Conditions: Biliary Atresia
Keywords: Biliary Atresia Kasai Biliary Tract Diseases Bile Duct Diseases Congenital Abnormalities
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 75
Healthy volunteers: no

Brief summary:
A study to evaluate the efficacy and safety of maralixibat in infants with Biliary Atresia (BA) after Hepatoportoenterostomy (HPE, also known as the Kasai procedure).

Detailed description:
This is a double-blind randomized, placebo-controlled study in subjects with Biliary Atresia with a primary endpoint at Week 26 followed by long-term open-label period during which all subjects will receive maralixibat to Week 104.

Arms:
arm 1: The double-blind period comprised of 4-8 weeks of dose escalation followed by 18 - 22 weeks of stable dosing treatment, after which participants were transferred to the open-label arm. arm 2: The double-blind period comprised of 4-8 weeks of dose escalation followed by 18 - 22 weeks of stable dosing treatment, after which participants were transferred to the open-label arm. arm 3: The Open-Label period comprised of 4-8 weeks of dose escalation followed by 70 - 74 weeks of stable dosing treatment. During the OLE, all participants, regardless of treatment assignment in the double-blind period, received maralixibat.

Interventions: intervention 1: Maralixibat intervention 2: Placebo
Intervention descriptions: intervention 1: A small molecule inhibitor of the ileal bile acid transporter (IBAT) intervention 2: Identical to maralixibat except for the active drug substance

Protocol document:
Prot_000.pdf: 
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
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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 
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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 
 
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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  
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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). 
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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. 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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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. 
Number: CLIN-000163               Version: 6.0               Status: Approved    Approved Date: 10 May 2023
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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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SAP_001.pdf: 
MRX-701 
Statistical Analysis Plan 
V1.0 
CONFIDENTIAL 
Page 1 of 63 
STATISTICAL ANALYSIS PLAN 
Study 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 
Name of Test Drug: 
Maralixibat 
Study Number: 
MRX-701 
Protocol Version (Date): 
Protocol Version 6 (25 April 2023) 
Analysis Type: 
Primary and Final Analysis  
Analysis Plan Version: 
1.0 
Analysis Plan Date: 
02 November 2023 
Analysis Plan Author: 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
   
 
 
 
 
 
   


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MRX-701 
Statistical Analysis Plan 
V1.0 
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Page 4 of 63 
Table of Contents 
Document History ........................................................................................................................... 3 
Table of Contents ............................................................................................................................ 4 
List of Tables .................................................................................................................................. 6 
List of Figures ................................................................................................................................. 6 
List of Abbreviations ...................................................................................................................... 7 
1. 
OVERVIEW ....................................................................................................................... 9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 9 
2.1. 
Double-Blind Period Study Objectives ......................................................................... 9 
2.1.1. Primary Objective ..................................................................................................... 9 
2.1.2. Secondary Objectives ................................................................................................ 9 
2.1.3. Exploratory Objectives ............................................................................................ 10 
2.2. 
Open-Label Extension Period Study Objectives ......................................................... 10 
2.3. 
Study Endpoints .......................................................................................................... 10 
2.3.1. Safety Endpoints ..................................................................................................... 10 
2.3.2. Efficacy Endpoints .................................................................................................. 11 
 Primary Efficacy Endpoint ............................................................................. 11 
 Secondary Efficacy Endpoints ........................................................................ 11 
 Exploratory Efficacy Endpoints ...................................................................... 11 
3. 
OVERALL STUDY DESIGN AND PLAN ..................................................................... 12 
3.1. 
Overall Design ............................................................................................................ 12 
3.2. 
Sample Size and Power ............................................................................................... 14 
3.3. 
Study Population ......................................................................................................... 14 
3.4. 
Treatments Administered ............................................................................................ 14 
3.5. 
Blinding and Unblinding............................................................................................. 14 
3.6. 
Schedule of Assessments ............................................................................................ 15 
4. 
STATISTICAL ANALYSES AND REPORTING .......................................................... 20 
4.1. 
Introduction ................................................................................................................. 20 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 21 
4.3. 
Primary Analysis ......................................................................................................... 21 
4.4. 
Final Analysis ............................................................................................................. 21 
5. 
ANALYSIS POPULATIONS .......................................................................................... 21 
6. 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSES ........................... 22 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 22 
6.1.1. Baseline ................................................................................................................... 22 
6.1.2. Adjustments for Covariates ..................................................................................... 22 
6.1.3. Multiple Comparisons ............................................................................................. 22 
6.1.4. Handling of Dropouts or Missing Data ................................................................... 23 
 
 
 


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 MMRM Analysis Method ............................................................................... 24 
 Multiple Imputation Methods ......................................................................... 25 
 Missing
 Scores .................................................................................. 29 
 Missing Adverse Event Severity/Relationship ............................................... 29 
6.1.5. Analysis Visit Windows .......................................................................................... 30 
6.1.6. Investigative Sites ................................................................................................... 31 
6.1.7. Treatment Period Definitions .................................................................................. 31 
6.1.8. Derived Variables .................................................................................................... 31 
6.1.9. Data Adjustments/Handling/Conventions ............................................................... 35 
7. 
STUDY PARTICIPANTS AND DEMOGRAPHICS ...................................................... 38 
7.1. 
Disposition of Participants and Withdrawals .............................................................. 38 
7.2. 
Protocol Violations and Deviations ............................................................................ 39 
7.3. 
Demographics and Baseline Characteristics ............................................................... 39 
7.4. 
Prior and Concomitant Medications/Therapies .......................................................... 40 
7.5. 
Exposure and Compliance .......................................................................................... 41 
8. 
EFFICACY ANALYSIS .................................................................................................. 41 
8.1. 
Primary Efficacy Analysis .......................................................................................... 41 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 42 
8.3. 
Sensitivity and Supportive Analyses for Primary and Secondary Endpoints ............. 43 
8.4. 
Adjustment for Multiplicity ........................................................................................ 44 
8.5. 
Exploratory Efficacy Analysis .................................................................................... 44 
9. 
SAFETY AND TOLERABILITY ANALYSIS ............................................................... 45 
9.1. 
Adverse Events ........................................................................................................... 46 
9.1.1. Adverse Events That Led to Discontinuation of Study Drug .................................. 47 
9.1.2. Deaths and Serious Adverse Events ........................................................................ 47 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 47 
9.3. 
Vital Signs and Weight/Height Measurements ........................................................... 47 
9.4. 
Electrocardiograms ..................................................................................................... 47 
9.5. 
Concomitant Medications/Therapies .......................................................................... 48 
10. 
OTHER PLANNED ANALYSIS ..................................................................................... 48 
10.1. Healthcare Utilization ................................................................................................. 48 
10.2. Pharmacokinetic Analyses .......................................................................................... 48 
11. 
Changes from Protocol Planned Analysis......................................................................... 48 
12. 
REFERENCES ................................................................................................................. 49 
13. 
TABLES, LISTINGS, AND FIGURES ........................................................................... 51 
13.1. Planned Table Descriptions ........................................................................................ 51 
13.1.1. Participant Data ....................................................................................................... 52 
13.1.2. Efficacy Data ........................................................................................................... 52 
 
 
 
 


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13.1.3. Safety Data .............................................................................................................. 56 
13.1.4. Other Data ............................................................................................................... 57 
13.2. Planned Figure Descriptions ....................................................................................... 58 
13.2.1. Efficacy Data ........................................................................................................... 58 
13.3. Planned Listing Descriptions ...................................................................................... 58 
13.4. Standard Layout for all Tables, Listings, and Figures ................................................ 59 
Appendix 1 
Listing of Safety and Efficacy Laboratory Analytes .......................................... 61 
Appendix 2 
Listing of Lipid-Soluble Vitamin Deficiency Events ......................................... 63 
 
List of Tables 
Table 1 
Schedule of Assessments: Screening and Double-Blind Period ................................. 16 
Table 2 
Schedule of Assessments:  Open-Label Extension and Follow-Up Periods ............... 18 
Table 3 
Analysis Visit Windows for Parameters Collected at 
  
 .......................................................................................................................... 30 
Table 4 
Analysis Visit Windows For Parameters Collected at 
 .... 30 
Table 5 
Participant Data Summary Tables .............................................................................. 52 
Table 6 
Efficacy Data Summary Tables .................................................................................. 52 
Table 7 
Safety Data Summary Tables ...................................................................................... 56 
Table 8 
Other Data Summary Tables ....................................................................................... 57 
Table 9 
Efficacy Data Summary Figures ................................................................................. 58 
 
