Conditions: Progressive Familial Intrahepatic Cholestasis (PFIC)
Keywords: Bile duct diseases Intrahepatic Cholestasis Cholestasis PFIC Pruritus Cholestatic Liver Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 33
Healthy volunteers: no

Brief summary:
This is an open label study in children with Progressive Familial Intrahepatic Cholestasis (PFIC) designed to evaluate the safety and efficacy of LUM001, also known as Maralixibat (MRX). Efficacy will be assessed by evaluating the effect of LUM001 on pruritus and the biochemical markers of pruritus associated with PFIC.

Detailed description:
The study is divided into 5 parts: a 4-week dose escalation period, a 4-week stable dosing period, a 5-week stable dosing period, a 59-week long-term exposure period, and an optional follow-up treatment period for eligible participants who continue treatment with LUM001. Participants in the optional follow-up treatment period will continue to receive study drug until they are eligible to enter another LUM001 study or until LUM001 is available commercially, whichever occurs first.

Arms:
arm 1: Participants will receive LUM001, also known as Maralixibat (MRX) twice a day (BID).

Interventions: intervention 1: LUM001 (Maralixibat)
Intervention descriptions: intervention 1: LUM001 also known as Maralixibat (MRX) oral dose up to twice a day (BID).

Protocol document:
Prot_000.pdf: 
 
 
 
CLINICAL PROTOCOL 
PROTOCOL NUMBER: LUM001-501 
 
 
INDIGO STUDY 
 
OPEN LABEL STUDY OF THE EFFICACY AND LONG TERM SAFETY OF LUM001, AN APICAL 
SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTi), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS WITH PROGRESSIVE FAMILIAL 
INTRAHEPATIC CHOLESTASIS 
 
 
Protocol Amendment 4.1:   08 February 2019 
Protocol History 
Protocol Amendment 4:  20 December 2016 
Protocol Amendment 3: 
Protocol Amendment 2: 
02 November 2015 
05 November 2014 
Protocol Amendment 1 (United Kingdom & Europe): 07 May 2014 
Protocol Amendment 1 (United States): 10 December 2013 
Original Protocol: 23 October 2013 
Developed in Collaboration with ChiLDREN 
 
 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA  
CONFIDENTIAL 
This document is a confidential communication of Mirum Pharmaceuticals, Inc.  It is agreed that no unpublished 
information contained herein will be published or disclosed without prior approval from the Sponsor.  However, 
this document can be disclosed to an appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) or authorized representatives of national regulatory authorities under the condition that they respect its 
confidential information. 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
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LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
 
SPONSOR SIGNATURE PAGE 
 
LUM001-501 
 
 
INDIGO STUDY 
 
OPEN LABEL STUDY OF THE EFFICACY AND LONG TERM SAFETY OF LUM001, AN APICAL 
SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTi), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS WITH PROGRESSIVE FAMILIAL 
INTRAHEPATIC CHOLESTASIS 
 
Protocol Amendment 4.1:   08 February 2019 
 
Protocol History: 
  
                                      Original Protocol: 23 October 2013 
Protocol Amendment 1 (United States): 10 December 2013 
Protocol Amendment 1 (United Kingdom & Europe): 07 May 2014 
Protocol Amendment 2: 05 November 2014 
Protocol Amendment 3: 02 November 2015 
Protocol Amendment 4:  20 December 2016 
 
 
 
 
 
Sponsor:  
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA  


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08 February 2019 
 
 
 
TITLE PAGE 
Study Drug: 
LUM001 
Protocol Number: 
LUM001-501 
Amendment Number: 
4.1 
Date: 
08 February 2019 
EudraCT No: 
2013-003833-14 
IND No: 
119916 
Study Phase: 
Phase 2 
Protocol Title: 
Open Label Study of the Efficacy and Long Term Safety of LUM001, 
an Apical Sodium-Dependent Bile Acid Transporter Inhibitor 
(ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric 
Patients with Progressive Familial Intrahepatic Cholestasis 
Sponsor: 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
Medical Monitor: 
Cagil Ozen, MD 
 
Premier Research 
 
Office: +1 215 282 5406 
 
Cell: +1 267 838 2380 
 
Email: medmonitorLUM501@premier-research.com 
Medical Lead: 
Thomas Jaecklin, MD 
Mirum Pharmaceuticals AG 
Innere Margarethenstrasse 5 
4051 Basel 
Switzerland 
 
Phone:  +41(0) 79 850 77 18  
 
 
Email:  tjaecklin@mirumpharma.com 
Compliance Statement: This study will be conducted in accordance with all applicable 
clinical research guidelines including the International Conference on 
Harmonization (ICH) Guidelines for current Good Clinical Practice 
(GCP).  Study documents will be maintained in accordance with 
applicable regulations. 


Mirum Pharmaceuticals, Inc. 
LUMOOl-501 Protocol Amendment 4.1 
CONFIDENTIAL 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Mi~;;;P, 
. 
Signature: 
• 
< 
( <._;---
Thomas JaecG in, 
D 
Date: 
SVP Clinical Development 
Page4 
08 February 2019 
I agree to conduct this study in accordance with the requirements of this clinical study protocol 
and also in accordance with the following: 
• 
Declaration of Helsinki (Oct 2008) 
• 
Established principles of Good Clinical Practice (ICH E6; GCP) (Harmonized) 
• 
US Code of Federal Regulations (CFR); Food and Drug Administration (FDA) 
(where applicable) 
• 
European Union (EU) Directives and national laws (where applicable) 
Clinical Study Title: 
OPEN LABEL STUDY OF THE EFFICACY AND LONG TERM SAFETY OF LUMOOl, AN 
APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTi), IN 
THE TREATMENT OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS 
WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS. 
Protocol Number: 
Amendment Number: 
Date: 
Sponsor: 
As Agreed: 
Investigator's Signature 
LUMOOl-501 
4.1 
08 February 2019 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
Investigator's Name (Please print) 
Date 


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EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Premier 
Research Serious Adverse Event Form within 24 hours to the Premier Research 
Pharmacovigilance Department. Applicable fax numbers and e-mail address can be found on the 
form (sent under separate cover) and below. 
Premier Research SAE Reporting: 
US and Canadian sites: fax 215-972-8765, or e-mail GlobalPV-US@premier-research.com 
EU/ROW sites: fax +421 2 6820 3713 or e-mail PVDS-ROW@premier-research.com 
For all urgent protocol- or safety-related issues during and outside of business hours, the 
investigator must contact the Premier Research Medical Monitor: 
Cagil Ozen, MD, Medical Director 
North America (US and Canada) sites: 
Central phone number: +1 512 686 1256 (US) 
European and ROW sites: 
Central phone number: +44 118 936 4096 (United Kingdom) 
For non-emergencies, the Premier Research Medical Monitor may be contacted by e-mail: 
medmonitorLUM501@premier-research.com    
 
 


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PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints to Mirum within 
24 hours. This includes any instances wherein the quality or performance of a Mirum product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 11. 
Please use the information below as applicable to report the Product Quality Complaint: 
Origin of Product Quality Complaint 
E-mail Address 
North and South America 
medinfo@mirumpharma.com 
European Union and Rest of World 
medinfo@mirumpharma.com 
Telephone numbers (provided for reference if needed): 
Mirum, Menlo Park, CA (USA) 
1-650-667-4085 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
TITLE PAGE ...................................................................................................................................3 
PROTOCOL SIGNATURE PAGE .................................................................................................4 
EMERGENCY CONTACT INFORMATION ................................................................................5 
PRODUCT QUALITY COMPLAINTS..........................................................................................6 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
PROTOCOL AMENDMENT 4.1 .................................................................................................13 
PROTOCOL AMENDMENT 4 ....................................................................................................16 
PROTOCOL AMENDMENT 3 ....................................................................................................38 
PROTOCOL AMENDMENT 2 ....................................................................................................48 
PROTOCOL AMENDMENT 1 (UNITED STATES) ..................................................................52 
PROTOCOL AMENDMENT 1 (UNITED KINGDOM & EUROPE) .........................................54 
1 
STUDY SYNOPSIS AND SCHEDULE OF PROCEDURES ..............................................57 
2 
LIST OF ABBREVIATIONS AND TERMS .........................................................................78 
3 
STUDY OBJECTIVES ..........................................................................................................82 
4 
BACKGROUND AND RATIONALE ...................................................................................83 
4.1 
Therapeutic Rationale ..............................................................................................83 
4.2 
Progressive Familial Intrahepatic Cholestasis ..........................................................84 
4.3 
Pruritus .....................................................................................................................85 
4.4 
LUM001 ...................................................................................................................86 
 
Nonclinical Studies ...........................................................................................86 
4.4.1.1 
Pharmacology ....................................................................................................86 
4.4.1.2 
Pharmacokinetics ..............................................................................................87 
4.4.1.3 
Toxicology ........................................................................................................87 
 
Previous Clinical Experience ............................................................................88 
4.5 
Rationale for Dose and Schedule of Administration ................................................89 
5 
INVESTIGATIONAL PLAN .................................................................................................93 
5.1 
Study Design ............................................................................................................93 
5.2 
Data and Safety Monitoring Board ..........................................................................93 
5.3 
Number of Study Centers .........................................................................................93 
5.4 
Number of Subjects ..................................................................................................93 
5.5 
Overall Study Duration and Follow-up ....................................................................93 
 
Screening ...........................................................................................................96 
 
Treatment ..........................................................................................................97 


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5.5.2.1 
Dose Escalation Period .....................................................................................97 
5.5.2.2 
Stable Dosing Period .........................................................................................98 
5.5.2.3 
Long-term Exposure Period ..............................................................................98 
5.5.2.4 
Optional Follow-up Treatment Period (Post-Week 72) ....................................99 
5.5.2.5 
Safety Follow-up Period .................................................................................100 
 
Electronic Diary ..............................................................................................100 
5.6 
End of Study ...........................................................................................................100 
6 
SUBJECT ENROLLMENT .................................................................................................102 
6.1 
Screening ................................................................................................................102 
6.2 
Enrollment ..............................................................................................................102 
6.3 
Replacement of Subjects ........................................................................................102 
7 
SUBJECT ELIGIBILITY .....................................................................................................103 
7.1 
Inclusion Criteria ....................................................................................................103 
7.2 
Exclusion Criteria ...................................................................................................104 
7.3 
Eligibility for Optional Follow-up Treatment Period ............................................105 
 
Inclusion Criteria .............................................................................................105 
 
Exclusion Criteria............................................................................................105 
8 
STUDY PROCEDURES ......................................................................................................106 
8.1 
Study Schedule .......................................................................................................106 
 
Screening Period (Day -42 to Day -1).............................................................106 
 
Dose Escalation Treatment Period (Day 0 to Week 4) ...................................106 
 
140 µg/kg/day Stable Dosing Treatment Period (Week 5 to Week 8) ............107 
 
280 µg/kg/day Stable Dosing Treatment Period (Week 9 to Week 13) ..........108 
 
Long-Term Exposure Period (Week 14 to Week 72) .....................................108 
 
Early Termination for Subjects without Participation in the Optional 
Follow-up Treatment Period ...........................................................................109 
 
Optional Follow-up Treatment Period (Post-Week 72) ..................................109 
 
End of Treatment or Early Termination ..........................................................115 
 
Safety Follow-up Period .................................................................................116 
8.2 
Genetic Testing ......................................................................................................116 
8.3 
Physical Examination, Weight and Height, Vital Signs .........................................116 
8.4 
Laboratory Assessments .........................................................................................117 
8.5 
Pruritus and Quality of Life Assessments ..............................................................117 
 
Itch Reported Outcome (ItchRO™) ................................................................117 
 
Clinician Scratch Scale ...................................................................................118 
 
Pediatric Quality of Life Inventory (PedsQL) ................................................118 
 
Patient Impression of Change .........................................................................119 
 
Caregiver Impression of Change .....................................................................119 


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Caregiver Global Therapeutic Benefit ............................................................119 
 
Palatability ......................................................................................................119 
8.6 
Metabolomic and Proteomic Investigations ...........................................................119 
8.7 
Restriction on the Lifestyle of Subjects .................................................................120 
 
Contraception Requirements ...........................................................................120 
 
Fasting Requirements ......................................................................................121 
9 
STUDY DRUG .....................................................................................................................122 
9.1 
Study Drug Description ..........................................................................................122 
 
LUM001 ..........................................................................................................122 
9.2 
Packaging and Labeling .........................................................................................122 
9.3 
Drug Accountability ...............................................................................................122 
10 TREATMENT OF SUBJECTS ............................................................................................123 
10.1 
Study Drug Administration ....................................................................................123 
10.2 
Treatment Compliance ...........................................................................................124 
10.3 
Concomitant Medications ......................................................................................124 
10.4 
Other Protocol-required Drugs ...............................................................................124 
10.5 
Safety Monitoring Rules ........................................................................................124 
 
General Monitoring Rules ...............................................................................124 
 
Safety Monitoring Rules .................................................................................125 
10.5.2.1 Safety Monitoring for Liver Chemistry Tests .................................................126 
10.5.2.2 Stopping Rules for Liver Chemistry Elevations .............................................127 
10.5.2.3 Safety Monitoring for Triglycerides ...............................................................127 
10.5.2.4 Safety Monitoring for Fat Soluble Vitamins ...................................................127 
10.5.2.5 Monitoring/Stopping Rules for Coagulation Panel Results ............................127 
10.6 
Adjustment of Dose ................................................................................................127 
10.7 
Withdrawal of Subjects from the Study .................................................................128 
11 SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...............................130 
11.1 
Regulatory Requirements .......................................................................................130 
11.2 
Definitions ..............................................................................................................130 
 
Adverse Event .................................................................................................130 
 
Adverse Reaction and Suspected Adverse Reaction .......................................131 
 
Serious Adverse Event (SAE) .........................................................................131 
11.3 
Monitoring and Recording Adverse Events ...........................................................132 
 
Serious Adverse Events...................................................................................132 
 
Non-Serious Adverse Events ..........................................................................133 
 
Evaluation of Adverse Events (Serious and Non-Serious) .............................133 
11.3.3.1 Relationship to the Study Drug .......................................................................133 
11.3.3.2 Severity ...........................................................................................................133 


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11.3.3.3 Action Taken with Study Drug .......................................................................134 
11.3.3.4 Treatment Given for Adverse Event ...............................................................134 
11.3.3.5 Outcome of the Adverse Event .......................................................................134 
11.4 
Procedures for Handling Special Situations ...........................................................135 
 
Pregnancy Reporting .......................................................................................135 
 
Dosing Errors ..................................................................................................135 
 
Abnormalities of Laboratory Tests .................................................................136 
12 STATISTICAL CONSIDERATIONS .................................................................................137 
12.1 
Sample Size Considerations ...................................................................................137 
12.2 
Populations .............................................................................................................137 
 
Safety Population ............................................................................................137 
 
Efficacy Populations .......................................................................................137 
 
Demographic and Baseline Characteristics .....................................................138 
12.2.3.1 Subject Disposition .........................................................................................138 
12.2.3.2 Baseline Data ..................................................................................................138 
 
Safety Analyses ...............................................................................................138 
12.2.4.1 Safety Assessments .........................................................................................138 
 
Planned Method of Analysis ...........................................................................139 
 
Safety Analysis ...............................................................................................139 
12.2.6.1 Adverse Events ...............................................................................................139 
12.2.6.2 Laboratory Tests..............................................................................................139 
12.2.6.3 Physical Exams, Vital Signs and Weight/Height Measurements....................140 
12.2.6.4 Concomitant Medications ...............................................................................140 
12.2.6.5 Study Drug Exposure ......................................................................................140 
12.2.6.6 Serum Alpha-fetoprotein .................................................................................140 
 
Interim Analyses .............................................................................................140 
 
Additional Analyses ........................................................................................141 
 
Efficacy Analyses ...........................................................................................141 
12.2.9.1 Efficacy Variables ...........................................................................................141 
12.2.9.2 Primary Efficacy Analysis ..............................................................................143 
12.2.9.3 Secondary, Exploratory and Other Efficacy Analyses ....................................144 
 
Exploratory Genetic Analyses.........................................................................144 
 
Exploratory Responder Analyses (Metabolomic and Proteomic 
Investigations) .................................................................................................144 
 
Palatability Analyses .......................................................................................145 
13 INVESTIGATOR’S REGULATORY OBLIGATIONS .....................................................146 
13.1 
Informed Consent ...................................................................................................146 
13.2 
Ethical Conduct of the Study .................................................................................146 


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13.3 
Independent Ethics Committee/Institutional Review Board ..................................146 
13.4 
Confidentiality ........................................................................................................147 
14 ADMINISTRATIVE AND LEGAL OBLIGATIONS ........................................................148 
14.1 
Study Personnel ......................................................................................................148 
14.2 
Pre-study Documentation Required .......................................................................148 
14.3 
Protocol Amendments ............................................................................................148 
14.4 
Study Termination ..................................................................................................149 
14.5 
Study Documentation and Storage .........................................................................149 
14.6 
Study Monitoring ...................................................................................................149 
14.7 
Language ................................................................................................................150 
14.8 
Compensation for Injury ........................................................................................150 
15 REFERENCES .....................................................................................................................151 
16 APPENDICES ......................................................................................................................153 
16.1 
Schedule of Procedures ..........................................................................................154 
 
Schedule of Procedures A-D: Study Entry – Week 120 .................................155 
 
Schedule of Procedures E-F: Rollover under Protocol Amendment 4 ...........164 
 
Schedule of Procedures G-I: Subject Re-Entry under Protocol 
Amendment 4 ..................................................................................................169 
 
Schedule of Procedures J – Study Termination and End of Treatment 
Procedures .......................................................................................................176 
16.2 
List of Laboratory Analytes ...................................................................................178 
16.3 
Liver Disease Diagnoses Excluded from PFIC Definition ....................................179 
16.4 
Itch Reported Outcome Instrument (ItchRO™) .....................................................180 
 
Patient Itch Reported Outcome Instrument, ItchRO(Pt)™ .............................181 
 
Observer Itch Reported Outcome Instrument, ItchRO(Obs)™ ......................183 
16.5 
Clinician Scratch Scale ...........................................................................................187 
16.6 
Pediatric Quality of Life Inventory (PedsQL™) ....................................................188 
 
