male and 20 female animals per dose level in the main study and 60 animals of 
each sex per dose level in the toxicokinetic (TK) part of the study.  In contrast to other 
nonclinical studies on maralixibat but in line with the TK results from the non-GLP pilot 
study in same-aged animals (Study R9976M-SHP625 described above), systemic exposures 
were seen in this study, with an average AUC of 13,900 hr*ng/mL on the first day of dosing 
(PND 7) at the highest tested dose (250 mg/kg).  Plasma AUCs did not significantly increase 
with increases in dose, indicating saturation of absorption at the lowest dose (50 mg/kg) and 
thus a high estimated oral bioavailability (approximately 17%) at the lowest dose on the first 
day of dosing.  Estimated bioavailability significantly decreased over the course of the study, 
to <0.5% at all dose levels after the last dose on PND 21.  Thus, maralixibat absorption was 
highest in the youngest pups but similar to that seen in adult animals in the oldest pups, likely 
due to increased permeability in the immature gastrointestinal (GI) tract of neonatal pups.  
Despite these high plasma exposures, maralixibat was well tolerated in this study and showed 
no obvious signs of toxicity, with no effect on survival, clinical findings, body weights, food 
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consumption, sexual maturation, clinical pathology, or histopathologic examinations at any 
dose level evaluated. 
Clinical data from other pediatric cholestatic diseases, including completed Phase 2 studies in 
progressive familial intrahepatic cholestasis (PFIC; Study LUM001-501) and Alagille 
syndrome (ALGS; Studies LUM001-301, -302, -303, -304, and -305), show consistent and 
clinically meaningful improvements in signs and symptoms of cholestasis in participants 
aged ≥1 year treated with maralixibat.  This includes significant reductions in sBA, bilirubin, 
and ALT, as well as improvements in growth and other indicators of disease modification.  
Data also suggest that patients with PFIC treated for up to 5 years with maralixibat 
experience long-term avoidance of liver transplantation.  Further, maralixibat has been 
shown to have an acceptable safety profile in more than 1600 exposed participants overall 
and more than 119 children ≥12 months of age with cholestatic liver disease.  The most 
common treatment-related adverse events (AEs) were mechanism based, mild to moderate in 
nature, and included self-limited diarrhea, abdominal pain, and nausea.  No worsening of 
LSV malabsorption was noted in clinical studies so far.  In September 2021, LIVMARLI® 
(maralixibat) oral solution was approved in the United States for the treatment of cholestatic 
pruritus in patients with ALGS 1 year of age and older.   
Please refer to the latest version of the Maralixibat IB for the overall benefit/risk assessment 
and the most current information regarding the drug metabolism, PK, efficacy, and safety of 
maralixibat.  
By virtue of its ability to inhibit bile acid absorption and lower circulating bile acid levels, 
maralixibat is being developed by Mirum Pharmaceuticals, Inc. (Mirum) as a potential 
therapeutic agent for the treatment of BA. 
2 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
Clinical data from other forms of pediatric cholestatic, including ongoing and completed 
Phase 2 studies in PFIC and ALGS, indicate that maralixibat improves the signs and 
symptoms of cholestasis and may improve markers of liver injury as well as long-term 
liver-related outcomes.  This includes reductions in sBA, as well as improvements in growth 
and other measures suggestive of disease modification, including transplant and biliary 
diversion event-free survival.  Maralixibat has demonstrated an acceptable safety profile in 
more than 1600 exposed participants overall, including more than 119 children ≥12 months 
of age with cholestatic liver disease. 
In disease states, bile acids have been shown to induce damage and necrosis in hepatocytes 
and cholangiocytes (Monte et al. 2009).  Elevated sBA levels are associated with increased 
morbidity and mortality in several cholestatic diseases.  Specifically, large increases in sBA 
levels are a well-known feature of BA.  For example, in one study, sBA levels at Kasai 
(88.96±28.70 µM) and liver transplantation (165.48±43.55 µM) greatly exceeded those of 
pediatric control patients with non-cholestatic liver disease (4.94±5.43 µM; 
Chen et al. 2008).  The importance of bile acid toxicity to hepatocytes in BA is highlighted 
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by clinical data that show sBA levels to be inversely correlated with native liver survival and 
to be predictive of overall outcome (Harpavat et al. 2019).  It is based on these findings that 
high bile acid levels are understood to be an important driver of liver disease in patients with 
BA after HPE.  
Liver disease and failure are arguably the most important complications for patients with BA 
after HPE.  Up to 50% of BA patients require liver transplantation at 2 years after HPE.  
Liver transplantation is an important clinical event for patients with end-stage liver disease in 
BA, carrying significant medical risk, both acutely and long term (e.g., immunosuppression).  
Importantly for this population, a consistent body of literature has demonstrated that biliary 
drainage, as measured by bilirubin levels at 3 and 6 months after HPE, is a clinically 
meaningful prognostic indicator for long-term native liver survival in BA (Kasai et al.1989; 
Chusilp et al. 2016; Shneider et al. 2016).  Based on these data, serum bilirubin is frequently 
used as a clinical marker of HPE success and long-term outcome (including potential future 
requirement of liver transplantation).  
Given the above, reducing the level of serum and hepatic bile acids in patients with BA is 
hypothesized to slow or prevent liver injury, and therefore improve long-term transplant-free 
survival.  Based on the understanding of maralixibat’s mechanism of action and its ability to 
durably reduce sBA in pediatric cholestasis for >6 years, maralixibat has the potential to 
reduce the long-term liver sequelae of BA.  In the short term (<1 year), reductions in both the 
bile acid pool and markers of liver injury are anticipated, and these may translate into lower 
total serum bilirubin values, a prognostic marker for improved longer-term outcomes.  
The primary endpoint for this study therefore compares mean change in total serum bilirubin 
from baseline to Week 26 of treatment between the placebo and maralixibat groups.  In 
addition, the impact of maralixibat on transplant-free survival and the incidence of other 
liver-associated events will also be analyzed as important secondary outcomes, both in the 
double-blind portion of the study and during the long-term extension period.  Given the 
importance of bile acids in BA liver disease and maralixibat’s mechanism of action, changes 
in sBA levels will be a secondary endpoint for the double-blind portion of this study. 
2.2 
Study Objectives and Endpoints 
2.2.1 
Primary Objective and Endpoint 
Objective 
To evaluate the efficacy of maralixibat on biliary drainage after HPE in 
participants with BA 
Endpoint 
Mean change in total serum bilirubin levels from baseline through Week 26 
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3.1.1.1 
Clinical Efficacy  
Available clinical data across multiple indications, including data from studies in children 
with cholestatic liver disease (PFIC and ALGS), suggests that IBAT inhibition leads to 
clinically meaningful treatment effects, including improvements in sBA levels, pruritus, 
growth, and possibly transplant-free survival.  