List of Figures 
Figure 1 
Study Design ............................................................................................................... 13 
Figure 2 
Standardized Layout ................................................................................................... 60 
 


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List of Abbreviations 
Abbreviation 
Definition 
7αC4 
7α-hydroxyl-4-cholesten-3-one 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate transferase 
APRI 
AST-to-platelet ratio index 
ATC 
anatomical therapeutic chemical 
BA 
biliary atresia 
BID 
twice daily 
BL 
baseline 
BMI 
body mass index 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CSR 
clinical study report 
 
 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
EM 
expectation-maximization 
EMA 
European Medicine Agency 
EOT 
end of treatment 
ET 
early termination 
FDA 
US Food and Drug Administration 
 
 
GGT 
gamma-glutamyl transpeptidase 
HPE 
hepatoportoenterostomy 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
INR 
international normalized ratio 
IP 
investigational product 
IRT 
interactive response technology 
ITT 
intent to treat 
LLOQ 
lower limit of quantitation 
LS 
least squares 
LSV 
lipid-soluble vitamin 
MAR 
missing at random 
MCMC 
Markov-Chain Monte-Carlo 
MI 
multiple imputation 


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Page 8 of 63 
Abbreviation 
Definition 
MMRM 
mixed-effects model for repeated measurements 
MNAR 
missing not at random 
NT 
not treated 
OLE 
open-label extension 
PDGP 
protocol deviation guidance plan 
 
 
PELD 
Pediatric End-Stage Liver Disease 
PG 
propylene glycol 
PK 
pharmacokinetic 
PP 
Per protocol 
PT 
preferred term 
Q1 
first quartile 
Q3 
third quartile 
QD 
once daily 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
REML 
restricted maximum likelihood 
RSS 
Royal Statistical Society 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acid 
SD 
standard deviation 
SE 
standard error 
SI 
International System of Units 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TIP 
target IBAT population 
TLFs 
Tables, Listings, and Figures 
TSB 
total serum bilirubin 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
ULOQ 
upper limit of quantitation 
VBL 
baseline visit 
WHO 
World Health Organization 
WHO-DD 
World Health Organization - Drug Dictionary 
 


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Statistical Analysis Plan 
V1.0 
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Page 9 of 63 
1. 
OVERVIEW 
This statistical analysis plan (SAP) describes the planned analysis and reporting for 
Study MRX-701 (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), Protocol Version 6, dated 25-Apr-2023.  Reference materials for this 
SAP include the protocol and the accompanying sample data collection documents.  Operational 
aspects related to collection and timing of planned clinical assessments are not repeated in this 
SAP unless relevant to the planned analysis. 
The structure and content of this SAP provide sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials (ICH 1998).  All work planned and reported for this SAP will follow internationally 
accepted guidelines, published by the American Statistical Association (ASA 2018) and the 
Royal Statistical Society (RSS 2014), for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts.  Also, post hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any post hoc 
or unplanned exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Study MRX-701. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Double-Blind Period Study Objectives 
2.1.1. Primary Objective 
To evaluate the efficacy of maralixibat on biliary drainage after hepatoportoenterostomy (HPE) 
in participants with biliary atresia (BA). 
2.1.2. Secondary Objectives 
The secondary objectives are: 
• 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 
 










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Page 14 of 63 
3.2. 
Sample Size and Power 
Estimates for placebo response and variance are drawn from Bezerra et al. (2014).  Under the 
assumption of no change over time in total bilirubin levels in the placebo group, a standard 
deviation of 3 mg/dL and a sample size of 33 participants per treatment arm provides 80% power 
to detect an expected reduction in total bilirubin compared with placebo of approximately 
30% or 2.1 mg/dL by Week 26 of treatment, at the 2-sided alpha-level of 0.05, with use of a 
1:1 randomization scheme.  With allowance for a 10% attrition rate, 72 participants (36 per 
group) were planned for enrollment into the study. 
3.3. 
Study Population 
The study population comprises male and female participants with a body weight ≥2500 g 
(before or during the screening period) who are ≥21 days and <90 days of age at time of HPE or 
Kasai procedure.  For a complete list of inclusion and exclusion criteria, refer to Sections 4.1 and 
4.2 in the protocol, respectively.  
3.4. 
Treatments Administered 
Participants are randomized for the double-blind portion of the study to one of two treatment 
groups: 
• Maralixibat 
• Placebo 
All participants who enter the OLE portion of the study receive open-label maralixibat. 
3.5. 
Blinding and Unblinding 
All participants, investigators, and study personnel involved in the conduct of the study, 
including data management, are blinded to treatment assignment. 
The treatment assignment was not to be unblinded during the study except in emergency 
situations where the identification of the study drug is required for further treatment of the 
participant.  The Investigator was to make an effort to contact the medical monitor before 
unblinding or as soon as possible after the Investigator has been unblinded without revealing the 
treatment assignment to the medical monitor.  In any event, the medical monitor and Sponsor 
were to be informed about the code break as soon as possible. 
If the treatment assignment was unblinded, the date and the signature of the person who was 
unblinded and the reason for unblinding was to be recorded in the source documents.  Upon 
breaking the blind, the participant was to be withdrawn from the study but was to be followed for 
safety purposes.  Unblinding was to be processed through the interactive response technology 
(IRT) system.  
Data that may potentially unblind treatment assignment (i.e., maralixibat serum concentrations, 
treatment allocation, postbaseline sBA levels) are to be handled with special care during the data 


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cleaning and review process.  Prior to unblinding, any data that may potentially unblind study 
site personnel or study team personnel are to be presented as blinded information or otherwise 
will not be made available.  If applicable, unblinded data were to be made available to quality 
assurance representatives for the purposes of conducting independent audits. 
3.6. 
Schedule of Assessments 
A detailed schedule of assessment for the study, as presented in the protocol, is provided in 
Table 1 for the double-blind period and in Table 2 for the OLE period.  










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4. 
STATISTICAL ANALYSES AND REPORTING 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed p rimarily using SAS (release 9.4 or higher).  
Continuous (quantitative) variable summaries will include the number of participants with 
nonmissing values (n), mean, standard deviation (SD) and/or standard error (SE) if appropriate, 
median, Q1, Q3, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
participants who are in the particular category for each possible value.  In general, the 
denominator for the percentage calculation will be based upon the total number of participants in 
each treatment group with available data in the analysis population, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data.  Measures of location (mean and median) will 
be reported to 1 degree of precision more than the observed data, and measures of spread (i.e., 
SD or SE) will be reported to 2 degrees of precision more than the observed data.  Confidence 
intervals (CIs) are reported to the same degree of precision as parameter they are calculated for. 
The minimum and maximum values for derived and select observed values will be reported as 
follows, with measures of location and spread following the above rules.  Derived values for 
corrected sodium (mEq/L) and PELD scores will be presented as integers.  Derived values for 
summary and total scale scores will be presented to 1 decimal place.  sBA levels (total 
and subspecies) and derived values of height, weight, and BMI z-scores, APRI, retinol:RBP 
molar ratio (mol/mol), and ratio of αtocopherol to the sum of cholesterol and triglycerides (mg/g) 
will be reported to 2 decimal places. 
Percentages will be presented to 1 decimal place, unless otherwise specified.  Where the number 
of participants in a particular category is zero, a percentage (i.e., 0.0%) will not be displayed. 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a p-value of <0.05 will be considered statistically significant.  Corresponding 95% 
CIs will be presented for statistical tests. 
A p-value of ≤0.10 but ≥0.05 will be considered evidence of a trend. 
To control for the overall type I error rate, hierarchical testing based on a fixed sequence 
procedure will be used (see Section 6.1.3).  If statistical significance is declared for the primary 
efficacy analysis, formal hypothesis testing will be done for the secondary efficacy endpoints in 
the prespecified sequence until a nonsignificant result is reached.  All other p-values from 
secondary endpoints, after a nonsignificant p-value is reached, will be considered nominal and 
will be interpreted with appropriate caution when considering the extent to which results from 
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By-participant listings will be presented for all participants in the Safety Analysis Set and sorted 
by participants identification (ID) number, visit date, and time (if applicable).  Data collected on 
log forms, such as adverse events (AEs), will be presented in chronological order for each 
participant.  Age, sex, race, and ethnicity will be included in the listings, as space permits. 
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
A DMC will be involved in the management of this study.  DMC meetings will be held 
periodically for the duration of the study.  The purpose of the DMC is to review the progress of 
the study, with regard to safety, and to make recommendations to stop or modify the study if 
safety concerns are identified.  In addition to scheduled meetings, the DMC will convene for 
ad hoc meetings in case of any safety concerns arising during the conduct of the study. 
Further details regarding the DMC can be found in the DMC Charter, which was available prior 
to the enrollment of the first participant.  There is no study stop planned based on the efficacy 
results during the study, and no alpha spending will occur prior to the Primary Analysis. 
4.3. 
Primary Analysis  
A single and formal Primary Analysis will be performed after the last participant has completed 
Week 26 or prematurely discontinued the study.   
4.4. 
Final Analysis  
The final analysis will be performed after all participants have completed or prematurely 
discontinued the study and will focus on the Week 104 endpoints from the OLE.   
5. 
ANALYSIS POPULATIONS 
The following analysis populations are planned for this study: 
• Safety Population:  The Safety Population will consist of all participants who 
receive at least 1 dose of study drug. 
• Intent-To-Treat (ITT) Population:  The ITT Population will consist of all 
randomized participants. 
• Per-Protocol (PP) Population:  The PP Population will consist of all participants 
in the ITT Population who receive at least 1 dose of study drug and do not have 
any important protocol violations or deviations that have a potential impact on the 
efficacy analysis.  Important protocol violations/deviations will be identified prior 
to database lock. 
• Target IBAT Population:  The target IBAT population (TIP) will consist of 
participants who do not normalize total bilirubin in the early stages of the study.  
The criteria for selection into this population will be determined based on the 


