Conditions: Progressive Familial Intrahepatic Cholestasis (PFIC)
Keywords: Cholestasis Maralixibat Mutation PFIC PFIC2 Bile Duct Diseases Liver Diseases Biliary Tract Diseases Digestive System Diseases Pediatric
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 93
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether the investigational treatment (maralixibat) is safe and effective in pediatric participants with Progressive Familial Intrahepatic Cholestasis (PFIC).

Detailed description:
This study was conducted at multiple sites in North America, Europe, Asia and South America.

Arms:
arm 1: Participants will receive Maralixibat oral solution (up to 600 microgram per kilogram \[mcg/kg\]) orally twice daily for 26 weeks. arm 2: Participants will receive placebo matched to maralixibat oral solution twice daily for 26 weeks.

Interventions: intervention 1: Maralixibat intervention 2: Placebo
Intervention descriptions: intervention 1: Maralixibat oral solution (up to 600 mcg/kg) orally twice daily for 26 weeks. intervention 2: Placebo matching to maralixibat orally twice daily for 26 weeks.

Protocol document:
Prot_000.pdf: 
PROTOCOL: MRX-502 
TITLE: 
MRX-502: Randomized Double-blind Placebo-controlled Phase 3 Study 
to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of 
Subjects with Progressive Familial Intrahepatic Cholestasis (PFIC) – 
MARCH-PFIC 
SHORT TITLE: 
A Placebo-controlled study of Maralixibat in Subjects with Progressive 
Familial Intrahepatic Cholestasis (MARCH-PFIC) 
DRUG: 
Maralixibat (formerly SHP625 or LUM001) 
IND: 
EudraCT: 
119916 
2019-001211-22 
SPONSOR: 
Mirum Pharmaceuticals Inc. 
950 Tower Lane 
Foster City, CA 94404 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: Alexander Miethke, MD 
PROTOCOL 
HISTORY: 
Amendment 4, 10 May 2022 
Amendment 3, 16 Jun 2020 
Amendment 2, 22 Nov 2019 
Amendment 1: 29 Apr 2019 
Version 1: 14 Mar 2019 
This document contains confidential and proprietary information of Mirum and is disclosed pursuant to 
confidentiality and non-disclosure obligations.  This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Mirum Pharmaceuticals Inc. 


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Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 3 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Changes are presented in strikethrough for deleted text and bold for added text: 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Synopsis 
Text revised 
Updated to reflect changes in 
the protocol 
Section 2.1 Rationale for 
the Study 
Updated text 
Clarification 
There is currently As of study initiation, there is no approved treatment for PFIC, and available medical 
approaches have limited efficacy. 
The current study is designed to confirm the effect of higher doses of maralixibat on pruritus, growth 
parameters in PFIC2 and relevant serum markers of the disease (ALT, TSB, and sBA) by using higher doses 
than those used to date in Study LUM001-501 assess it effect on a broader PFIC population. Because all 
treatment responders in Study LUM001-501 were subjects with PFIC2, the primary and secondary efficacy 
analyses will be limited to this subpopulation. The current study therefore aims to confirm the efficacy and 
safety of maralixibat and to support a regulatory approval for the treatment of pruritus in PFIC 2 patients.  
The supplemental cohort will be used to assess the efficacy and safety of maralixibat in PFIC (PFIC1, 
PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) and other PFIC patient subpopulations will also be assessed 
based on the rationale that maralixibat also has the potential to lead to sBA and pruritus reduction in those 
the broader PFIC population and its subtypes.  
Section 2.2.1 Primary 
Objective 
Updated text 
To clarify population 
• 
To evaluate the efficacy of maralixibat vs. versus placebo on the severity of pruritus in 
participants with PFIC2 the primary cohort 
Section 2.2.2 Secondary 
Objectives 
Text added 
Secondary objectives and 
endpoints updated to better 
capture clinically meaningful 
measures in the primary cohort 
and the broader PFIC 
population.  The hierarchical 
testing was updated 
accordingly 
• To evaluate the efficacy of maralixibat vs. placebo on the frequency of pruritus in the primary 
cohort 
• To evaluate the efficacy of maralixibat versus. placebo on total sBA levels in participants with 
PFIC2 the primary cohort 
• To evaluate the efficacy of maralixibat versus placebo on the severity of pruritus in 
participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 
• To evaluate the efficacy of maralixibat versus placebo on total sBA levels in participants with 
PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 4 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 2.2.2 Secondary 
Objectives (continued) 
Text added 
Secondary objectives and 
endpoints updated to better 
capture clinically meaningful 
measures in the primary cohort 
and the broader PFIC 
population.  The hierarchical 
testing was updated 
accordingly 
• To evaluate the efficacy of maralixibat versus placebo on the proportion of responders for the 
ItchRO (Obs) pruritus score in participants with PFIC2 and participants with PFIC (PFIC1, 
PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6)  
• To evaluate the efficacy of maralixibat versus placebo on the sBA responder rate in 
participants with PFIC2 and participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, 
and PFIC6)  
• To evaluate the safety, tolerability, and PKpharmacokinetics of maralixibat vs.versus placebo in 
all participants who receive at least 1 dose of study medication (safety population) PFIC 
subjects 
Section 2.2.3 Exploratory 
Objectives 
Text revised and added 
Exploratory objectives and 
endpoints updated to better 
capture clinically meaningful 
measures in the primary cohort, 
the broader PFIC population, 
and other subgroups of interest. 
Additional endpoints may be explored to further characterize the efficacy and safety of maralixibat 
relative to placebo. 
• To evaluate the efficacy of maralixibat vs placebo in the primary cohort on the following 
parameters: 
o 
Liver biochemistry 
o 
Other measures of pruritus 
o 
Health-related quality of life 
o 
Responder rates of various pruritus measures and biomarkers 
o 
Quality of sleep 
o 
Subject growth 
o 
Other Patient Reported Outcomes (PRO), including Caregiver Impression of Severity (CIS), 
Patient Impression of Severity of Pruritus (PIS), or ItchRO(Pt) 
o 
Markers of bile acid metabolism: bile acid subspecies, C4, (FGF-19), autotaxin 
o 
Noninvasive fibrosis markers: Fibrosis-4 (FIB-4), AST to Platelet Ratio Index (APRI) 
o 
Time to liver-associated events  
o 
To evaluate the impact of maralixibat on healthcare utilization 
o 
To evaluate the primary, secondary, and exploratory endpoints in the supplemental cohort 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 5 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 3.1 Study Design 
and Flow Chart 
Text revised 
For clarity 
The primary analysis will be conducted in the ITT population of subjects with documented biallelic 
mutations in ABCB11 (PFIC2), based on standard-of-care genotyping (primary cohort criteria).  
Subjects with other PFIC subtypes (e.g., PFIC 1/3/4, or new PFIC mutation variants) or postsurgical subjects 
(e.g., after internal or external biliary diversion surgery or subjects with reversal of biliary diversion surgery) 
will be enrolled in a separate supplemental cohort and analyzed evaluated as part of secondary and for 
exploratory purposes analyses (see Section 9.8).  
Section 6.2.2 Allocation of 
Treatment to Subjects 
Text added 
Text added to specify that the 
SAP will detail how the 
assignment of siblings occurs. 
Siblings will be randomized in a blinded manner to the same treatment group.  Additional details will be 
included within the SAP. 
Section 7.2.1 Genetic 
Testing Results 
Text added 
For clarity of PFIC subtypes 
ATP8B1 (PFIC1), ABCB11 (PFIC2), ABCB4 (PFIC3), and TJP2 (PFIC4), NR1H4 (PFIC5), and MYO5B 
(PFIC6) mutations are predictive of PFIC. 
Section 9.5 Validation 
Analysis Plan 
Added section 
To include a blinded analysis to 
confirm the responder 
definition 
A blinded analysis of the ItchRO(Obs) instrument will be performed before database lock according to 
the validation analysis plan (VAP).  The blinded analysis will be used to estimate a threshold of 
clinically meaningful change (i.e., responder definition) in the 4-week average morning ItchRO(Obs) 
pruritus scores.  The analysis will be performed by a group independent from both the study team and 
Mirum Pharmaceuticals.  Blinded data will be used for this analysis; data will be collapsed across 
treatment groups. 
Details of the analysis will be included in a standalone VAP, which will describe analyses that will be 
used to assess the measurement properties of the ItchRO(Obs) in alignment with scientific 
recommendations outlined in the FDA’s Patient Focused Drug Development Guidance 3 (i.e., 
reliability, validity, ability to detect change, and anchor-based meaningful within-person clinically 
meaningful change criteria).  Criteria for defining within-person clinically meaningful change for the 
ItchRO(Obs) will be detailed in the SAP. 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 6 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.7 Sample Size 
Calculation and Power 
Considerations 
Added and deleted text 
To clarify sample size 
calculation. To remove power 
calculation for endpoints other 
than the primary endpoint. To 
clarify primary cohort.  
The sample size was calculated for to ensure enrollment of an adequate number of PFIC2 participants 
who fulfill criteria for the primary cohort (primary endpoint)the primary cohort, defined as all PFIC2 
subjects. The sample size is chosen to provide at least 80% power for the analysis of the primary endpoint in 
the primary cohort.  
Including a 10% dropout rate based on the previous PFIC study and rounding up to the next even number, 
approximately 30 participants with PFIC2 subjects (15 subjects in each treatment group) will be 
randomized in the primary cohort of the study for the primary analysis.  
As for the secondary efficacy endpoint as measured by the mean change from baseline in the 4-week average 
morning ItchRO(Obs) frequency score from Week 15 to Week 26, with a between-treatment group LS mean 
difference of 0.676, the pooled SD of 0.580, and the effect size of 1.166, a total of 26 complete subjects 
(13 subjects in each treatment group) will provide 81% power for the comparison between the maralixibat 
treatment group and placebo, based on a 2-sided, 2-sample t-test at the 0.05 level of significance. Similar 
assumptions were made as for the primary endpoint. 
Section 9.8 Analysis 
Populations 
Removed and added text 
Removed text to clarify that the 
ITT Population will include all 
randomized subjects.  Added 
text to clarify the cohorts for 
the primary analysis of the 
primary and secondary efficacy 
endpoints. 
The intent-to-treat (ITT) population will consist of all randomized subjects. Additional subgroups of the 
ITT population will be specified based on the presence/absence of post-baseline efficacy assessments for 
particular efficacy endpoints.  
The per protocol population will consist of all subjects in the ITT population who receive at least 1 dose of 
study medication and do not have any major protocol violations or deviations.  Major protocol 
violations/deviations will be identified prior to database lock.  
The primary and secondary efficacy endpoints will be analyzed for each of the analysis populations 
described above.  The primary analysis on the primary and secondary efficacy endpoints will be conducted in 
participants with PFIC2 in the ITT population.  The primary analysis on the secondary efficacy 
endpoints will be conducted in participants with PFIC2 and participants with PFIC (PFIC1, PFIC2, 
PFIC3, PFIC4, PFIC5, and PFIC6) in the ITT population.   
The Any exploratory efficacy endpoints will be analyzed in the ITT population.   Exploratory analyses may 
be performed on participants with PFIC2, PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6), 
and other PFIC populations of interest.  The final list of exploratory endpoints will be described in the 
SAP.  
Subjects in the ITT population with no post-baseline efficacy assessments for a particular efficacy endpoint 
will be excluded from the analyses of that efficacy endpoint. 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 7 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.8.1 PFIC 
Populations for Analyses 
Section added 
Added to provide definitions of 
analyses subgroups 
The following definitions will be used for the PFIC populations in the analyses of the various endpoints 
in this study: 
Primary and Secondary Endpoints: 
• 
PFIC2: Participants with PFIC2 who fulfill criteria for the primary cohort 
(see Section 4) 
• 
PFIC: Participants with PFIC1, PFIC2 (who fulfill criteria for the primary cohort), 
PFIC3, PFIC4, PFIC5, and PFIC6.  
Exploratory Endpoints: 
PFIC2 and PFIC populations (as above) and 
• 
PFIC1: Participants with PFIC1 
• 
PFIC3: Participants with PFIC3 
• 
PFIC4: Participants with PFIC4 
• 
PFIC5: Participants with PFIC5 
• 
PFIC6: Participants with PFIC6 
• 
Truncated PFIC2: Participants with PFIC2 with mutations leading to premature 
protein truncation or failure of protein production 
• 
All participants: All participants enrolled 
Each of the above-defined PFIC populations, with the exception of the All participants, will exclude 
any participants with biliary surgery at baseline and genotype variations affecting only 1 allele 
(heterozygous). 
In the PFIC population (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6), participants with biallelic 
disease causing variation in ATP8B1 (PFIC1), ABCB11 (PFIC2), ABCB4 (PFIC3), TJP2 (PFIC4), 
NR1H4 (PFIC5), and MYO5B (PFIC6) may be included. The number of participants with each 
variation will depend on the genotype prevalence within the enrolled study population. 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 8 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10 Efficacy 
Analysis 
Text deleted and added 
Removed duplicative text 
where appropriate and clarified 
efficacy analyses to be 
performed. 
Efficacy analyses on the primary and secondary efficacy endpoints will be performed in the ITT and per 
protocol populations. Analyses will be conducted in the ITT population separately for the primary cohort, 
overall supplemental cohort, all cohorts combined, and in the PFIC1 and PFIC3 sub-cohort (separately) 
given sufficient sample size. Analysis of the primary and secondary efficacy endpoints will also be 
performed on the primary cohort in the per protocol population. 
Analyses on the exploratory efficacy endpoints will be performed in the ITT population separately on the 
primary cohort, overall supplemental cohort, all cohorts combined, and in the PFIC1 and PFIC3 sub-cohorts 
(separately) given sufficient sample size. 
The primary and secondary efficacy analysis will be performed for the ITT population.  Analysis of 
the primary and secondary efficacy endpoints will also be performed in the per-protocol population.  
Analyses on the exploratory efficacy endpoints will be performed in the ITT population.separately on   
Exploratory analyses may be performed in participants with PFIC2, PFIC (PFIC1, PFIC2, PFIC3, 
PFIC4, PFIC5, and PFIC6), and other PFIC populations of interest.  Final list of exploratory 
endpoints will be described in the SAP.  
Efficacy analyses will be conducted in the ITT population separately on the primary cohort, the PFIC cohort, 
PFIC1 sub-cohort, PFIC3 sub-cohort, and all cohorts combined. Analysis of the primary and secondary 
efficacy endpoints will also be performed on the primary cohort in the PP population. 
Analyses on the exploratory efficacy endpoints will be performed in the ITT population separately on the 
primary cohort, the PFIC cohort, PFIC1 sub-cohort, PFIC3 sub-cohort, and all cohorts combined.  
The primary efficacy analysis will be performed in the primary cohort for the ITT population. 
For the PFIC population (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6), PFIC type will also be 
used as a covariate in the analysis. For this analysis, due to the small sample sizes, PFIC4, PFIC5, and 
PFIC6 will be grouped together.  


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 9 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.1 Primary 
Efficacy Endpoint 
Text deleted and text added 
Updated to clarify the scoring 
of ItchRO(Obs) and ItchRO(Pt) 
severity scores, to anchor the 
timing of averages to the first 
dose of study drug, and to 
clarify how to construct 
monthly scores.  Additionally, 
language regarding estimands 
and the handling of intercurrent 
events was included. 
The primary efficacy endpoint is defined as the mean change in the average morning ItchRO(Obs) severity 
score between baseline and Week 15 through Week 26, using 4-week average morning ItchRO(Obs) severity 
scores.  
Weekly scores will be calculated relative to the initiation of treatment.  For each week, a weekly score 
will be calculated if at least 4 days’ worth of data are provided.  If more than 50% of scores are 
missing for a particular week, the weekly average score will be treated as missing.  Average scores will 
be calculated for the following periods: Through Week 6 (42 days), Weeks 7-10, 11-14, 15-18, 19-22, 
and 23-26 (28 days).  For each period, the average of the weekly scores will be calculated.  At least 
50% of the weekly scores must be available in order to compute an average for the period.  Post-
baseline average morning ItchRO(Obs) severity scores will be calculated as the sum of the morning 
ItchRO(Obs) severity scores divided by the number of morning ItchRO(Obs) severity scores for the 6-week 
(42-day) time period during the dose-escalation phase (i.e., through Week 6) and the 4-week (28-day) time 
periods prior to each visit during the stable dosing phase (i.e., Weeks 7–10, 11–14, 15–18, 19–22, and 
23–26). The baseline average morning ItchRO(Obs) score is defined as the 4-week average morning 
ItchRO(Obs) severity score prior to the first dose of study medication. 
If 25% or more morning ItchRO(Obs) severity scores for the 6- or 4-week treatment period before a given 
study visit are missing, the average morning ItchRO(Obs) severity score at that visit will be treated as 
missing.   


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 10 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.1 Primary 
Efficacy Endpoint 
(continued) 
Text deleted and text added 
Updated to clarify the scoring 
of ItchRO(Obs) and ItchRO(Pt) 
severity scores, to anchor the 
timing of averages to the first 
dose of study drug, and to 
clarify how to construct 
monthly scores.  Additionally, 
language regarding estimands 
and the handling of intercurrent 
events was included. 
Primary Analysis for Primary Efficacy Endpoint 
For this study, the primary estimand is the improvement in pruritus measured as change from 
baseline in the average morning ItchRO(Obs) severity score 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 inter-current 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.  A treatment policy 
estimand will be utilized for the analysis where all data will be incorporated.  Intercurrent events will 
be handled as follows: 
• 
Change in or administration of any allowed concomitant medication will be handled using a 
treatment policy strategy. 
• 
Administration of any prohibited concomitant medication will be handled using a 
hypothetical strategy assuming that the prohibited medications are not available and hence 
were not taken, so as to assess the treatment effect for the randomized treatment groups in 
addition to allowed concomitant medication. 
• 
Discontinuation of randomized treatment due to all of the following reasons will be handled 
using a treatment policy strategy: 
o 
Lack of efficacy 
o 
Safety concerns 
o 
Lack of compliance to study treatment 
• 
Discontinuation of randomized treatment due to other reasons (including loss to follow-up) 
will be handled using a hypothetical strategy, assuming that randomized treatment had not 
been discontinued. 
• 
Liver transplant or death:  Neither of these are expected in the study.  In the unlikely event 
that either of these events occur, they will be analyzed using a composite strategy, assuming 
worse possible score for all subsequent assessments. 
The primary analysis on the primary efficacy endpoint will be conducted over in participants with PFIC2 
who fulfill criteria for primary cohort the in the ITT population. 
 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 11 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.2 Adjustment 
for Multiplicity 
Added and deleted text 
To prioritize clinically 
meaningful endpoints in the 
statistical testing hierarchy 
In order to maintain study-wide Type I error control, a hierarchical testing procedure will be used in the 
comparisons between maralixibat and placebo on the primary and secondary efficacy endpoints on the 
primary cohort in the ITT population.  The hierarchical order for testing the null hypotheses is as follows: 
 (1) mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 through 
Week 26, (2) mean change in the average morning ItchRO(Obs) frequency score between baseline and 
Week 15 through Week 26, (3) mean change in total sBA level between baseline and Week 26, and (4) the 
proportion of subjects who experience an sBA control (defined as a reduction to <102 µMol/L, or a reduction 
of >75%, or normalization) from baseline through Week 26. 
1. Primary:  Mean change in the average morning ItchRO(Obs) severity score between baseline 
and Week 15 through Week 26 in participants with PFIC2  
2. Secondary:  Mean change in total sBA level between baseline and average of Weeks 18, 22, 
and 26 in PFIC2 participants who fulfill criteria for the primary cohort 
3. Secondary:  Mean change in the average morning ItchRO(Obs) severity score between 
baseline and Week 15 through Week 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, 
PFIC4, PFIC5, and PFIC6) 
4. Secondary:  Mean change in total sBA level between baseline and average of Weeks 18, 22, 
and 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 
5. Secondary:  Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in participants 
with PFIC2, using the average value from the three 4-week periods (Weeks 15-18, 19-22, and 
23-26) 
6. Secondary:  Proportion of sBA responders from Week 18 to Week 26 in participants with 
PFIC2, using the average value from Weeks 18, 22, and 26 values 
7. Secondary:  Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in participants 
with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 
8. Secondary:  Proportion of sBA responders from Week 18 to Week 26 in participants with 
PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6)  
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. 
The effect of such a procedure is that no confirmatory claims can be based on the endpoint(s) that 
have a rank lower than that endpoint whose null hypothesis was the first that could not be rejected.  
Those tests will be considered as exploratory and no formal conclusions will be drawn. 
For Europe and the rest of the world excluding the United States, the hierarchical testing will be performed 
on all of the endpoints listed above, in the order listed.  For the United States, sBA endpoints (endpoint 
numbers 2, 4, 8, and 10) will be excluded from the hierarchical testing. 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 12 
MRX-502 Protocol Amendment 4 
 
 
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Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.3 Secondary 
Efficacy Endpoints 
Added and deleted text 
Secondary objectives and 
endpoints updated to better 
capture clinically meaningful 
measures in the primary cohort 
and the broader PFIC 
population.  The hierarchical 
testing was updated 
accordingly. 
The secondary efficacy endpoints are defined as: 
• Mean change in the average morning ItchRO(Obs) frequency score between baseline and Week 15 
through Week 26, using 4-week average morning ItchRO(Obs) frequency scores.  
• Mean change in total sBA level between baseline and Week 26 
• Proportion of subjects who experience an sBA control (defined as a reduction to <102 µMol/L, or a 
reduction of >75%, or normalization) from baseline through Week 26 Mean change in total sBA 
level between baseline and average of Weeks 18, 22, and 26. 
• Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 
• Mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 
through Week 26 in participants with PFIC 
• Proportion of ItchRO(Obs) responders from Week 15 to Week 26  
• For the purpose of determining response, the average value from the three 4-week periods 
(Weeks 15-18, 19-22, and 23-26) will be computed and used. 
ItchRO(Obs) responder definition: 
Criteria for clinically meaningful change in the ItchRO(Obs) (responder definition) will be 
established by the VAP and described in detail in the SAP.  
• Proportion of sBA responders from Week 18 to Week 26 
• For the purpose of determining response, the average value from Weeks 18, 22, and 26 values 
will be computed and used. 
sBA responder definition: 
• 
≥75% reduction in sBA 
OR 
• 
sBA level <102 µmol/L (applies only if baseline sBA level was >102 µmol/L) 
Post-baseline average morning ItchRO(Obs) frequency scores will be calculated as the sum of the morning 
ItchRO(Obs) frequency scores divided by the number of morning ItchRO(Obs) frequency scores for the 
6-week (42-day) time period during the dose-escalation phase (i.e., through Week 6) and the 4 week (28-day) 
time periods prior to each visit during the stable dosing phase (i.e., Weeks 7–10, 11–14, 15–18, 19–22, and 
23–26). The baseline average morning ItchRO(Obs) frequency score is defined as the 4-week average 
morning ItchRO(Obs) frequency score prior to the first dose of study medication. 
If 25% or more morning ItchRO(Obs) frequency scores for the 6- or 4-week treatment period before a given 
study visit are missing, the average morning ItchRO(Obs) frequency score at that visit will be treated as 
missing. 
Serum bile acid from each scheduled clinic visit will be used in the analysis of mean change from baseline in 
sBA. 


Mirum Pharmaceuticals 
CONFIDENTIAL 
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MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.3 Secondary 
Efficacy Endpoints 
Added and deleted text 
Updated the hypothesis tests to 
be performed due to the 
adjustment of the secondary 
endpoints. 
Analysis for Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed in participants with PFIC2 and participants with PFIC 
(PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) as described in Section 9.10.  Analysis similar to 
that described for the primary efficacy endpoint, including the sensitivity analyses, will be performed for 
each of the secondary efficacy endpoints.  Analyses will be conducted separately on the primary cohort, 
overall supplemental cohort, all cohorts combined, PFIC1 sub-cohort, and PFIC3 sub-cohort in the ITT 
population.  Analysis of the secondary efficacy endpoints will also be performed on the primary cohort in the 
per protocol population.  Analysis on the PFIC1 and PFIC3 sub-cohorts will only be performed given 
sufficient sample size.  
For the binary (responder) outcomes of the proportion of subjects who experience an sBA control (defined 
as a reduction to <102 µMol/L, or a reduction of >75%, or normalization) from baseline through Week 26, 
the number and proportion of subjects that are considered a “responder” will be summarized by treatment 
group at the end of study visit (Week 26/EOT).  Barnard’s exact test will be used to calculate the p-value for 
the difference between treatment groups. 
The null hypotheses for the secondary efficacy endpoints of the equality of maralixibat and placebo are: 
H02: mean change in the average morning ItchRO(Obs) frequency score between baseline and 
Week 15 through Week 26 in the 2 treatment groups are equal 
H03: mean change in total sBA level between baseline and Week 26 in the 2 treatment groups 
are equal 
H04: proportion of subjects who experience an sBA control (defined as a reduction to 
<102 µMol/L, or a reduction of >75%, or normalization) from baseline through Week 26 
in the 2 treatment groups are equal 
H02: mean change in total sBA level between baseline and average of Weeks 18, 22, and 
26 on participants with PFIC in the 2 treatment groups are equal 
H03: mean change in the average morning ItchRO(Obs) severity score between baseline 
and Week 15 through Week 26 on participants with PFIC (PFIC1, PFIC2, PFIC3, 
PFIC4, PFIC5, and PFIC6)  in the 2 treatment groups are equal 
H04: mean change in total sBA level between baseline and average of Weeks 18, 22, and 
26 on participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 
in the 2 treatment groups are equal 
H05: proportion of ItchRO(Obs) responders from Week 15 to Week 26 on participants 
with PFIC2 in the 2 treatment groups are equal 
H06: proportion of sBA responders from Week 15 to Week 16 on participants with 
PFIC2 in the 2 treatment groups are equal, using the average from Weeks 18, 22, 
and 26 sBA values 
H07: proportion of ItchRO(Obs) responders from Week 15 to Week 26 on participants 
with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) in the 2 treatment 
groups are equal 
H08: proportion of sBA responders from Week 18 to Week 26 on participants with 
PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) in the 2 treatment 
groups are equal 


Mirum Pharmaceuticals 
CONFIDENTIAL 
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MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.4 Exploratory 
Efficacy Endpoints 
Text added and deleted 
Exploratory endpoints updated 
to better capture clinically 
meaningful measures in the 
primary cohort, the broader 
PFIC population, and other 
subgroups of interest.   
The exploratory efficacy endpoints are defined as:  The final exploratory endpoint list will be described in 
detail in the SAP.  Analyses on the exploratory efficacy endpoints will be performed in the ITT 
population.  Exploratory analyses may be performed  in participants with PFIC2, PFIC (PFIC1, 
PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6), and other PFIC populations of interest as described in the 
SAP. 
• Mean change in liver-associated laboratory test level between baseline and Week 15 through 
Week 26 
• Mean change from baseline in liver-associated laboratory tests (i.e., ALT, total and conjugated bilirubin) 
to Weeks 2, 6, 10, 14, 18, 22, and 26 
• Proportion of participants with elevated baseline liver biochemistry (i.e., >ULN at baseline), whose 
liver biochemistry normalize (≤ULN) at Weeks 2, 6, 10, 14, 18, 22, and 26 
• Mean change from baseline in FIB-4, and APRI, MELD, and PELD score to Weeks 2, 6, 10, 14, 18, 
22, and 26 
• Proportion of days with a morning, evening, and highest daily ItchRO(Obs) severity score ≤1 at the 
participant level from baseline to Week 6 (overall and weekly), Weeks 7-10, 11-14, 15-18, 19-22, 23-26, 
and 15-26 
• Proportion of days with a morning, evening, and highest daily ItchRO(Obs) frequency score ≤1 at 
the participant level from baseline to Week 6 (overall and weekly), Weeks 7-10, 11-14, 15-18,  
19-22, 23-26, and 15-26 
• Proportion of days with a morning, evening, and highest daily ItchRO(Pt) severity score ≤1 at the 
participant level from baseline to Week 6 (overall and weekly), Weeks 7-10, 11-14, 1518, 19-22,  
23-26, and 15-26 
• Proportion of days with a morning, evening, and highest daily ItchRO(Pt) frequency score ≤1 at 
the participant level from baseline to Week 6 (overall and weekly), Weeks 7-10, 11-14, 15-18, 
19-22, 23-26, and 15-26 
• Mean change in the average morning ItchRO(Obs) frequency score between baseline and Week 15 
through Week 26  
• Mean change from baseline in average (6-week average for Week 6 and 4-week average 
afterwards) morning, evening, and highest daily ItchRO(Obs) severity and frequency scores to 
Weeks 6, 10, 14, 18, 22, 26, and Weeks 15-26 combined 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 15 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.4 Exploratory 
Efficacy Endpoints 
(continued) 
Text added and deleted 
Exploratory endpoints updated 
to better capture clinically 
meaningful measures in the 
primary cohort, the broader 
PFIC population, and other 
subgroups of interest.   
• Mean change from baseline in weekly average morning, evening, and highest daily ItchRO(Obs) 
severity and frequency scores to each post-baseline week, and Weeks 15-26 combined 
• Mean change from baseline in average (6-week average for Week 6 and 4-week average 
afterwards) morning, evening, and highest daily ItchRO(Pt) severity and frequency scores to 
Weeks 6, 10, 14, 18, 22, 26, and Weeks 15-26 combined 
• Mean change from baseline in weekly average morning, evening, and highest daily ItchRO(Pt) 
severity and frequency scores to each post-baseline week, and Weeks 15-26 combined 
• Mean change from baseline in CSS, CIS, and PIS at Weeks 2, 4, 6, 10, 14, 18, 22, and 26 
• Proportion of participants in each change from baseline category of the CSS, CIS, and PIS at 
Weeks 2, 4, 6, 10, 14, 18, 22, and 26  
• Proportion of responders at Weeks 6, 10, 14, 18, 22, 26, and any of those weeks, where a responder is 
defined as having:  
• a) Clinically meaningful 4-week average morning ItchRO(Obs) severity decrease from 
baseline AND a normalization or reduction from baseline in sBA of ≥75%, or average sBA 
level <102 µmol/L  
• b) Clinically meaningful 4-week average morning ItchRO(Obs) severity decrease from 
baseline  
• c) a normalization or reduction from baseline in sBA of ≥75%, or average sBA level 
<102 µmol/L 
• Number and proportion of participants achieving morning ItchRO(Obs) severity scores ≤1 for 
more than 50% of the time from baseline to Week 6, Weeks 7-10, 11-14, 15-18, 1922, 23-26, and 
15-26 
• Mean change over time in quality of life as measured by the PedsQL 
• Mean change from baseline in average sleep disturbance scores over time (4-week average score at 
Weeks 6, 10, 14, 18, 22, and 26), based on sleep-related questions on the EDQ(Obs) morning, 
PedsQL (parent), and PedsQL (child) questionnaires, individually 


Mirum Pharmaceuticals 
CONFIDENTIAL 
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MRX-502 Protocol Amendment 4 
 
 
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Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.4 Exploratory 
Efficacy Endpoints 
(continued) 
Text added and deleted 
Exploratory endpoints updated 
to better capture clinically 
meaningful measures in the 
primary cohort, the broader 
PFIC population, and other 
subgroups of interest.   
• Proportion of “no” answers for sleep-related questions on the ItchRO(Obs) morning, 
ItchRO(Obs) evening, and ItchRO(Pt) morning, individually, at the participant level for baseline 
to Week 6, Weeks 7-10, 11-14, 15-18, 19-22, 23-26, 15-26, and overall 
• Proportion of participants with improvement from baseline (i.e., change from baseline <0) in 
EDQ(Obs) sleep score at Weeks 6, 10, 14, 18, 22, and 26 (using 4-week average scores) 
• Proportion of EDQ sleep scores ≤2 at the participant level post-baseline through Week 26 
• Mean change from baseline in height z-score and weight z-score at Weeks 2, 4, 6, 10, 14, 18, 22, 
and 26 
• Proportion of participants who experience an improvement from baseline in height z-score or weight 
z-score (i.e., change from baseline >0) at Weeks 2, 4, 6, 10, 14, 18, 22, and 26  
• Mean change, and % change from baseline in total sBA level to Weeks 2, 6, 10, 14, 18, 22, and 26 
• Mean change from baseline in bile acid subspecies, C4, FGF-19, and autotaxin to Weeks 10, 18, and 26 
• Time to liver-associated events (PEBD surgery, listing for liver transplantation, liver decompensation 
[hepatic encephalopathy, variceal bleeding, ascites, and spontaneous bacterial peritonitis] events, HCC, 
death) 
• Correlation analyses between sBA and pruritus severity 
The ItchRO(Obs) frequency scores will be calculated using the same approach as the ItchRO(Obs) 
severity scores.   
The SAP will describe the subscales/domains, including the scoring algorithms, for each of the PedsQL 
questionnaires.  Liver biochemistry (e.g., TSB, ALT), and sBA normalization levels, along with definitions 
of elevated liver biochemistry levels and liver disease severity scores, will be covered in the SAP. 


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 17 
MRX-502 Protocol Amendment 4 
 
 
Maralixibat 
 
 
 
Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 9.10.4 Exploratory 
Efficacy Endpoints 
Added and deleted text 
Simplified the language by 
removing duplicative 
descriptions of endpoints. 
Analysis for Exploratory Efficacy Endpoints 
Analyses will be conducted separately on the primary cohort, overall supplemental cohort, all cohorts 
combined, PFIC1 sub-cohort, and PFIC3 sub-cohort in the ITT population.  Analysis on the PFIC1 and 
PFIC3 sub-cohorts will only be performed given sufficient sample size.   
Efficacy endpoints with binary outcomes include: 1) the proportion of responders, where a responder is 
defined as having a 4-week average morning ItchRO(Obs) severity decrease from baseline of ≥ 1.0 AND a 
normalization or reduction from baseline in sBA of ≥ 70%, 2) the proportion of subjects with elevated 
baseline liver biochemistry, whose liver biochemistry normalize, and 3) the proportion of subjects who 
experience an improvement from baseline in height z-score or weight z-score (i.e., change from baseline >0). 
For these responder-type endpoints, the number and proportion of subjects that are considered a “responder” 
will be summarized by treatment group for each visit, including the end of study visit (Week 26/EOT).  
Barnard’s exact test will be used to calculate the p-value for the difference between treatment groups at each 
study visit. 
Section 9.11 Safety and 
Tolerability Analysis 
Updated text 
To clarify subgroups analyzed 
Analyses will be conducted separately on the participants with PFIC2 primary cohort and the participants 
with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6). All participants cohort.  
Section 9.12.1 Healthcare 
Utilization 
Added text 
For consistency with synopsis 
Healthcare resource utilization between baseline and Week 26 will be analyzed.  


Mirum Pharmaceuticals 
CONFIDENTIAL 
Page 18 
MRX-502 Protocol Amendment 4 
 
 
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Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 4 
Amendment Date 
10 MAY 2022 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Appendix 10 Management 
of Clinical Study 
Procedures and Participants 
during COVID-19 
Pandemic or Other Force 
Majeure 
Deleted wording regarding remote visit 
approval.  
Updated SAE reporting language. 
Added section for “Guidance Regarding 
Vaccination against COVID-19.” 
To provide guidance regarding 
COVID-19 vaccinations.   
For all remote visits, medical monitor and Mirum medical approval is required.  
SAEs are reportable to the Sponsor within sponsor immediately without undue delay after becoming 
aware of the event and no later than 24 hours of awareness. 
Guidance Regarding Vaccination against COVID-19 
• Participants should be requested to contact the site upon planned vaccination against COVID-19.  
The vaccine should be entered in the eCRF as a concomitant medication and any new or worsened 
symptom or sign recorded as an adverse event and assessed for seriousness.  Maralixibat is taken 
orally, is minimally absorbed with systemic levels below the lower limit of quantification, and 
binds with and inhibits the ileal bile acid transporter (IBAT) in the distal ileum.  The vaccine is 
administered and acts systemically; hence, no drug-drug interaction is expected, and no need for 
unblinding is foreseen. 
Minor formatting and editorial changes have been made throughout the protocol for clarity and consistency. 
 


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ...........................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ..................................................3 
TABLE OF CONTENTS .........................................................................................................19 
LIST OF TABLES ...................................................................................................................23 
LIST OF FIGURES .................................................................................................................23 
LIST OF APPENDICES ..........................................................................................................23 
STUDY SYNOPSIS ................................................................................................................24 
ABBREVIATIONS .................................................................................................................32 
1 
BACKGROUND INFORMATION ......................................................................37 
1.1 
Indication and Current Treatment Options ......................................................37 
1.2 
Product Background and Clinical Information ................................................38 
2 
STUDY OBJECTIVES AND PURPOSE .............................................................40 
2.1 
Rationale for the Study ....................................................................................40 
2.2 
Study Objectives ..............................................................................................40 
2.2.1 
Primary Objective ................................................................................40 
2.2.2 
Secondary Objectives ...........................................................................40 
2.2.3 
Exploratory Objectives ........................................................................41 
3 
STUDY DESIGN...................................................................................................41 
3.1 
Study Design and Flow Chart ..........................................................................41 
3.1.1 
Rationale for Treatment and Dose Escalation .....................................42 
3.1.2 
Rationale for Primary Endpoint ...........................................................43 
3.1.3 
Rationale for Study Population ............................................................44 
3.2 
Duration and Study Completion Definition .....................................................44 
3.3 
Sites and Regions .............................................................................................44 
4 
STUDY POPULATION ........................................................................................45 
4.1 
Inclusion Criteria .............................................................................................45 
4.2 
Exclusion Criteria ............................................................................................46 
4.3 
Reproductive Potential .....................................................................................47 
4.3.1 
Female Contraception ..........................................................................47 
4.3.2 
Male Contraception ..............................................................................48 
4.4 
Withdrawal/Discontinuation from Study .........................................................48 
4.4.1 
Reasons for Discontinuation from Study .............................................48 
4.4.2 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ...............49 
5 
PRIOR AND CONCOMITANT TREATMENT ..................................................50 
5.1 
Prior Treatment ................................................................................................50 
5.2 
Concomitant Treatment ...................................................................................50 


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5.2.1 
Permitted Treatment .............................................................................50 
5.2.2 
Prohibited Treatment ...........................................................................51 
6 
STUDY MEDICATION ........................................................................................51 
6.1 
Identity of Investigational Product ...................................................................51 
6.1.1 
Blinding the Treatment Assignment ....................................................51 
6.2 
Administration of Study Medication ...............................................................52 
6.2.1 
Interactive Response Technology for Study Medication 
Management .........................................................................................52 
6.2.2 
Allocation of Treatment to Subjects ....................................................52 
6.2.3 
Dosing ..................................................................................................52 
6.2.4 
Unblinding the Treatment Assignment ................................................53 
6.3 
Labeling, Packaging, Storage, and Handling ...................................................54 
6.3.1 
Labeling ...............................................................................................54 
6.3.2 
Packaging .............................................................................................54 
6.3.3 
Storage .................................................................................................55 
6.4 
Drug Accountability.........................................................................................55 
6.5 
Subject Compliance .........................................................................................56 
7 
STUDY PROCEDURES .......................................................................................56 
7.1 
Study Schedule.................................................................................................56 
7.1.1 
Screening Period (Day -42 to Day 0) ...................................................57 
7.1.2 
Dose Escalation Period: Visit 1 (Week 0) to Visits 3–4 (Week 4–6) ..57 
7.1.3 
Stable Dosing Period............................................................................58 
7.1.3.1 
Visits 3–8 (Weeks 4, 6, 10, 14, 18, and 22) ................................58 
7.1.3.2 
Subject Contact (Weeks 5, 8, 12, 16, 20, and 24) .......................58 
7.1.3.3 
Visit 9 [End of Treatment (EOT)/Early Termination (ET)] 
(Week 26) ...................................................................................58 
7.1.4 
Safety Follow-up (Day 7 Post-treatment) ............................................59 
7.1.5 
Additional Care of Subjects After the Study .......................................59 
7.2 
Study Evaluations and Procedures ...................................................................59 
7.2.1 
Genetic Testing Results .......................................................................59 
7.2.2 
Efficacy ................................................................................................59 
7.2.2.1 
Itch Reported Outcome (ItchRO™) ............................................59 
7.2.2.2 
Serum Bile Acids and Other Cholestasis Biomarkers ................61 
7.2.3 
Medical History, Disease History, and Medication History ................61 
7.2.4 
Demographics ......................................................................................61 
7.2.5 
Safety ...................................................................................................61 
7.2.5.1 
Physical Examination..................................................................61 
7.2.5.2 
Adverse Event Collection ...........................................................62 
7.2.5.3 
Vital Signs (including Height and Weight) ................................62 
7.2.5.4 
Electrocardiograms .....................................................................62 


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7.2.5.5 
Clinical Laboratory Evaluations .................................................63 
7.2.5.6 
Pregnancy Test ............................................................................65 
7.2.5.7 
Ultrasound Liver Imaging ...........................................................65 
7.2.6 
Others ...................................................................................................65 
7.2.6.1 
Health-related Quality of Life and Pruritus Assessment ............65 
7.2.6.2 
Clinical Pharmacology Assessments ..........................................67 
7.2.6.3 
Healthcare Utilization .................................................................67 
7.2.7 
Volume of Blood to Be Drawn from Each Subject .............................67 
8 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ...................68 
8.1 
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events ................................................................................................68 
8.1.1 
Treatment-Emergent Adverse Event (TEAE) ......................................69 
8.1.2 
Unexpected Adverse Event ..................................................................69 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ..............69 
8.1.4 
Severity Categorization ........................................................................70 
8.1.5 
Relationship Categorization .................................................................70 
8.1.6 
Outcome Categorization ......................................................................71 
8.1.7 
Symptoms of the Disease Under Study ...............................................71 
8.1.8 
Clinical Laboratory and Other Safety Evaluations ..............................71 
8.1.9 
Pregnancy .............................................................................................72 
8.1.10 
Abuse, Misuse, Overdose, and Medication Error ................................72 
8.2 
Serious Adverse Event Reporting Procedures .................................................73 
8.2.1 
Reference Safety Information ..............................................................73 
8.2.2 
Reporting Procedures ...........................................................................73 
8.2.3 
Serious Adverse Event Definition .......................................................73 
8.2.4 
Serious Adverse Event Collection Time Frame ...................................74 
8.2.5 
Serious Adverse Event Onset and Resolution Dates ...........................74 
8.2.6 
Fatal Outcome ......................................................................................74 
8.2.7 
Regulatory Agency, Institutional Review Board, Ethics 
Committee, and Site Reporting ............................................................75 
8.3 
Safety Monitoring Rules ..................................................................................75 
8.3.1 
General Guidelines ...............................................................................75 
8.3.2 
Close Monitoring Criteria for Liver Parameters ..................................76 
8.3.3 
Guidelines for Interruption of Study Medication for Specific Liver 
Parameters ............................................................................................77 
8.3.4 
Rules for Study Medication Discontinuation Following 
Abnormalities of Liver Parameters ......................................................78 
8.3.5 
Safety Monitoring for Lipid Soluble Vitamins ....................................78 
8.3.6 
Safety Monitoring for Coagulation Panel Results ...............................81 


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8.3.7 
Study Medication Discontinuation Rules for Diarrhea ........................81 
9 
DATA MANAGEMENT AND STATISTICAL METHODS ..............................82 
9.1 
Data Collection ................................................................................................82 
9.2 
Clinical Data Management ..............................................................................82 
9.3 
Data Handling Considerations .........................................................................82 
9.4 
Statistical Analysis Process ..............................................................................82 
9.5 
Validation Analysis Plan..................................................................................83 
9.6 
Data Monitoring Committee ............................................................................83 
9.7 
Sample Size Calculation and Power Considerations .......................................84 
9.8 
Analysis Populations ........................................................................................85 
9.8.1 
PFIC Populations for Analyses ............................................................86 
9.9 
Subject Disposition, Demographics, and Baseline Characteristics .................86 
9.10 
Efficacy Analyses ............................................................................................87 
9.10.1 
Primary Efficacy Endpoint ..................................................................87 
9.10.2 
Adjustment for Multiplicity .................................................................92 
9.10.3 
Secondary Efficacy Endpoints .............................................................93 
9.10.4 
Exploratory Efficacy Endpoints ...........................................................95 
9.11 
Safety and Tolerability Analyses .....................................................................99 
9.11.1 
Adverse Events ..................................................................................100 
9.11.2 
Vital Signs and Weight/Height Measurements ..................................101 
9.11.3 
Laboratory Assessments ....................................................................101 
9.11.4 
Electrocardiograms ............................................................................101 
9.11.5 
Liver Ultrasound ................................................................................101 
9.11.6 
Concomitant Treatments ....................................................................101 
9.12 
Other Analyses ...............................................................................................102 
9.12.1 
Healthcare Utilization ........................................................................102 
9.12.2 
Pharmacokinetic Analyses .................................................................102 
10 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ........................102 
10.1 
Sponsor’s Responsibilities .............................................................................102 
10.1.1 
Good Clinical Practice Compliance ...................................................102 
10.1.2 
Indemnity/Liability and Insurance .....................................................103 
10.1.3 
Public Posting of Study Information ..................................................103 
10.1.4 
Study Suspension, Termination, and Completion..............................103 
10.2 
Investigator’s Responsibilities .......................................................................104 
10.2.1 
Good Clinical Practice Compliance ...................................................104 
10.2.2 
Protocol Adherence and Investigator Agreement ..............................104 
10.2.3 
Documentation and Retention of Records .........................................104 
10.2.3.1 
Case Report Forms ....................................................................104 


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10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ................................................................................105 
10.2.3.3 
Audit/Inspection ........................................................................105 
10.2.3.4 
Financial Disclosure ..................................................................105 
10.3 
Ethical Considerations ...................................................................................106 
10.3.1 
Informed Consent/Assent ..................................................................106 
10.3.2 
Institutional Review Board or Ethics Committee ..............................106 
10.4 
Privacy and Confidentiality ...........................................................................106 
10.5 
Study Results/Publication Policy ...................................................................107 
11 
REFERENCES ....................................................................................................108 
12 
APPENDICES .....................................................................................................111 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ...........................................................................34 
Table 2 
Sample Daily Exposure (mg/day) in Pediatric Subjects ............................43 
Table 3 
Prohibited Treatments and Time Restriction Prior to Baseline .................51 
Table 4 
List of Laboratory Analytes .......................................................................64 
Table 5 
Blood Sample Prioritization and Approximate Volume of Blood to Be 
Drawn from Each Subject ..........................................................................68 
Table 6 
Close Monitoring Criteria for Treatment-Emergent Elevated ALT and 
TSB ............................................................................................................76 
Table 7 
Recommended Starting Doses for Lipid Soluble Vitamins .......................79 
 
LIST OF FIGURES 
Figure 1 
Study Design Flow Chart ...........................................................................42 
Figure 2 
Flow Diagram for Treatment of Worsening of Lipid Soluble Vitamin 
Deficiency ..................................................................................................81 
 
LIST OF APPENDICES 
Appendix 1 
Clinical Outcomes Assessments ..............................................................112 
Appendix 2 
Observer Itch Reported Outcome Instrument ItchRO(Obs) ....................113 
Appendix 3 
Patient Itch Reported Outcome Instrument ItchRO(Pt) ...........................117 
Appendix 4 
Pediatric Quality of Life Inventory (PedsQL) .........................................120 
Appendix 5 
Impression of Severity Questionnaires ....................................................121 
Appendix 6 
Exploratory Diary Questionnaire .............................................................122 
Appendix 7 
Clinician Scratch Score ............................................................................125 
Appendix 8 
Patient Impression of Change (PIC) ........................................................126 
Appendix 9 
Caregiver Impression of Change (CIC) ...................................................127 
Appendix 10 
Management of Clinical Study Procedures and Participants during 
COVID-19 Pandemic or Other Force Majeure ........................................129 


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STUDY SYNOPSIS 
Protocol Number: MRX-502 
Drug: Maralixibat (formerly SHP625 or 
LUM001) 
Title of the Study: Randomized Double-blind Placebo-controlled Phase 3 Study to Evaluate the Efficacy 
and Safety of Maralixibat in the Treatment of Subjects with Progressive Familial Intrahepatic Cholestasis 
(PFIC) – MARCH-PFIC 
Short Title: A Placebo-controlled study of Maralixibat in Subjects with Progressive Familial Intrahepatic 
Cholestasis (PFIC)  
Number of Subjects (total and for each treatment arm): 
Up to approximately 30 subjects with PFIC2 will be enrolled in the primary cohort to achieve 26 subjects 
(13 per treatment group) completing the study.  Subjects in the primary cohort will be randomized 1:1 to the 
maralixibat or placebo treatment groups. 
A supplemental cohort of up to 60 subjects with other PFIC subtypes will also be included and randomized 
1:1 to the maralixibat or placebo treatment groups.   
Investigator(s): International, multicenter study 
Site(s) and Region(s):  
Study will be conducted at multiple sites in North America, Europe, Asia, and South America.  Other regions 
may be added, if necessary, for enrollment purposes. 
Study Period (planned): 2019 to 2022 
Clinical Phase: 
3 
Objectives 
Primary Objective 
• 
To evaluate the efficacy of maralixibat versus placebo on the severity of pruritus in participants 
with PFIC2  
Secondary Objectives 
• 
To evaluate the efficacy of maralixibat versus placebo on total serum bile acid (sBA) levels in 
participants with PFIC2  
• 
To evaluate the efficacy of maralixibat versus placebo on the severity of pruritus in participants with 
PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 
• 
To evaluate the efficacy of maralixibat versus placebo on total sBA levels in participants with PFIC 
(PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6)  
• 
To evaluate the efficacy of maralixibat versus placebo on the proportion of responders for the 
ItchRO(Obs) pruritus score in participants with PFIC2 and participants with PFIC (PFIC1, PFIC2, 
PFIC3, PFIC4, PFIC5, and PFIC6) 
• 
To evaluate the efficacy of maralixibat versus placebo on the sBA responder rate in participants 
with PFIC2 and participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 
• 
To evaluate the safety, tolerability, and pharmacokinetics of maralixibat versus placebo in all 
participants who receive at least 1 dose of study medication (safety population) 
Exploratory Objectives 
Additional endpoints may be explored to further characterize the efficacy and safety of maralixibat relative to 
placebo. 


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Rationale 
As of study initiation, there is no treatment approved for PFIC, and available medical approaches have 
limited efficacy.  Preliminary data from the first interim analyses from the Phase 2 Study LUM001-501 (an 
open-label study of the efficacy and long term safety of maralixibat in the treatment of cholestatic liver 
disease in pediatric subjects with PFIC) indicate that a subgroup of subjects with PFIC2 experienced 
clinically significant improvements following maralixibat treatment as manifested by a large reduction or 
normalization of sBA, reduction in pruritus (ItchRO[Obs]), and normalization of total serum bilirubin (TSB) 
and ALT for those with elevated baseline values.  Also, twice-daily (BID) dosing led to a higher response 
rate compared with the previously used once-daily (QD) dosing.  The current study is designed to confirm 
the effect of higher doses of maralixibat in PFIC2 and assess its effect on a broader PFIC population.  
Investigational Product, Dose, and Mode of Administration 
Subjects in the current study will receive maralixibat oral solution based on their individual body weight, up 
to 600 µg/kg BID.  Fixed concentrations of maralixibat oral solutions (i.e., 5, 10, 15, and 20 mg/mL) will be 
used.  To accurately measure the required volume, 0.5-, 1.0-, and 3.0-mL sized dosing dispensers will be 
provided.  The investigational product (IP) requires refrigerated storage conditions (2°C–8°C). 
As much as possible, the morning dose should be administered approximately 30 minutes before breakfast 
and the evening dose approximately 30 minutes before the main evening meal.  The doses will be 
administered prior to meals rather than every 12 hours to better cover the luminal bile acid release associated 
with meals. 
Methodology 
This is a 6-month, international, multicenter, randomized, double-blind, placebo-controlled Phase 3 study in 
subjects with PFIC.  The study will be followed by the long-term extension Study MRX-503, during which 
all subjects who complete Study MRX-502 will have the opportunity to be treated with maralixibat. 
Subjects will be randomized in a 1:1 ratio to the maralixibat or placebo treatment groups, respectively, stratified 
by cohort.  The cohorts are defined as follows: 
• 
Primary cohort, defined as subjects with non-truncated PFIC2  
• 
Supplemental cohort, defined as: 
o 
Subjects with PFIC1, PFIC3 or PFIC4  
o 
Subjects with PFIC after internal or external biliary diversion surgery or for whom internal 
or external biliary diversion surgery was reversed  
o 
Subjects with PFIC phenotype without a known mutation or with another known mutation 
not described above  
Within the supplemental cohort, subjects will be randomized 1:1 by the following subcohorts: 
a) PFIC1; b) PFIC3; c) all other supplemental cohort subjects. 
The study will be divided into 4 parts:  
1. Screening period (up to 6 weeks) 
2. Dose Escalation period (4–6 weeks) 
3. Stable Dosing period (20–22 weeks) 
4. Safety Follow-up period (7 days; for subjects discontinuing early and for subjects not enrolling into 
the extension study MRX-503) 
Subjects randomized to placebo will remain on placebo for the entire duration of the study.  The Dose 
Escalation period will consist of the following weekly steps: 
Dose level 1:  150 μg/kg maralixibat BID for 1 week 
Dose level 2:  300 μg/kg maralixibat BID for 1week 
Dose level 3:  450 μg/kg maralixibat BID for 1 week 
Dose level 4:  600 μg/kg maralixibat BID for the remaining duration of the study 


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Dose escalation should occur in the absence of major safety (e.g., liver parameters) or tolerability concerns 
(e.g., gastrointestinal [GI]-related treatment-emergent adverse events [TEAEs]) related or possibly related to 
study medication.  Subjects with such safety concerns can be down-titrated to a lower, previously tolerated 
dose level for 1 week before continuing dose escalation.  The minimum dose to continue in the study will be 
150 µg/kg maralixibat BID; subjects who cannot tolerate this dose will be discontinued from the study.  
Investigators have until Week 6 to determine the maximum tolerated dose; if re-challenges or further dose 
escalations fail, the subject will remain on the maximum tolerated dose level for the remainder of the Stable 
Dosing period to complete up to 20 weeks of stable dosing.  Dose reductions are allowed for the 
above-mentioned safety or tolerability reasons down to a minimum level of 150 µg/kg BID.  Subjects who 
cannot tolerate this dose will be discontinued from the study. 
During the Stable Dosing period, subjects will be allowed a maximum of 28 days (both morning and 
afternoon dose missed) of cumulative dose interruption.  During the last 12 Weeks of the Stable Dosing 
period (Week 15-26), subjects will be allowed a maximum of 17 days (both morning and afternoon dose) of 
cumulative dose interruption, but not more than 7 consecutive days.  Subjects may remain on study during 
dose interruptions and should continue to complete all regularly scheduled subject study visits and 
assessments.  After any dose interruption, subjects will reinitiate dosing at their maximum tolerated dose.  
Any dose interruption longer than the maximum allowed will be documented as a protocol deviation.   
Any subject who has over 56 days (both morning and afternoon dose) of cumulative dose interruption during 
the Stable Dosing period should be discontinued from the study.   
Figure 1 
Study Design Flow Chart 
 
 
 
BID=twice daily; Scr=screening; W=week 
600 µg/kf Bio--. 
600 µg/kg BIO (or maximum ~
dose) 
450 µg/kg BID 
300 µg/kg BIO 
1 SOµg/kg BID 
Stable Dosing 
(4-6 weeks).a 
(20-22 weeks) ;a 
W O 
W1 
W2 
W3 
W4 ws W6 
ws 
W10 W12 
W14 W16 
W18 W20 W22 W24 W26* 
w21• 
(if applicable) 
t 
t • t • t• t • t • t • t • t • t • 
t = Clinic Visit 
• 
= Telephone or Email Contact 
• = End of Treatment/Earl Termination 
a Dose escalation may occur over 4-6 weeks depen ding on tolerability. Stable dosing will occur over 20-22 weeks, depending on the duration of the dose escalation period. 
b Safety follow-up visit for subjects. not continuing Into the extension s.tudy {MRX-503). 


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Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Informed consent and assent (as applicable) per Institutional Review Board/Ethics Committee 
(IRB/EC)  
2. Male or female subjects with a body weight ≥5 kg, who are ≥12 months and <18 years of age at 
time of baseline 
3. Cholestasis as manifested by total sBA ≥3× ULN (applies to primary cohort only) 
4. An average AM ItchRO(Obs) score ≥1.5 during 4 consecutive weeks of the screening period, leading 
to the baseline visit (Visit 1) 
5. Completion of at least 21 valid* morning ItchRO(Obs) entries during 4 consecutive weeks of the 
screening period, leading to the baseline visit (Visit 1) (*valid=completed and not answered as “I 
don’t know”; maximum allowed invalid reports=7, no more than 2 invalid reports during the last 
7 days before randomization) 
6. Diagnosis of PFIC based on the following: 
Chronic cholestasis as manifested by persistent (>6 months) pruritus in addition to biochemical 
abnormalities and/or pathological evidence of progressive liver disease 
and 
Primary Cohort: 
Subjects with genetic testing results consistent with biallelic disease-causing variation in 
ABCB11 (PFIC2), based on standard-of-care genotyping  
Supplemental Cohort:  
i. 
Subjects with genetic testing results consistent with biallelic disease-causing variation 
in ATP8B1 (PFIC1), ABCB4 (PFIC3), or TJP2 (PFIC4), based on standard-of-care 
genotyping 
ii. 
Subjects with PFIC phenotype without a known mutation or with another known 
mutation not described above or with intermittent cholestasis as manifested by 
fluctuating sBA levels 
iii. 
Subjects with PFIC after internal or external biliary diversion surgery or for whom 
internal or external biliary diversion surgery was reversed 
7. Male and females of non-childbearing potential.  Males and non-pregnant, non-lactating females of 
childbearing potential who are sexually active must agree to use acceptable methods of 
contraception during the study and 30 days following the last dose of the study medication.  
Females of childbearing potential must have a negative pregnancy test result. 
8. Access to email or telephone for scheduled remote visits 
9. Ability to read and understand the questionnaires (both caregivers and subjects above the age of 
assent) 
10. Access to consistent caregiver(s) during the study 
11. Subject and caregiver willingness to comply with all study visits and requirements 
Exclusion Criteria 
1. Predicted complete absence of bile salt excretion pump (BSEP) function based on the type of 
ABCB11 mutation (PFIC2), as determined by a standard-of-care genotyping (applies to primary 
cohort only).  Subjects can enter the study in the supplemental cohort (under inclusion criteria 6.ii or 
6.iii). 


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2. Recurrent intrahepatic cholestasis, indicated by a history of sBA levels <3x ULN or intermittent 
pruritus (applies to primary cohort only) 
3. Current or recent history (<1 year) of atopic dermatitis or other non-cholestatic diseases associated 
with pruritus 
4. History of surgical disruption of the enterohepatic circulation (applies to primary cohort only) 
5. Chronic diarrhea requiring intravenous fluid or nutritional intervention for the diarrhea and/or its 
sequelae at screening or during the 6 months prior to screening 
6. Previous or need for imminent liver transplant 
7. Decompensated cirrhosis (international normalized ratio [INR] >1.5, albumin <30 g/L, history or 
presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy) 
8. ALT or total serum bilirubin (TSB) >15× ULN at screening 
9. Presence of other liver disease 
10. 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 
11. Possibly malignant liver mass on imaging, including screening ultrasound 
12. Known diagnosis of human immunodeficiency virus (HIV) infection 
13. Any prior cancer diagnosis (except for in situ carcinoma) within 5 years before the screening visit 
(Visit 0)  
14. Any known history of alcohol or substance abuse 
15. Administration of bile acids or lipid binding resins, or phenylbutyrates during the screening period 
16. Criterion has been deleted as of Amendment 3. 
17. Administration of any investigational drug, biologic, or medical device during the screening period 
18. Previous use of an ileal bile acid transporter inhibitor (IBATi) 
19. History of nonadherence to medical regimens, unreliability, medical condition, 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 subject, or lead to 
nonadherence with the study protocol or inability to conduct the study procedures 
20. Known hypersensitivity to maralixibat or any of its excipients 
Enrollment in the study will be considered complete once the target number of subjects has been reached in 
the primary cohort.  Enrollment into the supplemental cohort will be capped at a maximum of 60 subjects. 
Maximum Duration of Subject Involvement in the Study: 
• 
Planned duration of Screening period: up to 6 weeks 
• 
Planned duration of Dose Escalation period: 4–6 weeks (maximum 6 weeks) 
• 
Planned duration of Stable Dosing period: 20–22 weeks (minimum 20 weeks) 
• 
Planned duration of Safety follow-up: 7 days (for subjects discontinuing early for reasons other than 
safety/tolerability and subjects not enrolling into the extension study MRX-503) 
Active treatment duration: up to 26 weeks 
Total study duration: up to 33 weeks 


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Endpoints and Statistical Analysis: 
Subject Populations 
• 
The intent-to-treat (ITT) population will consist of all randomized subjects.   
• 
The per-protocol population will consist of all subjects in the ITT population who receive at least 
1 dose of study medication and do not have any major protocol violations or deviations.  Major 
protocol violations/deviations will be identified prior to database lock. 
• 
The safety population will consist of all subjects who receive at least 1 dose of study medication. 
Endpoints 
Efficacy Endpoints 
Primary Efficacy Endpoint 
• 
Mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 
through Week 26, using 4-week average morning ItchRO(Obs) severity scores 
Secondary Efficacy Endpoints 
• 
Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 
• 
Mean change in the average morning ItchRO(Obs) severity score between baseline and Week 15 
through Week 26 in participants with PFIC 
• 
Proportion of ItchRO(Obs) responders from Week 15 to Week 26 
o 
For the purpose of determining response, the average value from the three 4-week periods 
(Weeks 15-18, 19-22, and 23-26) will be computed and used. 
• 
Proportion of sBA responders from Week 18 to Week 26 
o 
For the purpose of determining response, the average value from Weeks 18, 22, and 26 values 
will be computed and used. 
Safety & Tolerability Endpoints  
• 
Treatment emergent AEs will be further summarized by severity and relationship to study 
medication.  Adverse events related to study medication, AEs leading to withdrawal, SAEs, and 
deaths will be similarly summarized. 
• 
Change from baseline in clinical laboratory values, physical examination findings (including body 
weight, height, and body mass index [BMI]), vital signs, and electrocardiogram (ECG) parameters 
Other Endpoints 
• 
Healthcare resource utilization between baseline and Week 26 will be analyzed. 
• 
Systemic concentrations of maralixibat in plasma will be determined at pre-dose and at 
approximately 2.5 hours after the morning dose at Week 10 and Week 26 (EOT/ET) 
The primary and secondary efficacy endpoints will be evaluated in participants with PFIC2 and participants 
with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6).  
All safety analyses will be performed in the safety population and separately in participants with PFIC2  and 
participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, PFIC6).   


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In general, baseline is defined as all data collected at Visit 1 (Day 0) or the last assessment before the first 
dose of the study medication if the data are not collected at Visit 1 (Day 0).  Baseline ItchRO and EDQ 
average scores are defined as the 4-week average score prior to the first dose of study medication. 
Statistical Methodology for Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the mean change in the average morning ItchRO(Obs) severity 
score between baseline and Week 15 through Week 26, using 4-week average morning ItchRO(Obs) severity 
scores.  The baseline average morning ItchRO(Obs) score is defined as the 4-week average morning 
ItchRO(Obs) severity score prior to the first dose of the study medication. 
The primary analysis on the primary efficacy endpoint will be conducted in participants with PFIC2 who 
fulfill criteria for the primary cohort in the ITT population.  A restricted maximum likelihood (REML)-based 
mixed-effects model for repeated measures (MMRM) will be used as the primary analysis method.  The 
repeated measures include post-baseline visits during the dose escalation phase (i.e., Week 6) and stable 
dosing phase (i.e., Weeks 10, 14, 18, 22, and 26), with change from baseline in the 6- or 4-week average 
morning ItchRO(Obs) severity score as the dependent variable.  The MMRM model will include the fixed, 
categorical effects of treatment group, visit, and treatment group-by-visit interaction as well as the 
continuous, fixed covariates of baseline 4-week average morning ItchRO(Obs) severity score and the 
baseline score-by-visit interaction.  The unstructured variance/covariance matrix will be used to model the 
variances and covariances for the 6 time points (periods) included in the model.  The unstructured 
variance/covariance does not impose any restrictions on the pattern of the matrix elements.  Every attempt 
(e.g., relaxing the convergence criteria, increasing the iteration limit, choosing reasonable starting values for 
the estimates) will be made to ensure convergence using the unstructured modeling of within-subject 
correlations.  The primary efficacy analysis will compare maralixibat and placebo using the contrast 
(difference in least squares [LS] mean) between treatment groups during the last 12 weeks of the study 
(i.e., Weeks 15 to 26 combined).  
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 last 12 weeks of the study is ≤0.05.  Least squares means will be calculated for 
each treatment group for each post-baseline period in the model.  The difference between maralixibat and 
placebo change from baseline in average morning ItchRO(Obs) severity score will be estimated, with the 
corresponding 2-sided 95% confidence interval (CI) constructed for each period, and the last 12 weeks 
(i.e., last 3 periods) 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.  
Sensitivity and supportive analysis for the primary efficacy endpoint will be conducted in PFIC2 participants 
who fulfill criteria for the primary cohort in the ITT population using the MMRM model as the primary 
analysis. 
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. 
Adjustment for Multiplicity 
In order to maintain study-wide Type I error control, 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.  
Analysis for Secondary Efficacy Endpoints 
Analysis similar to that described for the primary efficacy endpoint, including the sensitivity analyses, will 
be performed for the secondary efficacy endpoints.  Analyses will be conducted separately in participants 
with PFIC2 and participants with PFIC (PFIC1, PFIC2. PFIC3. PFIC4, PFIC5, PFIC6) in the ITT population.  
Analysis of the secondary efficacy endpoints will also be performed on both populations in the per-protocol 
population.  


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For the binary (responder) outcomes, the number and proportion of subjects that are considered a 
“responder” will be summarized by treatment group at the end-of-study visit (Week 26/EOT).  Barnard’s 
exact test will be used to calculate the p-value for the difference between treatment groups.  
All tests will be performed as 2-sided tests at the 0.05 level of significance. 
Statistical Methodology for Exploratory Efficacy Endpoints 
Any analyses on the exploratory efficacy endpoints will be performed in the ITT population.  Exploratory 
analyses may be performed separately on participants with PFIC2, PFIC (PFIC1, PFIC2, PFIC3, PFIC4, 
PFIC5, and PFIC6) and other PFIC populations of interest.  All tests will be performed as 2-sided tests at the 
0.05 level of significance. 
Sensitivity analysis will not be performed on the exploratory endpoints. 
Statistical Methodology for Safety Endpoints 
All safety analyses will be performed in the safety population and separately in participants with PFIC2 and 
participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, PFIC6).  Safety measures will be summarized 
descriptively.  For quantitative variables, descriptive statistics including number of observations, mean, 
median, standard deviation, minimum, and maximum will be presented for the observed and change from 
baseline (Visit 1) values at each study visit.  Qualitative variables will be summarized using counts and 
percentages. 
Adverse events and concomitant treatments will be coded with standard dictionaries and will be summarized 
by treatment received. 
Statistical Methodology for Pharmacokinetic Endpoint(s) 
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, median, 
minimum, maximum, and geometric mean) will be determined for maralixibat concentrations at each 
nominal time point and sampling time.   