Study LUM001-304 in participants with ALGS aged ≥1 year, was a 4-week, randomized 
placebo-controlled drug withdrawal study with a long-term treatment period up to 5 years 
using maralixibat doses of 400 µg/kg QD and then BID.  Maralixibat led to significant and 
sustained reductions in sBA and pruritus, with a significant difference between maralixibat 
and placebo during the randomized withdrawal period.  Over this period, improvement in 
linear growth as well as improvements in xanthomas were observed.  BID doses (up to 
400 µg/kg BID) led to further improvement in sBA and pruritus, although not in a 
statistically significant manner, while the safety profile was comparable between the two 
dose levels.  
Study LUM001-501 in participants with PFIC aged ≥1 year was a single-arm study using 
maralixibat doses up to 280 µg/kg QD and then BID.  A subset of participants showed a 
profound and sustained treatment response including normalization or ≥75% reduction from 
baseline in sBA levels, control of pruritus or ≥1.0-point reduction from Itch Reported 
Outcome (Observer) baseline, improvements in growth (height and weight), normalization of 
liver parameters, and remaining transplant-free with more than 5 years of maralixibat 
treatment.  BID dosing (up to 280 µg/kg BID) led to similar rapid and sustained treatment 
response in additional participants while showing a similar safety profile as the QD dosing, 
indicating that higher doses and a BID dosing regimen may improve the responder rate to 
maralixibat treatment.  Therefore, doses up to 600 µg/kg BID are evaluated in the ongoing 
Phase 3 randomized double blinded, placebo-controlled study in participants with PFIC.   
The 600 µg/kg BID dosing regimen is further supported by documentation of dose-dependent 
increase in fBA excretion, the direct pharmacodynamic marker of IBAT inhibition, up to 
total daily doses of maralixibat 100 mg (weight-based equivalent of 1400 µg/kg/day) in the 
dose finding study (SHP625-101) conducted in overweight and obese healthy volunteers.  
BID dosing (50 mg BID; 700 µg/kg BID equivalent) led to a further increase in fBA 
excretion compared with 100 mg QD (1400 µg/kg QD equivalent).  The safety profile was 
comparable across the tested dose range, with the exception of increased stool frequency at 
higher doses.  
3.1.1.2 
Clinical Safety and Tolerability 
In the completed and ongoing Phase 2 studies, maralixibat has been administered to 
>119 pediatric participants (≥12 months age) with cholestatic liver disease at doses up to a 
maximum daily dose of 1200 µg/kg/day.  Dosing of 400 and 800, as well as 280 and 
560 µg/kg/day in Study LUM001-304 and LUM001-501, respectively, demonstrated a 
consistent safety profile.  No maximal tolerated dose has been determined at single doses up 
to 7000 µg/kg and multiple doses up to 1400 µg/kg/day.  Furthermore, no dose-related safety 
findings have been identified to date. 
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The maralixibat development program, conducted in >1600 participants across multiple 
indications as well as healthy volunteers, provides safety data for treatment exposures to over 
5 years.  GI symptoms (abdominal pain, diarrhea) were the most commonly reported 
treatment-related AEs and were mostly mild to moderate in severity and transient in nature.  
Doses of maralixibat, up to 1200 µg /kg/day (600 µg /kg/day BID), are expected to be safe in 
children with cholestatic liver disease. 
3.1.1.3 
Nonclinical Safety Data Justify Dosing of Children <1 year of age 
The use of maralixibat in children aged <1 year is supported by the absence of adverse 
effects in multiple GLP juvenile toxicity studies conducted in rats.  In separate studies, rats 
were dosed from PND 7 to PND 21, and from PND 21 to PND 63.  No adverse effects were 
observed in these GLP studies up to the highest doses tested.  Rat pups were dosed starting as 
young as PND 7, which from a whole animal development perspective is generally 
representative of a preterm human infant.  Therefore, data from these studies support the use 
of maralixibat in clinical studies in the youngest human infants.  Large safety margins were 
established in these studies (the highest dose tested in the youngest rat pups was 
250 mg/kg/day, equivalent to ~60,000 µg/kg/day in human infants) and predict a minimal 
risk of toxicity in human infants. 
In summary, based on the absence of adverse effects in juvenile toxicity studies and the 
acceptable safety profile in >1600 participants across multiple indications, including 
119 children with cholestatic liver disease, at single doses up to 7000 µg/kg and multiple 
doses up to 1400 µg/kg/day, maralixibat is expected to be safe at the doses proposed in the 
ongoing or planned clinical studies.  Together with the dose-dependent increase in fBA 
excretion, and the documentation of higher responder rates in clinical studies in participants 
with cholestatic liver disease, doses up to 600 µg/kg BID are considered to have a favorable 
benefit-risk profile in patients with a potentially life-threatening progressive liver disease.  
Several safeguards are foreseen in Study MRX-701 to ensure the safety and wellbeing of 
study participants.  Doses will be increased in a stepwise fashion with careful monitoring of 
each individual participant’s tolerability and safety parameters.  In addition, throughout the 
study, pharmacokinetics and safety parameters will be reviewed on a frequent basis in an 
unblinded fashion by an independent data monitoring committee and will be monitored in 
real time by the Principal Investigator (PI) and medical monitor.  In summary, given the 
safeguards in place to ensure participant’s safety and the absence of safety signals from 
clinical and nonclinical studies conducted to date, as well as the clinically relevant treatment 
benefits documented with maralixibat in other pediatric cholestasis indications, the overall 
benefit-risk profile of Study MRX-701, including its dosing regimen, is considered favorable. 
3.1.2 
Rationale for Primary Endpoint 
The primary endpoint is mean change from baseline in total bilirubin based on published data 
demonstrating that bilirubin levels at 6 months after HPE are predictive of long-term 
outcome (native liver survival; Kasai et al. 1989; Hung et al. 2006; de Vries et al. 2012; 
Chusilp et al. 2016; Shneider et al. 2016) in patients with BA.  A reduction in bilirubin levels 
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after 26 weeks of treatment would indicate a potential improvement in long-term outcomes 
for patients with BA.  In addition, bilirubin is a measure of the degree of cholestasis and is 
routinely monitored in patients with BA post-Kasai to determine the success of HPE surgery 
and for clinical decision making for subsequent a potential liver transplantation.  In other 
pediatric cholestatic indications (PFIC and ALGS) with maralixibat treatment, reduction in 
sBA has led to normalization in bilirubin levels and other liver parameters indicating general 
improvements in liver function, growth, and symptoms associated with cholestasis. 
Estimates for a clinically relevant treatment effect are assumed to be approximately 30%, or 
mean change in total bilirubin of -2.1 mg/dL between treatment groups, assuming that this 
would lead to a higher proportion of study participants with bilirubin in the low-risk category 
(<2.0 mg/dL) in the maralixibat group compared with the placebo group.  This threshold of 
bilirubin has been linked with a significantly different treatment course with respect to native 
liver survival (see Figure 2; Shneider et al. 2016). 
Figure 2 
Kaplan-Meier Analysis of Outcome Based on Total Bilirubin Level 
3 Months after HPE 
 