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placebo-treated participants and natural history data and then applied to the 
maralixibat-treated participants.  
Membership in the analysis populations will be determined prior to database lock except for the 
TIP, which requires unblinded data by its definition. 
6. 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSES 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
In general, baseline values are defined as data measured or collected at the baseline visit, VBL 
(Day 0), before the first dose of study drug is administered.  If data are not measured or collected 
at the baseline visit, then the last nonmissing measurement before receiving the first dose of 
study drug is used as the baseline value. 
Baseline and all postbaseline sBA samples are assayed at Frontage Laboratories. 
For liver-biochemistry laboratory parameters (i.e., ALT, AST, ALP, total bilirubin, direct 
bilirubin, GGT, and albumin) baseline is defined as the average of data collected post-Kasai 
between and including Screening and VBL (Day 0), or the last nonmissing measurement before 
receiving the first dose of study drug if only one value is available.  Predose measurements 
obtained from a local laboratory will be used only if no other data are available.  For the derived 
noninvasive fibrosis markers of APRI and PELD, the same (derived/average) liver-biochemistry 
baseline value will be used. 
6.1.2. Adjustments for Covariates 
Efficacy variables that are continuous measures assessed over time will be analyzed using a 
mixed-effects model for repeated measures (MMRM) with change from baseline as the 
dependent variable and fixed, categorical effects of site, treatment group, analysis visit, and 
treatment group-by-visit interaction as well as the continuous, fixed covariates of baseline and 
baseline-by-visit interaction. 
No other covariates will be included in the analyses of the efficacy endpoints. 
6.1.3. Multiple Comparisons 
The type I error rate of α=0.05 will be maintained for the study by using sequential (hierarchical) 
testing for primary and secondary efficacy endpoints.  
The testing will be done in the following order: 
1. Primary:  mean change in TSB from baseline through Week 26 
2. Secondary:  proportion of participants with TSB levels <2 mg/dL through Week 26 
3. Secondary:  mean change in total sBA levels from baseline through Week 26 


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4. Secondary:  proportion of participants observed to have a liver-related clinical event, 
including liver transplantation, liver decompensation (hepatic encephalopathy, variceal 
bleeding, new persistent ascites), or death through Week 26 
5. Secondary:  proportion of participants undergoing liver transplantation or death through 
Week 26 
6. Secondary:  proportion of participants observed to develop clinically evident portal 
hypertension defined as splenomegaly (spleen size >2 cm below the costal margin 
palpated on physical examination) and thrombocytopenia (platelet count <150 x 109/L) or 
clinically evident ascites or endoscopic evidence of esophageal or gastric varices through 
Week 26 
7. Secondary:  proportion of participants with TSB levels ≤1.2 mg/dL at Week 26 
8. Secondary:  proportion of participants with sBA levels ≤40 mmol/L at Week 26 
 
Because the testing is sequential, the type I error rate of α=0.05 is maintained.  Failure at any 
stage in the sequence implies no type I error control for the additional subsequent tests.  All 
p-values for each comparison without adjustments will be provided in the summary tables for 
informational purposes. 
6.1.4. Handling of Dropouts or Missing Data 
Although all possible efforts will be made to ensure that participants stay in the study and that all 
data are collected as scheduled, the occurrence of missing data cannot be completely eliminated. 
The primary analysis population for all efficacy analyses will be the ITT Population.  For the 
analysis of primary efficacy endpoint and the secondary efficacy endpoint of mean change in 
total sBA, several methods will be used to handle missing data for TSB, including:  
• MMRM 
• multiple imputation (MI) using standard missing at random (MAR) approach 
• MI using tipping-point approach 
The MMRM method will be used as the primary analysis method on all continuous, repeated 
efficacy measures.  Sensitivity analyses using the 2 MI methods will be performed on the 
primary efficacy endpoint to assess the robustness of alternate imputation assumptions.  
For the secondary endpoint proportion of TSB level < 2 mg/dL, the MI generated for the primary 
endpoint will be used to impute the through Week 26.  
The above procedures are described in the below subsections, along with the handling of missing 
individual laboratory data and AE severity and relationship to study drug.  