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ABBREVIATIONS 
ABCB4 
ATP binding cassette subfamily B member 4 
ABCB11 
ATP binding cassette subfamily B member 11 
ADR 
adverse drug reaction 
AE 
adverse event 
AFP 
α-fetoprotein 
ALG 
Alagille syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APRI 
AST-to-platelet ratio index 
ASBTi 
apical sodium-dependent bile acid transporter inhibitor 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
ATP8B1 
ATPase phospholipid transporting 8B1 
β-hCG 
beta-human chorionic gonadotropin 
BID 
twice daily (dosing) 
BL 
baseline 
BMI 
body mass index 
BSEP 
Bile Salt Excretion Pump 
C4 
7α-hydroxy-4-cholesten-3-one 
CBC 
complete blood count 
CI 
confidence interval 
CIC 
Caregiver Impression of Change 
CIS 
Caregiver Impression of Severity 
COA 
Clinical Outcomes Assessment 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CSS 
Clinician Scratch Scale 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
EDQ 
exploratory diary questionnaire 
EOT 
end of treatment 
ET 
early termination 
FDA 
US Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
GI 
gastrointestinal 
GCP 
Good Clinical Practice 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 


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ItchRO™ 
Itch Reported Outcome 
ItchRO(Obs)™ 
Observer-reported Itch Reported Outcome Instrument 
ItchRO(Pt)™ 
Patient-reported Itch Reported Outcome Instrument 
IRT 
interactive response technology 
ITT 
intent-to-treat (ITT) (population) 
LC-MS 
liquid chromatography–mass spectrometry 
LDH 
lactate dehydrogenase 
LS 
least squares 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model for end-stage liver disease 
MMRM 
mixed effect model for repeated Measures 
MNAR 
missing not at random 
PEBD 
partial external biliary diversion  
PedsQL 
Pediatric Quality of Life Inventory 
PELD 
pediatric end-stage liver disease 
PFIC 
progressive familial intrahepatic cholestasis 
PG 
propylene glycol 
PIC 
Patient Impression of Change 
PIS 
Patient Impression of Severity 
PK 
pharmacokinetics 
QD 
once daily (dosing) 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acid 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent AE 
TJP2 
tight junction protein 2 gene 
TSB 
total serum bilirubin 
ULN 
upper limit of normal 
VAP 
validation analysis plan 
WHO-DD 
World Health Organization Drug Dictionary 
 


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Table 1 
Schedule of Assessments 
Proceduresp 
Screening a 
Dose Escalation (4-6 weeks) 
  
Stable Dosing (20-22 weeks) 
Follow-up  
Visit/Subject 
Contact # 
Screening / 
V0 
Baseline / 
V1 
Subject 
contact 
V2 
Subject 
contact 
V3 
Subject 
contact 
V4 
Subject 
contact 
V5 
Subject 
contact 
V6 
Subject 
contact 
V7 
Subject 
contact 
V8 
Subject 
contact 
EOT/ET 
V9b 
Study Week 
-6 
0 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
27 
Study Day 
Day -42 
0 
7 
14 
21 
28 
35 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
189 
Window (in days) 
(-5) 
  
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±2) 
Informed 
Consent/Assent 
(10.3.1) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility 
Assessment 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics (7.2.4) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History  
(7.2.3) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical & Vital 
signsc  
(7.2.5.1,7.2.5.3) 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
ECG (7.2.5.4) 
X 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
Liver Ultrasoundd 
(7.2.5.7) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Pregnancy Teste 
(7.2.5.6) 
S 
U 
  
  
  
U 
  
U 
  
U 
  
U 
  
U 
  
U 
  
S 
  
Confirm PFIC 
Genotype Resultsf 
(7.1.1 and 7.2.1) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
eDiary Device 
Provided / Returnedg  
P 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
R 
  
ItchRO(Obs), 
ItchRO(Pt) & EDQ 
(7.2.2.1, 7.2.6.1.7) 
Twice-daily completion of ItchRO & EDQ 
  
Review eDiary & 
Assess Compliance 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Randomized 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CISh (7.2.6.1.2) 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
PISi (7.2.6.1.3) 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
PIC (7.2.6.1.5) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  


Mirum Pharmaceuticals 
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Proceduresp 
Screening a 
Dose Escalation (4-6 weeks) 
  
Stable Dosing (20-22 weeks) 
Follow-up  
Visit/Subject 
Contact # 
Screening / 
V0 
Baseline / 
V1 
Subject 
contact 
V2 
Subject 
contact 
V3 
Subject 
contact 
V4 
Subject 
contact 
V5 
Subject 
contact 
V6 
Subject 
contact 
V7 
Subject 
contact 
V8 
Subject 
contact 
EOT/ET 
V9b 
Study Week 
-6 
0 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
27 
Study Day 
Day -42 
0 
7 
14 
21 
28 
35 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
189 
Window (in days) 
(-5) 
  
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±2) 
CIC (7.2.6.1.6) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
PedsQLj (7.2.6.1.1) 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Clinician Scratch 
Scale (7.2.6.1.4) 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
CBC with Differential 
(7.2.5.5, 8.3.2) 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Coagulation  
(7.2.5.5, 8.3.6) 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Chemistry Panel 
(7.2.5.5, 8.3.2, 8.3.3) 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Lipid Panelk (7.2.5.5) 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Urinalysis (7.2.5.5) 
  
X 
  
  
  
  
  
X 
  
X 
  
  
  
X 
  
  
  
X 
  
FGF-19, Autotaxin, 
C4k (7.2.2.2, 7.2.5.5) 
  
X 
  
  
  
  
  
X 
  
X 
  
  
  
X 
  
  
  
X 
  
sBA collectionk 
(7.2.2.2, 7.2.5.5) 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Lipid Soluble 
Vitaminsk,l  
(7.2.5.5, 8.3.5) 
  
X 
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
AFP Sample (7.2.5.5) 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
PK Samplem (7.2.6.2) 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
Serum storage sample 
(7.2.5.5) 
  
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Healthcare Utilization 
(7.2.6.3) 
  
  
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
Study Medication 
Suppliedn  (6) 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Study Medication 
Administrationo (6) 
  
Twice-daily administration  
  
Assess AEs (8) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and 
Concomitant 
Treatments (5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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AFP=a-fetoprotein; C4=7a-hydroxy-4-cholesten-3-one; CBC=complete blood count; CIS=Caregiver Impression of Severity; CIC=Caregiver Impression of 
Change; ECG=electrocardiogram; EDQ=exploratory diary questionnaire; EOT=end of treatment; ET=early termination; FGF-19=fibroblast growth factor-19;  
ItchRO=Itch Reported Outcome; P=Provided; PedsQL=Pediatric Quality of Life Inventory; PIC=Patient Impression of Change; PIS=Patient Impression of 
Severity of Pruritus; PK=pharmacokinetic; R=Returned; S=Serum; U= Urine; V=visit 
a 
Subjects who initially fail to meet eligibility criteria may be re-assessed during the 6-week screening period prior to being captured as a screen failure.  
Subjects may also be re-screened. 
b 
Study sites should record dates of any future scheduled procedures related to PFIC (e.g., PEBD, ileal exclusion, liver transplant, or listed for liver transplant), 
if known at this visit. 
c 
Blood pressure, heart rate, temperature, respiration rate.  Height and weight will be measured by trained staff using standardized methodology, incl. 
calibrated stadiometer or headboard and calibrated balance, respectively. 
d 
Screening ultrasound not required if an ultrasound or liver MRI less than 6 months old is available. 
e 
Females of childbearing potential only; result must be reviewed prior to dispensing study medication. 
f 
Genotyping results will be reviewed by sponsor or designee. 
g 
Caregivers and age-appropriate subjects will be instructed to complete their eDiary twice daily (morning and evening). 
h 
To be completed by caregivers for all subjects 
i 
To be completed only by subjects aged ≥9 years at screening 
j 
To be completed by subjects and caregivers using the age-appropriate PedsQL module 
k 
Subjects should make every effort to fast at least 6 hours prior to collection.  Water intake is permitted if necessary but not recommended. 
l 
Blood samples must be drawn before administration of vitamin supplementation. 
m 
PK samples will be drawn pre-dose, and approximately 2.5 hours after the morning dose. 
n 
If needed, study medication may be supplied via direct-to-patient shipments in between site visits, see Section 6.4. 
o 
Subjects will self-administer (or will be administered) the first dose of study medication in the clinic on Visit 1/Day 0 after breakfast under the supervision 
of the investigator or trained site staff. 
p 
See Appendix 10 for management of study procedures during pandemic. 


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1 
BACKGROUND INFORMATION 
1.1 
Indication and Current Treatment Options  
Progressive familial intrahepatic cholestasis (PFIC) is a rare autosomal recessive liver 
disorder characterized by intrahepatic cholestasis due to canalicular bile transport defects.  
There are more than 4 subtypes of PFIC classified based on different mutations.  PFIC1, 2, 
and 3 result from mutations in the ATPase phospholipid transporting 8B1 (ATP8B1), ATP 
binding cassette subfamily B member 11 (ABCB11), and ATP binding cassette subfamily B 
member 4 (ABCB4) genes, respectively, and all share the main clinical manifestations of 
cholestasis and pruritus.  PFIC4 is based on mutations in the tight junction protein 2 gene 
(TJP2) and leads to failure of protein localization, disruption of tight-junction structure, and 
severe cholestatic liver disease (Sambrotta, 2014).  In children, PFIC represents 10%–15% of 
causes of cholestasis and 10%–15% of indications for liver transplantations (Davit-Spraul et 
al., 2009).  PFIC2 is the most common subtype and is diagnosed in approximately 50%–60% 
of PFIC patients (Al Mehaidib and Al Shahrani, 2013) while PFIC1 (also known as Byler’s 
disease) and PFIC3 account for approximately 10%–20% (Alissa et al., 2008; Davit-Spraul et 
al., 2009) and 30%–40% of the PFIC population, respectively (Al Mehaidib and Al Shahrani, 
2013).  
PFIC is associated with early mortality, morbidity, and devastating consequences on patients’ 
quality of life.  In the absence of surgery, PFIC1 and PFIC2 are very aggressive diseases with 
only 10%–15% of PFIC1 and PFIC2 (depending on the variant) subjects surviving through 
the age of 18 (Jericho, 2015).  PFIC2 is associated with a continuous progressive course of 
symptoms (Al Mehaidib and Al Shahrani, 2013).  While extrahepatic involvement such as 
pancreatitis or diarrhea can be a feature of PFIC1, the initial presentation and evolution of the 
disease in PFIC2 tends to be more severe than in PFIC1, with persistent jaundice occurring 
within the first months of life and rapid progression to cirrhosis and liver failure within the 
first years of life (Pawlikowska et al., 2010).  Interruption of the entero-hepatic circulation of 
bile acids through partial external biliary diversion (PEBD) surgery can lead to promising 
results with respect to pruritus, jaundice, and histology, both in patients with PFIC1 and 
PFIC2.  Schukfeh, 2012 reported a dramatic 1 year outcome in patients undergoing PEBD 
with 13/21 (62%) of patients normalizing serum bile acids (sBAs) and liver function; 
however, other groups have reported overall failure rates of PEBD of up to 30% with 
30%-50% of patients requiring repeat surgery (Halaweish and Chwals, 2010).  Additionally, 
PEBD must be performed before liver fibrosis and cirrhosis are established for optimal 
benefit.  For the vast majority of patients who do not undergo PEBD or do not respond, liver 
transplantation may be the only treatment option (Emerick et al., 2008; Yang et al., 2009; 
Arnell et al., 2010; Schukfeh et al., 2012).  
As of study initiation, given the clinical outcomes associated with PFIC, including the 
profound negative impact on patients’ and caregivers’ quality of life, and the fact that there 
are no approved treatments, there is a clear unmet medical need for a novel treatment for this 
disease. 


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1.2 
Product Background and Clinical Information 
Maralixibat chloride (maralixibat; formerly SHP625, LUM001) is a potent inhibitor 
(IC50=0.3 nM) of the apical sodium-dependent bile acid transporter/ileal bile acid 
transporter/solute carrier family 10 (sodium/bile acid co-transporter family) member 2 
(ASBT/IBAT/SLC10A2), a transmembrane protein localized on the luminal surface of ileal 
enterocytes (hereafter referred to as IBAT).  Maralixibat was designed to be minimally 
absorbed, therefore maximizing the local exposure of the molecule to the receptor and 
minimizing systemic exposure of the drug and limiting drug-drug interactions and systemic 
toxicity.  These characteristics include a high molecular weight of 740 Da and the addition of 
a positively charged quaternary amino moiety that can interact with the negatively charged 
surface of the enterocyte cell membrane and prevent absorption.  
The pharmacokinetics (PK), safety, and efficacy of maralixibat were assessed in a previous 
clinical development program that evaluated maralixibat as a potential lipid-lowering agent 
in patients with hypercholesterolemia.  The hypercholesterolemia program was terminated by 
the previous sponsor for strategic and commercial reasons, and current development efforts 
are focused on rare pediatric cholestatic liver diseases, including Alagille syndrome (ALGS) 
and PFIC. 
Maralixibat plasma levels (parent and potential metabolites) after chronic oral administration 
in adults, adolescents, and children are consistent with a drug that is minimally absorbed.  
Plasma concentrations, when measured, have been low to undetectable at most timepoints 
following oral doses at or below 20 mg in adults and in pediatric patients with ALGS 
receiving doses up to 280 μg/kg/day (maximum dose 20 mg/day).  These results are 
consistent with the low absolute bioavailability (≤1%) observed in nonclinical studies with 
maralixibat and in a clinical study where a dose of 5 mg 14C-maralixibat was administered.  
These data support the conclusion that maralixibat is minimally absorbed in humans.  While 
the low bioavailability of maralixibat may complicate many classical drug development 
aspects such as characterization of PK (Cmax, t1/2, etc.), receptor occupancy, dose ranging and 
PK-PD correlation, etc., the potential for systemic adverse interactions with other drugs is 
expected to be less than for well-absorbed drugs.  Drug interaction studies with both 
lovastatin and simvastatin and with atorvastatin indicated no clinically significant 
interactions with maralixibat and these statins (both parent and active metabolite). 
The previous hypercholesterolemia clinical program comprised 12 studies across which a 
total of >1400 adult subjects were exposed to maralixibat.  Maralixibat was found to be safe 
at investigated daily doses up to 100 mg over 28 days and up to 40 mg over 10 weeks.  The 
most commonly reported adverse drug reactions (ADRs) were abdominal cramping/pain and 
diarrhea/loose stools, which are believed to be mechanism-based due to elevated bile acid 
concentrations in the colon.  The majority of adverse events (AEs) were characterized as 
mild or moderate in severity, except for severe nausea, diarrhea, or abdominal pain in 
6 subjects.  Except for a single serious AE (SAE) of cholecystitis reported in 1 study, no 
other SAEs related to maralixibat have been reported in these studies and no clinically 
significant laboratory abnormalities were documented in maralixibat-treated subjects.  


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More than 180 subjects have been exposed to maralixibat, some for longer than 3 years, in 
the current cholestatic liver disease program, which includes 4 completed Phase 2 studies 
(2 studies in ALGS, 1 study in primary biliary cholangitis, and 1 study in primary sclerosing 
cholangitis), 1 completed Phase 1 study in overweight/obese adult male subjects, and 
4 ongoing Phase 2 studies (3 studies in ALGS and 1 study in PFIC).  Consistent with the 
previous clinical program, the most commonly reported ADRs in this program have been 
abdominal cramping/pain and diarrhea/loose stools, the majority of which have been mild or 
moderate in severity.  Reported related SAEs include abdominal pain (2 cases), abdominal 
pain upper (3 cases), diarrhea, cholangitis, blood bilirubin increased, international normalized 
ratio (INR) increased, pancreatitis, alanine aminotransferase (ALT) increased, autoimmune 
hepatitis, hematochezia, and anemia.  No deaths or important new risks have been identified 
to date.  A program-wide review of liver safety parameters, including an independent 
external expert adjudication of selected cases, indicated that maralixibat may cause ALT 
elevations in a certain percentage (2%–5% probably, 10%–20% probably or possibly related 
events) of subjects with ALGS.  No predictors of this treatment response have been identified 
so far.  None of the observed events were serious and none led to liver-related morbidity or 
mortality.  There is no evidence to date that this effect is due to a direct hepatotoxic effect 
from the minimal amount of maralixibat that is systemically absorbed.  It is more likely that 
the observed abnormalities might rather be due to an indirect, compensatory effect on the 
liver from intestinal IBAT inhibition instead.  The long-term consequences of the observed 
ALT elevations remain unclear.  There is currently no evidence that maralixibat causes 
bilirubin elevations in patients with ALGS, and there is insufficient evidence of an 
association between bilirubin or liver enzyme elevations and maralixibat treatment in patients 
with PFIC. 
In the ongoing Phase 2 study in subjects with PFIC (Study LUM001-501), an open-label 
study of the efficacy and long-term safety of maralixibat in the treatment of cholestatic liver 
disease in pediatric patients with PFIC, preliminary data from a first interim analysis 
demonstrated significant improvements in a subgroup of 6 out of 25 subjects with PFIC2 at 
doses of up to 280 µg/kg once daily (QD).  A subsequent dose increase to 280 µg/kg twice 
daily (BID) produced a similar improvement in 1 additional PFIC2 subject who did not 
respond to the previous dose regimen.  These improvements consisted of normalization or 
≥70% decrease in sBA levels, concomitant with an increase in 7α-hydroxy-4-cholesten-3-one 
(C4) levels, a disappearance or clinically meaningful improvement in pruritus, as well as an 
increase in quality-of-life scores.  Liver-related parameters (aspartate aminotransferase 
[AST]/ALT and total serum bilirubin [TSB]) were also normalized in those subjects with 
abnormal baseline values.  Finally, the treatment responders experienced a significant 
catch-up growth, as indicated by a positive height and weight z-score change from baseline, 
as compared with those subjects who did not respond to maralixibat treatment.  
As of study initiation, based on the high unmet medical need, the current absence of 
approved pharmacological therapy, the complications with surgical treatment options (liver 
transplantation and PEBD) with the need for lifelong immunosuppression or stoma care, and 
the overall benign safety profile and unabsorbed nature of maralixibat, the benefit-risk ratio 
is considered supportive of the present study.  Always refer to the latest version of the 
maralixibat chloride Investigator’s Brochure (IB) for the overall risk/benefit assessment and 


Mirum Pharmaceuticals 
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the most accurate and current information regarding the drug metabolism, PK, efficacy, and 
safety of maralixibat.  
2 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
As of study initiation, there is no approved treatment for PFIC, and available medical 
approaches have limited efficacy.  Preliminary data from the first interim analysis from 
the Phase 2 Study LUM001-501 in subjects with PFIC indicate that a subgroup of subjects 
with PFIC2 experienced clinically significant improvements following maralixibat 
treatment as manifested by a large reduction or normalization of sBA, reduction in 
ItchRO(Obs), and normalization of TSB and ALT for those with elevated baseline values.  
Also, BID dosing led to a higher response rate compared with the previously used QD 
dosing.  The current study is designed to confirm the effect of higher doses of maralixibat in 
PFIC2 and assess its effect on a broader PFIC population. Because all treatment responders 
in Study LUM001-501 were subjects with PFIC2, the primary efficacy analyses will be 
limited to this subpopulation.   
The efficacy and safety of maralixibat in PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and 
PFIC6) and other patient subpopulations will also be assessed based on the rationale that 
maralixibat also has the potential to lead to sBA and pruritus reduction in the broader PFIC 
population and its subtypes. 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
• To evaluate the efficacy of maralixibat versus placebo on the severity of pruritus in 
participants with PFIC2  
2.2.2 
Secondary Objectives 
• To evaluate the efficacy of maralixibat versus placebo on total sBA levels in 
participants with PFIC2  
• To evaluate the efficacy of maralixibat versus placebo on the severity of pruritus in 
participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6)  
• To evaluate the efficacy of maralixibat versus placebo on total sBA levels in 
participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6)  
• To evaluate the efficacy of maralixibat versus placebo on the proportion of 
responders for the ItchRO(Obs) pruritus score in participants with PFIC2 and 
participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6)  


Mirum Pharmaceuticals 
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• To evaluate the efficacy of maralixibat versus placebo on the sBA responder rate in 
participants with PFIC2 and participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, 
PFIC5, and PFIC6)  
• To evaluate the safety, tolerability, and pharmacokinetics of maralixibat versus 
placebo in all participants who receive at least 1 dose of study medication (safety 
population) 
2.2.3 
Exploratory Objectives 
Additional endpoints may be explored to further characterize the efficacy and safety of 
maralixibat relative to placebo. 
3 
STUDY DESIGN 
3.1 
Study Design and Flow Chart 
This is a 6-month international, multicenter, randomized, double-blind, placebo-controlled 
Phase 3 study in subjects with PFIC aged ≥12 months and <18 years at time of baseline.  
The primary analysis will be conducted in the ITT population of subjects with documented 
biallelic mutations in ABCB11 (PFIC2), based on standard-of-care genotyping (primary 
cohort criteria).  Subjects with a predicted complete absence of bile salt excretion pump 
(BSEP) function based on the type of ABCB11 mutation (PFIC2), as determined by a 
standard-of-care genotype, are excluded from the primary cohort and can enroll only in the 
supplemental cohort.  Subjects with other PFIC subtypes (e.g., PFIC1/3/4, or new PFIC 
mutation variants) or postsurgical subjects (e.g., after internal or external biliary diversion 
surgery or subjects with reversal of biliary diversion surgery) will be enrolled in a separate 
supplemental cohort and evaluated as part of secondary and exploratory analyses (see 
Section 9.8).  
Subjects in the primary cohort will be randomized in a 1:1 ratio to receive maralixibat or 
placebo.  Subjects in the supplemental cohort will be randomized in a 1:1 ratio to receive 
maralixibat or placebo within the following subcohorts: a) PFIC1; b) PFIC3; c) all other 
supplemental cohort subjects.  For further information about the treatment allocation, refer 
to Section 6.2.2.  All subjects will receive study treatment in addition to standard-of-care 
therapy, including antipruritic concomitant treatment (for prohibited treatments, see 
Section 5.2.2). 
In the primary cohort, approximately 30 subjects will be enrolled in order to achieve 
26 subjects (13 per treatment group) completing the study.  In the supplemental cohort, 
overall enrollment will be capped at a maximum of 60 subjects.  
The study will be divided into 4 parts (see Figure 1): 
1. Screening period (up to 6 weeks) 
2. Dose Escalation period (4–6 weeks) 


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3. Stable Dosing period (20–22 weeks) 
4. Safety Follow-up period (7 days; for subjects discontinuing early and for subjects 
not enrolling into the extension Study MRX-503; see Section 7.1.4) 
Figure 1 
Study Design Flow Chart 
 
BID=twice daily; Scr=screening; V=visit; W=week 
 
For information about the schedule of assessments throughout the study, refer to Table 1 and 
Section 7.  For information on dosing, including dose escalation requirements, refer to 
Section 6.2.3. 
3.1.1 
Rationale for Treatment and Dose Escalation 
The lower age limit for enrollment in this study is 1 year, based on the fact that the 
gastrointestinal (GI) tract is fully mature at 1 year in humans and higher plasma exposures 
were observed in rats with immature GI tracts in juvenile toxicokinetic studies.  Given the 
extremely low absorption of maralixibat in adults, minimal exposure to plasma is anticipated 
in eligible pediatric patients, so the pediatric doses have been selected based upon body 
surface area scaling of doses shown to be safe and tolerable in adults in a Phase 1 healthy 
volunteer study.  In Study SHP625-101, a blinded, placebo-controlled, randomized, 
multiple-dose study, bile acids levels in feces increased with escalating doses up to 100 mg 
QD and 50 mg BID of maralixibat, without any meaningful changes in the safety or 
tolerability profile.  Thus, higher doses of maralixibat might be more efficacious, whereas a 


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BID regimen has the potential to allow for more complete coverage of the distal ileum 
throughout the day.  Of note, these doses correspond to approximately 1400 µg/kg QD and 
700µg/kg BID in a 70-kg adult, respectively. 
Ideally, dosing in pediatric subjects should be scaled from that in adults based on intestinal 
length—that is, milligram of drug per centimeter of intestine.  Differing relationships 
between intestinal mucosal surface area, age, and body weight have been reported, including 
data indicating that the average length of the small intestine increases with age from birth 
through 20 years; this relationship followed a curve that is similar to the height and weight 
growth curves (Weaver et al. 1991).  However, a plateau had not been reached at the 
maximum age examined (20 years), precluding predictions of intestinal length for older 
adults and thus scaling to infants and children based on estimated intestinal length.  An 
analysis of intestinal length as a function of age, weight, and height in adult cadavers was 
conducted by Hounnou et al. (2002). Their analysis demonstrated that age had a negative 
correlation and body weight a positive correlation with intestinal length.  Taken as a whole, 
the existing analyses are inconclusive with respect to the dependent variables that predict 
intestinal length.  Consequently, the most reasonable approach is to calculate doses in a 
pediatric subject from those in adults using a direct mg/kg scaling.  For reference, in an 
average adult subject weighing 70 kg, the proposed maximum target dose of 600 µg/kg BID 
corresponds to a total daily dose of 42 mg BID.  Doses up to 400 µg/kg BID are generally 
well tolerated in the currently ongoing maralixibat Phase 2 studies in children with PFIC and 
ALGS. 
Sample daily exposure (mg-day) across proposed dose levels for subjects ranging in weight 
from 5–70 kg is provided in Table 2.  
Table 2 
Sample Daily Exposure (mg/day) in Pediatric Subjects 
Weight 
(kg) 
Daily Exposure of Maralixibat (mg) 
Dose Level 1 
(150 μg/kg - BID) 
Dose Level 2 
(300 μg/kg - BID) 
Dose Level 3 
(450 μg/kg - BID) 
Dose Level 4 
(600 μg/kg - BID) 
5 
1.5  
3.0 
4.5 
6.0 
10 
3.0 
6.0 
9.0 
12.0 
20 
6.0 
12.0 
18.0 
24.0 
30 
9.0 
18.0 
27.0 
36.0 
40 
12.0 
24.0 
36.0 
48.0 
50 
15.0 
30.0 
45.0 
60.0 
60 
18.0 
36.0 
54.0 
72.0 
70 
21.0 
42.0 
63.0 
84.0 
 
3.1.2 
Rationale for Primary Endpoint 
The primary endpoint is the mean change in the average morning ItchRO(Obs) severity score 
between baseline and Week 15 to 26.  The selection of ItchRO(Obs) as the primary endpoint 
of therapeutic response to maralixibat treatment was based on the clinically significant 


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improvements observed in 7 subjects in the ongoing Phase 2 PFIC Study LUM001-501.  
Initial efficacy data collected from the first interim data analysis demonstrated signals of 
broad, significant, and sustained efficacy in a subgroup of 7 subjects, all with PFIC2.  
Among other positive clinical outcomes, these subjects experienced large reductions in 
pruritus, as measured by improvements in ItchRO(Obs) score of ≥1.0.  These clinically 
significant reductions were sustained through 48 weeks of treatment for most subjects, 
showed little variability throughout the study, and closely mirrored the results frequently 
observed after PEBD (Yang et al. 2009; Stapelbroek et al. 2010). Full treatment effect is 
usually observed by 12 weeks of treatment.  A seventh subject was identified as exhibiting a 
partial response that was characterized by significant improvements in sBA (reduction of 
88% from baseline) and in ItchRO(Obs) scores.  Both measures of efficacy remained largely 
sustained for the duration of the study for all these subjects, except during intercurrent 
illnesses (e.g., GI or upper respiratory infections).  This pattern of consistent, monotonic, and 
concomitant improvements across multiple parameters in these subjects is consistent with 
what has previously been described following biliary diversion surgery and inconsistent with 
the usual natural history of PFIC, which is characterized by progressive deterioration in liver 
function without periods of normalization of pruritus, bile acids, or liver enzymes. 
3.1.3 
Rationale for Study Population 
Limiting the primary analysis to subjects with PFIC2 is based on the following: 
1. All responders in Study LUM001-501 are subjects with PFIC2; 2. PFIC2 patients most 
commonly lack extrahepatic abnormalities; and 3. PFIC2 represents the most prevalent 
subgroup of PFIC patients and, therefore, constitutes the biggest unmet need.  
3.2 
Duration and Study Completion Definition 
The subject’s maximum duration of participation is expected to be up to 33 weeks.  
The Study Completion Date is defined as the date the final subject, across all sites, completes 
his or her final protocol-defined assessment.  Note that this includes the follow-up visit or 
contact, whichever is later (refer to Section 7.1.4 for the defined follow-up period for this 
protocol) but not the long-term clinical follow-up of persistent safety findings.  
At the end of the 26-week double-blind treatment period, subjects will have the opportunity 
to enroll into the long-term, extension study (MRX-503).  Subjects who do not enroll into 
the treatment extension study or who discontinue at any time during this study will have a 
final safety follow-up telephone call 7 days after the last dose of study medication (see 
Section 7.1.4).  Subjects who discontinue from the study for safety reasons are followed as 
long as clinically indicated or until no further improvement with an adverse outcome is 
expected. 
3.3 
Sites and Regions 
The study will be conducted in approximately 40 sites in North America, Europe, Asia, and 
South America.  Other regions may be added, if necessary, for enrollment purposes. 


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4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
A subject will not be considered eligible for the study without meeting all the criteria below. 
1. Informed consent and assent (as applicable) per Institutional Review Board/Ethics 
Committee (IRB/EC) 
2. Male or female subjects with a body weight ≥5.0 kg who are ≥12 months and 
<18 years of age at time of baseline 
3. Cholestasis as manifested by total sBA ≥3× ULN (applies to primary cohort only) 
4. An average AM ItchRO(Obs) score ≥1.5 during 4 consecutive weeks of the screening 
period, leading to the baseline visit (Visit 1) 
5. Completion of at least 21 valid* morning ItchRO(Obs) entries during 4 consecutive 
weeks of the screening period, leading to the baseline visit (Visit 1) 
(*valid=completed and not answered as “I don’t know”; maximum allowed invalid 
reports=7, no more than 2 invalid reports during the last 7 days before randomization) 
6. Diagnosis of PFIC based on: 
Chronic cholestasis as manifested by persistent (>6 months) pruritus in addition 
to biochemical abnormalities and/or pathological evidence of progressive liver 
disease 
and 
Primary Cohort: 
Subjects with genetic testing results consistent with biallelic disease-causing 
variation in ABCB11 (PFIC2), based on standard-of-care genotyping  
Supplemental Cohort:  
i. Subjects with genetic testing results consistent with biallelic 
disease-causing variation in ATP8B1 (PFIC1), ABCB4 (PFIC3), or 
TJP2 (PFIC4), based on standard-of-care genotyping 
ii. Subjects with PFIC phenotype without a known mutation or with 
another known mutation not described above or with intermittent 
cholestasis as manifested by fluctuating sBA levels 
iii. Subjects with PFIC after internal or external biliary diversion surgery 
or for whom internal or external biliary diversion surgery was reversed 
7. Male and females of non-childbearing potential.  Males and non-pregnant, 
non-lactating females of childbearing potential who are sexually active must agree to 
use acceptable methods of contraception during the study and 30 days following the 
last dose of the study medication.  Females of childbearing potential must have a 
negative pregnancy test result. 


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8. Access to email or telephone for scheduled remote visits 
9. Ability to read and understand the questionnaires (both caregivers and subjects above 
the age of assent) 
10. Access to consistent caregiver(s) during the study 
11. Subject and caregiver willingness to comply with all study visits and requirements 
4.2 
Exclusion Criteria 
A subject will be excluded from the study if any of the following exclusion criteria are met: 
1. Predicted complete absence of bile salt excretion pump (BSEP) function based on the 
type of ABCB11 mutation (PFIC2), as determined by a standard-of-care genotyping 
(applies to primary cohort only).  Subjects can enter the study in the Supplemental 
Cohort (under inclusion criteria 6.ii or 6.iii). 
2. Recurrent intrahepatic cholestasis, indicated by a history of sBA levels <3x ULN or 
intermittent pruritus (applies to primary cohort only) 
3. Current or recent history (<1 year) of atopic dermatitis or other non-cholestatic 
diseases associated with pruritus 
4. History of surgical disruption of the enterohepatic circulation (applies to primary 
cohort only) 
5. Chronic diarrhea requiring intravenous fluid or nutritional intervention for the diarrhea 
and/or its sequelae at screening or during the 6 months prior to screening 
6. Previous or need for imminent liver transplant 
7. Decompensated cirrhosis (international normalized ratio [INR] >1.5, and/or 
albumin <30 g/L, history or presence of clinically significant ascites, and/or variceal 
hemorrhage, and/or encephalopathy) 
8. ALT or TSB >15× ULN at screening 
9. Presence of other liver disease 
10. 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 
11. Possible malignant liver mass on imaging, including screening ultrasound 
12. Known diagnosis of human immunodeficiency virus (HIV) infection 
13. Any prior cancer diagnosis (except for in situ carcinoma) within 5 years before the 
screening visit (Visit 0) 
14. Any known history of alcohol or substance abuse 
15. Administration of bile acids or lipid binding resins or phenylbutyrates during the 
screening period 
16. Criterion has been deleted as of Amendment 3.  


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17. Administration of any investigational drug, biologic, or medical device during the 
screening period 
18. Previous use of an ileal bile acid transporter inhibitor (IBATi) 
19. History of nonadherence to medical regimens, unreliability, medical condition, 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 subject, or lead to nonadherence with the study protocol or inability to 
conduct the study procedures. 
20. Known hypersensitivity to maralixibat or any of its excipients 
4.3 
Reproductive Potential 
Local, country-specific guidelines should always be followed where there is regional 
variation for which methods of contraception are considered acceptable. 
4.3.1 
Female Contraception 
• Females are considered to be of non-childbearing potential if they are premenarchal 
and either Tanner Stage 1 or younger than age 9 years. 
• Females of childbearing potential must have a negative β-hCG pregnancy test result 
as outlined in Table 1.  Results of pregnancy test must be reviewed prior to 
dispensing study medication.  
• Females of childbearing potential must agree to abstain from sexual activity that 
could result in pregnancy or, if they are sexually active or become sexually active 
during the study, agree to use acceptable methods of contraception, as defined below, 
throughout the study period and for 30 days following the last dose of study 
medication.  If hormonal contraceptives are used, they should be administered 
according to the package insert.  
Acceptable methods of contraception are: 
• Intrauterine devices plus condoms 
• Double-barrier methods (e.g., condoms and diaphragms with spermicidal gel or foam) 
• Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for 
at least 30 days prior to the screening visit (Visit 0), plus condoms.  Note: If subject 
becomes sexually active during the study, they should use one of the other acceptable 
methods noted above in addition to the hormonal contraceptive until it has been 
stabilized for 30 days. 


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4.3.2 
Male Contraception 
Contraception is required for all sexually active male subjects and their partners.  All male 
subjects must agree not to donate sperm, and to use 1 of the following approved methods of 
contraception until 30 days following the last dose of study medication: 
• Male condom with spermicide 
• Intrauterine device with spermicide (use by female sexual partner) 
• Female condom with spermicide (use by female sexual partner) 
• Contraceptive sponge with spermicide (use by female sexual partner) 
• Intravaginal system (e.g., vaginal ring with spermicide, a diaphragm with spermicide, 
or a cervical cap with spermicide) (use by female sexual partner) 
• Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner). 
4.4 
Withdrawal/Discontinuation from Study 
A subject may withdraw from the study at any time for any reason without prejudice to future 
medical care by the physician or at the institution.  The investigator or sponsor may 
discontinue the subject from the study at any time (refer to Section 4.4.1).  The investigator is 
encouraged to discuss discontinuation of a subject with the medical monitor when possible.  
The reason for termination and the date of stopping study medication must be recorded in 
source documents.  The evaluations listed for the Week 26 visit (Visit 9) are to be performed 
as completely as possible for any subject who discontinues early (see Section 7.1.3.3). 
Subjects who discontinue from the study for safety reasons are followed as long as clinically 
indicated or until no further improvement with an adverse outcome is expected.  
Subjects who discontinue from the study will not be replaced. 
4.4.1 
Reasons for Discontinuation from Study 
Medically important events that in the opinion of the investigator or medical monitor would 
compromise the subject’s ability to safely continue the study would warrant the subject’s 
discontinuation from the study.  The reason for discontinuation must be recorded in the 
subject’s source document.  If a subject is discontinued for more than 1 reason, each reason 
should be documented in the source and the most clinically relevant reason should be 
indicated.  


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Reasons for discontinuation include but are not limited to: 
• Death 
• Noncompliance with study procedures  
• Adverse event 
• Withdrawal by subject/parent/guardian 
• Physician decision 
• Loss to follow-up 
• Pregnancy 
• Imminent need for liver transplant 
• Initiation or increase in dose of anti-pruritic or prohibited medication (see 
Section 5.2.2) 
• Progressive disease (defined as progression of underlying PFIC which, in the opinion 
of the investigator, is due to the disease itself and can be explained by the natural 
history of PFIC—i.e., worsening of pruritus, cholestasis, or liver disease) and not due 
to medications or other factors. 
• Other  
Additional reasons may be referenced on the Case Report Form (CRF). 
If subjects discontinue from the study due to disease progression and require rescue therapy 
with either PEBD or listing for liver transplant, both the reason for discontinuation and 
outcome (i.e., PEBD, cholecystostomy tube, ileal exclusion, liver transplant, or listed for 
liver transplant) should be recorded in the subject’s source document.  If known, the date of 
the future scheduled procedure should also be recorded.  The information regarding PEBD, 
liver transplant, or listing for transplant will be collected in the CRF at the time the subject 
completes/early terminates from the study (Visit 9; EOT/ET) until the completion of the 
follow-up period (Week 27). 
4.4.2 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up 
at any time point prior to the last scheduled contact (office visit or telephone contact).  At 
least 1 of these documented attempts must include a written communication sent to the 
subject’s last known address via courier or mail (with an acknowledgement of receipt 
request) asking that the subject return to the site for final safety evaluations and return any 
unused study medication. 


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5 
PRIOR AND CONCOMITANT TREATMENT 
5.1 
Prior Treatment 
Specific prior concomitant treatments and therapies administered for underlying liver 
disease, treatment of pruritus, or treatment of cholestasis will be collected.  Prior treatment 
information must be recorded in the subject’s source document for data collection.  
5.2 
Concomitant Treatment  
A subject should not be instructed to discontinue use of any medication or treatment to 
participate in this study until informed consent (or assent as applicable) has been obtained.  
Concomitant treatment refers to all treatment, including concomitant therapies, as well as 
herbal treatments, vitamins, behavioral treatment, non-pharmacological treatment, such as 
psychotherapy, taken between the dates of the first dose of study medication and the end of 
the subject’s participation in the study (Week 26 or Week 27), inclusive.  Concomitant 
treatment information must be recorded in the subject’s source document.  Investigators must 
ensure that subjects receive lipid soluble vitamin supplements, as needed, for the duration of 
the study.  
5.2.1 
Permitted Treatment 
The following medications to treat cholestasis/pruritus are allowed during the study if the 
subject has been on a stable dosing regimen (i.e., same dose and frequency in the 30 days 
prior to the screening visit [Visit 0]) and will continue this dosing regimen throughout study 
participation.  The investigator must contact the medical monitor to discuss any changes to 
and introduction of concomitant treatments to treat cholestasis/pruritus not listed here that 
could impact the outcome of the study.  Dose adaptations to body weight changes are 
allowed. 
• Ursodeoxycholic or cholic acid 
• Rifampicin 
• Diphenhydramine 
• Hydroxyzine 
• Naltrexone 
• Naloxone 
• Phenobarbital 
• Antihistamines 


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5.2.2 
Prohibited Treatment 
Table 3 details the prohibited treatments and the time restriction period prior to Baseline 
(Visit 1/Day 0).  None of the medications listed in Table 3 are allowed during the conduct of 
the study. 
Table 3 
Prohibited Treatments and Time Restriction Prior to Baseline 
Prohibited Treatment 
Time Restriction prior to Baseline (Visit 1/Day 0) 
Bile acid or lipid binding resins 
Any time during the screening period 
Phenylbutyrates 
Any time during the screening period 
Any investigational drug, biologic, or medical 
device  
Any time during the screening period 
Another IBATi/ASBTi 
Any time before the study 
IBATi=ileal bile acid transporter inhibitor; ASBTi=apical sodium-dependent bile acid transporter inhibitor 
 
6 
STUDY MEDICATION 
6.1 
Identity of Investigational Product 
The IP is maralixibat chloride (maralixibat; formerly SHP625, LUM001), which will be 
provided as an oral solution form (e.g., 5, 10, 15, and 20 mg/mL) along with either 0.5, 1.0, 
or 3.0-mL sized dosing dispensers.  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).  Maralixibat and placebo (the study medication) are presented in 
30-mL volumes packaged in 30-mL size amber colored PET bottles and require refrigerated 
storage conditions (2°C–8°C). 
One of the excipients in the maralixibat oral solution is propylene glycol (PG); in order to 
limit subject exposure to PG, a specific strength of oral solution will be prescribed to a given 
subject based on body weight and target dose.  The dosing plan will limit PG exposure to 
≤26 mg/kg/day and, at the same time, will provide reasonable (not too high or too low) 
dosing volumes to ensure accurate dosing.  
Additional information is provided in the maralixibat chloride IB and the pharmacy manual. 
6.1.1 
Blinding the Treatment Assignment 
The placebo solution will contain all components of the IP except the active drug substance.  
All packaged study medication components, including the dosing dispensers, will be 
identical in order to maintain the blind.  


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6.2 
Administration of Study Medication 
6.2.1 
Interactive Response Technology for Study Medication Management 
An interactive response technology (IRT) will be used for screening and enrolling subjects, 
randomization, study medication supply dispensation and management, inventory 
management and supply ordering, study medication expiration tracking and management, 
and emergency unblinding.  Please refer to the study manual for additional details regarding 
the IRT.  
The investigator or designee will access the IRT at the screening visit (Visit 0) to record 
subject-specific information (i.e., unique subject number, age [years and months], etc.).  
At the baseline visit (Visit 1), the investigator or designee will again access the IRT to either 
document a screen failure or, if the subject has met all entry criteria, to randomize the 
subject.  For randomized subjects, the IRT will provide one or more bottle identification 
number(s) to dispense for treatment.  
A user manual with specific functions and instructions for the IRT will be provided to the 
site, and site personnel will receive training.  
6.2.2 
Allocation of Treatment to Subjects  
Individual subject treatment is automatically assigned by the IRT.  Subjects will be 
randomized after confirmation of study eligibility in a 1:1 ratio via a computer-generated 
randomization schedule to receive maralixibat or placebo, stratified by cohort (refer to 
Section 3.1).  The subject’s randomization number represents a unique number 
corresponding to the treatment allocated to the subject.  
Siblings will be randomized in a blinded manner to the same treatment group.  Additional 
details are included within the SAP. 
6.2.3 
Dosing 
Subjects will be administered (or will self-administer) varying volumes of ready-to-use oral 
solution study medication at each dosing visit, starting with the baseline visit (Visit 1).  The 
dosing volume is determined based on the individual body weight, the dose level according 
to the dose escalation plan (150, 300, 450, or 600 μg/kg), and the strength of solution being 
administered (5, 10, 15, or 20 mg/mL).  
At each dosing visit, the investigator or designee will access the IRT, and enter the subject’s 
weight and information on dose escalation status.  This information will be used by the IRT 
to identify the appropriate strength of solution and dosing volume, and to assign a 
corresponding bottle number(s) to be dispensed to the subject.  Additional details will be 
provided in the pharmacy manual.  


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Subjects will take the first dose of study medication at the baseline visit (Visit 1) under the 
supervision of the investigator or trained staff.  
Study medication administration will take place during the Dose Escalation and Stable 
Dosing periods of the study based on a BID regimen.  The morning dose should be 
administered approximately 30 minutes before breakfast and the evening dose approximately 
30 minutes before the main evening meal.  The doses will be administered prior to meals 
rather than q12h in order to better cover the luminal bile acid release associated with meals.  
Study medication should be administered approximately at the same time each day 
throughout the study.  The interval between administration of study medication and any 
concomitant treatment should not change during the study.  The morning doses administered 
at the site during the site visits should be taken from the new bottles allocated during that 
respective visit and not from the bottles returned by the subject.  
For subjects assigned to maralixibat, the Dose Escalation period will consist of the following 
weekly steps: 
• Dose level 1:  150 μg/kg maralixibat BID for 1 week 
• Dose level 2:  300 μg/kg maralixibat BID for 1 week 
• Dose level 3:  450 μg/kg maralixibat BID for 1 week 
• Dose level 4:  600 μg/kg maralixibat BID for the remaining duration of the study 
Dose escalation should occur in the absence of major safety (e.g., liver parameters) or 
tolerability (e.g., GI-related TEAEs) concerns related or possibly related to study medication.  
Subjects with such safety concerns can be down-titrated to a lower, previously tolerated dose 
level for 1 week before continuing dose escalation.  The minimum dose to continue in the 
study will be 150 µg/kg maralixibat BID; subjects who cannot tolerate this dose will be 
discontinued from the study.  Investigators should also review study medication compliance 
during the Dose Escalation period to ensure that subjects have adequate exposure to study 
medication to assess safety and tolerability.  Any compliance concerns should be discussed 
with the medical monitor. 
Investigators have up to Week 6 to determine the maximum tolerated dose; if re-challenges 
or further dose escalations fail, the subject will remain on the maximum tolerated dose level 
for the remainder of the Stable Dosing period to complete a minimum of 20 weeks of stable 
dosing. 
During the Stable Dosing period, subjects will remain on the maximum tolerated dose level 
for the remainder of the study.  Dose reductions are allowed for safety or tolerability reasons 
down to a minimum level of 150 µg/kg BID.  Subjects who cannot tolerate this dose will be 
discontinued from the study. 
6.2.4 
Unblinding the Treatment Assignment 
The treatment assignment must not be unblinded during the study except for expedited safety 
reporting and in emergency situations where the identification of the study medication is 
required for further treatment of the subject.  The investigator should make an effort to 


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contact the medical monitor before emergency unblinding occurs 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 must be informed about the 
code break as soon as possible. 
In the event that the treatment assignment is unblinded, the date and the signature of the 
person who was unblinded, and the reason for unblinding are recorded in the source 
documents.  Upon breaking the blind in emergency situations, the subject will be withdrawn 
from the study, but should be followed up for safety purposes.  Unblinding will be processed 
through the IRT vendor, and instructions will be available in the user manual.  
Except for samples collected at the screening and baseline visits, sBA results will remain 
blinded for all sites and the blinded study team until after database lock. 
6.3 
Labeling, Packaging, Storage, and Handling 
6.3.1 
Labeling  
All study medication is labeled according to country-specific requirements.  Additional labels 
may, on a case-by-case basis, be applied to the study medication in order to satisfy local or 
institutional requirements, but must not: 
• Contradict the clinical study label. 
• Obscure the clinical study label. 
• Identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior full agreement. 
6.3.2 
Packaging  
Study medication is packaged in the following labeled containers: 
• Ready-to-use oral solution of maralixibat 5 mg/mL 
• Ready-to-use oral solution of maralixibat 10 mg/mL 
• Ready-to-use oral solution of maralixibat 15 mg/mL 
• Ready-to-use oral solution of maralixibat 20 mg/mL 
• Maralixibat matching placebo 
The sponsor or designee will provide 0.5, 1.0, and 3.0 mL sized oral dosing dispensers, bottle 
adapters, and Child Resistant Caps to clinical sites.  Changes to sponsor-supplied packaging 
may not occur without full agreement in advance by the sponsor. 


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6.3.3 
Storage 
The investigator has overall responsibility for ensuring that study medication is stored in a 
secure, limited-access location at refrigerated storage conditions (2°C–8°C).  Temperature 
monitoring is required at the storage location to ensure that the study medication is 
maintained within an established temperature range.  The sponsor must be notified 
immediately upon discovery of any excursion from the established range, or if there are any 
changes to the storage area of the study medication that could affect the integrity of the study 
medication. 
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 subjects.  The investigator or designee will 
acknowledge receipt of the study medication, documenting shipment content and condition.  
Accurate records of all study medication dispensed, used, returned, and/or destroyed must be 
maintained. 
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 in 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, direct from site to patient 
shipment of medication is allowed between visits. 
The investigator or his/her designee will dispense the study medication only to subjects 
included in this study following the procedures set out in the study protocol.  Each subject 
will be given only the study medication assigned.  All dispensed medication will be 
documented in IRT.  
The investigator is responsible for ensuring the retrieval of all study supplies from subjects.  
Subjects 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.  
Other than study medication dispensed to subjects, no stock or returned inventory may be 
removed from the site where originally shipped without prior knowledge and written consent 
by the sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and 
national laws must be adhered to for the transfer. 
The sponsor or its representatives must be permitted access to review the supplies storage, 
distribution procedures and records provided that the blind of the study is not compromised. 
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
study medication, and empty/used study medication packaging are to be returned or 
destroyed.  Study medication must be counted and verified by clinical site personnel and the 
sponsor (or designated CRO) prior to return or destruction.  Shipment return or destruction 


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forms must be completed prior to shipment from the site or destruction.  Shipment of all 
returned study medication must comply with local, state, and national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile study 
medication delivered with those used and returned.  All study medication must be accounted 
for, and all discrepancies investigated and documented to the sponsor’s satisfaction. 
6.5 
Subject Compliance 
Subject compliance with study procedures and treatment compliance will be assessed at each 
treatment visit by the site staff.  
During the Dose Escalation period, subject compliance will be reviewed as part of the dose 
escalation assessment.  Any concerns with compliance should be discussed with the medical 
monitor. 
During the Stable Dosing period, subjects will be allowed a maximum of 28 days (both 
morning and afternoon dose) of cumulative dose interruption.  During the last 12 weeks of 
the Stable Dosing period (Week 15–26), subjects will be allowed a maximum of 17 days 
(both morning and afternoon dose) of cumulative dose interruption, but not more than 
7 consecutive days.  Any dose interruption longer than the maximum allowed will be 
documented as a protocol deviation.  Subjects may remain on study during dose interruptions 
and should continue to complete all regularly scheduled subject study visits and assessments 
as outlined in Table 1.  After any dose interruption, subjects will reinitiate dosing at their 
maximum tolerated dose.  
Any subject who has over 56 days (both morning and afternoon dose) of cumulative dose 
interruption during the Stable Dosing period should be discontinued from the study.  
Procedures outlined in Section 7.1.3.3 should be followed for any subject who is 
discontinued early from the study. 
7 
STUDY PROCEDURES 
See Appendix 10 for management of study procedures during pandemic. 
7.1 
Study Schedule 
The study procedures and assessments to be performed throughout the study can be found in 
the schedule of assessments in Table 1.  Further instructions about study assessments are 
provided in this section and in Section 7.2. 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent (or assent as 
applicable) from the subject (as per local requirements).  For information about informed 
consent process see Section 10.3.1.  


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Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site, the subject number is assigned to subjects according to the sequence of 
presentation for study participation.  
Where possible and permitted, study visits can be organized through qualified health care 
professionals to perform study assessments at the subject’s home (or other agreed upon 
location), once approved by the Principal Investigator and medical monitor. 
7.1.1 
Screening Period (Day -42 to Day 0) 
The screening period starts when informed consent (or assent as applicable) is signed.  The 
duration of the screening period is up to 6 weeks during which all procedures listed for the 
screening visit (Visit 0) in Table 1 must be completed.  The screening period will last at a 
minimum 4 weeks to confirm the morning ItchRO(Obs) score ≥1.5 and will allow for the 
evaluation of each subject’s eligibility for inclusion into the study.  
Subjects who meet eligibility criteria after completion of all screening visit (Visit 0) 
assessments will enter the 26-week double-blind treatment period.  This period should not 
commence until all screening assessments required to confirm eligibility for randomization 
have been completed and the PFIC genotype results have been confirmed by sponsor or 
designee.  
If the subject does not meet eligibility criteria following completion of screening assessments, 
the investigator or designee will document the subject as a screen failure in the IRT.  A screen 
failure is a subject who has given informed consent and failed to meet the inclusion and/or met 
at least 1 of the exclusion criteria and has not been randomized or administered study 
medication.  
In exceptional cases, subjects who initially fail to meet all eligibility criteria may be 
re-screened at a later timepoint, after consultation with the medical monitor. 
Screen failure subject numbers cannot be reassigned to randomized subjects. 
A 5-day visit window will be permitted in the case the 42-day screening period needs to be 
extended.  This window will allow for blood sample retesting at the investigator's discretion. 
7.1.2 
Dose Escalation Period: Visit 1 (Week 0) to Visits 3–4 (Week 4–6) 
Subjects who continue to meet all eligibility criteria will be randomized at the baseline visit 
(Visit 1) 1:1 to receive either maralixibat or placebo as described in Section 6.2.3.  The 
investigator or assigned site staff will access the IRT to randomize the subject and dispense 
the study medication (Section 6.2.1).  
The double-blind Dose Escalation treatment period will comprise of 4–6 weeks (maximum 
6 weeks).  All assessments and procedures listed for Visits 1-2 and interim contacts (4-week 
Dose Escalation) or Visits 1-3 and interim contacts (6-week Dose Escalation), in Table 1 
should be completed during this period.  Subject contacts may be by telephone or email. 


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During this period, a ±2-day visit window will be permitted, unless otherwise specified.  
Visit dates and acceptable windows are calculated from the baseline visit (Visit 1/Day 0).  
7.1.3 
Stable Dosing Period 
7.1.3.1 
Visits 3–8 (Weeks 4, 6, 10, 14, 18, and 22) 
Subjects will return to the site for Visits 3–8, or Visits 4–8 for subjects requiring 6-week dose 
escalations.  Assessments and procedures will be performed as outlined in Table 1. 
For Visits 3–4, a ±2-day visit window will be permitted.  For Visits 5–8, a ±3-day visit 
window will be permitted.  Visit dates and acceptable windows are calculated from the 
baseline visit (Visit 1/Day 0).  
7.1.3.2 
Subject Contact (Weeks 5, 8, 12, 16, 20, and 24) 
Subjects/caregivers will receive an email or a telephone call on Weeks 5, 8, 12, 16, 20, and 
24 during which the use of concomitant treatments and AEs will be reviewed as outlined in 
Table 1.  For subjects requiring 6 weeks of dose escalation, the first subject contact during 
the Stable Dosing period will occur at Week 8.  
For subject contacts through Week 8, a ±2-day visit window will be permitted.  For subject 
contacts from Week 12 through 24, a ±3-day visit window will be permitted.  Visit dates and 
acceptable windows are calculated from the baseline visit (Visit 1/Day 0).  
7.1.3.3 
Visit 9 [End of Treatment (EOT)/Early Termination (ET)] (Week 26) 
Subjects will return to the site for Visit 9 at the end of treatment (EOT) or upon early 
termination (ET) and the procedures and assessments outlined in Table 1 will be performed. 
If study medication is permanently discontinued early, regardless of the reason, the subject 
will be discontinued from the study (refer to Section 4.4), and the evaluations listed for the 
Week 26 (Visit 9/ET) are to be performed.  The subject should undergo the ET assessments 
at the visit during which study medication was discontinued, or the subject should be 
scheduled for an additional ET visit as soon as possible, if study medication was 
discontinued between visits.  
Subjects who discontinue prematurely at any time during the study will also have a final 
safety follow-up telephone call 7±2 days after the last dose of study medication.  See 
Section 7.1.4.  At the EOT/ET Visit, subjects who discontinue prematurely and subjects who 
will not participate in the MRX-503 extension study will be asked if they are willing to 
provide informed consent and assent (as appropriate) for the investigator and/or designee to 
contact them, their caregivers and/or their family doctor/primary care physician to obtain 
information on how their disease has progressed and whether or not they have had PEBD 
surgery or have been listed for, or had a liver transplant or any other procedure relevant to the 
management of their cholestatic liver disease (i.e., PEBD, cholecystostomy tube, ileal 
exclusion, liver transplant, or listed for liver transplant, other). Any increase in concomitant 


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medications or introduction of new medication for the treatment of pruritus and/or cholestatic 
liver disease will also be collected.  The follow-up will be done at least annually (from the 
date of the EOT/ET Visit), documented and entered in the CRF accordingly, until disease 
progression or an event occurs (whichever comes first). 
The subject should be asked prior to Visit 9/EOT if he or she would like to participate in the 
MRX-503 extension study, because the Baseline visit of MRX-503 should occur on the same 
day as Visit 9/EOT in this study. 
7.1.4 
Safety Follow-up (Day 7 Post-treatment) 
The safety follow-up period for this protocol is 7 days from the last dose of study medication.  
Subjects/caregivers who do not enroll into the extension study (MRX-503) will have a final 
safety follow-up telephone call at Week 27. 
Subjects who discontinue prematurely at any time during the study will have a final safety 
follow-up telephone call 7 days after the last dose of study medication.  Subjects who 
discontinue from the study for safety reasons are also followed-up as long as clinically 
indicated or until no further improvement with an adverse outcome is expected.  All AEs and 
SAEs that are not resolved at the time of this contact will be followed to closure by the site 
(see Section 8.1).  
7.1.5 
Additional Care of Subjects After the Study 
No aftercare is planned for this study for those subjects who do not enroll in the extension 
study (MRX-503). 
7.2 
Study Evaluations and Procedures 
7.2.1 
Genetic Testing Results 
ATP8B1 (PFIC1), ABCB11 (PFIC2), ABCB4 (PFIC3), TJP2 (PFIC4), NR1H4 (PFIC5), and 
MYO5B (PFIC6) mutations are predictive of PFIC.  Standard of care genotyping results will 
be reviewed and documented by the sponsor or designee for confirmation of PFIC subtype 
and for determination of cohort assignment.  
7.2.2 
Efficacy 
7.2.2.1 
Itch Reported Outcome (ItchRO™) 
Pruritus will be assessed using the Itch caregiver/patient reported outcome measure 
(ItchRO™) administered as a twice daily electronic diary as described in Appendix 2 and 
Appendix 3. Caregivers for all subjects will complete the Observer instrument: ItchRO(Obs).  
The ItchRO(Obs) should be completed by the same caregiver for consistency, whenever 
possible.  


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The ItchRO(Obs) eligibility must be determined after a minimum of 4 weeks of ItchRO(Obs) 
twice-daily diary entry.  If the subject does not meet eligibility after 4 weeks, ItchRO(Obs) 
eligibility should be re-assessed at week 5, and also at week 6 if eligibility is not met at 
week 5.  A maximum of 3 attempts can be made to determine ItchRO(Obs) eligibility during 
the screening period.  
Only subjects ≥9 years of age at screening (Visit 0) will complete the patient instrument: 
ItchRO(Pt).  If a subject turns 9 years of age at any point after screening (Visit 0), they will 
not complete the ItchRO(Pt).  Due to the expected lower number of subjects old enough to 
rate ItchRO(Pt), this measure will only be analyzed as an exploratory outcome.  
Subjects and caregivers will be trained on the use of the electronic diary during the screening 
visit (Visit 0).  Pruritus will be assessed and recorded twice daily, via ItchRO, beginning with 
the day after the screening visit (Visit 0) and every day throughout the duration of the study, 
as described in Appendix 2 and Appendix 3.  
Exceptionally, a paper version may be made available in place of an electronic diary to 
accommodate cultural restrictions for a limited number of subjects/families to complete the 
required assessments.  However, any requests for paper version will need to be proactively 
approved by the sponsor, who would provide any officially licensed instruments for data 
collection. 
ItchRO(Obs)TM 
The severity of pruritus will be measured by the completion of the first question in the 
ItchRO(Obs) (how severe were your child’s itch-related symptoms).  The frequency of 
pruritus will be measured by completion of the third question in the ItchRO(Obs) (how 
much of the time was your child rubbing or scratching).  Caregivers will rate the severity and 
frequency of pruritus using 5 choices to describe their itching condition.  The sixth choice, 
“I don’t know” will not count toward their severity or frequency score (categorized as 
missing data) and is included to account for rare occasions that the designated caregiver 
cannot observe the child, or the child could not communicate the severity or frequency of 
their itching condition.  Capturing “I don’t know” should be kept at an absolute minimum, as 
this will lead to missing data. 
ItchRO(Pt)TM 
The severity of pruritus will be measured by the completion of the first question in the 
ItchRO(Pt) (how itchy did you feel).  The frequency of pruritus will be measured by 
completion of the third question in the ItchRO(Pt) (how much of last night/today did feeling 
itchy make you rub or scratch).  Subjects will rate the severity and frequency of pruritus 
using 5 choices to describe their itching condition. 
During the 26-week treatment period, subjects/caregivers will be required to submit twice 
daily assessments using the electronic diary.  The electronic diary will be returned to the 
study center at the final treatment evaluation visit (Visit 9). 


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7.2.2.2 
Serum Bile Acids and Other Cholestasis Biomarkers 
Blood samples will be collected as described in Table 1 to measure levels of cholestasis 
biomarkers including total sBA, sBA subspecies, C4, FGF-19, and autotaxin as well as 
liver-related parameters.  Subjects are encouraged to fast at least 6 hours prior to collection 
(water intake is permitted if necessary but not recommended).  
Total sBA and targeted bile acid subspecies will be quantified with liquid 
chromatography-mass spectrometry (LC-MS) methodology for exploratory assessments.  In 
addition, screening total sBA will be assessed with an enzymatic assay for inclusion criteria 
evaluation.  C4, a key intermediate in the pathway for bile acid synthesis from cholesterol, 
will be determined by a validated LC-MS/MS method. 
Samples collected for biomarker evaluation may be utilized for additional assessments of 
related analytical methodology or other exploratory analysis. 
7.2.3 
Medical History, Disease History, and Medication History 
At the screening visit (Visit 0) the investigator must record all clinically or medically 
relevant information, including PFIC disease history, regardless of how much time has 
elapsed since the date of any diagnosis.  
Refer to Section 5.1 for full details on collection of medication history.  Prior treatment 
information, including any prior treatments for PFIC, must be recorded on the appropriate 
CRF page.  
7.2.4 
Demographics 
Subject demographic information including gender, age (full date of birth), and race will be 
collected during the screening visit (Visit 0).  Variance in pediatric age-related reference 
ranges is significant, and the full date of birth is required to ensure correct interpretation of 
the laboratory report. 
Local, country-specific guidelines should be followed where there is regional variation for 
collection of demographic information. 
7.2.5 
Safety 
The name and address of each third-party vendor (e.g., clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files. 
7.2.5.1 
Physical Examination 
Abnormalities (including presence of hepatomegaly, splenomegaly, edema, ascites, jaundice, 
or scleral icterus) identified at the screening visit (Visit 0) will be documented in the 
subject’s source documents.  Significant changes after the screening visit (Visit 0) should be 
assessed as potential AEs.  Refer to Section 8 for additional details. 


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Physical examination assessments at each visit should also include specific assessments for 
signs of hepatomegaly, splenomegaly, edema, ascites, jaundice, and scleral icterus. 
7.2.5.2 
Adverse Event Collection 
At each study visit and subject contact, subjects or their caregivers will be questioned in a 
general way to ascertain if AEs have occurred since the previous visit (e.g., “Have you had 
any health problems since your last visit?”).  Adverse events will be collected from the time 
informed consent is signed (refer to Section 8). 
7.2.5.3 
Vital Signs (including Height and Weight) 
Vital signs include blood pressure, heart rate, temperature, and respiration rate.  Blood 
pressure should be determined by cuff using the same method, the same arm, and the same 
position, following 5 minutes of rest throughout the study.  Any deviations from baseline 
(Visit 1) vital signs that are deemed clinically significant in the opinion of the investigator 
are to be recorded as an AE. 
Height will be collected at the screening visit (Visit 0) and at all site visits during the 
treatment period.  Height will be measured by trained site staff in children who can stand on 
their own (generally ≥2 years) or not (usually <2 years) using a calibrated stadiometer or 
headboard, respectively, via 2 independent measurements, recorded to the nearest 0.1 cm 
(and a third measurement if values differ by >0.5 cm).  The same stadiometer should be used 
for all study visit measurements.  
Weight will be assessed, recorded to the nearest 0.1 kg, using a calibrated balance or 
electronic scale (children who can stand on their own, generally ≥2 years of age) or infant 
scale (children <2 years).  
Standardized instructions based on regulatory guidance for height and weight measurements 
will be provided in the study manual. 
7.2.5.4 
Electrocardiograms 
The following parameters will be collected: heart rate, RR interval, PR interval, QRS 
duration, uncorrected QT interval, rhythm (sinus or specify other rhythm), ECG normal or 
abnormal (if abnormal specify abnormality). 
QT interval corrected using both Bazett’s and Fridericia’s formula (QTcB and QTcF) will be 
derived from data collected in the eCRF. 
ECGs should be recorded in the supine position, if possible after at least 10 minutes rest to 
ensure a stable baseline.  A standard 12-lead ECG will be performed at screening (Visit 0), 
baseline (Visit 1), at Visit 5 and Visit 9 (ET/EOT).  ECGs will be recorded locally in source 
documents and results captured in the eCRF. 


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7.2.5.5 
Clinical Laboratory Evaluations 
All clinical laboratory evaluations will be performed according to the central laboratory 
manual.  Reference ranges are to be supplied by the laboratory and will be used to assess the 
clinical laboratory data for clinical significance and out-of-range pathological changes.  The 
investigator or sub-investigator must assess out-of-range clinical laboratory values for 
clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant.  Abnormal clinical laboratory values, which are unexpected or not explained by 
the subject’s clinical condition, may, at the discretion of the investigator or sponsor, be 
repeated as soon as possible until confirmed, explained, or resolved. 
Clinical laboratory assessments will be performed as listed in Table 4.  
Unscheduled local laboratory values are not required to be collected in the CRF except for 
those that are directly relevant to the monitoring of an AE/SAE; collection of other values 
may be requested by the sponsor. 


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Table 4 
List of Laboratory Analytes 
Serum β-hCG  
(if indicated) 
CBC with 
Differential 
Hematocrit 
Hemoglobin 
MCV, MCH, 
MCHC 
Red blood cells 
Platelets 
White blood cells 
WBC Differential 
(% and absolute) 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Coagulation 
aPTT (sec) 
INR 
PT (sec) 
Clinical Chemistry 
Albumin 
ALP 
Amylase 
ALT (SGPT) 
AST (SGOT) 
Bicarbonate 
Bilirubin, direct 
(conjugated) 
Total serum bilirubin 
(TSB) 
Blood urea nitrogen 
(BUN) 
Calcium 
Chloride 
Creatinine 
GGT  
Glucose 
Lipase 
Phosphate 
Potassium 
Sodium 
Total protein 
Uric Acid 
Measured serum 
Osmolality 
Lipid Panela 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Triglycerides (TG) 
 
Cholestasis 
Biomarkersa 
Total serum bile acids 
(sBA) 
Serum bile acid 
subspecies 
7α-hydroxy-4-
cholesten-3-one (C4) 
FGF-19 
Autotaxin 
 
 
Lipid Soluble 
Vitaminsa 
25-hydroxy vitamin D 
Retinol 
Retinol binding protein 
(RBP) 
α-Tocopherol 
Urinalysis 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Occult blood and cells 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic examinationb 
Oxalate 
Urinary creatinine 
 
Maralixibat Levels 
Maralixibat in plasma 
 
Marker of 
hepatocellular 
carcinoma 
α-Fetoprotein (AFP) 
AFP=α-fetoprotein; ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial 
thromboplastin time; AST=aspartate aminotransferase; β-hCG=beta human chorionic gonadotropin; FGF-
19=fibroblast growth factor 19; FIB-4=fibrosis-4; GGT=gamma-glutamyl transferase; PT=prothrombin time; 
MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean 
corpuscular volume; RBP=Retinol binding protein: SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum 
glutamic-pyruvic transaminase; WBC=white blood cell. 
a Blood samples for the analysis of cholestasis biomarkers, lipid panel and lipid soluble vitamins should be drawn 
prior to administration of vitamin supplementation and as much as possible approximately 6 hours after food or 
formula (water intake is permitted if necessary but not recommended).  Other biomarkers [e.g., lysophosphatidic 
acid (LPA),] may be measured.  At the discretion of the sponsor, samples will be collected and appropriately stored 
for subsequent analysis, as needed. 
b Will be performed on abnormal findings unless otherwise specified. 
 
Serum bile acid results will remain blinded to sites and to the blinded study team until after 
database lock of study MRX-502 except for results at screening (Visit 0).  Anion gap and 
osmolar gap as well as corrected sodium, α-Tocopherol/Total Lipids Ratio, Retinol/RBP 
Molar Ratio, FIB-4, and APRI will be calculated. 
A serum storage sample will be collected as a back-up sample in case re-analysis is needed. 


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7.2.5.6 
Pregnancy Test  
A serum β-HCG pregnancy test is performed on all females of childbearing potential at the 
screening visit (Visit 0), and the final treatment evaluation visit (Visit 9) or ET visit.  A urine 
pregnancy test is performed on all female subjects of childbearing potential at other visits as 
outlined in Table 1, or if pregnancy is suspected or on withdrawal of the subject from the 
study. 
7.2.5.7 
Ultrasound Liver Imaging 
An abdominal ultrasound will be performed at the screening visit (Visit 0) and at Week 26 
(Visit 9; EOT/ET) to determine the presence of any liver mass.  A screening ultrasound is not 
required if the results of an ultrasound or liver MRI completed in the last 6 months are 
available, and the clinical status of the subject has not changed significantly since the time of 
the test. 
7.2.6 
Others  
7.2.6.1 
Health-related Quality of Life and Pruritus Assessment 
For any health-related quality of life assessments with age-specific modules or instruments 
performed starting at screening (EDQ[Obs] or EDQ[Pt]), the subject’s age at the screening 
visit (Visit 0) will be used for the determination of the appropriate module or instrument to 
be used for the study.  
For any health-related quality of life assessments with age-specific modules or instruments 
performed starting at baseline (PedQL and PIS), the subject’s age at the screening visit 
(Visit 0) will be used for the determination of the appropriate module to be used for the 
study.  
The same module or instrument will be completed for the duration of the study, regardless of 
subsequent birthdays throughout the study.  
7.2.6.1.1 
Pediatric Quality of Life 
The PedsQL™ is a questionnaire that will be administered to subjects and caregivers using 
the age-appropriate PedsQL module (refer to Appendix 4).  Subjects aged 8 to 12 years, and 
13 to 18 years will self-complete the PedsQL Child Report, and the PedsQL Teenager 
Report, respectively.  Caregivers of subjects will complete the age-appropriate Parent 
PedsQL report (i.e., Report for Infants, Toddlers, Young Children, Children, and Teenagers).  
The PedsQL is a validated, modular instrument designed to measure health-related quality of 
life (HRQoL) in children and adolescents (Varni et al., 2001). In addition to the core generic 
PedsQL module, the multidimensional fatigue and family impact questionnaires will also be 
administered as outlined in Table 1 using the age-appropriate module (refer to Appendix 4).  