HPE=hepatoportoenterostomy. 
Note:  Survival with native liver relative to age in days after HPE is shown in the 3 Kaplan-Meier curves, 
derived by dividing the cohort of participants on the basis of their total serum bilirubin level 3 months after 
HPE.  At 3 months after HPE, total bilirubin level was <2 mg/dL in 38 children, between 2 and 6 mg/dL in 
30 children, and >6 mg/dL in 19 children. 
 
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3.1.3 
Rationale for Study Population 
Maralixibat has the potential for meaningful clinical benefit in a disease with a high unmet 
medical need.  There is currently no approved pharmacotherapy for BA, and available 
medical approaches (e.g., steroids, immunoglobulins) have failed to show efficacy in clinical 
studies (Davenport et al. 2013; Bezerra et al. 2014; Mack et al. 2019).  Standard of care is 
therefore mainly supportive, focusing primarily on re-establishing bile flow via surgical HPE 
(Kasai procedure), usually performed within the first 2 months of life, and on promoting 
growth through nutritional support and preventing or treating secondary complications 
(Wong and Davenport 2019).  However, despite this approach, HPE outcomes can vary 
widely, with approximately one-third of patients attaining a good long-term outcome (native 
liver and non-jaundice), one-third undergoing a progressive 2- to 4-year path of liver failure 
leading to an eventual liver transplant, and the final third undergoing rapid liver failure 
requiring transplant within 6 to 12 months (Shneider et al. 2006; Goda et al. 2013; 
Nightingale et al. 2017).  Given this, BA remains the leading cause of pediatric liver 
transplant worldwide, with approximately 40% of patients requiring a transplant by 2 years 
of age despite undergoing HPE.  No pharmacological therapy has been shown to delay the 
time to death or liver transplantation. 
The early course of BA is characterized by an inflammatory condition.  Due to the 
cholestasis, there is an accumulation of toxic bile acids, which likely contribute to the 
hepatocyte injury.  This is followed by either a rapid reduction in liver function, leading to 
liver failure and the need for transplantation within 6 to 12 months, or a more slowly 
progressive fibrotic phase of hepatic disease that erodes function and results in failure over 
many years.  The optimal therapeutic window for an IBAT inhibitor, such as maralixibat, in 
the treatment of BA is likely during the early, inflammatory phase of the disease before the 
fibrotic/cirrhotic phase of disease.  Given this, the study has been designed to enroll 
participants shortly after the HPE procedure to reduce the pathophysiological effects of sBA 
exposure to the hepatocytes though pharmacological interruption of the enterohepatic 
circulation.  
3.2 
Duration and Study Completion Definition 
A participant’s duration of participation for the double-blind portion of MRX-701 is expected 
to be up to 26 weeks followed by an OLE of 78 weeks to at least Week 104.  Participants 
who complete the double-blind phase of the study and continue in the OLE phase will 
receive maralixibat regardless of whether they were assigned to the maralixibat group or the 
placebo group in the double-blind phase of the study. 
The study completion date is defined as the date the final participant, across all sites, 
completes his or her final protocol-defined assessment.  Note that this includes the follow-up 
visit or contact, whichever is later (see Section 7.1.6 for the defined follow-up period for this 
study), but not the long-term clinical follow-up of persistent safety findings.  
Participants who discontinue at any time during this study will have early termination (ET) 
assessments days after the last dose of study medication and a safety follow-up phone call 
or email 
days after last dose (see Section 7.1.6).  Participants who discontinue from the 
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study for safety reasons will be followed as long as clinically indicated or until the safety 
finding is considered ongoing, stable, or resolved. 
3.3 
Sites and Regions 
The study will be conducted in North America, Europe, and Asia.  Other regions may be 
added. 
4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
A participant will be considered eligible for the study if he or she meets all the criteria below. 
1. Informed consent (by the legally authorized representative) per the Institutional 
Review Board/Independent Ethics Committee (IRB/IEC)  
2. Male or female participants with a body weight ≥2500 g (before or during the 
screening period) who are ≥21 days old and ≤90 days old at the time of HPE or Kasai 
procedure 
3. Gestational age ≥
 weeks at birth (Those with gestational age <
 weeks with no 
present clinical or developmental preterm complications that could impact 
participation in the study may be included after evaluation and approval by the 
medical monitor.) 
4. HPE or Kasai Procedure within 3 weeks prior to randomization 
5. Clinical diagnosis of BA at laparotomy (with subsequent confirmation on histology of 
the biliary remnant) 
6. Caregiver willingness to comply with all study visits and requirements, including 
ability to read and understand the questionnaires and, if applicable, capable of 
diluting study medication per investigator training and written instructions 
7. Caregiver access to email or phone for remote participant contacts 
 