Parent Report for Infants (ages 1-12 months) .................................................189 
 
Parent Report for Infants (ages 13-24 months) ...............................................192 
 
Parent Report for Toddlers (ages 2–4 years)...................................................195 
 
Parent Report for Young Children (ages 5-7 years) ........................................197 
 
Parent Report for Children (ages 8-12 years) .................................................199 
 
Parent Report for Teenagers (ages 13-18 years) .............................................201 
 
Pediatric Quality of Life Inventory v 4.0 for Young Children (ages 5-7 
years) ...............................................................................................................203 
 
Pediatric Quality of Life Inventory for Children (ages 8-12 years) ................206 
 
Pediatric Quality of Life Inventory for Teenagers (ages 13-18 years) ...........208 
 
Multidimensional Fatigue Scale Parent Report for Toddlers (ages 2-4 


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years) ...............................................................................................................210 
 
Multidimensional Fatigue Scale Parent Report for Young Children  (ages 
5-7 years) .........................................................................................................212 
 
Multidimensional Fatigue Scale Parent Report for Children (ages 8-12 
years) ...............................................................................................................214 
 
Multidimensional Fatigue Scale Parent Report for Teenagers  (ages 13-
18 years) ..........................................................................................................216 
 
Multidimensional Fatigue Scale Young Child Report (ages 5-7 years) .........218 
 
Multidimensional Fatigue Scale Child Report (ages 8-12 years) ...................221 
 
Multidimensional Fatigue Scale Teen Report (ages 13-18 years) ..................223 
 
Family Impact Module v 2.0 ...........................................................................225 
16.7 
Patient Impression of Change (PIC) .......................................................................228 
16.8 
Caregiver Impression of Change (CIC) .................................................................229 
16.9 
Caregiver Global Therapeutic Benefit (CGTB) .....................................................230 
16.10 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 ..........231 
16.11 
Palatability Questionnaire ......................................................................................232 
 
LIST OF TABLES 
Table 1: 
Improvement in Biochemical Markers and Pruritus After Partial 
External Biliary Diversion in PFIC Disease and Alagille Syndrome 
Subjects ..........................................................................................................86 
Table 2: 
Sample Daily Exposure (mg/day) in Pediatric Subjects ................................90 
Table 3: 
GI-associated Adverse Events in Study 003 .................................................91 
Table 4: 
Composition of LUM001 1.0 mL Oral Solution .........................................122 
Table 5: 
Composition of LUM001 0.5 mL Oral Solution .........................................122 
 
LIST OF FIGURES 
Figure 1: 
Interruption of Enterohepatic Circulation with an ASBT/IBAT 
Inhibitor .........................................................................................................83 
Figure 2: 
Types of Progressive Familial Intrahepatic Cholestasis ................................84 
Figure 3: 
Serum Bile Salt Concentration and Degree of Itch .......................................86 
Figure 4: 
Study Design for LUM001-501 (Up to and including Week 72) ..................94 
Figure 5:  
Optional Follow-up Treatment under Protocol Amendment 4, without 
Afternoon Dose Escalation (ADE) ..............................................................112 
Figure 6:  
Optional Follow-up Treatment under Protocol Amendment 4, with 
Afternoon Dose Escalation (ADE) ..............................................................113 
 
 


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PROTOCOL AMENDMENT 4.1 
Protocol Number: 
LUM001-501 
Protocol Title: 
OPEN LABEL STUDY OF THE EFFICACY AND LONG TERM 
SAFETY OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS 
WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 
Amendment: 
4.1 
Date: 
08 February 2019 
 
The LUM001-501 protocol is being amended to reflect the change of sponsorship from Lumena 
Pharmaceuticals LLC (Lumena Pharmaceuticals LLC is an indirect wholly-owned subsidiary of 
Shire North American Group, Inc) to Mirum Pharmaceuticals, Inc.   
The following changes have been made to the Protocol Amendment 4 (20 December 2016). 
Note that correction of typos and grammatical errors are not captured in the below table.  


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New text indicated in bold; deleted text indicated in strikethrough. 
Section 
Description of Change 
Cover page, Sponsor; 
Title Page, Sponsor; 
Sponsor Signature 
page, Sponsor 
Changed from: 
 Lumena Pharmaceuticals LLC* 
300 Shire Way 
Lexington, MA 02421 
USA 
 
*Lumena Pharmaceuticals LLC is an indirect wholly-
owned subsidiary of Shire North American Group, Inc  
 
 
To:  
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
 
Title Page, Medical 
Lead;  
Sponsor Signature 
page, Sponsor (Mirum) 
Approval 
Changed from: 
 
Medical Lead:  
Thomas Jaecklin, MD 
 
Shire 
 
Zahlerweg 10 
6300 Zug 
Switzerland 
Phone:  +41(0) 79 850 77 18   
Email:  thomas.jaecklin@shire.com 
To:  
 
Medical Lead: 
Thomas Jaecklin, MD, MSc 
 
Mirum Pharmaceuticals AG 
Innere Margarethenstrasse 5 
4051 Basel 
Switzerland 
 
Phone:  +41(0) 79 850 77 18   
Email:  tjaecklin@mirumpharma.com 
 
 
 
 
Changed from:  
 
Sponsor Medical  
Monitor: 
Susanne Schmidt, MD 
 
 
To: 
 
Medical Monitor: 
Cagil Ozen, MD 
 
 
Emergency Contact 
Information 
Changed the Premier Medical Monitor from Susanne Schmidt to Cagil Ozen. 
 


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Section 
Description of Change 
Product Quality 
Complaints 
Changed from: 
 
Origin of Product Quality 
Complaint 
E-mail Address 
North and South America 
PQC@shire.com 
European Union and Rest of World 
PQCROW@shire.com 
Telephone numbers (provided for reference if needed): 
Shire, Lexington, MA (USA) 
1-800-828-2088 
To:  
Origin of Product Quality 
Complaint 
E-mail Address 
North and South America 
medinfo@mirumpharma.com 
European Union and Rest of 
World 
medinfo@mirumpharma.com 
Telephone numbers (provided for reference if needed): 
Mirum, Menlo Park, CA (USA) 
1-650-667-4085 
 
10.3 Concomitant 
Medications 
Changed From:  No new medications used to treat pruritus may be added during the 
course of the study.   
 
To: 
No new medications used to treat pruritus may be added during the 
period from Baseline (Day 0) until Week 13 (timepoint for primary 
analysis). 
Schedule of Procedures 
D 
Added clarifying footnote regarding baseline reference value for participants re-
entering in Protocol Amendment 3 after dose interruption of > 7 days: 
11     For participants re-entering under Protocol Amendment 3, Baseline 
laboratory values are considered those collected at re-entry visit DE-2 weeks 
Schedule of Procedures 
G 
Added clarifying footnote regarding baseline reference value for participants re-
entering in Protocol Amendment 4 after dose interruption of > 7 days:: 
8     For participants re-entering under Protocol Amendment 4, Baseline 
laboratory values are considered those collected at re-entry visit PA4 DE-2 weeks 
 


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PROTOCOL AMENDMENT 4 
Protocol Number: 
LUM001-501 
Protocol Title: 
OPEN LABEL STUDY OF THE EFFICACY AND LONG TERM 
SAFETY OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS 
WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 
Amendment: 
4 
Date: 
20 December 2016 
 
The LUM001-501 protocol is being amended to allow continued participation in the Optional 
Follow-Up Treatment Period, beyond what was previously described in Protocol Amendment 
3.  Study treatment in the Optional Follow-up Treatment Period will continue until the first of the 
following occurs: (i) the subjects are eligible to enter another LUM001 study or (ii) LUM001 is 
available commercially. 
 
This amendment also describes the way in which eligible subjects who had previously 
discontinued from the study may re-enter and receive study treatment in the optional follow-up 
treatment period (After Week 72).   
Additional objectives for the Optional Follow-up Treatment Period have been added, as 
follows:  
• exploration of a twice daily (BID) dosing regimen and higher daily dosing of LUM001; 
• identification of genetic indicators of treatment response,  including use of exome 
sequencing;  
• assessment of alpha-fetoprotein (AFP) levels, a marker of hepatocellular carcinoma; 
• assessment of the palatability of the LUM001 formulation in all patients, by-proxy in 
patients <4 years old and by patient questionnaire in children ≥4 years old; and 
• an exploratory objective to allow the possibility of analysis of serum markers of 
treatment response using metabolomic and proteomic analysis on previously collected 
serum samples.  
Lastly, this amendment updates the contraceptive requirements to align with the Heads of 
Medicine Clinical Trials Facilitation Group Recommendations Related to Contraception and 
Pregnancy Testing (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf ). 
The following changes have been made to the Protocol Amendment 3 (02 November 2015). 
Note that correction of typos and grammatical errors are not captured in the below table.  
New text indicated in bold; deleted text indicated in strikethrough. 


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Section 
Description of Change 
Cover page, Sponsor; 
Title Page, Sponsor; 
Sponsor Signature 
page, Sponsor 
Changed from: 
 
Lumena Pharmaceuticals LLC 
 
12531 High Bluff Drive, Suite 110 
San Diego, CA 92130 
USA 
 
To:  
Lumena Pharmaceuticals LLC* 
300 Shire Way 
Lexington, MA 02421 
USA 
 
*Lumena Pharmaceuticals LLC is an indirect wholly-owned subsidiary of Shire 
North American Group, Inc 
Title Page, Medical 
Lead;  
Sponsor Signature 
page, Sponsor (Shire) 
Approval 
Changed from: 
 
Medical Lead:  
Beatriz Caballero, MD 
 
Shire Human Genetic Therapies,Inc. 
 
Zahlerweg 10 
6300 Zug 
Switzerland 
 
Phone:  +41(0) 41 288 42 30   
 
Email: bcaballero@shire.com  
 
 
To:  
 
Medical Lead: 
Thomas Jaecklin, MD 
 
Shire 
 
Zahlerweg 10 
6300 Zug 
Switzerland 
Phone:  +41(0) 79 850 77 18   
Email:  thomas.jaecklin@shire.com 
 
 
 
Emergency Contact 
Information 
Inserted new page containing emergency contact information for reporting of serious 
adverse events (SAEs) to be aligned with Shire protocol template. 
Product Quality 
Complaints 
Inserted new page containing product quality complaint information for reporting of 
investigational product quality complaints to be aligned with Shire protocol template. 
Synopsis, Objectives; 
Section 3, Study 
Objectives 
Objectives of Optional Follow-up Treatment  Period (After Week 72): 
• 
To offer eligible subjects in the LUM001-501 study continued study treatment 
at beyond Week 72 until the first of the following occurs:  (i) up the subjects are 
eligible to 52 weeks of additional treatment (Week 124), enter another LUM001 study 
or (ii) in the event that a new study opens to enrollment LUM001 is available 
commercially. 
Synopsis, Objectives; 
Section 3, Study 
Objectives 
Objectives of Optional Follow-up Treatment  Period (After Week 72): 
• 
To obtain safety and efficacy data in subjects treated long-term on LUM001 
including genotyping characteristics. 
Synopsis, Objectives; 
Section 3, Study 
Objectives 
• 
To explore a twice a day (BID) dosing regimen and higher daily dosing of 
LUM001. 


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Section 
Description of Change 
Synopsis, Objectives; 
Section 3, Objectives 
• 
To identify genetic indicators of treatment response, including use of 
exome sequencing. 
Synopsis, Objectives; 
Section 3, Study 
Objectives 
• 
To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular 
carcinoma. 
Synopsis, Objectives; 
Section 3, Objectives 
• 
To assess palatability of the LUM001 formulation. 
Synopsis, Objectives; 
Section 3, Study 
Objectives 
Exploratory Objective: 
• 
To allow the possibility of analysis of serum markers of treatment 
response using metabolomic and proteomic analysis on previously collected serum 
samples. 
Synopsis, Study 
Design; 
Section 5.1, Study 
Design 
The study is divided into 5 parts: …. and an optional 52 week follow-up treatment 
period for eligible subjects who choose to stay on treatment with LUM001.   
 
During this optional follow-up treatment period, subjects may have their dose of 
LUM001 increased to a maximum of 560 μg/kg/day (280 μg/kg BID), based on 
ongoing efficacy (sBA level and ItchRO score) and safety assessment. 
Synopsis, Inclusion 
Criteria; 
Section 7.1, Inclusion 
Criteria 
5. 
Males and females of child-bearing potential who are sexually active 
females, or are not currently sexually active during the study, but become sexually 
active during the period of the study and 30 days following the last dose of study 
drug, must be prepared to agree and use an effective method (≤ 1% failure rate) of 
acceptable contraception during the trial. Effective methods of contraception are 
considered to be described in Section 8.7.1. 
a. 
Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection); 
or 
b. 
Barrier method, e.g., (a) condom (male or female) or (b) diaphragm, with 
spermicide; or 
c. 
Intrauterine device (IUD). 
Synopsis, Inclusion 
Criteria; 
Section 7.3, Exclusion 
Criteria 
Eligible Subjects for 52-week Optional Follow-up Treatment Period: 
 
Inclusion Criteria 
Subjects will be considered eligible for the 52-week Optional Follow-up Treatment 
Period if they have meet the following criteria: 
1. 
The subject has either:  
• 
completed the protocol through the Week 72 visit with no major safety 
concerns. Subjects who were , OR 
• 
• 
discontinued due to safety reasons judged unrelated to relatively 
normal values for this patient population the study drug, and blood tests have 
returned to levels acceptable for this patient population/individual and subject does 
not meet any of the protocol’s stopping rules at re-entry. … Subjects who have 
undergone a surgical disruption of the enterohepatic circulation will not be eligible to 
enter into the follow up treatment period. [Subjects who were discontinued for other 
reasons will be considered on an individual basis.] 
2. 
Females of childbearing potential must have a negative urine or serum 
pregnancy test (β-hCG) at the time of entry into the optional follow-up treatment 
period. 
3. 
Informed consent and assent (per IRB/EC) as appropriate. 
 
Exclusion Criteria 


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Description of Change 
Subjects will be excluded from the Optional Follow-up Treatment Period if they 
meet any of the following criteria: 
1. 
Surgical disruption of the enterohepatic circulation. 
2. 
Investigational drug other than LUM001, biologic, or medical device 
within 30 days prior to re-entry, or 5 half-lives of the study agent, whichever is 
longer. 
Synopsis, Treatment 
Groups; 
Section 5.5.2, 
Treatment; 
Section 10.1, Study 
Drug Administration 
All subjects will receive LUM001, up to 280 560 μg/kg/day (given as twice-daily doses 
of 280 μg/kg) or a maximum daily dose of 20 25 mg/day BID. 
Synopsis, Study Drug 
Dosage and 
Administration; 
Section 10.1, Study 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.5.2, 
Treatment 
 
 
Subjects who weigh 10 kg or more at screening will receive a 1.0 mL grape-flavored 
solution containing LUM001. Subjects who weigh less than 10 kg at screening will 
receive 0.5 mL grape flavored solution containing LUM001. The volume administered, 
either 1.0 mL or 0.5 mL will not change during the course of the study. Each daily 
subject dose will be administered in the morning orally once a day (QD) or twice a 
day (BID) using the syringe provided.  The first dose should be taken at least 30 
minutes before breakfast (qAM, ac). Study drug should be administered prior to the 
first meal of the day and the second dose, where applicable, should be taken at 
least 30 minutes prior to dinner (main evening meal).  The doses will not be 
administered q12h in order to better cover the luminal bile acid release associated 
with dinner and to minimize the risk of disturbing sleep due to the potential for 
abdominal pain and diarrhea at night.  It is recommended that the dose should be 
taken at approximately the same time every day each day for the duration of the 
treatment period. 
 
QD Dosing Regimen 
For QD dosing, the required dose will be delivered in 0.5 mL volume for subjects 
who weigh less than 10 kg and in 1.0 mL for subjects who weigh 10 kg or more. 
 
BID Dosing Regimen 
For BID dosing, the required dose is delivered in half the dosing volume:  0.25 mL 
BID for subjects who weigh less than 10 kg and 0.50 mL BID for subjects who 
weigh 10 kg or more. 
For subjects weighing less than 10 kg at study entry, once a weight of 10 kg is 
reached while in the study, the subject will be moved from 0.5 mL total daily 
dosing volume (0.25 mL BID) to 1.0 mL total daily dosing volume (0.50 mL BID). 
 
Study Drug Dosage 
Baseline through Week 72: 
 
For the first 72 weeks of the study, each subject will receive either 1.0 mL or 0.5 mL 
of solution containing LUM001 orally as follows, administered as a daily morning 
dose: 
• 
Dose Level 1: 14 µg/kg/day. 
• 
Dose Level 2: 35 µg/kg/day. 
• 
Dose Level 3: 70 µg/kg/day. (up to a maximum daily dose of 5mg). 
• 
Dose Level 4: 140 µg/kg/day. (up to a maximum daily dose of 10mg).  
• 
Dose Level 5: 280 µg/kg/day. (up to a maximum daily dose of 20mg).  


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Section 
Description of Change 
 
 
 
 
 
 
Section 5.5.2.4, 
Optional Follow-up 
Treatment Period 
(Post-Week 72) 
 
 
 
 
 
 
 
 
Synopsis;  
Section 5.5.2.3, Long-
term Exposure Period 
At Week 72, all subjects will be assessed by the investigator to determine their 
willingness and eligibility to roll-over into the optional follow-up treatment period. 
Following the completion of the Week 72 study visit, subjects who choose to participate 
in the optional follow-up treatment period will enter under one of the following 
LUM001 dosing scenarios: 
 
Optional Follow-up Treatment Period (Post-Week 72): 
Subjects who are eligible for the optional follow-up treatment period will continue 
treatment under dosing scenarios based on whether their LUM001 dosing will 
continue without interruption or interruption of <7 continuous days, or with 
interruption ≥7 days.  Eligibility for BID dosing will be determined based on 
efficacy as measured by sBA level and ItchRO score. 
 