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7.2.6.1.2 
Caregiver Impression of Severity of Pruritus 
The CIS is a questionnaire that will be administered to caregivers as outlined in Table 1 and 
Appendix 5.  The CIS is designed to assess the caregiver’s perception of itch severity of their 
children.  The questionnaire will be administered with a recall period of 1 week.  
7.2.6.1.3 
Patient Impression of Severity of Pruritus 
The PIS is a questionnaire that will be administered to subjects as outlined in Table 1 and 
Appendix 5.  Subjects aged ≥9 years will self-complete the questionnaire.  The PIS is 
designed to assess the subject’s perception of their itch severity.  The questionnaire will be 
administered with a recall period of 1 week. 
7.2.6.1.4 
Clinician Scratch Scale 
The CSS provides an assessment of itch severity.  The clinician’s assessment of the subject’s 
pruritus will focus on scratching and visible damage to the skin as a result of scratching as 
observed by the physician.  The CSS uses a 5-point scale, in which 0 designates no evidence 
of scratching and 4 designates cutaneous mutilation with bleeding, hemorrhage and scarring.  
A clinician’s assessment of pruritus made by the principal investigator or sub-investigator 
using the CSS will be recorded at screening, baseline (Visit 1), and at additional study visits 
as outlined in Table 1.  To the extent possible, assessments should be made by the same 
individual during study visits. 
7.2.6.1.5 
Patient Impression of Change (PIC) 
The PIC is designed to assess the subject’s perception of his/her itching at Week 26 (EOT) 
(see Appendix 8) compared to his/her itching prior to the start of treatment with study drug.  
The PIC will be completed, by subjects who are 9 years of age or older at the Week 26 
(EOT) visit (see Table 1).  
7.2.6.1.6 
Caregiver Impression of Change (CIC) 
The CIC is designed to assess the caregiver’s perception of the subject’s itch related 
symptoms and xanthoma severity at Week 26 (EOT) compared to his/her itch related 
symptoms and xanthoma severity prior to the start of treatment with study drug (see 
Appendix 9).  The CIC will be completed by all caregivers at the Week 26 (EOT) visit (see 
Table 1).  
7.2.6.1.7 
Exploratory Diary Questionnaire 
Pruritus will be assessed using the EDQ caregiver/patient reported outcome measure 
administered as a twice daily electronic diary as described in Appendix 7.  Caregivers for all 
subjects aged <9 years will complete the Observer instrument: EDQ(Obs).  Subjects ≥9 years 
of age will complete the patient instrument: EDQ(Pt).  
Subjects and caregivers will be trained on the use of the electronic diary during the screening 
visit (Visit 0).  Pruritus will be assessed and recorded twice daily by subjects or caregivers, 


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via EDQ, beginning with the day after the screening visit and every day throughout the 
duration of the study, as described in Table 1. 
During the 26-week treatment period, subjects/caregivers will be required to submit twice 
daily assessments using the electronic diary.  The electronic diary will be returned to the 
study center at Visit 9 (EOT/ET). 
7.2.6.2 
Clinical Pharmacology Assessments 
Blood samples (anticoagulant K3 EDTA) will be drawn pre-dose and 2.5 hours (with a 
30-minute window) post-morning dose at Week 10 (Visit 5) and Week 26 (Visit 9; EOT/ET) 
to assess the plasma level of maralixibat.  For Visit 5 and Visit 9, the subject dose should be 
taken while on-site, under supervision of the site staff. 
Actual PK blood sample collection time versus time of dosing will be recorded.  The 
investigator should ensure that every effort will be made to collect all PK blood samples at 
the precise protocol scheduled time.  PK blood collection must not deviate from the nominal 
collection time set forth in the protocol by more than the allowable window (-30 minutes).  
Samples drawn outside the window will be considered a protocol deviation.  
7.2.6.3 
Healthcare Utilization 
The number of hospitalizations related to underlying disease, length of stay for 
hospitalizations, and emergency room visits (days) and any surgeries and procedures specific 
to subject’s PFIC condition will be collected during post-baseline visits as outlined in 
Table 1.  The date of visit/admission, date of discharge, relationship/issue, and discharge 
status will be collected.  The number of days the caregiver missed from work due to the 
events collected for healthcare utilization will also be collected. 
7.2.7 
Volume of Blood to Be Drawn from Each Subject  
As detailed in Table 5, it is expected that approximately 104 mL of blood will be drawn 
during the study.  According to the Ethical Considerations for Clinical Trials on Medicinal 
Products Conducted with the Paediatric Population, the volume of blood drawn from a 
subject should not exceed 3 % of the total blood volume during a period of 4 weeks and 
should not exceed 1% at any single time (Ethical Considerations, 2017).  Should the volume 
of blood required for a single visit or a 30-day period exceed the maximum allowable 
amount, the investigator will draw blood in the priority order listed in Table 5 until the 
maximum amount has been reached.  Lab draws missing due to the maximum allowable 
amount being reached will not be considered protocol deviations.  Further instructions will be 
provided in the study manual or laboratory manual.  


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Table 5 
Blood Sample Prioritization and Approximate Volume of Blood to Be 
Drawn from Each Subject 
Order of 
Priority 
Assessment 
Minimal 
Sample Volume 
Required (mL) 
Number of 
Samples 
Total Volume 
(mL) 
1 
Total serum bile acid (tSBA) 
1 
9 
9 
2 
Safety 
Chemistry 
panel/β-hCGa 
(including lipid panel) 
2.5 
9 
22.5 
Coagulation 
1.8 
9 
16.2 
CBC with differential 
1 
9 
9 
AFPb 
0.7 
3 
2.1 
Lipid soluble vitamins 
2.6 
7 
18.2 
3 
Pharmacokinetic samples 
1 
4 
4 
4 
C4 
1 
5 
5 
5 
Cholestasis biomarkersc 
2 
5 
10 
6 
Serum storage sample 
1 
8 
8 
Total mL 
104 
AFP=α-fetoprotein; β-hCG=beta-human chorionic gonadotropin; C4=7α-hydroxy-4-cholesten-3-one; eCRF=electronic 
case report form. 
a β-hCG testing for females of child-bearing potential only. 
b Results from local AFP drawn as standard of care may be entered in the eCRF instead of taking additional samples. 
c  Cholestasis biomarkers will include: autotaxin, FGF-19 and sBA subspecies. 
Note: The amount of blood to be drawn for each assessment is an estimate.  The amount of blood to be drawn may vary 
according to the instructions provided by the manufacturer or laboratory for an individual assessment; however, the total 
volume drawn over the course of the study should be approximately 104 mL. 
 
8 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT 
8.1 
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4.  This includes events occurring during the screening phase of 
the study, regardless of whether or not study medication is administered.  For subjects who 
enroll in the extension study (MRX-503) prior to the 7-day safety follow-up visit (Week 27), 
AEs will be collected/reported in MRX-502 up to the time of consent to study MRX-503. 


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Where possible, a diagnosis rather than a list of symptoms should be recorded.  If a diagnosis 
has not been made, then each symptom should be listed individually.  All AEs should be 
captured on the appropriate AE pages in the CRF and in source documents. 
All AEs must be followed to closure, regardless of whether the subject is still participating in 
the study.  Closure indicates that an outcome is reached, stabilization achieved (the 
investigator does not expect any further improvement or worsening of the event), or the event 
is otherwise explained.  When appropriate, medical tests and examinations are performed so 
that resolution of event(s) can be documented. 
8.1.1 
Treatment-Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting 
at or after the initiation of treatment with an IP or medicinal product or any existing event 
that worsens in either intensity or frequency following exposure to the IP or medicinal 
product. 
8.1.2 
Unexpected Adverse Event 
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information (RSI).  “Unexpected” also refers to the AEs that are mentioned in the IB as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the 
product but are not specifically mentioned as occurring with the particular product under 
investigation.  
The expectedness of AEs will be determined by the sponsor using the IB as the RSI.  This 
determination will include considerations such as the number of AEs previously observed, 
but not on the basis of what might be anticipated form the pharmacological properties of a 
product. 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected.  
The event(s) must meet all of the following: 
• Suspected adverse reaction 
• Serious 
• Unexpected 
• Assessed as related to study treatment 
All SUSARs must be reported as described in Section 8.2.7. 


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8.1.4 
Severity Categorization 
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity.  An event that changes in severity should be captured 
as a new event.  Worsening of pre-treatment events, after initiation of study medication, must 
be recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia 
prior to dosing of study medication, but the dyspepsia becomes severe and more frequent 
after first dose of study medication has been administered, a new AE of severe dyspepsia 
[with the appropriate date of onset] is recorded on the appropriate CRF). 
The medical assessment of severity is determined by using the following definitions: 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living. 
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention.  
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research subject. 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
8.1.5 
Relationship Categorization 
A physician/investigator must make the assessment of relationship to study medication for 
each AE.  The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the study medication.  If there 
is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the study medication and the 
occurrence of the AE, then the AE should be considered “related.” The causality assessment 
must be documented in the source document. 
The following additional guidance may be used to determine the relationship: 
Term 
Relationship Definition 
Related 
The temporal relationship between the event and the administration of the study 
medication is compelling and/or follows a known or suspected response pattern to that 
product, and the event cannot be explained by the subject’s medical condition, other 
therapies, or accident. 
Not 
Related 
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the study medication and the event. 
 


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8.1.6 
Outcome Categorization 
The outcome of AEs must be recorded on the CRF.  Outcomes are as follows: 
• Fatal 
• Not recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with Sequelae  
• Recovering/Resolving 
• Unknown 
Action taken (i.e., dose increased, dose not changed, dose reduced, drug interrupted, drug 
withdrawn, not applicable, or unknown) will also be recorded on the AE CRF. 
8.1.7 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease and are part of the 
efficacy data to be collected in the study; however, disease progression resulting in study 
discontinuation should be recorded as an AE.  
8.1.8 
Clinical Laboratory and Other Safety Evaluations 
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent 
an AE if the change is clinically relevant or if, during treatment with the study medication, a 
shift of a parameter is observed from a normal value to an abnormal value, or a further 
worsening of an already abnormal value.  When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range, either 
while continuing treatment or after the end of treatment with the study medication, and the 
range of variation of the respective parameter within its reference range, must be taken into 
consideration. 
Laboratory abnormalities should not be classified as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the 
efficacy data to be collected in the study; however, significant worsening of laboratory 
parameters should be recorded as an AE.  Laboratory abnormalities related to disease 
progression that result in interruption of study medication should be captured as AEs. 
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
findings which were not present at the pretreatment assessment performed closest to the start 
of study treatment, further investigations should be performed until the values return to 
within the reference range or until a plausible explanation (e.g., concomitant disease) is 
found for the abnormal values. 


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The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE. 
8.1.9 
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4. 
Any report of pregnancy for any female study participant or the partner of a male subject must 
be reported within 24 hours to the sponsor or designated CRO medical monitor using the 
pregnancy report form.  
The pregnant female study participant must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant.  It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion due to 
a congenital abnormality or a complication of pregnancy or a congenital abnormality 
diagnosed at any time during the pregnancy or post-partum are considered SAEs and must be 
reported using the serious adverse event form.  An elective abortion of a normal pregnancy 
without complications is not considered an SAE. 
In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the serious adverse event form as well as the 
pregnancy report form. 
8.1.10 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
medical monitor according to the SAE reporting procedure whether or not they result in an 
AE/SAE as described in Section 8.2.  Note: The 24-hour reporting requirement for SAEs 
does not apply to reports of abuse, misuse, overdose, or medication errors unless these result 
in an SAE.  
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• Abuse – Persistent or sporadic intentional intake of study medication when used for a 
non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society 
• Misuse – Intentional use of study medication other than as directed or indicated at 
any dose (Note: this includes a situation where the study medication is not used as 
directed at the dose prescribed by the protocol) 


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• Overdose – Intentional or unintentional intake of a dose of study medication 
exceeding the protocol-prescribed daily dose 
• Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of a study medication.  For studies, medication errors are reportable to the 
sponsor only as defined below. 
Cases of subjects missing doses of the study medication are not considered reportable as 
medication errors.  The administration and/or use of the unassigned or expired study 
medication is/are always reportable as a medication error. 
8.2 
Serious Adverse Event Reporting Procedures 
8.2.1 
Reference Safety Information 
The RSI for this study is the maralixibat chloride IB which the sponsor has provided under 
separate cover to all investigators. 
8.2.2 
Reporting Procedures 
All SAEs must be reported by the investigator to the medical monitor within 24 hours of 
becoming aware of the event.  Note: The 24-hour reporting requirement for SAEs does not 
apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.10) unless 
they result in an SAE. 
The investigator or designee must complete, sign, and date the serious adverse event form, 
verify the accuracy of the information recorded on the form with the corresponding source 
documents (Note: Source documents are not to be sent unless requested), and submit the 
form following the instructions in the study manual.  Follow-up information should be 
reported as soon as available.  
8.2.3 
Serious Adverse Event Definition 
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to 
be related to study medication or not) that at any dose: 
• Results in death 
• Is life-threatening.  Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it was 
more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
preexisting conditions, which have not worsened after initiation of treatment, should 
not be classified as SAEs.  For example, an admission for a previously scheduled 


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ventral hernia repair would not be classified as an SAE; however, complication(s) 
resulting from a hospitalization for an elective or previously scheduled surgery that 
meet(s) serious criteria must be reported as SAE(s). 
• Results in persistent or significant disability/incapacity 
• Is a congenital abnormality/birth defect 
• Is an important medical event.  Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization; or the development of drug 
dependency or drug abuse.  
8.2.4 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to study) are collected from the time the subject signs 
the informed consent until the defined follow-up period stated in Section 7.1.4 and must be 
reported within 24 hours of the first awareness of the event.  For subjects who enroll in the 
extension study (MRX-503) prior to the 7-day safety follow-up visit (Week 27), SAEs will 
be collected/reported in MRX-502 up to the time of the subject consent for MRX-503. 
In addition, any SAE(s) considered “related” to the study medication and discovered by the 
investigator at any interval after the study has completed must be reported within 24 hours of 
the first awareness of the event. 
8.2.5 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria.  The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
resolve, or the date the event is considered chronic.  In the case of hospitalizations, the 
hospital admission and discharge dates are considered the onset and resolution dates, 
respectively. 
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent form or leading up to the onset date of the SAE, or following the resolution date of 
the SAE, must be recorded as an AE, if appropriate. 
8.2.6 
Fatal Outcome 
Any SAE that results in the subject’s death (e.g., the SAE was noted as the primary cause of 
death) must be recorded on the CRF with an outcome of “fatal” and the date of death 
recorded as the resolution date.  For all other events ongoing at the time of death that did not 
contribute to the subject’s death, the outcome should be recorded as “not resolved,” without a 
resolution date recorded. 


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For any SAE that results in the subject’s death or any ongoing events at the time of death, 
unless another study medication action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the study medication should be recorded as “dose not 
changed” or “not applicable” (if the subject never received study medication).  The study 
medication action taken of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor is responsible for notifying the relevant regulatory authorities (US central 
IRBs/EU central ECs) of related, unexpected SAEs. 
In addition, the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the maralixibat program.  
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur, as required. 
During the course of the study, the sponsor shall inform the regulatory authorities of any 
SUSARs occurring with maralixibat that occur globally as follows: 
(a) if it is neither fatal nor life threatening, within 15 days after becoming aware of the 
information; and 
(b) if it is fatal or life threatening, within 7 days after becoming aware of the information. 
For fatal and life-threatening events, the sponsor shall, within 8 days after having informed 
the regulatory authorities, submit a complete report including an assessment of the 
importance and implication of any findings made. 
In addition, local, country-specific guidelines should always be followed where there is 
regional variation in reporting. 
8.3 
Safety Monitoring Rules 
8.3.1 
General Guidelines 
The following guidelines are provided for the monitoring of selected laboratory parameters. 
Confirmation Guidance: At any time during the study, the initial clinical laboratory results 
meeting the safety monitoring criteria presented below must be confirmed by performing 
measurements on new specimens (retest).  
Retests should be conducted by the central laboratory.  Retests at a local laboratory are 
acceptable on an as-needed basis.  Local laboratory results are sent to the investigator and 
medical monitor for review (these should include the normal range of the local laboratory).  
These results should be captured in the relevant CRF.  


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Retest collection should take place within 48 to 72 hours of the availability of the initial 
findings of potential concern.  The results from the retest must be available prior to the next 
scheduled study visit or subject contact. 
The baseline value for the purpose of the safety monitoring is the average between the value 
obtained during the screening visit (Visit 0) and the baseline visit (Visit 1), unless a 
confounder (e.g., intercurrent illness) causes variability outside of what is expected for the 
underlying disease based on the investigator's judgement (in which case a third value will 
need to be obtained). 
8.3.2 
Close Monitoring Criteria for Liver Parameters 
Table 6 provides the criteria for close monitoring of liver parameters.  
Table 6 
Close Monitoring Criteria for Treatment-Emergent Elevated ALT 
and TSB 
Parameter 
Baseline Value 
Close Monitoring Criteria 
ALT 
<30 U/L 
≥100 U/L 
>30 to ≤150 U/L 
>3× BL or ≥250 U/L 
whichever comes first 
>150 to ≤450 U/L 
≥(BL + 100 U/L) 
TSB 
Any 
≥(BL + 3 mg/dL) 
ALT=alanine aminotransferase; BL=baseline; TSB=total serum bilirubin. 
Frequency of repeat measurements:   If at any time during the study, an ALT or TSB result 
meets the close monitoring criteria, the measurement(s) must be re-confirmed.  Subjects with 
a confirmed ALT or TSB level that is continuing to rise after meeting the close monitoring 
criteria should have their liver chemistry retested as clinically indicated, until levels stabilize 
or begin to recover. 
Further investigation into liver chemistry elevations: For subjects with a confirmed increase 
in ALT or TSB level, meeting the close monitoring criteria, the following investigations 
should be considered, as clinically indicated: 
• Close and frequent monitoring of liver enzyme and serum bilirubin tests as clinically 
indicated.  Frequency of retesting can decrease if abnormalities stabilize, recover, or 
the study medication has been interrupted or discontinued and the subject has no 
symptomatic manifestations of hepatitis or immunological reaction.  
• Symptoms as well as prior, current, and intercurrent diseases/illnesses 


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• Use of or recent change in use of concomitant treatment (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets. 
• History for exposure to environmental chemical agents and travel 
• Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, HCVRNA, CMV 
IgM, and EBV antibody panel) 
• Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
• AST, creatine phosphokinase (CPK), and lactate dehydrogenase (LDH) 
• CBC with differential blood count (eosinophils) 
• Reticulocyte count, PT/INR 
Additional investigations of liver parameters, including gastroenterology/hepatology 
consultations, and/or hepatic imaging, may be performed at the discretion of the investigator, 
in consultation with the medical monitor 
8.3.3 
Guidelines for Interruption of Study Medication for Specific Liver 
Parameters 
If the confirmed laboratory results meet any of the criteria below and the event is without an 
alternative explanation (i.e., intercurrent illness, disease progression, natural history of the 
disease), interruption of study medication should be considered: 
The close monitoring criteria of both ALT and TSB are met simultaneously 
OR 
An increase of ALT or TSB is accompanied by signs and symptoms (e.g., 
nausea/vomiting, right upper quadrant pain) or an immunological reaction (e.g., rash, 
>5% eosinophilia, fever) 
The following thresholds are met for either ALT or TSB: 
Parameter 
Baseline value 
Observed change threshold 
ALT 
≤30 U/L 
≥300 U/L 
>30 to ≤150 U/L 
>(5× BL AND 300 U/L) OR 
≥450 U/L 
whichever comes first 
>150 to ≤450 U/L 
≥(BL + 300 U/L) 
TSB 
Any 
≥(BL + 5 mg/dL) 
ALT=alanine aminotransferase; BL=baseline; TSB=total serum bilirubin 
 


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Frequency of repeat measurements: Subjects with a confirmed ALT or TSB level meeting 
interruption criteria should have their liver chemistry tests retested every 72 hours or as 
clinically indicated, until levels stabilize or begin to recover. 
Further investigation for increased liver chemistry results: For subjects with a confirmed 
increase in ALT or TSB level above the threshold, the investigations outlined in 
Section 8.3.2 should be considered, as clinically indicated. 
Study medication may be re-started as long as the subject does not meet the dosing 
interruption criteria based on retest, does not meet criteria outlined in Section 8.3.4, liver 
parameters have returned to or near baseline, and an alternative explanation was found for 
the increased liver parameter (i.e., intercurrent illness, disease progression, or natural history 
of the underlying disease). The investigator and the medical monitor or qualified designee 
should confer as to whether additional close monitoring is needed. 
8.3.4 
Rules for Study Medication Discontinuation Following Abnormalities 
of Liver Parameters 
Study medication should not be restarted: 
• If the subject had a probable Drug-induced Livery Injury (DILI) in the opinion of the 
investigator and medical monitor; in case of disagreement, cases may be subject to 
independent expert adjudication  
• If the subject reports signs/symptoms of acute hepatitis, liver decompensation (i.e., 
variceal hemorrhage, ascites, hepatic encephalopathy) or hypersensitivity reaction 
• If the subject had liver parameters elevations meeting criteria in Section 8.3.3 without 
alternative explanations or that are inconsistent with the natural history of the disease 
• After meeting stopping criteria subsequent to a re-challenge (i.e., meeting stopping 
criteria after re-introduction of study medication) that is likely related to study 
medication  
• After 2 previous interruptions for safety reasons, unless there is a compelling reason 
why the subject should continue with dosing (i.e., interruptions were due to disease 
progression, natural history, intercurrent illness) and provided that the subject is still 
compliant with the study protocol as per Section 6.5 
If study medication is permanently discontinued, the subject will be discontinued from the 
study and will be expected to complete the ET study procedures (Visit 9/ET). 
8.3.5 
Safety Monitoring for Lipid Soluble Vitamins  
Lipid soluble vitamin (LSV) status will be assessed at every study visit per the schedule of 
assessments (Table 1); blood samples will be obtained at the study visit before the daily dose 
of vitamins is administered. 


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In subjects with LSV deficiency, study medication must be interrupted if clinical symptoms of 
deficiency occur.  Clinical symptoms include, but are not limited to: 
• Vitamin A: Night blindness, degeneration of the retina, xerophthalmia, follicular 
hyperkeratosis, keratomalacia, or Bitot’s spots 
• Vitamin D: Rickets, osteomalacia, costochondral beading, epiphyseal enlargement, 
cranial bossing, bowed legs 
• Vitamin E: Numbness/tingling, decreased deep tendon reflexes, hemolytic anemia, 
limited extraocular movements, especially upward gaze 
Subjects may restart dosing once clinical symptoms resolve and LSV levels begin to improve 
unless the subject has been previously discontinued for the same symptomatic LSV 
deficiency.  Each subject may be re-challenged after symptomatic LSV deficiency only 
twice.  
In the event of a confirmed level that falls either below the subject’s baseline or below the 
lower limit of normal (refer to central laboratory manual), whichever is lower, for a vitamin 
(25-hydroxy vitamin D, retinol, retinol binding protein, α-tocopherol), or INR (as a proxy for 
vitamin K status), without clinical symptoms of deficiency, the investigator should make the 
appropriate modification to the subject’s vitamin supplementation regimen (see also 
Section 8.3.6 for INR monitoring).  
Appropriate starting doses and vitamins formulations should be used for new cases of LSV 
deficiency (see Table 7, adapted from Shneider et al., Pediatrics 2012).  Doses should be 
increased, as clinically indicated, to optimize the LSV levels.  Parenteral formulations should 
be used (where available) if enteral supplements are unsuccessful at improving LSV 
deficiency. 
Table 7 
Recommended Starting Doses for Lipid Soluble Vitamins 
Vitamin 
Starting Dose 
Vitamin A 
Starting dose 5000 IU orally of water miscible product 
(or appropriate intramuscular dose) 
Vitamin D (25-hydroxy vitamin 
D) 
Starting dose of 2000 IU orally daily of cholecalciferol 
(appropriate ergocalciferol or intramuscular dose may be used) 
or UVB phototherapy at the discretion of the investigator 
Vitamin E (α tocopherol) 
Starting dose of 25 IU/kg of TPGS (appropriate intramuscular 
dose vitamin E can be given if available) 
Vitamin K 
Starting dose of 2.5 mg orally for weight ≤30 kg or 5 mg for 
weight >30 kg (appropriate intramuscular or IV dose may be 
used) 
 


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The response to the change in regimen will be assessed at the next scheduled on-site study 
visit.  LSV supplements are escalated in monthly intervals over a 3-month period.  If during 
this period the LSV levels are persistently below the subject’s baseline value or the lower 
limit of normal, whichever is lower, and there is an absence of clinical symptoms, the 
investigator will be given the option of: 
• Consultation with a LSV expert to ensure the optimal doses/formulations of LSV 
supplements were administered 
o If, in the judgement of the expert, the doses/formulations of the administered 
supplements were optimal and yet their respective levels have not improved or 
further deteriorated, the subject will be discontinued from study medication. 
o If the expert recommends further optimization via supplementation, the 
investigator, in discussion with the medical monitor, may decide to continue 
study medication, administer the modified dose/formulation and re-check 
LSV levels at the next scheduled on-site visit.  If, the levels of LSV levels 
have decreased further or have not improved, the subject will be permanently 
discontinued from study medication. 
• Permanent withdrawal of the subject from the study. 
Figure 2 provides a flow diagram representing the protocol recommendations for treatment of 
and discontinuation due to worsening of LSV deficiency. 


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Figure 2 
Flow Diagram for Treatment of Worsening of Lipid Soluble Vitamin 
Deficiency 
 
LSV=lipid soluble vitamins. 
8.3.6 
Safety Monitoring for Coagulation Panel Results 
In the event of a confirmed laboratory result for INR >1.5 (BL ≤ULN) OR an increase of 
0.4 over BL (BL >ULN) despite adequate Vitamin K supplementation, the investigator and 
the medical monitor may consider a temporary interruption of study medication.  Dosing may 
resume when the INR falls below 1.5 or returns to the subject’s baseline level. 
8.3.7 
Study Medication Discontinuation Rules for Diarrhea 
Study medication should be discontinued if a subject has severe diarrhea that requires 
hospitalization and/or an IV or nutritional supplementation or leads to severe electrolyte 
disturbances. 
Clinical 
Symptoms
LSV Deficiency Observed
Interrupt / Discontinue 
Study Medication
Incremental LSV 
Supplementation
(up to 12 weeks)
Expert Recommended Optimization 
of LSV Supplementation (4 weeks)
Expert 
Opinion
Requested
Continue Study Medication
Yes
No
Effective
Ineffective
No
Ineffective
(Persistent LSV decrease)
Yes
Effective (LSV improving)
Expert Opinion:
Existing Supplementation Optimal?
Yes
No
(Persistent LSV decrease)
(LSV improving)


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9 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the study 
CRF Completion Guidelines for all data requiring transcription of the source.  A study 
monitor will visit each site in accordance with the monitoring plan and review the CRF data 
against the source data for completeness and accuracy.  Discrepancies between source data 
and data entered on the CRF will be addressed by qualified site personnel.  When a data 
discrepancy warrants correction, the correction will be made by authorized site personnel.  
Data collection procedures will be discussed with the site at the site initiation visit and/or at 
the investigator’s meeting.  Unscheduled assessments (e.g., local labs) are not required to be 
collected in the CRF except for those that are directly relevant to the monitoring of an 
AE/SAE; collection of other values may be requested by the sponsor. 
The study will be monitored according to ICH GCP guidelines. 
9.2 
Clinical Data Management 
A clinical database will be designed to collect data as specified in the data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy 
of the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification 
are to be communicated to the site for resolution.  Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner. 
9.3 
Data Handling Considerations 
Data that may potentially unblind the treatment assignment (i.e., maralixibat serum 
concentrations, treatment allocation, post-baseline sBA levels) will be handled with special 
care during the data cleaning and review process.  Prior to unblinding, any data that may 
potentially unblind study site personnel or study team personnel will be presented as blinded 
information or otherwise will not be made available.  If applicable, unblinded data may be 
made available to quality assurance representatives for the purposes of conducting 
independent audits.  
9.4 
Statistical Analysis Process 
All pre-defined statistical analyses will be performed after the database is locked.  All 
statistical analyses will be performed using SAS® (SAS Institute, Cary, NC, USA) 
version 9.4 or higher.  
The SAP will provide the comprehensive statistical methods and definitions for the analysis 
of the efficacy and safety data, as well as describe the approaches to be taken for 


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summarizing other study information such as subject disposition, demographics and baseline 
characteristics, medical and PFIC disease history, study medication exposure, and prior 
medications.  The SAP will also include define how missing data will be addressed.  All 
study data will be presented in subject listings. 
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical 
analysis and study conclusions.  
9.5 
Validation Analysis Plan  
A blinded analysis of the ItchRO(Obs) instrument will be performed before database lock 
according to the validation analysis plan (VAP).  The blinded analysis will be used to 
estimate a threshold of clinically meaningful change (i.e., responder definition) in the 4-week 
average morning ItchRO(Obs) pruritus scores.  The analysis will be performed by a group 
independent from both the study team and Mirum Pharmaceuticals.  Blinded data will be 
used for this analysis; data will be collapsed across treatment groups. 
Details of the analysis will be included in a standalone VAP, which will describe analyses 
that will be used to assess the measurement properties of the ItchRO(Obs) in alignment with 
scientific recommendations outlined in the FDA’s Patient Focused Drug Development 
Guidance 3 (i.e., reliability, validity, ability to detect change, and anchor-based meaningful 
within-person clinically meaningful change criteria).  Criteria for defining within-person 
clinically meaningful change for the ItchRO(Obs) will be detailed in the SAP. 
9.6 
Data Monitoring Committee 
A data monitoring committee (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 make recommendations 
to the sponsor to stop or modify the study if safety concerns are identified.  
• The DMC will pay particular attention to the safety profile of the highest dose level 
(600 µg/kg BID).  Should the DMC review determine that this dose is not safe, 
further dosing at this level, must be halted, and the relevant regulatory authority 
informed. 
• The DMC will also be able to request the frequency of safety laboratory tests be 
increased during the dose escalation period if this is considered necessary based on 
their review of safety data. 
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.  In particular, an ad hoc DMC 
meeting will be held within 2 weeks if ≥2 similar possibly/probably related SAEs or Grade 4 
TEAEs are observed.  The DMC will perform an unblinded review of these cases and 
provide recommendations to the sponsor regarding the continuation of specific dose levels, 
or the study overall.  Study drug would be reduced or stopped in those subjects who 


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experienced these triggering events, as per investigator judgment; study medication in all 
other participants will continue unless and investigators are otherwise advised by the DMC. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the enrollment of the first subject.  There is no study stop planned based on the 
efficacy results during the study and no alpha spending will occur prior to the completion of 
the study. 
9.7 
Sample Size Calculation and Power Considerations 
The sample size was calculated to ensure enrollment of an adequate number of PFIC2 
participants who fulfill criteria for the primary cohort (primary endpoint).  The sample size is 
chosen to provide at least 80% of power for the analysis of the primary endpoint. 
The primary efficacy endpoint is the mean change from baseline in the average morning 
ItchRO(Obs) severity score for the last 12 weeks of the study (Weeks 15–26). 
The following assumptions were made in estimating the sample size for study MRX-502: 
• Between-treatment group (placebo to active) LS mean difference of 0.663 
• Pooled SD of 0.563 
• Effect size of 1.178 in the mean change from baseline in the 4-week average morning 
ItchRO(Obs) score 
The estimations of LS mean difference, SD and effect size for the sample size justification 
are based on ItchRO(Obs) data from the maralixibat Phase 2 studies.  Maralixibat-treated 
subjects with PFIC2 from Study LUM001-501 were compared to placebo-treated subjects 
with ALGS from Studies LUM001-301 and LUM001-302 as no placebo data are available 
from Study LUM001-501.  Since impact and symptoms of itching reported by PFIC patients 
are also reported by ALGS patients, (i.e., mood changes, scratching, difficulty falling asleep, 
skin damage, blood from scratching etc.), it is reasonable to assume that the ItchRO 
outcomes from the ALGS placebo-controlled studies will inform outcomes for this PFIC 
study due to the similarities in the features of pruritus.  Two fundamental assumptions were 
made: A) the placebo effect in subjects with ALGS is similar to the one expected in subjects 
with PFIC2.  Subjects with ALGS in study LUM001-301/302 had a slightly higher BL 
ItchRO(Obs) value compared to subjects with PFIC in Study LUM001-501.  As subjects with 
higher BL pruritus generally report a higher placebo response, the use of ALGS subjects 
from study LUM001-301/302 would therefore lead to a slightly more conservative 
assumption of the expected effect and sample size.  The 2 populations were similar in the 
other BL characteristics.  Besides from the small difference in BL characteristics there are no 
obvious reasons to believe why the placebo response in subjects with ALGS and PFIC should 
be difference.  Therefore, the comparison of ALGS placebo subjects with treated PFIC 
subjects is considered a valid approximation for the purpose of assessing the effect size, data 
variability and the calculation of the sample size.  B) the placebo effect does not change after 


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3 months of treatment; as Studies LUM001-301 and -302 were 13-week studies, data beyond 
13 weeks were imputed using the last observation carried forward. 
With the assumed values, a total of 26 complete subjects (13 subjects in each treatment 
group) will be required to provide 80% power for the comparison of the primary endpoint 
measure between the maralixibat treatment group and placebo, based on a 2-sided, 2-sample 
t-test at the 0.05 level of significance.  
Including a 10% dropout rate based on the previous PFIC study and rounding up to the next 
even number, approximately 30 participants with PFIC2 (15 subjects in each treatment 
group) will be randomized for the primary analysis. 
9.8 
Analysis Populations 
The following efficacy analysis populations are defined: 
The intent-to-treat (ITT) population will consist of all randomized subjects. 
The per-protocol population will consist of all subjects in the ITT population who receive 
at least 1 dose of study medication and do not have any major protocol violations or 
deviations.  Major protocol violations/deviations will be identified prior to database lock.  
The primary and secondary efficacy endpoints will be analyzed for each of the analysis 
populations described above.  The primary analysis on the primary efficacy endpoint will be 
conducted in participants with PFIC2 in the ITT population.  The primary analysis on the 
secondary efficacy endpoints will be conducted in participants with PFIC2 and participants 
with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) in the ITT population.   
Any exploratory efficacy endpoints will be analyzed in the ITT population.  Exploratory 
analyses may be performed on participants with PFIC2, PFIC (PFIC1, PFIC2, PFIC3, PFIC4, 
PFIC5, and PFIC6), and other PFIC populations of interest.  The final list of exploratory 
endpoints will be described in the SAP.   
The safety population will consist of all subjects who receive at least 1 dose of study 
medication. 
Safety, tolerability, and PK analyses will be conducted in the safety population. 
Because PFIC is a rare disease, siblings are allowed to enroll in the study.  Each sibling (if 
any) will be considered for each analysis population described above.  A sensitivity analysis 
on the primary and secondary efficacy endpoints will include only 1 sibling in each efficacy 
analysis population.  The choice of sibling will be made at random, and the method will be 
pre-specified in the SAP. 


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9.8.1 
PFIC Populations for Analyses 
The following definitions will be used for the PFIC populations in the analyses of the various 
endpoints in this study: 
Primary and Secondary Endpoints: 
• PFIC2: Participants with PFIC2 who fulfill criteria for the primary cohort 
(see Section 4)  
• PFIC: Participants with PFIC1, PFIC2 (who fulfill criteria for the primary 
cohort), PFIC3, PFIC4, PFIC5, and PFIC6.  
Exploratory Endpoints:  
PFIC2 and PFIC populations (as above) and 
• PFIC1: Participants with PFIC1 
• PFIC3: Participants with PFIC3  
• PFIC4: Participants with PFIC4 
• PFIC5: Participants with PFIC5 
• PFIC6: Participants with PFIC6 
• Truncated PFIC2: Participants with PFIC2 with mutations leading to 
premature protein truncation or failure of protein production 
• All-participants: All participants enrolled 
Each of the above-defined PFIC populations, with the exception of the All participants, will 
exclude any participants with biliary surgery at baseline and genotype variations affecting 
only 1 allele (heterozygous). 
In the PFIC population (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6), participants with 
biallelic disease causing variation in ATP8B1 (PFIC1), ABCB11 (PFIC2), ABCB4 (PFIC3), 
TJP2 (PFIC4), NR1H4 (PFIC5), and MYO5B (PFIC6) may be included.  The number of 
participants with each variation will depend on the genotype prevalence within the enrolled 
study population. 
9.9 
Subject Disposition, Demographics, and Baseline Characteristics 
Subject disposition, demographics and baseline characteristics, PFIC disease history, prior 
medications, and treatment exposure and compliance will be summarized by treatment group.  


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Study completion status and reasons for discontinuation will also be displayed.  The analysis 
population(s) to be used for these summaries will be provided in the SAP. 
Medical and surgical history and protocol violations/deviations will be presented in subject 
listings. 
9.10 
Efficacy Analyses 
The primary and secondary efficacy analysis will be performed for the ITT population.  
Analysis of the primary and secondary efficacy endpoints will also be performed in the per 
protocol population.  Analyses on the exploratory efficacy endpoints will be performed in the 
ITT population.  Exploratory analyses may be performed in participants with PFIC2, PFIC 
(PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6), and other PFIC populations of interest.  
Final list of exploratory endpoints will be described in the SAP.   
For the PFIC population (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6), PFIC type will 
also be used as a covariate in the analysis.  For this analysis, due to the small sample sizes, 
PFIC4, PFIC5, and PFIC6 will be grouped together. 
In general, the baseline is defined as all data collected at Visit 1 (Day 0) or the last 
assessment before the first dose of the study medication if the data are not collected at Visit 1 
(Day 0).  Baseline ItchRO and EDQ average scores are defined as the 4-week average score 
prior to the first dose of study medication. 
For all efficacy analyses, subjects 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 subject 
(i.e., the planned treatment regimen) rather than the actual treatment given.  All efficacy data 
will be presented in subject listings. 
9.10.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the mean change in the average morning 
ItchRO(Obs) severity score between baseline and Week 15 through Week 26, using 4-week 
average morning ItchRO(Obs) severity scores.  
Weekly scores will be calculated relative to the initiation of treatment.  For each week, a 
weekly score will be calculated if at least 4 days’ worth of data are provided.  If more than 
50% of scores are missing for a particular week, the weekly average score will be treated as 
missing.  Average scores will be calculated for the following periods:  Through Week 6 
(42 days), Weeks 7–10, 11–14, 15–18, 19–22, and 23–26 (28 days).  For each period, the 
average of the weekly scores will be calculated.  At least 50% of the weekly scores must be 
available in order to compute an average for the period.  The baseline average morning 
ItchRO(Obs) score is defined as the 4-week average morning ItchRO(Obs) severity score 
prior to the first dose of study medication. 


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Primary Analysis for Primary Efficacy Endpoint 
For this study, the primary estimand is the improvement in pruritus measured as change from 
baseline in the average morning ItchRO(Obs) severity score 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.  A treatment policy estimand will be utilized for the analysis where all data 
will be incorporated.  Intercurrent events will be handled as follows: 
• Change in or administration of any allowed concomitant medication will be handled 
using a treatment policy strategy. 
• Administration of any prohibited concomitant medication will be handled using a 
hypothetical strategy assuming that the prohibited medications are not available and 
hence were not taken, so as to assess the treatment effect for the randomized 
treatment groups in addition to allowed concomitant medication. 
• Discontinuation of randomized treatment due to all of the following reasons will be 
handled using a treatment policy strategy: 
o Lack of efficacy 
o Safety concerns 
o Lack of compliance with study treatment 
• Discontinuation of randomized treatment due to other reasons (including loss to 
follow-up) will be handled using a hypothetical strategy, assuming that randomized 
treatment had not been discontinued. 
• Liver transplant or death:  Neither of these are expected in the study.  In the unlikely 
event that either of these events occur, they will be analyzed using a composite 
strategy, assuming worst possible score for all subsequent assessments. 
The primary analysis on the primary efficacy endpoint will be conducted in participants with 
PFIC2 who fulfill criteria for the primary cohort in the ITT population.  A restricted 
maximum likelihood (REML)-based mixed-effects model for repeated measures (MMRM) 
will be used as the primary analysis method.  The repeated measures include post-baseline 
visits during the dose escalation phase (i.e., Week 6) and stable dosing phase (i.e., Weeks 10, 
14, 18, 22, and 26), with change from baseline in the 6- or 4-week average morning 
ItchRO(Obs) severity score as the dependent variable.  The MMRM model will include the 
fixed, categorical effects of treatment group, visit, and treatment group-by-visit interaction as 
well as the continuous, fixed covariates of baseline 4-week average morning ItchRO(Obs) 
severity score and the baseline score-by-visit interaction. 


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The unstructured variance/covariance matrix will be used to model the variances and 
covariances for the 6 time points (periods) included in the model.  The unstructured 
variance/covariance does not impose any restrictions on the pattern of the matrix elements.  
Every attempt (e.g., relaxing the convergence criteria, increasing the iteration limit, choosing 
reasonable starting values for the estimates) will be made to ensure convergence using the 
unstructured modeling of within-subject correlations.  However, if the numerical algorithm 
for estimation of the mixed model fails to converge, 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 (co)variance structure which 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 using the contrast 
(difference in least squares [LS] means) between treatment groups across the last 12 weeks of 
the study (i.e., Weeks 15–18, 19–22, and 23–26 combined).  The analytical solution of the 
overall treatment effect obtained from MMRM is an equally weighted average of the 
3 individual period-specific estimates over the time period of interest (i.e., the last 12 weeks 
of the study).  Significance tests will be based on LS means using a 2-sided significance level 
(2-sided 95% confidence intervals [CIs]). 
The null hypothesis for the primary efficacy endpoint of the equality of maralixibat and 
placebo is: 
H01: mean change in average morning ItchRO(Obs) severity score between 
baseline and Week 15 through Week 26 in the 2 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 last 12 weeks of the study is ≤0.05.  Least squares 
(LS) means will be calculated for each treatment group for each post-baseline period in the 
model.  The difference between maralixibat and placebo change from baseline in average 
morning ItchRO(Obs) severity score will be estimated, with the corresponding 2-sided 
95% CI constructed for each period, and the last 12 weeks (i.e., last 3 periods) 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. 
Rationale for Primary Analysis Method 
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 


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from individual subjects 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 
(co)variances, 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 subjects with missing data (Cnaan et al., 1997, 
Molenberghs et al., 2004, Molenberghs and Kenward, 2007). 
Despite careful planning and study conduct, the occurrence of missing data cannot be 
completely eliminated.  As a direct likelihood method, the MMRM method is a preferred 
approach for handling missing data in such designs.  MMRM is a full multivariate model in 
nature, which avoids potential bias as a predetermined model and operates in a more general 
missing at random (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 
(European Medicines Agency, 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; Siddiqui et al., 2009, Mallinckrodt et al., 2008, 
Mallinckrodt et al., 2013). 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 and Rubin, 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 subjects 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 al., 2008). 
Sensitivity and Supportive Analysis for Primary Efficacy Endpoint 
Sensitivity and supportive analysis will be performed on the primary efficacy endpoint to 
quantify the possible impact of missing data and the use of potentially correlated sibling data 
(if needed), and to demonstrate the robustness of the conclusions.  As a sensitivity analysis, 
the primary efficacy endpoint will be analyzed in PFIC2 participants who fulfill criteria for 
the primary cohort in the ITT population using the MMRM model, described above. 
Summary statistics on average morning ItchRO(Obs) severity scores by treatment group and 
visit, including the end of study visit (Week 26/EOT), will also be presented.  Additionally, a 
figure with the LS mean ±SE of change from baseline in the average morning ItchRO(Obs) 
severity score will be presented by treatment group and visit.  


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Missing Data 
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.  Therefore, 
analysis valid under MNAR is desired.  Both a MNAR- and MAR-based analyses will be the 
basis upon which sensitivity of missing data are assessed. 
Sensitivity analyses to deal with missing data will use multiple imputation (MI) methods 
where missing values are imputed individually under both a plausible MNAR and MAR 
scenario.  Multiple imputation is a simulation-based approach where missing values are 
replaced using an appropriate stochastic model given the observed data and covariates, 
creating multiple completed data sets.  These completed datasets are then analyzed using 
standard analysis methods (i.e., MMRM), and the different parameter estimates across the 
datasets are then combined to produce a unique point estimate and standard error taking into 
account the uncertainty of the imputation process.  The following 2 sensitivity 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.  
Complete details of the multiple imputation procedures, including the methodology, number 
of imputations, and the seed of the pseudorandom number generator used to randomly 
generate imputations for the missing values, will be pre-specified in the SAP prior to 
unblinding. 
Standard MAR Imputation 
The MAR imputation model will impute missing values using a regression-based multiple 
imputation model (Little and Yau, 1996).  For subjects with complete data up to a particular 
visit, a multiple regression model will be fit that includes the outcome at that visit as the 
dependent variable and observed data (e.g., outcomes at previous visits, treatment, and 
baseline) as independent variables.  Separate models will be similarly constructed for each 
visit.  Using these regression models, a missing value for a subject at a particular visit will be 
imputed as a draw from the predictive distribution given the outcomes at previous visits 
(some possibly imputed), treatment group, etc.  This process will be repeated a given number 
of times (as specified in the SAP), 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 in the SAP, 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. 
Placebo-Based Imputation 
The placebo-based imputation analysis model assumes a MNAR mechanism and is within 
the pattern-mixture model framework.  The pattern-mixture model approach models the 
distribution of a response as the mixture of a distribution of the observed responses and a 


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distribution of the missing responses.  Conceptually, pattern mixture models typically assess 
the outcome variable separately for different groups (patterns) and then combine results 
across groups for final inference (Mallinckrodt et al., 2008, Ratitch and O’Kelly, 2011).  The 
pattern-mixture model approach will be applied in the SAS MI procedure by using the 
MNAR statement.  The MNAR imputation model will specify a subset of observations to 
derive the imputation model, which is used for pattern imputation based on the placebo 
group. 
The underlying assumption is that a subject on the active treatment with missing data follows 
the distribution of the placebo responses, i.e., the means and the intra-subject correlations 
based on the placebo responses will apply.  This sensitivity analysis stress-tests the MAR 
assumption that withdrawals will tend to have efficacy similar to subjects who remain in the 
study in their respective treatment arm.  On the contrary, the placebo-based pattern 
imputation assumes MNAR; that after discontinuation, subjects on the IP will tend to have 
efficacy close to subjects on placebo. 
The imputations for this model are based on the distribution of placebo group responses over 
time.  That is, an imputation model for the missing observations in the maralixibat treatment 
group is constructed not from the observed data in the active treatment group but rather from 
the observed data in the placebo treatment group.  This model is also the imputation model 
that is used to impute missing observations in the placebo group.  
Sibling Data 
If siblings are randomized and evaluable for efficacy, the primary analysis method described 
above for the primary efficacy endpoint will be repeated as a sensitivity analysis in which 
only one of sibling pairs or multiples will be used.  The choice of which sibling to use in the 
sensitivity analysis will made before the MRX-502 study is unblinded.  The choice of sibling 
will be made at random. 
9.10.2 
Adjustment for Multiplicity 
In order to maintain study-wide Type I error control, 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.  The hierarchical order for testing the null 
hypotheses is as follows: 
1. Primary:  Mean change in the average morning ItchRO(Obs) severity score between 
baseline and Week 15 through Week 26 in participants with PFIC2  
2. Secondary:  Mean change in total sBA level between baseline and average of 
Weeks 18, 22, and 26 in participants with PFIC2  
3. Secondary:  Mean change in the average morning ItchRO(Obs) severity score 
between baseline and Week 15 through Week 26 in participants with PFIC (PFIC1, 
PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 


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4. Secondary:  Mean change in total sBA level between baseline and average of 
Weeks 18, 22, and 26 in participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, 
PFIC5, and PFIC6) 
5. Secondary:  Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in 
participants with PFIC2 using the average value from the three 4-week periods 
(Weeks 15-18, 19-22, and 23-26) 
6. Secondary:  Proportion of sBA responders from Week 18 to Week 26 in participants 
with PFIC2, using the average value from Weeks 18, 22, and 26 values 
7. Secondary:  Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in 
participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 
8. Secondary:  Proportion of sBA responders from Week 18 to Week 26 in participants 
with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6)  
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. 
The effect of such a procedure is that no confirmatory claims can be based on the endpoint(s) 
that have a rank lower than that endpoint whose null hypothesis was the first that could not 
be rejected.  Those tests will be considered exploratory and no formal conclusions will be 
drawn. 
9.10.3 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are defined as: 
• Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 
• Mean change in the average morning ItchRO(Obs) severity score between baseline and 
Week 15 through Week 26 in participants with PFIC 
• Proportion of ItchRO(Obs) responders from Week 15 to Week 26  
• For the purpose of determining response, the average value from the three 4-week 
periods (Weeks 15–18, 19–22, and 23–26) will be computed and used. 
ItchRO(Obs) responder definition: 
Criteria for clinically meaningful change in the ItchRO(Obs) (responder definition) 
will be established by the VAP and described in detail in the SAP. 
• Proportion of sBA responders from Week 18 to Week 26 
• For the purpose of determining response, the average value from Weeks 18, 22, and 
26 values will be computed and used. 


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sBA responder definition: 
 
≥75% reduction in sBA 
OR 
 
sBA level <102 µmol/L (applies only if baseline sBA level was >102 µmol/L) 
Serum bile acid from each scheduled clinic visit will be used in the analysis of mean change 
from baseline in sBA. 
Analysis for Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed in participants with PFIC2 and participants 
with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) as described in Section 9.10.  
Analysis similar to that described for the primary efficacy endpoint, including the sensitivity 
analyses, will be performed for each of the secondary efficacy endpoints.  
For the binary (responder) outcomes, the number and proportion of subjects that are 
considered a “responder” will be summarized by treatment group at the end-of-study visit 
(Week 26/EOT).  Barnard’s exact test will be used to calculate the p-value for the difference 
between treatment groups. 
The null hypotheses for the secondary efficacy endpoints of the equality of maralixibat and 
placebo are: 
H02: mean change in total sBA level between baseline and average of Weeks 18, 
22, and 26 on participants with PFIC2 in the 2 treatment groups are equal 
H03: mean change in the average morning ItchRO(Obs) severity score between 
baseline and Week 15 through Week 26 on participants with PFIC (PFIC1, 
PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) in the 2 treatment groups are 
equal 
H04: mean change in total sBA level between baseline and average of Weeks 18, 
22, and 26 on participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, 
PFIC5, and PFIC6) in the 2 treatment groups are equal 
H05: proportion of ItchRO(Obs) responders from Week 15 to Week 26 on 
participants with PFIC2 in the 2 treatment groups are equal using the 
average value from the three 4-week periods (Weeks 15-18, 19-22, and 
23-26) 
H06: proportion of sBA responders from Week 15 to Week 16 on participants 
with PFIC2 in the 2 treatment groups are equal, using the average from 
Weeks 18, 22, and 26 sBA values 


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H07: proportion of ItchRO(Obs) responders from Week 15 to Week 26 on 
participants with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) 
in the 2 treatment groups are equal 
H08: proportion of sBA responders from Week 18 to Week 26 on participants 
with PFIC (PFIC1, PFIC2, PFIC3, PFIC4, PFIC5, and PFIC6) in the 
2 treatment groups are equal 
A hierarchical testing procedure, as described in Section 9.10.2, 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).  
All tests will be performed as 2-sided tests at the 0.05 level of significance. 
9.10.4 
Exploratory Efficacy Endpoints 
The final exploratory endpoint list will be described in detail in the SAP.  Analyses on the 
exploratory efficacy endpoints will be performed in the ITT population.  Exploratory 
analyses may be performed in participants with PFIC2, PFIC (PFIC1, PFIC2, PFIC3, PFIC4, 
PFIC5, and PFIC6), and other PFIC populations of interest as described in the SAP.  
• Mean change in liver-associated laboratory test level between baseline and Week 15 
through Week 26 
• Mean change from baseline in liver-associated laboratory tests to Weeks 2, 6, 10, 14, 18, 
22, and 26 
• Proportion of participants with elevated liver biochemistry (i.e., >ULN at baseline), 
whose liver biochemistry normalize (≤ULN) at Weeks 2, 6, 10, 14, 18, 22, and 26 
• Mean change from baseline in FIB-4, APRI, MELD and PELD score to Weeks 2, 6, 10, 
14, 18, 22, and 26 
• Proportion of days with a morning, evening, and highest daily ItchRO(Obs) severity 
score ≤1 at the participant level from baseline to Week 6 (overall and weekly), 
Weeks 7 10, 11-14, 15-18, 19-22, 23-26, and 15-26 
• Proportion of days with a morning, evening, and highest daily ItchRO(Obs) frequency 
score ≤1 at the participant level from baseline to Week 6 (overall and weekly), 
Weeks 7-10, 11-14, 15-18, 19-22, 23-26, and 15-26 
• Proportion of days with a morning, evening, and highest daily ItchRO(Pt) severity score 
≤1 at the participant level from baseline to Week 6 (overall and weekly), Weeks 7-10, 
11-14, 15-18, 19-22, 23-26, and 15-26 


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• Proportion of days with a morning, evening, and highest daily ItchRO(Pt) frequency 
score ≤1 at the participant level from baseline to Week 6 (overall and weekly), 
Weeks 7-10, 11-14, 15-18, 19-22, 23-26, and 15-26 
• Mean change in the average morning ItchRO(Obs) frequency score between baseline and 
Week 15 through Week 26  
• Mean change from baseline in average (6-week average for Week 6 and 4-week average 
afterwards) morning, evening, and highest daily ItchRO(Obs) severity and frequency 
scores to Weeks 6, 10, 14, 18, 22, 26, and Weeks 15-26 combined 
• Mean change from baseline in weekly average morning, evening, and highest daily 
ItchRO(Obs) severity and frequency scores to each post-baseline week, and Weeks 15-26 
combined 
• Mean change from baseline in average (6-week average for Week 6 and 4-week average 
afterwards) morning, evening, and highest daily ItchRO(Pt) severity and frequency scores 
to Weeks 6, 10, 14, 18, 22, 26, and Weeks 15-26 combined 
• Mean change from baseline in weekly average morning, evening, and highest daily 
ItchRO(Pt) severity and frequency scores to each post-baseline week, and Weeks 15-26 
combined 
• Mean change from baseline in CSS, CIS, and PIS at Weeks 2, 4, 6, 10, 14, 18, 22, and 26 
• Proportion of participants in each change from baseline category of the CSS, CIS, and 
PIS at Weeks 2, 4, 6, 10, 14, 18, 22, and 26  
• Proportion of responders at Weeks 6, 10, 14, 18, 22, 26, and any of those weeks, where a 
responder is defined as having:  
• a) Clinically meaningful 4-week average morning ItchRO(Obs) severity decrease 
from baseline AND a normalization or reduction from baseline in sBA of ≥75%, or 
average sBA level <102 µmol/L  
• b) Clinically meaningful 4-week average morning ItchRO(Obs) severity decrease 
from baseline  
• c) a normalization or reduction from baseline in sBA of ≥75%, or average sBA level 
<102 µmol/L 
• Number and proportion of participants achieving morning ItchRO(Obs) severity scores 
≤1 for more than 50% of the time from baseline to Week 6, Weeks 7-10, 11-14, 15-18, 
19-22, 23-26, and 15-26 
• Mean change over time in quality of life as measured by the PedsQL 
• Mean change from baseline in average sleep disturbance scores over time (4-week 
average score at Weeks 6, 10, 14, 18, 22, and 26), based on sleep-related questions on the 
EDQ(Obs) morning, PedsQL (parent), and PedsQL (child) questionnaires, individually 


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• Proportion of “no” answers for sleep-related questions on the ItchRO(Obs) morning, 
ItchRO(Obs) evening, and ItchRO(Pt) morning, individually, at the participant level for 
baseline to Week 6, Weeks 7-10, 11-14, 15-18, 19-22, 23-26, 15-26, and overall 
• Proportion of participants with improvement from baseline (i.e., change from baseline 
<0) in EDQ(Obs) sleep score at Weeks 6, 10, 14, 18, 22, and 26 (using 4-week average 
scores) 
• Proportion of EDQ sleep scores ≤2 at the participant level post-baseline through Week 26 
• Mean change from baseline in height z-score and weight z-score at Weeks 2, 4, 6, 10, 14, 
18, 22, and 26 
• Proportion of participants who experience an improvement from baseline in height 
z-score or weight z-score (i.e., change from baseline >0) at Weeks 2, 4, 6, 10, 14, 18, 22, 
and 26  
• Mean, change, and % change from baseline in total sBA level to Weeks 2, 6, 10, 14, 18, 
22, and 26 
• Mean change from baseline in bile acid subspecies, C4, FGF-19, and autotaxin to 
Weeks 10, 18, and 26 
• Time to liver-associated events (PEBD surgery, listing for liver transplantation, liver 
decompensation [hepatic encephalopathy, variceal bleeding, ascites, and spontaneous 
bacterial peritonitis] events, HCC, death) 
• Correlation analyses between sBA and pruritus severity 
The ItchRO(Obs) frequency scores will be calculated using the same approach as the 
ItchRO(Obs) severity scores.  
ItchRO(Pt), EDQ(Obs), and EDQ(Pt) will be scored and analyzed in the same manner as 
ItchRO(Obs) noted above.  
Height and weight z-scores are based on a subject’s gender and age at each scheduled visit.  
For subjects less than 24 months of age, the World Health Organization (WHO) growth 
charts are recommended by the Centers for Disease Control (CDC) and will be used to derive 
z-scores.  For subjects at least 24 months of age, the CDC growth charts will be used to 
derive z-scores. 
Severity scores for the EDQ are based on the EDQ(Obs) question of “How bad was your 
child’s itch at its worst?” and on the EDQ(Pt) question of “How bad was your itch at its 
worst.” “Non-severity” scores are based on all other EDQ questions. 
The additional questions included in the ItchRO instrument that are not scored will be 
presented in subject listings. 


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To assess possible improvements in sleep, sleep-related questions from the ItchRO, EDQ, 
and PedsQL questionnaires will be identified and summarized.  For ItchRO(Obs), quality of 
sleep information is collected on the morning and evening diary as it relates to contributing 
to the observer-rated severity score (1=Yes; 0=No).  For ItchRO(Pt), the morning diary asks 
2 sleep-related questions: “Did feeling itchy make it hard to fall asleep last night?” and “Did 
feeling itchy wake you up last night?” (1=Yes; 0=No).  For EDQ(Obs), quality of sleep is 
assessed through the question, “Because of itch, my child had trouble staying asleep,” which 
is scored on a 5-point scale.  For the ItchRO and EDQ sleep-related questions, 4-week 
(morning and/or evening) average scores will be derived.  
For PedsQL (parent and subject reports), quality of sleep is assessed by scoring difficulty in 
falling asleep, and/or difficulty/trouble in sleeping (mostly) through the night, on 3-point 
scales for young child subject reports or 5-point scales for all others. 
The SAP will describe the subscales/domains, including the scoring algorithms, for each of 
the PedsQL questionnaires.  Liver biochemistry (e.g., TSB, ALT), sBA normalization levels, 
along with definitions of elevated liver biochemistry levels and liver disease severity scores, 
will be covered in the SAP. 
Analysis for Exploratory Efficacy Endpoints 
An MMRM model with the proportion of days with a morning ItchRO(Obs) severity score 
≤1 for each post-baseline time period as the outcome variable will be used to compare 
treatment differences for Weeks 0–6, 7–10, 11–14, 15–18, 19–22, and 23–26.  The MMRM 
model will include the fixed, categorical effects of treatment group, time period, and 
treatment group-by-time period interaction as well as the continuous, fixed covariates of 
baseline 4-week average morning ItchRO(Obs) severity scores and the baseline 
score-by-time period interaction.  Least squares means will be calculated for each treatment 
group for each post-baseline time period in the model.  The difference between maralixibat 
and placebo change from baseline in the outcome variable will be estimated, with the 
corresponding 2-sided 95% CI constructed for each time period.  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 time period.  In addition, an analysis of 
covariance (ANCOVA) model, with the proportion of days with morning ItchRO(Obs) 
severity score ≤1 for the last 12-weeks of the study (i.e., Weeks 15 to 26) as the outcome 
variable, treatment group as a factor, and baseline 4-week average morning ItchRO(Obs) 
severity scores as a covariate, will be used to compare the treatment difference for the 
proportion of days with morning ItchRO(Obs) severity score ≤1 for the last 12 weeks of the 
study.  The proportion of days with morning ItchRO(Obs) severity score ≤1 for each subject 
will also be summarized by treatment group for each post-baseline time period (i.e., baseline 
to Week 6, Weeks 7–10, Weeks 11–14, Weeks 15–18, Weeks 19–22, Weeks 23–26, and 
Week 15–26. 
Analysis 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 


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continuous variables.  The repeated measures in the MMRM model will include the 
post-baseline visits as specified for each above-listed endpoint, with change from baseline 
value as the dependent variable.  The MMRM model will include the fixed, categorical 
effects of treatment group, visit, and treatment group-by-visit interaction as well as the 
continuous, fixed covariates of baseline and the baseline-by-visit interaction.  Least squares 
means will be calculated for each treatment group for each post-baseline 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 ItchRO 
and EDQ 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 number of observations, mean, 95% CI on the mean, standard deviation, 
median, minimum, and maximum on 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, the number and proportion of subjects that are considered a 
“responder” will be summarized by treatment group for each visit, including the end of study 
visit (Week 26/EOT).  Barnard’s exact test will be used to calculate the p-value for the 
difference between treatment groups at each study visit. 
The number and proportion of subjects in each 5-point scale (0 to 4) of the CSS, CIS, and 
PIS, as well as the change from baseline in scale, will be summarized by treatment group for 
each visit including the end of study visit (Week 25/EOT).  The Cochran-Mantel-Haenszel 
(CMH) test will be applied to test for treatment difference in the change from baseline scores 
at each study visit.  Quality of sleep as assessed by the PedsQL parent and subject 
questionnaires will use similar analysis methods. 
Kaplan-Meier curves will be used to estimate the distribution of time to liver-associated 
events (PEBD surgery, listing for liver transplantation, liver decompensation [hepatic 
encephalopathy, variceal bleeding, ascites, and spontaneous bacterial peritonitis] events, 
HCC, and death) for each treatment group.  The median and other quartiles for time to 
liver-associated events, 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. 
All tests will be performed as 2-sided tests at the 0.05 level of significance. 
Sensitivity analyses will not be performed on the exploratory efficacy endpoints. 
9.11 
Safety and Tolerability Analyses 
All safety analyses will be performed on the safety population, defined as all subjects who 
were randomized and received at least 1 dose of study medication.  Analyses will be 


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conducted separately in participants with PFIC2 and participants with PFIC (PFIC1, PFIC2, 
PFIC3, PFIC4, PFIC5 and PFIC6). 
For all safety and tolerability analyses, subjects will be analyzed by the treatment received 
and the overall active treatment group.  For active treatment, the dose of IP received at the 
end of the dose-escalation period, or the last dose received if the subject discontinued from 
the IP during the dose escalation period, will be used.  
Safety data collected at the baseline visit (Visit 1/Day 0) or the last preceding visit if not 
collected at Visit 1 will be used as the baseline value for safety analyses. 
Safety measures including AEs, clinical laboratory values, physical examination findings 
(including body weight, height, and body mass index [BMI]), vital signs, ECGs, ultrasound 
liver imaging, and concomitant treatment usage will be summarized descriptively.  For 
quantitative variables, descriptive statistics including number of observations, mean, median, 
standard deviation, 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. 
All safety and tolerability data will be presented in subject listings. 
9.11.1 
Adverse Events 
In general, TEAEs are defined as AEs that start or deteriorate on or after the first dose of 
study medication and no later than 7 days following the last dose of study medication (for 
subjects not participating in the extension study) or reported through the Week 26/EOT visit 
(for subjects participating in the extension study).  For any subjects who die during the study 
and the date of death is between the date of first dose of study medication and the date of 
study discontinuation (as entered by the site), inclusive, all AEs (including those resulting in 
death) that occur during the study will be considered as TEAEs irrespective of the last dose 
and will be included in the TEAE summaries.  All summaries of AEs will be based on 
TEAEs unless specified otherwise. 
Adverse events of special interest (AESIs) will be outlined in the SAP and summarized. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and proportion of subjects who experience the event according to 
MedDRA system organ class (SOC) and preferred term will be presented by treatment group.  
Treatment-emergent AEs will be further summarized by severity and relationship to study 
medication.  Adverse events related to study medication, AEs leading to withdrawal, SAEs, 
and deaths will be similarly summarized. 
Subject listings of AEs will include the dose of study medication at the onset of the event. 


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9.11.2 
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 and height measurements will 
also be summarized as a z-score for a subject’s age and gender.  Potentially clinically 
important (PCI) values for select vital signs results will be defined in the SAP.  The number 
and proportion of subjects with PCI values will be presented by treatment group.  
9.11.3 
Laboratory Assessments 
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 subjects 
with clinical laboratory values below, within, or above the normal range by time point and in 
relation to baseline will be tabulated for each safety laboratory analyte by treatment group in 
a shift table.  Potentially clinically important laboratory ranges will be defined in the SAP for 
select laboratory tests.  The number and proportion of subjects with PCI laboratory values 
will be presented by treatment group.  
Efficacy laboratory tests (i.e., total sBA, sBA subspecies, ALT, total and conjugated 
bilirubin, C4, FGF-19, autotaxin, FIB-4, and APRI) will not be included in safety summaries. 
9.11.4 
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 subjects with normal and abnormal ECG results will also be 
summarized.  These summaries will be presented by study visit and treatment group. 
Potentially clinically important values for ECG results will be defined in the SAP.  The 
number and proportion of subjects with potentially clinically important values will be 
presented by treatment group. 
9.11.5 
Liver Ultrasound 
Liver ultrasound (or MRI) results will be presented in subject listings. 
9.11.6 
Concomitant Treatments 
Prior and concomitant treatments will be summarized descriptively by treatment group using 
the number and proportion of subjects. 
Prior medications will be presented separately from concomitant treatments.  Medications 
that started prior to the first dose of study medication will be considered prior medications 
whether or not they were stopped prior to the first dose of study medication.  Any 
medications continuing or starting after the first dose of study medication will be considered 
to be concomitant.  If a medication starts prior to the first dose of study medication and 


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continues after the first dose of study medication, it will be considered both prior and 
concomitant. 
Medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). 
9.12 
Other Analyses 
9.12.1 
Healthcare Utilization 
Healthcare resource utilization between baseline and Week 26 will be analyzed. Healthcare 
resource utilization variables include the number of hospitalizations, emergency room visits, 
the length of stay for hospitalization (days), surgeries and procedures related to the subject’s 
PFIC condition, and the number of days the caregiver missed from work due to healthcare 
resource utilization events.  Descriptive statistics including number of observations, mean, 
95% CI on the mean, median, minimum, and maximum will be presented by visit for 
continuous variables.  For categorical variables, the number and proportion of subjects will 
be presented. 
9.12.2 
Pharmacokinetic Analyses 
Systemic concentrations of maralixibat in plasma will be determined at pre-dose and at 
approximately 2.5 hours after the morning dose at Week 10 and Week 26 (EOT/ET).  
Summary statistics (number of observations, mean, standard deviation, coefficient of 
variation, median, minimum, maximum, and geometric mean) will be determined for 
maralixibat concentrations at each nominal time point and sampling time.  
10 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in 
the Declaration of Helsinki.  
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate. 
10.1 
Sponsor’s Responsibilities 
10.1.1 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations, ICH GCP Guideline E6 (1996) and E6 
R2 (2017), EU Directive 2001/20/EC, as well as all applicable national and local laws and 
regulations. 


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Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study.  The sponsor (or a nominated designee) is responsible for the preparation, submission, 
and confirmation of receipt of any regulatory authority approvals required prior to release of 
study medication for shipment to the site. 
10.1.2 
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. 
10.1.3 
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. 
10.1.4 
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 suspended or terminated, the sponsor will ensure that applicable sites, 
regulatory agencies and IRBs/ECs are notified as appropriate.  Additionally, the 
discontinuation of a registered clinical study which has been posted to a designated public 
website will be updated accordingly. 
Should the study be temporarily suspended due to safety concerns, re-initiation will follow 
local laws and regulations (see Section 9.5). 
The study may be terminated because of the following:  the manifestation of an unjustifiable 
risk, a relevant toxicity with an unfavorable change to the benefit-risk ratio, a change in 
scientific knowledge (e.g., another toxicological or clinical study) with a negative impact on 
the evaluation of the benefit-risk ratio, a request or order from the competent authorities, the 
inability to complete recruitment within the prescribed timeframe, or the withdrawal of the 
authorization to manufacture or import the investigative product. In addition, interruption or 
premature termination of a clinical study can result if a study site is deemed unsuitable (by 


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the sponsor, authority, or Ethics Committee) or deviations from the approved SAP or the 
achievement or non-achievement of statistical objectives occur. 
10.2 
Investigator’s Responsibilities 
10.2.1 
Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory 
requirements and guidelines.  
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related tasks, and shall, upon request of the 
sponsor, provide documented evidence of any licenses and certifications necessary to 
demonstrate such qualification.  Curriculum vitae for investigators and sub-investigators are 
provided to the study sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
10.2.2 
Protocol Adherence and Investigator Agreement 
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document.  The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria.  Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  
Upon study completion, the investigator will provide the sponsor, IRB/EC, and regulatory 
agency with final reports and summaries as required by (inter)national regulations. 
10.2.3 
Documentation and Retention of Records 
10.2.3.1 
Case Report Forms 
Electronic CRFs should be handled in accordance with instructions from the sponsor.  
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation.  CRFs must be completed 
by the investigator or designee as stated in the site delegation log. 


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All data submitted in the electronic CRF must be reviewed, approved and signed for by the 
investigator.  All data, except data entered directly into the eDiary, will have separate source 
documentation. 
The clinical research associate (CRA)/study monitor will verify the contents against the 
source data per the monitoring plan.  If the data are unclear or contradictory, queries are sent 
for corrections or verification of data. 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include but are not limited to 
subject’s medical file, daily dosing records and clinical laboratory reports. 
The investigator must permit authorized representatives of the sponsor; the respective 
national, local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities 
and to have direct access to original source records relevant to this study, regardless of 
media. 
The consent form includes a statement by which the subject agrees to the monitor/auditor 
from the sponsor or its representatives, national or local regulatory authorities, or the 
IRB/EC, having access to source data.  Non-study site personnel will not disclose any 
personal information or personal medical information. 
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 Food 
and Drug Administration, European Medicines Agency, UK Medicines and Healthcare 
products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and in 
accordance with local country-specific regulations and may not be destroyed without written 
permission from the sponsor. 
10.2.3.3 
Audit/Inspection 
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 European Medicines Agency, 
the Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the 
sponsor or its representatives, and the IRB/EC for each site. 
10.2.3.4 
Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor.  The following information is collected: any significant payments from the sponsor 
or subsidiaries such as a grant to fund ongoing research, compensation in the form of 


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equipment, retainer for ongoing consultation or honoraria; any proprietary interest in IP; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54.2(b). 
10.3 
Ethical Considerations 
10.3.1 
Informed Consent/Assent 
It is the responsibility of the investigator or designee to obtain written informed consent (or 
assent as applicable) from all study subjects prior to any study-related procedures including 
screening assessments.  All consent and assent documentation must be in accordance with 
applicable regulations and GCP.  Each subject or the subject’s legally authorized 
representative, as applicable, is requested to sign and date the subject informed consent form 
or a certified translation if applicable, after the subject has received and read (or been read) 
the written subject information and received an explanation of what the study involves, 
including but not limited to: the objectives, potential benefits and risk, inconveniences, and 
the subject’s rights and responsibilities.  A copy of the informed consent and assent 
documentation (i.e., a complete set of subject information sheets and fully executed signature 
pages) must be given to the subject or the subject’s legally authorized representative, as 
applicable.  Signed consent and assent forms must remain in each subject’s study file and 
must be available for verification at any time. 
The PI provides the sponsor with a copy of the consent form (or assent as applicable) that 
was reviewed by the IRB/EC and received their favorable opinion/approval.  A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party 
(i.e., sponsor or coordinating PI) is responsible for this action. 
10.3.2 
Institutional Review Board or Ethics Committee 
This protocol, the informed consent document (approved by the sponsor or their designee), 
relevant supporting information and all types of subject recruitment information will be 
submitted to the IRB/EC for review, and all must be approved prior to site initiation.  Study 
medication supplies will not be released until written IRB/EC approval has been received.  
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
amendments to the protocol and revisions of all informed consent documents, unless there is 
a subject safety issue. 
The IRB/EC will be kept apprised of the progress of the study and of any changes made to 
the protocol.  The IRB/EC will also be informed of any serious and significant AEs. 
10.4 
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 


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1996.  A site that is not a covered entity as defined by HIPAA must provide documentation 
of this fact. 
The confidentiality of subject records in EU countries will be protected in accordance to the 
General Data Protection Regulation guideline. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the sponsor and/or its representatives 
may review medical records and data collected during the study.  These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market maralixibat; national or local regulatory authorities; and the IRBs/ECs 
which gave approval for the study to proceed.  The sponsor and/or its representatives 
accessing the records and data will take all reasonable precautions in accordance with 
applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities. 
Subjects are assigned a unique identifying number; however, their initials and date of birth 
may also be collected, if permitted under local laws governing privacy.  
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth, where allowed per local law, may be 
transferred to, and used in, other countries which may not afford the same level of protection 
that applies within the countries where this study is conducted.  The purpose of any such 
transfer would include: to support regulatory submissions, to conduct new data analyses to 
publish or present the study results, or to answer questions asked by regulatory or health 
authorities. 
10.5 
Study Results/Publication Policy 
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.  
All publications relating to sponsor products or projects must undergo appropriate technical 
and intellectual property review, with sponsor agreement to publish prior to release of 
information.  
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral or other form. 