4.2 
Exclusion Criteria 
A participant will be considered ineligible for the study if he or she meets any of the criteria 
below: 
1. Chronic diarrhea requiring ongoing IV fluid or nutritional intervention at screening, 
during the screening period, or during the 30 days prior to screening 
2. History of surgical disruption of the enterohepatic circulation other than HPE 
3. Has had any of the following:  HPE performed by laparoscopy, undergone a second 
HPE, or has undergone an exploratory bile duct procedure 
4. Participant not tolerating enteral feeds at screening or during the screening period 
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5. Evidence of another pathology involving the intrahepatic bile ducts (e.g., paucity, 
sclerosing cholangitis) 
6. Diagnosis of polysplenia syndrome, including evidence of BA splenic malformation 
syndrome, or major malformation of another organ system 
7. Diagnosis of cystic BA (based on clinician judgment, including but not limited to 
ultrasonography and cholangiography results)  
8. Decompensated cirrhosis (international normalized ration [INR] >1.5 after correction 
of possible vitamin K deficiency, history or presence of clinically significant ascites, 
known varices, variceal hemorrhage, and/or encephalopathy) 
9. Previous or imminent need for liver transplantation 
10. Known hypersensitivity to maralixibat or any of its excipients 
11. Previous use of an IBAT inhibitor, N-acetyl cysteine, immunoglobulins, or traditional 
or herbal medicine remedies that are used to treat liver diseases or with a safety 
profile known to impact liver parameters 
12. Receipt of investigational drug, biologic, or medical device within 30 days or 
5 half-lives (whichever is longer) prior to screening 
13. Treatment with other medications containing propylene glycol (PG) or alcohol or any 
substrate for alcohol dehydrogenase (e.g., ethanol).  For participants <1 month of age 
only  
14. Known caregiver history of unreliability, mental instability, or cognitive impairment 
that, in the opinion of the investigator or sponsor medical monitor, could compromise 
the validity of informed consent, compromise the safety of the participant, or lead to 
nonadherence with the study protocol or inability to conduct the study procedures 
15. Presence of other significant liver disease or any other conditions or abnormalities 
which, in the opinion of the investigator or sponsor medical monitor, may 
compromise the safety of the participant or interfere with participation in or 
completion of the study (prior or current cytomegalovirus infection is allowed) 
16. History or presence of any other disease or condition known to interfere with the 
absorption, distribution, metabolism, or excretion of drugs, including bile salt 
metabolism in the intestine (e.g., inflammatory bowel disease), per investigator 
discretion 
 