Subjects who enter the optional follow-up treatment period without LUM001 
dosing interruption or with an interruption of <7 continuous days will be dosed in 
the following manner: 
• 
Subjects with normal sBA level AND ItchRO score <1.5 will be maintained 
at the same dose level and will continue morning dosing only. 
• 
Subjects with sBA level above normal AND/OR ItchRO score ≥1.5 will 
start BID dosing (afternoon dose escalation; ADE) as follows: 
o 
The morning dose will be continued at the same dose level, but the 
volume of the morning dose will be reduced by half at the same 
time that the afternoon dose is initiated. 
o 
The afternoon dose will be initiated at half the maximum 
tolerated morning dose and will continue at this dose for a period 
of 4 weeks.  If this dose level is tolerated, the afternoon dose then 
will be doubled, to a maximum dose of280 µg/kg (or up to the 
maximum tolerated dose). 
o 
The maximum daily dose will be 280 µg/kg BID, i.e. 560 
µg/kg/day(max. 25 mg BID). 
 
Subjects who are eligible to roll over into the optional follow-up treatment period with a 
LUM001 dosing interruption of ≥7 days, will be dose escalated up to 280 µg/kg/day or a 
maximum tolerated dose following a 4 week dose escalation beginning at Dose Level 2 
(35 µg/kg/day). Subjects who do not wish to enter the optional follow-up treatment 
period with a LUM001 dosing interruption of ≥7 days initially will receive morning 
dosing only and will undergo dose escalation (DE) in the following manner: 
• 
The morning dose will be initiated at Dose Level 2 (35 µg/kg) and doubled 
in weekly intervals to a maximum dose of 280 µg/kg, or up to the 
maximum tolerated dose. 
• 
Once the morning dose of 280 µg/kg or maximum tolerated dose is 
achieved, sBA and ItchRO score will be evaluated. 
• 
Subjects with normal sBA AND ItchRO score <1.5 after morning dose 
escalation will be maintained at the same dose level and will continue 
morning dosing only. 
• 
Subjects with sBA above normal AND/OR ItchRO score ≥1.5 will begin 
BID dosing (afternoon dose escalation) as outlined above. 
 
Subjects will continue to receive study drug until they are eligible to enter another 
LUM001 study or until LUM001 is available commercially, whichever occurs first. 
 


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Section 
Description of Change 
The maximum daily dose will be 280 µg/kg BID, i.e. 560 µg/kg/day (maximum 
25 mg).  If a subject experiences intolerance (eg, gastrointestinal symptoms such as 
diarrhea, abdominal pain, cramping) at any time during the study, the physician 
Investigator in consultation with the Sponsor Medical Monitor may lower the dose 
for the remainder of the study. If the subject is on a BID dosing regimen, dose 
lowering should first be attempted with the afternoon dose. 
 
The sBA value used for determination of ADE eligibility will be the most recent 
available value.  The ItchRO score used for ADE eligibility will be derived from 
the most recent 2 week electronic diary collection period.   
 
If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, 
abdominal pain, cramping) at any time during the study, the physician investigator in 
consultation with the Sponsor Medical Monitor may lower the dose to a previously 
tolerated dose for the remainder of the study. 
Synopsis, Rationale for 
Dose and Schedule 
Selection 
To reduce the risk of loose stools, diarrhea and abdominal pain/cramps in this study up 
to Week 72, the LUM001 doses will be escalated over the first a period of 4-8 weeks.  
Dosing will start at 14 up to a maximum dose of 280 µg/kg/day, and will then be 
increased at 7 day intervals to 140 µg/kg/day (equivalent to 10 mg daily dose in a 70 kg 
adult). At the Week 8 visit, study drug  BID (or maximum tolerated dose).  The 
morning dose will be further is initiated and escalated to 280 µg/kg/day. For subjects 
in the 52-week optional follow-up treatment period with ≥7 days since the last first; the 
afternoon dose of LUM001, dosing will start at 35 µg/kg/day, is only initiated and will 
then be increased over the first 4 weeks up to 280 µg/kg/day escalated in patients with 
elevated sBA level and/or to ItchRO ≥1.5 on the maximum (or maximum tolerated) 
morning dose starting at Dose Level 2 (35 µg/kg/day). 
 
This escalation regimen is supported by the safety profile observed in completed and 
ongoing clinical studies of LUM001. and allows for subjects to reach 280 µg/kg/day or 
a maximum tolerated dose within a 4-week period.  
 
Twice daily dosing is used in this study based on the findings of a healthy 
volunteers study in adult males (Study SHP625-101), which demonstrated that bile 
acid levels in feces increase with escalating doses and twice-daily regimen of 
LUM001 (up to 100 mg QD and 50 mg BID).  In this study, subjects who were 
randomized to LUM001 treatment received 1 of 4 doses of LUM001 (10, 20, 50, 100 
mg) during 7 days.  No titration was used in this study. There was a dose-
dependent increase in total fecal BA excretion. In addition, BID dosing (i.e. 50 mg 
BID) led to a further increase in fecal BA excretion as compared to QD dosing (i.e. 
100 mg QD).  It is therefore hypothesized that twice-daily dosing has the potential 
to allow for more complete target engagement throughout the day at the level of 
the distal ileum. 
The higher dosing level is also supported by favorable results from a juvenile 
toxicity study conducted in rats administered LUM001 for 43 days (PND21 
through PND63).  As expected for a drug intentionally designed to be minimally 
absorbed, systemic LUM001 exposure was very low and consistent with levels that 
were previously determined in several oral gavage studies in adult rats. No adverse 
effects were observed on postnatal growth and development of offspring at the 
highest doses tested (200 mg/kg/day in males, 1000 mg/kg/day in females).  This 
study was initiated in juvenile animals at PND21, which from a whole animal 
development perspective is typically representative of a 2-year old child.  However, 
given the fact that LUM001 is a minimally absorbed drug, of particular 
importance is the age at which the GI tract is considered functionally mature.  In 


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08 February 2019 
 
 
 
Section 
Description of Change 
humans this is considered to have occurred by 12 months of age; likewise, 
postnatal maturation of the GI tract in rats occurs during the first 3 weeks of life.  
Therefore, results from this study can be used to support the dosing levels 
proposed here for children 12 months of age and older. 
 
If the subject is on a twice daily dosing regimen, dose reduction should first be 
attempted with the afternoon dose.  Subjects who were previously down-titrated 
may be re-challenged during the long-term exposure period. 
Synopsis, Study Visit; 
Schedule and 
Procedures 
Clarified titles of study design schemes and updated figures to reflect the addition of the 
extended follow-up treatment period beyond what was previously described in Protocol 
Amendment 3.  
Synopsis, Study Visit; 
Schedule and 
Procedures 
 
 
 
Synopsis; Section 
8.1.7,  Optional 
Follow-up Treatment 
Period (Post-Week 72) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At clinic visits during the treatment periods, blood sampling for study drug 
determination will be completed according to the region’s sampling schedule (refer to 
Section 16.1). 
 
Optional Follow-up Treatment Period (post-Week 72 to Week 124):  ):   
Subjects who are eligible to roll over on to the follow-up treatment period will continue 
to receive study drug at the dose they were receiving at Week 72 for up to 52 weeks of 
additional treatment or in the event that a new study opens to enrollment, whichever 
occurs first. until the first of the following occurs:  (i) the subjects are eligible to 
enter another LUM001 study or (ii) LUM001 is available commercially.  Included 
below are schematics describing the flow of study visits within this period. 
 
Figure 2: Optional Follow-up Treatment Period (<7 days from last LUM001 dose 
between Protocol Amendment 2 and Amendment 3) 
Applies to the following subject population: 
• 
Subjects who experienced no interruption in LUM001 dosing, or 
interruption <7 days between Protocol Amendment 2 and Protocol 
Amendment 3. 
 
New figure added here 
------------ 
 
Subjects who are eligible to roll over into the follow-up treatment period with no 
LUM001 dosing interruption or an interruption of <7 days will be maintained at the 
same dose level initially receive study drug at the dose they were receiving at Week 
72.  Once Protocol Amendment 4 is implemented at the site, a determination about 
Afternoon Dose Escalation (ADE) will be made.  The subject then will move to 
Figure 5 or Figure 6, depending on whether they meet criteria for initiating 
Afternoon Dose Escalation.   
 
Figure 3: Optional Follow-up Treatment (≥7 days from last LUM001 dose between 
Protocol Amendment 2 and Protocol Amendment 3) 
Applies to the following subject population: 
• 
Subjects who experienced an interruption in LUM001 dosing ≥7 days 
between Protocol Amendment 2 and Protocol Amendment 3.  
New figure added here 
------------ 


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08 February 2019 
 
 
 
Section 
Description of Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Once Protocol Amendment 4 is implemented at the site, a determination about 
Afternoon Dose Escalation (ADE) will be made.  The subject will then move to 
Figure 5 or Figure 6, depending on whether they meet criteria for initiating 
Afternoon Dose Escalation.   
 
Figure 4: Optional Follow-up Treatment (≥7 days from last LUM001 dose between 
Protocol Amendment 3 and Protocol Amendment 4) 
Applies to the following subject population: 
• 
Subjects who experienced an interruption in LUM001 dosing ≥7 days 
between Protocol Amendment 3 and Protocol Amendment 4.  
New figure added here 
------------ 
Subjects with ≥7 days since last dose of LUM001 prior to site implementation of 
Protocol Amendment 4 will be dose escalated up to 280 µg/kg/day or to the highest 
tolerated dose starting at Dose Level 2 (35 μg/kg/day), in a similar fashion as 
outlined in Figure 4.  
The dose escalation (DE) period will proceed as follows: 
• 
DE Week -2 Clinic Visit: obtain consent for Protocol Amendment 4, 
obtain weight and draw labs.   
• 
DE Day 0 Clinic Visit: Investigator evaluates laboratory results, study 
drug is dispensed and subject begins at 35 μg/kg/day dose level. 
• 
DE Week 1 Telephone Contact: subject escalates to 70 μg/kg/day dose 
level if prior dose level was tolerated. 
• 
DE Week 2 Clinic Visit: subject escalates to 140 μg/kg/day dose level if 
prior dose level was tolerated. 
• 
DE Week 3 Telephone Contact: subject escalates to 280 μg/kg/day dose, if 
prior dose level was tolerated. 
• 
DE Week 4 Clinic Visit: subject continues in follow-up treatment period at 
280 μg/kg/day, or maximum tolerated dose. 
• 
At DE Week 8 Telephone Contact:  eligibility for ADE will be assessed.  
The subject will then move to Figure 5 or 6, depending on whether they 
meet criteria for initiating Afternoon Dose Escalation.   
 
Figure 5: Optional Follow-up Treatment under Protocol Amendment 4, without 
Afternoon Dose Escalation (ADE) 
Applies to the following subject population: 
• 
Subjects deemed ineligible for ADE. 
New figure added here 
------------ 
Subjects Deemed Ineligible for ADE: 
Subjects with normal sBA level AND ItchRO score <1.5 will be deemed ineligible 
for ADE; such patients will be maintained at the same dose level and will continue 
morning dosing only.  Subjects will have study activities then repeated in recurring 
12-week periods as follows, until study completion or termination: 
• 
Recurring Period Week 4 (i.e., beginning Week 88 or 4 weeks after 
consent to Protocol Amendment 4) Telephone Contact:  Collection of 
concomitant medications and any adverse events. 
• 
Recurring Period Week 8 (e.g., Weeks 92, 104, 116, etc) Telephone 
Contact: Collection of concomitant medications and any adverse events.  


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Section 
Description of Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Recurring Period Week 12 (e.g., Weeks 96, 108, 120, etc) Clinic Visit:  
Physical exam, body weight and height, vital signs, and blood samples for 
clinical laboratory testing, including fasting lipid panel.  Blood will also be 
collected for determination of fat-soluble vitamins.  Urine samples for 
clinical laboratory testing will be collected at every visit.  ItchRO 
compliance will be assessed, the electronic diary will be issued, the 
clinician scratch scale will be administered, and the PedsQL questionnaire 
will be administered.  Additionally, a palatability questionnaire will be 
completed.  Female subjects who are of childbearing potential will have a 
urine pregnancy test prior to dispensing study drug.  Study drug 
compliance will be assessed and study drug will be dispensed upon 
completion of other study procedures. 
 
Figure 6: Optional Follow-up Treatment under Protocol Amendment 4, with 
Afternoon Dose Escalation (ADE) 
Applies to the following subject population:  
• 
Subjects whose sBA levels have not normalized and/or whose ItchRO 
score is ≥1.5 and therefore qualify for introduction of afternoon dosing. 
New figure added here 
------------ 
 
Subjects deemed eligible for ADE, i.e., who have sBA level above normal AND/OR 
ItchRO score ≥1.5, will begin BID dosing (afternoon dose escalation; ADE) as 
follows: 
• 
On ADE Day 0, morning dosing will continue at 280 µg/kg or the 
maximum tolerated dose.  Dosing must have been stable for ≥4 weeks 
prior to initiation of ADE. The morning dose will be continued at the same 
dose level, 280 µg/kg or maximum tolerated dose; however, the volume of 
the morning dose will be reduced by half. 
• 
On ADE Day 0, the afternoon dose will be initiated at half the maximum 
tolerated morning dose and will continue at this dose level for a period of 4 
weeks.  If this dose level is tolerated, the afternoon dose then will be 
doubled (i.e., at ADE Week 4) to a maximum dose of 280 µg/kg (i.e., up to 
a maximum 560 µg/kg/day or maximum tolerated dose). 
 
The following procedures will occur during the ADE period: 
• 
ADE Day 0 Clinic Visit:   Physical exam, body weight and height, vital 
signs, and blood and urine samples for clinical laboratory testing, 
including fasting lipid panel.  Blood will also be collected for 
determination of fat-soluble vitamins.  Plasma sample will be obtained for 
LUM001 PK.  The clinician scratch scale and the PedsQL questionnaire 
will be administered.  Female subjects who are of childbearing potential 
will have a urine pregnancy test prior to dispensing study drug.  Study 
drug compliance will be assessed and study drug will be dispensed upon 
completion of other study procedures. Concomitant medications and any 
adverse events will be collected. 
• 
ADE Week 1 and Week 2 Telephone Contact:  Collection of concomitant 
medications and any adverse events.  Subject/caregiver will be reminded 
of dosing instructions. 
• 
ADE Week 4 Clinic Visit:  Physical exam, body weight and height, vital 
signs, and blood and urine samples for clinical laboratory testing, 
including fasting lipid panel.  Blood will also be collected for 


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Section 
Description of Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.7 (only, not 
synopsis), Optional 
Follow-up Treatment 
Period (Post-Week 72)  
 
 
determination of fat-soluble vitamins.  Plasma sample will be obtained for 
LUM001 PK.  The clinician scratch scale and the PedsQL questionnaire 
will be administered.  Female subjects who are of childbearing potential 
will have a urine pregnancy test prior to dispensing study drug.  Study 
drug compliance will be assessed and study drug will be dispensed upon 
completion of other study procedures. Concomitant medications and any 
adverse events will be collected. 
• 
ADE Week 5 and Week 6 Telephone Contact:  Collection of concomitant 
medications and any adverse events.  Subject/caregiver will be reminded 
of dosing instructions. 
• 
ADE Week 8 Clinic Visit:  Physical exam, body weight and height, vital 
signs, and blood and urine samples for clinical laboratory testing, 
including fasting lipid panel.  Blood will also be collected for 
determination of fat-soluble vitamins.  Plasma sample will be obtained for 
LUM001 PK.  The clinician scratch scale and the PedsQL questionnaire 
will be administered.  Female subjects who are of childbearing potential 
will have a urine pregnancy test prior to dispensing study drug.  Study 
drug compliance will be assessed and study drug will be dispensed upon 
completion of other study procedures. Concomitant medications and any 
adverse events will be collected. 
 
Thereafter, subjects will have study activities repeated in recurring 12-week 
periods as outlined within Figure 5, until study completion or termination. 
 
If any subject experiences intolerance, the Investigator, in consultation with the Sponsor 
Medical Monitor, may lower the dose to a previously tolerated dose at any time during 
the entire follow-up treatment period. If the subject is on a twice daily dosing 
regimen, dose lowering should first be attempted with the afternoon dose. 
 
During the follow-up treatment period, subjects will return to the clinic every 3 months, 
at Weeks 84, 96, 108, 120, and 124. 
 
At completion of the Follow-up Treatment Period or early discontinuation: a 
safety follow-up phone call will be made 30 days after the last dose of study drug. 
This call will be made for all subjects who complete the study, as well as any 
subject who terminates from the study early. Concomitant medications and 
adverse events noted during this phone call will be recorded. 
 
The PedsQL will be administered at DE Day 0 (for subjects requiring dose escalation) 
and at Weeks 84, 96, 108, 120, and 124. every clinic visit within each recurring 12-
week period, and at the EOT visit. Additionally, it will be collected at Protocol 
Amendment 4 DE Day 0, ADE Day 0, ADE Week 4, and ADE Week 8. The Patient 
and Caregiver Impression of Change (PIC & CIC), and the Caregiver Global 
Therapeutic Benefit assessments will be completed at Weeks 108, 120, and 124.the 
EOT visit. 
 
Subjects/caregivers will receive follow-up phone calls at Weeks 80, 88, 92, 100, 104, 
112, and 116, and twice within each recurring 12-week period. and every 3 months 
hence for the subsequent visits. 
 
Twice daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects during the 2 weeks following the Week 84, 96, 108, and 120 clinic 


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Section 
Description of Change 
visits. , at Protocol Amendment 4 DE Week 4, and every clinic visits (not including 
the EOT visit). visit within each recurring 12-week period.   
 
With the exception of the Week 120 and Week 124 EOT visit (Study Termination),, 
additional study drug will be supplied at each clinic visit during the follow-up treatment 
period.  Used and unused study drug will be collected at the Week 124every visit. 
 