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11 
REFERENCES 
Al Mehaidib A, Al Shahrani A. 1381 Progressive familial intrahepatic cholestasis in Arabs. J 
Hepatol 2013;58:S555-6. 
Alissa FT, Jaffe R, Shneider BL. Update on progressive familial intrahepatic cholestasis. J 
Pediatr Gastroenterol Nutr 2008;46:241-52. 
Arnell H, Papadogiannakis N, Zemack H, et al. Follow-up in children with progressive 
familial intrahepatic cholestasis after partial external biliary diversion. J Pediatr 
Gastroenterol Nutr 2010;51:494-9. 
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. 
Davit-Spraul A, Gonzales E, Baussan C, et al. Progressive familial intrahepatic cholestasis. 
Orphanet J Rare Dis 2009;4:1. 
Emerick KM, Elias MS, Melin-Aldana H, et al. Bile composition in Alagille syndrome and 
PFIC patients having partial external biliary diversion. BMC Gastroenterol 2008;8:47. 
Ethical Considerations for Clinical Trials on Medicinal Products Conducted with Minors. 
2017. Accessed at:  
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/2017_09_18_ethical_consid_ct_with_minors.pdf 
European Medicines Agency. 2010. Guideline on missing data in confirmatory clinical trials. 
Halaweish I, Chwals WJ. Long-term outcome after partial external biliary diversion for 
progressive familial intrahepatic cholestasis. J Pediatr Surg 2010;45:934-7. 
Hounnou G, Destrieux C, Desme J, et al. Anatomical study of the length of the human 
intestine. Surg Radiol Anat 2002;24:290-4. 
Jericho H. Bile acid pool dynamics in progressive familial intrahepatic cholestasis with 
partial external bile diversion. J Pediatr Gastroenterol Nutr 2015;60:368-74. 
Kenward MG, 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. New York: 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. 


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Mallinckrodt CH, Lane PW, Schnell D, et al. Recommendations for the primary analysis of 
continuous endpoints in longitudinal clinical trials. Drug Information Journal 
2008;42:303-19. 
Mallinckrodt CH, Roger J, Chuang-Stein C, et al. Recent developments in the prevention and 
treatment of missing data. Drug Information Journal 2013;48:68-80. 
Molenberghs G, Kenward MG. Missing data in clinical studies. New York: Wiley:2007. 
Molenberghs G, Thijs H, Jansen I, et al. Analyzing incomplete longitudinal clinical trial data. 
Biostatistics 2004;5:445-64. 
Pawlikowska L, Strautnieks S, Jankowska I, et al. Differences in presentation and 
progression between severe FIC1 and BSEP deficiencies. J Hepatol 2010;53:170-8. 
Ratitch B, O'Kelly M. 2011. Implementation of pattern-mixture models using standard 
SAS/STAT procedures. Proceedings of PharmaSUG 2011 (Pharmaceutical Industry SAS 
Users Group), SP04, Nashville. 
Sambrotta M. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 
2014;46:326-8. 
Schafer JL. Analysis of incomplete multivariate data. New Yori: Chapman & Hall:1997. 
Schukfeh N, Metzelder ML, Petersen C, et al. Normalization of serum bile acids after partial 
external biliary diversion indicates an excellent long-term outcome in children with 
progressive familial intrahepatic cholestasis. J Pediatr Surg 2012;47:501-5. 
Shneider BL, Magee JC, Bezerra JA, et al. Efficacy of fat-soluble vitamin supplementation in 
infants with biliary atresia. Pediatrics 2012;130:607-14. 
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. 
Stapelbroek JM, van Erpecum KJ, Klomp LWJ, et al. Liver disease associated with 
canalicular transport defects: current and future therapies. J Hepatol 2010;52:258-71. 
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Medical 
Care 2001;39:800-12. 
Verbeke G, Molenberghs G. Linear mixed models for longitudinal data. New York: Springer: 
2000. 
Weaver LT, Austin S, Cole TJ. Small intestinal length: a factor essential for gut adaptation. 
Gut 1991;32:1321-3. 


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Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of 
intractable pruritis associated with intrahepatic cholestasis. Gastroenterology 1988;95:130-6. 
Yang H, Porte RJ, Verkade HJ, et al. Partial external biliary diversion in children with 
progressive familial intrahepatic cholestasis and Alagille disease. J Pediatr Gastroenterol 
Nutr 2009;49:216-21. 


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12 
APPENDICES 


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Appendix 1 
Clinical Outcomes Assessments 
The following COAs will be utilized in this study: 
Clinical Outcomes Assessment 
Completed by* 
ItchRO(Obs)™ 
Caregiver 
ItchRO(Pt)™ 
Subjects aged ≥9 years 
PedsQL Child Report 
Subjects aged 8–12 years 
PedsQL Teenager Report 
Subjects aged 13–18 years 
Parent PedsQL Report 
Caregivers using age-appropriate report (Report for Infants, 
Toddlers, Young Children, Children, or Teenagers) 
PIS  
Subjects aged ≥9 years 
CIS 
Caregiver 
EDQ(Obs) 
Caregivers for subjects aged <9 years 
EDQ(Pt) 
Subjects aged ≥9 years 
PIC 
Subjects aged ≥9 years 
CIC 
Caregiver 
CIS=Caregiver Impression of Severity of Pruritus; ItchRO(Obs)™=Itch Reported Outcome observer 
instrument; ItchRO(Pt)™=Itch Reported Outcome patient instrument; PedsQL=Pediatric Quality of Life 
Inventory; PIS=Patient Impression of Severity; EDQ:  Exploratory Diary Questionnaire; PIC: Patient 
impression of Change; CIC: Caregiver Impression of Change 
∗ 
For the ItchRO and EDQ, the subject’s age at the screening visit (Visit 0) will be used for the determination 
of the appropriate module to be used for the study.  
For the PedQL and PIS, the subject’s age at the screening visit (Visit 0) will be used for the determination 
of the appropriate module to be used for the study.  
The same module will be used for the duration of the study regardless of subsequent birthdays throughout 
the study.  
For the PIC, subjects aged ≥9 years at Visit 9/EOT should complete the diary. 


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


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


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


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


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Appendix 3 
Patient Itch Reported Outcome Instrument ItchRO(Pt) 
ItchRO(Pt): Morning Diary  
Think about whether itching kept you awake or woke you up last night.  Think about whether 
you felt like rubbing or scratching.  
How itchy did you feel last night after you went to bed until you woke up this morning? 
Select one response below. 
 I didn’t feel itchy 
 I felt a little bit itchy 
 I felt pretty itchy 
 I felt very itchy 
 I felt very, very itchy 
 
Did feeling itchy make it hard to fall asleep last night? 
 Yes 
 No 
 
Did feeling itchy wake you up last night? 
 Yes 
 No 


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How much of the night did feeling itchy make you rub or scratch? 
 None of the night 
 Just a tiny bit of the night 
 Half of the night 
 Most of the night 
 All night 
 


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ItchRO(Pt): Evening Diary 
Think about how itchy you were all day.  Think about whether you felt like rubbing or 
scratching. 
How itchy were you all day today from the time when you woke up until now? 
Select one response below. 
 I didn’t feel itchy 
 I felt a little bit itchy 
 I felt pretty itchy 
 I felt very itchy 
 I felt very, very itchy 
 
Did feeling itchy make you rub or scratch today? 
 No 
 Yes, but it left no marks 
 Yes, and it left marks, but my skin wasn’t red 
 Yes, and it left red marks 
 Yes, and my skin bled 
 
How much of today did feeling itchy make you rub or scratch? 
 None of the day 
 Just a tiny bit of the day 
 Half of the day 
 Most of the day 
 All day 


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Appendix 4 
Pediatric Quality of Life Inventory (PedsQL) 
Child’s age at 
screening (Visit 0) 
Questionnaires required to be completed at Day 0, Week 4 or 6a, 
Week 10, Week 14, Week 18, Week 22, and Week 26 (EOT/ET) 
Who 
completes? 
1–12 months 
 
 
Parent Report for Infants (1–12 months) 
Parent 
 
Family Impact Module 
Parent 
13–24 months 
 
 
Parent Report for Infants (13–24 months) 
Parent 
 
Family Impact Module 
Parent 
2–4 years old 
 
 
Parent Report for Toddlers (2–4) 
Parent 
 
Multidimensional Fatigue Scale, Parent Report (2–4) 
Parent 
 
Family Impact Module 
Parent 
5–7 years old 
 
 
Parent Report for Young Children (5–7) 
Parent 
 
Multidimensional Fatigue Scale, Parent Report for Young Children 
(5–7) 
Parent 
 
Family Impact Module 
Parent 
8–12 years old 
 
 
Parent Report for Children (8–12) 
Parent 
 
QOL inventory for Children (8–12) 
Subject  
 
Multidimensional Fatigue Scale, Parent Report for Children (8–12) 
Parent 
 
Multidimensional Fatigue Scale, Child Report for ages (8–12) 
Subject  
 
Family Impact Module 
Parent 
13–18 years old 
 
 
Parent Report for Teenagers (13–18) 
Parent 
 
QOL inventory for Teenagers (13–18) 
Subject  
 
Multidimensional Fatigue Scale, Parent Report for Teenagers 
(13-18) 
Parent 
 
Multidimensional Fatigue Scale, Teen Report for Children (13–18) 
Subject  
 
Family Impact Module 
Parent  
 


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Appendix 5 
Impression of Severity Questionnaires 
Patient Impression of Severity (PIS) 
Q: Overall, how severe was your itching (pruritus) over the past 7 days? 
Select one response below. 
 I didn’t feel itchy at all 
 I felt a little bit itchy 
 I felt pretty itchy 
 I felt very itchy 
 I felt very, very itchy 
 
Caregiver Impression of Severity (CIS) 
Q: Based on observations or what your child told you about his/her itching (pruritus), how 
severe were your child’s itch-related symptoms over the past 7 days? 
Select one response below. 
 None 
 Mild 
 Moderate 
 Severe 
 Very severe 


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Appendix 6 
Exploratory Diary Questionnaire 
Observer Morning Diary 
Instructions: Based on what you saw or what your child told you, think about your child’s 
itching from when he/she went to bed last night until he/she woke up this morning. 
1) It was hard for my child to stop scratching or rubbing. 
1 – Never  
2 – Rarely  
3 – Sometimes 
4 – Often  
5 – Almost Always 
2) My child scratched until he/she bled. 
1 – Never  
2 – Rarely  
3 – Sometimes 
4 – Often  
5 – Almost Always 
3) Because of itch, my child had trouble staying asleep. 
1 – Never  
2 – Rarely  
3 – Sometimes 
4 – Often  
5 – Almost Always 
4) How bad was your child's itch at its worst? 
1 – No itch  
2 – Mild 
3 – Moderate 
4 – Severe 
5 – Very Severe 
 


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Observer Evening Diary 
Instructions: Based on what you saw or what your child told you, think about your child’s 
itching from when he/she woke up this morning until he/she went to bed. 
1) It was hard for my child to stop scratching or rubbing. 
1 – Never  
2 – Rarely  
3 – Sometimes 
4 – Often  
5 – Almost Always 
2) My child scratched until he/she bled. 
1 – Never  
2 – Rarely  
3 – Sometimes 
4 – Often  
5 – Almost Always 
3) How bad was your child's itch at its worst? 
1 – No itch  
2 – Mild 
3 – Moderate 
4 – Severe 
5 – Very Severe 
 


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Patient Morning Diary 
Instructions: Think about your itching from when you went to bed last night until you 
woke up this morning. 
1) How bad was your itch at its worst? 
1 – No itch  
2 – Mild 
3 – Moderate 
4 – Severe 
5 – Very Severe 
 
Patient Evening Diary 
Instructions: Think about your itching from when you woke up this morning until you 
went to bed. 
1) How often did you itch? 
1 – Never  
2 – Rarely  
3 – Sometimes 
4 – Often  
5 – Almost Always 
2) How bad was your itch at its worst? 
1 – No itch  
2 – Mild 
3 – Moderate 
4 – Severe 
5 – Very Severe 
 


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Appendix 7 
Clinician Scratch Score 
This scoring scale was originally developed to assess pruritus before and after surgical 
intervention in children with ALGS and PFIC (Whitington and Whitington 1988).  
The clinician will rate the subject’s pruritus, as evidenced by scratching, according to the 
following scale: 
Score 
Description 
0 
None 
1 
Rubbing or mild scratching when undistracted 
2 
Active scratching without evident skin abrasions 
3 
Abrasion evident 
4 
Cutaneous mutilation, haemorrhage and scarring evident 
 


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Appendix 8 
Patient Impression of Change (PIC) 
The PIC is designed to assess the subject’s perception of his/her itching at Week 26 (EOT) 
compared to his/her itching prior to the start of treatment with study drug.  The PIC will be 
completed, by subjects who are 9 years of age or older at the Week 26 (EOT) visit (see 
Table 1) 
The questionnaire is designed for self-administration and uses a 7-point scale in which 1 
designates the best outcome and 7 designate the worst outcome.  
 
PIC 
 
How much has your itching changed, if at all, since you started this study? 
 
Much better (1) 
Better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Worse (6) 
Much worse (7) 
 


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Appendix 9 
Caregiver Impression of Change (CIC) 
The CIC is designed to assess the caregiver’s perception of the subject’s itch related 
symptoms and xanthoma severity at Week 26 (EOT) compared to his/her itch related 
symptoms and xanthoma severity prior to the start of treatment with study drug.  The CIC 
will be completed by all caregivers at the Week 26 (EOT) visit (see Table 1). 
The questionnaire is designed for self-administration and uses a 7-point scale in which 
1 designates the best outcome and 7 designates the worst outcome.  
 
CIC 
 
How would you rate the change in your child’s itch related symptoms since the start of the 
study? 
 
Much better (1) 
Better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Worse (6) 
Much worse (7) 
 


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How would you rate the change in your child’s xanthoma severity since the start of the 
study? 
 
Much better (1) 
Better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Worse (6) 
Much worse (7) 
 


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Appendix 10 
Management of Clinical Study Procedures and Participants during 
COVID-19 Pandemic or Other Force Majeure 
This appendix provides guidance for participant safety and ongoing access to medical care 
and investigational product during the global novel coronavirus 2019-nCoV (COVID-19) 
pandemic.  During this global public health crisis, pragmatic and harmonized actions are 
required to ensure the necessary flexibility and procedural simplifications that are needed to 
maintain the integrity of the clinical studies and to ensure the rights, safety, and wellbeing of 
study participants and the safety of clinical study staff. 
The measures detailed here are implemented across Mirum studies on a temporary basis until 
the pandemic is considered resolved by governmental and public health organizations, as 
applicable. 
Regardless of the guidance provided below, consideration should be given to public health 
advice at the study locations and individual benefit/risk in treatment decisions for participants 
at the study site during the pandemic (EMA 2020; FDA 2020).  Logistical requirements 
should also be considered, such as the ability of participants to travel to the study site, 
accessibility of public transportation, site restrictions on clinical studies, etc. 
The safety of the study participants is of primary importance, and risks of involvement in the 
study, in particular with added challenges due to COVID-19, will be weighed against 
anticipated benefit for the study participants and society. 
Study Participation 
Study sites may continue to recruit new participants, if deemed appropriate on benefit-risk 
assessment as described, and provided that ALL of the following activities to preserve study 
integrity can be met: 
• Upon discussion with the site monitor, the study site has confirmed the ability to enroll 
and manage studies and participants effectively and in compliance with the protocol and 
this appendix. 
• Upon discussion with the sponsor, medical monitor, or designee, the study site has 
confirmed that appropriate safety monitoring can take place, in compliance with the 
protocol and this appendix. 
• Data will continue to be entered into the electronic Case Report Form (eCRF) and queries 
resolved in a timely manner. 
• The site monitor is able to access the study site to perform onsite monitoring or is able to 
perform remote monitoring of data. 
 


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CONFIDENTIAL 
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Conduct of Telephone/Virtual or Alternative Visits 
Due to the current pandemic, it is conceivable that not all participant visit commitments can 
be fulfilled.  If a participant or caregiver is unable or unwilling to attend a study visit or a 
study site is unable to permit onsite visits by participants and caregivers, adaptation of the 
onsite visit to a telephone visit, virtual visit, or use of an alternative location for assessment 
(including but not limited to local laboratories, family physician, home visit) is recommended 
to ensure continuity of participant care during the study (as an interim measure).  Priority 
should be given to maintaining ongoing safety follow-up.  Study sites should speak with their 
site monitor before performing a telephone or virtual visit so he or she may provide guidance 
regarding logistics that may need consideration.  Study sites should contact the medical 
monitor if the participant must miss more than one onsite visit in succession because multiple 
incomplete visits may have the potential to impact evaluation of study endpoints as well the 
participant’s safety.  
The decision to accept protocol deviations for missed assessments is based on the risk to the 
participant of discontinuing study participation versus missed assessments, such as safety 
laboratory assessments.  Where possible, a homecare visit should be organized to avoid 
missing visits or assessments. 
Alternative Blood Sample Collection: 
Where possible and permitted, homecare can be organized through qualified health care 
professionals, trained on the study protocol, to collect samples at the participant’s home (or 
other agreed upon location).  It is preferred that this alternative blood sample collection is 
performed in a manner to support delivery of samples to the central laboratory, but the 
analysis of samples may be performed at local laboratories, if necessary.  If the analyses are 
performed at the local laboratories, the site will follow up with the participant to obtain the 
results and local laboratory reference ranges for data entry into EDC as soon as they are 
available. 
Safety Reporting and Maralixibat Treatment Recommendations for COVID-19 
The sponsor recognizes that COVID-19 presents an increased risk for all participants.  Due to 
the potential impact of COVID-19 on multiple organ systems, the sponsor recommends the 
following dose modification and management plan for participants with confirmed or 
suspected COVID-19 while receiving treatment with maralixibat. 
The following safety reporting guidelines are required:  
All confirmed or suspected COVID-19–related adverse events (AEs) must be recorded in the 
eCRF and the Serious Adverse Event (SAE) Report Form if the event meets the seriousness 
criteria.  SAEs are reportable to the sponsor immediately without undue delay after becoming 
aware of the event and no later than 24 hours of awareness.  All study-drug interruptions or 
modifications must be recorded on the AE and drug administration eCRFs. 


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If an event is suspected to be COVID-19 infection, continuation of study drug, and any dose 
modifications should be assessed on a case-by-case basis, depending on the participant’s 
health status, and discussed with the medical monitor if needed.  The COVID-19 infection 
should be managed as per local treatment guidance and investigator’s clinical judgment. 
Drug-Drug Interaction Guidance Regarding Medication Used to Treat COVID-19 
• The study protocol and Investigator’s Brochure should be referenced for drug-drug 
interaction information.  For further information the medical monitor can be contacted. 
Guidance Regarding Vaccination against COVID-19 
• Participants should be requested to contact the site upon planned vaccination against 
COVID-19.  The vaccine should be entered in the eCRF as a concomitant medication and 
any new or worsened symptom or sign recorded as an adverse event and assessed for 
seriousness.  Maralixibat is taken orally, is minimally absorbed with systemic levels 
below the lower limit of quantification, and binds with and inhibits the ileal bile acid 
transporter (IBAT) in the distal ileum.  The vaccine is administered and acts systemically; 
hence, no drug-drug interaction is expected, and no need for unblinding is foreseen. 
Documenting Alternative Contacts with Participants: 
If an onsite visit is replaced by a telephone or virtual study visit, the following are guidelines 
for data capture: 
• If the visit is listed as onsite but is performed remotely, data should be captured as per 
a normal visit (i.e., document the remote visit in the source documents and complete 
the relevant eCRF pages to capture the visit date, and any possible assessment that 
can be obtained, such as AEs, study drug administration, and/or concomitant 
medications and any additional safety or efficacy information).  All assessments that 
cannot be performed should be marked as not done in the CRF.  Any protocol 
deviations related to COVID-19 should be recorded in the clinic notes, prefixed 
COVID-19.   
• Visits that require procedures that cannot be performed remotely should be discussed 
with the site monitor because this may impact efficacy or safety analyses and should 
be documented as a protocol deviation due to COVID-19. 
Site-to-Participant Drug Shipment Instructions during Pandemic Containment 
If a participant is unable to go to the study site because of pandemic containment, the study 
site may ship the study drug to the home of the participant (or other agreed location) 
following approval by the sponsor.  
For such shipment, the following conditions must be met: 
• The sponsor is responsible for delivery of the study drug to the study site.  Organization 
of shipments from the site to the participant will be the responsibility of the study site. 


Mirum Pharmaceuticals 
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• The participant or caregiver is informed about the shipment method, confirms the address 
for receipt of the drug, and agrees that his or her personal information (i.e., contact 
information) may be given to a professional carrier. 
• The investigator or designee (e.g., pharmacy) securely packages the drug for shipment.  
• A professional carrier is used by the investigator or designee to ship the drug securely 
and maintain chain of custody, with evidence provided.  Maralixibat should be stored and 
shipped as directed in the Pharmacy Manual.  Shipments that are expected to be 
completed within 48 hours from pickup to delivery do not generally require any specific 
temperature monitoring.  
• To respect participant confidentiality, the carrier should be given only the contact 
information of the recipient.  The sponsor should not receive any personal information 
about the participant. 
• A procedure is defined with the carrier to immediately upon delivery confirm the receipt 
of the drug by the recipient and that it is received in good condition. 
• The site contacts the recipient to confirm the receipt of the drug and to confirm it is 
delivered in the expected conditions (e.g., not leaking, not broken) and gives instructions 
about the drug administration and storage.  If the drug is delivered and is not within the 
expected conditions, the site will give instructions to the participant about the next steps. 
• The investigator or designee completes the drug accountability forms with each shipment 
made directly to a participant. 
• All documentation (originals/copies, as applicable) related to the site-to-participant drug 
shipment should be filed in the investigator site file, including the list of the medication 
being delivered, the quantity involved, and documentation of receipt by the study 
participant.  
• Participants should retain unused study drug and containers and return them to the 
investigator the next time they visit the investigator site 
 
COVID-19 Specific Remote Source Data Verification 
The source documents/source data considered for remote source data verification (rSDV) are 
those related to the primary endpoint, AEs/SAEs, important medical events, or the reasons 
for exclusion of a participant from the study. 
Remote access to source documents/source data for monitoring purposes may only take place 
in justified exceptional cases and only to the extent strictly necessary (i.e., only when direct 
access to study source data is not available due to COVID-19 pandemic restrictions).  
The following 3 options for source data reconciliation without the study monitor being 
physically present at the study site may be used, based on the site-specific source 
documentation/source data: 
• The study site will provide the study monitor, under the responsibility of the 
investigator, with copies of the source documents/source data in which personal 


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


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REFERENCES 
United States Food and Drug Administration.  FDA guidance on conduct of clinical trials of 
medical products during COVID-19 public health emergency. March 2020 (updated 
30 August 2021). Available online at https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/fda-guidance-condu,ct-clinical-trials-medical-products-during-
covid-19-public-health-emergency. 
European Medicines Agency. Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic. Version 3, 28 April 2020 (Updated Version 4, 
4 February 2021). Available online at 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. 

SAP_001.pdf: 
 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 1 of 89 
 
Sponsor 
Mirum Pharmaceuticals, Inc. 
Protocol Title: 
Randomized Double-blind Placebo-controlled Phase 3 Study to 
Evaluate the Efficacy and Safety of Maralixibat in the Treatment 
of Children with Progressive Familial Intrahepatic Cholestasis 
(PFIC) – MARCH-PFIC 
Protocol Number: 
MRX-502 
Premier Research PCN: 
MIRU8967 
Document Version: 
Final Version 2.0 
Document Date:  
29Sep2022 
 
Approvals 
Role 
Signatures 
Biostatistician 
Print Name:  Jana Steinmetz 
Sign Name: 
 
 
 
 
 
Peer Reviewer 
Print Name:  Mary Poole 
Sign Name: 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 2 of 89 
 
Role 
Signatures 
Mirum 
Pharmaceuticals, 
Inc. Representative 
Print Name:  Will Garner 
Sign Name: 
 
 
 
 
 
Mirum 
Pharmaceuticals, 
Inc. Representative 
Print Name:  Tiago Nunes 
Sign Name: 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 3 of 89 
 
Document History  
Version 
Date 
Change(s) 
Author 
1.0 
21Sep2022 
Initial version   
Jana Steinmetz 
2.0 
29Sep2022 
Minor:  Update document header to read 
‘Protocol Number MRX-502 (Amendment 4)’ 
across all pages; some pages in Version 1.0 did 
not include ‘(Amendment 4)’ 
Jana Steinmetz 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 4 of 89 
 
Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 3 
Table of Contents ............................................................................................................................ 4 
List of Tables .................................................................................................................................. 6 
List of Figures ................................................................................................................................. 7 
List of Abbreviations ...................................................................................................................... 8 
1. 
Overview ........................................................................................................................... 11 
2. 
Study Objectives and Endpoints ....................................................................................... 11 
2.1. 
Study Objectives ......................................................................................................... 11 
2.1.1. Primary Objective ................................................................................................... 11 
2.1.2. Secondary Objectives .............................................................................................. 11 
2.1.3. Exploratory Objectives ............................................................................................ 12 
2.2. 
Study Endpoints .......................................................................................................... 13 
2.2.1. Safety Endpoints ..................................................................................................... 13 
2.2.2. Efficacy Endpoints .................................................................................................. 13 
 Primary Efficacy Endpoint ............................................................................. 13 
 Secondary Efficacy Endpoints ........................................................................ 13 
 Exploratory Efficacy Endpoints ...................................................................... 14 
2.2.3. Other Endpoints ....................................................................................................... 17 
3. 
Overall Study Design and Plan ......................................................................................... 17 
3.1. 
Overall Design ............................................................................................................ 17 
3.2. 
Sample Size and Power ............................................................................................... 20 
3.3. 
Study Population ......................................................................................................... 21 
3.4. 
Treatments Administered ............................................................................................ 21 
3.4.1. Dose Escalation Period ............................................................................................ 22 
3.4.2. Stable Dosing Period ............................................................................................... 22 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................. 22 
3.6. 
Blinding and Unblinding............................................................................................. 23 
3.7. 
Schedule of Assessments ............................................................................................ 23 
4. 
Statistical Analysis and Reporting .................................................................................... 27 
4.1. 
Introduction ................................................................................................................. 27 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 28 
5. 
Analysis Populations ......................................................................................................... 28 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 5 of 89 
 
5.1. 
Subject Grouping ........................................................................................................ 29 
6. 
General Issues for Statistical Analysis .............................................................................. 29 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 29 
6.1.1. Baseline ................................................................................................................... 29 
6.1.2. Adjustments for Covariates ..................................................................................... 30 
6.1.3. Multiple Comparisons ............................................................................................. 30 
6.1.4. Handling of Dropouts or Missing Data ................................................................... 31 
 MMRM Analysis Method ............................................................................... 32 
 Multiple Imputation Methods ......................................................................... 33 
 Missing ItchRO/EDQ/PedsQL Scores ............................................................ 41 
 Missing Responder Definition Data ............................................................... 41 
 Missing Adverse Event Severity/Relationship ............................................... 42 
6.1.5. Analysis Visit Windows .......................................................................................... 42 
6.1.6. Investigative Sites ................................................................................................... 43 
6.1.7. Treatment Period Definitions .................................................................................. 43 
6.1.8. Derived Variables .................................................................................................... 43 
6.1.9. Data Adjustments/Handling/Conventions ............................................................... 50 
7. 
Study Subjects and Demographics.................................................................................... 55 
7.1. 
Disposition of Subjects and Withdrawals ................................................................... 55 
7.2. 
Protocol Violations and Deviations ............................................................................ 56 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 56 
7.4. 
Prior Medications/Therapies ....................................................................................... 58 
7.5. 
Exposure and Compliance .......................................................................................... 58 
8. 
Efficacy Analysis .............................................................................................................. 59 
8.1. 
Primary Efficacy Analysis .......................................................................................... 59 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 61 
8.3. 
Sensitivity and Supportive Analyses for Primary and Secondary Endpoints ............. 62 
8.4. 
Adjustment for Multiplicity ........................................................................................ 63 
8.5. 
Exploratory Efficacy Analysis .................................................................................... 63 
9. 
Safety and Tolerability Analysis ....................................................................................... 64 
9.1. 
Adverse Events ........................................................................................................... 65 
9.1.1. Adverse Events Leading to Discontinuation of Study Drug ................................... 66 
9.1.2. Deaths and Serious Adverse Events ........................................................................ 66 
9.1.3. Events of Clinical Interest ....................................................................................... 66 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 6 of 89 
 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 67 
9.3. 
Vital Signs and Weight/Height Measurements ........................................................... 67 
9.4. 
Electrocardiograms ..................................................................................................... 67 
9.5. 
Liver Ultrasound ......................................................................................................... 67 
9.6. 
Concomitant Medications/Therapies .......................................................................... 67 
10. 
Other Planned Analysis..................................................................................................... 68 
10.1. Healthcare Utilization ................................................................................................. 68 
10.2. Pharmacokinetic Analyses .......................................................................................... 68 
11. 
Changes from Protocol Planned Analysis......................................................................... 68 
12. 
References ......................................................................................................................... 71 
13. 
Tables, Listings, and Figures ............................................................................................ 72 
13.1. Planned Table Descriptions ........................................................................................ 73 
13.1.1. Subject Data ............................................................................................................ 73 
13.1.2. Efficacy Data ........................................................................................................... 74 
13.1.3. Safety Data .............................................................................................................. 81 
13.1.4. Other Data ............................................................................................................... 82 
13.2. Planned Figure Descriptions ....................................................................................... 83 
13.2.1. Efficacy Data ........................................................................................................... 83 
13.3. Planned Listing Descriptions ...................................................................................... 84 
13.4. Standard Layout for all Tables, Listings, and Figures ................................................ 85 
Appendix 1:  Listing of Safety and Efficacy Laboratory Analytes .............................................. 87 
Appendix 2:  Listing of Lipid Soluble Vitamin Deficiency Events.............................................. 89 
 
List of Tables 
Table 1:  Schedule of Assessments ............................................................................................... 24 
Table 2:  Analysis Visit Windows ................................................................................................ 42 
Table 3:  Subject Data Summary Tables....................................................................................... 73 
Table 4:  Efficacy Data Summary Tables ..................................................................................... 74 
Table 5:  Safety Data Summary Tables ........................................................................................ 81 
Table 6:  Other Data Summary Tables ......................................................................................... 82 
Table 7:  Efficacy Data Summary Figures .................................................................................... 83 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 7 of 89 
 
List of Figures 
Figure 1.   Study Design Flow Chart ............................................................................................ 19 
Figure 2.   Standardized Layout .................................................................................................... 86 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 8 of 89 
 
List of Abbreviations 
Abbreviation 
Definition 
ALGS 
alagille syndrome 
APRI 
AST to platelet ratio index 
ATC 
anatomical therapeutic chemical 
BID 
twice daily 
BL 
baseline 
C4 
7α hydroxyl-4-cholesten-3-one 
CI 
confidence interval 
CIS 
caregiver impression of severity 
CMH 
Cochran-Mantel-Haenszel 
CSS 
clinician scratch scale 
DMC 
data monitoring committee 
ECI 
events of clinical interest 
EDQ 
exploratory diary questionnaire 
EM 
expectation-maximization 
EOT 
end of treatment 
ET 
early termination 
FGF-19 
fibroblast growth factor-19 
FIB-4 
fibrosis-4 
HCC 
hepatocellular carcinoma 
INR 
international normalized ratio 
ItchRO™ 
Itch Reported Outcome 
ItchRO(Obs)™ 
Observer-reported Itch Reported Outcome 
ItchRO(Pt)™ 
Patient-reported Itch Reported Outcome 
IRT 
interactive response technology 
K-M 
Kaplan-Meier 
LLOQ 
lower limit of quantitation 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 9 of 89 
 
Abbreviation 
Definition 
LS 
least squares 
LSV 
lipid soluble vitamin 
MAR 
missing at random 
MCMC 
Markov-Chain Monte-Carlo 
MELD 
Model for End-Stage Liver Disease 
MI 
multiple imputation 
MMRM 
mixed-effects model for repeated measurements 
MNAR 
missing not at random 
nt-PFIC2 
non-truncating PFIC2 
Obs 
observer 
PEBD 
partial external biliary diversion 
PedsQL 
pediatric quality of life 
PELD 
Pediatric End-Stage Liver Disease 
PFIC 
progressive familial intrahepatic cholestasis 
PIS 
patient impression of severity 
PRO 
patient reported outcomes 
Pt 
patient 
PT 
preferred term 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
sBA 
serum bile acid 
SD 
standard deviation 
SE 
standard error 
SI 
International System of Units 
SOC 
system organ class 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 10 of 89 
 
Abbreviation 
Definition 
t-PFIC2 
truncating PFIC2 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TSB 
total serum bilirubin 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit normal 
ULOQ 
upper limit of quantitation 
VAP 
validation analysis plan 
WHO 
World Health Organization 
WHO-DD 
World Health Organization - Drug Dictionary 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 11 of 89 
 
1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Mirum 
Pharmaceuticals, Inc. protocol number MRX-502 (Randomized Double-blind Placebo-controlled 
Phase 3 Study to Evaluate the Efficacy and Safety of Maralixibat in the Treatment of Subjects 
with Progressive Familial Intrahepatic Cholestasis [PFIC]), Amendment 4, dated 10-May-2022. 
Reference materials for this statistical plan 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 provides 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 Mirum Pharmaceuticals, Inc.’s 
study MRX-502. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is to evaluate the efficacy of maralixibat vs. placebo on the severity of 
pruritus in the primary cohort, as defined in Section 5.1. 
2.1.2. Secondary Objectives 
The secondary objectives are: 
• To evaluate the efficacy of maralixibat vs. placebo on total serum bile acid (sBA) levels 
in the primary cohort 
• To evaluate the efficacy of maralixibat vs. placebo on the severity of pruritus in the PFIC 
cohort, as defined in Section 5.1  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 12 of 89 
 
• To evaluate the efficacy of maralixibat vs. placebo on total sBA levels in the PFIC cohort 
• To evaluate the efficacy of maralixibat vs. placebo on the ItchRO(Obs) responder rate in 
the primary cohort. 
• To evaluate the efficacy of maralixibat vs. placebo on the sBA responder rate in the 
primary cohort. 
• To evaluate the efficacy of maralixibat vs. placebo on the ItchRO(Obs) responder rate in 
the PFIC cohort.  
• To evaluate the efficacy of maralixibat vs. placebo on the sBA responder rate in the PFIC 
cohort. 
• To evaluate the safety, tolerability, and pharmacokinetics (PK) of maralixibat vs. placebo 
in all participants who received at least 1 dose of study medication (Safety Population) 
2.1.3. Exploratory Objectives 
The exploratory objectives are: 
• To evaluate the efficacy of maralixibat vs placebo in the primary cohort and in the PFIC 
cohort on the following parameters: 
o Liver biochemistry 
o Non-invasive fibrosis markers: Fibrosis-4 (FIB-4), AST to Platelet Ratio Index 
(APRI), pediatric end-stage liver disease (PELD) score, model for end-stage liver 
disease (MELD) score  
o Other measures of pruritus including ItchRO(Obs), for parameters not utilized for 
primary and secondary objectives, ItchRO(Pt), CSS and other Patient Reported 
Outcomes (PRO), including Caregiver Impression of Severity (CIS), Patient 
Impression of Severity of Pruritus (PIS), and Exploratory Diary Questionnaire 
(EDQ) 
o Responder rates for pruritus severity and total sBA 
o Health-related quality of life 
o Quality of sleep 
o Subject growth 
o Markers of bile acid metabolism: Bile acid subspecies, C4, FGF-19, autotaxin 
o Time to liver-associated events  
• To evaluate the impact of maralixibat on healthcare utilization 
• To evaluate the correlation between sBA and severity of pruritus in terms of levels and 
changes from baseline 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The safety and tolerability endpoints of this study include the following: 
• Incidence of adverse events (AEs) including serious, related to study drug, leading to 
withdrawal, events of clinical interest, along with AEs by severity and by relationship to 
study drug 
• Change from baseline in clinical laboratory values 
• Change from baseline in physical examination findings (including body weight, height, 
and BMI) 
• Change from baseline in vital signs 
• Change from baseline in electrocardiogram (ECG) measures 
• Concomitant treatment usage 
Vital signs include heart rate, respiratory rate, body temperature, and blood pressure.  
Safety laboratory tests, and associated units of measure, that will be used for reporting are listed 
in Appendix 1. Note that bilirubin (total and direct), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), GGT, FGF-19, and total sBA are 
considered as both safety and efficacy laboratory tests. 
2.2.2. Efficacy Endpoints 
For the sequential (hierarchical) testing and the specific study populations used for each primary 
and secondary endpoints, please refer to Section 6.1.3 (Multiple Comparisons). 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is defined as the mean change in the average 
morning ItchRO(Obs) severity score between baseline and Week 15 through Week 26, using 
4-week average morning ItchRO(Obs) severity scores in the primary cohort.  
 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study include the following:  
• Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 in 
the primary cohort (considered as the key secondary endpoint) 
• Mean change in the average morning ItchRO(Obs) severity score between baseline and 
Week 15 through Week 26, using 4-week average morning ItchRO(Obs) severity scores 
in the PFIC cohort 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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• Mean change in total sBA level between baseline and average of Weeks 18, 22, and 26 in 
the PFIC cohort 
• Proportion of ItchRO(Obs) responders from Week 15 to Week 26 (reference 
Section 6.1.8) in the primary cohort 
• Proportion of sBA responders from Week 18 to Week 26 (reference Section 6.1.8) in the 
primary cohort 
• Proportion of ItchRO(Obs) responders from Week 15 to Week 26 (reference 
Section 6.1.8) in the PFIC cohort 
• Proportion of sBA responders from Week 18 to Week 26 (reference Section 6.1.8) in the 
PFIC cohort 
 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints of this study will be evaluated in the primary cohort and the 
PFIC cohort, unless otherwise noted, and include the following:  
• Mean change from baseline in total sBA level to Weeks 2, 6, 10, 14, 18, 22, and 26 
• Mean change from baseline in liver-associated laboratory test levels (i.e., ALT, AST, 
ALP, total bilirubin, direct bilirubin, GGT, albumin) to Weeks 2, 6, 10, 14, 18, 22, 26, 
and average of Weeks 18, 22, and 26 
• Mean change from baseline in FIB-4, APRI, MELD and PELD score to Weeks 2, 6, 10, 
14, 18, 22, 26, and average of Weeks 18, 22, and 26 
• Mean change from baseline in average morning ItchRO(Obs) severity scores to Week 6, 
10, 14, 18, 22, and 26, using 6-week average for Week 6 and 4-week average afterwards 
• Mean change from baseline in average evening ItchRO(Obs) severity scores to Weeks 6, 
10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, and 
Weeks 15 to 26 combined 
• Mean change from baseline in average highest daily ItchRO(Obs) severity scores to 
Weeks 6, 10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average 
afterwards, and Weeks 15 to 26 combined 
• Mean change from baseline in average morning ItchRO(Obs) frequency scores to Weeks 
6, 10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, 
and Weeks 15 to 26 combined 
• Mean change from baseline in average evening ItchRO(Obs) frequency scores to Weeks 
6, 10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, 
and Weeks 15 to 26 combined 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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• Mean change from baseline in average highest daily ItchRO(Obs) frequency scores to 
Weeks 6, 10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average 
afterwards, and Weeks 15 to 26 combined 
• Mean change from baseline in average morning ItchRO(Pt) severity scores to Weeks 6, 
10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, and 
Weeks 15 to 26 combined 
• Mean change from baseline in average evening ItchRO(Pt) severity scores to Weeks 6, 
10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, and 
Weeks 15 to 26 combined 
• Mean change from baseline in average highest daily ItchRO(Pt) severity scores to Weeks 
6, 10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, 
and Weeks 15 to 26 combined 
• Mean change from baseline in average morning ItchRO(Pt) frequency scores to Weeks 6, 
10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, and 
Weeks 15 to 26 combined 
• Mean change from baseline in average evening ItchRO(Pt) frequency scores to Weeks 6, 
10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, and 
Weeks 15 to 26 combined 
• Mean change from baseline in average highest daily ItchRO(Pt) frequency scores to 
Weeks 6, 10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average 
afterwards, and Weeks 15 to 26 combined 
• Number of days with a morning ItchRO(Obs) severity score ≤1 at the participant level for 
the last 84 days (i.e., study day 99 through 182, inclusive) of the study 
• Mean change from baseline in CSS at Weeks 2, 4, 6, 10, 14, 18, 22, 26, and Weeks 18, 
22, and 26 combined  
• Mean change from baseline in CIS at Weeks 4, 6, 10, 14, 18, 22, 26, and Weeks 18, 22, 
and 26 combined 
• Mean change from baseline in PIS at Weeks 4, 6, 10, 14, 18, 22, 26, and Weeks 18, 22, 
and 26 combined 
• Mean change from baseline in average morning EDQ(Obs) severity scores to Weeks 6, 
10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, and 
Weeks 15 to 26 combined 
• Mean change from baseline in average evening EDQ(Obs) severity scores to Weeks 6, 
10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, and 
Weeks 15 to 26 combined 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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• Mean change from baseline in average highest daily EDQ(Obs) severity scores to Weeks 
6, 10, 14, 18, 22, 26, using 6-week average for Week 6 and 4-week average afterwards, 
and Weeks 15 to 26 combined 
• Number and proportion of participants achieving morning ItchRO(Obs) severity scores 
≤1 for more than 50% of the time from post-baseline to Week 6, Weeks 7 to 10, Weeks 
11 to 14, Weeks 15 to 18, Weeks 19 to 22, Weeks 23 to 26, and Week 15 to Week 26 
• Mean change from baseline over time in quality of life as measured by the PedsQL 
(parent) total scale score at Weeks 4, 6, 10, 14, 18, 22, 26, and Weeks 18, 22, and 26 
combined 
• Mean change from baseline in average morning EDQ(Obs) sleep disturbance scores to 
Weeks 6, 10, 14, 18, 22, and 26, using 6-week average for Week 6 and 4-week average 
afterwards, and Weeks 15 to 26 combined 
• Proportion of participants with improvement from baseline (i.e., change from baseline 
<0) in morning EDQ(Obs) sleep disturbance score at Weeks 6, 10, 14, 18, 22, and 26, 
using 6-week average scores for Week 6 and 4-week average scores afterwards 
• Proportion of morning EDQ(Obs) sleep disturbance scores ≤2 at the participant level 
post-baseline through Week 26 
• Mean change from baseline in height z-score and weight z-score at Weeks 2, 4, 6, 10, 14, 
18, 22, 26, and Weeks 18, 22, and 26 combined 
• Mean change and % change from baseline in total sBA level to Weeks 2, 6, 10, 14, 18, 
22, 26, and Weeks 18, 22, and 26 combined 
• Number and proportion of subjects with total sBA % decrease from baseline to Weeks 2, 
6, 10, 14, 18, 22, and 26 within the following categories: >75%, 0-75%, and <0% 
• Mean change from baseline in C4, FGF-19, and autotaxin to Weeks 6, 10, 18, and 26 in 
the primary cohort 
• Time to first liver-associated event (PEBD surgery, listing for liver transplantation, liver 
decompensation [hepatic encephalopathy, variceal bleeding, ascites, and spontaneous 
bacterial peritonitis] events, HCC, death) 
Severity scores for the EDQ are based on the EDQ(Obs) question of “How bad was your child’s 
itch at its worst?” and on the EDQ(Pt) question of “How bad was your itch at its worst”. 
“Non-severity” scores are based on all other EDQ questions. 
To assess possible improvements in sleep, the sleep-related question from the EDQ(Obs) 
questionnaire will be summarized. For EDQ(Obs), sleep disturbance is assessed on the morning 
diary through the question, “Because of itch, my child had trouble staying asleep”. Responses are 
scored on a 5-point scale, where1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Almost 
Always. For the EDQ sleep-related question, 6-week average scores will be derived for 
Weeks 1-6 and 4-week average scores will be derived for the remaining time periods. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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2.2.3. Other Endpoints 
Other endpoints of this study include the following and will be evaluated in the primary cohort, 
the PFIC cohort, and all cohorts combined (i.e., all subjects):  
• Impact of maralixibat treatment on healthcare utilization (incidence of PFIC-related 
hospitalization, total inpatient days, selected surgical procedures, emergency room visits, 
and caregiver days missed from work, etc.) between clinic visits from baseline through 
Week 27 follow-up visit. 
• Plasma levels of maralixibat at pre-dose and approximately 2.5 hours after the morning 
dose at Week 10 and Week 26 (EOT/ET). 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is a 6-month international, multicenter, randomized, double-blind, placebo-controlled 
phase 3 study in participants with PFIC who are ≥12 months and <18 years of age at time of 
baseline. This study will be followed by a long-term extension study (MRX-503), during which 
all participants who complete study MRX-502 will have the opportunity to be treated with 
maralixibat.   
Subjects in the primary cohort will be randomized in a 1:1 ratio to receive maralixibat or 
placebo.  Subjects in the supplemental cohort will be randomized in a 1:1 ratio to receive 
maralixibat or placebo within the following subcohorts: a) PFIC1; b) PFIC3; c) all other 
supplemental cohort subjects. 
For the purposes of the randomization stratification and enrollment objectives, the primary and 
supplemental cohorts are defined as follows: 
• 
Primary cohort, defined as participants with genetic testing results consistent with 
biallelic disease-causing variation in ABCB11 (PFIC2), based on standard of care 
genotyping, excluding those PFIC2 participants with complete absence of bile salt 
excretion pump (BSEP) function, and do not fall under the definition of the supplemental 
cohort. 
• 
Supplemental cohort, defined as: 
o Subjects with genetic testing results consistent with biallelic disease causing 
variation in ATP8B1 (PFIC1), ABCB4 (PFIC3), or TJP2 (PFIC4), based on 
standard-of-care genotyping 
o Subjects with PFIC phenotype without a known mutation or with another known 
mutation not described above or with intermittent cholestasis as manifested by 
fluctuating sBA levels  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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o Subjects with PFIC after internal or external biliary diversion surgery or for 
whom internal or external biliary diversion surgery was reversed  
Further information about the treatment allocation is provided in Section 3.5. 
In the primary cohort, approximately 30 participants will be enrolled in order to achieve 26 
participants (13 per treatment group) completing the study. In the supplemental cohort, overall 
enrollment will be capped at a maximum of 60 participants. 
The primary analysis will be conducted in the ITT population of participants in the primary 
cohort. For analysis purposes, post-randomization cohort definitions have been defined (see 
Section 5.1).   
The study will be divided into 4 parts: 
1. Screening period (up to 6 weeks) 
2. Dose Escalation period (4-6 weeks) 
3. Stable Dosing period (20-22 weeks) 
4. Safety Follow-up period (7 days from the last dose of study drug for participants not 
continuing into the extension study [MRX-502]) 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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Figure 1.   Study Design Flow Chart 
 
BID=twice daily; Scr=screening; V=visit; W=week 
Subjects randomized to placebo will remain on placebo for the entire duration of the study. The 
Dose Escalation period will consist of the following weekly steps: 
 
Dose level 1:  150 μg/kg maralixibat BID for 1 week 
 
Dose level 2:  300 μg/kg maralixibat BID for 1 week 
 
Dose level 3:  450 μg/kg maralixibat BID for 1 week 
 
Dose level 4:  600 μg/kg maralixibat BID for the remaining duration of the study 
Study drug is administered twice daily over a 26-week treatment period. A participant’s 
maximum duration of participation is expected to be up to 33 weeks. 
At the end of the 26-week double-blind treatment period, participants will have the opportunity 
to enroll into the long-term, extension study (MRX-503). Subjects who do not enroll into the 
treatment extension study or who discontinue at any time during this study will have a final 
safety follow-up phone call 7 days after the last dose of study drug. Subjects who discontinue 
from the study for safety reasons are followed-up as long as clinically indicated or until no 
further improvement with an adverse event is expected. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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The study will be conducted in approximately 40 sites in North America, Europe, Asia, and 
South America. Other regions may be added, if necessary, for enrollment purposes. 
3.2. 
Sample Size and Power 
The sample size was calculated to ensure enrollment of an adequate number of PFIC2 
participants who fulfill criteria for the primary cohort (primary endpoint).  The sample size is 
chosen to provide at least 80% of power for the analysis of the primary endpoint. 
The primary efficacy endpoint is the mean change from baseline in the average morning 
ItchRO(Obs) severity score for the last 12 weeks of the study (Weeks 15-26). 
The following assumptions were made in estimating the sample size for study MRX-502: 
• Between-treatment group (placebo to active) LS mean difference of 0.663 
• Pooled SD of 0.563 
• Effect size of 1.178 in the mean change from baseline in the 4-week average 
morning ItchRO(Obs) score 
The estimations of LS mean difference, SD and effect size for the sample size justification are 
based on ItchRO(Obs) data from the maralixibat Phase 2 studies.  Maralixibat-treated subjects 
with PFIC2 from Study LUM001-501 were compared to placebo-treated subjects with ALGS 
from Studies LUM001-301 and LUM001 302 as no placebo data are available from Study 
LUM001-501.  Since impact and symptoms of itching reported by PFIC patients are also 
reported by ALGS patients, (i.e., mood changes, scratching, difficulty falling asleep, skin 
damage, blood from scratching etc.), it is reasonable to assume that the ItchRO outcomes from 
the ALGS placebo-controlled studies will inform outcomes for this PFIC study due to the 
similarities in the features of pruritus.  Two fundamental assumptions were made: A) the placebo 
effect in subjects with ALGS is similar to the one expected in subjects with PFIC2.  Subjects 
with ALGS in study LUM001-301/302 had a slightly higher BL ItchRO(Obs) value compared to 
subjects with PFIC in Study LUM001-501.  As subjects with higher BL pruritus generally report 
a higher placebo response, the use of ALGS subjects from study LUM001-301/302 would 
therefore lead to a slightly more conservative assumption of the expected effect and sample size.  
The 2 populations were similar in the other BL characteristics.  Besides from the small difference 
in BL characteristics there are no obvious reasons to believe why the placebo response in 
subjects with ALGS and PFIC should be difference.  Therefore, the comparison of ALGS 
placebo subjects with treated PFIC subjects is considered a valid approximation for the purpose 
of assessing the effect size, data variability and the calculation of the sample size.  B) the placebo 
effect does not change after 3 months of treatment; as Studies LUM001-301 and -302 were 13-
week studies, data beyond 13 weeks were imputed using the last observation carried forward. 
With the assumed values, a total of 26 complete subjects (13 subjects in each treatment group) will 
be required to provide 80% power for the comparison of the primary endpoint measure between 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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the maralixibat treatment group and placebo, based on a 2-sided, 2-sample t-test at the 0.05 level 
of significance. 
Including a 10% dropout rate based on the previous PFIC study and rounding up to the next even 
number, approximately 30 participants (15 participants in each treatment group) will be 
randomized in the primary cohort of the study. 
3.3. 
Study Population 
The study population is comprised of male and female participants with a body weight ≥ 5.0 kg, 
who are ≥12 months and <18 years of age at time of baseline, with a confirmed diagnosis of 
PFIC based on clinical/laboratory features and standard of care genotyping. Subjects will not be 
considered eligible for the study without having cholestasis as manifested by total sBA (primary 
cohort only) ≥ 3 x ULN (upper limit normal) and an average morning ItchRO(Obs) severity 
score ≥ 1.5 during 4 consecutive weeks leading to the baseline visit. 
3.4. 
Treatments Administered 
Subjects will be randomized to one of two treatment groups: 
• maralixibat 
• placebo 
Eligible participants will be randomly assigned to study drug in a 1:1 allocation ratio, stratified 
by cohort (see Section 3.1). Subjects will self-administer (or will be administered) varying 
volumes of ready-to-use oral solution study drug at each dosing visit, starting with the baseline 
visit (Visit 1/Day 0). The dosing volume is determined based on the individual body weight, the 
dose level according to the dose escalation plan (150, 300, 450 or 600 μg/kg), and the strength of 
solution being administered (5, 10, 15, or 20 mg/mL).  
Subjects will take the first dose of study drug at the baseline visit (Visit 1/Day 0) under the 
supervision of the Investigator or trained staff.  
Study drug administration will take place during the Dose Escalation and Stable Dosing periods 
of the study based on a BID regimen. The morning dose should be administered approximately 
30 minutes before breakfast and the evening dose approximately 30 minutes before the main 
evening meal. The doses will be administered prior to meals rather than q12h in order to better 
cover the luminal bile acid release associated with meals. Study drug should be administered 
approximately at the same time each day throughout the study. The interval between 
administration of study drug and any concomitant treatment should not change during the study. 
Dosing will occur over a 26-week treatment period. 


 
Statistical Analysis Plan,  
 
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Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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3.4.1. Dose Escalation Period 
For participants assigned to maralixibat, the Dose Escalation period will consist of the following 
weekly steps: 
• 
Dose level 1:  150 μg/kg maralixibat BID for 1 week 
• 
Dose level 2:  300 μg/kg maralixibat BID for 1 week 
• 
Dose level 3:  450 μg/kg maralixibat BID for 1 week 
• 
Dose level 4:  600 μg/kg maralixibat BID for the remaining duration of the study 
Dose escalation should occur in the absence of major safety (e.g., liver parameters) or tolerability 
(e.g., GI-related TEAEs) concerns related or possibly related to study medication.  Subjects with 
such safety concerns can be down-titrated to a lower, previously tolerated dose level for 1 week 
before continuing dose escalation.  The minimum dose to continue in the study will be 150 µg/kg 
maralixibat BID; subjects who cannot tolerate this dose will be discontinued from the study. 
3.4.2. Stable Dosing Period 
Investigators have up to Week 6 to determine the maximum tolerated dose; if re-challenges or 
further dose escalations fail, the participant will remain on the maximum tolerated dose level for 
the remainder of the Stable Dosing period to complete a minimum of 20 weeks of stable dosing. 
During the Stable Dosing period, participants will remain on the maximum tolerated dose level 
for the remainder of the study. Dose reductions are allowed for safety or tolerability reasons 
down to a minimum level of 150 µg/kg BID. Subjects who cannot tolerate this dose will be 
discontinued from the study. 
3.5. 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet study entry criteria will be randomly assigned to maralixibat or placebo in a 
1:1 allocation ratio. The randomization schedule will be computer generated by an independent 
biostatistician using a permuted block algorithm and will randomly allocate each treatment group 
to randomization numbers. The randomization numbers will be assigned sequentially through a 
central interactive response technology (IRT) system as participants are entered into the study. 
The randomization schedule will be stratified by cohort as described in Section 3.1. 
The IRT system will be used for screening and enrolling participants, randomization, study drug 
supply dispensation and management, inventory management and supply ordering, study drug 
expiration tracking and management, and emergency unblinding. Individual participant treatment 
is automatically assigned by the IRT to participants who meet study entry criteria. The 
participant’s randomization number represents a unique number corresponding to the treatment 
allocated to the participant. 


 
Statistical Analysis Plan,  
 
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Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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At each dosing visit, the Investigator or designee will access the IRT system, and enter 
participant-specific information (e.g., unique participant number, age [years and months], 
weight, and information on dose escalation status). For randomized participants, this information 
will be used by the IRT to identify the appropriate strength of solution and dosing volume, and to 
assign a corresponding bottle number(s) to be dispensed to the participant. 
Siblings enrolled in the study will be assigned in a blinded manner by the IRT system to the 
same treatment arm.  
The randomization schedule will be prepared by Premier Research before the start of the study. 
No one involved in the study performance will have access to the randomization schedule before 
the official unblinding of treatment assignment. Subjects who discontinue from the study will not 
be replaced. Study center will not be a blocking factor in the randomization schedule. 
3.6. 
Blinding and Unblinding 
All participants, investigators, and study personnel involved in the conduct of the study, 
including data management, will be blinded to treatment assignment. 
The treatment assignment must not 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 should make an effort to contact the medical monitor before unblinding occurs 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 must be 
informed about the code break as soon as possible. 
If the treatment assignment is unblinded, the date and the signature of the person who was 
unblinded, and the reason for unblinding are recorded in the source documents. Upon breaking 
the blind, the participant will be withdrawn from the study, but should be followed up for safety 
purposes. Unblinding will be processed through the IRT system, and instructions will be 
available in the user manual.  
Data that may potentially unblind treatment assignment (i.e., maralixibat serum concentrations, 
treatment allocation, post-baseline sBA levels) will be handled with special care during the data 
cleaning and review process. Prior to unblinding, any data that may potentially unblind study site 
personnel or study team personnel will be presented as blinded information or otherwise will not 
be made available. If applicable, unblinded data may be made available to quality assurance 
representatives for the purposes of conducting independent audits. 
3.7. 
Schedule of Assessments 
A detailed schedule of assessment for the study is provided in Table 1.  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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Table 1:  Schedule of Assessments 
Proceduresp 
Screening a 
Dose Escalation (4-6 weeks) 
  
Stable Dosing (20-22 weeks) 
Follow-up  
Visit/Subject Contact 
# 
Screening / 
V0 
Baseline 
/ V1 
Subject 
contact 
V2 
Subject 
contact 
V3 
Subject 
contact 
V4 
Subject 
contact 
V5 
Subject 
contact 
V6 
Subject 
contact 
V7 
Subject 
contact 
V8 
Subject 
contact 
EOT/ET 
V9b 
Study Week 
-6 
0 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
27 
Study Day 
Day -42 
0 
7 
14 
21 
28 
35 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
189 
Window (in days) 
(-5) 
  
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±2) 
Informed 
Consent/Assent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Assessment 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical & Vital signsc 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
ECG 
X 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
Liver Ultrasoundd 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Pregnancy Teste 
S 
U 
  
  
  
U 
  
U 
  
U 
  
U 
  
U 
  
U 
  
S 
  
Confirm PFIC 
Genotype Resultsf 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
eDiary Device Provided 
/ Returnedg  
P 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
R 
  
ItchRO(Obs), 
ItchRO(Pt) & EDQ 
Twice-daily completion of ItchRO & EDQ 
  
Review eDiary & 
Assess Compliance 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Randomized 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CISh 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
PISi 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
PIC 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
CIC 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 25 of 89 
 
Proceduresp 
Screening a 
Dose Escalation (4-6 weeks) 
  
Stable Dosing (20-22 weeks) 
Follow-up  
Visit/Subject Contact 
# 
Screening / 
V0 
Baseline 
/ V1 
Subject 
contact 
V2 
Subject 
contact 
V3 
Subject 
contact 
V4 
Subject 
contact 
V5 
Subject 
contact 
V6 
Subject 
contact 
V7 
Subject 
contact 
V8 
Subject 
contact 
EOT/ET 
V9b 
Study Week 
-6 
0 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
27 
Study Day 
Day -42 
0 
7 
14 
21 
28 
35 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
189 
Window (in days) 
(-5) 
  
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±3) 
(±2) 
PedsQLj 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Clinician Scratch Scale 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
CBC with Differential 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Coagulation 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Chemistry Panel 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Lipid Panelk 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Urinalysis 
  
X 
  
  
  
  
  
X 
  
X 
  
  
  
X 
  
  
  
X 
  
FGF-19, Autotaxin, C4k 
  
X 
  
  
  
  
  
X 
  
X 
  
  
  
X 
  
  
  
X 
  
sBA collectionk 
X 
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Lipid Soluble 
Vitaminsk,l 
  
X 
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
AFP Sample 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
PK Samplem 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
  
Serum storage sample 
  
X 
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Healthcare Utilization 
  
  
  
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
Study drug Suppliedn  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Study drug 
Administrationo  
  
Twice-daily administration  
  
Assess AEs  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Treatments  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 26 of 89 
 
AFP=a-fetoprotein; C4=7a-hydroxy-4-cholesten-3-one; CBC=complete blood count; CIS=Caregiver Impression of Severity; CIC=Caregiver Impression of 
Change; ECG=electrocardiogram; EDQ=exploratory diary questionnaire; EOT=end of treatment; ET=early termination; FGF-19=fibroblast growth factor-19;  
ItchRO=Itch Reported Outcome; P=Provided; PedsQL=Pediatric Quality of Life Inventory; PIC=Patient Impression of Change; PIS=Patient Impression of 
Severity of Pruritus; PK=pharmacokinetic; R=Returned; S=Serum; U= Urine; V=visit 
a 
Subjects who initially fail to meet eligibility criteria may be re-assessed during the 6-week screening period prior to being captured as a screen failure.  
Subjects may also be re-screened 
b 
Study sites should record dates of any future scheduled procedures related to PFIC (e.g., PEBD, ileal exclusion, liver transplant, or listed for liver transplant), 
if known at this visit 
c 
Blood pressure, heart rate, temperature, respiration rate. Height and weight will be measured by trained staff using standardized methodology, incl. 
calibrated stadiometer or headboard and calibrated balance, respectively 
d 
Screening ultrasound not required if an ultrasound or liver MRI less than 6 months old is available 
e 
Females of childbearing potential only; result must be reviewed prior to dispensing study drug 
f 
Genotyping results will be reviewed by Sponsor or designee 
g 
Caregivers and age-appropriate participants will be instructed to complete their eDiary twice daily (morning and evening) 
h 
To be completed by caregivers for all participants 
i 
To be completed only by participants aged ≥9 years at screening 
j 
To be completed by participants and caregivers using the age-appropriate PedsQL module 
k 
Subjects should make every effort to fast at least 6 hours prior to collection. Water intake is permitted if necessary but not recommended 
l 
Blood samples must be drawn before administration of vitamin supplementation 
m 
PK samples will be drawn pre-dose, and approximately 2.5 hours after the morning dose  
n 
If needed, study drug may be supplied via direct-to-patient shipments in between site visits, see Section 6.4 of the protocol (amendment 4). 
o 
Subjects will self-administer (or will be administered) the first dose of study drug in the clinic on Visit 1/Day 0 after breakfast under the supervision of the 
Investigator or trained site staff. 
p 
See Appendix 10 of the protocol (amendment 4) for management of study procedures during pandemic. 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 27 of 89 
 
4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of participants with 
non-missing values (n), mean, 2-sided 95% CI for the mean, standard deviation (SD) and/or 
standard error (SE) if appropriate, median, 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 
the analysis population (and cohort where applicable) with available data for each treatment 
group, 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) for the mean are reported to the same degree of precision as the mean. 
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), calculated osmolarity (mOsm/kg), osmolar gap (mOsm/kg), anion 
gap (mEq/L), MELD and PELD scores will be presented as integers. Derived values for PedsQL 
summary and total scale scores will be presented to 1 decimal place. Serum bile acid levels (total 
and sub-species), and derived values of height, weight, and BMI z-scores, EDQ and ItchRO 
average scores, FIB-4, APRI, retinol:RBP molar ratio (mol/mol), and ratio of α-tocopherol 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% 
confidence intervals (CIs) will be presented for statistical tests. 
A p-value of ≤ 0.10 but > 0.05 will be considered evidence of a trend. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 28 of 89 
 
To control for the overall type I error rate, hierarchical testing based on a fixed sequence 
procedure will be used. If statistical significance is declared for the primary efficacy analysis, 
formal hypothesis testing will be done for the secondary efficacy endpoints in the pre-specified 
sequence until a non-significant result is reached. All other p-values from secondary endpoints, 
after a non-significant p-value is reached, will be considered nominal and will be interpreted 
with appropriate caution when considering the extent to which results from secondary endpoints 
provide support for evidence of efficacy. 
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
A data monitoring committee (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 make recommendations to the 
Sponsor 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 will be 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 completion of the 
study. 
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. 
Membership in the analysis populations will be determined prior to database lock. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 29 of 89 
 
The primary efficacy endpoint and the key secondary efficacy endpoint (i.e., change from 
baseline in sBA) will be analyzed for the ITT and PP analysis populations. The other secondary 
and exploratory efficacy endpoints will be analyzed in the ITT population. 
The number of participants excluded from each analysis will be presented. 
Safety, tolerability, and PK analyses will be conducted in the Safety Population. 
Because PFIC is a rare disease, siblings are allowed to enroll in this study. Each sibling will be 
considered for each analysis population described above. A sensitivity analysis on the primary 
efficacy endpoint and the key secondary efficacy endpoint will include only 1 sibling in the ITT 
analysis population. The choice of sibling will be made at random. The method of choosing a 
sibling is described in Section 6.1.9. 
5.1. 
Subject Grouping 
The following subject cohorts will be used for the analysis of the various endpoints in this study. 
Subject cohorts are identified according to the centrally adjudicated PFIC type which are 
recorded on the Genotype Adjudication file (see Section 6.1.9). 
• Primary cohort: All non-truncated PFIC2 (nt-PFIC2) participants. 
• PFIC cohort: PFIC1, nt-PFIC2, PFIC3, PFIC4, PFIC5 and PFIC6 participants 
(i.e., all genotypes except for truncating PFIC2 [t-PFIC2] participants, and 
participants with heterozygosis, low or fluctuating sBAs, a history of surgery, or 
where there is no established variant linked to PFIC disease) 
• Full cohort: All participants enrolled. 
Each of the above-defined cohorts, with the exception of the Full cohort, will exclude any 
participants with previous documented surgery to address PFIC at baseline. 
6. 
General Issues for Statistical Analysis 
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, Visit 1 
(Day 0), before the first dose of study drug is administered. If data is not measured or collected at 
the baseline visit, then the last non-missing measurement before receiving the first dose of study 
drug is used as the baseline value. 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 30 of 89 
 
Baseline and all post-baseline sBA samples are assayed at Frontage Laboratories, while 
screening sBA samples are assayed at ACM Global Laboratories. Only pre-dose samples assayed 
at Frontage Laboratories will be used as a baseline sample. 
Baseline ItchRO and EDQ average morning, evening, and highest scores (observer and patient) 
are constructed as the average of 4 weekly (7-day) average scores in the period consisting of the 
28 days immediately before the date of first dose of study drug. The numerator and denominators 
used in the derivation of weekly average and time period scores are based on the number of non-
missing daily and weekly scores, respectively. 
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 between 
Screening and Visit 1 (Day 0), or the last non-missing measurement before receiving the first 
dose of study drug if only one value is available. Pre-dose measurements obtained from a local 
laboratory will only be used if no other data are available. For the derived non-invasive fibrosis 
markers of APRI, FIB-4, PELD, and MELD, 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 treatment group, analysis visit, and treatment 
group-by-visit interaction as well as the continuous, fixed covariates of baseline and baseline-by-
visit interaction. 
For the PFIC cohort (as defined in Section 5.1), PFIC type will also be used as a covariate in the 
MMRM analysis. For this analysis, due to the small sample sizes, PFIC4, PFIC5, and PFIC6 will 
be grouped together. Within the PFIC cohort, 4 levels of PFIC types are included in the 
covariate: nt-PFIC2, PFIC1, PFIC3, and other (PFIC4, PFIC5, and PFIC6 group). 
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, noting the primary and PFIC cohorts are defined 
in Section 5.1: 
1. Primary:  Mean change in the average morning ItchRO(Obs) severity score between 
baseline and Week 15 through Week 26 in the primary cohort 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 31 of 89 
 
2. Key Secondary:  Mean change in total sBA level between baseline and average of Weeks 
18, 22, and 26 in the primary cohort 
3. Secondary:  Mean change in the average morning ItchRO(Obs) severity score between 
baseline and Week 15 through Week 26 in the PFIC cohort 
4. Secondary:  Mean change in total sBA level between baseline and average of Weeks 18, 
22, and 26 in the PFIC cohort 
5. Secondary:  Proportion of ItchRO(Obs) responders from Week 15 to Week 26 (reference 
Section 6.1.8) in the primary cohort 
6. Secondary:  Proportion of sBA responders from Week 18 to Week 26 (reference Section 
6.1.8) in the primary cohort 
7. Secondary:  Proportion of ItchRO(Obs) responders from Week 15 to Week 26 in the 
PFIC cohort 
8. Secondary:  Proportion of sBA responders from Week 18 to Week 26 in the PFIC cohort 
 
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 
While all possible efforts will be made to ensure that participants stay in the study and all data is 
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 key secondary efficacy endpoint, based on the ITT 
Population over the primary and PFIC cohorts (separately), several methods will be used to 
handle missing data for average morning ItchRO(Obs) severity and total sBA, including:  
• MMRM 
• multiple imputation (MI) using standard MAR approach 
• MI using tipping point approach 
The MMRM method will be used for the primary analysis on all continuous, repeated efficacy 
measures. Sensitivity analyses using the 2 MI methods will be performed on the primary efficacy 
endpoint and the key secondary efficacy endpoint to assess the robustness of alternate imputation 
assumptions.  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 32 of 89 
 
The above procedures are described in the below sub-sections, along with the handling of 
missing individual ItchRO and EDQ scores, PedsQL scale scores, and adverse event severity and 
relationship to study drug.  
 