4.3 
Reproductive Potential 
Because this study will be conducted in prepubescent pediatric participants, discussion of 
reproduction is not applicable. 
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4.4.2 
Participants “Lost to Follow-Up” Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any participant lost to 
follow-up at any time before the last scheduled contact (office visit or telephone contact).  At 
least 1 of these documented attempts must include a written communication sent to the 
participant’s last known address via courier or registered mail (with an acknowledgment of 
receipt request) asking that the participant return to the site for final safety evaluations and 
return any unused study medication. 
5 
PRIOR AND CONCOMITANT TREATMENT 
5.1 
Prior Treatments 
Information on specific prior medications and therapies will be collected throughout the 
study.  Prior treatments refer to treatments prior to the first dose of study medication.  This 
information must be recorded in the participant’s source documents and the relevant case 
report form (CRF) for data collection.  
5.2 
Concomitant Treatments  
A participant should be instructed to continue use of any medication or treatment until 
informed consent (by the legally authorized representative) has been obtained.  Concomitant 
treatments refer to all treatments, including concomitant therapies as well as herbal 
treatments, vitamins, and nonpharmacological treatments administered between the dates of 
the first dose of study medication and the end of the participant’s participation in the study.  
Concomitant treatment information must be recorded in the participant’s source documents.  
Investigators must ensure that participants receive LSV supplements, as needed, for the 
duration of the study.  
Throughout this study, standard-of-care medications individual to the clinician/center will be 
allowed if this is recorded within concomitant medication records.  Standard of care includes 
but is not limited to the use of steroids, antibiotics, aldactone, furosemide, albumin, 
rifampicin, and UDCA.  Standard of care excludes the use of N-acetylcysteine and 
immunoglobulins. 
Table 3 lists the prohibited treatments and the time restriction period prior to baseline. 
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6.3 
Labeling, Packaging, Storage, and Handling 
All study medication will be labeled according to country-specific requirements.  Additional 
labels may, on a case-by-case basis, be applied to the study medication in order to satisfy 
local or institutional requirements but must not contradict or obscure the clinical study label 
or identify the study participant by name.  Additional labels may not be added without the 
sponsor’s prior full agreement. 
Study medication is packaged in labeled containers of ready-to-use oral solution of 
maralixibat 
 mg/mL or matching placebo.  The sponsor or designee will 
provide 0.5-, 1.0-, and 3.0-mL-sized dosing dispensers, vials for formulation dilution, and 
bottle adapters (if required) to clinical sites.  
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 or their agreed designee 
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. 
6.4 
Drug Accountability 
Investigators will be provided with sufficient amounts of the study medication to carry out 
this protocol for the agreed number of participants.  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 by the study site. 
The investigator has overall responsibility for administering/dispensing study medication.  
Where permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained on the protocol and who works under the direct supervision of the 
investigator.  Study medication will be dispensed at baseline and each visit in quantities 
sufficient for dosing until the next scheduled visit.  If necessary, and where permitted, direct 
medication shipment from site to participant is allowed between visits. 
The investigator or designee will dispense the study medication only to the caregivers of 
participants included in this study following the procedures set out in the study protocol.  
Each participant’s caregiver will be given only the study medication assigned.   
The investigator is responsible for ensuring the retrieval of all study supplies from 
participants.  Caregivers must be instructed to bring their unused and empty/used study 
medication to every visit.  Drug accountability must be assessed at the bottle level.  The 
pharmacist/delegated person will record details on the drug accountability form or similar.  
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During dose escalation, a 
day visit window will be permitted, unless otherwise specified.  
Visit dates and acceptable windows are calculated from the baseline visit.  
7.1.3 
Stable-Dosing Period:  Double-Blind Visits from Week 10 to Week 26  
Assessments and procedures will be performed as outlined in Table 1.  A 
day visit window 
will be permitted.  Visit dates and acceptable windows are calculated from the baseline visit.  
During the double-blind stable-dosing period, participants/caregivers will receive emails 
and/or a phone calls during which the use of concomitant treatments, breastfeeding status, 
AEs, and study drug compliance will be reviewed, as outlined in Table 1.  
7.1.4 
Dose-Escalation Period:  OLE Visits from Week 26 to Week 34 
The open-label dose escalation will comprise 4 to 8 weeks (maximum 8 weeks).  During the 
OLE, all participants, regardless of treatment assignment in the double-blind period, will 
receive maralixibat.  The assessments detailed in Table 2 should be completed during this 
period.  In the event of escalation to the maximum dose ahead of 8 weeks, participants will 
continue with the same cadence of visits for the remainder of the dose-escalation period, as 
laid out in the Table 2. 
During dose escalation, a 
day visit window will be permitted, unless otherwise specified.  
Visit dates and acceptable windows are calculated from Week 26.  
The Week 26 visit will be 1) the final visit of the double-blind stable dosing period and 2) the 
first visit of the open-label period.   
7.1.5 
Stable-Dosing Period:  OLE Visits at Week 36+  
During the first stage of the OLE stable-dosing period, participant contact will alternate 
between a phone or email contact and a clinical visit.  This will comprise the following:  
• Participants/caregivers will receive an email or a phone call, during which the use of 
concomitant treatments, breastfeeding status, AEs, and study drug compliance will be 
reviewed as outlined in Table 2. 
• Alternating with emails or phone calls, participants will return to the site for a study 
clinic visit.  Assessments and procedures will be performed as outlined in Table 2.  A 
7-day visit window will be permitted.   
7.1.6 
Early Termination/End of Treatment  
Participants will return to the site at EOT or upon ET, and the procedures and assessments 
outlined in Table 2 will be performed.  If a participant has undergone a clinic visit for the 
study within the preceding 7 days, blood and other clinical assessments do not need to be 
repeated unless there is clinical suspicion of abnormality.  Breastfeeding status, AE 
assessment, participant dosing compliance, and prior and concomitant treatments will be 
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and participant number, participant initials (if applicable), and date and kept in the source 
documents at the study site.  Clinically significant abnormalities should be recorded on the 
relevant section of the Medical History/AE electronic CRF, as appropriate. 
Additional ECGs may be performed based on clinical indication as per investigator and/or 
medical monitor judgment.  
7.2.2.3 
Clinical Laboratory Evaluations 
Venous blood samples are required for samples analyzed by the central laboratory.  For local 
safety assessments, if the investigator is unable to collect a venous sample, capillary blood 
samples may be used if compliant with local laboratory standard operating procedures.  
Clinical laboratory assessments are listed in Appendix 3.  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 subinvestigator must 
assess out-of-range clinical laboratory values for clinical significance, indicating whether the 
values are clinically significant.  Abnormal clinical laboratory values that are unexpected or 
not explained by the participant’s clinical condition may, at the discretion of the investigator 
or sponsor, be repeated as soon as possible until confirmed, explained, or resolved. 
Complete blood count and coagulation results may be collected as part of standard of care 
(local laboratory) if blood is drawn within 3 days before or after the study visit.  In such case, 
the investigator or designee will be asked to provide the reference ranges. 
Unscheduled local laboratory values relevant to the monitoring of an AE/serious adverse 
event (SAE) or clinically significant laboratory abnormalities must be captured in the 
relevant CRF; collection of other local laboratory values may be requested by the sponsor. 
The sBA, 
 and PK results will remain blinded to sites and to the blinded study team 
(see Section 6.1.2 for exceptional circumstances).  
Clinical chemistry samples must be sent to the central laboratory.  Total bilirubin is the 
primary endpoint of the study and must be measured by the central laboratory. 
Anion gap and osmolar gap (when clinically indicated), corrected sodium, α-tocopherol/total 
lipids ratio, retinol/retinol-binding protein molar ratio (when clinically indicated), 
 