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MMRM Analysis Method 
Efficacy variables that are continuous measures assessed over time will be analyzed using a 
MMRM model as the primary analysis method, with change from baseline as the dependent 
variable and fixed, categorical effects of site, treatment group, visit, and treatment group-by-visit 
interaction as well as the continuous, fixed covariates of baseline and baseline-by-visit 
interaction.  Site is used as a surrogate for HPE surgeon. 
The MMRM method has been demonstrated extensively as an appropriate choice for the primary 
analysis in longitudinal confirmatory clinical trials with continuous endpoints (Mallinckrodt et 
al. 2008).  This analysis method, which is from a broader class of direct-likelihood analyses 
methods, makes use of fully and partially observed data sequences from individual participants 
by estimating the covariance between data from different time points (Molenberghs and 
Kenward 2007).  Further, it is often useful to implement MMRM using an unstructured approach 
to modeling both the treatment-by-time means and the variances and covariances, leading to 
what is essentially a multivariate normal model wherein treatment group means at the primary 
time point are adjusted to reflect both the actual observed data and the projected outcomes from 
the participants with missing data (Cnaan et al. 1997; Molenberghs et al. 2004; Molenberghs and 
Kenward 2007). 
As a direct likelihood method, the MMRM method is a preferred approach for handling missing 
data in such designs and will be used as the primary analysis method for all efficacy endpoints 
where assessments are made over time.  MMRM is a full multivariate model in nature, which 
avoids potential bias as a predetermined model and operates in a more general MAR framework 
(Mallinckrodt et al. 2001).  Data are considered MAR if, conditional upon the independent 
variables in the analytic model, the missingness depends on the observed outcomes of the 
variable being analyzed but does not depend on the unobserved outcomes of the variable being 
analyzed.  This assumption implies that the behavior of the post-dropout observations can be 
predicted from the observed variables and therefore that treatment effect can be estimated 
without bias using the observed data (EMA 2010).  For studies of missing data in a controlled 
clinical trial setting, MAR is usually considered as a plausible underlying missing mechanism 
(Molenberghs and Kenward 2007; Mallinckrodt et al. 2008, 2013; Siddiqui et al, 2009).  The 
assumption of MAR is often reasonable because, particularly in longitudinal studies wherein the 
evolution of treatment effects is assessed by design over time, the observed data and the models 
used to analyze them can explain much of the missingness (Little et al. 1987; Verbeke and 
Molenberghs 2000).  This point may be especially relevant in well-controlled studies, in which 
extensive efforts are made to observe all outcomes and factors that influence them while 
participants are following protocol-defined procedures.  Thus, longitudinal clinical trials by their 
very design aim to reduce the amount of missing not at random (MNAR) data (missingness 
explained by unobserved responses), thereby increasing the plausibility of MAR (Mallinckrodt et 
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In most randomized clinical trials that collect data over time, the great majority of missing data 
follow a monotone pattern.  That is, once a participant has missing data for some visit, data will 
be missing for all subsequent visits.  Typically, there is also a small amount of nonmonotone 
missing data (i.e., some participants have missing values for intermediate visits, but have 
nonmissing data at subsequent visits).  
The following 2 MI analysis models, one based on the standard MAR approach and the other 
based on the MNAR approach, will be used to examine robustness of the primary analysis 
results.  
Standard MAR Imputation 
The MAR imputation model will impute missing values using a regression-based multiple 
imputation model (Little and Yau 1996).  For participants with complete data up to a particular 
timepoint (e.g., laboratory results for the primary endpoint and the secondary endpoint of mean 
change in total sBA), a multiple regression model will be fit that includes the outcome at that 
time point as the dependent variable and observed data (e.g., outcomes at previous time points, 
treatment, and baseline) as independent variables.  Separate models will be similarly constructed 
for each time point.  With use of these regression models, a missing value for a participant at a 
particular time point will be imputed as a draw from the predictive distribution given the 
outcomes at previous time points (some possibly imputed), treatment group, etc.  This process 
will be repeated a given number of times (as specified below), resulting in the same number of 
complete analysis data sets.  The MMRM analyses will be performed separately for each of the 
completed analysis data sets, and the results will be combined into one multiple imputation 
inference (Little and Yau 1996; Schafer 1997).  This strategy is appropriate for data sets that 
have a monotone missing data pattern.  If the data set does not precisely have this pattern, a 
monotone data augmentation method, as described below in Step 1, will be used to impute the 
small amount of missing data that is required to make the missing data pattern monotone before 
applying the MI algorithm described above. 
Multiple imputation based on a standard MAR imputation approach will be performed in SAS 
with use of a general three-step approach: 
Step 1:  If the data have a non-monotone pattern of missingness, then a monotone data 
augmentation method using Markov-Chain Monte-Carlo (MCMC) will be used to impute data 
that are missing and required to make the missing data pattern monotone.  Twenty datasets with 
a monotonic missing pattern will be generated.  This method will use a noninformative Jeffreys 
prior to derive the posterior mode from the expectation-maximization (EM) algorithm as the 
starting values for the MCMC method.  Intermittent missing values will be imputed using the 
MCMC method assuming a multivariate normal distribution over all variables included in the 
imputation model (i.e., treatment group, baseline, and each postbaseline visit).  The MCMC 
statement of the MI procedure in SAS (PROC MI) will specify the CHAIN=MULTIPLE option, 
so that the procedure uses multiple chains and completes the default 200 burn-in iterations before 
each imputation, and the IMPUTE=MONOTONE option to create the 20 partially imputed 
datasets with a monotone missing pattern.  The seed of the pseudorandom number generator used 
to randomly generate imputations for the missing values in Step 1 is 
 










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If >1 assessment occurs within a single visit window, then the analysis will use the assessment 
closest to the target day.  If 2 assessments within the same visit window are equidistant from the 
target day, then the analysis will use the later assessment. 
Efficacy assessments performed >7 days after study drug was stopped will be excluded from 
efficacy analyses.  
6.1.6. Investigative Sites 
An investigative site is defined as a single principal investigator (including subinvestigators) who 
enrolls participants for the study.  If an investigator has multiple practice locations, these 
locations are considered a single investigative site. 
There is the potential that a participant could be transferred to a principal investigator who did 
not enroll the participant.  Unless otherwise specified, the investigative site of the enrolling 
investigator will be used for the unique participant ID.  
The primary presentations and analyses will be based on data pooled across investigative sites.  
6.1.7. Treatment Period Definitions 
• “Dose Escalation Period” is defined for analysis purposes as the period of time between 
the first dose of study drug and the end of study Week 8 (i.e., through the Week 8 visit 
date). 
• “Stable Dosing Period” is defined for analysis purposes as the period of time between 
the beginning of Week 9 (i.e., Week 8 participant contact date plus 1 day) and the 
end-of-treatment (EOT) visit (inclusive). 
6.1.8. Derived Variables 
Select derived variables will be rounded for presentation purposes (see Section 4.1). 
• Age (days) at baseline = date of first dose – date of birth + 1 
• Date of Birth:  The reported date of birth will be used. 
• UDCA usage at baseline:  A participant with reported use of ursodeoxycholic acid 
(UDCA), based on ATC Class Level 5 (chemical substance), with a start date on or prior 
to the first dose of study drug and either ongoing or with a stop date on or after the first 
dose of study drug would be considered as using UDCA at baseline. 


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• Time since original diagnosis of BA (days) = (date of first dose – date of original 
diagnosis of BA)  
• Time since HPE (days) = (date of first dose – date of HPE)  
• Change from baseline = postbaseline value at time point – value at baseline 
• % Change from baseline = 100 x change from baseline / value at baseline 
• APRI = 100 x  
𝐴𝐴𝐴𝐴𝐴𝐴 ቀ𝑈𝑈
𝐿𝐿ቁ / 𝐴𝐴𝐴𝐴𝐴𝐴 𝑈𝑈𝑈𝑈𝑈𝑈 ቀ𝑈𝑈
𝐿𝐿ቁ
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ൬103
µ𝐿𝐿൰  , where ULN = upper limit of normal 
• Ratio of Alpha Tocopherol to the sum of Cholesterol and Triglycerides (mg/g) = 
1000 x alpha tocopherol (mg/dL) / [cholesterol (mg/dL) + triglycerides (mg/dL)] 
For alpha tocopherol concentrations reported as below the minimum quantitation limit, 
half of the minimum quantitation limit is used in the calculation. 
• Corrected Sodium (mEq/L) = sodium (mEq/L) + (0.002 x triglycerides [mg/dL]) 
• PELD Scores 
PELD score will be calculated for children under 12 years of age at the baseline visit.   
PELD Score = 4.80 × ln(total bilirubin [mg/dL]) + 18.57 × ln(INR) – 6.87 × ln(albumin 
[g/dL]) + 4.36 (if patient <1 year: scores for patients listed for liver transplantation before 
the patient's first birthday continue to include the value assigned for age (<1 year) until 
the patient reaches the age of 24 months) + 6.67 (if the patient has growth failure, where 
growth failure is defined as a weight z-score < -2.00) 
Laboratory values in the PELD equation that are <1.0 will be set to 1.0 for the calculation 
of the PELD score. 
Scores from PELD will be summarized. 
• Treatment Duration (days) =  
Date of last dose of study drug – Date of first dose of study drug + 1 day – 
Prescribed dose interruptions 
For participants who are missing the date of last dose of study drug, the last known 
contact date will be used in the calculation of treatment duration.  Prescribed dose 
interruptions are captured as gaps in dates between log lines in the study drug 
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• Head Circumference Z-Scores 
Head circumference z-scores are based on a participant’s sex and age at each scheduled 
visit. The World Health Organization (WHO) growth charts will be used to derive 
z-scores (WHO 2000). 
 