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 treatment group, visit, and treatment group-by-visit 
interaction as well as the continuous, fixed covariates of baseline and baseline-by-visit 
interaction. For PFIC cohort analyses, PFIC type (i.e., PFIC1, nt-PFIC2, PFIC3, and the 
combination of PFIC4, PFIC5, and PFIC6) will also be included in the MMRM model as a 
covariate. 
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 et al, 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 et al, 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 and safety 
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 missing at 
random (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 et al, 2007; Siddiqui et al, 2009, Mallinckrodt et al, 2008, 
Mallinckrodt et al, 2013). 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 et al, 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 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 33 of 89 
 
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 al, 2008). 
The following SAS pseudocode will be used for the MMRM models: 
proc mixed data = example;   
      class <subjectid> <visit> <treatment>; 
      model chg = <baseline score> <treatment> <visit> <treatment>*<visit> <baseline score>*<visit> / 
ddfm = kr;         ***  PFIC type is included in the model for analyses of the PFIC cohort ***; 
      repeated <visit> / subject = <subjectid>(<treatment>) type = un; 
      lsmeans <treatment>*<visit> / cl pdiff; 
lsmestimate <treatment>*<visit> 'Weeks 15-18 MRX LS Mean=0'    0 0 1 0 0 0 0 0 0 0 0 0  divisor=1 / cl; 
lsmestimate <treatment>*<visit> 'Weeks 15-18 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 1 0 0 0 divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 15-18 MRX LS Mean = Placebo LS Mean' 0 0 1 0 0 0 0 0 -1 0 0 0 
divisor=1 / cl;       
lsmestimate <treatment>*<visit> 'Weeks 19-22 MRX LS Mean=0'    0 0 0 1 0 0 0 0 0 0 0 0  divisor=1 / cl; 
lsmestimate <treatment>*<visit> 'Weeks 19-22 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 0 1 0 0 divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 19-22 MRX LS Mean = Placebo LS Mean' 0 0 0 1 0 0 0 0 0 -1 0 0 
divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 23-26 MRX LS Mean=0'    0 0 0 0 1 0 0 0 0 0 0 0  divisor=1 / cl; 
lsmestimate <treatment>*<visit> 'Weeks 23-26 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 0 0 1 0 divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 23-26 MRX LS Mean = Placebo LS Mean' 0 0 0 0 1 0 0 0 0 0 -1 0 
divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 15-26 MRX LS Mean=0'    0 0 1 1 1 0 0 0 0 0 0 0  divisor=3 / cl; 
lsmestimate <treatment>*<visit> 'Weeks 15-26 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 1 1 1 0 divisor=3 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 15-26 MRX LS Mean = Placebo LS Mean' 0 0 1 1 1 0 0 0 -1 -1 -1 
0  divisor=3 / cl; 
run; 
 
 
Multiple Imputation Methods 
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. Therefore, 
analysis valid under MNAR will also be performed. Both MNAR- and MAR-based analyses 
using MI methods will be the basis upon which sensitivity of the analysis to missing data are 
assessed. 
Any participant who withdraws or is discontinued from the study or who misses a scheduled visit 
or assessment up through Week 26 will have their primary and key secondary efficacy missing 
data analyzed as imputed using MI techniques. This analysis will be presented as a sensitivity 
analysis. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 34 of 89 
 
Multiple imputation is a simulation-based approach where missing values are replaced using an 
appropriate stochastic model given the observed data and covariates, creating multiple completed 
data sets. These completed datasets are then analyzed using standard analysis methods (MMRM 
for this study), and the different parameter estimates across the datasets are then combined to 
produce unique point estimates, standard errors, and confidence intervals taking into account the 
uncertainty of the imputation process.  
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 non-monotone 
missing data (i.e., some participants have missing values for intermediate visits, but have non-
missing 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 et al, 1996). For participants with complete data up to a particular 
timepoint (e.g., time period average score for the primary endpoint and analysis visit for the key 
secondary endpoint), 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. Using 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 et al, 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 
using a general three-step approach: 
Step 1:  If the data has 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 is missing and required to make the missing data pattern monotone. Twenty datasets with a 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 35 of 89 
 
monotonic missing pattern will be generated. This method will use a non-informative 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 post-baseline 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 3590145. 
Assumptions underlying the partial imputation step are such that participants with missing data 
follow the same model as other participants in their respective treatment arm that have complete 
data. 
If the raw data has a monotone pattern of missingness, then the same procedures described above 
can be followed to create 20 identical datasets that will be used as an input dataset for the next 
step. 
Pseudocode for imputation of primary efficacy missing data is provided below: 
proc mi data=example nimpute=20 seed=3590145 minimum = 0 maximum = 4 out=example_1;  
 
by <treatment>; 
 
MCMC chain=multiple impute=monotone; 
  
var <baseline score> <week 1-6>………… <week 23-26>; 
run; 
 
Step 2:  Using a standard MAR-based MI approach, the remaining missing data will be imputed 
using a method for monotone missingness. The dataset that contains the multiple (20) partially 
imputed datasets is first sorted by imputation number and treatment group. The MI procedure 
used to complete the imputation will use a BY imputation number statement and request one 
imputed dataset within each BY group. The variables in the imputation model include treatment 
group, baseline, and each post-baseline visit. The final 20 fully imputed datasets will be 
generated using a regression-based multiple imputation model (PROC MI statement 
MONOTONE REGRESSION). For participants with complete data up to a particular visit, a 
multiple regression model will be fit that includes the outcome at that visit as the dependent 
variable and outcomes at previous visits and treatment group as independent variables. Using 
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) and treatment group. The seed number of 9482038 will be used for the 
imputation procedure described in Step 2. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 36 of 89 
 
For both Steps 1 and 2, minimum and maximum values for average ItchRO severity scores (i.e., 
0 and 4) will be specified in the MI procedure to avoid imputed values outside the possible range 
of values. When an intended imputed value is less than the minimum or greater than the 
maximum value specified, the MI procedure in SAS will redraw another value for imputation. 
Pseudocode for this step is below:  
proc sort data= example_1; 
 
by <imputationnumber> <treatment>; 
run; 
 
proc mi data= example_1 nimpute=1 seed=9482038 minimum = 0 maximum = 4 out= example_2; 
 
by <imputationnumber>; 
 
monotone regression; 
 
var <treatment> <baseline score> <week 1-6>………… <week 23-26>; 
run; 
 
Step 3:  MMRM analyses will be performed separately for each of the 20 complete analysis 
datasets, and the results will be combined into one multiple imputation inference (estimated 
treatment effect, standard error, p-value and associated 95% confidence interval) using the SAS 
MIANALYZE procedure. The treatment difference will be tested at the 2-sided 0.05 level and 
corresponding 95% CIs will be calculated. In the case that there is no missing data for a 
particular visit, p-values and 95% confidence intervals will come from the MMRM analysis on 
the observed data. 
SAS pseudocode for the MMRM analysis is as follows: 
ods output   lsmestimates= lsm_diff; 
proc mixed data = example_3;   
 
by <imputationnumber>; 
       
class <subjectid> <treatment> <visit>; 
      
model chg = <baseline score> <treatment> <visit> <treatment>*<visit> <baseline score>*<visit> 
/ddfm = kr;    ***  PFIC type is included in the model for analyses of the PFIC cohort ***;      repeated 
<visit> / subject = <subjectid>(<treatment>) type = un; 
      lsmeans <treatment>*<visit> / cl pdiff; 
 lsmestimate <treatment>*<visit> 'Weeks 15-18 MRX LS Mean=0'    0 0 1 0 0 0 0 0 0 0 0 0  divisor=1 / cl; 
 lsmestimate <treatment>*<visit> 'Weeks 15-18 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 1 0 0 0 divisor=1 / 
cl;   
 lsmestimate <treatment>*<visit> 'Weeks 15-18 MRX LS Mean = Placebo LS Mean' 0 0 1 0 0 0 0 0 -1 0 0 0 
divisor=1 / cl;       
lsmestimate <treatment>*<visit> 'Weeks 19-22 MRX LS Mean=0'    0 0 0 1 0 0 0 0 0 0 0 0  divisor=1 / cl; 
lsmestimate <treatment>*<visit> 'Weeks 19-22 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 0 1 0 0 divisor=1 / cl;   


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 37 of 89 
 
lsmestimate <treatment>*<visit> 'Weeks 19-22 MRX LS Mean = Placebo LS Mean' 0 0 0 1 0 0 0 0 0 -1 0 0 
divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 23-26 MRX LS Mean=0'    0 0 0 0 1 0 0 0 0 0 0 0  divisor=1 / cl; 
lsmestimate <treatment>*<visit> 'Weeks 23-26 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 0 0 1 0 divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 23-26 MRX LS Mean = Placebo LS Mean' 0 0 0 0 1 0 0 0 0 0 -1 0 
divisor=1 / cl;   
 lsmestimate <treatment>*<visit> 'Weeks 15-26 MRX LS Mean=0'    0 0 1 1 1 0 0 0 0 0 0 0  divisor=3 / cl; 
lsmestimate <treatment>*<visit> 'Weeks 15-26 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 1 1 1 0 divisor=3 / cl;   
lsmestimate <treatment>*<visit> 'Weeks 15-26 MRX LS Mean = Placebo LS Mean' 0 0 1 1 1 0 0 0 -1 -1 -1 
0  divisor=3 / cl; 
run; 
 
 
proc mianalyze data=diff; 
   by <visit> ; 
   modeleffects estimate; 
   STDERR stderr; 
   ods output parameterestimates=dif_2; 
run; 
 
proc mianalyze data=lsm; 
   by <visit> <treatment>; 
   modeleffects estimate; 
   stderr stderr; 
   ods output parameterestimates=lsmn_2; 
run; 
 
Pseudocode for imputation of key secondary efficacy missing data is provided below. There is a 
potential need to add option MAXITER=nnn to the MI procedure if the analysis fails to converge 
with 200 iterations. 
 
Step 1: 
proc mi data=example nimpute=XX seed=3590145 minimum = yy maximum = yy out=example_1;  
 
by <treatment>; 
 
MCMC chain=multiple impute=monotone; 
  
var <baseline> <week 2>………… <week 26>; 
run; 
 
XX will be determined based on the proportion of missing data across visits. The minimum and 
maximum values for total sBA level will be specified as the minimum and maximum values of the 
calculated results. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 38 of 89 
 
Step 2: 
proc sort data= example_1; 
 
by <imputationnumber> <treatment>; 
run; 
 
proc mi data= example_1 nimpute=1 seed=9482038 minimum = yy maximum = yy  out= example_2; 
 
by <imputationnumber>; 
 
monotone regression; 
 
var <treatment> <baseline> <week 2>………… <week 26>; 
run; 
 
Step 3: 
ods output  lsmestimates= lsm_diff; 
proc mixed data = example_3;   
 
by <imputationnumber>; 
       
class <subjectid> <treatment><visit> ; 
model chg = <baseline> <treatment> <visit> <treatment>*<visit> <baseline>*<visit> /ddfm = kr; 
***  PFIC type is included in the model for analyses of the PFIC cohort ***;  
repeated <visit> / subject = <subjectid>(<treatment>) type = un;  
lsmeans <treatment>*<visit> / cl pdiff; 
lsmestimate <treatment>*<visit> 'Week 18 MRX LS Mean=0'   0 0 1 0 0 0 0 0 0 0 0 0 0 0 divisor=1 / cl; 
lsmestimate <treatment>*<visit> 'Week 18 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 0 1 0 0 0 0 divisor=1 / cl;   
 lsmestimate <treatment>*<visit> 'Week 18 MRX LS Mean = Placebo LS Mean' 0 0 1 0 0 0 0 0 0 -1 0 0 0 0 
divisor=1 / cl;       
lsmestimate <treatment>*<visit> 'Week 22 MRX LS Mean=0'   0 0 0 0 1 0 0 0 0 0 0 0 0 0  divisor=1 / cl; 
lsmestimate <treatment>*<visit> 'Week 22 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 0 0 0 1 0 0 divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Week 22 MRX LS Mean = Placebo LS Mean' 0 0 0 0 1 0 0 0 0 0 0 -1 0 0 
divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Week 26 MRX LS Mean=0'    0 0 0 0 0 1 0 0 0 0 0 0 0 0  divisor=1 / cl; 
lsmestimate <treatment>*<visit> 'Week 26 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 0 0 0 0 1 0 divisor=1 / cl;   
lsmestimate <treatment>*<visit> 'Week 26 MRX LS Mean = Placebo LS Mean' 0 0 0 0 0 1 0 0 0 0 0 0 -1 0 
divisor=1 / cl;   
 lsmestimate <treatment>*<visit> 'Weeks 18-26 MRX LS Mean=0'    0 0 1 0 1 1 0 0 0 0 0 0 0 0  divisor=3 / 
cl; 
lsmestimate <treatment>*<visit> 'Weeks 18-26 Placebo LS Mean=0' 0 0 0 0 0 0 0 0 0 1 0 1 1 0 divisor=3 / 
cl;   
lsmestimate <treatment>*<visit> 'Weeks 18-26 MRX LS Mean = Placebo LS Mean' 0 0 1 0 1 1 0 0 0 -1 0 -1 
-1 0  divisor=3 / cl; 
run; 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 39 of 89 
 
 
proc mianalyze data=diff; 
   by <visit> ; 
   modeleffects estimate; 
   STDERR stderr; 
   ods output parameterestimates=dif_2; 
run; 
 
proc mianalyze data=lsm; 
   by <visit> <treatment>; 
   modeleffects estimate; 
   stderr stderr; 
   ods output parameterestimates=lsmn_2; 
run; 
 
 
Tipping Point Analysis 
As a sensitivity analysis to the standard MAR imputation approach, a tipping point analysis will 
be performed in order to determine the inflection point at which the inference under the MNAR 
assumption changes substantially. This will be used to check the robustness of the imputation. 
The sensitivity analysis will be performed by using a specified sequence of shift parameters, 
which will adjust the imputed values for observations in each treatment group. The range of shift 
parameters to be included in this analysis are -2 to 2 by 0.2. Thus, the value at which the results 
of the analysis are shifted from significant (i.e., α ≤ 0.05) to non-significant (i.e., α > 0.05) will 
be determined.  
A heatmap figure will be generated to display p-values corresponding to all combinations of 
shifts from the imputed data. 
The seed number of 2740211 will be used for the imputation procedure described in Step 2. 
Steps 1 and 3 of the analysis will be the same as for the multiple imputation analysis as described 
in the Standard MAR Imputation above. However, Step 2 of the analysis is the step that the shift 
parameters will be applied. Pseudocode for Step 2 is as follows: 
proc mi data=example_1  seed=2740211 nimpute =1 OUT= example_2; 
    
class <treatment>; 
    
by <imputationnumber>; 
    
monotone regression; 
var <baseline score> <week 1-6>………… <week 23-26>;  
mnar adjust ( <week 1-6>/ shift=YY adjustobs=(treatment ='active') ); 
mnar adjust ( <week 1-6>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 7-10>/ shift =YY adjustobs =( treatment ='active')); 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 40 of 89 
 
mnar adjust ( <week 7-10>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 11-14>/ shift =YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 11-14>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 15-18>/ shift = YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 15-18>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 19-22>/ shift =YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 19-22>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 23-26>/ shift =YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 23-26>/ shift =YY adjustobs =( treatment ='placebo') ); 
run; 
 
YY will encompass the range of shift parameters as pre-specified above. 
For the secondary endpoint the planned range of shift parameters to be included in this analysis 
are -100 to 100 by 1. 
Pseudocode for Step 2 for imputation of key secondary efficacy missing data is as follows: 
proc mi data=example_1  seed=2740211 nimpute =1 OUT= example_2; 
    
class <treatment>; 
    
by <imputationnumber>; 
    
monotone regression; 
var <baseline> <week 2>………… <week 26>;  
mnar adjust ( <week 2>/ shift=YY adjustobs=(treatment ='active') ); 
mnar adjust ( <week 2>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 6>/ shift =YY adjustobs =( treatment ='active')); 
mnar adjust ( <week 6>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 10>/ shift =YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 10>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 14>/ shift = YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 14>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 18>/ shift =YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 18>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 22>/ shift =YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 22>/ shift =YY adjustobs =( treatment ='placebo') ); 
mnar adjust ( <week 26>/ shift =YY adjustobs =( treatment ='active') ); 
mnar adjust ( <week 26>/ shift =YY adjustobs =( treatment ='placebo') ); 
run; 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 41 of 89 
 
 
Missing ItchRO/EDQ/PedsQL Scores 
In deriving the highest daily ItchRO/EDQ severity/frequency score, if either the morning or 
evening reports are not completed, the available score is used as the highest daily score. If both 
morning and evening reports are not completed, the highest daily score for that day is treated as 
missing data. 
For weekly (7-day) morning/evening/highest ItchRO(Obs)/ItchRO(Pt)/EDQ(Obs)/EDQ(Pt) 
severity/frequency scores, if >50% (i.e., >3 of 7) of the daily scores are missing, the average 
score for that weekly time period will be treated as missing. 
For 4- and 6-week time period ItchRO/EDQ scores (i.e., baseline, post-baseline to Week 6, 
Week 7 to 10, Week 11 to 14, Week 15 to 18, Week 19 to 22, and Week 23 to 26), if >50% of 
the weekly scores are missing, the respective time period score will be treated as missing. Thus, 
to derive a 4-week time period score, 2 or more of the respective weekly scores must be non-
missing; for a 6-week time period score, 3 or more weekly scores must be non-missing. 
For Pediatric Quality of Life Inventory (PedsQL) scale scores, if >50% of the items in the scale 
are missing, the scale score is not computed. 
 
Missing Responder Definition Data 
For the sBA responder endpoint, a participant is defined as a non-responder if the baseline value 
is missing OR sBA values are missing at all of the 3 time points (i.e., Weeks 18, 22, and 26). 
For the ItchRO responder endpoint, a participant is defined as a non-responder from Week 15 to 
26 if the 4-week average baseline score is missing OR all of the three 4-week average (post-
baseline) scores (i.e., Weeks 15-18, 19-22, and 23-26) are missing. 
For the number of days the morning ItchRO(Obs) severity score is ≤1 over the last 84 days (i.e., 
study day 99 through 182, inclusive, relative to the day of 1st dose of study drug), days with 
missing data would not be considered to have met the “≤1” criteria for that day. In computing the 
total number of days that the score is ≤1 within the specified time period (for each participant), 
missing data will be treated as having a score of >1. 
For the number and proportion of participants achieving morning ItchRO(Obs) severity scores 
≤1 for more than 50% of the time within pre-specified time periods, days with missing data 
would not be considered to have met the “≤1” criteria for that day. In computing the % of time 
the score is ≤1 within each time period for each participant, the denominator of the proportion 
would include all days within the specified time period (i.e., days with missing and non-missing 
data), while the numerator only includes those days that the score is 0 or 1. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 42 of 89 
 
For the proportion of participants with improvement from baseline in EDQ sleep scores, a 
participant is defined as having no improvement (i.e., non-responder) for an analysis visit if the 
4-week average baseline score is missing OR the 4-week (or 6-week for the first time period) 
average sleep score at the analysis visit is missing.   
For the proportion of EDQ sleep scores ≤2, missing scores are treated as a non-responder 
(i.e., >2). 
 
 
Missing Adverse Event Severity/Relationship 
For analysis purposes, the following rules will be applied for missing AE severity or relationship 
to study drug. An AE that does not have a recorded relationship to study drug value will be 
considered as “Related” to study drug. If the severity of an AE is missing, the severity will be 
reported as “Missing”. 
6.1.5. Analysis Visit Windows 
Analyses of all visit-based efficacy and safety variables will be performed using the analysis visit 
windows defined by study day relative to the first dose of study drug as outlined below in Table 2. 
Scheduled visits will be selected over unscheduled visits. The below table addresses scheduled 
post-baseline in-clinic visits; baseline assessments are described in Section 6.1.1. 
Table 2:  Analysis Visit Windows 
Analysis 
Visit 
Analysis 
Visit Name 
Target Day 
of Planned 
Visit 
Assessment 
Window 
(Study Days1) 
2 
Week 2 
14 
12 ─ 20 
4 
Week 4 
28 
21 ─ 34 
6 
Week 6 
42 
35 ─ 55 
10 
Week 10 
70 
56 – 83 
14 
Week 14 
98 
84 – 111 
18 
Week 18 
126 
112 – 139 
22 
Week 22 
154 
140 – 167 
26 
 Week 26 
182 
168 ─ x 
1 Study day relative to the date of first dose of study drug. 
2 Only data collected post-dose on Day 1 will be considered. 
x = last dose date plus 7 days 
For those participants who discontinue early from the study, Table 2 will also be used to assign 
the appropriate analysis visit.  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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The study day will be calculated for each scheduled or ET post-baseline visit and compared to 
the assessment window presented in Table 2 to define the visit window used for analyses. The 
analysis visit windows only apply to those visits that are applicable to the specific assessment. 
For example, if the scheduled or ET visit falls at Week 4 but a specific assessment (e.g., sBA 
sample) was not scheduled at that visit (see Table 1, Schedule of Assessments), then that 
assessment will not be used for analyses. 
If more than 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 the last dose of study drug will not be included in 
any efficacy analyses.  
6.1.6. Investigative Sites 
An investigative site is defined as a single principal investigator (including sub-investigators) 
who enroll 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 that 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 6 (i.e., through the Week 6 visit 
date). 
• “Stable Dosing Period” is defined for analysis purposes as the period of time between the 
beginning of Week 7 (i.e., Week 6 visit date plus 1 day) and the EOT visit (inclusive). 
6.1.8. Derived Variables 
Select derived variables will be rounded for presentation purposes (see Section 4.1). 
• Age (years) at baseline 
The reported age in years at baseline will be used.  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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• Age (months) at baseline 
The reported age in years and months at baseline will be used:  
Age (months) at baseline = (12 x Reported age in years at baseline) + Reported 
number of months at baseline 
• Date of Birth 
Date of Birth = Baseline Visit Date – [ 365.25 x ( Age in yrs + (months/12) ) ] 
Age in years and months at baseline, as reported on the CRF, is used. If only age in years 
(at baseline) is reported, then 6 months will be used. 
If the derived date of birth is later than the PFIC diagnosis date, the earliest complete 
medical history event start date, or the earliest complete reported prior/concomitant 
treatment start date, will be used to derive the date of birth by selecting the earliest of 
these 3 dates. 
• Age Group at baseline: 1 if age (full years) at baseline is 1 to < 6 years 
 
2 if age (full years) at baseline is 6 to <13 years 
 
3 if age (full years) at baseline is 13 to 18 years 
• UDCA usage at baseline:  A subject reporting the use of 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 be ongoing or have a stop date on or after the first dose of study drug would be 
considered as using UDCA at baseline. 
• Rifampicin usage at baseline:  A subject reporting the use of Rifampicin, based on ATC 
Class Level 5 (chemical substance), with a start date on or prior to the first dose of study 
drug and either be ongoing or have a stop date on or after the first dose of study drug 
would be considered as using Rifampicin at baseline. 
• Time since original diagnosis of PFIC (months) = (date of first dose – date of original 
diagnosis of PFIC) / 30.4375 
• Change from baseline = post-baseline value at time point – value at baseline 
For average ItchRO and EDQ scores, “value” is the average score as defined 
below. 
• % Change from baseline = 100 x change from baseline / value at baseline 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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• Highest daily ItchRO and EDQ scores = maximum of morning and evening scores 
If either the morning or evening reports are not completed, the available score is used as 
the highest daily score. If both morning and evening reports are not completed, the 
highest daily score for that day is treated as missing data. 
• Baseline ItchRO and EDQ scores: 
Baseline morning, evening, and highest ItchRO and EDQ scores used for analysis 
purposes are calculated using the daily scores from the 28 days (4 weeks) immediately 
before the date of first dose.  Pre-dose weekly scores are first calculated for each of the 
4-week, 7-day periods.  The “first” 7-day period (immediately before the first dose date) 
is considered ‘Week -1’, whereas the “last” 7-day period is considered as ‘Week -4’.  For 
each subject and ItchRO/EDQ efficacy variable, a baseline score is derived as the average 
of the 4 pre-dose weekly average scores. 
The handling of missing daily and weekly average scores is addressed in Section 6.1.4.3. 
The numerator and denominators used in the derivation of weekly average and time 
period scores are based on the number of non-missing daily and weekly scores, 
respectively. 
• Post-baseline ItchRO and EDQ scores: 
Post-baseline morning, evening, and highest ItchRO and EDQ scores used for analysis 
purposes are calculated using the daily scores from the 182 days (26 weeks) immediately 
after the date of first dose.  Post-dose weekly scores are first calculated for each of the 
26-week, 7-day periods.  The first 7-day period is considered ‘Week 1’, whereas the last 
7-day period is considered as ‘Week 26’.  For each subject and ItchRO/EDQ efficacy 
variable, post-baseline scores are derived as the average of the 4- or 6-week post-dose 
weekly average scores for the following time periods:  post-baseline to Week 6 (42 days), 
Week 7 to 10 (28 days), Week 11 to 14 (28 days), Week 15 to 18 (28 days), Week 19 to 
22 (28 days), and Week 23 to 26 (28 days). 
The handling of missing daily and weekly average scores is addressed in Section 6.1.4.3. 
The numerator and denominators used in the derivation of weekly average and time 
period scores are based on the number of non-missing daily and weekly scores, 
respectively.  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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• ItchRO(Obs) Responder is defined as a subject having a 4-week average morning 
ItchRO(Obs) severity change from baseline of ≤-1.0 OR an average severity score 
of ≤1.0.  
For the purpose of determining response, the average severity score from the three 
4-week periods (Weeks 15-18, 19-22, and 23-26) will be computed and used. 
Before the database lock, the definition of an ItchRO(Obs) Responder may be re-defined 
based on outcomes of the ItchRO instrument validation performed on the analysis of data 
blinded to treatment. This blinded analysis, performed according to the Validation 
Analysis Plan (VAP), will be used to estimate a threshold of clinically meaningful change 
(i.e., responder definition) in the 4-week average morning ItchRO(Obs) pruritus scores. 
Details of the analysis will be included in a standalone VAP; results will be presented in 
a standalone validation analysis report.   
• sBA Responder is defined as a subject having an average sBA level of <102 µmol/L 
(applies only if baseline sBA level was ≥102 µmol/L), OR a ≤-75% average percent 
change from baseline. 
For the purpose of determining response, the average sBA value from Weeks 18, 22, and 
26 values will be computed and used. 
• FIB-4 =  
𝐴𝐴𝐴𝐴𝐴𝐴 (𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦) 𝑥𝑥 𝐴𝐴𝐴𝐴𝐴𝐴ቀ𝑈𝑈
𝐿𝐿ቁ
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ൬103
µ𝐿𝐿൰ 𝑥𝑥 √𝐴𝐴𝐴𝐴𝐴𝐴ቀ𝑈𝑈
𝐿𝐿ቁ  , where age is years at sample collection time point 
• APRI =  100 x  
𝐴𝐴𝐴𝐴𝐴𝐴 ቀ𝑈𝑈
𝐿𝐿ቁ / 𝐴𝐴𝐴𝐴𝐴𝐴 𝑈𝑈𝑈𝑈𝑈𝑈 ቀ𝑈𝑈
𝐿𝐿ቁ
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ൬103
µ𝐿𝐿൰  , where ULN = upper limit 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] ) 
• Retinol: RBP Molar Ratio (mol/mol) = 0.0734 x retinol (µg/dL) / RBP (mg/dL) 
• Anion Gap (mEq/L) = Sodium (mEq/L) – Chloride (mEq/L) – Bicarbonate (mEq/L) 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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• Osmolar Gap (mOsm/kg) = MO – CO,   
where MO = measured osmolality (mOsm/kg),  
CO = calculated osmolality (mOsm/kg) 
 = [2 x (Sodium (mEq/L) + Potassium (mEq/L) )] + [Glucose (mg/dL) / 18] 
+ [BUN (mg/dL) / 2.8] 
• PELD/MELD Scores 
Pediatric end-stage liver disease (PELD) score will be calculated for children under 12 
years of age at the baseline visit.  For children 12 years or older at the baseline visit, the 
model for end-stage liver disease (MELD) score will be calculated. 
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. 
MELD Score = 3.78 × ln (total bilirubin [in mg/dL]) + 11.2 × ln(INR) + 9.57 × 
ln(creatinine [in mg/dL]) + 6.43. 
Laboratory values in the MELD equation that are <1.0 will be set to 1.0 and serum 
creatinine values greater than 4.0 mg/dL (equivalent of 353.6 μmol/L) will be set to 4.0 
for calculation of the MELD score. 
Scores from PELD and MELD will be summarized separately. 
• Treatment Duration (days) =  
Date of last dose of study drug – Date of first dose of study drug + 1 day 
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.  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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• Study Drug Exposure (days) =  
Treatment duration (days) – Number of days that a participant reported missing 
both morning and evening doses (between the date of first and last dose) 
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 study drug exposure. 
• Compliance (%) = 100 x Study drug exposure (days) / Treatment duration (days) 
Study drug compliance will not be calculated for participants whose date of last study 
drug is unknown. 
• Total Dose (µg/kg) = ∑ [ Number of doses takeni x Dose received (µg/kg)i ] 
where,  
i = 1 to k, (k = number of time periods participant is receiving a constant dose) 
• Average Daily Dose (µg/kg/day) = Total Dose (µg/kg) / Treatment Duration (days) 
Dose variables (total dose and average daily dose) not calculated for placebo 
participants. 
• PedsQL Scoring Algorithm 
For each item of the PedsQL instrument (parent and participant), a 5-point response scale 
is used (0 = never, 1 = almost never, 2 = sometimes, 3 = often, 4 = almost always). Items 
are reverse-scored and linearly transformed to a 0-100 scale (0 → 100, 1 → 75, 2 → 50, 
3 → 25, 4 → 0), so that higher scores indicate better HRQoL (less negative impact). 
Scale scores are computed as the sum of the items divided by the number of items 
answered (this accounts for missing data). If more than 50% of the items in the scale are 
missing, the scale score is not computed. See PedsQL (2021) reference in Section 12 for 
scoring instructions on the PedsQL. 
PedsQL scale scores are computed for the following: 
 Total Scale Score – computed as the sum of the items over the number of 
items answered on the PedsQL Generic Core Scales (up to 45 items) 
 Physical Health Summary Score – computed as the sum of the items over 
the number of items answered in the Physical Functioning Scale (and 
Physical Symptoms Scale for infants) from the PedsQL Generic Core 
Scales (up to 19 items) 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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 Psychosocial Health Summary Score – computed as the sum of the items 
over the number of items answered in the Emotional, Social, and 
Nursery/Day Care/School Functioning Scales for children ages 2 to 18 
years or Emotional, Social, and Cognitive Functioning Scales for infants 
(<2 years) from the PedsQL Generic Core Scales (up to 26 items) 
 Multidimensional Fatigue Scale Score – computed as the sum of the 
items over the number of items answered in the PedsQL 
Multidimensional Fatigue Scales (18 items) 
 Family Impact Total Scale Score – computed as the sum of the items over 
the number of items answered in the PedsQL Family Impact module (36 
items) 
 Parent Functioning Summary Score – computed as the sum of the items 
over the number of items answered in the Physical, Emotional, Social, 
and Cognitive Functioning Scales from the PedsQL Family Impact 
module (20 items) 
 Family Impact Summary Score – computed as the sum of the items over 
the number of items answered in the Daily Activities and Family 
Relationships Scales from the PedsQL Family Impact module (8 items) 
Total scale, physical health summary, psychosocial health summary, and 
multidimensional fatigue scale scores are computed individually for the parent and 
participant reports. Family impact and parent functioning total scale and summary scores 
are based on parent-reported items. 
• Treatment-Emergent Adverse Event (TEAE) = In general, TEAEs are defined as AEs 
that start or deteriorate on or after the first dose of study drug and no later than 7 days 
following the last dose of study drug (for participants not participating in the extension 
study) or reported through the Week 26/EOT visit (for participants participating in the 
extension study). For participants with > 7 days of study drug interruption/withdrawal, 
the definition of a TEAE considers both the date of the last dose prior to drug interruption 
and the actual last dose (see Section 6.1.9). 
Any event which started before the first dose and worsens in either intensity or frequency 
or changes from non-serious to serious on or after the first dose date will also be 
designated as a TEAE. 
For any participants who die during the study and the date of death is between the date 
of first dose of study drug and the date of study discontinuation (as entered by the site), 
inclusive, all AEs (including those resulting in death) that occur during the study will be 
considered as TEAEs irrespective of the last dose and will be included in the TEAE 
summaries. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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• Body Weight, Height and BMI Z-Scores 
Height, weight, and body mass index (BMI) z-scores are based on a participant’s sex and 
age at each scheduled visit. For participants less than 24 months of age, the World Health 
Organization (WHO) growth charts will be used to derive z-scores (WHO, 2000). For 
participants at least 24 months of age, the Center for Disease Control (CDC) growth 
charts will be used to derive z-scores (CDC, 2000). 
• 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. 
PFIC Type and Subtype 
The PFIC type (and BSEP subtype for PFIC2) is centrally assessed by a blinded PFIC genetics 
expert based on a review of the genotype report. Analyses will be performed according to 
centrally adjudicated PFIC type which will be recorded on the Genotype Adjudication file, and 
not what is reported within the IRT system or on the eCRF. A listing of any discrepancies 
between the PFIC type recorded in IRT or the eCRF and the centrally adjudicated PFIC type will 
be presented.  
Subject Age 
The age of a participant at screening will be used to determine the age-specific module or 
instrument for the appropriate ItchRO and EDQ clinical outcome questionnaire or assessment 
(i.e., ItchRO, EDQ, PedsQL, PIS). The same module or instrument will be completed for the 
duration of the study, regardless of subsequent birthdays throughout the study. 
The PIC will be completed by subjects who are 9 years of age or older at the Week 26 (EOT) 
visit. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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Handling of Siblings 
Because PFIC is a rare disease, siblings are allowed to enroll in the study. Siblings enrolled in 
the study will be assigned in a blinded manner to the same treatment arm. The data from all 
enrolled participants (including siblings) will be used for all primary efficacy and safety analysis. 
The data for only 1 sibling will be used for a sensitivity analysis on the primary efficacy 
endpoint and the key secondary efficacy endpoint for the primary and PFIC cohorts, 
independently, in the ITT Population. The choice of sibling to use in the sensitivity analysis will 
be made at random, unless only 1 sibling is evaluable in the specific cohort and ITT Population 
and the other sibling is not. In this case, the evaluable sibling will be used in the sensitivity 
analyses. Sibling selection for the purposes of the sensitivity analysis will be completed prior to 
data lock. 
Adverse Event and Concomitant Medication Coding 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1. 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, non-pharmacological 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 (Week 26 or Week 27), inclusive. For participants not 
continuing into the extension study, this period of participation is from the first day of screening 
through the last contact at Week 27. For participants continuing into the extension study, this 
period is from the first day of screening through the Week 26 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. 
Medications that treat pruritus include ATC preferred terms of rifampicin, phenobarbital, 
alimemazine, brompheniramine maleate, cetirizine hydrochloride, desloratadine, 
dexchlorpheniramine maleate, dimetindene maleate, ketotifen fumarate, levocetirizine 
dihydrochloride, loratadine, mequitazine, promethazine, promethazine hydrochloride, ornithine 
aspartate, ursodeoxycholic acid, colestyramine, naltrexone, naltrexone hydrochloride, and 
sertraline. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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For participants participating in the extension study, concomitant treatments that are ongoing as 
of the Week 26 visit are closed-out with a stop date of “ongoing”. Concomitant treatments that 
are continuing from the core study (MRX-502) are copied into the extension study database with 
start dates entered as the original start date in the core study. 
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 term recorded 
includes “Worsened” (e.g., “Worsened Headaches”). 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).  
For participants participating in the extension study, AEs that are ongoing as of the Week 26 
visit are closed-out with a stop date of “ongoing”. Adverse events that are continuing from the 
core study (MRX-502) are copied into the extension study database with start dates entered as 
the original start date in the core study. 
Events of Clinical Interest 
The following events have been defined as events of clinical interest (ECI) due to the nature of 
PFIC disease as well as of maralixibat: 
• Diarrhoea events 
• Lipid soluble vitamin (LSV) deficiency events 
• Elevated transaminases events 
• Elevated bilirubin events 
PFIC is associated with LSV deficiency and fluctuating transaminase elevations. Maralixibat is 
associated with gastrointestinal disturbances such as diarrhoea. 
The list of PTs used to identify LSV deficiency events are provided in Appendix 2.  
Diarrhoea events include PTs of: 
- 
‘Diarrhoea’, 
- 
‘Intermittent Diarrhoea’,  
- 
‘Increased stool frequency’  
- 
‘Gastroenteritis’  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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Elevated transaminases events include PTs of: 
- 
‘Elevated liver enzymes’  
- 
‘Transaminases abnormal’ 
- 
‘Transaminases increased’ 
- 
‘Alanine aminotransferase increased’,  
- 
‘Aspartate aminotransferase increased’  
- 
‘Aspartate aminotransferase abnormal’ 
- 
‘Alanine aminotransferase abnormal’ 
 Elevated bilirubin events include the PT of: 
- 
‘Blood bilirubin increased’, 
- 
‘Blood bilirubin abnormal’ 
- 
‘Hyperbilirubinaemia’ 
Partial Date Imputation 
If partial dates occur, the convention for replacing missing dates for the purpose of calculating 
derived variables is as follows: 
Partial PFIC Diagnosis Dates 
For partial original PFIC 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). 
Partial AE or Medication Dates 
Adverse events 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 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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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 subject’s age in years and months 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 non-missing repeat 
laboratory value will be used for data analysis. 
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. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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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 subjects 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 subject does not report a liver-associated event, then the time to first liver-associated event is 
censored at the last contact date. 
7. 
Study Subjects and Demographics 
Subject disposition, demographics, disease history and baseline disease, important protocol 
deviations, prior medications, and study drug exposure and compliance will be summarized, 
unless otherwise noted, by randomized treatment group and overall for the primary cohort, the 
PFIC cohort, and all cohorts combined (all subjects) in the Safety Population. 
7.1. 
Disposition of Subjects and Withdrawals 
Subject disposition will be tabulated in all subjects, including screen failures. 
Subject 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 number of 
participants screened for eligibility, the number of screen failures, the number of participants 


 
Statistical Analysis Plan,  
 
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Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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randomly assigned to study treatment, and the number of families with siblings enrolled in the 
study, along with the total number of siblings. 
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, 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 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 non-
important deviation is identified as any protocol deviation that does not meet the criteria for an 
important deviation. Potentially important deviations will be reviewed by the Sponsor and 
Premier to determine the final classification as per the final Protocol Deviation Guidance Plan.  
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 the primary cohort, 
the PFIC cohort, and all cohorts combined (all subjects). 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 and approval from the Sponsor. 
Additionally, inclusion and exclusion criteria not met and reasons for screen failures will be 
listed. 
7.3. 
Demographics and Other 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 1 to <6, 6 to <13, and 13-18 years of age, will 
also be presented. Given the small number of participants in the study, age categories may be 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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combined for presentation and analysis (e.g., <9 and ≥9). Unless otherwise noted, age is the 
participant’s age at the baseline visit for all evaluations and presentations. 
Subjects reporting more than 1 race will be counted in a “More than one race” category for 
purposes of tabulating summary statistics for race. 
Disease History and Baseline Disease Characteristics 
Summary statistics will also be presented for the following baseline variables: 
• PFIC type 
• BSEP phenotype 
• time since original diagnosis of PFIC (months) 
• participants with liver masses detected on ultrasound 
• participants with baseline UDCA usage 
• participants with baseline Rifampicin usage 
• participants above and below the median baseline sBA level; where the median is 
calculated separately for the primary cohort, PFIC cohort, and all subjects 
• baseline pruritus assessments: 
–  clinician scratch scale (CSS) score 
–  patient impression of severity (PIS) 
–  caregiver impression of severity (CIS) 
–  ItchRO (Obs) 4-week morning average severity score 
–  ItchRO (Pt) 4-week morning average severity score 
–  ItchRO (Obs) 4-week evening average severity score 
–  ItchRO (Pt) 4-week evening average severity score 
–  ItchRO (Obs) 4-week highest daily average severity score 
–  ItchRO (Pt) 4-week highest daily average severity score 
–  ItchRO (Obs) 4-week morning average frequency score 
–  ItchRO (Pt) 4-week morning average frequency score 
–  ItchRO (Obs) 4-week evening average frequency score 
–  ItchRO (Pt) 4-week evening average frequency score 
–  ItchRO (Obs) 4-week highest daily average frequency score 
–  ItchRO (Pt) 4-week highest daily average frequency score 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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• baseline levels of biochemical markers of cholestasis and liver disease and other important 
baseline laboratory tests: 
–  total serum bile acids (sBA) 
–  ALT 
–  ALP 
–  AST 
–  GGT 
–  bilirubin (total and direct) 
–  albumin 
–  FGF-19 
–  autotaxin 
–  7α hydroxyl-4-cholesten-3-one (C4) 
–  25-hydroxyvitamin D 
–  alpha tocopherol 
–  prothrombin intl. normalized ratio 
–  vitamin A 
–  APRI 
–  FIB-4 
–  PELD score 
–  MELD score 
 
Subject demographics and baseline characteristics, and medical and surgical history information 
and prior medications, will be presented in a participant listing by randomized treatment group. 
7.4. 
Prior Medications/Therapies 
Prior treatments will be summarized descriptively by treatment group using the number and 
proportion of participants by ATC Class Level 2 (therapeutic main group) and ATC Class Level 
5 (chemical substance). 
Prior treatments will be presented separately from concomitant treatments.  
7.5. 
Exposure and Compliance 
Treatment exposure will be calculated for each participant exposed to maralixibat during the 
study and summarized descriptively. This analysis will be conducted for the overall 26-week 
treatment period. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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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 separately on the primary cohort and 
the PFIC cohort. Analysis of the primary efficacy endpoint and the key secondary efficacy 
endpoint (i.e., change from baseline in sBA level) will also be performed on the primary cohort 
in the PP population. 
Analyses on the exploratory efficacy endpoints will be performed in the ITT population 
separately on the primary cohort and the PFIC cohort. 
The primary efficacy analysis will be performed in the primary cohort for the ITT population. 
For all efficacy analyses, participants will be analyzed by the randomized treatment group 
assignment (maralixibat or placebo), based on the intent-to-treat 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 the PFIC cohort analyses, PFIC type will also be used as a covariate in the MMRM analysis. 
For this analysis, due to the small sample sizes, PFIC4, PFIC5, and PFIC6 will be grouped 
together. Within the PFIC cohort, 4 PFIC types are include in the covariate: nt-PFIC2, PFIC1, 
PFIC3, and other (PFIC4, PFIC5, and PFIC6 group). 
8.1. 
Primary Efficacy Analysis  
For this study, the primary estimand is the improvement in pruritus measured as change from 
baseline in the average morning ItchRO(Obs) severity score 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 inter-current 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 inter-current events 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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in this study. To this end, a restricted maximum likelihood (REML)-based MMRM model 
conducted on the primary cohort in the ITT population will be used as the primary analysis 
method.  
The repeated measures include post-baseline time periods during the dose escalation period (i.e., 
Week 1-6) and stable dosing period (i.e., Weeks 7-10, 11-14, 15-18, 19-22, and 23-26), with 
change from baseline in the 6- or 4-week average morning ItchRO(Obs) severity score as the 
dependent variable. The MMRM model will include the fixed, categorical effects of treatment 
group, time period, and treatment group-by-time period interaction as well as the continuous, 
fixed covariates of baseline 4-week average morning ItchRO(Obs) severity score 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 which 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 et al, 1997). 
The primary efficacy analysis will compare maralixibat and placebo using the contrast 
(difference in least squares [LS] means) between treatment groups across the last 12 weeks of the 
study (i.e., Weeks 18, 22, and 26 combined). 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 (i.e., the last 12 weeks of the study). Significance tests 
will be based on LS means using a 2-sided significance level (2-sided 95% confidence intervals 
[CIs]). 
The null hypothesis for the primary efficacy endpoint of the equality of maralixibat and placebo 
is: 
H01: mean change in average morning ItchRO(Obs) severity score between baseline 
and Week 15 through Week 26 over the primary cohort 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 last 12 weeks of the study of less than or equal to 0.05. 
Least squares (LS) means will be calculated for each treatment group for each post-baseline time 
period in the model. The difference between maralixibat and placebo change from baseline in 
average morning ItchRO(Obs) severity score will be estimated, with the corresponding 2-sided 
95% CI constructed for each time period, and the last 12 weeks (i.e., last 3 visits) of the study 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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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 over the primary cohort in the ITT population is rejected at the 0.05 (2-sided) 
significance level. 
8.2. 
Secondary Efficacy Analysis 
Analysis similar to that described for the primary efficacy endpoint will be performed for each of 
the change from baseline secondary efficacy endpoints. For responder-type endpoints, the 
number and proportion of participants that 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. 
The null hypotheses for the secondary efficacy endpoints of the equality of maralixibat and 
placebo are: 
H02: mean change in total sBA level between baseline and average of Weeks 18, 22, 
and 26 over the primary cohort in the two treatment groups are equal 
H03: mean change in the average morning ItchRO(Obs) severity score between 
baseline and Week 15 through Week 26 over the PFIC cohort in the two 
treatment groups are equal 
H04: mean change in total sBA level between baseline and average of Weeks 18, 22, 
and 26 over the PFIC cohort in the two treatment groups are equal 
H05: proportion of ItchRO(Obs) responders from Week 15 to Week 26 on 
participants in the primary cohort in the 2 treatment groups are equal 
H06: proportion of sBA responders from Week 15 to Week 16 on participants in the 
primary cohort in the 2 treatment groups are equal  
H07: proportion of ItchRO(Obs) responders from Week 15 to Week 26 on 
participants in the PFIC cohort in the 2 treatment groups are equal  
H08: proportion of sBA responders from Week 18 to Week 26 on participants in the 
PFIC cohort in the 2 treatment groups are equal  


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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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 secondary efficacy 
endpoints to quantify the possible impact of missing data and the use of potentially correlated 
sibling data, and to demonstrate the robustness of the conclusions. 
Sensitivity analysis will be performed on the primary efficacy endpoint and key secondary 
efficacy endpoint in the primary cohort and PFIC cohort, individually, in the ITT analysis 
population.  
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). 
If siblings are evaluable for efficacy, the primary analysis method described above for the 
primary efficacy endpoint and the key secondary efficacy endpoint will be repeated as a 
sensitivity analysis in which only one of sibling pairs or multiples will be used. The choice of 
which sibling to use in the sensitivity analysis will be made at random before the MRX-502 
study is unblinded (see Section 6.1.9). 
Summary statistics on the primary efficacy endpoint and the key secondary efficacy endpoint 
will also be presented descriptively by treatment group and visit, overall and for each of the 
following subgroups on the primary cohort in the ITT analysis population: 
• Region (Asia, Europe, Middle East, North America, and South and Central America) 
• Age at baseline (1 year to <6 years old, 6 years to < 13 years, and 13-18 years old) 
• Sex (male, female) 
• Race (White, Asian, Black or African American, American Indian or Alaska Native, 
Multiple) 
• Baseline sBA (< median, ≥ median; where only subjects in the primary cohort are used 
to calculate the baseline median sBA level) 
• Baseline ursodeoxycholic acid (UDCA) usage (yes, no) 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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• Baseline Rifampicin usage (yes, no) 
• BSEP type of primary cohort (non-truncating PFIC2) participants (BSEP 1, BSEP 2) 
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 will be conducted for the exploratory efficacy endpoints separately on the primary 
cohort and the PFIC cohort.  
Analysis 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. The repeated measures in the MMRM model will include the post-baseline 
visits as specified for each above-listed endpoint, with change from baseline value as the 
dependent variable. The MMRM model will include the fixed, categorical effects of treatment 
group, visit, and treatment group-by-visit interaction as well as the continuous, fixed covariates 
of baseline and the baseline-by-visit interaction. Least squares means will be calculated for each 
treatment group for each post-baseline 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 ItchRO (Obs and Pt) and EDQ (Obs and Pt) 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 number of 
observations, mean, 95% CI on the mean, standard deviation, median, minimum, and maximum 
on 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 that are considered a “responder” will be summarized by treatment 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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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. For 
the OL and ARW treatment phases, the number and percentage of subjects at each level of the 7- 
or 5-point scale, for PIC/CIC or CGTB respectively, will be presented overall and for each 
treatment group during the RW phase. For the RW phase, the number and percentage of subjects 
at each level will be presented by the randomized treatment group. For ordinal non-binary 
outcomes, the CMH test will be used to take the ordinal nature of the variable into account.  
The number and proportion of subjects with total sBA % decrease from baseline to Weeks 2, 6, 
10, 14, 18, 22, 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. 
A Student’s t-test, assuming unequal variances, will be used to compare treatment differences on 
the number of days the morning ItchRO(Obs) severity score ≤ 1 over the last 84 days (i.e., study 
day 99 through 182, inclusive). Satterthwaite’s method for computing standard error of the mean 
of the difference will be used. A conservative approach will be taken for subjects with missing 
morning severity scores during this 84-day period, including those subject that withdraw early 
from the study. Missing data will be treated as a severity score of >1.   
Time to first liver-associated event (PEBD surgery, listing for liver transplantation, liver 
decompensation [hepatic encephalopathy, variceal bleeding, ascites, and spontaneous bacterial 
peritonitis] events, HCC, and death) will be compared among treatments using 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. 
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. Analyses will be conducted 
separately on the primary cohort, the PFIC cohort, and all cohorts combined (all subjects). 
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 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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otherwise specified. For quantitative variables, descriptive statistics including number of 
observations, mean, median, standard deviation, 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 (Visit 1/Day 0) or the last preceding visit if not 
collected at Visit 1 will be used as the baseline value for safety analyses. 
All safety and tolerability data will be presented in participant listings. 
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). 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(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. Treatment-emergent adverse events related to study drug, AEs leading to withdrawal, 
SAEs, and deaths 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 leading to permanent study drug discontinuation 
• 
TEAEs resulting in death 
A participant reporting multiple cases of the same AE will be counted once within each SOC and 
similarly counted once within each PT. Treatment-emergent AEs 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. 
Additionally, the following subgroup analyses will be explored for the summary of TEAEs and 
the incidence of TEAEs by SOC and PT indicated above: 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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• Age at baseline (1 year to <6 years old, 6 years to < 13 years, and 13-18 years old) 
• Sex (male, female) 
• Race (available races in the study) 
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 participant cohort 
(primary [nt-PFIC2], PFIC or other), 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. 
9.1.1. Adverse Events Leading to Discontinuation of Study Drug 
AEs that lead to permanent discontinuation of study drug will be tabulated by treatment group. 
Subject listings of AEs that lead 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 lead to permanent 
discontinuation of study drug. Subject 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, participant cohort, 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 from the 1st and last 
dose, MedDRA PT, and relationship to study drug. 
9.1.3. Events of Clinical Interest 
Due to the nature of PFIC disease, as well as maralixibat, the following events have been defined 
as ECI: diarrhoea events, LSV deficiency events, elevated transaminases, and elevated bilirubin. 
For each of the ECI, the PTs are described in Section 6.1.9. 
The incidence of ECI will be summarized in the same manner as AEs that lead to permanent 
discontinuation of study drug. 
The clinical protocol references adverse events of special interest; however, the study has no 
such events. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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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 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 (i.e., total sBA, ALT, AST, ALP, total and direct bilirubin, GGT, C4, 
FGF-19, autotaxin, FIB-4, APRI, PELD and MELD) will not be included in safety summaries or 
listings. A separate participant listing for efficacy labs 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. 
9.5. 
Liver Ultrasound 
Liver ultrasound (or MRI) results will be presented in participant listings. 
9.6. 
Concomitant Medications/Therapies 
Concomitant treatments will be summarized descriptively by treatment group using the number 
and proportion of participants by ATC Class Level 2 (therapeutic main group) and ATC Class 
Level 5 (chemical substance). 
Prior treatments will be presented separately from concomitant treatments. Any treatments 
continuing or starting after the first dose of study drug will be considered concomitant. If a 


 
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Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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treatment 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 pharmacokinetic analyses will be performed on the Safety Population, 
conducted separately on the primary cohort, the PFIC cohort, and all cohorts combined (all 
subjects). 
10.1. Healthcare Utilization 
Healthcare resource utilization variables include the number of hospitalizations, emergency room 
visits, the length of stay for hospitalization (days), surgeries and procedures related to the 
participant’s PFIC condition, and the number of days the caregiver missed from work due to 
healthcare resource utilization events. Healthcare utilization data is collected at Weeks 2, 6, 10, 
14, 18, 22, 26, and the Week 27 follow-up and covers the time period since the last on-site visit. 
Subjects that visit the emergency room and the visit results in the subject being admitted to the 
hospital will be counted in both categories. 
Number and percent of subjects and number of occurrences will be presented across the entire 
post-baseline study period, between clinic visits from baseline through Week 27 Follow-up, by 
treatment group for PFIC-related hospitalizations and ER visits. For length of hospital stays and 
number of days a caregiver missed work, summary statistics on a subject-level basis will be 
presented. 
10.2. Pharmacokinetic Analyses 
Systemic concentrations of maralixibat in plasma will be determined at pre-dose and at 
approximately 2.5 hours after the morning dose at Week 10 and Week 26 (EOT/ET). Summary 
statistics (number of observations, mean, standard deviation, 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 PP Population has been re-defined as 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. 
The sensitivity analysis using placebo-based MI for handling missing data has been replaced 
with a tipping point approach. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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The number and proportion of subjects with total sBA % decrease from baseline to Weeks 2, 6, 
10, 14, 18, 22, and 26 within the following categories: >75%, 0-75%, and <0% have been added 
as an exploratory endpoint. The analysis will be performed using a CMH test. 
The number of days morning ItchRO(Obs) severity score ≤1 for the last 12 weeks (84 days) of 
the study has been added as an exploratory endpoint. The analysis will be performed using a 
Student’s t-test.  
The following exploratory endpoints listed in the protocol have been removed. They may be 
included after the finalization of the analysis plan for adhoc or posthoc analyses: 
• Proportion of participants with elevated liver biochemistry (i.e., >ULN at baseline), 
whose liver biochemistry normalize (≤ULN) at Weeks 2, 6, 10, 14, 18, 22, and 26 
• Mean change from baseline in weekly average morning, evening, and highest daily 
ItchRO(Obs) severity and frequency scores, individually, to each post-baseline week, and 
Weeks 15 to 26 combined 
• Proportion of days with a morning/evening/highest daily ItchRO(Obs)/ItchRO(Pt) 
severity/frequency score ≤1, individually, at the participant level from baseline to Week 6 
(overall and weekly), Weeks 7-10, 11-14, 15-18, 19-22, 23-26, and 15-26 
• Proportion of participants in each change from baseline category of the CSS at Weeks 2, 
4, 6, 10, 14, 18, 22, and 26  
• Proportion of participants in each change from baseline category of the CIS and PIS, 
individually, at Weeks 4, 6, 10, 14, 18, 22, and 26 
• Mean change from baseline in average (6 week average for Week 6 and 4 week average 
afterwards) morning, evening, and highest daily EDQ(Pt) severity scores, individually, to 
Weeks 6, 10, 14, 18, 22, 26, and Weeks 15 to 26 combined 
• Proportion of responders at Weeks 6, 10, 14, 18, 22, 26, and any of those weeks, where a 
responder is defined as having:  
a) 4-week average morning ItchRO(Obs) severity change from baseline of ≤-1.0 
or an average score of ≤1.0 AND a normalization or change from baseline in 
sBA of ≤-75%, or average sBA level <102 µmol/L  
b) 4-week average morning ItchRO(Obs) severity change from baseline of ≤-1.0 
or a score of ≤1.0 
c) a normalization or percent change from baseline in sBA of ≤-75%, or average 
sBA level <102 µmol/L 


 
Statistical Analysis Plan,  
 
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Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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• Mean change from baseline in average sleep disturbance scores over time (4-week 
average score at Weeks 6, 10, 14, 18, 22, 26, and average of Weeks 18, 22, and 26), 
based on sleep-related questions on the PedsQL (parent), Child PedsQL (young child), 
and Child PedsQL (child and teen) questionnaires, individually 
• Proportion of “no” answers for sleep-related questions on the ItchRO(Obs) morning, 
ItchRO(Obs) evening, and ItchRO(Pt) morning, individually, at the participant level for 
post-baseline to Week 6, Weeks 7 to 10, Weeks 11 to 14, Weeks 15 to 18, Weeks 19 to 
22, Weeks 23 to 26, Week 15 to Week 26, and overall (post-baseline to Week 26) 
• Proportion of participants who experience an improvement from baseline in height z-
score or weight z-score (i.e., change from baseline >0) at Weeks 2, 4, 6, 10, 14, 18, 22, 
and 26 
• Mean change from baseline in bile acid subspecies to Weeks 10, 18, and 26 
• Mean change from baseline in C4, FGF-19, and autotaxin to Weeks 6, 10, 18, and 26 in 
the PFIC cohort 
• Proportion of participants with an elevated liver biochemistry laboratory value at baseline 
that normalize post-baseline for sBA, ALT, AST and TSB, independently 
• Correlation analyses between sBA and pruritus severity 
The exploratory objective of evaluating the efficacy of maralixibat vs placebo in the primary 
cohort on responder rates for various pruritus measures, sBA and biomarkers has been updated to 
only include responder rates for pruritus severity and total sBA. 
In general, analysis on continuous repeated-measures efficacy variables will include a 
comparison of maralixibat and placebo using the contrast between treatment groups across the 
last 12 weeks of the study (i.e., Weeks 18, 22, and 26 combined) as described in Section 8.1. 
Sensitivity analyses will be performed on the primary efficacy endpoint and the key secondary 
efficacy endpoint in the primary cohort and PFIC cohort, individually, in the ITT analysis 
population. The clinical protocol describes sensitivity analysis on the primary and all secondary 
efficacy endpoints. 
Analysis of the primary efficacy endpoint and the key secondary efficacy endpoint (i.e., change 
from baseline in sBA level) will be performed on the primary cohort in the PP population. The 
clinical protocol describes analysis in the PP population on all secondary efficacy endpoints. 
Treatment-emergent AEs will not be summarized by severity and relationship to study drug.  
The clinical protocol references adverse events of special interest; however, the study has no 
such events. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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Total lipids, referenced in the clinical protocol, were not measured.  For the following laboratory 
parameters the sum of cholesterol and triglycerides were used:  ratio of alpha tocopherol to the 
sum of cholesterol and triglycerides, and corrected sodium (see Section 6.1.8). 
The clinical protocol states that the number and proportion of subjects with potentially clinically 
important values for select vital signs, laboratory, and ECG results, individually, will be 
presented by treatment group. These analyses have been removed from the planned analysis. 
Continuous healthcare resource utilization measures will be summarized as the number and 
percent of subjects and number of occurrences, presented across the entire post-baseline study 
period (between clinic visits from baseline through Week 27 follow-up), instead of as described 
in the protocol. 
12. 
References 
ASA. (2018) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2018. http://www.amstat.org/about/ethicalguidelines.cfm 
CDC (2000). Centers for Disease Control growth charts – A SAS Program for the 2000 CDC 
Growth Charts (ages 0 to <20 years)  
(www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm)  
Cnaan A., Laird N. M., Slasor P. 1997. Using the general linear mixed model to analyse 
unbalanced repeated measures and longitudinal data. Stat Med., 16, 2349-2380. 
EMA (2010). European Medicines Agency. Guideline on Missing Data in Confirmatory Clinical 
Trials. 
ICH (1998). 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 J. H. 1997. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics, 53, 983-997. 
Little R., Rubin D. 1987. Statistical Analysis with Missing Data. New York: John Wiley. 
Little R., Yau L. 1996. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs, 
Biometrics. 52. 1324-1333. 
Mallinckrodt C. H., Clark W. S., David S. R. 2001. Accounting for dropout bias using mixed-
effects models. Journal of Biopharmaceuticals Statistics, 11, 9-21. 
Mallinckrodt C. H., Lane P. W., Schnell D., Peng Y., Mancuso J. P. 2008. Recommendations for 
the Primary Analysis of Continuous Endpoints in Longitudinal Clinical Trials. Drug Information 
Journal, 42, 303-319. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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Mallinckrodt C. H., Roger J., Chuang-Stein C., Molenberghs G., O'Kelly M., Ratitch B., 
Janssens M., Bunouf P. 2013. Recent Developments in the Prevention and Treatment of Missing 
Data. Drug Information Journal, 48, 68-80. 
Molenberghs G., Thijs H., Jansen I., et al. 2004. Analyzing incomplete longitudinal clinical trial 
data. Biostatistics, 5, 445-464. 
Molenberghs G., Kenward M. G. 2007. Missing Data in Clinical Studies. New York: Wiley. 
PedsQL (2021). The PedsQL Measurement Model for the Pediatric Quality of Life Inventory – 
Scoring Instructions (www.pedsql.org)  
RSS (2014). The Royal Statistical Society: Code of Conduct, 2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
Schafer J. L. 1997. Analysis of Incomplete Multivariate Data. New Yori: Chapman & Hall. 
Siddiqui O., Hung H. M., O'Neill R. 2009. MMRM vs. LOCF: a comprehensive comparison 
based on simulation study and 25 NDA datasets. Journal of Biopharmaceuticals Statistics, 19(2), 
227-246. 
Verbeke G., Molenberghs G. 2000. Linear Mixed Models for Longitudinal Data. New York: 
Springer. 
WHO (2000). World Health Organization growth charts – A SAS Program for the WHO Growth 
Charts (ages 0 to <2 years) (www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas-who.htm)  
13. 
Tables, Listings, and Figures 
All listings, tables, and figures will have a header showing the sponsor company name (Mirum 
Pharmaceuticals, Inc.) and protocol (MRX-502), and 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. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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• Adverse events 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. Adverse events 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=xxx), 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, 
minimum, and maximum. Other summaries (e.g., number missing, geometric mean, 
median, quartiles, 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. 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 protocol number MRX-502. The table numbers 
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, where 
possible. For cases where multiple study visits for the same parameter are tested, those visits are 
consolidated on a single table for ease of review and referencing results. Similarly, for cases 
where multiple analysis populations or cohort groups are presented, this data will be consolidated 
on a single table, when practical. 
The table shells will be provided under a separate document. 
13.1.1. Subject Data 
Table 3:  Subject Data Summary Tables 
Number 
Population 
Title 
14.1.1.1 
All Subjects 
Subject Disposition 
14.1.1.2 
Safety 
Number of Randomized and Completed Subjects by Country 


 
Statistical Analysis Plan,  
 
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Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
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14.1.1.3 
Safety 
Number of Randomized and Completed Subjects by Investigative Site 
14.1.2 
Safety 
Important Protocol Violations/Deviations 
14.1.3 
Safety 
Demographics and Baseline Characteristics 
14.1.4 
Safety 
Disease History and Baseline Disease Characteristics 
14.1.5 
Safety 
Prior Medications/Therapies 
14.1.6 
Safety 
Study Drug Compliance 
13.1.2. Efficacy Data  
Table 4:  Efficacy Data Summary Tables 
Number 
Population 
Title 
14.2.1.x  Primary Analysis 
14.2.1.1 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.1.2 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Obs) Severity Score 
MMRM Model Effects 
14.2.2.x  Secondary Analysis 
14.2.2.1.1 
ITT – PFIC Cohort Change from Baseline in ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.2.1.2 
ITT – PFIC Cohort Change from Baseline in ItchRO(Obs) Severity Score 
MMRM Model Effects 
14.2.2.2.1 
ITT 
Change from Baseline in Total sBA (µmol/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.2.2.2 
ITT 
Change from Baseline in Total sBA (µmol/L) 
MMRM Model Effects 
14.2.2.3 
ITT 
Proportion of Responders 
14.2.3.x  Sensitivity Analysis 
14.2.3.1.1 
ITT 
Change from Baseline in Morning ItchRO(Obs) Severity Score – 
Sibling Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.3.1.2 
ITT 
Change from Baseline in Morning ItchRO(Obs) Severity Score – 
Sibling Sensitivity Analysis 
MMRM Model Effects 


 
Statistical Analysis Plan,  
 
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Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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Number 
Population 
Title 
14.2.3.2 
ITT 
Change from Baseline in Morning ItchRO(Obs) Severity Score – 
Multiple Imputation Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.3.3 
ITT 
Change from Baseline in Morning ItchRO(Obs) Severity Score to 
Average of Last 12 Weeks – Tipping Point Sensitivity Analysis 
14.2.3.4.1 
ITT 
Change from Baseline in Total sBA (µmol/L) – Sibling Sensitivity 
Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.3.4.2 
ITT 
Change from Baseline in Total sBA (µmol/L) – Sibling Sensitivity 
Analysis 
MMRM Model Effects 
14.2.3.5 
ITT 
Change from Baseline in Total sBA (µmol/L) – Multiple Imputation 
Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.3.6 
ITT 
Change from Baseline in Total sBA (µmol/L) to Average of Weeks 18, 
22, and 26 – Tipping Point Sensitivity Analysis 
14.2.4.x  Exploratory Analysis 
14.2.4.1.1 
PP – Primary Cohort Change from Baseline in Morning ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.1.2 
PP – Primary Cohort Change from Baseline in Morning ItchRO(Obs) Severity Score 
MMRM Model Effects 
14.2.4.2.1 
PP – Primary Cohort Change from Baseline in Total sBA (µmol/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.2.2 
PP – Primary Cohort Change from Baseline in Total sBA (µmol/L) 
MMRM Model Effects 
14.2.4.3.1 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score 
Descriptive Statistics by Analysis Week 
14.2.4.3.2 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score by Region 
Descriptive Statistics by Analysis Week 
14.2.4.3.3 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score by Age at Baseline 
Descriptive Statistics by Analysis Week 


 
Statistical Analysis Plan,  
 
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Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
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Number 
Population 
Title 
14.2.4.3.4 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score by Sex 
Descriptive Statistics by Analysis Week 
14.2.4.3.5 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score by Race 
Descriptive Statistics by Analysis Week 
14.2.4.3.6 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score by Baseline Median sBA 
Descriptive Statistics by Analysis Week 
14.2.4.3.7 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score by Baseline UDCA Usage 
Descriptive Statistics by Analysis Week 
14.2.4.3.8 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score by Baseline Rifampicin Usage 
Descriptive Statistics by Analysis Week 
14.2.4.3.9 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning ItchRO(Obs) 
Severity Score by BSEP Type 
Descriptive Statistics by Analysis Week 
14.2.4.4.1 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) 
Descriptive Statistics by Analysis Week 
14.2.4.4.2 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Region 
Descriptive Statistics by Analysis Week 
14.2.4.4.3 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Age at Baseline 
Descriptive Statistics by Analysis Week 
14.2.4.4.4 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Sex 
Descriptive Statistics by Analysis Week 
14.2.4.4.5 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Race 
Descriptive Statistics by Analysis Week 
14.2.4.4.6 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Baseline Median sBA 
Descriptive Statistics by Analysis Week 
14.2.4.4.7 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Baseline UDCA Usage 
Descriptive Statistics by Analysis Week 
14.2.4.4.8 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Baseline Rifampicin 
Usage 
Descriptive Statistics by Analysis Week 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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Number 
Population 
Title 
14.2.4.4.9 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by BSEP Type 
Descriptive Statistics by Analysis Week 
14.2.4.5.1 
ITT 
Change from Baseline in ALT (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.5.2 
ITT 
Change from Baseline in ALT (U/L) 
MMRM Model Effects 
14.2.4.6.1 
ITT 
Change from Baseline in AST (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.6.2 
ITT 
Change from Baseline in AST (U/L) 
MMRM Model Effects 
14.2.4.7.1 
ITT 
Change from Baseline in Total Bilirubin (mg/dL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.7.2 
ITT 
Change from Baseline in Total Bilirubin (mg/dL) 
MMRM Model Effects 
14.2.4.8.1 
ITT 
Change from Baseline in Direct Bilirubin (mg/dL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.8.2 
ITT 
Change from Baseline in Direct Bilirubin (mg/dL) 
MMRM Model Effects 
14.2.4.9.1 
ITT 
Change from Baseline in ALP (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.9.2 
ITT 
Change from Baseline in ALP (U/L) 
MMRM Model Effects 
14.2.4.10.1 
ITT 
Change from Baseline in GGT (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.10.2 
ITT 
Change from Baseline in GGT (U/L) 
MMRM Model Effects 
14.2.4.11.1 
ITT 
Change from Baseline in FIB-4 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.11.2 
ITT 
Change from Baseline in FIG-4 
MMRM Model Effects 
14.2.4.12.1 
ITT 
Change from Baseline in APRI 
Tabulation of Fitted Summary Statistics from MMRM 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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Number 
Population 
Title 
14.2.4.12.2 
ITT 
Change from Baseline in APRI 
MMRM Model Effects 
14.2.4.13.1 
ITT 
Change from Baseline in PELD 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.13.2 
ITT 
Change from Baseline in PELD 
MMRM Model Effects 
14.2.4.14 
ITT 
Total sBA Shift from Baseline:  Number and Proportion of Subjects 
14.2.4.15 
ITT 
Number of Days Morning ItchRO(Obs) Severity Score ≤1 
Over the Last 84 Study Days 
14.2.4.16 
ITT 
Number and Proportion of Subjects with Morning ItchRO(Obs) Severity 
Score ≤1 for >50% of Time Period 
14.2.4.17.1.1 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Obs) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.17.1.2 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Obs) Frequency Score 
MMRM Model Effects 
14.2.4.17.2.1 
ITT – PFIC Cohort Change from Baseline in ItchRO(Obs) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.17.2.2 
ITT – PFIC Cohort Change from Baseline in ItchRO(Obs) Frequency Score 
MMRM Model Effects 
14.2.4.18.1.1 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Pt) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.18.1.2 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Pt) Severity Score 
MMRM Model Effects 
14.2.4.18.2.1 
ITT – PFIC Cohort Change from Baseline in ItchRO(Pt) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.18.2.2 
ITT – PFIC Cohort Change from Baseline in ItchRO(Pt) Severity Score 
MMRM Model Effects 
14.2.4.19.1.1 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Pt) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.19.1.2 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Pt) Frequency Score 
MMRM Model Effects 
14.2.4.19.2.1 
ITT – PFIC Cohort Change from Baseline in ItchRO(Pt) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 79 of 89 
 