.  Total lipids will be approximated by the sum of triglycerides and 
total cholesterol. 
Where possible and permitted, home care may be organized through qualified healthcare 
professionals to collect samples at the participant’s home (or other agreed-upon location).  
This applies to all types of blood-based assessments. 
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7.3 
Adverse Event Collection 
At each study visit, participants or their caregivers will be questioned in a general way to 
ascertain whether AEs have occurred since the previous visit (e.g., “Has your child had any 
health problems since your last visit?”).  
The investigator and/or designees are responsible for detecting, documenting, and recording 
events that meet the AE/SAE/adverse event of special interest (AESI) reporting criteria 
described in this section.  
7.3.1 
Adverse Event Collection Period 
All SAEs will be recorded from the signing of the informed consent form (ICF) until the end 
of study visit at the time points specified in the schedule of assessments. 
All AE/AESIs will be collected from first dose of study drug until the end of study visit at the 
time points specified in the schedule of assessments.  
All SAE/AESIs will be reported to the sponsor or designee immediately but no later than 
24 hours after awareness.  
7.3.2 
Follow-Up 
After the initial AE/SAE/AESI report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All events will be followed until the event resolves, 
stabilizes, is otherwise explained, or the participant is lost to follow-up.  
Investigators are not obligated to actively seek AEs or SAEs after study participants exit the 
study.  However, if the investigator learns of any SAEs that occurred in a participant after 
study exit and the investigator considers the event to be possibly related to the study 
treatment, the investigator must notify the sponsor immediately, but no later than 24 hours 
after awareness. 
7.3.3 
Expedited Safety Reporting 
The sponsor will comply with country-specific regulatory requirements relating to expedited 
safety reporting to regulatory authorities, IRBs/IECs, and investigators.  
An investigator who receives safety information (e.g., expedited safety report, periodic safety 
summaries) from the sponsor may need to notify the local IRB/IEC, according to local 
requirements.  
7.3.4 
Adverse Events of Special Interest 
An AESI is one of scientific and medical interest specific to the sponsor’s product or 
program.     
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• Medication Error:  An error made in prescribing, dispensing, administration, and/or 
use of an investigational product.  For studies, medication errors are reportable to the 
sponsor only as defined below.  
o Medication errors should be collected/reported for all products under 
investigation.  The administration and/or use of the unassigned treatment 
is/are always reportable as a medication error.  
o The administration and/or use of an expired investigational product should be 
considered as a reportable medication error.  
Note: Cases of participants missing doses of the investigational product are not 
considered reportable as medication errors.  
 
7.3.6 
Disease Progression 
Disease progression itself is not considered an AE unless it is considered atypical in 
presentation or considered to be related to the study drug.  Signs of symptoms of disease 
progression do not need to be reported as AEs/SAEs; however, if there is uncertainty as to 
their cause, they may be reported as AEs. 
7.3.7 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered related to 
the study treatment. 
NOTE:  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study treatment. 
Events meeting the AE definition:  
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition 
• New conditions detected or diagnosed after study treatment administration even 
though they may have been present before the start of the study 
 
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Events NOT meeting the AE definition: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
• Medical or surgical procedure (e.g., endoscopy, appendectomy):  the condition that 
leads to the procedure is the AE 
• Elective procedures and preplanned interventions for preexisting conditions that did 
not worsen since the start of the study 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
 
7.3.8 
Serious Adverse Event Definition 
An AE is considered serious if it meets at least 1 of the following criteria: 
• Results in death 
• Is life-threatening  
The term “life-threatening” in the definition of “serious” refers to an event in 
which the participant was at risk of death at the time of the event.  It does not 
refer to an event that hypothetically might have caused death if it were more 
severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization signifies that the participant has been admitted (for at least 
24 hours) at the hospital for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting.  Complications 
that occur during hospitalization are AEs.  If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious.  When in 
doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an AE. 
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• Results in persistent disability/incapacity 
A substantial disruption of a person’s ability to conduct normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Important Medical Events 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations, such as important medical events, that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition.  These events 
should be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an Emergency Department or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
 
7.3.9 
Recording and Follow-Up of AEs, AESIs, and SAEs 
When an AE/AESI/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.  The investigator should report all relevant AESI/SAE information 
within 24 hours after awareness following the instructions provided by the sponsor.  It is not 
acceptable for the investigator to send photocopies of the participant’s medical records in lieu 
of completion of the AE/SAE CRF.  There may be instances when copies of medical records 
for certain cases are requested by the sponsor or designee.  In this case, all participant 
identifiers, with the exception of the participant number, will be redacted on the copies of the 
medical records before submission to the sponsor or designee. 
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs/symptoms) should be documented as the event term.  If a participant dies 
during participation in the study or during a recognized follow-up period, the investigator 
should provide the sponsor or designee with a copy of any postmortem findings, including 
histopathology. 
7.3.10 
Assessment of Severity 
The investigator will make an assessment of the maximum intensity for each AE and SAE 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
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(CTCAE), version 5.0.  Should a participant 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 activities of daily living (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, not when it is graded as severe.  A 
semicolon indicates “or” within the description of the grade, not “and.” 
7.3.11 
Assessment of Causality 
The investigator is obligated to assess the relationship (related or not related) between study 
treatment and each occurrence of each AE.  Causal assessment is either “related” (which 
encompasses possibly related, probably related, or certainly related) or “not related” (which 
encompasses possibly unrelated, probably unrelated, or certainly unrelated).  The investigator 
will use clinical judgment to determine the relationship.  A “related possibility” of a 
relationship conveys that there are facts, evidence, and/or arguments to suggest a causal 
relationship rather than that a relationship cannot be ruled out.   
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study treatment administration will be 
considered and investigated.  For each AE/AESI/SAE, the investigator must document in the 
medical notes that he or she has reviewed the AE/AESI/SAE and has provided an assessment 
of causality.  
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee.  An assessment of 
causality must be reported for every event, even when only limited data are available.   
The investigator may change his or her opinion of causality in light of follow-up information 
and provide an SAE follow-up report with the updated causality assessment. 
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The following additional guidance may be used to determine the relationship: 
Term 
Relationship Definition 
Related 
• 
Absence of alternative causes (or difficult to assign to an alternative cause) 
• 
AE follows a strong or reasonable temporal sequence from administration of study drug 
• 
AE could not be reasonably explained by the patient’s clinical state, concurrent disease, or 
other concomitant therapy administered to the patient 
• 
Occurrence of the AE follows a known response pattern to study drug 
• 
The AE is confirmed with a positive rechallenge or supporting laboratory data 
Not 
Related 
• 
An AE that is clearly due to extraneous causes (e.g., concurrent disease, concomitant 
medications, disease under study) 
• 
Occurrence of the AE does not follow a reasonable temporal sequence from administration 
of the study drug 
• 
AE does not follow a known pattern of response to study drug 
• 
AE does not reappear or worsen when study drug is restarted 
• 
An alternative explanation is likely but not clearly identifiable 
AE=adverse event. 
 