• MUAC Z-Scores 
MUAC z-scores are based on a participant’s age at each scheduled visit and can be 
calculated only from age 2 months on (Abdel-Rahman et al. 2017). 
• Skinfold Thickness Z-Scores 
Skinfold thickness z-scores are based on a participant’s sex and age at each scheduled 
visit and can be calculated only from age 3 months based on WHO charts 
• Length of Stay for Hospitalizations (days) = Date of discharge – Date of admission + 
1 day 
• Time to Liver-Associated Event (days) = Date of liver-associated event – Date of first 
dose of study drug 
 
6.1.9. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings.  Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included in the data listings. 
All p-values will be displayed in four decimals and rounded using standard scientific notation 
(e.g., 0.xxxx).  If a p-value less than 0.0001 occurs, it will be shown in tables as <0.0001. 
Participant Age 
The age of a participant at screening will be used to determine the age-specific module or 
instrument for the appropriate assessment (i.e., 
).  The same module or instrument will be 
completed for the duration of the study, regardless of subsequent birthdays throughout the study. 
Adverse Event and Concomitant Medication Coding 
AEs will be coded using the Medical Dictionary for Regulatory Activities using (MedDRA) 
version 26.1.  Prior and concomitant medications will be coded using World Health Organization 
Drug Dictionary (WHO-DD Enhanced version September 2019), Anatomical Therapeutic 
Chemical (ATC) level 2 for ATC class and level 5 (clinical substance) for preferred term. 
Prior and Concomitant Treatment Definition and Data Handling 
A concomitant treatment refers to all treatment, including concomitant therapies as well as herbal 
treatments, vitamins, behavioral treatment, and nonpharmacological treatment such as 
psychotherapy taken between the dates of the first dose of study drug and the end of the 
participant’s participation in the study, inclusive.  For participants not continuing into the OLE, 


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this period of participation is from the first day of screening through the last contact.  For 
participants continuing into OLE, this period is from the first day of screening through the Week 
104 visit. 
Treatments that started before the first dose of study drug are considered prior treatments 
whether or not they were stopped prior to the first dose of study drug.  Any treatment continuing 
or starting after the first dose of study drug will be considered as concomitant.  If a treatment 
starts prior to the first dose of study drug and continues after the first dose of study drug, the 
medication will be considered as both prior and concomitant. 
TEAE Data Handling 
If an event worsens in severity during the study, the lower grade event is marked as “Not 
recovered/not resolved” on the AE case report form (CRF) and an end date entered.  A new event 
is recorded on the AE CRF with a start date that matches the end date, and the grading increases 
(e.g., from Grade 2 to Grade 3).  If an event becomes serious, the date that the event became 
serious is recorded on the AE CRF as the End Date of that AE and the Start Date of the 
corresponding serious adverse event (SAE).  
Adverse Events of Special Interest 
An AESI is one of scientific and medical interest specific to the sponsor’s product or program.  
The following events are AESIs for participants in this study and must be reported to the sponsor 
within 24 hours after awareness, irrespective of regulatory seriousness criteria or causality: 
• LSV deficiency requiring study drug discontinuation (per Section 7.4.5 in the Protocol) 
• Liver parameter disruption requiring study drug interruption and/or dose modification 
(per Section 7.4.2.3 in the Protocol) 
• Any events that are suspected and/or confirmed to be due to PG toxicity, which includes 
but is not limited to neurological complications, hemolysis, and cardiac arrhythmias  
Partial Date Imputation 
If partial dates are reported, the convention for replacing missing dates for the purpose of 
calculating derived variables is as follows: 
Partial BA Diagnosis Dates 
For partial original BA diagnosis dates:  a) if only the day is missing, and the month and year 
match the first dose date, then the day is assigned the first day of the month (01); otherwise the 
day assigned is 15; and b) if both the day and month are missing, then the day/month assigned is 
the first day of July (01JUL), as long as the date is before the first dose date; otherwise, the 
day/month assigned is the first day of January (01JAN).  If any of the imputed dates are prior to 
the birth date, then the day of diagnosis is imputed as the birthday. 


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Partial AE or Medication Dates 
AEs or medications with entirely missing start dates will be classified as treatment emergent or 
concomitant, as appropriate. 
For partial AE or concomitant treatment start dates:  a) if only the day is missing and the month 
and year match the first dose date and the end date is on or after the first dose date, then the date 
is assigned the first dose date; thus, the event/medication will be considered as treatment 
emergent/concomitant; if the month and/or year do not match the first dose date or the end date 
is prior to the first dose date, then the day is assigned the first day of the month (01); b) if both 
the day and month are missing and the year matches the first dose date and the end date is on or 
after the first dose date, then the date is assigned the first dose date; if the year does not match 
the first dose date or the end date is prior to the first dose date, then the day/month are assigned 
the first day of the year (01JAN). 
For partial end dates:  a) if only the day is missing, then the day is assigned the last day of the 
month; b) if both day and month are missing, they are assigned the last day of the year (31DEC). 
Partial Liver-Associated Event Date 
For partial liver-associated event date:  a) if only the day is missing, then the day is assigned the 
first day of the month (01); b) if both the day and month are missing and the year matches the 
first dose date, then the date is assigned the first dose date; if the year is after the first dose date, 
then the day/month are assigned the first day of the year (01JAN). 
Dates of Birth 
Partial or complete dates of birth are not reported by the investigative sites.  Complete date of 
birth is required, however, to derive a participant’s weight, height, and BMI z-scores.  The 
convention for imputing missing birth dates for the purpose of statistical analysis will be based 
on a participant’s age in days at baseline, as defined in Section 6.1.8. 
Lower and Upper Limit of Quantitation 
In general, for quantitative laboratory values reported as “<” or “≤” the lower limit of 
quantitation (LLOQ), one-half of the reported value (i.e., LLOQ/2) will be used for analysis.  
The exception to this data treatment is for plasma maralixibat concentrations that are reported as 
<LLOQ, where a value of zero will be used in calculating summary statistics. 
For quantitative laboratory values reported as “>” or “≥” the upper limit of quantitation (ULOQ), 
the reported value (i.e., ULOQ) will be used for analysis. 
Laboratory Test Results 
For analysis purposes, repeat laboratory test results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first nonmissing repeat 
laboratory value will be used for data analysis. 


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Local laboratory results are used where central laboratory results are not available. 
The International System of Units (SI) will be used in reporting all efficacy and safety laboratory 
values, unless otherwise specified in Appendix 1. 
Dose Used in Safety Analysis 
For all safety and tolerability analyses, participants will be analyzed by the treatment received.  
For the maralixibat treatment group, the dose of IP received at the end of the dose-escalation 
period or the last dose received if the participant discontinued from the IP during the dose 
escalation period will be used for the safety analysis, where specified. 
Treatment Received in Adverse Event Listings 
For all AE listings, treatment received at the start of the event will be presented.  For participants 
on maralixibat, dose in units of μg/kg/day will be reported.  For AEs that started within 7 days 
after the last dose of study drug, the last treatment received is listed.  For AEs that started 
>7 days after the last dose of study drug, treatment received is blank.  For AEs that started prior 
to the first dose of study drug, NT (Not Treated) will be listed. 
Treatment Duration and Exposure 
For participants who are missing the date of last study drug application, for any reason, the last 
known contact date will be used in the calculation of treatment duration and study drug exposure.  
Study drug compliance will not be calculated for those participants whose date of last study drug 
administration is unknown.   
Censoring for Time to First Liver-Associated Event 
If a participant does not have a liver-associated event reported, then the time to first 
liver-associated event is censored at the last contact date. 
7. 
STUDY PARTICIPANTS AND DEMOGRAPHICS 
Participant disposition, demographics, disease history and baseline disease characteristics, 
important protocol deviations, prior medications, and study drug exposure and compliance will 
be summarized, unless otherwise noted, by randomized treatment group and overall in the Safety 
Population. 
7.1. 
Disposition of Participants and Withdrawals 
Participant disposition will be tabulated in all participants, including screen failures. 
Participant disposition will include tabulations of the number and proportion of participants in 
each of the analysis populations, completed study treatment, and discontinued early from the 
study (along with reasons for withdrawal).  Percentages will be based on the number of 
participants in the Safety Population.  The participant disposition tabulation will also include the 