Number 
Population 
Title 
14.2.4.19.2.2 
ITT – PFIC Cohort Change from Baseline in ItchRO(Pt) Frequency Score 
MMRM Model Effects 
14.2.4.20.1 
ITT 
Change from Baseline in Clinician Scratch Scale (CSS) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.20.2 
ITT 
Change from Baseline in Clinician Scratch Scale (CSS) 
MMRM Model Effects 
14.2.4.21.1 
ITT 
Change from Baseline in Caregiver Impression of Severity (CIS) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.21.2 
ITT 
Change from Baseline in Caregiver Impression of Severity (CIS) 
MMRM Model Effects 
14.2.4.22.1 
ITT 
Change from Baseline in Patient Impression of Severity (PIS) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.22.2 
ITT 
Change from Baseline in Patient Impression of Severity (PIS) 
MMRM Model Effects 
14.2.4.23.1.1 
ITT – Primary 
Cohort 
Change from Baseline in EDQ(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.23.1.2 
ITT – Primary 
Cohort 
Change from Baseline in EDQ(Obs) Severity Score 
MMRM Model Effects 
14.2.4.23.2.1 
ITT – PFIC Cohort Change from Baseline in EDQ(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.23.2.2 
ITT – PFIC Cohort Change from Baseline in EDQ(Obs) Severity Score 
MMRM Model Effects 
14.2.4.24.1 
ITT 
Change from Baseline in Morning EDQ(Obs) Sleep Disturbance Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.24.2 
ITT 
Change from Baseline in Morning EDQ(Obs) Sleep Disturbance Score 
MMRM Model Effects 
14.2.4.25 
ITT 
Number and Proportion of Subjects with Improvement from Baseline in 
Morning EDQ(Obs) Sleep Disturbance Score 
14.2.4.26 
ITT 
Number and Proportion of Subjects with Morning EDQ(Obs) Sleep 
Disturbance Scores ≤2 from Post-Baseline through Week 26 
14.2.4.27.1 
ITT 
Change from Baseline in PedsQL Total Scale Score 
Tabulation of Fitted Summary Statistics from MMRM 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 80 of 89 
 
Number 
Population 
Title 
14.2.4.27.2 
ITT 
Change from Baseline in PedsQL Total Scale Score 
MMRM Model Effects 
14.2.4.28.1 
ITT 
Change from Baseline in Height z-Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.28.2 
ITT 
Change from Baseline in Height z-Score 
MMRM Model Effects 
14.2.4.29.1 
ITT 
Change from Baseline in Weight z-Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.29.2 
ITT 
Change from Baseline in Weight z-Score 
MMRM Model Effects 
14.2.4.30.1 
ITT 
Percent Change from Baseline in Total sBA 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.30.2 
ITT 
Percent Change from Baseline in Total sBA 
MMRM Model Effects 
14.2.4.31.1 
ITT 
Change from Baseline in 7 Alpha-hydroxy-4-cholesten-3-one (C4), 
ng/mL 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.31.2 
ITT 
Change from Baseline in 7 Alpha-hydroxy-4-cholesten-3-one (C4), 
ng/mL 
MMRM Model Effects 
14.2.4.32.1 
ITT 
Change from Baseline in Fibroblast Growth Factor 19 (pg/mL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.32.2 
ITT 
Change from Baseline in Fibroblast Growth Factor 19 (pg/mL) 
MMRM Model Effects 
14.2.4.33.1 
ITT 
Change from Baseline in Autotaxin (ng/mL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.33.2 
ITT 
Change from Baseline in Autotaxin (ng/mL) 
MMRM Model Effects 
14.2.4.34.1 
ITT 
Change from Baseline in Albumin (g/dL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.34.2 
ITT 
Change from Baseline in Albumin (g/dL) 
MMRM Model Effects 
14.2.4.35 
ITT 
Time to First Liver-Associated Event (Days) 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 81 of 89 
 
13.1.3. Safety Data 
Table 5:  Safety Data Summary Tables 
Number 
Population 
Title 
14.3.1 Study Drug Exposure 
14.3.1 
Safety 
Maralixibat Exposure 
14.3.2 Displays of Adverse Events 
14.3.2.1.1 
Safety 
Overall Summary of Treatment-Emergent Adverse Events 
14.3.2.1.2 
Safety 
Overall Summary of Treatment-Emergent Adverse Events by Age 
Group 
14.3.2.1.3 
Safety 
Overall Summary of Treatment-Emergent Adverse Events by Sex 
14.3.2.1.4 
Safety 
Overall Summary of Treatment-Emergent Adverse Events by Race 
14.3.2.2.1 
Safety 
Incidence of Treatment-Emergent Adverse Events 
14.3.2.2.2 
Safety 
Incidence of Treatment-Emergent Adverse Events by Age Group 
14.3.2.2.3 
Safety 
Incidence of Treatment-Emergent Adverse Events by Sex 
14.3.2.2.4 
Safety 
Incidence of Treatment-Emergent Adverse Events by Race 
14.3.3 Summary of Deaths, Other Serious and Significant Adverse Events 
14.3.3.1 
Safety 
Incidence of Treatment-Emergent Serious Adverse Events 
14.3.3.2 
Safety 
Incidence of Treatment Related Adverse Events 
14.3.3.3 
Safety 
Incidence of Treatment Related Adverse Events Leading to Permanent 
Discontinuation of Study Drug 
14.3.3.4.1 
Safety 
Incidence of Events of Clinical Interest – Diarrhoea Events 
14.3.3.4.2 
Safety 
Incidence of Events of Clinical Interest – LSV Deficiency Events 
14.3.3.4.3 
Safety 
Incidence of Events of Clinical Interest – Elevated Transaminases 
14.3.3.4.4 
Safety 
Incidence of Events of Clinical Interest – Elevated Bilirubin 
14.3.4 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
14.3.4.1 
Safety 
Listing of Serious Adverse Events 
14.3.4.2 
Safety 
Listing of Adverse Events Leading to Permanent Discontinuation of 
Study Drug 
14.3.4.3 
Safety 
Listing of Deaths 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 82 of 89 
 
Number 
Population 
Title 
14.3.5 Laboratory Data Summary Tables 
14.3.5.1 
Safety 
Summary of Safety Laboratory Data:  Chemistry 
14.3.5.2 
Safety 
Summary of Safety Laboratory Data:  Hematology 
14.3.5.3 
Safety 
Summary of Safety Laboratory Data:  Lipid Panel 
14.3.5.4 
Safety 
Summary of Safety Laboratory Data:  Lipid Soluble Vitamins (LSV) 
14.3.5.5 
Safety 
Summary of Safety Laboratory Data:  Alpha-Fetoprotein (ng/mL) 
14.3.5.6 
Safety 
Shift Table for Select Safety Laboratory Tests 
14.3.6 Physical Examination, Vital Signs, and ECG Safety Data Summary Tables 
14.3.6.1 
Safety 
Summary of Subject Height, Weight, and BMI z-Scores 
14.3.6.2 
Safety 
Summary of Vital Signs 
14.3.6.3.1 
Safety 
Summary of Electrocardiogram Parameters 
14.3.6.3.2 
Safety 
Summary of Electrocardiogram Interpretation 
14.3.7 Other Safety Data Summary Tables 
14.3.7 
Safety 
Summary of Concomitant Therapies/Medications 
13.1.4. Other Data 
Table 6:  Other Data Summary Tables 
Number 
Population 
Title 
14.4 Other Data Summary Tables 
14.4.1 
Safety 
Summary of Healthcare Utilization Measures 
14.4.2 
Safety 
Summary of Plasma Sample Maralixibat Concentrations (ng/mL) 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 83 of 89 
 
13.2. Planned Figure Descriptions 
The following are planned summary figures for protocol number MRX-502. The figure numbers 
are place holders only and will be determined when the figures are produced. 
Estimates from the MMRM model (over time) will be graphically displayed for select efficacy 
variables in the ITT population for the primary and PFIC cohorts, separately. These plots will 
display the LS Mean ±SE for each treatment group at each analysis visit/time period, as 
appropriate. Each of the treatment group LS means will be displayed side-by-side, with vertical 
lines emanating from each LS Mean to represent the standard error. At minimum, these graphical 
displays will be presented for the change from baseline in morning ItchRO(Obs) severity score 
and change from baseline in sBA levels, over time. The number of subjects with non-missing 
change from baseline values, for each treatment group and analysis visit, will be displayed along 
the horizontal axis at each time point, baseline through Week 26. 
Tipping point results, for the sensitivity analysis of the primary efficacy endpoint and the key 
secondary efficacy endpoint, will be presented in a heatmap. This figure will be generated to 
display p-values corresponding to all combinations of shifts from the imputed data. For the 
heatmap figure, each cell will be colored according to the p-value: green for p-values < 0.05; 
yellow for p-values of 0.05 to < 0.10; orange for p-values of 0.10 to < 0.20; and red for p-values 
of 0.20 to 1.00. 
Additional figures may be added post-hoc to further examine study data. 
13.2.1. Efficacy Data  
Table 7:  Efficacy Data Summary Figures 
Number 
Population 
Title 
14.2.1.x  Primary Analysis 
14.2.1.1 
ITT – Primary 
Cohort 
Plot of MMRM LS Mean (± SE) Change from Baseline in Morning 
ItchRO(Obs) Severity Score Over Time 
14.2.2.x  Secondary Analysis 
14.2.2.2.1 
ITT – Primary 
Cohort 
Plot of MMRM LS Mean (± SE) Change from Baseline in Total sBA 
(µmol/L) Over Time 
14.2.3.x  Sensitivity Analysis 
14.2.3.3 
ITT – Primary 
Cohort 
Heatmap Displaying p-values from Tipping Point Analysis on Change 
from Baseline in Morning ItchRO(Obs) Severity Score to Average of 
Last 12 Weeks 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 84 of 89 
 
Number 
Population 
Title 
14.2.3.6 
ITT – Primary 
Cohort 
Heatmap Displaying p-values from Tipping Point Analysis on Change 
from Baseline in Total sBA (µmol/L) to Average of Weeks 18, 22, 
and 26 
13.3. Planned Listing Descriptions 
In general, listings produced will include the participant data collected on associated CRF pages. 
All listings will be sorted by treatment, PFIC type, and subject ID. For safety data (i.e., study 
drug exposure, AEs, vital signs, laboratory tests, ECG, physical examination, and plasma 
maralixibat concentration levels), listings will be presented by treatment received. For all other 
listings (including efficacy laboratory tests), where applicable, data will be presented by 
randomized treatment group.  
For listings of efficacy variables, change from baseline values will be included, as appropriate. 
For adverse event listings, study day relative to the date of first dose of study drug will be 
provided along with stop and start dates. The dose of study drug at the onset of AEs in the 
maralixibat treatment group will also be provided. For partial event dates, study day will be 
derived using an imputed date as described in Section 6.1.9.   
Study day relative to the first dose of study drug will also be included on laboratory listings, 
along with laboratory collection dates, and on study drug exposure listings, along with start and 
stop dates. 
For the concomitant treatment listing, medications that are ongoing at the time of informed 
consent will be indicated. 
Weight, height, and BMI will be presented in the vital signs listing, rather than the physical 
examination listing. 
PedsQL listings will present total scale and summary scores, including PedsQL Total Scale 
Score, Physical Health Summary Score, Psychosocial Health Summary Score, Multidimensional 
Fatigue Scale Score, Family Impact Total Scale Score, Parent Functioning Summary Score, and 
Family Impact Summary Score. Subject listings of PedsQL raw scores for each of the model 
items will not be included. 
Assessments denoted as clinic visit “Week 26/ET” in listings will include assessments performed 
at the Early Termination visit for participants who withdraw early from the study. 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 85 of 89 
 
In all listings a blank line will be placed between participants. Within a data listing, if an item 
appears line after line (e.g., repetition of participant number), then only the first occurrence will 
be displayed. 
The listing shells will be provided under a separate document. 
13.4. Standard Layout for all Tables, Listings, and Figures 
The following standard layout will be applied to all Tables, Listings, and Figures (TLFs) in 
support of this study. Note that programming notes may be added if appropriate after each TLF 
shell.  
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 86 of 89 
 
Figure 2.   Standardized Layout 
Mirum Pharmaceuticals Inc. 
Page xx of xx 
Protocol: MRX-502 
Version xxxxx 
 
<Table, Listing, Figure> xx.x.x 
<Title of Table Listing or Figure> 
<Study Population and if applicable subgroup Description> 
____________________________________________________________________________________________________________ 
 
 
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> 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 87 of 89 
 
Appendix 1:  Listing of Safety and Efficacy Laboratory Analytes 
SAFETY LABS 
Hematology 
Erythrocytes (RBC), 
106/µL 
Hemoglobin, g/dL 
Hematocrit, % 
MCV, fL 
MCH, pg 
MCHC, g/dL 
Platelets, 103/µL 
Leukocytes (WBC), 
103/µL 
Differential  
(% and 103/µL) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
 
 
Clinical Chemistry 
Sodium, mEq/L 
Potassium, mEq/L 
Chloride, mEq/L 
Bicarbonate, mEq/L 
Protein, g/dL 
Calcium, mg/dL 
Phosphate, mg/dL 
Glucose, mg/dL 
Lipase, U/L 
BUN, mg/dL 
Creatinine, mg/dL 
Urate, mg/dL 
Corrected Sodium, 
mEq/L [3] 
Amylase, U/L 
Measured Osmolality, 
mOsm/kg 
Calculated Osmolality, 
mOsm/kg [3] 
Osmolar Gap, 
mOsm/kg [3] 
Anion Gap, mEq/L [3] 
 
 
Lipid Panel 
Triglycerides, mg/dL 
Cholesterol, mg/dL 
LDL-C, mg/dL 
HDL-C, mg/dL [1] 
Lipid Soluble Vitamins 
25-Hydroxy Vitamin D, ng/mL 
Vitamin A (retinol), µg/dL 
Retinol Binding Protein (RBP), 
mg/dL 
Alpha Tocopherol, mg/dL 
INR (surrogate marker for 
Vitamin K deficiency) 
Retinol: RBP Molar Ratio, 
mol/mol [3] 
Ratio of Alpha Tocopherol to 
the sum of Cholesterol and 
Triglycerides, mg/g [3] 
aPTT, sec (surrogate for LSV) 
PT, sec (surrogate for LSV) 
Marker of hepatocellular 
carcinoma 
Alpha-Fetoprotein (AFP), 
ng/mL 
 
 
Urinalysis [1] 
pH 
Specific Gravity 
Renal Epithelial Cells, /HPF 
Squamous Epithelial Cells, 
/HPF 
Granular Casts, /LPF 
Hyaline Casts, /LPF 
RBC Casts, /LPF 
Erythrocytes, /HPF 
Leukocytes, /HPF 
WBC Casts, /LPF 
Waxy Casts, /LPF 
Protein * 
Glucose * 
Ketones * 
Bilirubin * 
Nitrite * 
Urobilinogen * 
Leukocyte Esterase * 
Calcium Oxalate Crystals * 
Triple Phosphate Crystals * 
Uric Acid Crystals * 
Bacteria * 
Creatinine * 
Transitional Epithelial Cells * 
Occult Blood * 
Yeast Cells * 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 88 of 89 
 
EFFICACY LABS 
Clinical Chemistry 
Total Bilirubin, 
mg/dL [2] 
Direct Bilirubin 
(conjugated), 
mg/dL [2] 
ALT, U/L [2] 
AST, U/L [2] 
ALP, U/L [2] 
GGT, U/L [2] 
Albumin, g/dL [2] 
APRI [3] 
FIB-4 [3] 
PELD [3] 
MELD [3] 
 
 
 
 
 
 
Cholestasis Biomarkers 
Serum Bile Acids, µmol/L [2] 
7 alpha-hydroxy-4-cholesten-3-one (C4), ng/mL 
Autotaxin, ng/mL 
FGF-19, pg/mL [2] 
Bile Acid Subspecies, µmol/L 
   (15 subspecies) [1] 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; APRI = 
AST to platelet ratio index; AST = aspartate aminotransferase; FGF-19 = fibroblast growth factor 19; FIB-4 = fibrosis-4; 
GGT = gamma-glutamyl transferase; PT = prothrombin time; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; MELD = model for end-stage liver disease; PELD = pediatric end-
stage liver disease; WBC = white blood cell; * Qualitative urinalysis 
[1] Listing only 
[2] Safety and efficacy lab tests 
[3] Calculated lab parameters (see Sec 6.1.8);  
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Mirum Pharmaceuticals Inc.  
 
Protocol Number MRX-502 (Amendment 4) 
 
PCN Number MIRU8967 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
 
Final Version 2.0    |    29-Sep-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 89 of 89 
 
Appendix 2:  Listing of Lipid Soluble Vitamin Deficiency Events 
The following MedDRA Preferred Terms associated with lipid soluble vitamin (LSV) 
deficiency events are included as an AECI: 
- Vitamin A deficiency  
- Vitamin A abnormal 
- Vitamin A decreased 
- Vitamin D deficiency 
- Vitamin D abnormal 
- Vitamin D decreased 
- Vitamin E deficiency 
- Vitamin E decreased 
- Vitamin K deficiency 
- Vitamin K decreased 
- International normalised ratio increased 
- International normalised ratio abnormal 
- Blood 1,25-dihydroxycholecalciferol decreased 
- Blood 25-hydroxycholecalciferol decreased 


 
Table Shells 
 
Sponsor:  Mirum Pharmaceuticals Inc.  
 
Protocol:  Maralixibat-502 (Amendment 4)  
 
PCN Number: MIRU8967 
 
 
Sponsor 
Mirum Pharmaceuticals Inc. 
Protocol Title: 
Randomized Double-blind Placebo-controlled Phase 3 Study to 
Evaluate the Efficacy and Safety of Maralixibat in the Treatment 
of Children with Progressive Familial Intrahepatic Cholestasis 
(PFIC) – MARCH-PFIC 
Protocol Number: 
MRX-502 (Amendment 4) 
 
Premier Research PCN: 
MIRU8967 
Document Author: 
Jana Steinmetz 
Document Version: 
Final 1.0 
Document Date:  
09Oct2022 
 
 
 


 
Table Shells  
 
Sponsor:  Mirum Pharmaceuticals Inc.  
 
Protocol:  MRX-502 (Amendment 4)  
 
PCN Number:  MIRU8967 
 
CONFIDENTIAL  
Page 2 of 99 
1. 
Table Conventions, Titles, and Shells 
All tables will have a page header showing the sponsor company name (Mirum Pharmaceuticals 
Inc.) and protocol (MRX-502), and 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 will be developed in landscape orientation. 
• Abbreviations, general note, specific item footnotes, and source of data (as applicable), in 
this order, will be presented on each page of a table. 
• In general, specialized text styles, such as bolding, italics, borders, shading, and 
superscripted and subscripted text will not be used in tables unless they add significant 
value.  
• Only standard keyboard characters will be used in the tables. Special characters, such as 
nonprintable control characters, printer-specific characters, or font specific characters, 
will not be used. 
• Adverse events with missing MedDRA coding will have their system organ class and/or 
preferred term presented as “Not Coded”. The “Not Coded” frequencies will be sorted to 
the end of the tables. Adverse events 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 cohort, treatment group, subgroup, and 
classification factor, where appropriate, as totals in the column header as (N=xxx).  
• All population summaries for categorical variables will include all categories that were 
planned and for which the subjects 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. 
• In general, population summaries for continuous variables will include: n, mean, SD, SE, 
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, median, Q1, and Q3 will have 1 additional decimal 
place. The SD will have 2 additional decimal places. 
• All percentages are rounded and reported to a single decimal point (xx.x%).  


 
Table Shells  
 
Sponsor:  Mirum Pharmaceuticals Inc.  
 
Protocol:  MRX-502 (Amendment 4)  
 
PCN Number:  MIRU8967 
 
CONFIDENTIAL  
Page 3 of 99 
1.1. 
Planned Table Descriptions 
The following are planned summary tables for protocol number MRX-502. The table numbers 
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 the SAP, where 
possible. For cases where multiple subject cohorts or, in the case of ItchRO and EDQ morning, 
evening, and highest daily scores are presented, data columns are consolidated on a single table, 
when practical, for ease of review and referencing results. 
1.1.1. Subject Data 
Table 1:  Subject Data Summary Tables 
Number 
Population 
Title 
14.1.1.1 
All Subjects Subject Disposition 
14.1.1.2 
Safety 
Number of Randomized and Completed Subjects by 
Country 
14.1.1.3 
Safety 
Number of Randomized and Completed Subjects by 
Investigative Site 
14.1.2 
Safety 
Important Protocol Violations/Deviations 
14.1.3 
Safety 
Demographics and Baseline Characteristics 
14.1.4 
Safety 
Disease History and Baseline Disease Characteristics 
14.1.5 
Safety 
Prior Medications/Therapies 
14.1.6 
Safety 
Study Drug Compliance 
1.1.2. Efficacy Data  
Table 2:  Efficacy Data Summary Tables 
Number 
Population 
Title 
14.2.1.x  Primary Analysis 
14.2.1.1 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.1.2 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Obs) Severity Score 
MMRM Model Effects 
14.2.2.x  Secondary Analysis 
14.2.2.1.1 
ITT – PFIC 
Cohort 
Change from Baseline in ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 


 
Table Shells  
 
Sponsor:  Mirum Pharmaceuticals Inc.  
 
Protocol:  MRX-502 (Amendment 4)  
 
PCN Number:  MIRU8967 
 
CONFIDENTIAL  
Page 4 of 99 
Number 
Population 
Title 
14.2.2.1.2 
ITT – PFIC 
Cohort 
Change from Baseline in ItchRO(Obs) Severity Score 
MMRM Model Effects 
14.2.2.2.1 
ITT 
Change from Baseline in Total sBA (µmol/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.2.2.2 
ITT 
Change from Baseline in Total sBA (µmol/L) 
MMRM Model Effects 
14.2.2.3 
ITT 
Proportion of Responders 
14.2.3.x  Sensitivity Analysis 
14.2.3.1.1 
ITT 
Change from Baseline in Morning ItchRO(Obs) Severity Score – 
Sibling Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.3.1.2 
ITT 
Change from Baseline in Morning ItchRO(Obs) Severity Score – 
Sibling Sensitivity Analysis 
MMRM Model Effects 
14.2.3.2 
ITT 
Change from Baseline in Morning ItchRO(Obs) Severity Score – 
Multiple Imputation Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.3.3 
ITT 
Change from Baseline in Morning ItchRO(Obs) Severity Score 
to Average of Last 12 Weeks – Tipping Point Sensitivity 
Analysis 
14.2.3.4.1 
ITT 
Change from Baseline in Total sBA (µmol/L) – Sibling 
Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.3.4.2 
ITT 
Change from Baseline in Total sBA (µmol/L) – Sibling 
Sensitivity Analysis 
MMRM Model Effects 
14.2.3.5 
ITT 
Change from Baseline in Total sBA (µmol/L) – Multiple 
Imputation Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.3.6 
ITT 
Change from Baseline in Total sBA (µmol/L) to Average of 
Weeks 18, 22, and 26 – Tipping Point Sensitivity Analysis 


 
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Number 
Population 
Title 
14.2.4.x  Exploratory Analysis 
14.2.4.1.1 
PP – Primary 
Cohort 
Change from Baseline in Morning ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.1.2 
PP – Primary 
Cohort 
Change from Baseline in Morning ItchRO(Obs) Severity Score 
MMRM Model Effects 
14.2.4.2.1 
PP – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.2.2 
PP – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) 
MMRM Model Effects 
14.2.4.3.1 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score 
Descriptive Statistics by Analysis Week 
14.2.4.3.2 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score by Region 
Descriptive Statistics by Analysis Week 
14.2.4.3.3 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score by Age at Baseline 
Descriptive Statistics by Analysis Week 
14.2.4.3.4 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score by Sex 
Descriptive Statistics by Analysis Week 
14.2.4.3.5 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score by Race 
Descriptive Statistics by Analysis Week 
14.2.4.3.6 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score by Baseline Median sBA 
Descriptive Statistics by Analysis Week 
14.2.4.3.7 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score by Baseline UDCA Usage 
Descriptive Statistics by Analysis Week 


 
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Number 
Population 
Title 
14.2.4.3.8 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score by Baseline Rifampicin Usage 
Descriptive Statistics by Analysis Week 
14.2.4.3.9 
ITT – Primary 
Cohort 
Change from Baseline in Weekly Average Morning 
ItchRO(Obs) Severity Score by BSEP Type 
Descriptive Statistics by Analysis Week 
14.2.4.4.1 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) 
Descriptive Statistics by Analysis Week 
14.2.4.4.2 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Region 
Descriptive Statistics by Analysis Week 
14.2.4.4.3 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Age at Baseline 
Descriptive Statistics by Analysis Week 
14.2.4.4.4 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Sex 
Descriptive Statistics by Analysis Week 
14.2.4.4.5 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Race 
Descriptive Statistics by Analysis Week 
14.2.4.4.6 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Baseline 
Median sBA 
Descriptive Statistics by Analysis Week 
14.2.4.4.7 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Baseline 
UDCA Usage 
Descriptive Statistics by Analysis Week 
14.2.4.4.8 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by Baseline 
Rifampicin Usage 
Descriptive Statistics by Analysis Week 
14.2.4.4.9 
ITT – Primary 
Cohort 
Change from Baseline in Total sBA (µmol/L) by BSEP Type 
Descriptive Statistics by Analysis Week 
14.2.4.5.1 
ITT 
Change from Baseline in ALT (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.5.2 
ITT 
Change from Baseline in ALT (U/L) 
MMRM Model Effects 


 
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Number 
Population 
Title 
14.2.4.6.1 
ITT 
Change from Baseline in AST (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.6.2 
ITT 
Change from Baseline in AST (U/L) 
MMRM Model Effects 
14.2.4.7.1 
ITT 
Change from Baseline in Total Bilirubin (mg/dL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.7.2 
ITT 
Change from Baseline in Total Bilirubin (mg/dL) 
MMRM Model Effects 
14.2.4.8.1 
ITT 
Change from Baseline in Direct Bilirubin (mg/dL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.8.2 
ITT 
Change from Baseline in Direct Bilirubin (mg/dL) 
MMRM Model Effects 
14.2.4.9.1 
ITT 
Change from Baseline in ALP (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.9.2 
ITT 
Change from Baseline in ALP (U/L) 
MMRM Model Effects 
14.2.4.10.1 
ITT 
Change from Baseline in GGT (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.10.2 
ITT 
Change from Baseline in GGT (U/L) 
MMRM Model Effects 
14.2.4.11.1 
ITT 
Change from Baseline in FIB-4 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.11.2 
ITT 
Change from Baseline in FIB-4 
MMRM Model Effects 
14.2.4.12.1 
ITT 
Change from Baseline in APRI 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.12.2 
ITT 
Change from Baseline in APRI 
MMRM Model Effects 
14.2.4.13.1 
ITT 
Change from Baseline in PELD 
Tabulation of Fitted Summary Statistics from MMRM 


 
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Number 
Population 
Title 
14.2.4.13.2 
ITT 
Change from Baseline in PELD 
MMRM Model Effects 
14.2.4.14 
ITT 
Total sBA Shift from Baseline:  Number and Proportion of 
Subjects 
14.2.4.15 
ITT 
Number of Days Morning ItchRO(Obs) Severity Score ≤1 
Over the Last 84 Study Days 
14.2.4.16 
ITT 
Number and Proportion of Subjects with Morning ItchRO(Obs) 
Severity Score ≤1 for >50% of Time Period 
14.2.4.17.1.1 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Obs) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.17.1.2 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Obs) Frequency Score 
MMRM Model Effects 
14.2.4.17.2.1 
ITT – PFIC 
Cohort 
Change from Baseline in ItchRO(Obs) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.17.2.2 
ITT – PFIC 
Cohort 
Change from Baseline in ItchRO(Obs) Frequency Score 
MMRM Model Effects 
14.2.4.18.1.1 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Pt) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.18.1.2 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Pt) Severity Score 
MMRM Model Effects 
14.2.4.18.2.1 
ITT – PFIC 
Cohort 
Change from Baseline in ItchRO(Pt) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.18.2.2 
ITT – PFIC 
Cohort 
Change from Baseline in ItchRO(Pt) Severity Score 
MMRM Model Effects 
14.2.4.19.1.1 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Pt) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.19.1.2 
ITT – Primary 
Cohort 
Change from Baseline in ItchRO(Pt) Frequency Score 
MMRM Model Effects 
14.2.4.19.2.1 
ITT – PFIC 
Cohort 
Change from Baseline in ItchRO(Pt) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 


 
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Number 
Population 
Title 
14.2.4.19.2.2 
ITT – PFIC 
Cohort 
Change from Baseline in ItchRO(Pt) Frequency Score 
MMRM Model Effects 
14.2.4.20.1 
ITT 
Change from Baseline in Clinician Scratch Scale (CSS) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.20.2 
ITT 
Change from Baseline in Clinician Scratch Scale (CSS) 
MMRM Model Effects 
14.2.4.21.1 
ITT 
Change from Baseline in Caregiver Impression of Severity (CIS) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.21.2 
ITT 
Change from Baseline in Caregiver Impression of Severity (CIS) 
MMRM Model Effects 
14.2.4.22.1 
ITT 
Change from Baseline in Patient Impression of Severity (PIS) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.22.2 
ITT 
Change from Baseline in Patient Impression of Severity (PIS) 
MMRM Model Effects 
14.2.4.23.1.1 
ITT – Primary 
Cohort 
Change from Baseline in EDQ(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.23.1.2 
ITT – Primary 
Cohort 
Change from Baseline in EDQ(Obs) Severity Score 
MMRM Model Effects 
14.2.4.23.2.1 
ITT – PFIC 
Cohort 
Change from Baseline in EDQ(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.23.2.2 
ITT – PFIC 
Cohort 
Change from Baseline in EDQ(Obs) Severity Score 
MMRM Model Effects 
14.2.4.24.1 
ITT 
Change from Baseline in Morning EDQ(Obs) Sleep Disturbance 
Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.24.2 
ITT 
Change from Baseline in Morning EDQ(Obs) Sleep Disturbance 
Score 
MMRM Model Effects 
14.2.4.25 
ITT 
Number and Proportion of Subjects with Improvement from 
Baseline in Morning EDQ(Obs) Sleep Disturbance Score 


 
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Number 
Population 
Title 
14.2.4.26 
ITT 
Number and Proportion of Subjects with Morning EDQ(Obs) 
Sleep Disturbance Scores ≤2 from Post-Baseline through Week 
26 
14.2.4.27.1 
ITT 
Change from Baseline in PedsQL Total Scale Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.27.2 
ITT 
Change from Baseline in PedsQL Total Scale Score 
MMRM Model Effects 
14.2.4.28.1 
ITT 
Change from Baseline in Height z-Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.28.2 
ITT 
Change from Baseline in Height z-Score 
MMRM Model Effects 
14.2.4.29.1 
ITT 
Change from Baseline in Weight z-Score 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.29.2 
ITT 
Change from Baseline in Weight z-Score 
MMRM Model Effects 
14.2.4.30.1 
ITT 
Percent Change from Baseline in Total sBA 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.30.2 
ITT 
Percent Change from Baseline in Total sBA 
MMRM Model Effects 
14.2.4.31.1 
ITT 
Change from Baseline in 7 Alpha-hydroxy-4-cholesten-3-one 
(C4), ng/mL 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.31.2 
ITT 
Change from Baseline in 7 Alpha-hydroxy-4-cholesten-3-one 
(C4), ng/mL 
MMRM Model Effects 
14.2.4.32.1 
ITT 
Change from Baseline in Fibroblast Growth Factor 19 (pg/mL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.32.2 
ITT 
Change from Baseline in Fibroblast Growth Factor 19 (pg/mL) 
MMRM Model Effects 
14.2.4.33.1 
ITT 
Change from Baseline in Autotaxin (ng/mL) 
Tabulation of Fitted Summary Statistics from MMRM 


 
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Number 
Population 
Title 
14.2.4.33.2 
ITT 
Change from Baseline in Autotaxin (ng/mL) 
MMRM Model Effects 
14.2.4.34.1 
ITT 
Change from Baseline in Albumin (g/dL) 
Tabulation of Fitted Summary Statistics from MMRM 
14.2.4.34.2 
ITT 
Change from Baseline in Albumin (g/dL) 
MMRM Model Effects 
14.2.4.35 
ITT 
Time to First Liver-Associated Event (Days) 
1.1.3. Safety Data 
Table 3:  Safety Data Summary Tables 
Number 
Population Title 
14.3.1  Study Drug Exposure 
14.3.1 
Safety 
Maralixibat Exposure 
14.3.2  Displays of Adverse Events 
14.3.2.1.1 
Safety 
Overall Summary of Treatment-Emergent Adverse Events 
14.3.2.1.2 
Safety 
Overall Summary of Treatment-Emergent Adverse Events by Age 
Group 
14.3.2.1.3 
Safety 
Overall Summary of Treatment-Emergent Adverse Events by Sex 
14.3.2.1.4 
Safety 
Overall Summary of Treatment-Emergent Adverse Events by Race 
14.3.2.2.1 
Safety 
Incidence of Treatment-Emergent Adverse Events 
14.3.2.2.2 
Safety 
Incidence of Treatment-Emergent Adverse Events by Age Group 
14.3.2.2.3 
Safety 
Incidence of Treatment-Emergent Adverse Events by Sex 
14.3.2.2.4 
Safety 
Incidence of Treatment-Emergent Adverse Events by Race 
14.3.3  Summary of Deaths, Other Serious and Significant Adverse Events 
14.3.3.1 
Safety 
Incidence of Treatment-Emergent Serious Adverse Events 
14.3.3.2 
Safety 
Incidence of Treatment Related Adverse Events 
14.3.3.3 
Safety 
Incidence of Treatment Related Adverse Events Leading to 
Permanent Discontinuation of Study Drug 
14.3.3.4.1 
Safety 
Incidence of Events of Clinical Interest – Diarrhoea Events 
14.3.3.4.2 
Safety 
Incidence of Events of Clinical Interest – LSV Deficiency Events 


 
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Number 
Population Title 
14.3.3.4.3 
Safety 
Incidence of Events of Clinical Interest – Elevated Transaminases 
14.3.3.4.4 
Safety 
Incidence of Events of Clinical Interest – Elevated Bilirubin 
14.3.4  Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
14.3.4.1 
Safety 
Listing of Serious Adverse Events 
14.3.4.2 
Safety 
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Drug 
14.3.4.3 
Safety 
Listing of Deaths 
14.3.5  Laboratory Data Summary Tables 
14.3.5.1 
Safety 
Summary of Safety Laboratory Data:  Chemistry 
14.3.5.2 
Safety 
Summary of Safety Laboratory Data:  Hematology 
14.3.5.3 
Safety 
Summary of Safety Laboratory Data:  Lipid Panel 
14.3.5.4 
Safety 
Summary of Safety Laboratory Data:  Lipid Soluble Vitamins 
(LSV) 
14.3.5.5 
Safety 
Summary of Safety Laboratory Data:  Alpha-Fetoprotein (ng/mL) 
14.3.5.6 
Safety 
Shift Table for Select Safety Laboratory Tests 
14.3.6  Physical Examination, Vital Signs, and ECG Safety Data Summary Tables 
14.3.6.1 
Safety 
Summary of Subject Height, Weight, and BMI z-Scores 
14.3.6.2 
Safety 
Summary of Vital Signs 
14.3.6.3.1 
Safety 
Summary of Electrocardiogram Parameters 
14.3.6.3.2 
Safety 
Summary of Electrocardiogram Interpretation 
14.3.7  Other Safety Data Summary Tables 
14.3.7 
Safety 
Summary of Concomitant Therapies/Medications 
1.1.4. Other Data 
Table 4:  Other Data Summary Tables 
Number 
Population Title 
14.4  Other Data Summary Tables 
14.4.1 
Safety 
Summary of Healthcare Utilization Measures 
14.4.2 
Safety 
Summary of Plasma Sample Maralixibat Concentrations (ng/mL) 
 
 


 
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1.2. 
Planned Table Shells 
 
 


 
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Table 14.1.1.1 
Subject Disposition 
All Subjects 
 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
Status or 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
   Variable/Statistic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Screened for Eligibility 
 
 
 
 
 
 
 
 
 
 
xx 
Screen Failure  
 
 
 
 
 
 
 
 
 
 
xx 
Randomized [1] 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
Families with Siblings enrolled 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
Total number of Siblings 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Population [2] 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
ITT Population [1, 3] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Per-Protocol Population [4] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Completed Study Treatment  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Discontinued Early [1] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: ITT = intent-to-treat; PEBD = partial external biliary diversion 
Note: Percentages are based on the number of subjects in the Safety Population. Siblings (within the same family) are assigned in a blinded manner to the same 
treatment group. 
[1] One subject (Subject 023004) was randomized in error within the IRT system on 14Sep2020, the date of the baseline visit. This subject was not dispensed study 
drug, and was discontinued from the study due to ‘administrative error’ on the baseline visit day. On 15Oct2022, this same subject was re-randomized as Subject 
023005. This subject is only counted once, as Subject 023005, in the Randomized and ITT Population groups, and not counted in the Discontinued Early group.  
[2] The Safety Population includes all subjects who receive at least 1 dose of study drug. 
[3] The ITT Population includes all randomized subjects. 
[4] The Per-Protocol population includes all subjects 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.  
Source:  Reference Listings xx.x.x, xx.x.x 
 
 


 
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Table 14.1.1.1 (Cont’d) 
Subject Disposition 
All Subjects 
 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
Status or 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
   Variable/Statistic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Reason for Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
     Adverse Event 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Death 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Lost to follow-up 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Non-compliance with study drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Lack of efficacy 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Physician decision 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Pregnancy 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Liver transplant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     PEBD surgery 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Protocol violation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Withdrawal of consent 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Study terminated by sponsor 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Disease Progression 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 14.1.1.2  
Number of Randomized and Completed Subjects by Country 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Country 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxxx  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx xxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N.  
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 
 


 
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Table 14.1.1.3  
Number of Randomized and Completed Subjects by Investigative Site 
Safety Population 
 
Programming Notes:  Repeat Table 14.1.1.2 with Investigative Site and change 1st column header to ‘Investigative Site ID’.) 
 
 
 


 
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Table 14.1.2  
Important Protocol Violations/Deviations 
Safety Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
  
Maralixibat 
Placebo 
Overall 
 
Maralixibat 
Placebo 
Overall 
 
Maralixibat 
Placebo 
Overall 
 Category/Type [1] 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Inclusion 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Exclusion 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Study Drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Overdose/misuse 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Prohibited co-medication  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Assessment – efficacy 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Assessment – safety 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Laboratory/endpoint data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Visit Window 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
etc…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N.  
[1] Important protocol violations/deviations are grouped based on study specific protocol deviation categories as described in the Protocol Deviation Guidance Plan 
for the Maralixibat-502 clinical protocol. Subjects were counted only once for each category/type. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 
 
 


 
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Table 14.1.3  
Demographics and Baseline Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Age (years) [1] 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Age Category [1] 
 
 
 
 
 
 
 
 
 
 
 
    1 to <6 years 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    6 to <13 years 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    13 to 18 years 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
 
 
 
 
 
 
 
 
 
 
 
    Male 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Female 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Note: Percentages are 100*n/N.  
[1] Age at baseline visit. 
[2] Height, weight, and BMI z-scores are based on a subject’s sex and age at the baseline visit. The World Health Organization (WHO) grouth charts were used to derive z-scores 
for subjects less than 24 months old and the Center for Disease Control (CDC) grouth charts were used to derive z-scores for subjects equal to or greater than 24 months old. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
Programming Note:  If a particular category (e.g., race, ethnicity) is not reported, add a category for “Not reported”. Subjects reporting more than 1 race will be counted in a 
“More than one race” category for purpose of tabulating summary statistics for race.  
 


 
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Table 14.1.3 (Cont’d)  
Demographics and Baseline Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Race 
 
 
 
 
 
 
 
 
 
 
 
    American Indian or Alaska Native 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Asian 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Black or African American 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Native Hawaiian or Other Pacific Islander 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    White 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    More than one race 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Not Reported 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
 
 
 
 
 
    Hispanic or Latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Not Hispanic or Latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Not Reported 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Region 
 
 
 
 
 
 
 
 
 
 
 
    Asia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Europe 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Middle East 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    North America 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    South and Central America 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 14.1.3 (Cont’d) 
Demographics and Baseline Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Height z-score [2] 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Weight z-score [2] 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 14.1.3 (Cont’d) 
Demographics and Baseline Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
BMI z-score [2] 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Page 23 of 99 
 
Table 14.1.4  
Disease History and Baseline Disease Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis PFIC Type [1] 
 
 
 
 
 
 
 
 
 
 
 
    nt-PFIC2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    nt-PFIC2-IsBA 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    nt-PFIC2-surg 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    t-PFIC2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC1-surg 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC4-surg 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC6 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
    nt-PFIC2-het 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC1-het 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
    No-variant-found 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile; UDCA = ursodeoxycholic acid 
Note: Percentages are 100*n/N, unless otherwise noted. Subjects with PFIC1 through PFIC6 all have the biallelic disease. 
[1] nt-PFIC2 = non-truncated PFIC2 (primary cohort); nt-PFIC2-IsBA = non-truncated PFIC2 with low or fluctuating serum bile acids; nt-PFIC2-surg = non-truncated PFIC2 with a history of 
surgery; t-PFIC2 = truncated PFIC2; PFIC1-surg = PFIC1 with a history of surgery; PFIC4-surg = PFIC4 with a history of surgery; nt-PFIC2-het = non-truncated PFIC2 with heterozygosis; 
PFIC1-het = PFIC1 with heterozygosis; No-variant-found = No established variant linked to PFIC disease 
[2] nt-PFIC2 = partial loss of BSEP function; t-PFIC2 = complete loss of BSEP function 
Only applicable for PFIC2 subjects, with exception of one nt-PFIC2 subject (015002) with heterozygosis ABCB11 mutation; N/A for all other subjects.  
[3] One subject (015002) had heterozygous ABCB11 mutation, and another (021006) had heterozygous ATP8B1 mutation. 
[4] Partial dates were imputed based on the SAP. 
[5] For the number and percent of subjects below and above the median baseline sBA level, the median is calculated separately for the Primary Cohort, PFIC Cohort, and All Subjects. 
[6] PELD score is calculated for children <12 years of age at the baseline visit; MELD score is calculated for children 12 years or older at the baseline visit. 
Source:  Reference Listings xx.x.x, xx.x.x 
 


 
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Page 24 of 99 
 
Table 14.1.4 (Cont’d)  
Disease History and Baseline Disease Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=93) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis PFIC Type (genotype) 
 
 
 
 
 
 
 
 
 
 
 
    PFIC2 (ABCB11) [2] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        nt-PFIC2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
            BSEP1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
            BSEP2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        t-PFIC2 (BSEP3) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC1 (ATP8B1) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC3 (ABCB4) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC4 (TJP2) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PFIC6 (MYO5B) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Heterozygous variant [3]  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    No-variant-found 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Liver masses detected at baseline 
 
 
 
 
 
 
 
 
 
 
 
    Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Page 25 of 99 
Table 14.1.4 (Cont’d)  
Disease History and Baseline Disease Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Time Since Original Diagnosis of PFIC (months) [4] 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xxx 
xx, xxx 
xx, xxx 
 
xx, xxx 
xx, xxx 
xx, xxx 
 
xx, xxx 
xx, xxx 
xx, xxx 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline UDCA Usage 
 
 
 
 
 
 
 
 
 
 
 
    Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    
 
 
 
 
 
 
 
 
 
 
 
Baseline Rifampicin Usage 
 
 
 
 
 
 
 
 
 
 
 
    Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     
 
 
 
 
 
 
 
 
 
 
 
Clinical Scratch Scale (CSS) Score 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
Xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
    
 
 
 
 
 
 
 
 
 
 
 
        0 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Page 26 of 99 
Table 14.1.4 (Cont’d)  
Disease History and Baseline Disease Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Impression of Severity (PIS) 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
    
 
 
 
 
 
 
 
 
 
 
 
        0 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Caregiver Impression of Severity (CIS) 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
    
 
 
 
 
 
 
 
 
 
 
 
        0 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 14.1.4 (Cont’d)  
Disease History and Baseline Disease Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
ItchRO (Obs) 4-wk Morning Avg Severity Score 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
    
 
 
 
 
 
 
 
 
 
 
 
ItchRO (Pt) 4-wk Morning Avg Severity Score 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
ItchRO (Obs) 4-wk Evening Avg Severity Score 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
    
 
 
 
 
 
 
 
 
 
 
 
ItchRO (Pt) 4-wk Evening Avg Severity Score 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Page 28 of 99 
 
Table 14.1.4 (Cont’d)  
Disease History and Baseline Disease Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
ItchRO (Obs) 4-wk Highest Daily Avg Severity Score 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
    
 
 
 
 
 
 
 
 
 
 
 
ItchRO (Pt) 4-week Highest Daily Avg Severity 
Score 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
    Total Serum Bile Acid (umol/L) [5] 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
        Mean 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) xx.xx (xx.xx)  
xx.xx (xx.xx) xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
        Median 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
        Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
        Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
        < Median 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        ≥ Median 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 14.1.4 (Cont’d)  
Disease History and Baseline Disease Characteristics 
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Statistic or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Repeat summary statistics for the following:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    ItchRO (Obs & Pt) 4-wk avg frequency scores (6 variables); same order as for severity score  
 
 
 
 
 
 
    Alkaline Phosphate (U/L) 
 
 
 
 
 
 
 
 
 
 
 
    Aspartate Aminotransferase (U/L) 
 
 
 
 
 
 
 
 
 
 
 
    Alanine Aminotransferase (U/L) 
 
 
 
 
 
 
 
 
 
 
 
    Total Bilirubin (mg/dL)  
 
 
 
 
 
 
 
 
 
 
 
    Direct Bilirubin (mg/dL)  
 
 
 
 
 
 
 
 
 
 
 
    Fibroblast Growth Factor 19 (FGF-19) (ng/mL)  
 
 
 
 
 
 
 
 
 
 
 
    Autotaxin (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
    7 alpha-hydroxyl-4-cholesten-3-one (C4) (ng/mL) 
    25-Hydroxyvitamin D (ng/mL) 
    Alpha Tocopherol (mg/dL) 
    Prothrombin Intl. Normalized Ratio 
    Vitamin A (µg/dL) 
 
 
 
 
 
 
 
 
 
 
 
    GGT 
    Albumin (g/dL) 
 
 
 
 
 
 
 
 
 
 
 
    APRI 
 
 
 
 
 
 
 
 
 
 
 
    FIB-4 
 
 
 
 
 
 
 
 
 
 
 
    PELD [6] 
 
 
 
 
 
 
 
 
 
 
 
    MELD [6] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 14.1.5  
Prior Medications/Therapies  
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
ATC  
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
    Preferred Term [1] 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Subjects Taking any Prior Medications 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
ACT 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
ACT 2  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Preferred Term 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Preferred Term 2   
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
etc…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N.  
[1] Medications were coded using World Health Organization Drug Dictionary (WHO-DD Enhanced version September 2019) ATC level 2 and Chemical Substance (generic name). 
Subjects were counted only once for each Anatomical Therapeutic Chemical (ATC) or Preferred Term. Medications that started prior to the first dose of study drug will be 
considered a prior treatment, whether or not they were stopped prior to the first dose of study drug. If a treatment started prior to the first dose of study drug and continues 
after the first dose of study drug, it was considered both prior and concomitant. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.1.6  
Study Drug Compliance  
Safety Population 
 
 
Primary Cohort  
 
PFIC Cohort 
 
All Subjects 
Variable 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
Maralixibat 
Placebo 
Overall 
     Statistic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Compliance (%) 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
xx 
xx 
xx 
   Mean 
xx.xx 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
xx.xx 
   SD (SE) 
x.xxx (x.xxx) 
x.xxx (x.xxx) x.xxx (x.xxx)  
x.xxx (x.xxx) x.xxx (x.xxx) x.xxx (x.xxx) 
 
x.xxx (x.xxx) 
x.xxx (x.xxx) 
x.xxx (x.xxx) 
   Median 
xx.xx 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
xx.xx 
   Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
   Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 <80% 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  80-<90% 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  90-100% 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Note: Compliance (%) = 100* (Treatment duration in days - Number of days both morning and evening doses were missed) / Treatment duration in days), where Treatment 
duration (days) = Date of last dose of study drug – Date of first dose of study drug + 1 day. For subjects that are missing the date of last dose of study drug, the last known 
contact date is used to calculate treatment duration. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.1.1  
Change from Baseline in ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – Primary Cohort 
 
Post-Baseline 
Morning Score 
 
Evening Score 
 
Highest Daily Score 
Analysis Visit Time Period 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
   Statistic [1] 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
Weeks 1-6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    LS Mean (SE) 
x.xx (x.xxx) 
x.xx (x.xxx) 
 
x.xx (x.xxx) 
x.xx (x.xxx) 
 
x.xx (x.xxx) 
x.xx (x.xxx)  
      (95% CI for LS Mean) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
    p-value (CFB LS Mean = 0) 
x.xxxx 
x.xxxx 
 
x.xxxx 
x.xxxx 
 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
    LS Mean Change from Placebo (SE) 
x.xx (x.xxx) 
 
 
x.xx (x.xxx) 
 
 
x.xx (x.xxx) 
 
 
      (95% CI for LS Mean Change from Placebo) 
(x.xx, x.xx) 
 
 
(x.xx, x.xx) 
 
 
(x.xx, x.xx) 
 
 
    p-value  (Maralixibat LS Mean = Placebo LS Mean) 
x.xxxx 
 
 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for Time Periods:  Weeks 7-10, Weeks 11-14, Weeks 15-18, Weeks 19-22, Weeks 23-26, and Weeks 15-26 [2])  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: LS = Least-squares; SE = standard error of the mean; CFB = change from baseline; CI = confidence interval 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed categorical effects of treatment group, time 
period and treatment-by-time period interaction as well as the continuous fixed covariates of average baseline score and baseline score-by-time period interaction. 
[2] Average of time periods Weeks 15-18, 19-22, and 23-26 obtained from the MMRM as an equally weighted average of the 3 individual visit-specific estimates. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
Programming Note:  There is enough space to fit 2 time periods per page (based on output from t_mmrm.sas used on the 304 IA_NDA analysis). 
 
 
 
 


 
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Table 14.2.1.2  
Change from Baseline in ItchRO(Obs) Severity Score 
MMRM Model Effects 
ITT Population – Primary Cohort 
 
 
Overall p-value [1] 
MMRM Model Effect 
Morning Score 
Evening Score 
Highest Daily Score 
 
 
 
 
 
 
Treatment Group 
x.xxxx 
x.xxxx 
x.xxxx 
 
Time Period 
x.xxxx 
x.xxxx 
x.xxxx 
 
Treatment Group x Time Period Interaction 
x.xxxx 
x.xxxx 
x.xxxx 
 
Baseline (Covariate) 
x.xxxx 
x.xxxx 
x.xxxx 
 
Baseline (Covariate) x Time Period Interaction 
x.xxxx 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
[1] p-value for testing the statistical significance of each effect in the repeated measures model. Change from baseline were 
analyzed using a restricted maximum likelihood (REML)-based repeated-measures approach. An unstructured covariance 
structure was used to model the within-subject errors. The Kenward-Roger approximation was used to estimate denominator 
degrees of freedom and adjust standard errors.  
Source:  Reference Listings xxxxxxx, xxxxxx 
 
 
 


 
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Table 14.2.2.1.1  
Change from Baseline in ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1; change footnote [1] to:   
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed 
categorical effects of treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of 
average baseline score, baseline score-by-time period interaction, and PFIC type. 
 
 
 
 
Table 14.2.2.1.2  
Change from Baseline in ItchRO(Obs) Severity Score 
MMRM Model Effects 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2, but add a data row as the last row:  “PFIC Type (Covariate)” and add in the p-values from the model 
 
 
 
 
 


 
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Table 14.2.2.2.1  
Change from Baseline in Total sBA (µmol/L) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
Analysis Visit 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
   Statistic [1] 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
    LS Mean (SE) 
x.xx (x.xxx) 
x.xx (x.xxx) 
 
x.xx (x.xxx) 
x.xx (x.xxx) 
 
      (95% CI for LS Mean) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
    p-value (CFB LS Mean = 0) 
x.xxxx 
x.xxxx 
 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
 
    LS Mean Change from Placebo (SE) 
x.xx (x.xxx) 
 
 
x.xx (x.xxx) 
 
 
      (95% CI for LS Mean Change from Placebo) 
(x.xx, x.xx) 
 
 
(x.xx, x.xx) 
 
 
    p-value  (Maralixibat LS Mean = Placebo LS Mean) 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
(Continue for analysis visits:  Week 6, Week 10, Week 14, Week 18, Week 22, Week 26, and Weeks 18-26 [2]) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: LS = Least-squares; SE = standard error of the mean; CFB = change from baseline; CI = confidence interval 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed categorical effects 
of treatment group, analysis visit and treatment-by-visit interaction as well as the continuous fixed covariates of baseline score and baseline score-by-
visit interaction. For the PFIC Cohort, PFIC Type is included in the model as an additional covariate. 
[2] Average of Weeks 18, 22, and 26 obtained from the MMRM as an equally weighted average of the 3 individual visit-specific estimates. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
Programming Note:  There is enough space to fit 2 time periods per page (based on output from t_mmrm.sas used on the 304 IA_NDA analysis). 
 
 
 
 


 
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Table 14.2.2.2.2  
Change from Baseline in Total sBA (µmol/L)   
MMRM Model Effects 
ITT Population 
 
 
Overall p-value [1] 
MMRM Model Effect 
Primary Cohort 
PFIC Cohort 
 
 
 
Treatment Group 
x.xxxx 
<0.0001 
Time Point (Analysis Visit) 
x.xxxx 
x.xxxx 
Treatment Group x Time Point Interaction 
x.xxxx 
x.xxxx 
Baseline (Covariate) 
x.xxxx 
x.xxxx 
Baseline (Covariate) x Time Point Interaction 
x.xxxx 
x.xxxx 
PFIC Type (Covariate) [2] 
NA 
x.xxxx 
 
 
 
 
[1] p-value for testing the statistical significance of each effect in the repeated measures model. Change from 
baseline were analyzed using a restricted maximum likelihood (REML)-based repeated-measures approach. 
An unstructured covariance structure was used to model the within-subject errors. The Kenward-Roger 
approximation was used to estimate denominator degrees of freedom and adjust standard errors. 
[2] For the PFIC Cohort, PFIC Type is included in the MMRM model as an additional covariate.  
Source:  Reference Listings xxxxxxx, xxxxxx 
 
 
 


 
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Table 14.2.2.3 
Proportion of Responders 
ITT Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
Responder Type 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
    Category 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
ItchRO Responders [1] 
 
 
 
 
 
 
   Responder 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   Non-Responder 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
   p-value vs. Placebo [3] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
sBA Responders [2] 
 
 
 
 
 
 
   Responder 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   Non-Responder 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
   p-value vs. Placebo [3] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. 
[1] ItchRO responders are defined as a subject having a 4-week average morning ItchRO(Obs) severity change from baseline of 
≤-1.0 OR an average severity score of ≤1.0. For the purpose of determining response, the average severity score from the three 
4-week periods (Weeks 15-18, 19-22, and 23-26) are used.  A subject is defined as an ItchRO non-responder if the 4-week 
average baseline score is missing OR all three 4-week average (post-baseline) scores are missing. 
[2] sBA responders are defined as a subject having an average sBA level of <102 µmol/L (applies only if baseline sBA level was 
≥102 µmol/L), OR a ≤-75% average percent change from baseline. For the purpose of determining response, the average sBA 
value from Weeks 18, 22, and 26 values are used. A subject is defined as an sBA non-responder if the baseline sBA value is 
missing OR sBA values are missing at all 3 time points (i.e., Weeks 18, 22, and 26).   
[3] p-values comparing maralixibat to placebo treatment groups are calculated using a Barnard’s exact test.  
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.3.1.1  
Change from Baseline in Morning ItchRO(Obs) Severity Score – Sibling Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1; add following Note, and change footnotes [1] and [2] to:   
Note: The data from all enrolled subjects (including the 2 pairs of siblings) are used for primary efficacy analysis. The data for only 1 sibling is 
used for the sensitivity analysis. The choice of sibling is made at random before the database lock, as described in the SAP. 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed 
categorical effects of treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of 
average baseline score, and baseline score-by-time period interaction. For the PFIC Cohort, PFIC Type is included in the model as an additional 
covariate. 
[2] Average of time periods Weeks 15-18, 19-22, and 23-26 obtained from the MMRM as an equally weighted average of the 3 individual visit-
specific estimates. 
 
 
Table 14.2.3.1.2  
Change from Baseline in Morning ItchRO(Obs) Severity Score – Sibling Sensitivity Analysis 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2; change ‘Time Point (Analysis Visit)’ in 2nd data row to ‘Time Period’, and ‘Time Period’ in 
data rows 3 and 5 to ‘Time Period’ 
 
 
 
Table 14.2.3.2  
Change from Baseline in Morning ItchRO(Obs) Severity Score – Multiple Imputation Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1; add following Note, and change footnotes [1] and [2] (same as 14.2.3.1.1) to:   
Note: Multiple imputation is based on a standard Missing at Random (MAR) imputation approach. The MAR imputation model imputes missing 
values using a regression-based multiple imputation model. 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed 
categorical effects of treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of 
average baseline score, and baseline score-by-time period interaction. For the PFIC Cohort, PFIC Type is included in the model as an additional 
covariate. 
[2] Average of time periods Weeks 15-18, 19-22, and 23-26 obtained from the MMRM as an equally weighted average of the 3 individual visit-
specific estimates. 
 


 
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Table 14.2.3.3  
Change from Baseline in Morning ItchRO(Obs) Severity Score to Average of Last 12 Weeks – Tipping Point Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
 
 
Primary Cohort 
 
PFIC Cohort 
 
Shift Parameters for 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
Maralixibat, Placebo 
Statistic [1] 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
x.xx, x.xx 
LS Mean (SE) 
x.xx (x.xxx) 
x.xx (x.xxx) 
 
x.xx (x.xxx) 
x.xx (x.xxx) 
 
 
  (95% CI for LS Mean) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
p-value (CFB LS Mean = 0) 
x.xxxx 
x.xxxx 
 
x.xxxx 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
LS Mean Change from Placebo (SE) 
x.xx (x.xxx) 
 
 
x.xx (x.xxx) 
 
 
 
  (95% CI for LS Mean Change from Placebo) 
(x.xx, x.xx) 
 
 
(x.xx, x.xx) 
 
 
 
p-value  (Maralixibat LS Mean = Placebo LS Mean) 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
     (Continue for other shift parameters) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: LS = Least-squares; SE = standard error of the mean; CFB = change from baseline; CI = confidence interval 
Note: Average of time periods Weeks 15-18, 19-22, and 23-26 obtained from the MMRM as an equally weighted average of the 3 individual visit-specific 
estimates. 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed categorical effects of 
treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of average baseline score and baseline score-
by-time period interaction. For the PFIC Cohort, PFIC Type is included in the model as an additional covariate. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.3.4.1  
Change from Baseline in Total sBA (µmol/L) – Sibling Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1; add Note:   
Note: The data from all enrolled subjects (including the 2 pairs of siblings) are used for primary efficacy analysis. The data for only 1 sibling is 
used for the sensitivity analysis. The choice of sibling is made at random before the database lock, as described in the SAP. 
 
 
 
Table 14.2.3.4.2  
Change from Baseline in Total sBA (µmol/L) – Sibling Sensitivity Analysis 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.3.5  
Change from Baseline in Total sBA (µmol/L) – Multiple Imputation Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1;  add Note:   
Note: Multiple imputation is based on a standard Missing at Random (MAR) imputation approach. The MAR imputation model imputes missing 
values using a regression-based multiple imputation model. 
 
 
 
Table 14.2.3.5.2  
Change from Baseline in Total sBA (µmol/L) – Multiple Imputation Sensitivity Analysis 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 


 
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Table 14.2.3.6  
Change from Baseline in Total sBA (µmol/L) to Average of Weeks 18, 22, and 26 – Tipping Point Sensitivity Analysis 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.3.3; change Note and footnote to:   
Note: Average of Weeks 18, 22, and 26 obtained from the MMRM as an equally weighted average of the 3 individual visit-specific estimates. 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed categorical 
effects of treatment group, analysis visit and treatment-by-visit interaction as well as the continuous fixed covariates of baseline score and baseline 
score-by-visit interaction. For the PFIC Cohort, PFIC Type is included in the model as an additional covariate. 
 
 
 
 


 
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Table 14.2.4.1.1  
Change from Baseline in Morning ItchRO(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
Per Protocol Population – Primary Cohort 
 
Post-Baseline 
 
 
Analysis Visit Time Period 
Maralixibat 
Placebo 
   Statistic [1] 
(N=xx) 
(N=xx) 
 
 
 
Weeks 1-6 
 
 
 
 
 
    LS Mean (SE) 
x.xx (x.xxx) 
x.xx (x.xxx) 
      (95% CI for LS Mean) 
(x.xx, x.xx) 
(x.xx, x.xx) 
    p-value (CFB LS Mean = 0) 
x.xxxx 
x.xxxx 
 
 
 
    LS Mean Change from Placebo (SE) 
x.xx (x.xxx) 
 
      (95% CI for LS Mean Change from Placebo) 
(x.xx, x.xx) 
 
    p-value  (Maralixibat LS Mean = Placebo LS Mean) 
x.xxxx 
 
 
 
 
 
 
 
(Continue for Time Periods:  Weeks 7-10, Weeks 11-14, Weeks 15-18, Weeks 19-22, Weeks 23-26, 
and Weeks 15-26 [2]) 
 
 
 
 
 
 
 
Abbreviations: LS = Least-squares; SE = standard error of the mean; CFB = change from baseline; CI = confidence 
interval 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the 
dependent variable and fixed categorical effects of treatment group, time period and treatment-by-time period 
interaction as well as the continuous fixed covariates of average baseline score and baseline score-by-time 
period interaction. 
[2] Average of time periods Weeks 15-18, 19-22, and 23-26 obtained from the MMRM as an equally weighted 
average of the 3 individual visit-specific estimates. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.1.2  
Change from Baseline in Morning ItchRO(Obs) Severity Score 
MMRM Model Effects 
Per Protocol Population – Primary Cohort 
 
 
Overall 
MMRM Model Effect 
p-value [1] 
 
 
Treatment Group 
x.xxxx 
Time Period 
x.xxxx 
Treatment Group x Time Period Interaction 
x.xxxx 
Baseline (Covariate) 
x.xxxx 
Baseline (Covariate) x Time Period Interaction 
x.xxxx 
 
 
 
[1] p-value for testing the statistical significance of each effect in the repeated measures 
model. Change from baseline were analyzed using a restricted maximum likelihood (REML)-
based repeated-measures approach. An unstructured covariance structure was used to 
model the within-subject errors. The Kenward-Roger approximation was used to estimate 
denominator degrees of freedom and adjust standard errors.  
Source:  Reference Listings xxxxxxx, xxxxxx 
 
 
 


 
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Table 14.2.4.2.1  
Change from Baseline in Total sBA (µmol/L) 
Tabulation of Fitted Summary Statistics from MMRM 
Per Protocol Population – Primary Cohort 
 
 
 
 
Analysis Visit 
Maralixibat 
Placebo 
   Statistic [1] 
(N=xx) 
(N=xx) 
 
 
 
Week 2 
 
 
 
 
 
    LS Mean (SE) 
x.xx (x.xxx) 
x.xx (x.xxx) 
      (95% CI for LS Mean) 
(x.xx, x.xx) 
(x.xx, x.xx) 
    p-value (CFB LS Mean = 0) 
x.xxxx 
x.xxxx 
 
 
 
    LS Mean Change from Placebo (SE) 
x.xx (x.xxx) 
 
      (95% CI for LS Mean Change from Placebo) 
(x.xx, x.xx) 
 
    p-value  (Maralixibat LS Mean = Placebo LS Mean) 
x.xxxx 
 
 
 
 
 
 
 
(Continue for analysis visits:  Week 6, Week 10, Week 14, Week 18, Week 22, Week 26, and Weeks 18-26 [2]) 
 
 
 
 
 
 
 
Abbreviations: LS = Least-squares; SE = standard error of the mean; CFB = change from baseline; CI = confidence interval 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent 
variable and fixed categorical effects of treatment group, analysis visit and treatment-by-visit interaction as well as the 
continuous fixed covariates of baseline score and baseline score-by-visit interaction. 
[2] Average of Weeks 18, 22, and 26 obtained from the MMRM as an equally weighted average of the 3 individual visit-
specific estimates. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.2.2  
Change from Baseline in Total sBA (µmol/L) 
MMRM Model Effects 
Per Protocol Population – Primary Cohort 
 
 
Overall 
MMRM Model Effect 
p-value [1] 
 
 
Treatment Group 
x.xxxx 
Time Point (Analysis Visit) 
x.xxxx 
Treatment Group x Time Point Interaction 
x.xxxx 
Baseline (Covariate) 
x.xxxx 
Baseline (Covariate) x Time Point Interaction 
x.xxxx 
 
 
 
[1] p-value for testing the statistical significance of each effect in the repeated measures 
model. Change from baseline were analyzed using a restricted maximum likelihood (REML)-
based repeated-measures approach. An unstructured covariance structure was used to 
model the within-subject errors. The Kenward-Roger approximation was used to estimate 
denominator degrees of freedom and adjust standard errors.  
Source:  Reference Listings xxxxxxx, xxxxxx 
 
 
 


 
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Table 14.2.4.3.1  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Analysis Visit 
Maralixibat 
Placebo 
    Statistic 
(N=xx) 
(N=xx) 
 
 
 
Week 1 
 
 
    n 
xx 
xx 
    Mean 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
 
 
 
Week 2 
 
 
    n 
xx 
xx 
    Mean 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
 
 
 
        (Continue for analysis visits:  Week 3, 4, . . . , 26) 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean;  
Q1 = 25th percentile; Q3 = 75th percentile 
Note: Baseline morning ItchRO(Obs) severity score is the average of 4-weekly 
(7-day) average scores in the period consisting of the 28 days immediately 
before the date of first dose of study drug. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 
 


 
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Table 14.2.4.3.2  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score by Region 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
 
Europe 
 
Middle East 
 
North America 
 
South and Central America 
Analysis Visit 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
    Statistic 
(N=xx) 
(N=xx) 
 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
Xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        (Continue for analysis visits:  Week 3, 4, . . . , 26) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Note: There are no Primary Cohort subjects in Asia. Baseline morning ItchRO(Obs) severity score is the average of 4-weekly (7-day) average scores in the period consisting 
of the 28 days immediately before the date of first dose of study drug. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 
 


 
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Table 14.2.4.3.3  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score by Age at Baseline 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
 
1 to <6 Years 
 
6 to <13 Years 
 
13 to 18 Years 
Analysis Visit 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
    Statistic 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 1 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for analysis visits:  Week 3, 4, . . . , 26) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Note: Age groups based in full years. Baseline morning ItchRO(Obs) severity score is the average of 4-weekly (7-day) average scores in the period 
consisting of the 28 days immediately before the date of first dose of study drug. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.3.4  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score by Sex 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
 
Male 
 
 
Female 
Analysis Visit 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
    Statistic 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
Week 1 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
         (Continue for analysis visits:  Week 3, 4, . . . , 26) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Note: Baseline morning ItchRO(Obs) severity score is the average of 4-weekly (7-day) average scores in the period 
consisting of the 28 days immediately before the date of first dose of study drug. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.3.5  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score by Race 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.3.2, replacing the 4 Regions with the 4 Races: White, Black or African American, American Indian or Alaska 
Native, and More than One Race;  change 1st sentence in Note to “There is 1 Primary Cohort subject (038002) that did not report their race. No 
Primary Cohort subjects reported as Asian.” 
 
 
 
Table 14.2.4.3.6  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score by Baseline Median sBA 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.3.4, replacing the 2 Sexes with the 2 baseline sBA categories: < Baseline Median sBA, ≥ Baseline Median sBA;  
add the following as the 1st few sentences to the Note: “Three subjects (002003, 028003, and 031002), all in the Primary Cohort, are missing baseline 
sBA samples. Only subjects in the Primary Cohort are used to calculate the baseline median sBA level. ” 
 
 
 
Table 14.2.4.3.7  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score by Baseline UDCA Usage 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.3.4, replacing the 2 Sexes with the 2 baseline UDCA usage categories: Baseline UDCA Usage, No Baseline UDCA 
Usage;  add abbreviation for UDCA: “UDCA = ursodeoxycholic acid” with other abbreviations;  add the following as the 1st sentence to the Note:  
“A subject reporting the use of 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 be 
ongoing or have a stop date on or after the first dose of study drug would be considered as using UDCA at baseline.” 
 
 
 


 
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Table 14.2.4.3.8  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score by Baseline Rifampicin Usage 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.3.4, replacing the 2 Sexes with the 2 baseline Rifampicin usage categories: Baseline Rifampicin Usage, No Baseline 
Rifampicin Usage;  add the following as the 1st sentence to the Note:  
“A subject reporting the use of Rifampicin, based on ATC Class Level 5 (chemical substance), with a start date on or prior to the first dose of study drug and 
either be ongoing or have a stop date on or after the first dose of study drug would be considered as using Rifampicin at baseline.” 
 