Subjects will be encouraged to complete all study activities and visits. Any subject 
who withdraws from the study prior to completion of all treatment period clinic 
visits should undergo the following assessments as outlined for the End of 
Treatment/Early Termination visit:  Physical exam, body weight and height, vital 
signs, and blood and urine samples for clinical laboratory testing, including fasting 
lipid panel.  Blood will also be collected for determination of fat-soluble vitamins 
and AFP.  Female subjects who are of childbearing potential will have a urine 
pregnancy test.  Study drug compliance will be assessed.  Concomitant medications 
and adverse events will be collected.  The ItchRO, the clinician administered 
pruritus scale, the PedsQL, the Patient Impression of Change, the Caregiver 
Impression of Change, and the Caregiver Global Therapeutic Benefit assessments, 
and palatability questionnaire also will be completed.   
At completion of the Follow-up Treatment Period or early discontinuation: a 
safety follow-up phone call will be made 30 days after the last dose of study drug. 
This call will be made for all subjects who complete the study, as well as any 
subject who terminates from the study early. Concomitant medications and 
adverse events noted during this phone call will be recorded. 
Synopsis, Drug Level 
Evaluations; 
Section 8.1.7, Optional 
Follow-up Treatment 
Period (Post-Week 72) 
United States: … At all other blood draws, blood will be drawn approximately 4 hours 
post dosing for drug level analysis. morning dosing for drug level analysis.  
Additionally, for subjects in which afternoon dose escalation is initiated, samples 
will also be drawn at ADE Day 0, ADE Week 4, ADE Week 8, and at the three 
scheduled clinic visits following completion of the ADE period. 
United Kingdom, Europe and Australia: … At all other blood draws, blood will be 
drawn approximately 4 hours post dosing for drug level analysis. morning dosing for 
drug level analysis.  Additionally, for subjects in which afternoon dose escalation is 
initiated, samples will also be drawn at ADE Day 0, ADE Week 4, ADE Week 8, 
and at the three scheduled clinic visits following completion of the ADE period. 
Synopsis, Safety 
Evaluations; 
Section 12.2.4.1, 
Safety Assessments 
• 
Clinical laboratory results, including alpha-fetoprotein (AFP) as a screening 
for hepatocellular carcinoma. 
Synopsis, Efficacy 
Evaluations; 
Section 12.2.9.1, 
Efficacy Variables 
The main focus for the analyses of efficacy is the period from Baseline (Day 0) to Week 
13. The period from Baseline (Day 0) to Week 48 EOT will be analysed analyzed. 
 
The Primary efficacy evaluation will be mean endpoint:  
• 
Fasting serum bile acid level change from Baseline / (Day 0) to Week 13 in:•
 
Fasting serum bile acid level. 
Secondary evaluations for efficacy will include the mean change from Baseline / Day 0 
to Week 13 in endpoints: 
• 
Alanine aminotransferase (ALT) and bilirubin (total and direct).) change from 
Baseline (Day 0) to Week 13. 
• 
Pruritus as measured by ItchRO (Observer ItchRO/patient ItchRO). change 
from Baseline (Day 0) to Week 13.  (For each subject, the average daily score 
will be calculated using the 7 days pre-treatment for Baseline / Day 0, and the 
last 7 days of treatment for Week 13.) 


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Pattern of change in serum bile acids from Baseline (Day 0) to Week 124 will be 
evaluated and its appropriate analysis methodology will be outlined in the Statistical 
Analysis Plan (SAP) for the study. 
 
Secondary evaluations will be the mean change from Baseline (Day 0) compared to 
Week 48 in: 
• 
Biochemical markers of cholestasis and liver disease including alanine 
aminotransferase (ALT), and bilirubin (total and direct). 
• 
Pruritus as measured by the ItchRO instruments (ItchRO(Obs)TM, caregiver 
instrument/ItchRO(Pt) TM patient instrument). 
Additional evaluations of safety and efficacy surrogates will be specified in the 
Statistical Analysis Plan. 
 
Exploratory efficacy endpoints: 
• 
Change from Baseline (Day 0) in fasting serum bile acid level at Weeks 4, 8, 
24, 36, 48 60, 72, 84, 96, 108, 120, and 124 every three months thereafter, 
and at the End of Treatment (EOT) visit. 
• 
Change from Baseline (Day 0) in pruritus as measured by the average daily 
ItchRO (Observer ItchRO/patient ItchRO) at Weeks 4, 8, 28, 48, 86, 98, 110, 
and 122. 122, and every three months thereafter. 
• 
Change from Baseline (Day 0) for ALT, and bilirubin (total and direct) at 
Weeks 4, 8, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 124 every three months 
thereafter, and at the EOT visit. 
• 
Change from Baseline (Day 0) for other biochemical markers of cholestasis 
[total cholesterol, low-density lipoprotein cholesterol (LDL-C)] at Weeks 4, 8, 
13, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 124 every three months 
thereafter, and at the EOT visit. 
• 
Responder analysis: pruritus response rates as measured by ItchRO (Observer 
ItchRO/patient ItchRO) at Weeks 4, 8, 13, 28, 48, 86, 98, 110, and 122 122, 
and every three months thereafter, up to but not including the EOT visit. 
• 
Change from Baseline (Day 0) in the Clinician Scratch Scale, at Weeks 2, 4, 8, 
13, 24, 36, 48, 60, 72, 84, 96, 108, 120, and 124 every three months 
thereafter, and at the EOT visit. 
• 
Change from Baseline (Day 0) in bile acid synthesis [serum 7α-hydroxy-4-
cholesten-3-one (7αC4)] at Weeks 4, 8, 13, 24, 36, 48, 60, 72, 84, 96, 108, 120, 
and 124 every three months thereafter, and at the EOT visit. 
• 
Change from Baseline (Day 0) for PedsQL at Weeks 13, 24, 48, 72, 84, 96, 
108, 120, and 124 every three months thereafter, and at the EOT visit. 
• 
Patient Impression of Change (PIC) at Weeks 13, 48, 72, 108, 120, and 124 the 
EOT visit. 
• 
Caregiver Impression of Change (CIC) at Weeks 13, 48, 72, 108, 120, and 124 
the EOT visit. 
• 
Caregiver Global Therapeutic Benefit (CGTB) assessment at Weeks 13, 48, 72, 
108, 120, and 124 at the EOT visit. 
In addition, the following evaluations may be explored: 
• 
Change from Baseline (Day 0) for other biochemical markers [autotaxin and 
lysophosphatidic acid (LPA)] at Weeks 4, 8, 13, 36, 48, 60, 72, 84, 96, 108, 
120, and 124 every three months thereafter, and at the EOT visit. 
• 
Change from Baseline (Day 0) for measures of bile acid synthesis (FGF-19 and 
FGF-21) at Weeks 4, 8, 13, 36, 48, 60, 72, 84, 96, 108, 120, and 124 every 
three months thereafter, and at the EOT visit. 


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For subjects entering the 52-week optional follow-up treatment period with ≥7 days 
since last dose of LUM001, any of the above evaluations may also occur at clinic visits 
during the DE period. 
Synopsis, Interim 
Analyses; 
Section 12.2.7, Interim 
Analyses 
TwoThe following interim analyses are planned. 
… 
A third interim analysis will be performed after all enrolled subjects have 
completed at least 6 months of treatment under Protocol Amendment 4 (or the 
Early Termination visit). This analysis will provide an assessment of the long-term 
safety and efficacy of LUM001.  Subsequent interim analyses will be performed in 
yearly intervals. 
Synopsis, Exploratory 
Genetic Analyses; 
Section 12.2.10, 
Exploratory Genetic 
Analyses 
To better understand the role of genetics in treatment response, an additional 
blood sample will be taken for exome sequencing.  The data analysis will focus 
initially on genetic variation in candidate genes that may have a role in treatment 
response, such as ASBT/SLC10A2 and genes in its pathway (ie upstream or 
downstream of ASBT/SLC10A2) and genes implicated in PFIC (ATP8B1, ABCB11 
and ABCB4) with the goal of identifying genetic variation that may discriminate 
treatment responders from non-responders. Following examination of candidate 
genes, the data analysis may be expanded to evaluate genetic variation in 
additional regions of the exome.  This genetic analysis is more comprehensive and 
may provide valuable information beyond the ATP8B1 and ABCB11 genes. The 
submission of this blood sample is voluntary. The results of this analysis may 
identify relevant genetic variants, only some of which will be of known clinical 
benefit.   
Synopsis, Exploratory 
Responder Analyses – 
Metabolomic and 
Proteomic 
Investigations; 
Section 8.6, 
Metabolomic and 
Proteomic 
Investigations; 
Section 12.2.11, 
Exploratory Responder 
Analyses 
(Metabolomic and 
Proteomic 
Investigations) 
As part of a comprehensive approach to identify serum markers in PFIC patients 
that respond well to treatment, previously collected serum samples will be 
analyzed using both metabolomic and proteomic biomarker discovery approaches. 
Metabolomics addresses the activity of small molecules (<10 kDa) produced by 
active and living cells during their life cycle. These molecules are not accessible by 
genomic, transcriptomic or proteomic approaches. Metabolomics monitors the 
chemical transformations in metabolic cascades and can be used to identify 
observable differences between patient populations. A targeted mass spectrometry 
proteomic approach will allow for the identification and quantitation of greater 
than 150 unique proteins in each serum sample. Serum samples from both 
responding and non-responding patients will be analyzed in both biomarker 
discovery platforms and the data will be evaluated for potential markers that can 
significantly delineate responders from non-responders. 
Synopsis, Palatability 
Data; 
Section 8.5.7, 
Palatability; 
Section 12.2.12, 
Palatability Analyses 
 
Section 16.11, 
Palatability 
Questionnaire 
Palatability data will be collected at each clinic visit in the follow up treatment 
period, with the exception of the DE and ADE visits.  A palatability questionnaire 
will be completed by the subject and/or caregiver (dependent on age). 
 
 
 
Added palatability questionnaire 
   
Synopsis, Statistical 
Considerations 
 
This plan will be finalized before the interim analysis of the Week 13 data takes place. 
 
Safety measures including AEs, clinical laboratory tests, vital signs, physical exams, 
and concomitant medication usage will be summarized descriptively by study phase 


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Section 12, Statistical 
Considerations 
(Weeks 0-13, 14-48, 49-72, 73-124) and over the entire study duration (Weeks 0-72, 0-
1240-EOT Visit). 
Section 4.4.1.3, 
Toxicology 
As expected for a drug intentionally designed to work in the intestinal lumen and to be 
minimally absorbed, LUM001 exposure was very low and consistent with levels 
observed in adult rats. 
 
The higher dosing level implemented with Protocol Amendment 4 is supported by 
favorable results from a juvenile toxicity study conducted in rats administered 
LUM001 for 43 days (PND21 through PND63).  As expected for a drug 
intentionally designed to be minimally absorbed, systemic LUM001 exposure was 
very low and consistent with levels that were previously determined in several oral 
gavage studies in adult rats. No adverse effects were observed on postnatal growth 
and development of offspring at the highest doses tested (200 mg/kg/day in males, 
1000 mg/kg/day in females).  This study was initiated in juvenile animals at 
PND21, which from a whole animal development perspective is typically 
representative of a 2-year old child.  However, given the fact that LUM001 is a 
minimally absorbed drug, of particular importance is the age at which the GI tract 
is considered functionally mature.  In humans this is considered to have occurred 
by 12 months of age; likewise, postnatal maturation of the GI tract in rats occurs 
during the first 3 weeks of life.  Therefore, results from this study can be used to 
support the dosing levels proposed here for children 12 months of age and older. 
Section 4.5, Rationale 
for Dose and Schedule 
of Administration 
Updated Sample Daily Exposure (mg/day) in Pediatric Subjects table. 
 
To reduce the risk of loose stools and diarrhea in subjects in study LUM001-501 the 
LUM001 dose will be escalated over an up to 4-week period; dosing will start at 14 
µg/kg/day, and will then be increased at 7-day intervals to 35 µg/kg/day, 70 µg/kg/day, 
140 µg/kg/day and to a maximum of 280 µg/kg/day in the highest dose. 
 
To reduce the risk of loose stools and diarrhea in subjects in study LUM001-501, 
the LUM001 doses will be escalated over a period of 4-8 weeks up to a maximum 
dose of 280 µg/kg BID (or maximum tolerated dose).  For BID dosing, the morning 
dose is initiated and escalated first; the afternoon dose is only initiated and 
escalated in patients with elevated sBA and/or ItchRO ≥1.5 on the maximum (or 
maximum tolerated) morning dose. This escalation regimen is supported by the 
safety profile observed in completed and ongoing clinical studies of LUM001. 
 
Twice-daily dosing is used in this study based on the findings of a healthy 
volunteers study in adult males (Study SHP625-101), which demonstrated that bile 
acid levels in feces increase with escalating doses and twice-daily regimen of 
LUM001 (up to 100 mg QD and 50 mg BID).  In this study, subjects who were 
randomized to LUM001 treatment, received 1 of 4 doses of LUM001 (10, 20, 50, 
100 mg) during 7 days.  No titration was used in this study. There was a dose-
dependent increase in total fecal BA excretion.  In addition, BID dosing (i.e. 50 mg 
BID) led to a further increase in fecal BA excretion as compared to QD dosing (i.e. 
100 mg QD).  It is therefore hypothesized that twice-daily dosing has the potential 
to allow for more complete target engagement throughout the day at the level of 
the distal ileum. 
 
The higher dosing level is also supported by favorable results from a juvenile 
toxicity study conducted in rats administered LUM001 for 43 days (PND21 
through PND63).  As expected for a drug intentionally designed to be minimally 
absorbed, systemic LUM001 exposure was very low and consistent with levels that 


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were previously determined in several oral gavage studies in adult rats.  No 
adverse effects were observed on postnatal growth and development of offspring at 
the highest doses tested (200 mg/kg/day in males, 1000 mg/kg/day in females).  This 
study was initiated in juvenile animals at PND21, which from a whole animal 
development perspective, is typically representative of a 2-year old child.  
However, given the fact that LUM001 is a minimally absorbed drug, of particular 
importance is the age at which the GI tract is considered functionally mature.  In 
humans this is considered to have occurred by 12 months of age; likewise, 
postnatal maturation of the GI tract in rats occurs during the first 3 weeks of life.  
Therefore, results from this study can be used to support the dosing levels 
proposed here for children 12 months of age and older. 
Section 5.1, Study 
Design 
The study is divided into 5 parts: …  and an optional 52-week follow-up treatment 
period for eligible subjects who choose to stay on treatment with LUM001.  During the 
optional follow-up treatment period, subjects may be eligible for BID dosing based 
on efficacy as measured by sBA level and ItchRO score, and may have their dose of 
LUM001 increased to a maximum of 560 μg/kg/day (280 μg/kg BID).  Subjects’ 
participation in the optional follow-up treatment period will continue until the first of 
the following occur: i) completion of 52 weeks of additional treatment or ii) in the event 
that a new study of LUM001 opens to enrollment occurs: (i) subjects are eligible to 
enter another LUM001 study or (ii) LUM001 is available commercially. 
A second interim analysis will be performed after all evaluable subjects have 
completed the Week 48 (or Early Termination) study visit.  A third interim analysis 
will be performed after all enrolled subjects have completed at least 6 months of 
treatment under Protocol Amendment 4 (or the Early Termination visit).  
Subsequent interim analyses will be performed in yearly intervals.  See Section 
12.2.7 for additional information. 
Section 5.5.2, 
Treatment 
Study drug (LUM001) will be dispensed at the study site. … Subjects who weigh 10 kg 
or more at screening will receive a 1.0 mL grape-flavored solution containing LUM001. 
Subjects who weigh less than 10 kg at screening will receive a 0.5 mL grape-flavored 
solution containing LUM001. The volume administered will not change during the 
course of the study. Each daily dose will be administered in the morning at least 30 
minutes before breakfast (qAM, ac). Study drug should be administered approximately 
at the same time every day. 
 
Subjects who are eligible to participate in the optional follow-up treatment period 
will be dosed according to the LUM001 dosing scenarios described in Section 10.1, 
and may be eligible for BID dosing based on efficacy, as assessed by sBA level and 
ItchRO score.  The sBA value used for determination of ADE eligibility will be the 
most recent available value.  The ItchRO score used for ADE eligibility will be 
derived from the most recent 2-week electronic diary collection period. 
Section 5.5.2.3, Long-
term Exposure Period 
 
 
 
However, if a subject experiences intolerance due to gastrointestinal symptoms, the 
investigator, in consultation with the Sponsor Medical Monitor, may lower the dose to a 
previously tolerated dose. for the remainder of the study. 
 
During the long-term exposure period, the dose may be adjusted to account for a 
change of ≥10% in weight since the screening visit (e.g. the amount of drug dosed 
may be increased to reflect the subject’s weight increase). 
Section 5.5.2.4, 
Optional Follow-up 
Treatment Period 
Subjects eligible for the optional follow-up treatment period will continue 
treatment under dosing scenarios based on whether: 
-Their LUM001 dosing will continue without interruption or interruption of <7 
continuous days, or  
-Their LUM001 dosing will continue with interruption ≥7 days.   


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Eligibility for BID dosing will be determined based on efficacy as measured by sBA 
level and ItchRO score. 
Subjects who enter the optional follow-up treatment period without LUM001 
dosing interruption or with an interruption of <7 continuous days will be dosed in 
the following manner: 
• 
Subjects with normal sBA level AND ItchRO score <1.5 will be 
maintained at the same dose level and will continue morning dosing only. 
• 
Subjects with sBA level above normal AND/OR ItchRO score ≥1.5 will 
start BID dosing (afternoon dose escalation; ADE) as follows: 
− 
The morning dose will be continued at the same dose level, but the 
volume of the morning dose will be reduced by half at the same 
time that the afternoon dose is initiated. 
− 
The afternoon dose will be initiated at half the maximum tolerated 
morning dose and will continue at this dose for a period of 4 weeks.  
If this dose level is tolerated, the afternoon dose then will be 
doubled, to a maximum dose of 280 µg/kg (or up to the maximum 
tolerated dose). 
− 
The maximum daily dose will be 280 µg/kg BID, i.e. 560 µg/kg/day 
(max. 25 mg BID). 
 