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number of participants screened for eligibility, the number of screen failures, and the number of 
participants randomly assigned to study treatment. 
The number and proportion of randomized and completed participants by country and 
investigative site, individually, will also be tabulated.  Percentages will be based on the number 
of participants randomly assigned to study treatment. 
Study drug accountability and compliance listings will be prepared for all participants in the 
safety population, showing when the planned dosing schedule was not followed, along with the 
date and type of dosing deviation.  Other disposition and study conduct information, including 
important protocol deviations, will be listed. 
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be tracked, recorded, and reviewed prior to database lock, following the 
Protocol Deviation Guidance Plan (PDGP) for this study. 
Protocol deviations will be classified as “Important” or “Not Important.”  An important deviation 
poses as a relevant operational/study conduction deviation, a possible safety issue to the 
participant, or it has a potential impact on the statistical analysis of the clinical data.  A 
nonimportant deviation is identified as any protocol deviation that does not meet the criteria for 
an important deviation.  Potentially important deviations will be reviewed to determine the final 
classification as per the final PDGP.  
The number and proportion of participants with important protocol violations/deviations will be 
tabulated by category/type and treatment group in the Safety Population for all participants. 
These protocol violations/deviations will also be presented in a participant listing by randomized 
treatment group. 
The final decision regarding inclusion and exclusion of participants from the analysis 
populations will be based on a final listing of protocol deviations.  This will be determined 
during a (blinded) review meeting before any unblinding occurs or database freeze/lock, with 
input from the Clinical and Biostatistics team members. 
In addition, inclusion and exclusion criteria not met and reasons for screen failures will be listed. 
7.3. 
Demographics and Baseline Characteristics 
Summary statistics for age at baseline, sex, race, ethnicity, region, height, height z-score, weight, 
weight z-score, BMI, and BMI z-score will be presented.  
Tabulations for age group categories, defined as <median ≥median months of age, will also be 
presented.  Unless otherwise noted, age is the participant’s age at the baseline visit for all 
evaluations and presentations. 
Participants reporting >1 race will be counted in a “More than one race” category for purposes of 
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7.5. 
Exposure and Compliance 
Treatment exposure will be calculated for each participant exposed to maralixibat during the 
study and will be summarized descriptively.  This analysis will be conducted for the overall 
26-week treatment period and for the LTE period, separately.  
Treatment exposure summaries will include total treatment duration (days), treatment exposure 
(days), total dose (µg/kg), and average daily dose (µg/kg/day). 
Treatment compliance (%) will also be summarized.  For a given day, a participant is considered 
compliant with treatment if any amount of study drug was administered.  In addition to the 
presentation of descriptive statistics on compliance rates, treatment compliance will also be 
categorized and summarized as <80%, 80%–<90%, and 90%–100%. 
Study drug accountability will be presented in a participant listing by randomized treatment 
group. Dosing details will be listed separately. 
8. 
EFFICACY ANALYSIS 
Efficacy analyses will be conducted in the ITT population.  Analysis of the primary efficacy 
endpoint and secondary efficacy endpoints that achieve statistical significance in the hierarchical 
testing will also be performed in the PP population. 
Analyses on the exploratory efficacy endpoints will be performed in the ITT population. 
For all efficacy analyses, participants will be analyzed by the randomized treatment group 
assignment (maralixibat or placebo), based on the ITT principle that asserts that the effect of a 
treatment can be best assessed by evaluating on the basis of the intention to treat a participant 
(i.e., the planned treatment regimen) rather than the actual treatment given.  All efficacy data will 
be presented in participant listings. 
For all analyses, site will also be used as a covariate in the MMRM analysis. 
8.1. 
Primary Efficacy Analysis  
For this study, the primary estimand is the improvement in TSB measured as change from 
baseline in the average TSB in the maralixibat treatment group relative to the placebo group.  In 
the course of the 26-week randomized treatment period, participants may be exposed to possible 
known or unknown intercurrent events that could possibly impact the interpretation of the 
measures associated with the clinical question of interest, such as treatment discontinuation due 
to a specific adverse effect or perhaps a lack of effect.  The “Hypothetical Strategy” has been 
adopted for handling all known intercurrent events in this study.  To this end, a restricted 
maximum likelihood (REML)-based MMRM model conducted in the ITT population will be 
used as the primary analysis method.  
The repeated measures include postbaseline time periods during the dose escalation period (i.e., 
Weeks 1–8) and stable dosing period (i.e., Weeks 9–26), with change from baseline in TSB as 
the dependent variable.  The MMRM model will include the fixed, categorical effects of 


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treatment group, site, time period, and treatment group–by-time period interaction as well as the 
continuous, fixed covariates of baseline TSB and the baseline score-by-time period interaction.  
The MMRM analysis method is further described in Section 6.1.4.1.  
The unstructured variance/covariance matrix will be used to model the variances and covariances 
for the six time points included in the model.  The unstructured variance/covariance does not 
impose any restrictions on the pattern of the matrix elements.  If there is a convergence issue 
with the unstructured covariance model, the following variance/covariance matrix structures will 
be used in the following order: 1) heterogeneous Toeplitz, 2) heterogeneous autoregressive of 
order 1, and 3) heterogeneous compound symmetry.  The first variance/covariance structure that 
does not have a convergence problem will be the one used for the analysis.  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom (Kenward and Roger 
1997). 
The primary efficacy analysis will compare maralixibat and placebo with use of the contrast 
(difference in least squares [LS] means) between treatment groups across the last 12 weeks of the 
study
  The analytical solution of the overall treatment 
effect obtained from MMRM is an equally weighted average of the 3 individual visit-specific 
estimates over the time period of interest 
  Significance tests 
will be based on LS means using a 2-sided significance level (2-sided 95% CIs). 
The null hypothesis for the primary efficacy endpoint of the equality of maralixibat and placebo 
is: 
H01: Mean changes in TSB between baseline and 
 in the 
two treatment groups are equal 
The null hypothesis of equal treatment effect will be rejected if the statistical analysis results in a 
2-sided p-value for treatment over the 
 of < 0.05.  LS means will be 
calculated for each treatment group for each postbaseline time period in the model.  The 
difference between maralixibat and placebo change from baseline in TSB will be estimated, with 
the corresponding 2-sided 95% CI constructed for each time period and
 
 of the study combined.  The change from baseline LS means with standard error, 
95% CI for the LS means, p-value for testing if the LS mean is zero, LS mean difference 
between treatment groups (maralixibat minus placebo) with standard error, 95% CI for the LS 
mean difference, and p-value for testing if the treatment LS means are equal will be presented. 
The trial will be claimed successful if the hypothesis of no treatment effect on the primary 
efficacy endpoint in the ITT population is rejected at the 0.05 (2-sided) significance level. 
8.2. 
Secondary Efficacy Analysis 
Analyses similar to that described for the primary efficacy endpoint will be performed for each 
of the change from baseline secondary efficacy endpoints.  For categorical endpoints, the number 
and proportion of participants will be summarized by treatment group for each analysis visit or 
time period, as appropriate.  Barnard’s exact unconditional test will be used to calculate the 
p-value for the difference between treatment groups. 


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The null hypotheses for the secondary efficacy endpoints of the equality of maralixibat and 
placebo are: 
H02: Mean changes in total sBA level between baseline and Week 14 through 
Week 26 in the two treatment groups are equal  
H03: Proportions of participants with mean TSB levels <2 mg/dL at Weeks 14, 20, 
and 26 in the two treatment groups are equal  
H04: Proportions of participants observed to have a liver-related clinical event, 
including liver transplantation, liver decompensation (hepatic encephalopathy, 
variceal bleeding, new persistent ascites), discontinuations due to liver related 
events, or death through Week 26 in the two treatment groups are equal 
H05: Proportions of participants undergoing liver transplantation or death through 
Week 26 in the two treatment groups are equal 
H06: Proportions of participants observed to develop clinically evident portal 
hypertension defined as splenomegaly (spleen size >2 cm below the costal 
margin palpated on physical examination) and thrombocytopenia (platelet 
count <150 x 109/L) or clinically evident ascites or endoscopic evidence of 
esophageal or gastric varices through Week 26 in the two treatment groups are 
equal 
H07: Proportions of participants with mean TSB levels ≤1.2 mg/dL at Weeks 14, 20, 
and 26 in the two treatment groups are equal 
H08: Proportions of participants with mean sBA levels <40 mmol/L at Weeks 14, 
20, and 26 in the two treatment groups are equal 
 
A hierarchical testing procedure, as described in Section 6.1.3, will be used in the comparisons 
between maralixibat and placebo on the primary and secondary efficacy endpoints in the ITT 
population.  
All tests will be performed as 2-sided tests at the 0.05 level of significance. 
8.3. 
Sensitivity and Supportive Analyses for Primary and Secondary Endpoints 
Sensitivity and/or supportive analysis will be performed on the primary and selected secondary 
efficacy endpoints to quantify the possible impact of missing data and to demonstrate the 
robustness of the conclusions. 
Sensitivity analysis will be performed on the efficacy endpoints in the ITT analysis population 
that achieve statistical significance in the hierarchical testing.  These endpoints will be also 
evaluated in the PP analysis population. 