 
 
Table 14.2.4.3.9  
Change from Baseline in Weekly Average Morning ItchRO(Obs) Severity Score by BSEP Type 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.3.4, replacing the 2 Sexes with the 2 BSEP types: BSEP 1. BSEP 2 
 
 
 
 


 
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Table 14.2.4.4.1  
Change from Baseline in Total sBA (µmol/L) 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Analysis Visit 
Maralixibat 
Placebo 
    Statistic 
(N=xx) 
(N=xx) 
 
 
 
Week 2 
 
 
    n 
xx 
xx 
    Mean 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
 
 
 
Week 6 
 
 
    N 
xx 
xx 
    Mean 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
 
 
 
 (Continue for analysis visits:  Week 10, Week 14, Week 18, Week 22, and Week 26) 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean;  
Q1 = 25th percentile; Q3 = 75th percentile 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 
 


 
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Table 14.2.4.4.2  
Change from Baseline in Total sBA (µmol/L) by Region 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
 
Europe 
 
Middle East 
 
North America 
 
South and Central America 
Analysis Visit 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
    Statistic 
(N=xx) 
(N=xx) 
 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
Xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        (Continue for analysis visits:  Week 10, Week 14, Week 18, Week 22, and Week 26) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Note: There are no Primary Cohort subjects in Asia.  
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
Programming Notes:  Add ‘NE = not estimable’ to abbreviations where applicable 
 
 


 
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Table 14.2.4.4.3  
Change from Baseline in Total sBA (µmol/L) by Age at Baseline 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
 
1 to <6 Years 
 
6 to <13 Years 
 
13 to 18 Years 
Analysis Visit 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
    Statistic 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 6 
 
 
 
 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for analysis visits:  Week 10, Week 14, Week 18, Week 22, and Week 26) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Note: Age groups based in full years.  
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.4.4  
Change from Baseline in Total sBA (µmol/L) by Sex 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
 
Male 
 
 
Female 
Analysis Visit 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
    Statistic 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
Week 2 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
Week 6 
 
 
 
 
 
 
 
    n 
xx 
xx 
 
 
xx 
xx 
 
    Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
    Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
    Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
    (Continue for analysis visits:  Week 10, Week 14, Week 18, Week 22, and Week 26) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.4.5  
Change from Baseline in Total sBA (µmol/L) by Race 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.4.2, replacing the 4 Regions with the 4 Races: White, Black or African American, American Indian or Alaska 
Native, and More than One Race;  change 1st sentence in Note to “There is 1 Primary Cohort subject (038002) that did not report their race. No 
Primary Cohort subjects reported as Asian.” 
 
 
 
Table 14.2.4.4.6  
Change from Baseline in Total sBA (µmol/L) by Baseline Median sBA 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.4.4, replacing the 2 Sexes with the 2 baseline sBA categories: < Baseline Median sBA, ≥ Baseline Median sBA;  
add the following as the 1st few sentences to the Note: “Three subjects (002003, 028003, and 031002), all in the Primary Cohort, are missing baseline 
sBA samples. Only subjects in the Primary Cohort are used to calculate the baseline median sBA level.” 
 
 
 
Table 14.2.4.4.7  
Change from Baseline in Total sBA (µmol/L) by Baseline UDCA Usage 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.4.4, replacing the 2 Sexes with the 2 baseline UDCA usage categories: Baseline UDCA Usage, No Baseline UDCA 
Usage;  add abbreviation for UDCA: “UDCA = ursodeoxycholic acid” with other abbreviations;  add the following as the 1st sentence to the Note:  
“A subject reporting the use of 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 be 
ongoing or have a stop date on or after the first dose of study drug would be considered as using UDCA at baseline.” 
 
 
 


 
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Table 14.2.4.4.8  
Change from Baseline in Total sBA (µmol/L) by Baseline Rifampicin Usage 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.4.4, replacing the 2 Sexes with the 2 baseline Rifampicin usage categories: Baseline Rifampicin Usage, No Baseline 
Rifampicin Usage;  add the following as the 1st sentence to the Note:  
“A subject reporting the use of Rifampicin, based on ATC Class Level 5 (chemical substance), with a start date on or prior to the first dose of study drug and 
either be ongoing or have a stop date on or after the first dose of study drug would be considered as using Rifampicin at baseline.” 
 
 
 
Table 14.2.4.4.9  
Change from Baseline in Total sBA (µmol/L) by BSEP Type 
Descriptive Statistics by Analysis Week 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.4.4.4, replacing the 2 Sexes with the 2 BSEP types: BSEP 1. BSEP 2 
 
 
 
 


 
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Table 14.2.4.5.1  
Change from Baseline in ALT (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1 
 
 
 
Table 14.2.4.5.2  
Change from Baseline in ALT (U/L) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.4.6.1  
Change from Baseline in AST (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1 
 
 
 
Table 14.2.4.6.2  
Change from Baseline in AST (U/L) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 


 
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Table 14.2.4.7.1  
Change from Baseline in Total Bilirubin (mg/dL 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1 
 
 
 
Table 14.2.4.7.2  
Change from Baseline in Total Bilirubin (mg/dL) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.4.8.1  
Change from Baseline in Direct Bilirubin (mg/dL) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1 
 
 
 
Table 14.2.4.8.2  
Change from Baseline in Direct Bilirubin (mg/dL) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 


 
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Table 14.2.4.9.1  
Change from Baseline in ALP (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1 
 
 
 
Table 14.2.4.9.2  
Change from Baseline in ALP (U/L) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.4.10.1  
Change from Baseline in GGT (U/L) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1 
 
 
 
Table 14.2.4.10.2  
Change from Baseline in GGT (U/L) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 


 
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Table 14.2.4.11.1  
Change from Baseline in FIB-4 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1; add to Abbreviations: ‘FIB-4 = fibrosis-4’; add Note: 
Note: FIB-4 is based on a subject’s age in years at the time of sample collection. 
 
 
 
Table 14.2.4.11.2  
Change from Baseline in FIB-4 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.4.12.1  
Change from Baseline in APRI 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1; add to Abbreviations: ‘APRI = AST to platelet ratio index’ 
 
 
 
Table 14.2.4.12.2  
Change from Baseline in APRI 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 


 
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Table 14.2.4.13.1  
Change from Baseline in PELD 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1; add to Abbreviations: ‘PELD = pediatric end-stage liver disease’; add Note: 
Note: PELD score is calculated for children under 12 years of age at the baseline visit.  
 
 
 
Table 14.2.4.13.2  
Change from Baseline in PELD 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 


 
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Table 14.2.4.14  
Total sBA Shift from Baseline:  Number and Proportion of Subjects 
ITT Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
Analysis Visit 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
    % Decrease from Baseline 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 2 
nn 
nn 
 
 
nn 
nn 
 
 
nn 
nn 
 
      >75% (large decrease) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
      0 to 75% (decrease) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
      <0% (any increase) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
   p-value vs Placebo [1] 
x.xxxx 
 
 
 
x.xxxx 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 6 
nn 
nn 
 
 
nn 
nn 
 
 
nn 
nn 
 
    >75% (large decrease) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
    0 to 75% (decrease) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
    <0% (any increase) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
   p-value vs Placebo [1] 
x.xxxx 
 
 
 
x.xxxx 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 10 
nn 
nn 
 
 
nn 
nn 
 
 
nn 
nn 
 
    >75% (large decrease) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
    0 to 75% (decrease) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
    <0% (any increase) 
xx (xx.x%) 
x xx (xx.x%) 
 
 
x xx (xx.x%) 
xx (xx.x%) 
 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
   p-value vs Placebo [1] 
x.xxxx 
 
 
 
x.xxxx 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for analysis visits:  Week 14, Week 18, Week 22, and Week 26) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/Number of subjects with non-missing change from baseline in total sBA values at each visit. 
[1] p-value is calculated using a Cochran-Mantel-Haenszel (CMH) test. 
Source:  Reference Listing xx.x.x 
 
Programming Note:  nn is # of subjects with non-missing CFB in total sBA data.  For these ordinal non-binary outcomes, the CMH test is 
used to take the ordinal nature of the variable into account.  
 


 
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Table 14.2.4.15  
Number of Days Morning ItchRO(Obs) Severity Score ≤1 
Over the Last 84 Study Days 
ITT Population 
 
 
Primary Cohort 
 
 
PFIC Cohort 
 
Maralixibat 
Placebo 
 
 
Maralixibat 
Placebo 
 
Statistic 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
Mean 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
   (95% CI for Mean) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
Median 
xx.x 
xx.x 
 
 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max 
xx, xx 
xx, xx 
 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
Mean Change from Placebo 
xx.x 
 
 
 
xx.x 
 
 
   (95% CI for Mean Change from Placebo) 
(xx.x, xx.x) 
 
 
 
(xx.x, xx.x) 
 
 
p-value (Maralixibat Mean = Placebo Mean [1] 
x.xxxx 
 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile; CI = confidence 
interval 
Note: ItchRO scores have a range from 0 to 4, with the higher score indicating increasing itch severity. Missing data during the 84-
day period is treated using the most conservative approach (i.e., severity score >1). 
[1] Student’s 2 sample mean t-test, assuming unequal variances, is used to test for treatment differences. Satterthwaite’s method 
for computing standard error of the mean of the difference is used. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.16 
Number and Proportion of Subjects with Morning ItchRO(Obs) Severity Score ≤1 for >50% of Time Period 
ITT Population 
 
Post-Baseline 
Primary Cohort 
 
PFIC Cohort 
 
Analysis Visit Time Period 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
    Category 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
Weeks 1-6 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
Weeks 7-10 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
Weeks 11-14 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
Weeks 15-18 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
Weeks 19-22 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
       (Continue for Time Periods:  Weeks 23-26, and Weeks 15-26) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. Days with missing data are not considered to have met the ≤1 criteria for that day. In 
computing the % of time the score is ≤1 within each time period for each subject, the denominator of the proportion includes 
all days within the specified time period (i.e., days with missing and non-missing data), while the numerator only includes those 
days that the score is 0 or 1. 
[1] p-values comparing maralixibat to placebo treatment groups are calculated using a Barnard’s exact test.  
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.17.1.1  
Change from Baseline in ItchRO(Obs) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1 
 
 
 
Table 14.2.4.17.1.2  
Change from Baseline in ItchRO(Obs) Frequency Score 
MMRM Model Effects 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2 
 
 
 
Table 14.2.4.17.2.1  
Change from Baseline in ItchRO(Obs) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1; change footnote [1] to:   
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed 
categorical effects of treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of 
average baseline score, baseline score-by-time period interaction, and PFIC type. 
 
 
 
Table 14.2.4.17.2.2  
Change from Baseline in ItchRO(Obs) Frequency Score 
MMRM Model Effects 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2, but add a data row as the last row:  “PFIC Type (Covariate)” and add in the p-values from the model 
 
 
 


 
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Table 14.2.4.18.1.1  
Change from Baseline in ItchRO(Pt) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1 
 
 
 
Table 14.2.4.18.1.2  
Change from Baseline in ItchRO(Pt) Severity Score 
MMRM Model Effects 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2 
 
 
 
Table 14.2.4.18.2.1  
Change from Baseline in ItchRO(Pt) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1; change footnote [1] to:   
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed 
categorical effects of treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of 
average baseline score, baseline score-by-time period interaction, and PFIC type. 
 
 
 
Table 14.2.4.18.2.2  
Change from Baseline in ItchRO(Pt) Severity Score 
MMRM Model Effects 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2, but add a data row as the last row:  “PFIC Type (Covariate)” and add in the p-values from the model 
 
 
 


 
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Table 14.2.4.19.1.1  
Change from Baseline in ItchRO(Pt) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1 
 
 
 
Table 14.2.4.19.1.2  
Change from Baseline in ItchRO(Pt) Frequency Score 
MMRM Model Effects 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2 
 
 
 
Table 14.2.4.19.2.1  
Change from Baseline in ItchRO(Pt) Frequency Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1; change footnote [1] to:   
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed 
categorical effects of treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of 
average baseline score, baseline score-by-time period interaction, and PFIC type. 
 
 
 
Table 14.2.4.19.2.2  
Change from Baseline in ItchRO(Pt) Frequency Score 
MMRM Model Effects 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2, but add a data row as the last row:  “PFIC Type (Covariate)” and add in the p-values from the model 
 
 
 


 
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Table 14.2.4.20.1  
Change from Baseline in Clinician Scratch Scale (CSS) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, adding Week 4; add Note: 
Note: The CSS provides an assessment of itch severity.  The clinician’s assessment of the subject’s pruritus will focus on scratching and 
visible damage to the skin as a result of scratching as observed by the physician.  The CSS uses a 5-point scale, in which 0 designates no 
evidence of scratching and 4 designates cutaneous mutilation with bleeding, hemorrhage and scarring. 
 
 
 
Table 14.2.4.20.2  
Change from Baseline in Clinician Scratch Scale (CSS) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.4.21.1  
Change from Baseline in Caregiver Impression of Severity (CIS) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, replacing Week 2 with Week 4; add Note: 
Note: The CIS is designed to assess the caregiver’s perception of itch severity of their child, using a 5-point scale, in which 0 designates no 
itch and 4 designates very severe itch. The questionnaire is administered with a recall period of 1 week. 
 
 
 
Table 14.2.4.21.2  
Change from Baseline in Caregiver Impression of Severity (CIS) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 


 
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Table 14.2.4.22.1  
Change from Baseline in Patient Impression of Severity (PIS) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, replacing Week 2 with Week 4; add Note: 
Note: Subjects aged ≥9 years self-complete the PIS questionnaire.  The PIS is designed to assess the subject’s perception of their itch 
severity using a 5-point scale, in which 0 designates not feeling itchy at all and 4 designates feeling very, very itchy. The questionnaire is 
administered with a recall period of 1 week. 
 
 
 
Table 14.2.4.22.2  
Change from Baseline in Patient Impression of Severity (PIS) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 


 
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For next 6 EDQ(Obs) tables, add ‘Abbreviations: EDQ(Obs) = Exploratory Diary Questionnaire (Observer)’ 
 
 
Table 14.2.4.23.1.1  
Change from Baseline in EDQ(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1; add following Note: 
Note: Caregivers for all subjects aged <9 years complete the EDQ(Obs) instrument. 
 
 
 
Table 14.2.4.23.1.2  
Change from Baseline in EDQ(Obs) Severity Score 
MMRM Model Effects 
ITT Population – Primary Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2 
 
 
 
Table 14.2.4.23.2.1  
Change from Baseline in EDQ(Obs) Severity Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.1; add Note and change footnote [1] to:   
Note: Caregivers for all subjects aged <9 years complete the EDQ(Obs) instrument. 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed 
categorical effects of treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of 
average baseline score, baseline score-by-time period interaction, and PFIC type. 
 
 
 


 
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Table 14.2.4.23.2.2  
Change from Baseline in EDQ(Obs) Severity Score 
MMRM Model Effects 
ITT Population – PFIC Cohort 
 
Programming Notes:  Repeat Table 14.2.1.2, but add a data row as the last row:  “PFIC Type (Covariate)” and add in the p-values from the model 
 
 
 
Table 14.2.4.24.1  
Change from Baseline in Morning EDQ(Obs) Sleep Disturbance Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, except use time periods as in Table 14.2.1.1, including updating 1st column header; add 
Note and update footnotes [1] and [2] to:   
Note: Caregivers for all subjects aged <9 years complete the EDQ(Obs) instrument. Sleep disturbance is scored in the morning using a 5-
point scale, in which 1 designates because of itch my child never had trouble staying asleep and 5 designates because of itch my child 
almost always has trouble staying asleep. 
[1] Estimates are from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixed 
categorical effects of treatment group, time period and treatment-by-time period interaction as well as the continuous fixed covariates of 
average baseline score, and baseline score-by-time period interaction. For the PFIC Cohort, PFIC Type is included in the model as an 
additional covariate. 
[2] Average of time periods Weeks 15-18, 19-22, and 23-26 obtained from the MMRM as an equally weighted average of the 3 individual 
visit-specific estimates. 
 
 
 
Table 14.2.4.24.2  
Change from Baseline in Morning EDQ(Obs) Sleep Disturbance Score 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2; change ‘Time Point (Analysis Visit)’ in 2nd data row to ‘Time Period’, and ‘Time Period’ in 
data rows 3 and 5 to ‘Time Period’ 
 
 
 


 
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Table 14.2.4.25 
Number and Proportion of Subjects with Improvement from Baseline in Morning EDQ(Obs) Sleep Disturbance Score 
ITT Population 
 
Post-Baseline 
Primary Cohort 
 
PFIC Cohort 
 
Analysis Visit Time Period 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
    Category 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
Weeks 1-6 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
Weeks 7-10 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
Weeks 11-14 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
Weeks 15-18 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
Weeks 19-22 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
       (Continue for Time Period:  Weeks 23-26) 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: EDQ(Obs) = Exploratory Diary Questionnaire (Observer) 
Note: Percentages are 100*n/N. Caregivers for all subjects aged <9 years complete the EDQ(Obs) instrument. Sleep disturbance 
is scored in the morning using a 5-point scale, in which 1 designates because of itch my child never had trouble staying asleep 
and 5 designates because of itch my child almost always has trouble staying asleep. Improvement is defined as a change from 
baseline <0, using 4- or 6-week (for the first time period) average scores. A subject is defined as having no improvement (i.e., 
non-responder) for an analysis visit time period if the 4-week average baseline score is missing OR the average sleep score at 
the analysis visit is missing. 
[1] p-values comparing maralixibat to placebo treatment groups are calculated using a Barnard’s exact test.  
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.26 
Number and Proportion of Subjects with Morning EDQ(Obs) Sleep Disturbance Scores ≤2 from Post-Baseline through Week 26 
ITT Population 
 
Post-Baseline 
Primary Cohort 
 
PFIC Cohort 
 
Analysis Visit Time Period 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
    Category 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
Weeks 1-26 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   p-value vs. Placebo [1] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
Abbreviations: EDQ(Obs) = Exploratory Diary Questionnaire (Observer) 
Note: Percentages are 100*n/N. Caregivers for all subjects aged <9 years complete the EDQ(Obs) instrument. Sleep disturbance 
is scored in the morning using a 5-point scale, in which 1 designates because of itch my child never had trouble staying asleep 
and 5 designates because of itch my child almost always has trouble staying asleep. Missing scores are treated as a non-
responder (i.e., score >2). 
[1] p-values comparing maralixibat to placebo treatment groups are calculated using a Barnard’s exact test.  
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.2.4.27.1  
Change from Baseline in PedsQL Total Scale Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, removing Week 2 and adding Week 4; add Abbreviations and Note: 
Abbreviations: PedsQL = Pediatric Quality of Life Inventory 
Note: PedsQL individual item scores (0-4 scale) are reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 
3 = 25, 4 = 0), so that higher scores indicate better HRQoL (less negative impact). If >50% of the items in the scale are missing, the 
scale score is not computed. 
 
 
 
Table 14.2.4.27.2  
Change from Baseline in PedsQL Total Scale Score 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2; add Abbreviations: 
Abbreviations: PedsQL = Pediatric Quality of Life Inventory 
 
 
 
 
 


 
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Table 14.2.4.28.1  
Change from Baseline in Height z-Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, adding Week 4; add Note: 
Note: z-scores are based on a subject’s sex and age at each analysis visit. For subjects less than 24 months of age, the World Health 
Organization (WHO) growth charts are used to derive z-scores. For subjects at least 24 months of age, the Center for Disease Control 
(CDC) growth charts are used to derive z-scores. 
 
 
 
Table 14.2.4.28.2  
Change from Baseline in Height z-Score 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.4.29.1  
Change from Baseline in Weight z-Score 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, adding Week 4; add Note: 
Note: z-scores are based on a subject’s sex and age at each analysis visit. For subjects less than 24 months of age, the World Health 
Organization (WHO) growth charts are used to derive z-scores. For subjects at least 24 months of age, the Center for Disease Control 
(CDC) growth charts are used to derive z-scores. 
 
 
 
Table 14.2.4.29.2  
Change from Baseline in Weight z-Score 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 


 
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Table 14.2.4.30.1  
Percent Change from Baseline in Total sBA 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, changing ‘CFB’ to ‘% CFB’ in 1st column 
 
 
 
Table 14.2.4.30.2  
Percent Change from Baseline in Total sBA 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.4.31.1  
Change from Baseline in 7 Alpha-hydroxy-4-cholesten-3-one (C4), ng/mL 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, removing Weeks 2, 14, and 22; change footnote [2] to: 
[2] Average of Weeks 18 and 26 obtained from the MMRM as an equally weighted average of the 2 individual visit-specific estimates. 
 
 
 
Table 14.2.4.31.2  
Change from Baseline in 7 Alpha-hydroxy-4-cholesten-3-one (C4), ng/mL 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 


 
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Table 14.2.4.32.1  
Change from Baseline in Fibroblast Growth Factor 19 (pg/mL) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, removing Weeks 2, 14, and 22; add ‘Note: For analysis, one-half of the lower limit of 
quantitation (LLOQ=10.0 pg/mL) is used for values reported as <LLOQ.’; and change footnote [2] to: 
[2] Average of Weeks 18 and 26 obtained from the MMRM as an equally weighted average of the 2 individual visit-specific estimates. 
 
 
 
Table 14.2.4.32.2  
Change from Baseline in Fibroblast Growth Factor 19 (pg/mL) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
Table 14.2.4.33.1  
Change from Baseline in Autotaxin (ng/mL) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1, removing Weeks 2, 14, and 22; change footnote [2] to: 
[2] Average of Weeks 18 and 26 obtained from the MMRM as an equally weighted average of the 2 individual visit-specific estimates. 
 
 
 
Table 14.2.4.33.2  
Change from Baseline in Autotaxin (ng/mL) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 


 
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Table 14.2.4.34.1  
Change from Baseline in Albumin (g/dL) 
Tabulation of Fitted Summary Statistics from MMRM 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.1 
 
 
 
Table 14.2.4.34.2  
Change from Baseline in Albumin (g/dL) 
MMRM Model Effects 
ITT Population 
 
Programming Notes:  Repeat Table 14.2.2.2.2 
 
 
 
 


 
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Table 14.2.4.35  
Time to First Liver-Associated Event (Days) 
ITT Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
Kaplan-Meier 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
Estimates [1] 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
Number of Events (%) 
x (xx.x%) 
x (xx.x%) 
 
x (xx.x%) 
x (xx.x%) 
 
Number Censored (%) [2] 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
25th Percentile 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
(95% CI for 25th Percentile) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
(95% CI for Median) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
75th Percentile 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
(95% CI for 75th Percentile) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
    p-value [3] 
x.xxxx 
 
 
x.xxxx 
 
 
    p-value [4] 
x.xxxx 
 
 
x.xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CI = confidence interval 
Note: Liver-associated events include partial external biliary diversion (PEBD) surgery, listing for liver transplantation, liver 
decompensation (i.e., hepatic encephalopathy, variceal bleeding, ascites, and spontaneous bacterial peritonitis) events, 
hepatocellular carcinoma (HCC), and death. 
[1] Estimates calculated using Kaplan-Meier product-limit survival curve methodology. Missing estimates are due to insufficient 
events. 
[2] If a subject does not report a liver-associated event, then the time to first liver-associated event is censored at the last 
contact date. 
[3] p-value from a log-rank test, comparing maralixibat versus placebo. 
[4] p-value from a Wilcoxon test, comparing maralixibat versus placebo. 
Source:  Reference Listing xx.x.x 
 
 


 
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Table 14.3.1  
Maralixibat Exposure  
Safety Population 
 
Variable 
Primary Cohort 
PFIC Cohort 
All Subjects 
    Statistic 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
Average Daily Dose (µg/kg/day) 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Total Dose (µg/kg) 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Treatment Duration (days) 
 
 
 
    n 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
      [ Continue for:  Treatment Exposure (days) ] 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: SD = standard deviation; SE = standard error of the mean; Q1 = 25th percentile; Q3 = 75th percentile 
Note: Only subjects exposed to Maralixibat are included. Treatment duration (days) = Date of last dose of study drug – Date of first dose of 
study drug + 1 day. For subjects that are missing the date of last dose of study drug, the last known contact date is used to calculate treatment 
duration. Treatment exposure (days) = Treatment duration in days – Number of days both morning and evening doses were missed. 
Source:  Reference Listings xx.x.x, xx.x.x 
 


 
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Table 14.3.2.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
Subjects with at Least One Treatment-Emergent:  
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
   Adverse Event 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Categorized as Severe 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Categorized as Severe and Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Serious Adverse Event 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Serious Adverse Event Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Leading to Permanent Study Drug Discontinuation 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Leading to Death 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. AEs are coded using MedDRA Version 22.1. Subjects who reported more than one adverse event (AE) within each category were only 
counted once. A treatment-emergent AE (TEAE) is defined as an AE that starts or deteriorates on or after the first dose of study drug and no later than 7 days following the 
last dose of study drug (for subjects not participating in the extension study) or reported through the Week 26/EOT visit (for subjects participating in the extension study). 
For subjects with > 7 days of study drug interruption/withdrawal, the definition of a TEAE considers both the date of the last dose prior to drug interruption and the actual 
last dose. 
Source:  Reference Listing xx.x.x 
 
 
 


 
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Table 14.3.2.1.2 
Overall Summary of Treatment-Emergent Adverse Events by Age Group 
Safety Population 
 
Age Group:  1 to <6 years 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
Subjects with at Least One Treatment-Emergent:  
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
   Adverse Event 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Categorized as Severe 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Categorized as Severe and Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Serious Adverse Event 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Serious Adverse Event Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Leading to Permanent Study Drug Discontinuation 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event Leading to Death 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. AEs are coded using MedDRA Version 22.1. Subjects who reported more than one adverse event (AE) within each category were only 
counted once. A treatment-emergent AE (TEAE) is defined as an AE that starts or deteriorates on or after the first dose of study drug and no later than 7 days following the 
last dose of study drug (for subjects not participating in the extension study) or reported through the Week 26/EOT visit (for subjects participating in the extension study). 
For subjects with > 7 days of study drug interruption/withdrawal, the definition of a TEAE considers both the date of the last dose prior to drug interruption and the actual 
last dose. 
Source:  Reference Listing xx.x.x 
 
Programming Note:  Repeat table for the other 2 age groups:  ‘6 to <13 years’ and ’13 to 18 years’; N should be the total # of subjects in each age group, cohort, and 
treatment group 
 
 
 


 
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Table 14.3.2.1.3 
Overall Summary of Treatment-Emergent Adverse Events by Sex 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.2.1.2, replacing ‘Age Group: xxxxx’ at top of table with ‘Sex: xxxx’, repeating table for each sex (Male, Female)) 
 
 
 
 
Table 14.3.2.1.4 
Overall Summary of Treatment-Emergent Adverse Events by Race 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.2.1.2, replacing ‘Age Group: xxxxx’ at top of table with ‘Race: xxxx’, repeating table for each race (American 
Indian or Alaska Native, Asian, Black or African American, White, More than one race, and Not Reported) 
 
 
 
 
 
 
 


 
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Table 14.3.2.2.1 
Incidence of Treatment-Emergent Adverse Events 
Safety Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
System Organ Class 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
   Preferred Term 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
Number of Subjects with at Least One TEAE 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
System Organ Class #1 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #1 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #2 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #3 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
System Organ Class #2 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #1 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #2 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #3 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. AEs are coded using MedDRA Version 22.1. At each level of summarization (System Organ Class and Preferred Term), 
subjects who reported more than one adverse event (AE) were only counted once. 
Source:  Reference Listing xx.x.x 
 
 
Programming Note:  SOC and PT are sorted alphabetically by SOC and descending frequency of PT within each SOC 
 
 
 


 
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Table 14.3.2.2.2 
Incidence of Treatment-Emergent Adverse Events by Age Group 
Safety Population 
 
Age Group:  1 to <6 years 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
System Organ Class 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
   Preferred Term 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
Number (%) of Subjects with at Least One TEAE 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
System Organ Class #1 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #1 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #2 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #3 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
System Organ Class #2 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #1 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #2 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
   Preferred Term #3 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. AEs are coded using MedDRA Version 22.1. At each level of summarization (System Organ Class and Preferred Term), 
subjects who reported more than one adverse event (AE) were only counted once. 
Source:  Reference Listing xx.x.x 
 
 
Programming Note:  Repeat table for the other 2 age groups:  ‘6 to <13 years’ and ’13 to 18 years’. N should be the total # of subjects 
in each age group, cohort, and treatment group. 
SOC and PT are sorted alphabetically by SOC and descending frequency of PT within each SOC. 
 
 


 
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Table 14.3.2.2.3 
Incidence of Treatment-Emergent Adverse Events by Sex 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.2.2.2, replacing ‘Age Group: xxxxx’ at top of table with ‘Sex: xxxx’, repeating table for each sex (Male, Female) 
 
 
 
Table 14.3.2.2.4 
Incidence of Treatment-Emergent Adverse Events by Race 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.2.2.2, replacing ‘Age Group: xxxxx’ at top of table with ‘Race: xxxx’, repeating table for each race (American 
Indian or Alaska Native, Asian, Black or African American, White, More than one race, and Not Reported) 
 
 
 
Table 14.3.3.1 
Incidence of Treatment-Emergent Serious Adverse Events 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.2.2.1 
 
 
 
Table 14.3.3.2 
Incidence of Treatment Related Adverse Events 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.2.2.1 
 
 
 
Table 14.3.3.3 
Incidence of Treatment Related Adverse Events Leading to Permanent Discontinuation of Study Drug 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.2.2.1 
 
 


 
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Table 14.3.3.4.1 
Incidence of Events of Clinical Interest - Diarrhoea Events 
Safety Population 
 
Programming Note:  Same shell as 14.3.2.2.1, adding at end of Note: “Refer to SAP Sec. 6.1.9 for the preferred terms included in the 
definition of each event of clinical interest.” 
 
 
 
Table 14.3.3.4.2 
Incidence of Events of Clinical Interest – LSV Deficiency Events 
Safety Population 
 
Programming Note:  Same shell as 14.3.2.2.1, adding at end of Note: “Refer to SAP Sec. 6.1.9 for the preferred terms included in the 
definition of each event of clinical interest.” 
 
 
 
Table 14.3.3.4.3 
Incidence of Events of Clinical Interest – Elevated Transaminases 
Safety Population 
 
Programming Note:  Same shell as 14.3.2.2.1, adding at end of Note: “Refer to SAP Sec. 6.1.9 for the preferred terms included in the 
definition of each event of clinical interest.” 
 
 
 
Table 14.3.3.4.4 
Incidence of Events of Clinical Interest – Elevated Bilirubin 
Safety Population 
 
Programming Note:  Same shell as 14.3.2.2.1, adding at end of Note: “Refer to SAP Sec. 6.1.9 for the preferred terms included in the 
definition of each event of clinical interest.” 
 
 
 


 
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Table 14.3.4.1 
Listing of Serious Adverse Events 
Safety Population 
 
Subject 
ID 
 
 
Cohort 
[1] 
 
Treatment 
Received 
[2] 
System Organ Class/ 
  Preferred Term/ 
       Verbatim Term 
 
 
 
TEAE? 
Start Date 
  (Study Day) [3] 
End Date 
  (Study Day) [3] 
 
Event 
Duration 
(days) 
Severity/ 
  Relationship to 
       Study Drug 
Outcome/ 
  Study Drug  
    Action Taken 
Serious?/Life 
Threatening? 
Treatment 
Required 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
Primary 
600 
xxxxxxxxxx xxxxx xxxxx/ 
  xxxxxxxxxxxxxxxxx/ 
    xxxxxxxxxxxxxxxxxx 
Yes 
DDMMMYYYY 
         (xx) 
DDMMMYYYY 
         (xx) 
xx 
Moderate/ 
    Not Related 
xxxxxxxx/ 
   xxxx xxx xxxxxxx 
Yes/ 
No 
None 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
PFIC 
Placebo 
xxxxxxxxxxxxxxxx xxxxx/ 
  xxxxxxxxxx/ 
    xxxxxxxxxxxxxxx 
No 
DDMMMYYYY 
         (xx) 
DDMMMYYYY 
         (xx) 
xx 
Severe/ 
    Related 
xxxxxxxx/ 
   xxxx xxx xxxxxxx 
Yes/ 
No 
 
xxxxx; xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: AEs are coded using MedDRA Version 22.1. In determining treatment-emergent AEs (TEAEs) and study day, partial dates were imputed based on the SAP.  
[1] Subject cohorts include Primary, PFIC, or Other.  Subjects in the Primary Cohort, that are all a subset of the PFIC Cohort, are presented as ‘Primary’. 
[2] Treatment received at the start of the event, including dose (reported in units of μg/kg/day) for subjects on maralixibat. 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.  NT = Not Treated (for AEs that started prior 
to 1st dose of study drug) 
[3] Study Day is calculated relative to the date of the first dose of study drug. 
Source:  Reference Listing xx.x.x 
 
Programming Note:  Sort AEs (within subject) by start date and then by end date; events that are ongoing would be listed after those with end dates (for those 
events with the same start date).  For Treatment Required column, concatenate treatment required (e.g., Medication; Hospitalization).  If “Other” is answered, 
concatenate the specify (e.g., Medication; Other: change settings in hearing aid).  If subject was never dosed, Study Day will be reported as “NT”. 
 
 


 
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Table 14.3.4.2 
Listing of Adverse Events Leading to Permanent Discontinuation of Study Drug 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.4.1 
 
 
 
Table 14.3.4.3 
Listing of Deaths 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.4.1 
 
 
 


 
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Table 14.3.5.1 
Summary of Safety Laboratory Data:  Chemistry 
Safety Population 
 
< Lab Test (units) > 
 
Primary Cohort 
 
PFIC Cohort 
Analysis Visit 
Maralixibat (N=xx) 
  
Placebo (N=xx) 
 
Maralixibat (N=xx) 
 
Placebo (N=xx) 
    Statistic 
Obs 
CFB 
  
Obs 
CFB 
 
 
Obs 
CFB 
 
Obs 
CFB 
 
 
 
  
 
 
 
 
 
 
 
 
Baseline 
x 
 
  
x 
 
 
x 
 
 
x 
 
    n 
xx 
 
  
xx 
 
 
xx 
 
 
xx 
 
    Mean 
xx.x 
 
  
xx.x 
 
 
xx.x 
 
 
xx.x 
 
        (95% CI for Mean) 
(xx.x, xx.x) 
 
  (xx.x, xx.x) 
 
 
(xx.x, xx.x) 
 
 
(xx.x, xx.x) 
 
    SD (SE) 
xx.xx (xx.xx) 
 
  xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
 
 
xx.xx (xx.xx) 
 
    Median 
xx.x 
 
  
xx.x 
 
 
xx.x 
 
 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
 
  
xx.x, xx.x 
 
 
xx.x, xx.x 
 
 
xx.x, xx 
 
    Min, Max 
xx, xx 
 
  
xx, xx 
 
 
xx, xx 
 
 
xx, xx 
 
 
 
 
  
 
 
 
 
 
 
 
 
Week 2 
x 
x 
  
x 
x 
 
x 
x 
 
x 
X 
    N 
xx 
xx 
  
xx 
xx 
 
xx 
xx 
 
xx 
Xx 
    Mean 
xx.x 
xx.x 
  
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
        (95% CI for Mean) 
(xx.x, xx.x) 
(xx.x, xx.x) 
  (xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
    SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx)   xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
    Median 
xx.x 
xx.x 
  
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
  
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx 
xx.x, xx.x 
    Min, Max 
xx, xx 
xx, xx 
  
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
  
 
 
 
 
 
 
 
 
(Continue for each planned analysis visit:  Week 6, Week 10, Week 14, Week 18, Week 22, and Week 26) 
 
 
Abbreviations: Obs = observed values; CFB = change from baseline; CI = confidence interval; SD = standard deviation; SE = standard error of the mean; Q1 = 25th 
percentile; Q3 = 75th percentile 
Note: For analysis, one-half of the lower limit of quantitation (LLOQ) is used for values reported as <LLOQ. 
[1] Anion Gap (mEq/L) = sodium (mEq/L) – chloride (mEq/L) – bicarbonate (mEq/L) 
[2] Corrected Sodium (mEq/L) = sodium (mEq/L) + [0.002 x triglycerides (mg/dL)] 
[3] Calculated Osmolality (mOsm/kg) = [2 x (sodium (mEq/L) + potassium (mEq/L) )] + [glucose (mg/dL) / 18] + [BUN (mg/dL) / 2.8] 
[4] Osmolar Gap (mOsm/kg) = measured osmolality (mOsm/kg) – calculated osmolality (mOsm/kg) 
SOURCE: Listing x.x.x.x 
 
Programming Note: Repeat for each test in lab panel, left justified at top of table (as listed in SAP Appendix 1, under SAFETY LABS), noting 
footnotes required for derived labs; Min and Max values for the following derived labs should be rounded, for presentation purposes, as 
follows:  Anion Gap [1] (1 decimal), Corrected Sodium [2] (integer), Calculated Osmolality [3] (integer), and Osmolar Gap [4] (integer) 
 


 
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Table 14.3.5.2 
Summary of Safety Laboratory Data:  Hematology 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.5.1, replacing footnotes with: 
 
Abbreviations: Obs = observed values; CFB = change from baseline; CI = confidence interval; SD = standard deviation; SE = standard error of the mean; Q1 = 25th 
percentile; Q3 = 75th percentile 
Note: For analysis, one-half of the lower limit of quantitation (LLOQ) is used for values reported as <LLOQ. 
SOURCE: Listing x.x.x.x 
 
Programming Note (cont’d): Repeat for each test in lab panel, left justified at top of table (as listed in SAP Appendix 1, under SAFETY LABS) 
 
 
 
Table 14.3.5.3 
Summary of Safety Laboratory Data:  Lipid Panel 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.5.1, replacing footnotes with: 
 
Abbreviations: Obs = observed values; CFB = change from baseline; CI = confidence interval; SD = standard deviation; SE = standard error of the mean; Q1 = 25th 
percentile; Q3 = 75th percentile 
Note: For analysis, one-half of the lower limit of quantitation (LLOQ) is used for values reported as <LLOQ. 
SOURCE: Listing x.x.x.x 
 
Programming Note (cont’d): Repeat for each test in lab panel, left justified at top of table (as listed in SAP Appendix 1, under SAFETY 
LABS, except for HDL-C which will only be presented in a subject listing) 
 
 
 


 
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Table 14.3.5.4 
Summary of Safety Laboratory Data:  Lipid Soluble Vitamins (LSV) 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.5.1, removing Week 2 except for INR, PT, and aPTT, and replacing footnotes with: 
 
Abbreviations: Obs = observed values; CFB = change from baseline; CI = confidence interval; SD = standard deviation; SE = standard error of the mean; Q1 = 25th 
percentile; Q3 = 75th percentile 
Note: For analysis, one-half of the lower limit of quantitation (LLOQ) is used for values reported as <LLOQ. For concentrations reported as above the upper limit of 
quantitation (ULOQ), the ULOQ is used as the analysis value. 
[1] 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)] 
[2] Retinol:RBP Molar Ratio (mol/mol) = 0.0734 x retinol (µg/dL) / RBP (mg/dL) 
SOURCE: Listing x.x.x.x 
 
Programming Note (cont’d): Repeat for each test in lab panel, left justified at top of table (as listed in SAP Appendix 1, under SAFETY 
LABS), noting footnotes required for derived labs; Min and Max values for the 2 derived labs should be rounded, for presentation 
purposes, to 2 decimal places 
 
 
 
 
Table 14.3.5.5 
Summary of Safety Laboratory Data:  Alpha-Fetoprotein (ng/mL) 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.5.1 except remove ‘Lab Test:  xxxx’ before table; only present Baseline, Week 10, and Week 26, and 
replace footnotes with: 
 
Abbreviations: Obs = observed values; CFB = change from baseline; CI = confidence interval; SD = standard deviation; SE = standard error of the mean; Q1 = 25th 
percentile; Q3 = 75th percentile 
Note: For analysis, one-half of the lower limit of quantitation (LLOQ) is used for values reported as <LLOQ. 
SOURCE: Listing x.x.x.x 
 
 
 
 


 
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Table 14.3.5.6 
Shift Table for Select Safety Laboratory Tests 
Safety Population 
 
Primary Cohort 
Lab Test (Unit)/ 
    Analysis Visit  
        Post-Baseline 
Baseline 
Maralixibat  (N=xx) 
 
Placebo  (N=xx) 
Below 
Within 
Above 
Missing 
Total 
 
Below 
Within 
Above 
Missing 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
25-Hydroxyvitamin D (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
    Week 6 
 
 
 
 
 
 
 
 
 
 
 
        Below 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Within 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Above 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Missing 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   
 
 
 
 
 
 
 
 
 
 
 
         (Continue for Weeks 10, 14, 18, 22, and 26) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alpha Tocopherol (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
    Week 6 
 
 
 
 
 
 
 
 
 
 
 
        Below 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Within 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Above 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Missing 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Total 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
  (Continue for following lab tests:  Prothrombin Intl. Normalized Ratio, and Vitamin A (µg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: For analysis, one-half of the lower limit of quantitation (LLOQ) is used for values reported as <LLOQ. For concentrations reported as above the upper limit of quantitation 
(ULOQ), the ULOQ is used as the analysis value. 
Source:  Reference Listing xx.x.x 
 
 
Note to programmer:   Repeat for ‘PFIC Cohort’; start new page for each cohort and each lab test     
 


 
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Table 14.3.6.1 
Summary of Subject Height, Weight, and BMI z-Scores 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.5.1 except change ‘Lab Test:  xxxx’ to ‘<parameter> where parameter includes:  Height z-score, Weight z-
score, and BMI z-score; add Week 4, and replace footnotes with: 
 
Abbreviations: Obs = observed values; CFB = change from baseline; CI = confidence interval; SD = standard deviation; SE = standard error of the mean; Q1 = 25th 
percentile; Q3 = 75th percentile 
Note: z-scores are derived using a subject’s age and sex. For subjects less than 24 months of age, WHO growth charts are used to derive z-scores. For subjects at least 
24 months of age, CDC growth charts are used to derive z-scores. 
SOURCE: Listing x.x.x.x 
 
 
 
Table 14.3.6.2 
Summary of Vital Signs 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.5.1 except change ‘Lab Test:  xxxx’ to ‘<parameter> where parameter includes: Systolic BP (mmHg), Diastolic 
BP (mmHg), Heart Rate (bpm), Respiratory Rate (breaths/min), and Body Temperature (oC); add Week 4, and replace footnotes with: 
 
Abbreviations: Obs = observed values; CFB = change from baseline; CI = confidence interval; SD = standard deviation; SE = standard error of the mean; Q1 = 25th 
percentile; Q3 = 75th percentile 
SOURCE: Listing x.x.x.x 
 
 
 
Table 14.3.6.3.1 
Summary of Electrocardiogram Parameters 
Safety Population 
 
Programming Note:  Same shell as Table 14.3.5.1 except change ‘Lab Test:  xxxx’ to ‘<parameter> where parameter includes: PR Interval (msec), 
QRS Duration (msec), QTcB Interval (msec), and QTcF Interval (msec); only include Baseline, Week 10, and Week 26, and replace footnotes with: 
 
Abbreviations: Obs = observed values; CFB = change from baseline; CI = confidence interval; SD = standard deviation; SE = standard error of the mean; Q1 = 25th 
percentile; Q3 = 75th percentile; QTcB = QT interval corrected using Bazett’s formula; QTcF = QT Interval corrected using Fridericia’s formula 
SOURCE: Listing x.x.x.x 
 
 
 


 
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Table 14.3.6.3.2 
Summary of Electrocardiogram Interpretation 
Safety Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
Analysis Visit 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
   Category 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
Baseline 
nn 
nn 
 
nn 
nn 
 
   Abnormal – CS 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   Abnormal – NCS 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
Week 10 
nn 
nn 
 
nn 
nn 
 
   Abnormal – CS 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   Abnormal – NCS 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
Week 26 
nn 
nn 
 
nn 
nn 
 
   Abnormal – CS 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   Abnormal – NCS 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
Abbreviations: CS = Clinically Significant; NCS = Not Clinically Significant 
Note: Percentages are 100*n/Number of subjects with ECG interpretation data at each visit. 
Source:  Reference Listing xx.x.x 
 
 
Programming Note:  nn is # of subjects with non-missing ECG data 
 
 
 


 
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Table 14.3.7 
Concomitant Medications/Therapies 
Safety Population 
 
 
Programming Notes: Repeat Table 14.1.5 except for changing ‘Prior’ in 1st data row to ‘Concomitant’, and footnotes as below 
 
Note: Percentages are 100*n/N.  
[1] Medications were coded using World Health Organization Drug Dictionary (WHO-DD Enhanced version September 2019) ATC level 2 and Chemical Substance (generic 
name). Subjects were counted only once for each Anatomical Therapeutic Chemical (ATC) or Preferred Term. Any treatments continuing or starting after the first dose of 
study drug will be considered concomitant. If a treatment started prior to the first dose of study drug and continues after the first dose of study drug, it was considered 
both prior and concomitant. 
Source:  Reference Listings xx.x.x, xx.x.x 
 
 
 


 
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Table 14.4.1 
Summary of Healthcare Utilization Measures 
Safety Population 
 
 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
Healthcare Utilization Measure 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
    Statistic 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
Number of ER Visits [1] 
 
 
 
 
 
 
 
 
     Number and % of Subjects 
xx (x.x%) 
xx (x.x%) 
 
xx (x.x%) 
xx (x.x%) 
 
xx (x.x%) 
xx (x.x%) 
     Number of Occurrences 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
 
 
 
 
 
 
 
Number of PFIC-Related Hospitalizations [1] 
 
 
 
 
 
 
 
 
     Number and % of Subjects 
xx (x.x%) 
xx (x.x%) 
 
xx (x.x%) 
xx (x.x%) 
 
xx (x.x%) 
xx (x.x%) 
     Number of Occurrences 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
 
 
 
 
 
 
 
Length of Stay for Hospitalizations (days) [2] 
 
 
 
 
 
 
 
 
     Mean (SD) 
x.x (x.xx) 
x.x (x.xx) 
 
x.x (x.xx) 
x.x (x.xx) 
 
x.x (x.xx) 
x.x (x.xx) 
     Median 
x.x 
x.x 
 
x.x 
x.x 
 
x.x 
x.x 
     Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
Number of Days Caregiver Missed Work Due to 
Healthcare Resource Utilization Events [2] 
 
 
 
 
 
 
 
 
     Mean (SD) 
x.x (x.xx) 
x.x (x.xx) 
 
x.x (x.xx) 
x.x (x.xx) 
 
x.x (x.xx) 
x.x (x.xx) 
     Median 
x.x 
x.x 
 
x.x 
x.x 
 
x.x 
x.x 
     Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
Abbreviations: PFIC = progressive familial intrahepatic cholestasis; ER = emergency room; SD = standard deviation 
Note: Percentages are 100*n/N. Data are presented across the entire post-baseline study period, between clinic visits from baseline through Week 27 Follow-up. 
[1] Subjects that visit the Emergency Room and the visit results in the subject being admitted to the hospital will be counted in both the Number of Hospitalizations 
and the Number of ER Visits. 
[2] For those subjects reporting PFIC-related hospitalizations, summary statistics on the number of days are presented. 
Source:  Reference Listing xx.x.x 
 
 
 


 
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Table 14.4.2 
Summary of Plasma Sample Maralixibat Concentrations (ng/mL) 
Safety Population 
 
Analysis Visit 
Primary Cohort 
 
PFIC Cohort 
 
All Subjects 
 Sample Time Point 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
 
Maralixibat 
Placebo 
    Statistic 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
Week 10 
 
 
 
 
 
 
 
 
 Pre-Dose 
 
 
 
 
 
 
 
 
     n 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
     Mean 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
         (95% CI for Mean) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
     SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     CV (%) 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
     Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
     Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
     Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
     Geometric Mean 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 Post-Dose 
 
 
 
 
 
 
 
 
     n 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
     Mean 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
         (95% CI for Mean) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
     SD (SE) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
     CV (%) 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
     Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
     Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
 
xx.x, xx.x 
xx.x, xx.x 
     Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
     Geometric Mean 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
      (Repeat for Analysis Visits:  Week 14 and Week 26)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CI = confidence interval; SD = standard deviation; SE = standard error of the mean; CV = coefficient of variation 
Note: The lower limit of quantitation (LLOQ) is 0.250 ng/mL. For any concentration reported below this limit, a zero value is used in the calculation 
of summary statistics. Post-dose samples were drawn approximately 2.5 hours after the morning dose. 
Source:  Reference Listing xx.x.x 
 


 
 
 
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Sponsor 
Mirum Pharmaceuticals Inc. 
Protocol Title: 
Randomized Double-blind Placebo-controlled Phase 3 Study to 
Evaluate the Efficacy and Safety of Maralixibat in the Treatment 
of Children with Progressive Familial Intrahepatic Cholestasis 
(PFIC) – MARCH-PFIC 
Protocol Number: 
MRX-502 (Amendment 4) 
Premier Research PCN: 
MIRU8967 
Document Author: 
Taryn Robertson 
Document Version: 
Final 1.0 
Document Date:  
13Oct2022 
 
 
 
 


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Listing Shells 
 
PROGRAMMING NOTE FOR ALL LISTINGS (EXCEPT LISTING 16.2.2.1):  Sort by Treatment (Maralixibat or Placebo), then PFIC 
Type (ordered according to the list below), then Subject ID (and Study Day, when applicable), placing Treatment in sub-title. 
Present and sort by PFIC Type in the following order:   
nt-PFIC2 
PFIC1 
PFIC3 
PFIC4 
PFIC6 
nt-PFIC2-het 
nt-PFIC2-IsBA 
nt-PFIC2-surg 
t-PFIC2 
PFIC1-het 
PFIC1-surg 
PFIC4-surg 
No-variant-found 
 
Analysis Visit is presented in addition to Clinic Visit for all data that is available in a single ADaM dataset (ie, not for subject 
profile listings which merge data from across multiple ADaM datasets). 
 
Listing 16.1.1 
Subject Profile: Select Labs and Itch/Scratch Scores 
Listing 16.1.2 
Subject Profile: Pediatric Quality of Life Inventory – Total Scale and Summary Scores 
Listing 16.1.3 
Subject Profile: Efficacy and Safety Labs (Serum Bile Acid, Lipids, Lipid Soluble Vitamins, and Coagulation) 
Listing 16.1.4 
Subject Profile: Sodium and Lipid Soluble Vitamin Level Abnormalities 
Listing 16.2.1 
Analysis Populations and Siblings 
Listing 16.2.2.1 
Subject Disposition: Screen Failure Subjects Enrolled in Study 
Listing 16.2.2.2 
Subject Disposition and Completion: Intent-to-Treat Population 
Listing 16.2.3.1 
Randomized Subjects by Randomized Cohort and Phenotype 
Listing 16.2.3.2 
Subjects Where Randomized Cohort Conflicts with PFIC Type 
Listing 16.3.1 
Inclusion and Exclusion Criteria 
Listing 16.3.2 
Important Protocol Deviations 
Listing 16.4.1 
Demographics and Baseline Information 
Listing 16.4.2 
Long-Term Follow-Up Informed Consent and Disease Progression 
Listing 16.4.3 
Informed Consent 
Listing 16.4.4 
Medical History 
Listing 16.4.5 
Prior and Concomitant Medications/Therapies 
Listing 16.5.1 
Liver Imaging 
Listing 16.5.2 
Liver-Associated Events 
Listing 16.5.3 
Liver Transplant List 
Listing 16.6.1 
Study Drug Supplied and Compliance 
Listing 16.6.2 
Study Drug Exposure 
Listing 16.6.3 
Study Drug Accountability 
Listing 16.7.1 
Total Serum Bile Acid 


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Listing 16.7.2 
Serum Bile Acid Subspecies 
Listing 16.7.3 
Clinician Scratch Score 
Listing 16.7.4 
Itch Reported Outcomes (Subject and Caregiver) Average Morning and Evening Scores 
Listing 16.7.5 
Exploratory Diary Questionnaire (Subject and Caregiver) Average Morning and Evening Scores 
Listing 16.7.6.1 
PIC and CIC 
Listing 16.7.6.2 
PIS and CIS 
Listing 16.7.7 
Efficacy Laboratory Tests  
Listing 16.7.8 
Height, Weight, and BMI z-Score  
Listing 16.7.9 
Sleep Disturbance 
Listing 16.8.1 
Adverse Events 
Listing 16.8.2.1 
Adverse Events of Clinical Interest:  Diarrhoea Events 
Listing 16.8.2.2 
Adverse Events of Clinical Interest:  Lipid Soluble Vitamin Deficiency Events 
Listing 16.8.2.3 
Adverse Events of Clinical Interest:  Elevated Transaminases Events 
Listing 16.8.2.4 
Adverse Events of Clinical Interest:  Elevated Bilirubin Events 
Listing 16.8.3 
Treatment Related Adverse Events  
Listing 16.8.4.1 
Serious Adverse Events 
Listing 16.8.4.2 
Serious Related Adverse Events 
Listing 16.8.5 
Adverse Events Leading to Study Drug Discontinuation 
Listing 16.8.6 
Severe Adverse Events  
Listing 16.8.7 
Adverse Events Resulting in Death 
Listing 16.9.1 
Vital Signs 
Listing 16.9.2 
Physical Examination 
Listing 16.9.3 
12-Lead Safety ECG 
Listing 16.10.1 
Clinical Laboratory Tests:  Clinical Chemistry 
Listing 16.10.2 
Clinical Laboratory Tests:  Hematology 
Listing 16.10.3 
Clinical Laboratory Tests:  Urinalysis 
Listing 16.10.4 
Clinical Laboratory Tests:  Lipid Soluble Vitamins 
Listing 16.10.5 
Clinical Laboratory Tests:  Lipid Panel 
Listing 16.10.6 
Clinical Laboratory Tests:  Hepatocellular Carcinoma Marker - Alpha-Fetoprotein (AFP) 
Listing 16.10.7 
Clinical Laboratory Tests:  Timing of Sample Collection and Last Meal 
Listing 16.10.8 
Microbiology Tests  
Listing 16.10.9 
Pregnancy Tests 
Listing 16.10.10 
Plasma Sample Maralixibat Concentrations 
Listing 16.11 
Telephone Contact Log 
Listing 16.12 
Visit Dates and Type 
Listing 16.13 
Healthcare Utilization 
Listing 16.14 
COVID-19 Impact 
 


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Listing 16.1.1    
Subject Profile: Select Labs and Itch/Scratch Scores 
Safety Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PedsQL 
ItchRO 
 
 
Age [1]/ 
 
Study 
MRX 
 
 
 
Bilirubin 
 
 
PELD/ 
 
 
CIC/ 
 
Parent 
 
Morning Avg. 
PFIC 
 
Sex/   Analysis 
Day 
PFIC 
sBA [4] 
ALT 
AST 
(mg/dL) 
C4 
ATX 
MELD 
 
PIC 
 
Total 
Severity Score [7] 
Type 
Subject Country   Visit 
[2] 
Rcvd [3] 
(umol/L) (U/L) (U/L) 
Direct Total (ng/mL) (ng/mL) 
[5] 
APRI 
FIB-4 
[6] 
CSS 
Score 
Obs [8] 
Pt [9] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
xxxxxx x/x/xxx   Baseline 
-x 
NT 
xx.x 
xx 
xx 
x.x 
x.x 
xx.x 
xxxx 
xx 
x.x 
xxx 
 
x 
 
xx.x 
x.xx w 
x.xx 
 
 
 
  Week 2 
xx 
300 
xx.x b 
xx 
xx 
x.x 
x.x 
xx.x 
xxxx 
xx 
x.x 
xxx 
x/x 
x 
 
xx.x 
[8] 
[8] 
 
 
 
  Week 4 
xx 
600 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Continue for all analysis visits 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Abbreviations: sBA = serum Bile Acid; ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase; C4 = 7 alpha-hydroxy-4- cholesten-3-one (C4); ATX = Autotaxin; PELD = pediatric end-stage liver 
disease; MELD = model for end-stage liver disease; APRI = AST to platelet ratio index; FIB-4 = fibrosis-4; CIC = Caregiver Impression of Change; PIC = Patient Impression of Change; CSS = Clinician Scratch 
Scale; PedsQL = Pediatric Quality of Life; ItchRO = Itch Reported Outcome; ARG = Argentina; AUT = Austria; BEL = Belgium; BRA = Brazil; CAN = Canada; COL = Columbia; DEU = Germany; FRA = France; 
GBR = United Kingdom; ITA = Italy; LBN = Lebanon; MEX = Mexico; POL = Poland; SGP = Singapore; TUR = Turkey; USA = United States; Obs = Observer; Pt = Patient 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug.  
[3] Treatment received (MRX µg/kg BID) on the date of the assessment/sample collection or last MRX BID dose received if dose was missed or administered as QD.  NT = not treated (pre-dose or Placebo 
dose) 
[4] 'b' indicates ≥ 75% reduction from baseline (ie, CFB ≤ -75%) OR sBA < 102 umol/L. 
[5] PELD is calculated for children < 12 years of age at the baseline visit; MELD is calculated for children ≥ 12 years of age at baseline. 
[6] PIC is completed by subjects who are at least 9 years of age. 
[7] ItchRO weekly scores calculated relative to first dose of study drug. For each post-baseline analysis visit, average score is calculated for the following periods:  Week 1-6 (42 days), Weeks 7-10, 11-14, 
15-18, 19-22, and 23-26. Average ItchRO score at baseline is calculated averaging the 4-weekly average scores before the first dose of study drug.  
[8] ‘w’ indicates average ItchRO score change from baseline ≤ -1.0. 
[9] ItchRO self-report is completed by subjects who are at least 9 years of age. 
 
Programming Note:  Use data from ADaM.ADLB, ADQS. Use raw values; for example, <0.10, not analysis value.  
 


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Listing 16.1.2   
Subject Profile: Pediatric Quality of Life Inventory – Total Scale and Summary Scores 
Safety Population 
Treatment:  <Maralixibat or Placebo> 
PFIC 
 
Age [1]/ 
Sex/ 
  Analysis 
Study 
Total Scale 
Score 
 
Physical Health 
Summary Score 
 
Psychosocial Health 
Summary Score 
 
Multidimensional 
Fatigue Scale Score 
Family 
Impact 
Total Scale 
Parent 
Functioning 
Summary 
Family 
Impact 
Summary 
Type 
Subject Country  Visit 
Day [2] 
Parent 
Child 
 
Parent 
Child 
 
Parent 
Child 
 
Parent 
Child 
Score 
Score 
Score 
 
 
xxxxxx 
xxxxxx x/x/xxx  Baseline 
-x 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
xx.x 
xxx.x 
 
 
 
 Week 4 
xx 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 Week 6 
xx 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 Week 10 
xx 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 Week 14 
xx 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 Week 18 
xx 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for all analysis visits) 
           
 
Abbreviations: ARG = Argentina; AUT = Austria; BEL = Belgium; BRA = Brazil; CAN = Canada; COL = Columbia; DEU = Germany; FRA = France; GBR = United Kingdom; ITA = Italy; LBN = Lebanon; MEX = 
Mexico; POL = Poland; SGP = Singapore; TUR = Turkey; USA = United States 
Note: Pediatric Quality of Life (PedsQL) self-report is measured in subjects who are 5 to 18 years of age. Individual item scores (0-4 scale) are reverse-scored and linearly transformed to a 0-100 scale 
(0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher scores indicate better HRQoL (less negative impact). Total scale and summary scores are computed as the average score. If more than 50% of the 
items in the scale are missing, the scale score is not computed. For scoring each total scale and summary score, refer to SAP. 
[1] Age (years) at Screening. The age-based questionnaires are based on age at screening. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
 
 
Programming Note: Use data from ADaM.ADQS. 
 


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Listing 16.1.3   
Subject Profile: Efficacy and Safety Labs (Serum Bile Acid, Lipids, Lipid   Vitamins, and Coagulation) 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age [1]/ 
 
Study 
 
 
Lipids 
 
Lipid Soluble Vitamins 
 
Coagulation 
 
PFIC 
 
Sex/ 
Analysis 
Day 
sBA [3] 
 
CHOL 
LDL 
HDL 
TG 
 
VITD 
VITA 
VITE 
RBP 
 
aPTT 
PT 
 
 
Type 
Subject 
Country 
Visit 
[2] 
(umol/L)  (mg/dL) (mg/dL) (mg/dL) (mg/dL) 
 (ng/mL) (µg/dL) (mg/dL) (mg/dL) 
 
(sec) (sec) INR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
xxxxxx 
x/x/xxx 
Baseline 
-x 
xx.x 
 
xxx 
xxx 
xx 
xxx 
 
xx.x 
xx.x 
x.xx 
xx.xx 
 
xx.x 
xx.x 
x.x 
 
 
 
Week 2 
xx 
xx.x b 
 
xxx 
xxx 
xx 
xxx 
 
xx.x 
xx.x 
x.xx 
xx.xx 
 
xx.x 
xx.x 
x.x 
 
 
 
Week 6 
xx 
xx.x 
 
xxx 
xxx 
xx 
xxx 
 
xx.x 
xx.x 
x.xx 
xx.xx 
 
xx.x 
xx.x 
x.x 
 
 
 
Week 10 
xx 
xx.x 
 
xxx 
xxx 
xx 
xxx 
 
xx.x 
xx.x 
x.xx 
xx.xx 
 
xx.x 
xx.x 
x.x 
 
 
 
Week 14 
xx 
xx.x 
 
xxx 
xxx 
xx 
xxx 
 
xx.x 
xx.x 
x.xx 
xx.xx 
 
xx.x 
xx.x 
x.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    (Continue for all analysis visits)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: sBA = Serum Bile Acid; CHOL = Cholesterol; LDL = LDL Cholesterol; HDL = HDL Cholesterol; TG = Triglycerides; VITD = 25-Hydroxyvitamin D; VITA = Vitamin A; 
VITE = Alpha Tocopherol; RBP = Retinol Binding Protein; aPTT = Activated Partial Thromboplastin Time; PT = Prothrombin Time; INR = International Normalized Ratio; ARG = 
Argentina; AUT = Austria; BEL = Belgium; BRA = Brazil; CAN = Canada; COL = Columbia; DEU = Germany; FRA = France; GBR = United Kingdom; ITA = Italy; LBN = Lebanon; 
MEX = Mexico; POL = Poland; SGP = Singapore; TUR = Turkey; USA = United States 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug.  
[3] 'b' indicates ≥ 75% reduction (ie, CFB ≤ -75%) OR sBA < 102 umol/L. 
 
 
 
Programming Note:  Use data from ADaM.ADLB. Responder indicator needs to be added for sBA (see footnote 4).  Add abbreviations to ‘Note:’ as needed for missing labs 
 
 


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Listing 16.1.4   
Subject Profile: Sodium and Lipid Soluble Vitamin Levels 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
 
Alpha 
Tocopherol/ 
 
Retinol: 
 
 
Corrected 
 
PFIC 
Type 
 
 
Subject 
Age [1]/ 
Sex/ 
Country 
Analysis 
Visit 
Study 
Day [2] 
VITD 
(ng/ml) 
VITA 
(ug/dL) 
VITE 
(mg/dL)  
CHOL + TG 
Ratio (mg/g) 
[3] 
 
RBP 
(mg/dL) 
RBP Molar 
Ratio 
(mol/mol) [4] 
International 
Normalized 
Ratio 
Sodium  
(mEq/L) 
Sodium 
(mEq/L) 
[5] 
 
 
xxxxx 
xxxxxx x/M/xxx 
Baseline 
-x 
xx.x 
xx.x 
x.xx 
 
x.xx 
x.xx 
x.xx 
x.x 
xxx 
xxx 
 
 
 
Week 2 
xx 
xx.x 
xx.x 
x.xx 
 
x.xx 
x.xx 
x.xx 
x.x 
xxx 
xxx 
 
 
 
Week 4 
xxx 
xx.x 
xx.x 
x.xx 
 
x.xx 
x.xx 
x.xx 
x.x 
xxx 
xxx 
 
 
(Continue for all analysis visits) 
 
 
 
Abbreviations: ARG = Argentina; AUT = Austria; BEL = Belgium; BRA = Brazil; CAN = Canada; COL = Columbia; DEU = Germany; FRA = France; GBR = United Kingdom; ITA = 
Italy; LBN = Lebanon; MEX = Mexico; POL = Poland; SGP = Singapore; TUR = Turkey; USA = United States; VITD = 25-Hydroxyvitamin D; VITA = Vitamin A; VITE = Alpha 
Tocopherol; CHOL = Cholesterol; TG = Triglycerides; RBP = Retinol Binding Protein 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
[3] Ratio (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 (ie, 0.1 mg/dL), half of the minimum quantitation limit is used as the analysis value. 
[4] Molar Ratio (mol/mol) = 0.0734 x retinol (ug/dL) / RBP (mg/dL) 
[5] Corrected Sodium (mEq/L) = sodium (mEq/L) + [0.002 x triglycerides (mg/dL)] 
 
 
Programming Note: Use data from ADaM.ADLB. 
 
 


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Page 8 of 51 
 
 
Listing 16.2.1   
Analysis Populations and Siblings  
All Subjects 
 
Treatment:  <Maralixibat or Placebo> 
 
PFIC 
 
Sibling in 
                         Analysis Population 
Type 
Subject 
Study? [1] 
Safety 
ITT 
Per-Protocol 
 
 
 
 
 
 
xxxxxx 
XXXXXX 
 
Yes 
Yes 
Yes 
 
 
 
 
 
 
 
XXXXXX 
Yes 
Yes 
Yes 
Yes 
 
 
 
 
 
 
 
XXXXXX 
Yes 
Yes 
Yes 
No 
 
 
 
 
 
 
xxxxxx 
XXXXXX 
 
Yes 
Yes 
No 
 
 
 
 
 
 
 
Abbreviation: ITT = Intent-to-Treat 
Note: Safety population consists of all subjects who received at least 1 dose of study drug. ITT population consists of all randomized subjects.  
Per-protocol population consists of all subjects 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.  
[1] Siblings are assigned in a blinded manner to the same treatment arm. Each sibling is considered for the Safety, ITT, and Per-Protocol 
populations. One sibling within a family is considered for a sensitivity analysis on the primary and key secondary efficacy endpoints for the 
primary and PFIC cohorts in the ITT Population. The choice of sibling to use in the sensitivity analysis is made at random, unless only 1 sibling 
is evaluable in the specific cohort and ITT Population and the other sibling is not. In this case, the evaluable sibling will be used in sensitivity 
analyses.    
 
 
Programming Note: Use data from ADaM.ADSL 
 
 
 
 
 
 
 


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Page 9 of 51 
 
 
Listing 16.2.2.1   
Subject Disposition 
Screen Failure Subjects Enrolled in Study 
 
 
 
 
 
 
Protocol 
Date 
 
Subject 
Criteria Version 
Screened 
Screen Failure Reason 
 
 
 
 
XXXXXX 
Amendment 2 – 22NOV2019 
DDMMMYYYY 
EXCL08: XXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
INCL05: XXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
XXXXXX 
xxxxxxxxxxxx 
DDMMMYYYY 
INCL02: XXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
XXXXXX 
xxxxxxxxxxxxx 
DDMMMYYYY 
OTHER: XXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
XXXXXX 
xxxxxxxxxxxxx 
DDMMMYYYY 
XXXXXX: XXXXXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
Programming Note:  Only include subjects that were screen failures but were enrolled in the study, regardless of if the Sponsor granted a waiver.  
Use data from CRF.IE, CRF.SFR and CRF.STATFRM.  For Screen Failure Reason, use CRF.IE.IENUM || ‘:  ‘ || CRF.IE.IEREAS.  If CRF.SFR.SFREAS = 
OTHER then Reason = CRF.SFR.SFREAS||’: ‘||CRF.SFR.SFREASOT. 
 
 
 
 
 
 
 
 
 
 
 
 


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Page 10 of 51 
 
 
Listing 16.2.2.2   
Subject Disposition and Completion 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
 
Date of  
Specify 
Enroll 
 
Tol. 
 
 
Date of  
 
 
 
 
  
Discon- 
Reason for 
in 
Max 
Min. 
 
Date of 
Last Contact 
PFIC 
 
Date 
Date 
  
tinuation/ 
Discontinuation 
MRX 
Dose Dose?/ 
Date of 
Last Dose 
(Study Day) 
Type 
 Subject 
Screened  
Enrolled 
Status 
Completion 
from Study 
503? 
[1] 
LTFU? 
First Dose 
(Study Day) 
[2] 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
xxxxxx 
DDMMMYYYY DDMMMYYYY Comp 
DDMMMYYYY 
 
Yes 
600 
Yes/
Yes 
DDMMMYYYY 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
DDMMMYYYY DDMMMYYYY 
Disc 
DDMMMYYYY 
XXXXXXXXXXXXXX 
No 
300 
Yes/
No 
DDMMMYYYY 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx 
xxxxxx 
DDMMMYYYY DDMMMYYYY 
Disc 
DDMMMYYYY 
 
No 
450 
Yes/
No 
DDMMMYYYY 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: Comp = Completed; Disc = Discontinued; Max = Maximum; Tol. Min. Dose? = Did Subject Tolerate Minimum Drug Dose?; LTFU = Willing to provide Informed Consent and 
Assent as applicable for Long-Term Follow-Up Period? 
Note: Study Day is calculated relative to the date of the first dose of study drug.   
[1] Maximum dose presented in units of µg/kg/day. 
[2] Completed only if subject is lost to follow-up. 
 
 
Programming Note:  If subject discontinues the study prematurely for Reason=AE, Physician Decision, Protocol Violation, Withdrawal of Consent, or Other, then Reason for d/c is 
DS.DSTERM concatenated with DS.DSREASSP (e.g., Other: Family Emergency). If DS.DSTERM = Death then Reason for d/c is DS.DSTERM concatenated with DS.DSDEATH. If subject 
discontinues the study due to Lost to follow-up then Reason=Lost to follow-up concatenated with the DS.DSLFCOMT field (e.g., Lost to follow-up: xxxxxxxxxxxxxxx). Date of First 
Dose pulled from CRF.SDFD.  Use data from CRF.DS, SDFD and STATFRM. 
 