Subjects who enter the optional follow-up treatment period with a LUM001 dosing 
interruption of ≥7 days initially will receive morning dosing only and will undergo 
dose escalation (DE) in the following manner: 
• 
The morning dose will be initiated at Dose Level 2 (35 µg/kg) and doubled 
in weekly intervals to a maximum dose of 280 µg/kg , or up to the 
maximum tolerated dose. 
• 
Once the morning dose of 280 µg/kg or maximum tolerated dose is 
achieved, sBA and ItchRO score will be evaluated. 
• 
Subjects with normal sBA AND ItchRO score <1.5 after morning dose 
escalation will be maintained at the same dose level and will continue 
morning dosing only. 
• 
Subjects with sBA above normal AND/OR ItchRO score ≥1.5 will begin 
BID dosing (afternoon dose escalation) as outlined above. 
Subjects will continue to receive study drug until they are eligible to enter another 
LUM001 study or until LUM001 is available commercially, whichever occurs first. 
The maximum daily dose will be 280 µg/kg BID, i.e. 560 µg/kg/day (maximum 25 
mg).  If a subject experiences intolerance (eg, gastrointestinal symptoms such as 
diarrhea, abdominal pain, cramping) at any time during the study, the physician 
Investigator in consultation with the Sponsor Medical Monitor may lower the dose 
for the remainder of the study. If the subject is on a BID dosing regimen, dose 
lowering should first be attempted with the afternoon dose. 
The sBA value used for determination of ADE eligibility will be the most recent 
available value.  The ItchRO score used for ADE eligibility will be derived from 
the most recent 2-week electronic diary collection period.   
 
Subjects who are eligible to roll over on to the follow-up treatment period will continue 
to receive study drug at the dose they were receiving at Week 72 for up to 52 weeks of 
additional treatment or in the event that a new study opens to enrollment, whichever 
occurs first.  
 
Subjects who are eligible to roll over into the follow-up treatment period with no 
LUM001 dosing interruption or an interruption of <7 days will be maintained at the 
same dose level.  


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Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 
280 µg/kg/day or to the maximum tolerated dose starting at Dose Level 2 (35 
µg/kg/day). This escalation regimen is supported by the safety profile observed in 
completed and ongoing clinical studies of LUM001 and allows for subjects to reach 280 
µg/kg/day or a maximum tolerated dose within a 4-week period. The dose escalation 
(DE) period will proceed as follows: 
• 
DE Week -2 Clinic Visit: obtain consent, obtain weight and draw labs.   
• 
DE Day 0 Clinic Visit: Investigator evaluates laboratory results, study drug is 
dispensed and subject begins at 35 µg/kg/day dose level. 
• 
DE Week 73 Telephone Contact: subject escalates to 70 µg/kg/day dose level 
if prior dose level was tolerated.  
• 
DE Week 74 Clinic Visit: subject escalates to 140 µg/kg/day dose level if prior 
dose level was tolerated. 
• 
DE Week 75 Telephone Contact: subject escalates to 280 µg/kg/day dose, if 
prior dose level was tolerated. 
• 
DE Week 76 Clinic Visit: subject continues in Follow-up Treatment Period at 
280 µg/kg/day, or maximum tolerated dose. 
If a subject experiences intolerance due to gastrointestinal symptoms, the investigator, 
in consultation with the Sponsor Medical Monitor, may lower the dose to a previously 
tolerated dose. At the investigator’s discretion and in consultation with the Sponsor 
Medical Monitor, subjects who were previously down-titrated may be re-challenged 
during the long-term exposure period. 
During the long-term exposure period, subjects will return to the clinic at Weeks 24, 36, 
44, 48, 60 and 72. With the exception of Week 44, safety and clinical laboratory 
evaluations, blood sampling for study drug determination, and a physical exam 
(including collection of vital signs, height and weight measurements) will be completed 
at each clinic visit. In addition, the clinician scratch scale will be administered and study 
drug compliance will be assessed. The PedsQL will be completed at Weeks 24, 48, and 
72, and the Patient and Caregiver Impression of Change (PIC & CIC), and the Caregiver 
Global Therapeutic Benefit assessments will be completed at Weeks 48 and 72. At the 
Week 24 and Week 44 visits, electronic diaries will be issued and AEs and concomitant 
medications will be assessed and recorded.  
Subjects/caregivers will receive follow-up phone calls at Weeks 16, 20, 28, 32 and 40. 
Concomitant medications and any adverse events (AEs) will be evaluated and recorded 
at all clinic visits and at scheduled telephone contacts.  
At the physician investigator’s discretion, withdrawal of concomitant medications used 
for the treatment of pruritus may occur during the long-term exposure period.  
 
With the exception of Week 44, additional study drug will be supplied at each clinic 
visit during the long-term exposure period. 
Section 5.5.2.5, Safety 
Follow-up Period 
A safety follow-up phone call will be made by the study site 30 days after the last 
dose of study drug.  This call will be made for all subjects who complete the study, 
as well as any subject who terminates from the study early.  Concomitant 
medications and any AEs noted during this phone call will be recorded.  Subjects 
who complete the study or who discontinued early due to reasons other than safety 
may be eligible for participation in the optional follow-up treatment period under 
Protocol Amendment 4. 
 
Additional study drug will be supplied at each clinic visit during the follow-up 
treatment period. Unused Used study drug will be collected at the Week 124 each clinic 
visit and dosing compliance assessed 


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Section 5.5.3, 
Electronic Diary 
For subjects who enter the optional follow-up treatment period, twice daily completion 
of the electronic diary will occur during the 2 weeks that follow the Week 84, 96, 108, 
and 120 visits, Protocol Amendment 4 DE Week 4, and every clinic visits.visit 
within each recurring 12-week period. Electronic diaries will be provided to subjects 
and caregivers at the Week 24, 44, 84, 96, 108, and 120 visits, and re-training on the use 
of the diary will occur, as appropriate, at these visits. 
Section 5.6, End of 
Study 
For subjects who did not consent to the optional follow-up treatment period, a 
subject is considered to have completed treatment if treatment was not 
permanently discontinued prior to the Week 72 visit.  A follow-up phone contact is 
required for all subjects should the final visit occur earlier than 30 days from the 
final dose.  
 
For subjects who consented to the follow-up treatment period, an additional 
follow-up period disposition is collected in the eCRF.  The subject is considered to 
have completed treatment during the follow-up treatment period if study 
treatment was not permanently discontinued prior to the subject completing the 
EOT visit as defined in the most recent consent signed by the subject. A follow-up 
contact is required for all subjects should the final visit occur earlier than 30 days 
from the final dose. 
Section 6.2, Enrollment 
Subjects will be enrolled into the optional follow-up treatment period based on the 
eligibility criteria outlined in Section 7.3. 
Section 8.1.4, 
280 µg/kg/day Stable 
Dosing Treatment 
Period (Week 9 to 
Week 13) 
At all sites (US, UK, EU and Australia), blood sampling for plasma levels of LUM001 
will be collected at Week 13.  Blood will be drawn approximately 4 hours post morning 
dosing for drug level analysis. 
Section 8.1.5, Long-
Term Exposure Period 
(Week 14 to Week 72) 
However, if a subject experiences intolerance due to gastrointestinal symptoms, the 
investigator in consultation with the Sponsor Medical Monitor may lower the dose to a 
previously tolerated dose for the remainder of the study. 
… 
Used study drug will be collected at each clinic visit, and dosing compliance will be 
assessed. 
… 
At Week 72, all subjects will be assessed by the investigator to determine their 
willingness and eligibility to roll-over into the optional follow-up treatment period. 
Following completion of the Week 72 study visit, subjects who do not wish to enter 
the optional follow-up treatment period will be contacted via telephone by the 
study site approximately 30 days after the last dose of study drug.   
Section 8.1.6, Early 
Termination for  
Subjects without 
Participation in the 
Optional Follow-up 
Treatment Period 
(new section heading) 
Any subject who withdraws from the study prior to completion of all treatment period 
clinic visits should undergo all procedures specified for the Week 72 study termination 
visit. In addition the following assessments should be completed; the ItchRO (if prior to the 
Week 48 visit), the clinician administered pruritus scale, the PedsQL, the Patient 
Impression of Change, the Caregiver Impression of Change, and the Caregiver Global 
Therapeutic Benefit assessments, as defined for Early Termination (see Section 16.1).; 
Schedule J). For safety reasons, efforts must be made to follow subjects for at least 30 days 
following their last dose of study drug. 
Section 8.1.8, End of 
Treatment or Early 
Termination 
Any subject who completes or withdraws from the study should undergo all 
procedures specified for the EOT/ET visit (see Schedule J).  The following 
assessments are to be completed at the EOT/ET visit:  Physical exam, body weight 
and height, vital signs, and blood and urine samples for clinical laboratory testing, 
including fasting lipid panel.  Blood will also be collected for determination of fat-


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soluble vitamins and AFP.  Female subjects who are of childbearing potential will 
have a urine pregnancy test.  Study drug compliance will be assessed.  
Concomitant medications and adverse events will be collected.  The ItchRO, the 
clinician administered pruritus scale, the PedsQL, the Patient Impression of 
Change, the Caregiver Impression of Change, and the Caregiver Global 
Therapeutic Benefit assessments, and palatability questionnaire also will be 
completed, as defined for Early Termination (see Section 16.1).   
Section 8.1.9, Safety 
Follow-up Period 
A safety follow-up phone call will be made by the study site 30 days after the last 
dose of study drug.  This call will be made for all subjects who complete the study, 
as well as any subject who terminates from the study early.  Concomitant 
medications and any AEs noted during this phone call will be recorded.  
Subjects who complete the study or who discontinued early due to reasons other 
than safety may be eligible for participation in the optional follow-up treatment 
period. 
Section 8.2, Genetic 
Testing 
In addition, to better understand the role of genetics in treatment response, an 
additional blood sample will be taken for exome sequencing. The data analysis will 
focus initially on genetic variation in candidate genes that may have a role in 
treatment response, such as ASBT/SLC10A2 and genes in its pathway (ie upstream 
or downstream of ASBT/SLC10A2) and genes implicated in PFIC (ATP8B1, 
ABCB11 and ABCB4) with the goal of identifying genetic variation that may 
discriminate treatment responders from non-responders. Following examination of 
candidate genes, the data analysis may be expanded to evaluate genetic variation in 
additional regions of the exome. This genetic analysis is more comprehensive and 
may provide valuable information beyond the ATP8B1 and ABCB11 genes. The 
submission of this blood sample is voluntary. The results of this analysis may 
identify relevant genetic variants, only some of which will be of known clinical 
benefit. A blood sample for exome sequencing will be drawn once, at the time of 
consent under Protocol Amendment 4. 
Section 8.3,Physical 
Examination, Weight 
and Height, Vital 
Signs; Section 8.5.1, 
Itch Reported Outcome 
(ItchRO™); Section 
8.5.2, Clinician Scratch 
Scale; Section 8.5.3, 
Pediatric Quality of 
Life Inventory 
(PedsQL); Section 
8.5.4, Patient 
Impression of Change; 
Section 8.5.5, 
Caregiver Impression 
of Change; Section 
8.5.6, Caregiver Global 
Therapeutic Benefit 
Edited text to indicate all assessments will be performed as outlined in the Schedule of 
Procedures in Section 16.1. 
Section 8.7.1, 
Contraception 
Requirements 
Sexually active female subjects of childbearing potential must continue to use 
acceptable contraception with their partners, or refrain from sexual activity, from the 
time of screening until the end of the study, throughout the study period and for 30 
days following the last dose of the IP.  
Acceptable methods of contraception are condoms with contraceptive foam, oral, 
implantable or injectable contraceptives, contraceptive patch, intrauterine device, 
diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized. 


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Description of Change 
If hormonal contraceptives are used they should be administered according to the 
package insert. 
Females of child-bearing potential who are not currently sexually active must 
agree to use acceptable contraception, as defined below, if they become sexually 
active during the period of the study and 30 days following the last dose of the IP. 
Acceptable methods of contraception are: 
a. 
Hormonal contraceptives (e.g., oral contraceptive pill, depot, patch, 
intramuscular implant or injection, or vaginal ring), stabilized for at least 30 days 
if first use, plus condoms; and/or 
b. 
Barrier method, e.g., (i) condom (male or female) or (ii) diaphragm, with 
spermicide; or 
c. 
Intrauterine device (IUD). 
d. 
or a sexual partner who is surgically sterilized. 
 
Male Contraception: 
Contraception is required for all sexually-active male subjects and their partners. 
All male subjects agree not to donate sperm, and to use 1 of the following approved 
methods of contraception until 30 days following study discharge: 
 
a. 
Male condom with spermicide 
b. 
Intrauterine device with spermicide (use by female sexual partner) 
c. 
Female condom with spermicide (use by female sexual partner) 
d. 
Contraceptive sponge with spermicide (use by female sexual partner) 
e. 
Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with 
spermicide, or a cervical cap with spermicide) (use by female sexual partner) 
f. 
Oral, implantable, transdermal, or injectable hormonal contraceptive (use 
by female sexual partner). 
Section 9.1.1, LUM001 
Added new composition of LUM001 1.0 mL Oral Solution and Composition of 
LUM001 0.5 mL Oral Solution tables. 
Section 10.1, Study 
Drug Administration 
The dose may also be down-titrated, at the investigator’s discretion and in 
consultation with the Sponsor Medical Monitor, for subjects experiencing 
intolerance (eg, gastrointestinal symptoms such as diarrhea, abdominal pain, 
cramping) to a given dose.  If the subject is on twice daily dosing regimen, dose 
reduction should first be attempted with the afternoon dose.  Subjects who were 
previously down-titrated may be re-challenged during the long-term exposure 
period. 
Section 10.2, 
Treatment Compliance 
Subjects and/or caregivers will be asked to complete a paper diary indicating when they 
took their study medication and when they ate breakfast and, for subjects who receive 
a BID regimen, when they ate dinner (evening meal). 
Section 10.5.2, Safety 
Monitoring Rules 
Of note: the INR re-test should be conducted by the central laboratory, but may 
also be conducted at a local laboratory on an as needed basis.   
Section 10.6, 
Adjustment of Dose 
If the subject is on twice daily dosing regimen, dose lowering should first be 
attempted with the afternoon dose.   
Section 11.3.1, Serious 
Adverse Events 
The collection of SAEs will begin after the subject signs the informed consent/assent 
form and stop at the end of the subject’s follow-up period which is defined as Week 76 
for subjects who do not roll over into the optional treatment follow-up period, Week 
124 for subjects who do roll over into the optional treatment follow-up period, or 30 
days after the last dose of study drug for those subjects that terminate prior to the Week 
76 or Week 124 visit.    
Section 11.3.2, Non-
serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed 
consent/assent form and will stop at the end of the subject’s follow-up period, which is 


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Section 
Description of Change 
defined as Week 76 for subjects who do not roll over into the optional treatment follow-
up period, Week 124 for subjects who do roll over into the optional treatment follow-up 
period, or 30 days after the last dose of study drug for those subjects that terminate 
prior to the Week 76 or Week 124 visit.  The Investigator will monitor each subject 
closely and record all observed or volunteered AEs on the Adverse Event Case Report 
Form.  
Section 11.3.3.2, 
Severity 
Please also refer to Section 10.5.2 regarding specific safety monitoring for liver 
chemistry tests given that subjects with PFIC may have abnormal liver enzyme 
levels at baseline. 
Section 12.2.3.2, 
Baseline Data 
• 
Growth parameters including height and weight at baseline. 
Section 12.2.6.6, 
Serum Alpha-
fetoprotein 
Assessments of serum alpha-fetoprotein (AFP) will be listed for individual subjects 
and summarized using descriptive statistics by study visit. 
Section 16.1, Schedule 
of Procedures 
Added Overall Scheme and Corresponding Schedule of Procedures 
 
Added Schedule of Procedures E-F: Rollover under Protocol Amendment 4: 
 
Schedule of Procedures E – Extension of Optional Follow-up Treatment Period, for 
subjects ineligible for ADE, applicable as follows:  
• 
Subject did not yet complete the optional follow up treatment period as 
outlined under Protocol Amendment 3 and is able to consent to Protocol 
Amendment 4 activities without an interruption in  LUM001 dosing, OR 
• 
Subject completed optional follow up treatment period as outlined under PA3 
and dosing interruption was <7 days. 
• 
Subject deemed ineligible for ADE.   
 
Schedule of Procedures F – Extension of Optional Follow-up Treatment Period, for 
subjects eligible for ADE, applicable as follows:  
• 
Subject did not yet complete the optional follow up treatment period as 
outlined under Protocol Amendment 3.  (PA3) and is able to consent to 
Protocol Amendment 4 activities without an interruption in  LUM001 dosing 
OR 
• 
Subject completed the optional follow up treatment period as outlined under 
PA3 and dosing interruption was <7 days. 
• 
Subject deemed eligible for ADE. 
 
Added Schedule of Procedures G-I: Rollover under Protocol Amendment 4: 
 
Schedule of Procedures G – Optional Follow-up Treatment Period: Re-entry under 
Protocol Amendment 4, applicable as follows: 
• 
Subject previously completed (or early terminated from ) the optional follow 
up treatment period as defined under Protocol Amendment 3 and has 
subsequently experienced an interruption in LUM001 dosing ≥7days 
• 
Subject is considered eligible for study re-entry under Protocol Amendment 4 
• 
Subject eligibility will be assessed for afternoon dose escalation at Protocol 
Amendment 4 DE Week 8 shown in the table below.   
o 
If subject is found to be ineligible for ADE, subject will move from 
Schedule G to Schedule H. 
o 
If subject is found to be eligible for ADE, subject will move from 
Schedule G to Schedule I. 