7.4 
Safety Monitoring Guidelines 
All laboratory values will be monitored by the sponsor medical monitor as well as the PI.  
The only exceptions are sBA, 
 and PK values, which will remain blinded until the 
Study MRX-701 database is locked. 
A complete overview of safety monitoring guidelines pertaining to clinical laboratory tests, 
including DILI and associated stopping criteria, can be found in Section 7.4.2. 
7.4.1 
Data Monitoring Committee 
Throughout this study, the safety of participants will be closely monitored by an unblinded 
DMC.  The DMC will comprise 
 
and will be governed by a DMC charter.  
Regular review will occur on a rolling basis approximately 
 until the DMC 
advises otherwise.  This includes an MRX-701 study meeting that alternates with the 
programwide DMC review (
).  Enrollment will not be paused for the review. 
In addition, ad hoc and/or offline DMC reviews will occur in the following situations:  
• 
 
 
 
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7.4.2.2 
Enhanced Monitoring Criteria for Liver Parameters 
Throughout this study, liver parameters will be monitored as part of standard of care as well 
as part of the schedule of assessments for this study.  In addition, to address the period of BA 
after HPE, specific criteria will be used to assess for liver injury and to determine whether 
study medication should be temporarily interrupted.  These values should be considered in 
the setting of the natural course of BA liver disease alongside clinician judgment.  Other 
causes of 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 judgment.   
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. 
The baseline values for the purpose of the liver safety monitoring differ according to the 
study period:  
• Weeks 0 to 8 of study:  Values taken within 1 week of the procedure (referred to here 
as pre-HPE value) 
• Week 8 onward:  Lower of the two values recorded during Week 2 and Week 6 visits 
of the study period (referred to here as post-HPE value).  In the case of abnormal liver 
parameters that are secondary to an identified cause not related to study treatment 
during Weeks 2 and 6, investigators and medical monitor can agree on the most 
appropriate alternative post-HPE value to be used for further monitoring.    
 