 
 
 


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Page 11 of 51 
 
 
 
 
 
Listing 16.2.3.1   
Randomized Subjects by Randomized Cohort and Phenotype 
Intent-to-Treat Population 
 
 
Treatment:  <Maralixibat or Placebo> 
 
From Dummy Rand File 
 
PFIC Type From 
Enrollment Log 
 
Analysis 
 
Mutation 1 
 
Mutation 2 
 
Random 
ized 
Phenotype 
Mutation 
in Gene Subject 
Treatment 
Start Date 
Rand. 
Date 
Rand. 
Num. 
Trtmt Strata 
 
At 
Screen 
ing 
At 
Random 
ization 
 
BSEP 
Pheno. 
PFIC 
Type 
 
BSEP 
Pheno. 
cDNA 
Protein BSEP Zyg.  
cDNA 
Protein BSEP Zyg. 
Other 
Mutation 
 
PFIC2 - 
Primary 
Cohort 
ABCB11 xxxxxx 
DDMMYYYY DDMMYYYY xxxx 
MRX PFIC2  PFIC2 - 
Primary 
Cohort 
PFIC2 - 
Primary 
Cohort 
 BSEP 2 nt-PFIC2  
nt 
xxxxxxxx xxxxxxxx
xxxxx 
BSEP2 HET  xxxxxxxx
xx 
xxxxxxxx
xx 
BSEP2 HET 
 
 
 
 
xxxxxx 
DDMMYYYY DDMMYYYY xxxx 
MRX PFIC2  PFIC2 - 
Supplem
ental 
Cohort 
PFIC2 - 
Primary 
Cohort 
 BSEP 2 nt-PFIC2  
nt 
xxxxxxxx
xxxxx 
xxxxxxxx
xxxxxxxx
xxxxxxxx
xx 
BSEP3 HET  xxxxxxxx
xxxxxxxx
xx 
xxxxxxxx
xxxxx 
BSEP2 HET 
 
 
 
xxxxx 
xxxxxx 
DDMMYYYY DDMMYYYY xxxx 
MRX PFIC2  PFIC2 - 
Primary 
Cohort 
PFIC2 - 
Primary 
Cohort 
  
No-
variant-
found 
 
NA 
 
 
NA 
HOM  
 
 
 
HOM 
 
 
 
Abbreviations: Rand = Randomization; Trtmt = Treatment; BSEP = bile salt excretion pump; Pheno = Phenotype; cDNA = complementary DNA; Zyg = Zygocity; t = truncated; nt = not truncated; HET = Heterozygous; 
HOM = Homozygous; NA = not applicable 
Note: Sample is used to provide a full characterization and documentation of the mutation type in support of the diagnosis of PFIC. Mutation in Gene data is collected at Screening visit. 
 
 
Programming Note: Use data from CRF.RAND, ADSL, CRF.CPGR. 


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Page 12 of 51 
 
 
 
Listing 16.2.3.2     
Subjects Where Randomized Cohort Conflicts with PFIC Type  
Intent-to-Treat Population 
 
 
Treatment:  <Maralixibat or Placebo> 
 
From Dummy Rand File 
 
PFIC Type From 
Enrollment Log 
 
Analysis 
 
Mutation 1 
 
Mutation 2 
 
Random 
ized 
Phenotype 
Mutation 
in Gene Subject 
Treatment 
Start Date 
Rand. 
Date 
Rand. 
Num. 
Trtmt Strata 
 
At 
Screen 
ing 
At 
Random 
ization 
 
BSEP 
Pheno. 
PFIC 
Type 
 
BSEP 
Pheno. 
cDNA 
Protein BSEP Zyg.  
cDNA 
Protein BSEP Zyg. 
Other 
Mutation 
 
PFIC2 - 
Primary 
Cohort 
ABCB11 xxxxxx 
DDMMYYYY DDMMYYYY xxxx 
MRX PFIC2  PFIC2 - 
Primary 
Cohort 
PFIC2 - 
Primary 
Cohort 
 BSEP 2 nt-PFIC2  
nt 
xxxxxxxx xxxxxxxx
xxxxx 
BSEP2 HET  xxxxxxxx
xx 
xxxxxxxx
xx 
BSEP2 HET 
 
 
 
 
xxxxxx 
DDMMYYYY DDMMYYYY xxxx 
MRX PFIC2  PFIC2 - 
Supplem
ental 
Cohort 
PFIC2 - 
Primary 
Cohort 
 BSEP 2 nt-PFIC2  
nt 
xxxxxxxx
xxxxx 
xxxxxxxx
xxxxxxxx
xxxxxxxx
xx 
BSEP3 HET  xxxxxxxx
xxxxxxxx
xx 
xxxxxxxx
xxxxx 
BSEP2 HET 
 
 
 
xxxxx 
xxxxxx 
DDMMYYYY DDMMYYYY xxxx 
MRX PFIC2  PFIC2 - 
Primary 
Cohort 
PFIC2 - 
Primary 
Cohort 
  
No-
variant-
found 
 
NA 
 
 
NA 
HOM  
 
 
 
HOM 
 
 
 
Abbreviations: Rand = Randomization; Trtmt = Treatment; BSEP = bile salt excretion pump; Pheno = Phenotype; cDNA = complementary DNA; Zyg = Zygocity; t = truncated; nt = not truncated; HET = Heterozygous; 
HOM = Homozygous; NA = not applicable 
Note: Sample is used to provide a full characterization and documentation of the mutation type in support of the diagnosis of PFIC. Mutation in Gene data is collected at Screening visit. 
 
 
Programming Note: Use data from CRF.RAND, ADSL, CRF.CPGR. 
 
 


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Page 13 of 51 
 
 
 
 
 
Listing 16.3.1     
Inclusion and Exclusion Criteria 
All Subjects 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
Meet All 
 
Reason 
PFIC 
 
Protocol 
Eligibility 
Criteria 
Eligibility 
Type 
Subject 
Criteria Version 
Criteria? 
Not Met 
Criteria Not Met 
 
 
 
 
 
xxxx 
XXXXXX 
Original – 14MAR2019 
No 
Excl04 
xxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
XXXXXX 
Amendment 1 – 29APR2019 
No 
Excl04 
xxxxxxxxxxxxxxx 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Amendment 2 – 22NOV1029 
Yes 
 
 
 
 
 
 
 
 
 
XXXXXX 
Amendment 3 – 16JUN2020 
Yes 
 
 
 
 
 
 
 
 
 
 
 
Programming Note:  Use CRF.IE.IEPVER for Protocol Criteria Version.  See IEVER_ format in the eCRF document for proper decoding.  Use 
data from CRF.IE. 
 
 
 
 


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Page 14 of 51 
 
 
Listing 16.3.2   
Important Protocol Deviations 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
Excl 
 
 
 
 
 
 
 
 
Event 
Event Report 
from 
 
 
 
 
Sponsor 
 
PFIC 
 
Date 
Date 
PP 
 
 
Action 
 
Prior 
Date 
Type 
Subject 
(Study Day) [1] 
(Study Day) [1] 
Pop? 
Event Type 
Description 
Taken 
Comments 
Approval? 
Approved 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
Y 
Study/Protocol Procedure 
xxxxxxxxxxxxxxx xxxxxxx 
xxxx xxxxxxxx 
xxxxxx 
Yes 
DDMMMYYYY 
 
 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
 
Dosing Error (specify) 
xxxxxxxxxxxxxxxxxx xxxx 
xxxxxxxxxx 
xxxxxxxx xxxxx 
No 
 
 
 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
 
Dosing Error (specify) 
xxxxxxxxxxxxxxxx xxxxx 
xxx 
xxxxxxxxx 
xxxx 
No 
 
 
 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
 
Dosing Error (specify) 
xxxxxxxxxxxx xxxxxxxxx 
xxxxxxxxxx 
xxxxxx xxx xxxx 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
X 
Dosing Error (specify) 
xxxxxxxxxxxxxxx xxxxxx 
xxxxxxxxx 
xxx xxxxx 
No 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
 
Inclusion/Exclusion Criteria 
x xxxxxxx xxxxxxxxx 
xxx xxxxxxx 
xxxxx xxxxxxxxx 
No 
 
 
 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
 
Dosing Error (specify) 
xxxxxxxxxxxxx 
xxxxxxxx 
xxxxxxx xxxxx 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: Excl from PP Pop? = Subject Excluded from Per-Protocol Population? 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
 
 
Programming Note: Use data from SDTM.DV and SDTM.SUPPDV. This listing only includes those deviations which are identified as “Important” or “Important – Non Evaluable”. 
Present ‘Y’ or ‘N’ in the Excl from PP Pop? column. 
 
 


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Page 15 of 51 
 
 
 
Listing 16.4.1     
Demographics and Baseline Information 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Age at 
Age at 
 
 
 
 
 
 
 
 
 
 
 
Consent 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
(Years,  
(Years, 
 
 
Baseline 
Baseline 
Baseline 
 
 
ItchRO 
 
PFIC 
 
Months) 
Months) 
 
 
Weight 
Height 
BMI 
 
 
in  
eDiary 
Type 
Subject 
[1] 
[1] 
Country 
Sex 
(kg) 
(cm) 
(kg/m2) 
Ethnicity 
Race 
Paper? 
Restrictions 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
10, 4 
10, 5 
GBR 
Male 
xx.x 
xxx 
xx.x 
Hispanic or 
Latino 
White 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
1, 11 
2, 0 
USA 
Female 
xx.x 
xxx 
xx.x 
Not Hispanic 
or Latino 
Asian 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
5, 5 
5, 7 
FRA 
Female 
xx.x 
xxx 
xx.x 
Not Hispanic 
or Latino 
Black or 
African 
American 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ARG = Argentina; AUT = Austria; BEL = Belgium; BRA = Brazil; CAN = Canada; COL = Columbia; DEU = Germany; FRA = France; GBR = United Kingdom; ITA = 
Italy; LBN = Lebanon; MEX = Mexico; POL = Poland; SGP = Singapore; TUR = Turkey; USA = United States; BMI = body mass index; ItchRO = Itch Reported Outcomes 
[1] The subject's age at Screening is used to determine the appropriate age category for the ItchRO, Exploratory Diary Questionnaire, Patient Impression of Severity and 
PedsQL instruments. 
 
 
Programming Note:  For multiple races, concatenate using ‘, ‘ as the delimiter.  Use data from CRF.DM and AGE. 
 
 
 


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Page 16 of 51 
 
 
 
 
Listing 16.4.2     
Long-Term Follow-Up Informed Consent and Disease Progression 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Date of 
 
Date of 
 
 
 
 
 
 
 
 
 
LTFU 
Date of 
LTFU 
 
Disease 
 
 
 
 
Increase 
 
 
Parental 
LTFU 
Adult 
 
Progression Reason 
 
Occurrence 
 
in 
PFIC 
 
Informed 
Informed 
Informed 
 
Assessment Not 
Date of 
Of Disease 
 
Concomitant 
Type 
Subject 
Consent 
Assent [1] 
Consent [2] 
Timepoint 
Performed? Assessed 
Assessment 
Progression? 
Outcome 
Medications? 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX DDMMMYYYY 
NA 
NA 
Annual 
Yes 
 
DDMMMYYYY Yes: xxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxx 
PEBD Surgery 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX DDMMMYYYY 
NA 
NA 
Unscheduled 
Yes 
 
DDMMMYYYY No 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX DDMMMYYYY DDMMMYYYY DDMMMYYYY 
xxxxxxxxx 
No 
xxxxxxxxxxxxxxxxxx
xxxxxxxxxxx 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: LTFU = long-term follow-up; NA = not applicable 
[1] Assent is not applicable if the subject is younger than 18 years of age or age of consent at the time of consent. 
[2] Adult Informed Consent is applicable if subject turned 18 years old or the age of consent during study participation. 
 
 
 
Programming Note:  For Occurrence of Disease Progression, if CRF.DP.DPORRES = YES then concatenate DPORRES||’: ‘||DPSPEC.  For Outcome, if CRF.DP.DPOUTO = OTHER then 
concatenate ‘OTHER: ‘||DPOUTOSP. Use data from CRF.DP. 
 
 


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Page 17 of 51 
 
 
 
 
 
Listing 16.4.3     
Informed Consent 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Date of 
 
Subject 
 
Re-consented 
 
 
 
 
 
Parental 
Date of 
Turn 18 or 
 
For Major 
 
 
Re-consent 
PFIC 
 
Informed 
Informed 
Age of Consent?/ 
 
Protocol 
Re-consent 
Re-consent 
Protocol 
Type 
Subject 
Consent 
Assent [1] 
Sign AIC? 
Date of AIC [2] 
Amendment? 
Type 
Date 
Version 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
DDMMMYYYY 
NA 
No 
NA 
Yes 
Parental/Caregiver 
Informed Consent 
DDMMMYYYY 
Amendment 1C – 
05AUG2019 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY 
DDMMMYYYY 
No 
NA 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
DDMMMYYYY 
NA 
Yes/Yes 
DDMMMYYYY 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: AIC = Adult Informed Consent 
[1] Assent is not applicable if the subject is younger than 18 years of age or age of consent at the time of consent. 
[2] Adult Informed Consent is applicable if subject turned 18 years old or the age of consent during study participation. 
 
 
Programming Note: Use data from CRF.DM, ICR and AIC. 
 
 


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Page 18 of 51 
 
 
 
Listing 16.4.4     
Medical History 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
 
 
 
 
PFIC 
 
Any 
 
 
 
 
 
Type 
Subject 
History? 
System Organ Class 
Preferred Term 
Verbatim Term 
Start Date 
End Date 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes 
XXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXX 
XXXXXXXXXXXXX 
DDMMMYYYY 
ONGOING 
 
 
 
 
 
 
 
 
 
XXXXXX 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
Yes 
XXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXX 
XXXXXXXXXXXX 
YYYY 
MMMYYYY 
 
 
 
 
 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
XXXXXXXXXXX 
MMMYYYY 
ONGOING 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXX 
XXXXXXXXXXXXX 
DDMMMYYYY 
DDMMMYYYY 
 
 
 
 
 
 
 
 
 
Note: Events coded using MedDRA version 22.1. 
 
  
 
Programming Note:  Sort medical histories (within subject) by SOC, PT and Verbatim Term. If event is marked as Ongoing, then put “ONGOING” for End Date. Do not 
include ‘UN’ or ‘UNK’ in dates. If entire start or end date is missing then report as ‘Unknown’. Use data from CRF.MH. 
 
 
 
 


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Page 19 of 51 
 
 
Listing 16.4.5    
Prior and Concomitant Medications/Therapies 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
Ongoing 
 
 
 
 
 
 
Date of 
 
At Time 
Anatomic Therapeutic Class/ 
 
 
Dose (Unit)/ 
PFIC 
 
Informed 
Any 
Of IC 
  Preferred Term/ 
Start Date/ 
 
  Route/ 
Type 
Subject 
Consent 
Meds? 
[1] 
    Verbatim Term 
  End Date 
Indication 
    Frequency 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
DDMMMYYYY 
Yes 
Yes 
XXXXXXXXXX/ 
DDMMMYYYY/ 
XXXXXXXXXXXX 
XXXX (XXXX)/ 
 
 
 
 
 
  XXXXXX/ 
  ONGOING 
 
  XXXXXXX/ 
 
 
 
 
 
     XXXXXXXXXXXXXXXXXXX 
 
 
     XXXXXXX 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
DDMMMYYYY 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
DDMMMYYYY 
Yes 
Yes 
XXXXXXXXXX/ 
DDMMMYYYY/ 
XXXXXXXXXXXX 
XXXX (XX)/ 
 
 
 
 
 
  XXXXXX/ 
  ONGOING 
 
  XXXXXXX/ 
 
 
 
 
 
     XXXXXXXXXXXXXXXXXXX 
 
 
     XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
XXXXXXXXXX/ 
DDMMMYYYY/ 
XXXXXXXXXXXXX 
XXXX (XXXX)/ 
 
 
 
 
 
  XXXXXX/ 
  DDMMMYYYY 
 
  XXXXXXX/ 
 
 
 
 
 
     XXXXXXXXXXXXXXXXXXX 
 
 
     XXXXXXX 
 
 
 
 
 
 
 
 
 
 
Abbreviation: IC = Informed Consent 
Note: Medication coded using WHO-DD (Enhanced version September 2019), Anatomic Therapeutic Class (ATC) Level 2. Preferred term is ATC Level 5.  
[1] Indicates whether the medication was ongoing at the time of Informed Consent. Medications that are stopped prior to the time of informed consent are not recorded. 
Only therapies administered for liver disease should be captured prior to baseline. 
 
  
Programming Note:  Sort medications (within subject) by start date and then by end date. For any field where answer is “Other”, concatenate the specify (e.g., OTHER: 
mmol) . Use data from CRF.CM. 
 
 


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Page 20 of 51 
 
 
 
Listing 16.5.1    
Liver Imaging 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Method of 
 
 
 
Masses 
 
PFIC 
 
Liver 
Date of 
Masses 
 
in the 
 
Type 
Subject 
Imaging 
Imaging 
Observed? 
If Masses Observed, Specify 
Liver? 
If Masses in the Liver, Specify 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Ultrasound 
DDMMMYYYY 
Yes 
XXXXXX 
 
 
 
 
Ultrasound 
DDMMMYYYY 
No 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
Ultrasound 
DDMMMYYYY 
 
 
Yes 
XXXXXXXXX 
 
 
Ultrasound 
DDMMMYYYY 
 
 
Yes 
XXXXXXXX 
 
 
 
 
 
 
 
 
 
XXXXXX 
MRI 
DDMMMYYYY 
No 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Ultrasound 
DDMMMYYYY 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note:  Use data from CRF.IM where formnam = IM and IM2. 
 
 
 
 
 


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Page 21 of 51 
 
 
 
Listing 16.5.2   
Liver-Associated Events 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Liver- 
 
 
 
 
Associated 
 
Event 
PFIC 
 
Event 
 
Start Date 
Type 
Subject 
Reported? 
Event 
(Study Day) [1] 
 
 
 
 
 
xxxxx 
XXXXXX 
No 
 
 
 
 
 
 
 
 
XXXXXX 
Yes 
OTHER: xxxxxxxxxxxxxxx 
DDMMMYYYY 
(xx) 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes 
PEBD SURGERY 
DDMMMYYYY 
(xx) 
 
 
 
 
 
 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
 
 
Programming Note: Use data from CRF.LAE. 
 
 
 
 
 


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Page 22 of 51 
 
 
 
 
Listing 16.5.3   
Liver Transplant List 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Placed on 
Date Placed 
Still on 
 
Date Removed 
 
 
Liver 
On Liver 
Liver 
 
From Liver 
PFIC 
 
Transplant 
Transplant 
Transplant 
 
Transplant 
Type 
Subject 
List? 
List 
List? 
Reason for Removal 
List 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
No 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
Yes 
DDMMMYYYY 
Yes 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes 
DDMMMYYYY 
No 
xxxxxxxxxxxxxxxxxxxxxxxxx 
DDMMMYYYY 
 
 
 
 
 
 
 
 
 
 
Programming Note: Use data from CRF.LT. 
 
 
 
 
 


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CONFIDENTIAL  
 
 
 
Page 23 of 51 
 
 
 
Listing 16.6.1 
Study Drug Supplied and Compliance 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
Study 
Study Drug 
Study Drug 
Reason 
Bottle 
Date of Dosing Error 
 
 
 
 
PFIC 
 
Drug Quantity 
Supplied via 
Taken as 
Not Fully 
ID 
Start 
End 
Type of  
 
Compliance 
Type 
Subject 
Sufficient? 
Shipment? 
Prescribed? 
Supplied 
Numbers 
(Study Day) [1] 
(Study Day) [1] 
Dosing Error 
Comments 
% [2] 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
 
Yes 
No 
No 
 
xxxxx, 
xxxxx 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
XXXXXX 
XXXXXX 
xx.x% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
No 
 
xxxxxx 
DDMMMYYYY 
(xx) 
DDMMMYYYY 
(xx) 
XXXXXXXXX 
XXXXXXXXX 
 
 
 
Yes 
No 
Yes 
 
xxxxxx 
 
 
 
 
 
 
 
Yes 
No 
Yes 
 
xxxxxx 
 
 
 
 
 
 
 
Yes 
No 
Yes 
 
xxxxxx 
 
 
 
 
 
 
 
Yes 
No 
Yes 
 
xxxxxx 
 
 
 
 
 
 
 
No 
Yes 
Yes 
xxxxxxxxx 
 
 
 
 
 
 
 
 
Yes 
No 
Yes 
 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: ID = identification 
Note: Listing includes all dosing deviations, including those due to an adverse event. 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
[2] Compliance (%) = 100* (Treatment duration in days – Number of days both morning and evening doses were missed) / Treatment duration in days), where Treatment duration (days) = 
Date of last dose of study drug – Date of first dose of study drug + 1 day. For subject that are missing the date of last dose of study drug, the last known contact date is used to calculate 
treatment duration. 
 
Programming Note:  Use data from CRF.DA, formnam = DA3 and SDC.  % Compliance is in ADEX. 
 
 
 


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CONFIDENTIAL  
 
 
 
Page 24 of 51 
 
 
 
Listing 16.6.2  
Study Drug Exposure 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
 
 
 
 
 
Body 
Admini- 
 
 
 
 
 
 
 
Weight at 
stered 
 
 
 
Treatment 
 
PFIC 
 
Screening 
Study 
Dosage 
Start Date 
Stop Date 
Duration 
Total Dose 
Type 
Subject 
(kg) 
Drug? 
(µg/kg) 
(Study Day) [1] 
(Study Day) [1] 
(days) 
(µg/kg) [2] 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx.x 
Yes 
150  
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
x 
xxx 
 
 
 
Yes 
300 
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
x 
xxx 
 
 
 
Yes 
450 
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
x 
xxxx 
 
 
 
Yes 
600 
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
x 
xxxxx 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx.x 
xxx 
xxx 
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
x 
xxx 
 
 
 
xxx 
xxx 
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
x 
xxx 
 
 
 
xxx 
xxx 
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
x 
xxxxx 
 
 
 
xxx 
xxx   
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
xx 
xxxxxx 
 
 
 
xxx 
xxx  
DDMMMYYYY (xx) 
DDMMMYYYY (xx) 
xx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
[2] Total Dose (µg /kg) = Dose (µg/kg) x Number of doses taken between start and stop dates. For subjects who are missing the date of last dose of study drug, the 
last known contact date is used in the calculation of treatment duration and study drug exposure. 
 
 
Programming Note: Use data fromSDTM.EX. 
 
 


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CONFIDENTIAL  
 
 
 
Page 25 of 51 
 
 
 
Listing 16.6.3  
Study Drug Accountability 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
 
 
 
 
 
 
 
 
 
Dispensed?/ 
 
 
Dispense 
Volume 
Return 
Volume 
 
PFIC 
 
If No, 
 
Clinic 
Date 
Dispensed 
Date 
Returned 
 
Type 
Subject 
Reason 
Kit Number 
Visit 
(Study Day) [2] 
(mL) 
(Study Day) [1] 
(mL) 
Comments 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes 
xxxxx 
VISIT 1  
DDMMMYYYY (x) 
xx 
DDMMMYYYY (x) 
xx.x 
 
 
 
Yes 
xxxxx 
VISIT 2 
DDMMMYYYY (xx) 
xx 
DDMMMYYYY (xx) 
xx.x 
 
 
 
Yes 
xxxxx 
VISIT 3 
DDMMMYYYY (xx) 
xx 
DDMMMYYYY (xx) 
xx.x 
 
 
 
No/xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
 
 
 
Programming Note: Use data from CRF.DA, formnam = DA2. 
 
 
 


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Page 26 of 51 
 
 
 
Listing 16.7.1  
Total Serum Bile Acid 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
 
 
Total 
 
 
 
PFIC 
 
Age [1]/ 
Clinic 
Analysis 
Collection Date 
sBA 
Flag 
Change from Baseline [4] 
Type 
Subject 
Sex 
Visit 
Visit 
(Study Day) [2] 
(umol/L) 
[3] 
Observed 
Percent 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx/M 
Screening 
Screening 
DDMMMYYYY (-x) 
xxx.x 
 
 
 
 
 
 
Week 0 
Baseline 
DDMMMYYYY (xx) 
xxx.x 
 
xx.x 
xx.x 
 
 
 
Week x 
Week 2 
DDMMMYYYY (xx) 
xxx.x 
B 
xx.x 
xx.x 
 
 
 
Week x 
Week 6 
DDMMMYYYY (xx) 
xxx.x 
x 
xx.x 
xx.x 
 
 
 
Week x 
Week 10 
DDMMMYYYY (xx) 
xxx.x 
x 
xx.x 
xx.x 
 
 
 
Week x 
Week 14 
DDMMMYYYY (xxx) 
xxx.x 
x 
xx.x 
xx.x 
 
 
 
Week x 
Week 18 
DDMMMYYYY (xxx) 
xxx.x 
x 
xx.x 
xx.x 
 
 
 
Week x 
Week 22 
DDMMMYYYY (xxx) 
xxx.x 
x 
xx.x 
xx.x 
 
 
 
Week x 
Week 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline and all post-baseline sBA samples are assayed at Frontage Laboratories, while screening sBA samples are assayed at ACM 
Global Laboratories. Only pre-dose samples assayed at Frontage Laboratories are used as a baseline sample. 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug.  
[3] 'b' indicates ≥ 75% reduction from baseline OR sBA < 102 umol/L 
[4] Baseline is Day 0 value (prior to first dose of study drug).  
 
 
Programming Note:  Add footnote for sBA column if needed to explain abbreviation (eg, ‘ND = Not Done’); report sBA, observed CFB, 
and %CFB values to 1 decimal place. Use data from ADaM.ADLB. 
 
 
 
 


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Page 27 of 51 
 
 
 
Listing 16.7.2    
Serum Bile Acid Subspecies 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
PFIC 
 
Age [1]/ 
Sex/ 
Clinic 
 
Study 
 
 
Type 
Subject 
Country 
Visit 
Day [2] 
 
CDCA 
CHA 
DCA 
GCA GCDCA GDCA 
GLCA GUDCA 
LCA 
TCA TCDCA 
TDCA 
TLCA TUDCA UDCA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
3/M/GBR 
Screening 
-x 
 
x.xx 
x.xx 
x.xx xxx.xx 
xx.xx 
x.xx 
x.xx 
xxx.xx 
x.xx 
xx.xx 
xx.xx 
x.xx 
x.xx 
xx.xx 
x.xx 
 
 
 
Day 0 
-x 
 
x.xx 
x.xx 
x.xx xxx.xx 
xx.xx 
x.xx 
x.xx 
xxx.xx 
x.xx 
xx.xx 
xx.xx 
x.xx 
x.xx 
xx.xx 
x.xx 
 
 
 
Week 2 
xx 
 
x.xx 
x.xx 
x.xx xxx.xx 
xx.xx 
x.xx 
x.xx 
xxx.xx 
x.xx 
xx.xx 
xx.xx 
x.xx 
x.xx 
xx.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(   (Continue for all clinic visits) 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Abbreviations: ARG = Argentina; AUT = Austria; BEL = Belgium; BRA = Brazil; CAN = Canada; COL = Columbia; DEU = Germany; FRA = France; GBR = United Kingdom; ITA = Italy; LBN = 
Lebanon; MEX = Mexico; POL = Poland; SGP = Singapore; TUR = Turkey; USA = United States; CDCA = Chenodeoxycholic Acid; CHA = Cholic Acid; DCA = Deoxycholic Acid; GCA = 
Glycocholic Acid; GCDCA = Glycochenodeoxycholic Acid; GDCA = Glycodeoxycholic Acid; GLCA = Glycolithocholic Acid; GUDCA = Glycoursodeoxycholic Acid; LCA = Lithocholic Acid; TCA = 
Taurocholic Acid; TCDCA = Taurochenodeoxycholic Acid; TDCA = Taurodeoxycholic Acid; TLCA = Taurolithocholic Acid; TUDCA = Tauroursodeoxycholic Acid; UDCA = Ursodeoxycholic; BQL 
= below quantification limit 
Note: Serum bile acid components are presented in units of umol/L.  The lower quantification limit is 0.01 µmol/L for CA, GDCA, TDCA, TLCA, CDCA, GLCA, DCA, and LCA. For GCA, TCA, 
TUDCA, GUDCA, GCDCA, TCDCA, and UDCA, the lower limit is 0.2 µmol/L.  
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
 
 
Programming Note:  Use data from SDTM.LB. If Clinic Visit = ‘Week 0’ assign ‘Day 0’. Use raw values; for example, <0.10, not analysis value. 
 
 
 


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Page 28 of 51 
 
 
 
Listing 16.7.3  
Clinician Scratch Scale Score 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
Date of 
Clinician Scratch Scale Score 
PFIC 
 
 
Assessment 
Assessment 
 
Change from 
Type 
Subject 
Clinic Visit 
Completed? 
(Study Day) [1] 
Observed [2] 
Baseline [3] 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Screening 
Yes 
DDMMMYYYY (-xx) 
X 
 
 
 
Day 0 
Yes 
DDMMMYYYY (xx) 
X 
 
 
 
Week 2 
No 
 
 
 
 
 
Week 4 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
Week 6 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
Week 10 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
Week 14 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
Week 18 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
Week 22 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
Week 26 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
 
 
 
 
 
 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
[2] 0 = None; 1 = Rubbing or mild scratching when undistracted; 2 = Active scratching without evident skin abrasions; 3 = Abrasion 
evident; 4 = Cutaneous mutilation, haemorrhage and scarring evident. 
[3] Baseline is Day 0 value (prior to first dose of study drug). If Day 0 value is not available, the last value obtained during Screening is 
used as the baseline value. 
 
Programming Note: Use data from SDTM.QS. 
 
 


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Page 29 of 51 
 
 
 
Listing 16.7.4  
Itch Reported Outcomes (Subject and Caregiver) Average Morning and Evening Scores 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Analysis 
 
ItchRO (Pt) [3] Morning  
 
ItchRO (Pt) [3] Evening 
 
ItchRO (Obs) Morning 
 
ItchRO (Obs) Evening 
 
PFIC 
 
Age 
Visit 
 
Frequency 
 
Severity 
 
Frequency 
 
Severity 
 
Frequency 
 
Severity 
 
Frequency 
 
Severity 
 
Type 
Subject 
[1] 
Period [2] 
 
Score 
CFB 
 Score 
CFB 
 
Score 
CFB  Score 
CFB 
 
Score 
CFB  Score CFB 
 
Score 
CFB 
 
Score 
CFB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
X 
Baseline 
 
x.xx 
 
 
x.xx 
 
 
x.xx 
 
 
x.xx 
 
 
x.xx 
 
 x.xx 
 
 
x.xx 
 
 
x.xx 
 
 
 
 
 
Wks 1-6 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
x.xx 
x.xx  x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
 
 
 
Wks 7-10 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
x.xx 
x.xx  x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
 
 
 
Wks 11-14 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
x.xx 
x.xx  x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
 
 
 
Wks 15-18 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
x.xx 
x.xx  x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
 
 
 
Wks 19-22 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
x.xx 
x.xx  x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
 
 
 
Wks 23-26 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
x.xx 
x.xx  x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
X 
Baseline 
 
-- 
 
 
-- 
 
 
-- 
 
 
-- 
 
 
x.xx 
 
 x.xx 
 
 
x.xx 
 
 
x.xx 
 
 
 
 
 
Wks 1-6 
 
-- 
-- 
 
-- 
-- 
 
-- 
-- 
 
-- 
-- 
 
x.xx 
x.xx  x.xx 
x.xx 
 
x.xx 
x.xx 
 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for all analysis visit periods) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: ItchRO = Itch Reported Outcome; CFB = Change from Baseline, defined as post-baseline value minus baseline value; Pt = Patient; Obs = Observer 
Note: ItchRO scores have a range from 0 to 4, with the higher score indicating increasing itch frequency/severity.   
[1] Age (years) at Screening. 
[2] Average scores are calculated for each time period, averaging 7-day weekly averages. For each time period, the average of the 4 weekly scores is presented; or 6 weekly scores for Weeks 1-6. 
The baseline score is calculated as the average of the 4 weekly average scores before the first dose of study drug.  
[3] '--' indicates assessment is not applicable for subject age (i.e., if a subject was < 9 years old). 
 
 
Programming Note: Use data from ADAM.ADQS 
 
 
 


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Page 30 of 51 
 
 
 
Listing 16.7.5  
Exploratory Diary Questionnaire (Subject and Caregiver) Average Morning and Evening Scores 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Analysis 
EDQ (Pt) [4] Morning  
 
EDQ (Pt) [4] Evening 
 
EDQ (Obs) Morning  
EDQ (Obs) Evening  
PFIC 
 
Age 
Visit 
 
 
Severity 
 
Frequency 
 
Severity 
 
  
Severity 
 
 
 
Severity 
 
Type 
Subject 
[2] 
Period [3] 
   
Score 
CFB 
 
Score 
CFB  
Score 
CFB 
 
   Score 
CFB 
 
 
  Score 
CFB 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
xxxxx 
XXXXXX 
X 
Baseline 
   
x.xx 
 
 
x.xx 
 
 
x.xx 
 
 
   x.xx 
 
 
 
  
x.xx 
 
 
 
 
 
Wks 1-6 
   
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
   x.xx 
x.xx 
 
 
  
x.xx 
x.xx 
 
 
 
 
Wks 7-10 
   
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
   x.xx 
x.xx 
 
 
  
x.xx 
x.xx 
 
 
 
 
Wks 11-14 
   
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
   x.xx 
x.xx 
 
 
  
x.xx 
x.xx 
 
 
 
 
Wks 15-18 
   
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
   x.xx 
x.xx 
 
 
  
x.xx 
x.xx 
 
 
 
 
Wks 19-22 
   
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
   x.xx 
x.xx 
 
 
  
x.xx 
x.xx 
 
 
 
 
Wks 23-26 
   
x.xx 
x.xx 
 
x.xx 
x.xx  
x.xx 
x.xx 
 
   x.xx 
x.xx 
 
 
  
x.xx 
x.xx 
 
 
 
 
   
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
xxxxx 
XXXXXX 
X 
Baseline 
   
-- 
 
 
-- 
 
 
-- 
 
 
   x.xx 
 
 
 
  
x.xx 
 
 
 
 
 
Wks 1-6 
   
-- 
-- 
 
-- 
-- 
 
-- 
-- 
 
   x.xx 
x.xx 
 
 
  
x.xx 
x.xx 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
Abbreviation: EDQ = Exploratory Diary Questionnaire; CFB = Change from Baseline, defined as post-baseline value minus baseline value; Pt = Patient; Obs = Observer 
Note: EDQ scores have a range from 1 to 5, with the higher score indicating increasing itch frequency/severity.   
[1] Age (years) at Screening. 
[2] Average scores are calculated for each time period, averaging 7-day weekly averages. For each time period, the average of the 4 weekly scores is presented; or 6 weekly 
scores for Weeks 1-6. The baseline score is calculated as the average of the 4 weekly average scores before the first dose of study drug.  
[3] '--' indicates assessment is not applicable for subject age (i.e., if a subject was < 9 years old). 
 
 
 
 
Programming Note: Use data from ADAM.ADQS 
 
 


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Page 31 of 51 
 
 
 
Listing 16.7.6.1  
PIC and CIC 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
Patient Impression of Change (PIC) 
 
Caregiver Impression of Change (CIC) 
 
 
 
 
Date of 
 
 
 
Date of 
 
 
PFIC 
 
Clinic 
 
Assessment 
 
 
 
Assessment 
Itch 
Xanthoma 
Type 
Subject 
Visit 
Completed? 
(Study Day) [1] 
Score [2] 
 
Completed? 
(Study Day) [1] 
Score [2] 
Score [2] 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Week 26 EOT 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Week 26 EOT 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for all clinic visits) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: PIC is completed by subjects who are 9 years of age or older. 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
 
[2] 1 = Much better; 2 = Better; 3 = A little better; 4 = No change; 5 = A little worse; 6 = Worse; 7 = Much worse 
 
 
Programming note:  Merge records within a subject together by study visit; remove Visit column if there are visit discrepancies between 
assessments.  Use data from SDTM.QS. 
 
 
 


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Listing 16.7.6.2 
PIS and CIS 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
Patient Impression of Severity of Pruritus (PIS) 
 
Caregiver Impression of Severity of Pruritus (CIS) 
 
 
 
 
Date of 
 
 
 
Date of 
 
PFIC 
 
Clinic 
 
Assessment 
 
 
 
Assessment 
 
Type 
Subject 
Visit 
Completed? 
(Study Day) [1] 
Score [2] 
 
Completed? 
(Study Day) [1] 
Score [3] 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Day 0 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
 
 
Week 4 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
 
 
Week 6 
No 
 
 
 
No 
 
 
 
 
Week 10 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
 
 
Week 14 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
 
 
Week 18 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
 
 
Week 22 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
 
 
Week 26 EOT 
Yes 
DDMMMYYYY (xx) 
X 
 
Yes 
DDMMMYYYY (xx) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
[2] 0 = I didn’t feel itchy at all; 1 = I felt a little bit itchy; 2 = I felt pretty itchy; 3 = I felt very itchy; 4 = I felt very, very itchy 
[3] 0 = None; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very severe 
 
 
Programming note:  Merge records within a subject together by study visit; remove Visit column if there are visit discrepancies between 
assessments. Use data from SDTM.QS. 
 
 


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Page 33 of 51 
 
 
Listing 16.7.7 
Efficacy Laboratory Tests 
Intent-to-Treat Population 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
 
 
 
 
 
Local 
 
Standard 
Change 
PFIC 
 
Age [1]/ 
Laboratory Test 
Laboratory 
Clinic 
Analysis 
Collection Date Fasting? 
Lab?/ 
Test 
Reference Range 
from 
Type 
Subject 
Sex 
Category 
Test (units) 
Visit 
Visit 
(Study Day) [2] 
[3] 
Visit [4] 
Result [5] 
Low 
High 
Flag [6] Baseline [7] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx/M 
Cholestasis 
Serum Bile Acid (µmol/L) 
Week 0 
Baseline 
DDMMMYYYY 
(-x) 
X 
No 
xxx 
 
 
 
 
 
 
 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7α hydroxyl-4-cholesten-3-one 
(C4) (ng/mL) 
Week 0 
Baseline 
DDMMMYYYY 
(-x) 
X 
No 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Enzymes 
Alanine aminotransferase (U/L) 
xxxxxxx 
Baseline 
DDMMMYYYY 
(-x) 
X 
Yes/Baseline 
xxx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin (mg/dL) 
xxxxxxx 
Baseline 
DDMMMYYYY 
(-x) 
X 
 
xxx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for lab categories and lab tests specified in Programming Note) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
[3] Y = Yes; N = No; U = Unknown  
[4] Were the labs collected for a protocol-related visit in place of central lab collection?/If yes, for which visit? 
[5] 'x' indicates a concentration reported as below the minimum quantitation limit. Half of the minimum quantitation limit is used as the analysis value.  
[6] H = (High) The result is above the upper limit of the reference range for normal subjects; L = (Low) The result is below the lower limit of the reference range for normal subjects. 
[7] Baseline is Day 0 value (prior to first dose of study drug). If Day 0 value is not available, the last value obtained during Screening is used as the baseline value. 
 
 
 
Programming Note:  See Appendix 1 of SAP for list of efficacy lab tests (15 lab tests in total); do not include the 15 sBA subspecies since they are in 
Listing 16.7.2.  Round PELD and MELD to integers; round sBA (BILEAC), FIB-4 and APRI to 2 decimal places.  Use data from ADaM.ADLB. 
 
 


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Page 34 of 51 
 
 
 
Listing 16.7.8 
Height, Weight, and BMI z-Score 
    Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
PFIC 
Type 
Subject 
Age [1]/ 
Sex 
Clinic 
Visit 
 
Analysis 
Visit 
Vital  
Signs  
Collected? 
Date of  
Measurement 
(Study Day) [2] 
Height 
(cm) 
Weight 
(kg) 
 
BMI 
(kg/m2) 
Height 
z-Score 
Weight 
z-Score 
 
BMI 
z-Score 
 
xxxxx 
xxxxxx 
1/M 
Screening 
Screening 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
Week 0 
Baseline 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
xxxxx 
Week 2 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
xxxxxx 
Week 4 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
xxxxxxx 
Week 6 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
 
xxxxx 
xxxxxx 
x/X 
xxxxxxx 
Baseline 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
xxxxxxxx 
Week xx 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
xxxxxxx 
Week xx 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
xxxxxxxx 
Week xx 
Yes 
DDMMMYYYY (xx) 
xxx 
xx.x 
xx.x 
x.xx 
x.xx 
x.xx 
 
 
 
 
 
 
(Continue for all analysis visits) 
 
 
Abbreviation: BMI = Body Mass Index 
Note: Listing includes all records used for analysis purposes. A subject's sex and age (at each analysis visit) are used to derive z-scores. 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
 
Programming Note:  Use data from ADAM.ADVS. 
 
 


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Page 35 of 51 
 
 
 
Listing 16.7.9 
Exploratory Diary Questionnaire (Caregiver) Average Morning Scores in Sleep Disturbance 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Age at 
 
 
Sleep Disturbance Score 
PFIC 
 
Screening 
Analysis Visit 
 
 
Change from 
Type 
Subject 
(years) 
Period [1] 
 
Observed [3] 
Baseline 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx 
Baseline 
 
x.xx 
 
 
 
 
Wks 1-6 
 
x.xx 
x.xx 
 
 
 
Wks 7-10 
 
x.xx 
x.xx 
 
 
 
Wks 11-14 
 
x.xx 
x.xx 
 
 
 
Wks 15-18 
 
x.xx 
x.xx 
 
 
 
Wks 19-22 
 
x.xx 
x.xx 
 
 
 
Wks 23-26 
 
x.xx 
x.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Caregivers for all subjects aged <9 years complete the EDQ(Obs) instrument. Sleep disturbance is scored in 
the morning, in which the caregiver scores the following question: “Because of itch, my child had trouble staying 
asleep.”. 
[1] Average scores are calculated for each time period, averaging 7-day weekly averages. For each time period, 
the average of the 4 weekly scores is presented; or 6 weekly scores for Weeks 1-6. The baseline score is calculated 
as the average of the 4 weekly average scores before the first dose of study drug. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
[3] 1 = Never; 2 = Rarely; 3 = Sometime; 4 = Often; 5 = Almost Always 
 
 
Programming Note: Use ADAM.ADQS 
 
 
 
 


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Listing 16.8.1      
Adverse Events 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
PFIC 
Type 
Subject 
 
 
Any 
AEs? 
 
PFIC 
Rec 
[1] 
System Organ Class/ 
  Preferred Term/ 
       Verbatim Term 
TEAE? 
   Start Date 
  (Study Day) 
          [2] 
    End Date 
  (Study Day) 
         [2] 
 
Event 
Duration 
(days) 
Severity Grade/ 
  Relationship to 
       Study Drug 
Med PFIC Rec?/ 
  Outcome/ 
    Study Drug  
    Action Taken 
Serious?/ 
  Criteria  
  Met [3] 
Hospitalization 
Start Date- 
End Date/ 
  Comment 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes 
xxx 
xxxxxxxxxx xxxxx xxxxx/ 
  xxxxxxxxxxxxxxxxx/ 
    xxxxxxxxxxxxxxxxxx 
Yes 
DDMMMYYYY 
         (xx) 
DDMMMYYYY 
         (xx) 
xx 
Grade 1 (Mild)/ 
    Not Related 
Yes/ 
 Recovered/Resolved/ 
   Dose Not Changed 
No/ 
  None 
N/A/ 
  None 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes 
xxx 
xxxxxxxxxxxxxxxx xxxxx/ 
  xxxxxxxxxx/ 
    xxxxxxxxxxxxxxx 
No 
DDMMMYYYY 
         (xx) 
DDMMMYYYY 
         (xx) 
xx 
Grade x (xxxx)/ 
    Related 
xxx/ 
xxxxxxxx/ 
   xxxx xxx xxxxxxx 
Yes/ 
  HOSP; LT 
DDMMMYYYY-
DDMMMYYYY/ 
  xxxxxxxxx xxxxx 
  xxxxxxxx; xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: TEAE = Treatment-Emergent Adverse Event; Med PFIC Rec? = Medical Treatment Received? 
Note:  Adverse events coded using MedDRA version 22.1. In determining TEAEs and study day, partial dates were imputed based on the SAP. Treatment-emergent adverse events are AEs with a 
start date on or after the first dose of study drug and started prior to the last dose of study drug plus 7 days. For any subjects who die during the study and the date of death is between the 
date of first dose of study drug and the date of study discontinuation, all AEs that occur during the study are considered as TEAEs irrespective of the last dose.  
[1] Treatment received at the onset of the event; MRX dose reported in units of µg/kg/day. For AEs that started within 7 days after the last dose of study drug, the last MRX dose received is 
listed. For AEs that started > 7 days after the last dose of study drug, treatment received is blank. NT = Not Treated (for AEs that started prior to 1st dose of study drug) 
[2] Study Day is calculated relative to the date of the first dose of study drug.  
[3] CONG = Resulted in congenital anomaly or birth defect; DISAB = Resulted in significant incapacity or substantial disruption of normal life functions; FATAL = Resulted in death; HOSP = 
Required or prolonged hospitalization; LT = Was life-threatening; OTHER = Other medically important event that may jeopardize the subject. 
 
 
Programming Note:  Sort AEs (within treatment received, cohort and subject) by start date and then by end date; events that are ongoing would be listed after those with end 
dates (for those events with the same start date). For Comment, concatenate CRF.AE.AENARF1-4 with a ‘; ‘ delimiter. Use data from ADAM.ADAE. 
 
 


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Listing 16.8.2.1  
Adverse Events of Clinical Interest:  Diarrhoea Events 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
 
Listing 16.8.2.2  
Adverse Events of Clinical Interest:  Lipid Soluble Vitamin Deficiency Events 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
Listing 16.8.2.3  
Adverse Events of Clinical Interest:  Elevated Transaminases Events 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
Listing 16.8.2.4  
Adverse Events of Clinical Interest:  Elevated Bilirubin Events 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
 
Listing 16.8.3  
Treatment Related Adverse Events 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
 
 


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Listing 16.8.4.1  
Serious Adverse Events 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
 
Listing 16.8.4.2  
Serious Related Adverse Events 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
 
Listing 16.8.5 
Adverse Events Leading to Study Drug Discontinuation 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
 
 
Listing 16.8.6 
Severe Adverse Events 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
 
 
Listing 16.8.7 
Adverse Events Resulting in Death 
Safety Population 
Same shell as Listing 16.8.1, except remove ‘Any AEs?’ column 
 
 
 


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Page 39 of 51 
 
 
Listing 16.9.1  
Vital Signs 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
 
 
Systolic 
Diastolic 
 
 
 
 
 
Vital 
Date of 
Heart 
Respiratory 
Blood 
Blood 
 
PFIC 
 
 
Clinic 
Signs 
Measurement 
Rate 
Rate 
Pressure 
Pressure 
Temperature 
Type 
Subject 
Age [1] 
Visit 
Collected? 
(Study Day) [2] 
(beats/min) 
(rpm) 
(mmHg) 
(mmHg) 
(degrees C) 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx 
Screening 
Yes 
DDMMMYYYY (-xx) 
XX 
XX 
XXX 
XX 
XX.X 
 
 
 
Day 0 
Yes 
DDMMMYYYY (xx) 
XX 
XX 
XXX 
XX 
XX.X 
 
 
 
Week 2 
Yes 
DDMMMYYYY (xx) 
XX 
XX 
XXX 
XX 
XX.X 
 
 
 
Week 4 
No 
 
 
 
 
 
 
 
 
 
Week 6 
Yes 
DDMMMYYYY (xx) 
XX 
XX 
XXX 
XX 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for all clinic visits) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: H = High: The result is above the upper limit of the reference range for normal subjects; L = Low: The result is below the lower limit of the 
reference range for normal subjects 
Note: Normal reference ranges for heart rate, respiratory rate and blood pressure are based on the subject's age at time of the measurement.  
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
 
 
Programming Note: Use data from SDTM.VS. If Clinic Visit = ‘WEEK 0’ assign ‘Day 0’. 
 
 
 


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Page 40 of 51 
 
 
Listing 16.9.2  
Physical Examination 
Safety Population 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
Examination 
 
 
 
 
 
PFIC 
 
Clinic 
Examination 
Date 
Any/Changed 
 
 
 
Clinically 
Type 
Subject 
Visit 
Performed? 
(Study Day) [1] 
Abnormalities? [2] 
Body System 
Result 
Abnormal Finding 
Significant? 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Screening 
Yes 
DDMMMYYYY (-xx) 
Yes 
System 1 
Abnormal 
XXXXXXXXXXXXXXXXXX; 
Yes 
 
 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
System 2 
Normal 
 
 
 
 
 
 
 
 
System 3 
Normal 
 
 
 
 
Day 0 
Yes 
DDMMMYYYY (xx) 
No 
 
 
 
 
 
 
Week 2 
Yes 
DDMMMYYYY (xx) 
No 
 
 
 
 
 
 
Week 4 
Yes 
DDMMMYYYY (xx) 
Yes 
System 6 
 
XXXXXXXXXXXXX 
 
 
 
Week 6 
Yes 
DDMMMYYYY (xx) 
Yes 
System 6 
 
XXXXXXXXXXXXXXXXXX 
 
 
 
Week 10 
Yes 
DDMMMYYYY (xx) 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Screening 
Yes 
DDMMMYYYY (-xx) 
No 
 
 
 
 
 
 
Day 0 
Yes 
DDMMMYYYY (xx) 
No 
 
 
 
 
 
 
Week 2 
Yes 
DDMMMYYYY (xx) 
No 
 
 
 
 
 
 
Week 4 
Yes 
DDMMMYYYY (xx) 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for all clinic visits) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
[2] For Screening Visit, any abnormal findings are presented; for other visits, newly diagnosed or worsened clinically significant findings since previous visit are indicated. 
 
 
Programming Note:  For multiple Abnormal Findings within a Body System, separate text using a “;”. Use data from SDTM.PE. If Clinic Visit = ‘WEEK 0’ assign ‘Day 0’. 
 
 


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Page 41 of 51 
 
 
 
Listing 16.9.3 
12-Lead Safety ECG 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
 
 
 
 
 
 
Heart 
RR 
PR 
QRS 
Uncorrected 
 
 
Investigator 
 
PFIC 
 
 
ECG 
Date/Time 
Rate 
Interval Interval Duration QT Interval 
QTcB 
QTcF Interpretation: 
 
Type 
Subject 
Clinic Visit 
Performed?
Performed 
(bpm) 
(ms) 
(ms) 
(ms) 
(ms) 
(ms) 
(ms) Abnormality [1] 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX Screening 
Yes 
DDMMMYYYY:hh:mm 
99 
508 
120 
72 
294 
438 
376 Normal 
 
 
 
Day 0 
Yes 
DDMMMYYYY:hh:mm 
xxx 
xxx 
xxx 
xx 
xxx 
xxx 
xxx A-NCS: xxxxxxxxx 
xxxxxxxxxxxxxxx 
 
 
Week 10 
No 
 
 
 
 
 
 
 
 
 
 
 
 
Week 26 
Yes 
DDMMMYYYY:hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx xxxxxxxxx 
xxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX Screening 
Yes 
DDMMMYYYY:hh:mm 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx xxx: xxxxxxxxxx 
 
 
 
Day 0 
Yes 
DDMMMYYYY:hh:mm 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx xxxxxxxxx 
 
 
 
Week 10 
Yes 
DDMMMYYYY:hh:mm 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx xxxxxxxxx 
 
 
 
Week 26 EOT 
Yes 
DDMMMYYYY:hh:mm 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx xxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: QTcB = QT interval corrected using Bazett’s formula; QTcF = QT interval corrected using Fridericia’s formula 
[1] A-NCS = Abnormal-Not Clinically Significant; A-CS = Abnormal-Clinically Significant 
  
 
Programming Note: Use data from CRF.EG. 
 
 


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Page 42 of 51 
 
 
Listing 16.10.1  
Clinical Laboratory Tests:  Clinical Chemistry 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
Local 
 
 
Standard 
PFIC 
 
Age [1]/ 
Laboratory 
Clinic 
Collection Date 
Lab?/ 
Fasting? 
Test 
 
Reference Range 
Type 
Subject 
Sex 
Test 
Visit 
(Study Day) [2] 
Visit [3] 
[4] 
Result [5] 
Units 
Low 
High    [6] 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx/M 
xxxxxxxxxxxxxxxx 
Screening 
DDMMMYYYY (-x) 
No 
Y 
xxx 
xxx 
xx 
xx 
 
 
 
 
 
Day 0 
DDMMMYYYY (x) 
No 
Y 
xxx 
xxx 
xx 
xx 
x 
 
 
 
 
Week 2 
DDMMMYYYY (xx) 
Yes/Week 2 
Y 
xxx 
xxx 
xx 
xx 
 
 
 
 
 
Week 6 
DDMMMYYYY (xx) 
xx 
Y 
xxx 
xxx 
xx 
xx 
 
 
 
 
 
Week 10 
DDMMMYYYY (xx) 
xx 
Y 
xxx 
xxx 
xx 
xx 
 
 
 
 
 
Week 14 
DDMMMYYYY (xxx) 
xx 
Y 
xxx 
xxx 
xx 
xx 
 
 
 
 
 
Week 18 
DDMMMYYYY (xxx) 
xx 
Y 
xxx 
xxx 
xx 
xx 
 
 
 
 
 
Week 22 
DDMMMYYYY (xxx) 
xx 
U 
xxx 
xxx 
xx 
xx 
 
 
 
 
 
Week 26 
DDMMMYYYY (xxx) 
xx 
Y 
xxx 
xxx 
xx 
xx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      (Continue for all clinic visits) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug.  
[3] Were the labs collected for a protocol-related visit in place of central lab collection?/If yes, for which visit? 
[4] Y = Yes; N = No; U = Unknown 
[5] 'x' indicates a concentration reported as below the minimum quantitation limit. Half of the minimum quantitation limit is used as the analysis value. '+' indicates a concentration 
reported as above the maximum quantitation limit. The maximum quantitation limit is used as the analysis value. UNL = Unlabeled; SNS = Sample Not Submitted; QNS = Quantity Not 
Sufficient; NSA = Not Suitable for Analysis; NCAL = Not Calculated 
[6] H = (High) The result is above the upper limit of the reference range for normal subjects; L = (Low) The result is below the lower limit of the reference range for normal subjects. 
 
 
Programming Note:  Sort lab records (within subject) by laboratory test and then by collection date.  See Appendix 1 of SAP for listing of safety lab tests. Use data from SDTM.LB 
since labs from all vendors will be consolidated there. 
 
 


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Page 43 of 51 
 
 
Listing 16.10.2  
Clinical Laboratory Tests:  Hematology 
Safety Population 
Same shell as Listing 16.10.1 
 
 
Listing 16.10.3  
Clinical Laboratory Tests:  Urinalysis 
Safety Population 
Same shell as Listing 16.10.1 except remove Local Lab?/Visit column and adjust footnotes accordingly. 
 
 
Listing 16.10.4  
Clinical Laboratory Tests:  Lipid Soluble Vitamins 
Safety Population 
Same shell as Listing 16.10.1  
 
 
Listing 16.10.5   
Clinical Laboratory Tests:  Lipid Panel 
Safety Population 
Same shell as Listing 16.10.1 
 
 
Listing 16.10.6 
Clinical Laboratory Tests:  Hepatocellular Carcinoma Marker – Alpha-Fetoprotein (AFP) 
Safety Population 
Same shell as Listing 16.10.1 except remove Local Lab?/Visit column and adjust footnotes accordingly 
 
 


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Page 44 of 51 
 
 
 
Listing 16.10.7   
Clinical Laboratory Tests:  Timing of Sample Collection and Last Meal 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
Date of 
Date/Time of 
PFIC 
 
Age [1]/ 
Clinic 
Sample Collection 
Last Meal Prior to 
Type 
Subject 
Sex 
Visit 
(Study Day) [2] 
Sample Collection [3] 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx/M 
Screening 
DDMMMYYYY (-x) 
 
 
 
 
Day 0 
DDMMMYYYY (x) 
 
 
 
 
Week 2 
DDMMMYYYY (xx) 
DDMMMYYYY:hh:mm 
 
 
 
Week 6 
DDMMMYYYY (xx) 
DDMMMYYYY:hh:mm 
 
 
 
Week 10 
DDMMMYYYY (xx) 
DDMMMYYYY:hh:mm 
 
 
 
Week 14 
DDMMMYYYY (xx) 
DDMMMYYYY:hh:mm 
 
 
 
Week 18 
DDMMMYYYY (xxx) 
DDMMMYYYY:hh:mm 
 
 
 
Week 22 
DDMMMYYYY (xxx) 
DDMMMYYYY:hh:mm 
 
 
 
 
 
 
 
 
 
     (Continue for all clinic visits) 
 
 
 
 
 
 
 
 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
[3] Date/time of last meal prior to sample collection is collected on the Case Report Form. In cases where an unscheduled visit has the same 
date/time as a scheduled visit, the Date/Time of Last Meal Prior to Sample Collection were merged in by Sample Collection Date. 
 
 
Programming Note:  For Date/Time columns, may not need to add footnote. For example, “Date/Time of Last Meal Prior to Sample 
Collection data is collected on the Case Report Form. In cases where an unscheduled visit has the same date/time as a scheduled visit, the 
Date/Time of Last Meal Prior to Sample Collection was merged in by Sample Collection Date.” Use data from CRF.LB. 
 
 


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Page 45 of 51 
 
 
 
Listing 16.10.8 
Microbiology Tests 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
 
 
PFIC 
 
Age [1]/ 
Clinic 
Collection Date 
Microbiology 
Test 
 
Type 
Subject 
Sex 
Visit 
(Study Day) [2] 
Test 
Result [3] 
Units 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
xx/M 
Screening 
DDMMMYYYY (-x) 
xxxxxxxxxxxxxxxx 
xxx 
xxx 
 
 
 
Day 0 
DDMMMYYYY (x) 
 
xxx 
xxx 
 
 
 
Week 2 
DDMMMYYYY (xx) 
 
xxx 
xxx 
 
 
 
Week 6 
DDMMMYYYY (xx) 
 
xxx 
xxx 
 
 
 
Week 10 
DDMMMYYYY (xx) 
 
xxx 
xxx 
 
 
 
Week 14 
DDMMMYYYY (xxx) 
 
xxx 
xxx 
 
 
 
Week 18 
DDMMMYYYY (xxx) 
 
xxx 
xxx 
 
 
 
Week 22 
DDMMMYYYY (xxx) 
 
xxx 
xxx 
 
 
 
Week 26 
DDMMMYYYY (xxx) 
 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
      (Continue for all clinic visits) 
 
 
 
 
 
 
 
 
 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug.  
[3] UNL = Unlabeled; SNS = Sample Not Submitted; QNS = Quantity Not Sufficient; NSA = Not Suitable for Analysis; NCAL = Not Calculated 
 
 
Programming Note:  Sort microbiology records (within subject) by microbiology test and then by collection date. Include LBCAT = ‘EBV PANEL’, 
‘HCV RNA (PCR)’, HEP B SURFACE AG’, ‘HEP C ANTIBODY’, ‘HEPATITIS A AB, IGM’. Use data from SDTM.MB. 
 
 
 
 
 
 
 


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Page 46 of 51 
 
 
Listing 16.10.9 
Pregnancy Tests 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
Sample 
 
 
 
 
 
 
 
Age [1]/ 
 
Collected?/ 
 
 
 
 
 
PFIC 
 
Childbearing 
Clinic 
Reason Not 
Collection Date/Time 
Fasting? Sample 
Test 
 
Type 
Subject 
Potential 
Visit 
Collected? 
(Study Day) [2] 
[3] 
Type 
Result 
Units 
 
 
 
 
 
 
  
 
 
xxxxx 
XXXXXX 
XX/Yes 
Screening 
Yes 
DDMMMYYYY:hh:mm (-x) 
X 
Serum 
xxx 
xxx 
                  
 
 
 
 
 
 
 
 
 
 
 
Day 0 
Yes 
DDMMMYYYY:hh:mm (x) 
X 
Urine 
NEGATIVE 
 
 
 
 
Week 4 
No/xxxxxxx 
 
 
 
 
 
 
 
 
Week 10 
Yes 
DDMMMYYYY:hh:mm (xx) 
X 
Urine 
NEGATIVE 
 
 
 
 
Week 18 
Yes 
DDMMMYYYY:hh:mm (xx) 
X 
Urine 
NEGATIVE 
 
 
 
 
Week 26 
Yes 
DDMMMYYYY:hh:mm (xxx) 
X 
Urine 
NEGATIVE 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
XX/xxx 
Screening 
NA 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
Day 0 
NA 
 
 
 
 
 
 
 
 
Week 4 
Yes 
DDMMMYYYY:hh:mm (xx) 
X 
Urine 
NEGATIVE 
 
 
 
 
Week 26 EOT 
NA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Continue for all clinic visits) 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: NA = not applicable 
Note:  Listing for female subjects only; only females with at least 1 pregnancy test sample are included in the listing. 
[1] Age (years) at Baseline. 
[2] Study Day is calculated relative to the date of the first dose of study drug. 
[3] Y = Yes; N = No; U = Unknown  
 
Programming Note:  Listing should only include female subjects for which at least 1 pregnancy sample was collected. For these subjects, include each clinic visit. 
Use data from SDTM.LB. 
 
 


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Page 47 of 51 
 
 
Listing 16.10.10 
Plasma Sample Maralixibat Concentrations 
Safety Population 
 
Treatment:  <Maralixibat or Placebo>  
 
 
 
 
 
 
 
Date/Time of 
 
 
 
 
 
 
 
 
Last Meal Prior 
Maralixibat 
PFIC 
 
Clinic 
 
Sample 
Reason Not 
Collection 
to Sample 
Concentration 
Type 
Subject 
Visit 
Time Point 
Collected? 
Collected 
Date/Time 
Collection 
(ng/mL) 
 
 
 
 
 
 
 
 
 
xxxx 
XXXXXX 
Week 10 
PRE-DOSE 
Yes 
 
DDMMMYYYY:hh:mm 
 
BLQ 
 
 
 
 
 
 
 
 
 
 
 
 
+2.5H 
Yes 
 
DDMMMYYYY:hh:mm 
DDMMMYYYY:hh:mm 
XX.XX 
 
 
Week 26 
PRE-DOSE 
Yes 
 
DDMMMYYYY:hh:mm 
DDMMMYYYY:hh:mm 
XX.XX 
 
 
 
+2.5H 
No 
xxxxxxx xxxx xxx 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx 
XXXXXX 
Week 10 
PRE-DOSE 
 
 
DDMMMYYYY:hh:mm 
DDMMMYYYY:hh:mm 
BLQ 
 
 
 
 
 
 
 
 
 
 
 
 
+2.5H 
 
 
DDMMMYYYY:hh:mm 
DDMMMYYYY:hh:mm 
BLQ 
 
 
Week 26 EOT 
PRE-DOSE 
 
 
DDMMMYYYY:hh:mm 
DDMMMYYYY:hh:mm 
BLQ 
 
 
 
+2.5H 
 
 
DDMMMYYYY:hh:mm 
DDMMMYYYY:hh:mm 
BLQ 
 
 
 
 
 
 
(Continue for all clinic visits) 
 
 
 
 
 
 
 
 
Abbreviations: LLOQ = lower limit of quantitation; BLQ = below quantification limit 
Note:  LLOQ is 0.250 ng/mL. Any concentration below the LLOQ is reported as BLQ.  
 
 
 
Programming Note: Use data from CRF.PK. 
 
 
 
 
 


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Page 48 of 51 
 
 
 
Listing 16.11   
Telephone Contact Log 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
Subject/ 
 
Telephone/Email 
Any New/ 
Report new 
PFIC 
 
 
Caregiver 
Reason Not 
Contact Date 
Worsening 
Concomitant 
Type 
Subject 
Time Point 
Contacted? 
Contacted 
(Study Day) [1] 
AEs/SAEs? 
Medications? 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Week 1 
Yes 
 
DDMMMYYYY (x) 
No 
No 
 
 
Week 3 
Yes 
 
DDMMMYYYY (xx) 
No 
No 
 
 
Week 5 
No 
xxxxxxxxx xxxxx 
 
 
 
 
 
Week 8 
Yes 
 
DDMMMYYYY (xx) 
No 
No 
 
 
Week 12 
Yes 
 
DDMMMYYYY (xx) 
No 
No 
 
 
Week 16 
No 
xxxxxx xxxx 
 
 
 
 
 
Week 20 
Yes 
 
DDMMMYYYY (xx) 
No 
No 
 
 
Week 24 
Yes 
 
DDMMMYYYY (xx) 
Yes 
Yes 
 
 
Follow-up 
Yes 
 
DDMMMYYYY (NT) 
No 
No 
 
 
 
 
 
 
 
 
 
     (Continue for all time points) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviation: AEs = Adverse Events; SAEs = Serious Adverse Events 
[1] Study Day is calculated relative to the date of the first dose of study drug 
 
 
Programming Note:    If subject was never dosed, Study Day will be reported as “(NT)”.  Use data from CRF.TC1. 
 
 
 
 
 


Listing Shells 
Sponsor: Mirum Pharmaceuticals Inc. 
Protocol: MRX-502 (Amendment 4) 
PCN Number: MIRU8967 
 
 
 
CONFIDENTIAL  
 
 
 
Page 49 of 51 
 
Listing 16.12 
Visit Dates and Type 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
PFIC 
Type 
Subject 
Time Point 
Visit Date 
(Study Day) [1] 
 
Type of 
Visit 
Homecare 
Used?/If No, 
Explain 
 
Date of Call 
Continuing  
to 
Next Visit 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Screening 
DDMMMYYYY (x) 
In Clinic 
 
DDMMMYYYY 
Yes 
 
 
Baseline (Week 0) 
DDMMMYYYY (x) 
In Clinic 
 
 
Yes 
 
 
Subject Contact (Week 1) 
DDMMMYYYY (x) 
Telephone 
 
 
xxx 
 
 
Visit 2 (Week 2) 
DDMMMYYYY (x) 
Remote 
Yes 
 
xxx 
 
 
Subject Contact (Week 3) 
DDMMMYYYY (x) 
xxx 
 
 
xxx 
 
 
Visit 3 (Week 4) 
DDMMMYYYY (x) 
xxxxxx 
 
 
 
 
 
… 
DDMMMYYYY (x) 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Screening 
DDMMMYYYY (x) 
xxxxxxxx 
 
 
xxx 
 
 
Baseline (Week 0) 
DDMMMYYYY (x) 
xxxxx 
 
 
xxx 
 
 
Subject Contact (Week 1) 
DDMMMYYYY (x) 
xxxxxx 
 
 
xxx 
 
 
Visit 2 (Week 2) 
DDMMMYYYY (x) 
xxxxxx 
 
 
No 
 
 
Early Termination 
DDMMMYYYY (x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day is calculated relative to the date of the first dose of study drug. 
 
 
Programming Note: Use data from CRF.SV, CONT. 
 
 
 
 


Listing Shells 
Sponsor: Mirum Pharmaceuticals Inc. 
Protocol: MRX-502 (Amendment 4) 
PCN Number: MIRU8967 
 
 
 
CONFIDENTIAL  
 
 
 
Page 50 of 51 
 
 
 
Listing 16.13    
Healthcare Utilization 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
 
 
 
 
 
 
 
 
Number of 
 
 
Any 
 
 
Admitted 
 
Date of  
 
 
Work Days 
PFIC 
 
Medical 
Type of 
 
to 
Date of 
Surgery/ 
Date of 
Discharge 
Caregiver 
Type 
Subject 
Visits? 
Visit 
Reason for Visit 
Hospital? 
Admission 
Procedure 
Discharge 
Status 
Missed 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes 
OUTPATIENT 
XXXXXXXXXXXXXX 
Yes 
DDMMMYYYY 
DDMMMYYYY 
DDMMMYYYY 
OTHER: xxxxxxxxxxx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
XXXXXXXXXX 
XXXXXXXXXXXXX 
xxx 
DDMMMYYYY 
 
DDMMMYYYY 
 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Use data from CRF.HU. 
 
 
 
 
 


Listing Shells 
Sponsor: Mirum Pharmaceuticals Inc. 
Protocol: MRX-502 (Amendment 4) 
PCN Number: MIRU8967 
 
 
 
CONFIDENTIAL  
 
 
 
Page 51 of 51 
 
 
Listing 16.14   
COVID-19 Impact 
Intent-to-Treat Population 
 
Treatment:  <Maralixibat or Placebo> 
 
 
Subject 
 
 
Missed 
 
 
 
Study 
Study 
 
 
 
Affected by/ 
Type of 
 
Assessments? 
 
 
 
Drug 
Drug 
 
PFIC 
 
Visit Impacted Visit 
 
Efficacy/ 
ET Reason/ 
How IP 
Start Date/ 
Dispensation 
Administration Additional 
Type 
Subject 
by COVID-19? Adjustment 
Time Point 
Safety 
  Comments 
Impacted 
End Date 
Change 
Change 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
Yes/Week 14 
Missed 
DDMMMYYYY 
Yes/Yes 
 
 
 
 
 
xxxxxxxxxxxx 
 
 
Yes/Week 18 
Performed via 
telephone 
DDMMMYYYY 
No/No 
 
Dispensation 
Change 
DDMMMYYYY/ 
  DDMMMYYYY 
Delivered to 
subject offsite 
 
 
 
 
Yes/Week 26 
Other: xxxxxxxxxx 
DDMMMYYYY 
xx/xxx 
 
 
DDMMMYYYY/ 
  DDMMMYYYY 
XXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
XXXXXX 
 
Yes/Week 10 
Missed 
DDMMMYYYY 
Yes/Yes 
Subject Decision/ 
  XXXXXXXXXXXX 
Dosing 
Interruption 
DDMMMYYYY/ 
  DDMMMYYYY 
 
 
xxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ET = early termination; IP = investigational product 
 
 
Programming Note: If Other, specify is present in data, concatenate Other with specify data (e.g., Other: xxxxxx). Use data from CRF.COVID.