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Section 
Description of Change 
 
Schedule of Procedures H – Optional Follow-up Treatment Period: Re-entry under 
Protocol Amendment 4, subject ineligible for ADE 
 
Schedule of Procedures I – Optional Follow-up Treatment Period: Re-entry under 
Protocol Amendment 4, subject eligible for ADE 
 
Added Schedule of Procedures J - Study Termination and End of Treatment Procedures 
Section 16.2, List of 
Laboratory Analytes 
Added ABC4 under Screening Tests 
Added alpha-fetoprotein (AFP) under Marker of hepatocellular carcinoma 


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PROTOCOL AMENDMENT 3 
Protocol Number: 
LUM001-501 
Protocol Title: 
OPEN LABEL STUDY OF THE EFFICACY AND LONG TERM 
SAFETY OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS 
WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 
Amendment: 
3 
Date: 
02 November 2015 
 
The LUM001-501 protocol is being amended to include an Optional Follow-up Treatment 
Period (After Week 72) that is intended to offer the opportunity to eligible subjects treated in 
the LUM001-501 study to continue on treatment after Week 72 until the first to occur of the 
following: (i) up to 52 weeks of additional treatment (Week 124), or (ii) in the event that a new 
study opens to enrollment. 
The following changes have been made to the Protocol Amendment 2 (05 November 2014). 
Note that correction of typos and grammatical errors are not captured in the below table.  
New text indicated in red; deleted text indicated in strikethrough. 
Section 
Description of Change 
Title page; Sponsor 
Contact 
Added: 
Sponsor Medical Monitor: 
Susanne Schmidt, MD, PhD 
 
Premier Research 
 
Office: +1 215 282 5406 
 
Cell: +1 267 838 2380 
 
Email: medmonitorLUM501@premier-research.com 
Title page; Sponsor 
Contact  
Changed “Sponsor Contact” from: 
Ciara Kennedy, PhD 
Lumena Pharmaceuticals, Inc. 
Phone:  +1-858-337-7922 
Email: ckennedy@lumenapharma.com 
 
To “Sponsor Medical Lead”: 
Beatriz Caballero, MD 
Shire Human Genetic Therapies, Inc. 
Zahlerweg 10 
6300 Zug 
Switzerland 
Phone:  +41(0) 41 288 42 30 
Email: bcaballero@shire.com 
Synopsis; Objectives 
Section 3; Objectives 
Changed:  The Objectives of this study are: 
 
To:  Objectives of study (Up to and including Week 72): 


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Section 
Description of Change 
 
Added: 
Objectives of Optional Follow-up Treatment  Period (After Week 72):  
• 
To offer eligible subjects in the LUM001-501 study continued study treatment 
after Week 72 until the first of the following occur: (i) up to 52 weeks of 
additional treatment (Week 124), or (ii) in the event that a new study opens to 
enrollment. 
• 
To obtain safety and efficacy data in subjects treated long term on LUM001 
including genotyping characteristics. 
Synopsis; Objectives 
Section 3; Objectives 
Synopsis; Efficacy 
Evaluations 
Deleted: 
• 
To evaluate the long-term durability of effect of LUM001 in patients with 
PFIC during 48 weeks of treatment. 
Deleted:  
Durability of effect from efficacy analyses 
 
Rationale for this change: 
The objective evaluating durability of effect of LUM001 was removed.  Durability of 
effect cannot be assessed in this study since it is not placebo controlled and a treatment 
effect has not yet been established. 
Synopsis; Study 
Design 
Section5.1; Study 
Design 
Changed: 
The study is divided into 4 parts: a 4-week dose escalation period, a 4-week stable 
dosing period at 140 μg/kg/day, a 5-week stable dosing period at 280 μg/kg/day, and a 
59-week long-term exposure period. 
To:  
The study is divided into 5 parts: a 4-week dose escalation period, a 4-week stable 
dosing period at 140 μg/kg/day, a 5-week stable dosing period at 280 μg/kg/day, a 59-
week long-term exposure period, and an optional 52-week follow-up period for eligible 
subjects who choose to stay on treatment with LUM001. Subjects’ participation in the 
optional follow-up treatment period will continue until the first of the following occur: 
i) completion of 52 weeks of additional treatment or ii) in the event that a new study of 
LUM001 opens to enrollment. 
Synopsis; Study 
Population; Exclusion 
Criteria 
Section 7.2; Exclusion 
Criteria 
Added: 
Eligible subjects for  52-week optional follow-up treatment period: 
Subjects will be considered eligible for the 52-week optional follow-up treatment period 
if they have completed the protocol through the Week 72 visit with no safety concerns. 
Subjects who were discontinued due to safety reasons can be re-challenged if blood 
tests are back to relatively normal values for this patient population and subject does not 
meet any of the protocol’s stopping rules; the decision will be made by the investigator 
in consultation with the Sponsor Medical Monitor. Subjects who have undergone a 
surgical disruption of the enterohepatic circulation will not be eligible to enter into the 
follow up treatment period. Subjects who were discontinued for other reasons will be 
considered on an individual basis. 
Synopsis; Study Drug 
Dosage and 
Administration, 
Rationale for Dose and 
Schedule Selection 
Section 10.1 Study 
Drug Administration 
Changed:  
During this period the dose may be adjusted if there is a change of ≥10% in weight since 
the baseline visit. 
To:  
During this period the dose may be adjusted if there is a change of ≥10% in weight since 
the screening visit. 


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Section 
Description of Change 
Synopsis; Study Drug 
Dosage and 
Administration 
Section 5.5.2; 
Treatment 
Section 5.5.2.1; Dose 
Escalation Period 
Section 5.5.2.3; Long-
term Exposure Period 
Deleted: 
Dosing with LUM001 will continue at a fixed dose in a 59-week long-term exposure 
period to complete 72 weeks of total drug exposure. 
 
Added: 
At the investigator’s discretion and in consultation with the Sponsor Medical Monitor, 
subjects… 
 
At Week 72, all subjects will be assessed by the investigator to determine their 
willingness and eligibility to roll over into the 52-week optional follow-up treatment 
period. Following the completion of the Week 72 study visit, subjects who choose to 
participate in the optional follow-up treatment period will enter under one of the 
following LUM001 dosing scenarios: 
• 
Subjects who are eligible to roll over into the optional follow-up treatment 
period with no LUM001 dosing interruption or an interruption of <7 days will 
be maintained at the same dose level. 
• 
Subjects who are eligible to roll over into the optional follow-up treatment 
period with a LUM001 dosing interruption of ≥7 days, will be dose escalated up 
to 280 µg/kg/day or a maximum tolerated dose following a 4-week dose 
escalation beginning at Dose Level 2 (35 µg/kg/day). 
• 
Subjects who do not wish to enter the optional follow-up treatment period, will 
be contacted via telephone by the study site approximately 30 days after the last 
dose of study drug. 
Deleted: 
The anticipated adverse reaction or intolerance is gastrointestinal in nature (e.g., 
diarrhea, abdominal pain, cramping, etc.).  In the absence intolerance, escalation to the 
next dose level for an individual subject will occur following a scheduled phone call or 
visit, see Schedule of Procedures, Section .16.1. 
 
Added: 
If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, 
abdominal pain, cramping) at any time during the study, the physician … 
Synopsis; Rationale for 
Dose and Schedule 
Selection 
Added: 
To reduce the risk of loose stools, diarrhea and abdominal pain/cramps in this study up 
to Week 72, the LUM001 dose will be escalated over the first 4 weeks.   
 
For subjects in the 52-week optional follow-up treatment period with ≥7 days since the 
last dose of LUM001, dosing will start at 35 µg/kg/day, and will then be increased over 
the first 4 weeks up to 280 µg/kg/day or to the maximum tolerated dose starting at Dose 
Level 2 (35 µg/kg/day). This escalation regimen is supported by the safety profile 
observed in completed and ongoing clinical studies of LUM001 and allows for subjects 
to reach 280 µg/kg/day or a maximum tolerated dose within a 4-week period.  
During the long-term exposure period and the optional follow-up treatment period, the 
dose may be adjusted… 
 
The dose may also be down-titrated, at the investigator’s discretion and in consultation 
with the Sponsor Medical Monitor, for subjects experiencing intolerance to a given 
dose.  


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Section 
Description of Change 
Synopsis; Study Visit 
Schedule and 
Procedures 
Section 5.5; Overall 
Study Duration and 
Follow-up 
Added: 
Subjects who complete 72 weeks of treatment may be eligible to receive treatment for 
up to 52 weeks during the optional follow-up treatment period. 
Follow-up Treatment Scheme  
(no interruption in LUM001 dosing, or interruption <7 days)  
 
Follow-up Treatment Scheme  
(interruption in LUM001 dosing ≥7 days): 
 
 
Synopsis; Study Visit 
Schedule and 
Procedures 
Added: 
Week 72: Subjects will be evaluated by the investigator to determine whether they are 
eligible to roll over into the optional 52-week follow-up treatment period. Eligible 
subjects must have documented consents in order to continue in the optional follow-up 
treatment period. … Study drug will be discontinued at this visit if the subject chooses 
not to participate in the follow-up treatment period. 
= Clinic Visit
= Phone Contact
LUM001 70 µg/kg/day
LUM001 140 µg/kg/day
LUM001 280 µg/kg/day
LUM001 35 µg/kg/day
52-Week Optional Follow-Up Treatment Period
Study
Week
84
96
108
120
124
72
76
80
Follow
-up
88
92
100
128
116
112
104
LUM001 280 µg/kg/day or 
maximum tolerated dose
**In consultation with Medical Monitor, the dose may be lowered to a previously well-tolerated dose to address tolerability issues at any time during the study**
**At the Investigator’s discretion, subjects who were previously down-titrated may be re-challenged during the follow-up period**
= Clinic Visit
= Phone Contact
70 µg/kg/day
140 µg/kg/day
280 µg/kg/day
35 µg/kg/day
LUM001 280 µg/kg/day or 
maximum tolerated dose
59-Week Long-Term Exposure 
Study
Week
84
96
108
124
128
88
92
100
120
116
112
104
FTP 
Dose Escalation (DE)
Week
72
Delayed Rollover -
Dose interruption
>7 days
DE
-2
DE 
Day 0
DE 
73
DE 
76
DE 
75
DE 
74
80


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Synopsis; Study Visit 
Schedule and 
Procedures / Follow-up 
Treatment Period 
Section 5.5.2.4, Section 
8.1.6; Follow-up 
Period  
 
Section 8.1.8 
Optional Follow-up 
Treatment Period 
Added: 
Follow-up Treatment Period: For subjects who do not roll over into the follow-up 
treatment period, a safety follow-up phone call will be made by the study site 30 days 
after the last dose of study drug. This call will be made for all subjects who complete 
the study, as well as any subject who terminates from the study early.  Concomitant 
medications and any adverse events noted during this phone call will be recorded. 
Subjects who complete the study or who discontinued early due to reasons other than 
safety may be eligible for participation in a follow-up treatment period.  
Optional Follow-up Treatment Period (post-Week 72 to Week 124): Subjects who are 
eligible to roll over on to the follow-up treatment period will continue to receive study 
drug at the dose they were receiving at Week 72 for up to 52 weeks of additional 
treatment or in the event that a new study opens to enrollment, whichever occurs first. 
Subjects who are eligible to roll over into the follow-up treatment period with no 
LUM001 dosing interruption or an interruption of <7 days will be maintained at the 
same dose level. 
Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 
280 µg/kg/day or to the maximum tolerated dose starting at Dose Level 2 
(35 µg/kg/day). This escalation regimen is supported by the safety profile observed in 
completed and ongoing clinical studies of LUM001 and allows for subjects to reach 280 
µg/kg/day or a maximum tolerated dose within a 4-week period. The dose escalation 
(DE) period will proceed as follows: 
• 
DE Week -2 Clinic Visit: obtain consent, obtain weight and draw labs.   
• 
DE Day 0 Clinic Visit: Investigator evaluates laboratory results, study drug is 
dispensed and subject begins at 35 µg/kg/day dose level. 
• 
DE Week 73 Telephone Contact: subject escalates to 70 µg/kg/day dose level if 
prior dose level was tolerated.  
• 
DE Week 74 Clinic Visit: subject escalates to 140 µg/kg/day dose level if prior 
dose level was tolerated. 
• 
DE Week 75 Telephone Contact: subject escalates to 280 µg/kg/day dose, if 
prior dose level was tolerated. 
• 
DE Week 76 Clinic Visit: subject continues in Follow-up Treatment Period at 
280 µg/kg/day, or maximum tolerated dose.  
If any subject experiences intolerance, the investigator, in consultation with the Sponsor 
Medical Monitor, may lower the dose to a previously tolerated dose at any time during 
the entire follow-up treatment period. At the investigator’s discretion and in 
consultation with the Sponsor Medical Monitor, subjects who were previously down 
titrated may be re-challenged during the follow-up treatment period. During the follow-
up treatment period, subjects will return to the clinic every 3 months, at Weeks 84, 96, 
108, 120, and 124.  
Safety and clinical laboratory evaluations and a physical exam (including collection of 
vital signs, height and weight measurements) will be completed at each clinic visit. In 
addition, the clinician scratch scale will be administered and study drug compliance will 
be assessed. The PedsQL will be administered at DE Day 0 (for subjects requiring dose 
escalation) and at Weeks 84, 96, 108, and 124. The Patient and Caregiver Impression of 
Change (PIC & CIC), and the Caregiver Global Therapeutic Benefit assessments will be 
completed at Weeks 108, 120, and 124. Subjects/caregivers will receive follow-up 
phone calls at Weeks 80, 88, 92, 100, 104, 112, and 116. Concomitant medications and 
any AEs will be evaluated and recorded at all clinic visits and at scheduled telephone 
contacts. 


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Section 
Description of Change 
Twice daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects during the 2 weeks following the Week 84, 96, 108, and 120 clinic 
visits. Electronic diaries will be provided to subjects and caregivers at these visits and 
re-training on the use of the diary will occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications used 
for the treatment of pruritus may occur during the long-term exposure period.  
With the exception of the Week 120 and Week 124 visit (Study Termination), additional 
study drug will be supplied at each clinic visit during the follow-up treatment period. 
Unused study drug will be collected at the Week 124 visit. 
Synopsis; Efficacy 
Evaluations 
Section 12; Statistical 
Considerations 
Changed: 
The main focus for the analyses of efficacy is the period from Baseline (Day 0) to Week 
13. The period from Baseline (Day 0) to Week 48 will be analysed for durability of 
effect and the period from Weeks 48-72 has been added … 
To:  
The main focus for the analyses of efficacy is the period from Baseline (Day 0) to Week 
13. The period from Baseline (Day 0) to Week 48 will be analysed and the period from 
Weeks 48-72 and 73-124 have … 
Synopsis; Efficacy 
Evaluations 
Section 12.2.9.1; 
Efficacy Variables 
Deleted/Changed:  
Pattern of change in serum bile acids from Baseline (Day 0) to Week 48 124 will be 
evaluated to determine the durability of therapeutic effect. The durability of effect 
criteria and its appropriate analysis methodology… 
 
Secondary evaluations for the durability of the therapeutic effect will be… 
Additional evaluations of safety and durability of therapeutic effect efficacy surrogates 
will be specified in the Statistical Analysis Plan. 
 
Rationale for this change: 
The objective evaluating the durability of effect of LUM001 in subjects was removed as 
this cannot be assessed as this study is not placebo-controlled and an effect has not yet 
been established (through historical control for example). 
Synopsis; Efficacy 
Evaluations 
Section 12.2.9.1; 
Efficacy Variables; 
Section 16.7; Patient 
Impression of Change 
Section 16.8; Caregiver 
Impression of Change 
Section 16.9; Caregiver 
Global Therapeutic 
Benefit 
 
Added: 
Additional assessment time points at Week 72, 84, 96, 108, 120, and 124 were added to 
the efficacy parameters: 


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Section 
Description of Change 
• 
Change from Baseline (Day 0) in fasting serum bile acid level 
• 
Change from Baseline (Day 0) for ALT, and bilirubin (total and direct) 
• 
Change from Baseline (Day 0) for other biochemical markers of cholestasis 
[total cholesterol, low-density lipoprotein cholesterol (LDL-C)] 
• 
Change from Baseline (Day 0) in bile acid synthesis [serum 7α-hydroxy-4-
cholesten-3-one (7αC4)] 
• 
Change from Baseline (Day 0) for PedsQL  
• 
Change from Baseline (Day 0) for other biochemical markers [autotaxin and 
lysophosphatidic acid (LPA)] 
• 
Change from Baseline (Day 0) for measures of bile acid synthesis (FGF-19 and 
FGF-21) 
• 
Change from Baseline (Day 0) in the Clinician Scratch Scale 
Additional assessment time points at Week 48, 86, 98, 110, and 122 were added to the 
efficacy parameters: 
• 
Change from Baseline (Day 0) in pruritus as measured by the average daily 
ItchRO (Observer ItchRO/patient ItchRO) 
• 
Responder analysis; pruritus response rates as measured by ItchRO (Observer 
ItchRO/patient ItchRO) 
Additional assessment time points at Week 108, 120, and 124 were added to the 
efficacy parameters: 
• 
Patient Impression of Change (PIC) 
• 
Caregiver Impression of Change (CIC) 
• 
Caregiver Global Therapeutic Benefit (CGTB) 
For subjects entering the 52-week optional treatment period with ≥7 days since last dose 
of LUM001, any of the above evaluations may also occur at clinic visits during the DE 
period. 
Synopsis; Interim 
Analyses 
Section 12.2.7;Interim 
Analyses 
Deleted: 
This analysis will provide an assessment of the long-term safety and durability of effect 
efficacy of LUM001. 
Synopsis; Statistical 
Considerations 
Added: 
Safety measures including AEs, clinical laboratory tests, vital signs, physical exams, 
and concomitant medication usage will be summarized descriptively by study phase 
(Weeks 0-13, 14-48, 49-72, and 73-124) and over the entire study duration (Weeks 0-
72, and 0-124).   
Section 5.5.2; 
Treatment 
Deleted: 
Dosing will occur over a 13-week treatment period followed by a 59-week long-term 
exposure period. 
 
Added: 
Dosing will occur over a 13-week treatment period (comprised of 4-weeks dose 
escalation [Dose Level 1-4], 4-weeks stable dosing at 140 µg/kg/day, and 5-weeks 
stable dosing at 280 µg/kg/day), followed by a 59-week long-term exposure period. 