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The following sensitivity analyses will be performed on the primary and first two secondary 
analyses only if they achieve statistical significance.  Although the assumption of MAR, as used 
for the primary efficacy analysis method, is often reasonable in clinical trials, the possibility of 
MNAR data cannot be ruled out.  Sensitivity analyses to deal with missing data will use MI 
methods where missing values are imputed individually under both a plausible MAR and MNAR 
scenario.  Two sensitivity analysis models, one based on the standard MAR imputation approach 
and the other on a tipping-point analysis, will be used to examine robustness of the primary 
analysis results (see Section 6.1.4.2). 
Summary statistics on the primary efficacy endpoint and the second secondary efficacy endpoint 
will also be presented descriptively by treatment group and visit, overall and for each of the 
following subgroups in the ITT analysis population: 
• Region (Asia, Europe, Middle East, North America, and South and Central America) 
• Age at baseline (< median, ≥ median) 
• Sex (male, female) 
• Race (White, Asian, Black or African American, American Indian or Alaska Native, 
multiple) 
• Baseline TSB value (< median, ≥ median) 
• Baseline serum bile acid (< median, ≥ median) 
8.4. 
Adjustment for Multiplicity 
A hierarchical testing procedure will be used in the comparisons between maralixibat and 
placebo on the primary and secondary efficacy endpoints in the ITT population using the primary 
analysis method (as described for the primary endpoint).  The hierarchical order for testing the 
null hypotheses is listed in Section 6.1.3.  
The effect of such a procedure maintains study-wide Type I error control, ensuring that no 
confirmatory claims can be based on the endpoint(s) that have a testing rank lower than that 
endpoint whose null hypothesis was the first that could not be rejected.  Those tests will be 
considered as exploratory without any type I error control for the additional subsequent tests. 
8.5. 
Exploratory Efficacy Analysis 
Analyses similar to that described for the primary efficacy endpoint (i.e., MMRM) will be 
performed for each exploratory endpoint that is based on change from baseline values on 
continuous variables.  LS means will be calculated for each treatment group for each 
postbaseline visit in the model.  The difference between maralixibat and placebo change from 
baseline in each outcome variable will be estimated, with the corresponding 2-sided 95% CI 
constructed for each visit.  Change from baseline LS means with standard error, 95% CI for the 
LS means, p-value for testing if the LS mean is zero, LS mean difference between treatment 
groups (maralixibat minus placebo) with standard error, 95% CI for the LS mean difference, and 
p-value for testing if the treatment LS means are equal will be calculated for each visit.  For the 
endpoints that compare treatment groups across the last 12 weeks of the study, the same methods 
as described for the primary analysis of the primary efficacy endpoint will be applied.  The 
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both the observed and change from baseline values will also be summarized by treatment group 
for each visit, including the end of study visit (Week 26/EOT). 
For responder-type endpoints (i.e., efficacy variables involving binary outcomes), the number 
and proportion of participants who are considered a “responder” will be summarized by 
treatment group for each analysis visit or time period, as appropriate.  Barnard’s exact 
unconditional test will be used to calculate the p-value for the difference between treatment 
groups. 
For responder-type endpoints with ordinal measures, the Cochran-Mantel-Haenszel (CMH) test 
will be applied to test for no association between treatment group and the variable of interest.  
The number and proportion of participants with total sBA % decrease from baseline to Weeks 2, 
6, 14, 20, and 26 within the following categories: >75% (large decrease), 0%–75% (decrease), 
and <0% (increase) will be analyzed using a CMH test to test for no association between 
treatment group and the variable of interest at each analysis visit. 
Time to first liver-associated event (listing for liver transplantation, development of liver 
cirrhosis, development of portal hypertension, spontaneous bacterial peritonitis, hepatocellular 
carcinoma, cholangiocarcinoma, liver decompensation [hepatic encephalopathy, variceal 
bleeding, new persistent ascites], and death) will be compared among treatments through use of 
Kaplan-Meier product-limit survival curve estimates.  The median and other quartiles for time to 
first liver-associated event, along with 2-sided 95% CIs, will be estimated based on the 
Kaplan-Meier method.  Both a log-rank test and a Wilcoxon test will be used to test for treatment 
differences. 
Primary, secondary, and exploratory endpoints will be performed using the TIP, if possible. 
All tests will be performed as 2-sided tests at the 0.05 level of significance. 
Sensitivity analyses are not planned to be performed on the exploratory efficacy endpoints. 
9. 
SAFETY AND TOLERABILITY ANALYSIS 
All safety analyses will be performed on the Safety Population, defined as all participants who 
were randomized and received at least 1 dose of study drug.  
Safety measures including AEs, clinical laboratory values, physical examination findings 
(including body weight, height, and BMI), vital signs, ECGs, and concomitant treatment usage 
will be summarized descriptively.  No inferential statistical tests will be performed, unless 
otherwise specified.  For quantitative variables, descriptive statistics including number of 
observations, mean, median, Q1, Q3, SD, minimum, and maximum will be presented for 
observed and change from baseline values at each study visit.  Qualitative variables will be 
summarized using counts and percentages. 
Safety data collected at the baseline visit (VBL/Day 0) or the last preceding visit if not collected 
at VBL will be used as the baseline value for safety analyses. 
All safety and tolerability data will be presented in participant listings. 


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9.1. 
Adverse Events 
All summaries of AEs will be based on TEAEs unless specified otherwise.  TEAEs are defined 
as described in Section 6.1.8 (Derived Variables). 
AEs will be coded using MedDRA.  The number and proportion of participants who experience 
the event according to MedDRA system organ class (SOC) and preferred term (PT) will be 
presented by treatment group.  TEAEs related to study drug, AEs that led to withdrawal, SAEs, 
deaths, and AESIs will be similarly summarized. 
A summary of TEAEs will be presented by treatment group.  The summary will include the total 
number and percent of participants reporting: 
• 
Any TEAEs 
• 
Any treatment-related TEAE 
• 
Any severe TEAE 
• 
Any severe treatment-related TEAE 
• 
Any serious TEAE 
• 
Any serious treatment-related TEAE  
• 
Any TEAE that led to permanent study drug discontinuation 
• 
TEAEs that resulte in death 
• 
Any AESI 
 
A participant with multiple reported cases of the same AE will be counted once within each SOC 
and similarly counted once within each PT.  TEAEs summarized by SOC and PT will be sorted 
in alphabetical order of the SOC and by descending frequency order of the PT within each SOC. 
In addition, the following subgroup analyses will be explored for the summary of TEAEs and the 
incidence of TEAEs by SOC and PT indicated above: 
• Age at time of Kasai (<median and ≥median) 
• Sex (male, female) 
• Race (Asian and non-Asian) 
 
Missing and partially missing AE start and/or stop dates will be imputed, for the purpose of 
statistical analysis, according to the specifications described in Section 6.1.9. 
Listings of AEs will be presented in by-participant listings, detailing the treatment received at the 
start of the event, including dose for active study drug, SOC, PT, verbatim term given by the 
investigator, onset date and study day, end date and study day, event duration, severity, 
relationship to study drug, outcome, action taken with study drug, seriousness, and treatment 
required.  Events that are treatment emergent will be flagged. 


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9.1.1. Adverse Events That Led to Discontinuation of Study Drug 
AEs that led to permanent discontinuation of study drug will be tabulated by treatment group.  
Participant listings of AEs that led to permanent discontinuation of study drug will also be 
presented. 
9.1.2. Deaths and Serious Adverse Events 
Treatment-emergent SAEs will be summarized in the same manner as AEs that led to permanent 
discontinuation of study drug.  Participant listings of all SAEs will also be presented. 
Any deaths that occur during the study will be presented in a participant listing.  The listing will 
include participant ID, study drug and dose received at the time of death (or the last study 
drug/dose received prior to death), date of death, number of days between the first and last dose, 
MedDRA PT, and relationship to study drug. 
9.2. 
Clinical Laboratory Evaluations 
Safety laboratory test results will be summarized descriptively by study visit and treatment group 
as observed and change from baseline values.  The number and proportion of participants with 
clinical laboratory values below, within, or above the normal range by time point and in relation 
to baseline will be tabulated for each select lipid-soluble vitamin (LSV) laboratory analytes by 
treatment group in a shift table.  The shift table will include the following LSVs:  
25-hydroxyvitamin D (ng/mL), alpha tocopherol (mg/dL), INR, and vitamin A (µg/dL). 
All safety laboratory test parameters will be presented by panel in participant listings. 
Efficacy laboratory tests will not be included in safety summaries or listings.  A separate 
participant listing for efficacy laboratory results will be presented. 
9.3. 
Vital Signs and Weight/Height Measurements 
Vital signs (temperature, systolic and diastolic blood pressure, heart rate, and respiratory rate), 
weight, height, and BMI will be summarized descriptively by study visit and treatment group as 
observed and change from baseline values.  Weight, height, and BMI measurements will also be 
summarized as a z-score for a participant’s age and sex. 
9.4. 
Electrocardiograms 
Descriptive summaries will be presented for ECG measures of PR interval, QRS duration, and 
QT interval corrected using both Bazett’s and Fridericia’s formula (QTcB and QTcF).  The 
number and proportion of participants with normal, abnormal-not clinically significant, and 
abnormal-clinically significant ECG results will also be summarized. These summaries will be 
presented by study visit and treatment group. 