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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, participants’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national governmental 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 
The sponsor may suspend or terminate the study, or part of the study, at any time for any 
reason.  
If the study is terminated, the sponsor will notify all investigators to schedule safety 
follow-up visits for participants who at that time are still receiving treatment with 
maralixibat, or who have not yet had their safety follow-up visits. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, 
regulatory agencies, and IRBs/IECs are notified as appropriate.  
Should the study be temporarily suspended due to safety concerns, re-initiation will follow 
local laws and regulations. 
The discontinuation of a registered clinical study that has been posted to a designated public 
website will be updated accordingly. 
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9.2 
Investigator 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 participants 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 subinvestigators are 
provided to the study sponsor (or designee) before starting the study. 
If a potential research participant has a primary care physician, the investigator should, with 
the caregiver’s consent, inform them of the participant’s participation in the study. 
9.2.2 
Protocol Adherence and Investigator Agreement 
The investigator and any subinvestigators must adhere to the protocol as detailed in this 
document.  The investigator is responsible for enrolling only those participants 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/IEC and provide them with a detailed written explanation.  
Upon study completion, the investigator will provide the sponsor, IRB/IEC, and regulatory 
agency with final reports and summaries, as required by (inter)national regulations. 
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 
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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 laboratories) are not 
required to be collected in the CRF except for those that are directly relevant to the 
monitoring of an AE/SAE, or if a protocol-scheduled blood test has been performed at the 
local laboratory and not at the central laboratory; collection of other values may be requested 
by the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records that 
support the information recorded into the 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 by the 
investigator.  All data, except data entered directly into another platform (e.g., electronic, 
etc.), 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 will be 
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 the participant’s medical file, daily dosing records, and clinical laboratory reports. 
The ICF includes a statement by which the participant agrees to the sponsor’s 
monitor/auditor or its representatives, national or local regulatory authorities, or the IRB/IEC, 
having access to source data.  Non-study site personnel will not disclose any personal 
information or personal medical information. 
The study participant’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 an authorized representative of any regulatory agency (e.g., the United States 
Food and Drug Administration [FDA], European Medicines Agency [EMA], United 
Kingdom 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.  
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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, 
subsidiaries, or development partners such as a grant to fund ongoing research, compensation 
in the form of equipment, retainer for ongoing consultation or honoraria, any proprietary 
interest in intellectual property, and any significant equity interest in the sponsor or 
subsidiaries as defined in 21 Code of Federal Regulations (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 will be 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 as needed 
to perform monitoring and other site visits.  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. 
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 UK Medicines and 
Healthcare products Regulatory Agency, other regulatory authorities, the sponsor or its 
representatives, and the IRB/IEC 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. 
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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 
Any samples remaining after completing the specified tests may be used for 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 need 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. 
These remaining 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 participants 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 ICF.  
Identifiable samples can be destroyed at any time at the request of the participant.  During the 
conduct of the study, a participant can choose to withdraw consent to have specimens stored 
for future research.  However, withdrawal of consent regarding sample storage may not be 
possible after the study is completed.   
9.8 
Ethical Considerations 
9.8.1 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from the 
caregivers of all study participants prior to initiation of any study-related procedures 
including screening assessments.  All consent documentation must be in accordance with 
applicable regulations and ICH GCP requirements.  Each participant’s legally authorized 
representative (caregiver), as applicable, is requested to sign and date the participant ICF, 
after the caregiver has received and read (or been read) the written participant information 
and received an explanation of what the study involves, including but not limited to:  the 
objectives, potential benefits and risk, inconveniences, and the participant’s rights and 
responsibilities.  A copy of the ICF (i.e., a complete set of participant information sheets and 
fully executed signature pages) must be given to the participant’s caregiver, as applicable.  
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The ICF also includes a statement by which the participant’s caregiver agrees to the 
monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/IEC, to access applicable source data.  Signed ICFs must remain in 
each participant’s study file and must be available for verification at any time.  
The PI provides the sponsor with a copy of the ICF that was reviewed by the IRB/IEC and 
received their favorable opinion/approval.  A copy of the IRB/IEC’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 ICF (approved by the sponsor or their designee), relevant supporting 
information, and all types of participant recruitment information will be submitted to the 
IRB/IEC for review, and all must be approved prior to site initiation.  Study medication 
supplies will not be released until written IRB/IEC 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/IEC must approve any 
amendments to the protocol and revisions of all ICFs, unless there is a participant safety 
issue.  Protocol amendments will be filed with the appropriate regulatory agency(s) having 
jurisdiction over the conduct of the study. 
The IRB/IEC will be kept apprised of the progress of the study and of any changes made to 
the protocol.  The IRB/IEC will also be informed of any serious and significant AEs. 
9.9 
Study Site Initiation 
The investigator and any site personnel may not screen or enroll participants 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 
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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 the act must provide documentation of 
this fact. 
The confidentiality of participant 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 participants will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After a participant’s caregiver has consented for him or her to participate 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 
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 IRB/IECs that 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 participants’ identities.  
Participants are assigned a unique identifying number; however, their initials and dates of 
birth may also be collected, if permitted under local laws governing privacy.  
The results of studies containing participants’ unique identifying numbers, relevant medical 
records, and possibly initials and dates of birth, where allowed per local law, may be 
accessed by, and used in, other countries that may not afford the same level of protection that 
applies within the countries where this study is conducted.  Any such transfer would serve to 
support regulatory submissions, conduct new data analyses to publish or present the study 
results, or answer questions asked by regulatory or health authorities. 
The study monitor, other authorized representatives 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 
participants 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. 
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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 Web sites, or other disclosure of the study results, in printed, 
electronic, verbal, or other form. 
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Wong ZH, Davenport M. What happens after Kasai for biliary atresia? A European 
multicenter survey. Eur J Pediatr Surg 2019;29:1–6. 
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Appendix 3 
List of Potential Laboratory Analytes 
CBC with 
Differential a 
Hematocrit 
Hemoglobin 
MCV, MCH, MCHC 
Red blood cells 
Platelets 
White blood cells 
WBC differential 
(% and absolute) 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Reticulocyte count 
Red blood cell 
morphology 
Coagulation a 
aPTT 
INR 
PT 
Clinical Chemistry b 
Albumin 
ALP 
Amylase 
ALT 
AST  
Bicarbonate 
Bilirubin, indirect 
(unconjugated) 
Bilirubin, direct 
(conjugated) 
Total serum bilirubin  
Blood urea nitrogen  
Calcium 
Chloride 
Creatinine 
GGT  
Glucose 
Lipase 
LDH 
Phosphate 
Potassium 
Sodium 
Total protein 
Uric acid 
Measured serum 
osmolality c 
 
Cholestasis 
Biomarkers d, b 
Total serum bile acids  
 
 
Lipid Soluble Vitamins d 
25-hydroxy vitamin D 
Retinol/Vitamin A 
Retinol-binding proteine  
α-Tocopherol/Vitamin E 
Vitamin K f 
 
Lipid panel 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Triglycerides 
Urinalysis c 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Occult blood and cells 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic 
examination 
Oxalate 
Creatinine 
Microscopy 
 
Maralixibat Levels 
(PK) 
Maralixibat in plasma 
 
Other c 
HAV IgM 
HBsAg 
HCV Ab 
HCV RNA 
CMV IgM 
EBV Ab  
AFP  
CRP 
AFP=alpha-fetoprotein; ALP=alkaline phosphatase; 
aPTT=activated partial thromboplastin time; CBC=complete blood count; CMV=cytomegalovirus; CRP=C-
reactive protein; GGT=γ-glutamyltransferase; HBsAG=hepatitis B surface antigen; HCV=hepatitis C virus; 
HDL-C=high-density lipoprotein cholesterol; LDH=lactate dehydrogenase; LDL-C=low-density lipoprotein 
cholesterol; PT=prothrombin time; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular 
hemoglobin concentration; MCV=mean corpuscular volume; 
 
PK=pharmacokinetic; WBC=white blood cell. 
a  CBC and coagulation may be collected from those performed as part of standard of care/local laboratory if 
blood is drawn within 3 days of the clinic visit.  In such case, the investigator or designee will be asked to 
provide the reference ranges as applicable.  
b 
Clinical chemistry and serum bile acid samples must always be sent to the central laboratory. 
c  Performed when clinically indicated. 
d  Blood samples for the analysis of cholestasis biomarkers and lipid soluble vitamins should be drawn prior 
to administration of vitamin supplementation and as much as is possible, approximately 2 hours after food 
or formula (water intake is permitted if necessary but not recommended).  Other biomarkers (e.g., 
lysophosphatidic acid) may be measured.  At the discretion of the sponsor, samples will be collected and 
appropriately stored for subsequent analysis, as needed. 
e    Performed when clinically indicated or if clinically significant low serum retinol levels. 
f     Performed when clinically indicated or if clinically significant abnormal INR. 
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