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Section 
Description of Change 
Section 5.5.3; 
Electronic Diary 
Deleted/Added: 
Twice daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects beginning at the screening visit through the end of the Week 13 
visit and again during the 4 weeks that follow the Week 24 and Week 44 clinic visits 
and, for subjects who enter the optional follow-up treatment period, during the 2 weeks 
that follow the Week 84, 96, 108, and 120 clinic visits. Electronic diaries will be 
provided to subjects and caregivers at Weeks the Week 24, 44, 84, 96, 108, and 120 
visits, and re-training on the use of the diary will occur, as appropriate, at these 2 visits. 
Section 5.5.4; 
Follow-up 
Changed: 
Study drug (LUM001) will be discontinued at Week 72 and subjects will be followed 
for an additional 4 weeks.  A safety follow-up phone call will be made at Week 76.  
Subjects who complete the study may be eligible for participation in a long-term 
extension study of LUM001. 
To: 
Study drug (LUM001) will be discontinued at Week 72 if the subject chooses not to 
participate in the optional follow-up treatment period and subjects will be followed for 
an additional 4 weeks.  A safety follow-up phone call…   
Section 8.1.5; Long-
term Exposure Period 
Section 10.6; 
Adjustment of Dose 
Added: 
At the investigator’s discretion and in consultation with the Sponsor Medical Monitor, 
subjects who were previously down-titrated may be re-challenged. 
Section 8.2; Genetic 
Testing 
Added: 
ATP8B1 or ABCB11 mutations are predictive of PFIC. For subjects who do not have 
documentation of an ATP8B1 or ABCB11 mutation, blood samples for genotyping will 
be collected at the screening visit. The appropriate genetic counseling in accordance 
with local laws will be provided to any subject and their legal caregivers at a study visit 
following the receipt of results of genetic testing, at no cost to the subject. Subjects for 
whom prior genotyping was performed may need to have an optional repeat analysis 
performed if the original information collected at screening was insufficient for 
complete documentation of the diagnosis of PFIC including the type of mutation 
recorded. For those participants for which the type of the mutation cannot be 
documented, genetic testing may be conducted and the results recorded. 
Section 8.3; 
Physical Examination 
Added: 
For subjects who enter into the optional follow-up treatment period, physical 
examinations will also be conducted at Week 84, Week 96, Week 108, Week 120, and 
Week 124. For subjects with interruptions in LUM001 dosing of ≥7 days, additional 
physical examinations will be conducted during the DE period at DE -2, DE Day 0, DE 
Week 74, and DE Week 76. 
Section 8.5.1; Itch 
Reported Outcome 
 
Added: 
For subjects who enter the optional follow-up treatment period, daily completion of the 
diary will also be during the 2 weeks following the Week 84, 96, 108, and 120 clinic 
visits. 
Section 8.5.2; Clinician 
Scratch Scale 
Added: 
For subjects who enter the optional follow-up treatment period, the clinician scratch 
scale will also be administered at Weeks 84, 96, 108, 120, and 124. For subjects with 
interruptions in LUM001 dosing of ≥7 days, assessments will be conducted during the 
DE period at DE -2, DE Day 0, DE Week 74, and DE Week 76. 
Section 8.5.3; Pediatric 
Quality of Life 
Inventory  
Added: 
For subjects who enter the optional follow-up treatment period, the PedsQL will also be 
administered at Weeks 84, 96, 108, 120, and 124. For subjects with interruptions in 
LUM001 dosing of ≥7 days, the PedsQL will also be administered at DE Day 0. 


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Section 
Description of Change 
For subjects who enter the optional follow-up treatment period, the multidimensional 
fatigue and family impact questionnaires will also be administered at Weeks 84, 96, 
108, 120, and 124. 
Section 8.5.4; Patient 
Impression of Change 
Changed: 
The PIC will be completed, by subjects who were 9 years of age or older at the 
screening visit. It will be completed at the Weeks 13, 48 and 72 visits, see Section 16.7.  
For subjects who enter the optional follow-up treatment period, the PIC will also be 
administered at Weeks 108, 120, and 124. 
To: 
The PIC will be completed by subjects who were 9 years of age or older at the Week 13, 
Week 48, and Week 72 visits. For subjects who enter the optional follow-up treatment 
period, the PIC will be completed by subjects who were 9 years of age or older at the 
Weeks 108, 120, and 124 (see Section 16.7). 
Section 8.5.5; 
Caregiver Impression 
of Change 
Added: 
For subjects who enter the optional follow-up treatment period, the CIC will also be 
administered at Weeks 108, 120, and 124. 
Section 8.5.6; 
Caregiver Global 
Therapeutic Benefit 
Added: 
For subjects who enter the optional follow-up treatment period, the CGTB will also be 
administered at Weeks 108, 120, and 124. 
Section 10.1; Study 
Drug Administration 
Added: 
During the long-term exposure period (Week 14 to Week 72) of the study, and during 
the optional follow-up treatment period (Week 76 to Week 124)…. 
Section 10.3; 
Concomitant 
Medications  
Added/Changed: 
…administered during participation in the study (the period from the first day of 
screening through the last contact at Week 76128). 
Section 11.3.1; Serious 
Adverse Events  
Added/Changed: 
The collection of SAEs will begin after the subject signs the informed consent/assent 
form and stop at the end of the subject’s follow-up period which is defined as Week 
7276 for subjects who do not roll over into the optional treatment follow-up period, 
Week 124 for subjects who do roll over into the optional treatment follow-up period, or 
30 days after the last dose of study drug for those subjects that terminate the prior to the 
Week 72 76 or Week 124 visit. 
Section 11.3.2; Non-
Serious Adverse 
Events  
Added/Changed: 
The recording of non-serious AEs will begin after the subject signs the informed 
consent/assent form and will stop at the end of the subject’s follow-up period, which is 
defined as Week 76 for subjects who do not roll over into the optional treatment follow-
up period, Week 124 for subjects who do roll over into the optional treatment follow-up 
period, or 30 days after the last dose of study drug for those subjects that terminate prior 
to the Week 76 or Week 124 visit.   
Section 12; Statistical 
Considerations 
Added: 
Summaries will be provided by study phase (Weeks 0-13, 14-48 and, 49-72, 73-124) 
and over the entire study duration (Weeks 0-72 and 0-124), by visit… 
Section 12.2.6; Safety 
Analyses 
Added: 
Safety data, including AEs, clinical laboratory tests, vital signs, physical examinations, 
and concomitant medication usage will be summarized descriptively by study phase 
(Weeks 0-13, 14-48, 49-72, and 73-124) and over the entire study duration (Weeks 0-
124). 
Section 12.2.9.1; 
Efficacy Variables 
Added: 
For this instrument the caregiver and/or subject indicate the itch severity in the morning 
and in the evening each day during screening and during the designated study periods 


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Section 
Description of Change 
[Day 0 – 13, Week 24-28, Week 44-48, Week 84-86, Week 96-98, Week 108-110, and 
Week 120-122]. 
If a caregiver is not compliant with the ItchRO (Obs) at Weeks 13, 28, 48, 86, 98, 110, 
and 122, the average daily… 
Section 16.1; Schedule 
of Procedures 
Added: 
Two new Schedules of Procedures for the Optional Follow-up Treatment Period (Week 
72-Week 124) for 1) subjects with no interruption in LUM001 dosing or interruption <7 
days and 2) Subjects with interruption in LUM001 dosing ≥7 days. 


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PROTOCOL AMENDMENT 2 
Protocol Number: 
LUM001-501 
Protocol Title: 
OPEN LABEL STUDY OF THE EFFICACY AND LONG TERM 
SAFETY OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS 
WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 
Amendment: 
2 
Date: 
05 November 2014 
 
The following changes have been made to the Protocol Amendment 1 (US version dated 
December 10, 2013 and UK/EU version dated May 7, 2014). 
The inclusion criterion related to serum bile acid levels is changed from intrahepatic 
cholestasis manifested by “fasting total serum bile acid to >100 μmol/L” to “total serum bile 
acid >3x upper limit of normal for age.”  
The inclusion criterion related to the ability to read and understand English has been expanded 
to accommodate the following languages: English, Spanish, US Spanish, French, German or 
Polish.  
The exclusion criterion related to a surgical procedure resulting in disruption of the 
enterohepatic circulation at the time at screening has been clarified to indicate that subjects 
who have undergone reversal of such surgical procedures and have a permanently restored 
flow of bile acids from the liver to the terminal ileum may be eligible for the study upon 
consultation with the Sponsor Medical Monitor. 
An exclusion criterion has been added to specify that the administration of sodium 
phenylbutyrate within 30 days prior to the Baseline / Day 0 visit and during the study is 
prohibited.   
The number of subjects is increased from 12 subjects to approximately 24 evaluable subjects 
inclusive of the replacement of any subjects who may substantially violate the protocol. A 
minimum of 8 subjects with FIC1 (ATP8B1 related disease) subjects will be enrolled.  
The duration of the treatment period has been increased from 48 weeks to 72 weeks.  
The number of clinic visits is increased by 2 (total 12 clinical visits) to accommodate the 
extended duration of the study. Procedures and assessments for these 2 study visits have been 
added. 
Text has been included to indicate that all assessments completed by the subject and caregiver 
will be provided as validated translations in the following languages: English, Spanish, US 
Spanish, French, German or Polish.  


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The sampling schedules for pharmacokinetic (PK) analysis of LUM001 levels have been 
clarified to accommodate the requirement for more frequent PK sampling in the US, as was 
requested by the Food and Drug Administration (FDA), compared to the sampling schedule 
for the UK, EU and Australia. 
An ultrasound at the screening visit will not be required if the results of an ultrasound 
completed within 6 months are available to the investigator and the clinical status of the 
subject has not changed significantly since the time of the test.  
Revised text was added to indicate that a physical exam will be conducted only at the 
Screening, and the Weeks 24, 36, 48, 60 and 72 clinic visits.  
The frequency of study drug dispensation has been clarified to indicate that study drug will not 
be dispensed at the Week 44 visit. 
The section on Safety Monitoring Rules and Safety Monitoring for Liver Chemistry Tests 
were clarified to indicate that repeat testing is required within 48 to 72 hours of the availability 
of the initial report instead of within 48 to 72 hours of the initial collection. 
As second interim analysis has been added when all enrolled subjects have reached the 48 
week visit. 
The Statistical Considerations section has been updated to reflect the increase in the study’s 
duration and the increase in study visits. 
The following table provides a summary list of changes to the protocol: 
 
Section 
Description of Change 
Synopsis (Section 1), Study Design 
Overall Study Duration and Follow-up 
(Section 5.5) 
Changed treatment (duration) period to collect additional 
long-term exposure data from 39 weeks to 76 weeks, 
inclusive of a 4 week follow-up. Treatment period changed 
from 48 weeks to 72 weeks. 
Synopsis (Section 1), Study Visit Schedule and 
Procedures 
Study Design (Section 5.1) 
 
Changed long term exposure period from 35 weeks to 
59 weeks, treatment duration from 48 weeks to 72 weeks 
and study duration from 52 to 76 weeks, inclusive of a 4 
week follow-up. 
Added study visits at Weeks 60 and 72. 
Changed Study Termination (End of Study) from Week 48 
to Week 72. 
Added PedsQL evaluation at Week 72. 
Added Patient & Caregiver Impression of Change 
evaluation at Week 72. 
Synopsis (Section 1), Number of Subjects 
Number of Subjects (Section 5.4) 
Statistical Considerations (Section 12) 
Increased from 12 to approximately 24 evaluable subjects. 
At least 8 subjects with FIC1 will be enrolled (increased 
from 5). 
Synopsis (Section 1), Stable Dosing Periods 
(Section 5.5.5.2) 
Text has been clarified to indicate that at Week 8, the dose 
will be increased to level 5 only for subjects who tolerated 
dose level 4. 
Synopsis (Section 1), Inclusion Criterion #2a 
(Section 7.1) 
Criterion has been modified from “fasting total serum bile 
acid to >100 μmol/L” to “total serum bile acid >3x upper 
limit of normal for age”. 


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Section 
Description of Change 
Synopsis (Section 1), Inclusion Criterion #8 
(Section 7.1) 
Criterion has been expanded to specify that eligible 
subjects and caregivers must be able to read and understand 
the primary language(s) of the country in which the study 
is being conducted. 
Synopsis (Section 1), Exclusion Criterion #2 
(Section 7.2) 
Criterion clarified to indicate that subjects who have 
undergone reversal of a prior surgical procedure intended 
to disrupt enterohepatic circulation and who have a 
permanently restored flow of bile acids from the liver to 
the terminal ileum may be eligible for the study upon 
consultation with the Medical Monitor. 
Synopsis (Section 1), Exclusion Criterion #13 
(Section 7.2) 
Criterion clarified to specify that administration of bile acid 
or lipid binding resins within 30 days prior to Baseline / 
Day 0 and throughout the trial is excluded. 
Synopsis (Section 1), Exclusion Criterion #14 
(Section 7.2) 
Criterion added to exclude the administration of sodium 
phenylbutyrate within 30 days prior to Baseline / Day 0 
and throughout the trial. (As a result, the total number of 
exclusion criteria has increased from 16 to 17.) 
Synopsis (Section 1), Drug Level Evaluations, 
Study Procedures (Section 8), Section 16.1 
Added collection of PK samples at Weeks 60 and 72; 
Clarified sampling schedules. 
Number of Study Centers (Section 5.3) 
Changed from 3-7 centers to approximately 12 centers. 
Synopsis (Section 1), Study Visit Schedule and 
Procedures  
Screening Period (Section 8.1.1) 
Text inserted to indicate that a screening ultrasound will 
not be required if the results of an ultrasound  
completed within 6 months are available, provided the 
clinical status of the subject has not changed significantly 
since the time of the test. 
Synopsis (Section 1), Statistical Considerations 
(Section 12) 
Statistical considerations revised to reflect an additional 
interim analysis; updated analyses to reflect the increase in 
the study’s duration and number of visits. Clarified that the 
main focus for the analyses of efficacy is the period from 
Baseline (Day 0) to Week 13. The period from Baseline 
(Day 0) to Week 48 will be analysed for durability of effect 
and the period from Weeks 48-72 has been added to obtain 
additional safety data and to monitor biochemical markers 
of cholestasis. Specified that there will be two analysis 
populations for efficacy: the Per Protocol population (PP) 
will consist of all subjects in the MITT population who did 
not have a major protocol violation, inclusive of violation 
of entry the criteria. Subjects in this population will be 
referenced as evaluable. 
Physical Examination, Weight, Height, Vital 
Signs (Section 8.3) 
Dose Escalation Treatment Period (Day 0 to 
Week 4) (Synopsis and Section 8.1.2) 
Text revised to indicate that a physical examination on 
each subject should be completed at screening and at the 
Weeks 24, 36, 48, 60 and 72 clinic visits.   
Long-Term Exposure Period (Sections 5.5.2.3 
and 8.1.5) 
With the exception of the Week 44 and the Study 
Termination Visit (End of Study), additional study drug 
will be supplied at each clinic visit during the long-term 
exposure period. 
Long-term Exposure Period (Section 8.1.5) 
Added clinic visits at Weeks 60 and 72 and adjusted 
schedule of procedures as noted in Section 16.1. 
Follow-up Period (Week 73 to Week 76) 
(Section 8.1.6) 
Extended follow-up period to Weeks 73-76. 


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Section 
Description of Change 
Physical Examination, Weight and Height, Vital 
Signs (Section 8.3) 
Added assessments at Weeks 60 and 72. 
Early Termination  (Section 8.1.7) 
Changed Week 48 to Week 72. 
Genetic Testing (Section 8.2) 
Clarified that blood samples for genotyping will be 
collected at the screening visit for subjects who do not have 
documentation of an ATP8B1 or ABCB11 mutation; added 
text to indicate that genetic counseling will be provided in 
accordance with local laws. 
Pruritus and Quality of Life Assessments 
(Section 8.5) 
Added text to clarify that assessments completed by the 
subject and caregiver will be provided as validated 
instruments in the primary language(s) of the country in 
which the subject and caregiver are participating in the 
study. 
Clinician Scratch Scale (Section 8.5.2) 
Added assessments at Weeks 60 and 72. 
Pediatric Quality of Life Inventory PedsQL 
(Section 8.5.3) 
Added assessment at Week 72; clarified that age at baseline 
visit will be used as the age for the determination of the 
appropriate questionnaire to be used for the duration of the 
study, regardless of subsequent birthdays during the study. 
Patient Impression of Change (Sections 8.5.4 and 
16.7) 
Added assessment at Week 72; removed assessment at 
Screening. 
Caregiver Impression of Change (Sections 8.5.5 
and 16.8) 
Added assessment at Week 72. 
Caregiver Global Therapeutic Benefit 
(Section 8.5.6) 
Added assessment at Week 72. 
Replacement of Subjects (Section 6.3) 
Text has been added to indicate that subjects who 
substantially violate the protocol may be replaced in order 
to enroll approximately 24 evaluable subjects. 
Safety Monitoring Rules (Section 10.5.2), Safety 
Monitoring for Liver Chemistry Tests (Section 
10.5.2.1) 
Text has been modified to specify that confirmation 
specimen collections should take place within 48 to 
72 hours of the availability of the report. 
Schedule of Procedures (Section 16.1) 
Modified to reflect changes listed above 
Liver Disease Diagnoses Excluded from PFIC 
Definition (Section 16.3) 
Clarified criterion #8 to indicate that a confirmed diagnosis 
of bile acid synthesis defects is excluded; however, testing 
during screening for bile acid synthesis defects is not a 
required. 
Administrative Changes 
To correct typographical errors. 
 
 
 


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PROTOCOL AMENDMENT 1 (UNITED STATES) 
Protocol Number: 
LUM001-501 
Protocol Title: 
OPEN LABEL STUDY OF THE EFFICACY AND LONG TERM 
SAFETY OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS 
WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 
Amendment: 
1 (US) 
Date: 
10 December 2013 
 
The following changes have been made to the original protocol. 
In order to limit propylene glycol (PG) exposure to within the recommended limits 
(WHO acceptable daily intake limits of 25 mg/kg/day), the volume of study drug administered 
has been reduced from 1 mL to 0.5 mL for subjects who weigh less than 10 kg. 
The frequency for the evaluation of LUM001 plasma levels of has been clarified. Blood 
sampling for LUM001 determination will occur at baseline, and visits at Weeks 2, 4, 8, 13, 24, 
36 and 48. To maximize the information generated from sparse sampling, and based on a Tmax of 
LUM001 in adults of 2.3 hours, a blood sample for study drug determination will be collected at 
approximately 2 hours post-dosing at Week 4. At Weeks, 2, 8, 13, 24, 36 and 48, blood samples 
for study drug determination will be collected at approximately 4 hours post-dosing. 
Safety Monitoring Rules and Safety Monitoring for Liver Chemistry Tests will be modified to 
require repeat testing within 48 to 72 hours. 
The section “Further Investigation into Liver Chemistry Elevations” has been modified to 
include additional evaluations in the event of a confirmed ALT or total bilirubin level. 
Minor changes have been made to the text to improve the clarity of the protocol and/or correct 
minor inconsistencies. 