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9.5. 
Concomitant Medications/Therapies 
Concomitant treatments will be summarized descriptively by treatment group with use of the 
number and proportion of participants by ATC Class Level 2 (therapeutic main group) and ATC 
Class Level 5 (chemical substance). 
Prior therapies will be presented separate from concomitant therapies.  Any treatments 
continuing or starting after the first dose of study drug will be considered concomitant.  If a 
therapy starts prior to the first dose of study drug and continues after the first dose of study drug, 
it will be considered both prior and concomitant. 
10. 
OTHER PLANNED ANALYSIS 
Healthcare utilization and PK analyses will be performed on the Safety Population. 
10.1. Healthcare Utilization 
The number of outpatient clinic visits and hospitalizations related to underlying disease, length 
of stay for hospitalizations, Emergency Department visits (days), and any surgeries and 
procedures specific to the participant’s condition will be collected during postbaseline visits as 
outlined in the Table 1 and Table 2. The date of visit/admission, date of discharge, 
relationship/issue, and discharge status will be collected.  The number of days the caregiver 
missed work due to the events collected for healthcare utilization will also be collected.  
Participants that visit the Emergency Department and the visit results in the participant being 
admitted to the hospital will be counted in both categories. 
Number and percent of participants and number of occurrences will be presented across the 
entire postbaseline study period, between clinic visits from baseline through follow-up, by 
treatment group for BA-related hospitalizations and ER visits.  For length of hospital stays and 
number of days a caregiver missed work, summary statistics on a participant-level basis will be 
presented. 
10.2. Pharmacokinetic Analyses 
Systemic concentrations of maralixibat in plasma will be determined at predose and at 
approximately 2.5 hours after the morning dose at Week 10 and Week 26 (ET).  Summary 
statistics (number of observations, mean, SD, coefficient of variation, median, minimum, 
maximum, and geometric mean) will be determined for maralixibat concentrations at each 
analysis visit. 
11. 
Changes from Protocol Planned Analysis 
The order of the secondary endpoints was updated based on further evaluation of their 
importance.  
A new exploratory population, TIP, was defined. 


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12. 
REFERENCES 
Abdel-Rahman SM, Bi C, Thaete K. Construction of lambda, mu, sigma values for determining 
mid-upper arm circumference z scores in U.S. children aged 2 months through 18 years. Nutr 
Clin Pract 2017;32:68–76.  
ASA. Ethical guidelines for statistical practice. Prepared by the committee on professional 
ethics, April 2018. http://www.amstat.org/about/ethicalguidelines.cfm. 
Bezerra JA, Spino C, Magee J, et al. Use of corticosteroids after hepatoportoenterostomy for bile 
drainage in infants with biliary atresia: the START randomized clinical trial. JAMA 
2014;311:1850–9. 
CDC. Centers for Disease Control growth charts – a SAS program for the 2000 CDC Growth 
Charts (ages 0 to <20 years). 2000; available at: 
www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm. 
Cnaan A, Laird NM, Slasor P. Using the general linear mixed model to analyse unbalanced 
repeated measures and longitudinal data. Stat Med 1997;16:2349–80. 
European Medicines Agency. Guideline on missing data in confirmatory clinical trials. 2010. 
ICH. ICH Harmonised tripartite guideline. statistical principles for clinical trials e9. 1998. 
https://database.ich.org/sites/default/files/E9_Guideline.pdf. 
Kenward M G, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997;53:983–97. 
Little R, Rubin D. Statistical analysis with missing data. John Wiley: 1987. 
Little R, Yau L. Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics 
1996;52:1324–33. 
Mallinckrodt CH, Clark WS, David SR. Accounting for dropout bias using mixed-effects 
models. J Biopharm Stat 2001;11:9–21. 
Mallinckrodt CH, Lane PW, Schnell D, et al. Recommendations for the primary analysis of 
continuous endpoints in longitudinal clinical trials. Drug Inf J 2008;42:303–19. 
Mallinckrodt CH, Roger J, Chuang-Stein C, et al. Recent developments in the prevention and 
treatment of missing data. Drug Inf J 2013;48:68–80. 
Molenberghs G, Kenward MG. Missing data in clinical studies. Wiley: 2007. 
Molenberghs G, Thijs H, Jansen I, et al. Analyzing incomplete longitudinal clinical trial data. 
Biostatistics 2004;5:445–64. 
PedsQL (2021). The PedsQL measurement model for the pediatric quality of life inventory – 
scoring instructions; available at: www.pedsql.org. 
Royal Statistical Society. Code of conduct. 2014; available at: 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
Schafer JL. Analysis of incomplete multivariate data. Chapman & Hall 1997. 


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Siddiqui O, Hung HM, O'Neill R. MMRM vs. LOCF: a comprehensive comparison based on 
simulation study and 25 NDA datasets. J Biopharm Stat 2009;19:227–46. 
Verbeke G, Molenberghs G. Linear mixed models for longitudinal data. Springer 2000. 
WHO. World Health Organization growth charts – A SAS Program for the WHO growth charts 
(ages 0 to <2 years). 2000; available at 
www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas-who.htm. 


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13. 
TABLES, LISTINGS, AND FIGURES 
All listings, tables, and figures will have a header showing the company name (Mirum 
Pharmaceuticals, Inc.) and protocol (MRX-701), a page footer showing the file name and path, 
and the date/time of program execution along with the database data cut date. 
The following reporting conventions will be adopted for the presentation of study data.  These 
conventions will enhance the review process and help to standardize the presentation with 
common notations. 
General Reporting Conventions 
• All tables and data listings will be developed in landscape orientation. 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing.  
• Only standard keyboard characters should be used in tables and data listings.  Special 
characters, such as nonprintable control characters, printer-specific characters, or font 
specific characters, will not be used on a table, figure, or data listing. 
• AEs with missing MedDRA coding will have their System Organ Class and/or Preferred 
Term presented as “Not Coded” in the tables.  The “Not Coded” frequencies will be 
sorted to the end of the tables.  AEs that are not coded are not expected. 
• Programming notes may be inserted into the shells; these notes will not appear in the 
final output. 
Population Summary Conventions 
• Population sizes may be presented for each classification factor as totals in the column 
header as (N=xx), where appropriate.  
• All population summaries for categorical variables will include all categories that were 
planned and for which the participants may have had a response.  Percentages 
corresponding to null categories (cells) will be suppressed; however, counts and 
percentages of missing values may be needed.  Counts of zero will be presented as “0”—
without the percentage. 
• All population summaries for continuous variables will include n, mean, SD, median, Q1, 
Q3, minimum, and maximum.  Other summaries (e.g., number missing, geometric mean, 
95% CIs, and coefficient of variation [CV] or % CV) may be used as appropriate.  The 
precision of the maximum and minimum will match the maximum precision in the data.  
The mean and median will have 1 additional decimal place unless specified.  The SD will 
have 2 additional decimal places. 
• All percentages are rounded and reported to a single decimal point (xx.x%).  
13.1. Planned Table Descriptions 
The following are planned summary tables for Study MRX-701.  The table numbers and titles 
are place holders only and will be determined when the tables are produced.  The efficacy 
outputs are ordered to account for the hierarchical testing structure as outlined in Section 6.1.3, 


















MRX-701 
Statistical Analysis Plan 
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Figure 2 
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<Table, Listing, Figure> xx.x.x 
<Title of Table Listing or Figure> 
<Study Population and if applicable subgroup Description> 
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Body of Table, Listing or Figure 
 
 
___________________________________________________________________________________________________________ 
<Abbreviations: If applicable> 
<Note: If applicable> 
Footnote 1 <if applicable> Recommendation is to keep footnotes to a minimum 
Footnote 2 <if applicable> 
Footnote n <if applicable> 
 
<pgm path and name> 
<Executed on <date> at <time> on data from <data cut date>