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The following table provides a summary list of changes to the protocol: 
 
Section 
Description of Change 
Inclusion Criteria (Section 7.1) 
Text revised to include upper age limit of 18 years 
of age. 
Treatment (Section 5.5.2), Dose Escalation Period 
(Section 5.5.2.1), Study Drug Administration 
(Section 10.1) 
Text revised to indicate that subjects who weigh 10 
kg or more at screening will receive a 1.0 mL 
solution containing LUM001. Subjects who weigh 
less than 10 kg at screening will receive a 0.5 mL 
solution containing LUM001. The volume 
administered will not change during the course of 
the study. 
Study Design (Section 5.1) 
Blood samples will be collected at baseline and 
Weeks 2, 4, 8, 13, 24, 36 and 48 for study drug 
determination. At Week 4, blood will be drawn 
approximately 2 hours post-dosing for drug level 
analysis. At Weeks 2, 8, 13, 24, 36 and 48, blood 
will be drawn approximately 4 hours post dosing for 
drug level analysis. 
Study Drug Description (Section 9.1) 
A tabular description of the composition of the 
LUM001 0.5 mL solution has been included 
Safety Monitoring Rules (Section 10.5.2)  
Text has been modified to specify that confirmation 
specimen collections should take place as within 48 
to 72 hours of the initial collection. 
Safety Monitoring for Liver Chemistry Tests 
(Section 10.5.2.1) 
The section has been modified to require repeat 
testing within 48 to 72 hours:  “If at any time in the 
study an ALT or total bilirubin result meets the 
criteria shown in the table below, in relation to the 
subject’s baseline level, the initial measurement(s) 
should be confirmed within 48 to 72 hours of the 
initial collection.” 
Further Investigation into Liver Chemistry Elevations 
(Section 10.5.2.1) 
This section has been modified to include the 
following evaluations in the event of a confirmed 
elevation in ALT or total bilirubin level: 
• 
Close and frequent monitoring of liver enzyme 
and serum bilirubin tests as clinically 
indicated.  Frequency of retesting can decrease 
if abnormalities stabilize or the trial drug has 
been discontinued and the subject is 
asymptomatic. If the appropriate frequency of 
monitoring is not feasible study drug 
administration will be suspended. 
• 
Obtain a detailed history of symptoms and 
prior and concurrent diseases. 
• 
Obtain comprehensive history for concomitant 
drug use (including non-prescription 
medications, herbal and dietary supplement 
preparations), alcohol use, recreational drug 
use, and special diets. 


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Section 
Description of Change 
• 
Obtain a history for exposure to environmental 
chemical agents and travel. 
• 
Serology for viral hepatitis (HAV IgM, 
HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel). 
• 
Serology for autoimmune hepatitis [e.g., 
antinuclear antibody (ANA)]. 
Additional liver evaluations, including 
gastroenterology/hepatology consultations, hepatic 
CT or MRI scans, may be performed at the 
discretion of the Investigator, in consultation with 
the Sponsor Medical Monitor. 
Section 16.6 
Addition of the PedsQL quality of life questionnaire 
of children between the ages of 0-12 months. 
PROTOCOL AMENDMENT 1 (UNITED KINGDOM & EUROPE) 
Protocol Number: 
LUM001-501 
Protocol Title: 
OPEN-LABEL STUDY OF THE EFFICACY AND LONG-TERM 
SAFETY OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC PATIENTS 
WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS 
Amendment: 
1 (UK and EU) 
Date: 
07 May 2014 
 
The following changes have been made to the original protocol. 
In order to limit propylene glycol (PG) exposure to within the recommended limits 
(WHO acceptable daily intake limits of 25 mg/kg/day), the volume of study drug administered 
has been reduced from 1 mL to 0.5 mL for subjects who weigh less than 10 kg. 
Safety Monitoring Rules and Safety Monitoring for Liver Chemistry Tests will be modified to 
require repeat testing within 48 to 72 hours. 
The section “Further Investigation into Liver Chemistry Elevations” has been modified to 
include additional evaluations in the event of a confirmed ALT or total bilirubin level. 
Minor changes have been made to the text to improve the clarity of the protocol and/or correct 
minor inconsistencies. 
The following table provides a summary list of changes to the protocol: 
 
Section 
Description of Change 
Inclusion Criteria (Section 7.1) 
Text revised to include upper age limit of 18 years 
of age. 


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Section 
Description of Change 
Treatment (Section 5.5.2), Dose Escalation Period 
(Section 5.5.2.1), Study Drug Administration 
(Section 10.1) 
Text revised to indicate that subjects who weigh 
10 kg or more at screening will receive a 1.0 mL 
solution containing LUM001. Subjects who weigh 
less than 10 kg at screening will receive a 0.5 mL 
solution containing LUM001. The volume 
administered will not change during the course of 
the study. 
Study Drug Description (Section 9.1) 
A tabular description of the composition of the 
LUM001 0.5 mL solution has been included. 
Safety Monitoring Rules (Section 10.5.2)  
Text has been modified to specify that confirmation 
specimen collections should take place as within 48 
to 72 hours of the initial collection. 
Safety Monitoring for Liver Chemistry Tests 
(Section 10.5.2.1) 
The section has been modified to require repeat 
testing within 48 to 72 hours:  “If at any time in the 
study an ALT or total bilirubin result meets the 
criteria shown in the table below, in relation to the 
subject’s baseline level, the initial measurement(s) 
should be confirmed within 48 to 72 hours of the 
initial collection.” 
Further Investigation into Liver Chemistry Elevations 
(Section 10.5.2.1) 
This section has been modified to include the 
following evaluations in the event of a confirmed 
elevation in ALT or total bilirubin level: 
• 
Close and frequent monitoring of liver enzyme 
and serum bilirubin tests as clinically 
indicated.  Frequency of retesting can decrease 
if abnormalities stabilize or the trial drug has 
been discontinued and the subject is 
asymptomatic. If the appropriate frequency of 
monitoring is not feasible study drug 
administration will be suspended. 
• 
Obtain a detailed history of symptoms and 
prior and concurrent diseases. 
• 
Obtain comprehensive history for concomitant 
drug use (including non-prescription 
medications, herbal and dietary supplement 
preparations), alcohol use, recreational drug 
use, and special diets 
• 
Obtain a history for exposure to environmental 
chemical agents and travel.  
• 
Serology for viral hepatitis (HAV IgM, 
HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel). 
• 
Serology for autoimmune hepatitis 
[e.g., antinuclear antibody (ANA)]. 
 
Additional liver evaluations, including 
gastroenterology/hepatology consultations, hepatic 
CT or MRI scans, may be performed at the 
discretion of the Investigator, in consultation with 
the Sponsor Medical Monitor. 


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Section 
Description of Change 
Section 16.6 
Addition of the PedsQL quality of life questionnaire 
of children between the ages of 1-12 months. 
 
 


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1 
STUDY SYNOPSIS AND SCHEDULE OF PROCEDURES 
Sponsor 
Mirum Pharmaceuticals, Inc. 
Protocol Number 
LUM001-501 
Protocol Title 
Open Label Study of the Efficacy and Long Term Safety of LUM001, an Apical 
Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of 
Cholestatic Liver Disease in Pediatric Patients with Progressive Familial Intrahepatic 
Cholestasis 
Study Phase 
2 
Indication 
Treatment of Patients with Progressive Familial Intrahepatic Cholestasis (PFIC) 
Objectives 
Objectives of Study (Up to and including Week 72): 
• To evaluate the long-term safety and tolerability of LUM001 in pediatric subjects with 
PFIC. 
• To evaluate the effect of LUM001 on serum bile acid levels in pediatric subjects with 
PFIC at 13 weeks of treatment. 
• To evaluate the effect of LUM001 on biochemical markers of cholestasis and liver 
disease at 13 weeks of treatment. 
• To evaluate the effect of LUM001 on pruritus in pediatric subjects with PFIC at 
13 weeks of treatment. 
Objectives of Optional Follow-up Treatment  Period (After Week 72): 
• To offer eligible subjects in the LUM001-501 study continued study treatment beyond 
Week 72 until the first of the following occurs:  (i) the subjects are eligible to enter 
another LUM001 study or (ii) LUM001 is available commercially. 
• To obtain safety and efficacy data in subjects treated long-term on LUM001. 
• To explore a twice a day (BID) dosing regimen and higher daily dosing of LUM001. 
• To identify genetic indicators of treatment response, including use of exome sequencing.  
• To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma. 
• To assess palatability of the LUM001 formulation.  
Exploratory Objective: 
• To allow the possibility of analysis of serum markers of treatment response using 
metabolomic and proteomic analysis on previously collected serum samples. 
Study Design 
This is an open label study in children with PFIC designed to evaluate the safety and 
efficacy of LUM001. The study is divided into 5 parts: a 4-week dose escalation period, a 
4-week stable dosing period at 140 μg/kg/day, a 5-week stable dosing period at 
280 μg/kg/day, a 59-week long-term exposure period, and an optional follow-up treatment 
period for eligible subjects who choose to stay on treatment with LUM001.  During this 
optional follow-up treatment period, subjects may have their dose of LUM001 increased to 
a maximum of 560 μg/kg/day (280 μg/kg BID), based on ongoing efficacy (sBA level and 
ItchRO score) and safety assessment.  Subjects’ participation in the optional follow-up 
treatment period will continue until the first of the following occurs: (i) subjects are eligible 
to enter another LUM001 study or (ii) LUM001 is available commercially.  
Number of 
Subjects 
Approximately 24 evaluable subjects will be enrolled in this study. Of the 24 subjects, a 
minimum of 8 PFIC1 (ATP8B1-related disease) subjects will be enrolled in this study. 
Study Population 
Inclusion Criteria 
To participate in this study subjects must meet the following criteria: 


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1. Male or female subjects between the ages of 12 months and 18 years inclusive. 
2. Diagnosis of PFIC based on: 
a. 
Intrahepatic cholestasis manifest by total serum bile acid >3x upper limit of normal 
(ULN) for age. 
and, b or c: 
b. Two documented mutant alleles in ATP8B1, or ABCB11. 
c. 
Evidence of chronic liver disease, excluding those listed in (see Section 16.3), with 
one or more of the following criteria:  
1) Duration of biochemical or clinical abnormalities of >6 months, or 
2) Pathologic evidence of progressive liver disease, or  
3) Sibling of known individual affected by PFIC (predicted to be 
chronic). 
3. GGTP <100 IU/L at screening. 
4. Females of childbearing potential must have a negative urine or serum pregnancy test 
[β human chorionic gonadotropin (β-hCG)] during screening and a negative urine 
pregnancy test at the baseline visit. 
5. Males and females of child-bearing potential who are sexually active, or are not 
currently sexually active during the study, but become sexually active during the 
period of the study and 30 days following the last dose of study drug, must agree and 
use acceptable contraception during the trial.  
6. Informed consent and assent (per IRB/EC) as appropriate. 
7. Access to phone for scheduled calls from study site. 
8. Caregivers and children above the age of assent must have the ability to read and 
understand one of the following languages: English, Spanish, US Spanish, French, 
German or Polish. 
9. Subjects expected to have a consistent caregiver(s) for the duration of the first 
13 weeks of the study. 
10. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary 
device as required by the study. To accommodate potential cultural restrictions within 
the FIC1 affected population a paper version of the ItchRO diary will be made 
available. 
11. Caregivers (and age appropriate subjects) using the eDiary must digitally accept the 
licensing agreement in the eDiary software at the outset of the study. 
12. Caregivers (and age appropriate subjects) must complete at least 10 eDiary reports 
(morning or evening) during each of two consecutive weeks of the screening period, 
prior to assignment (maximum possible reports = 14 per week). Subjects using a paper 
diary must complete the same number of reports within the same timeframe. 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Chronic diarrhea requiring specific intravenous fluid or nutritional intervention for the 
diarrhea and/or its sequelae. 
2. Surgical disruption of the enterohepatic circulation at the time of screening. Subjects 
who have undergone reversal of a prior surgical procedure intended to disrupt 
enterohepatic circulation and who have a permanently restored flow of bile acids from 
the liver to the terminal ileum may be eligible for the study upon consultation with the 
Medical Monitor. 
3. Liver transplant. 


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4. Decompensated cirrhosis [international normalized ratio (INR) > 1.5, albumin 
< 30 g/L, history or presence of clinically significant ascites, variceal hemorrhage, 
and/or encephalopathy]. 
5. ALT >15 × ULN at screening. 
6. History or presence of other liver disease (see Section 16.1). 
7. History or presence of any other disease or condition known to interfere with the 
absorption, distribution, metabolism or excretion of drugs, including bile salt 
metabolism in the intestine (e.g., inflammatory bowel disease). 
8. Liver mass on imaging. 
9. Known diagnosis of human immunodeficiency virus (HIV) infection. 
10. Cancers except for in situ carcinoma, or cancers treated at least 5 years prior to 
screening with no evidence of recurrence. 
11. Any female who is pregnant or lactating or who is planning to become pregnant within 
20 weeks of assignment. 
12. Any known history of alcohol or substance abuse. 
13. Administration of bile acid or lipid binding resins within 30 days prior to  
Baseline / Day 0 and throughout the trial. 
14. Administration of sodium phenylbutyrate within 30 days prior to  
Baseline / Day 0 and throughout the trial. 
15. Investigational drug, biologic, or medical device within 30 days prior to screening, or 5 
half-lives of the study agent, whichever is longer. 
16. History of non-adherence to medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to non-
adherence with the study protocol based on Investigator judgment. 
17. Any other conditions or abnormalities which, in the opinion of the Investigator or 
Medical Monitor, may compromise the safety of the subject, or interfere with the 
subject participating in or completing the study. 
Eligible Subjects for Optional Follow-up Treatment Period: 
Inclusion Criteria 
Subjects will be considered eligible for the Optional Follow-up Treatment Period if they 
meet the following criteria: 
1. The subject has either:  
• 
completed the protocol through the Week 72 visit with no major safety 
concerns, OR 
• 
discontinued due to safety reasons judged unrelated to the study drug, and 
blood tests have returned to levels acceptable for this patient 
population/individual and  subject does not meet any of the protocol’s 
stopping rules at re-entry.  The decision will be made by the Investigator 
in consultation with the Medical Monitor.  [Subjects who were 
discontinued for other reasons will be considered on an individual basis.] 
2. Females of childbearing potential must have a negative urine or serum pregnancy 
test (β-hCG) at the time of entry into the optional follow-up treatment period. 
3. Informed consent and assent (per IRB/EC) as appropriate. 
Exclusion Criteria 
Subjects will be excluded from the Optional Follow-up Treatment Period if they meet any 
of the following criteria: 
1. Surgical disruption of the enterohepatic circulation. 
2. Investigational drug other than LUM001, biologic, or medical device within 30 
days prior to re-entry, or 5 half-lives of the study agent, whichever is longer. 


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Treatment 
Groups 
This is an open label study.  All subjects will receive LUM001, up to 560 μg/kg/day (given 
as twice-daily doses of 280 μg/kg) or a maximum daily dose of 25 mg BID.  
Study Drug 
Dosage and 
Administration 
Subjects will receive a grape-flavored solution containing LUM001. Each subject dose will 
be administered orally once a day (QD) or twice a day (BID) using the syringe provided.  
The first dose should be taken at least 30 minutes prior to the first meal of the day and the 
second dose, where applicable, should be taken at least 30 minutes prior to dinner (main 
evening meal).  The doses will not be administered q12h in order to better cover the 
luminal bile acid release associated with dinner and to minimize the risk of disturbing sleep 
due to the potential for abdominal pain and diarrhea at night.  It is recommended that the 
dose should be taken at approximately the same time each day for the duration of the 
treatment period. 
QD Dosing Regimen 
For QD dosing, the required dose will be delivered in 0.5 mL volume for subjects who 
weigh less than 10 kg and in 1.0 mL for subjects who weigh 10 kg or more. 
BID Dosing Regimen 
For BID dosing, the required dose is delivered in half the dosing volume:  0.25 mL BID for 
subjects who weigh less than 10 kg and 0.50 mL BID for subjects who weigh 10 kg or 
more. 
For subjects weighing less than 10 kg at study entry, once a weight of 10 kg is reached 
while in the study, the subject will be moved from 0.5 mL total daily dosing volume (0.25 
mL BID) to 1.0 mL total daily dosing volume (0.50 mL BID). 
Study Drug Dosage 
Baseline through Week 72: 
Initially, the LUM001 dose will be increased weekly over a 4-week period (Dose Levels 1-
4). At the end of 4 weeks, subjects will continue dosing for another 4 weeks using the 
Week 4 dose, or the highest tolerated dose below the Week 4 dose.  For those subjects who 
tolerated Dose Level 4, at the Week 8 visit the dose will be increased to Dose Level 5, and 
subjects will continue dosing for another 5 weeks (i.e., through Week 13) using the Week 5 
dose or the highest tolerated dose below the Week 5 dose. Beginning at Week 14, dosing 
with LUM001 will continue at a fixed dose in a 59-week long-term exposure period. 
During this period the dose may be adjusted if there is a change of ≥10% in weight since 
the screening visit. At the investigator’s discretion and in consultation with the Medical 
Monitor, subjects who were previously down-titrated may be re-challenged during the long-
term exposure period (Weeks 14 – Week 72).  
For the first 72 weeks of the study, each subject will receive either 1.0 mL or 0.5 mL of 
solution containing LUM001 orally as follows, administered as a daily morning dose: 
• 
Dose Level 1: 14 µg/kg/day. 
• 
Dose Level 2: 35 µg/kg/day. 
• 
Dose Level 3: 70 µg/kg/day. 
• 
Dose Level 4: 140 µg/kg/day. 
• 
Dose Level 5: 280 µg/kg/day. 
At Week 72, all subjects will be assessed by the investigator to determine their willingness 
and eligibility to roll-over into the optional follow-up treatment period. 
Optional Follow-up Treatment Period (Post-Week 72): 
Subjects eligible for the optional follow-up treatment period will continue treatment under 
dosing scenarios based on whether their LUM001 dosing will continue without interruption 


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or interruption of <7 continuous days, or with interruption ≥7 days.  Eligibility for BID 
dosing will be determined based on efficacy as measured by sBA level and ItchRO score. 
Subjects who enter the optional follow-up treatment period without LUM001 dosing 
interruption or with an interruption of <7 continuous days will be dosed in the following 
manner: 
• 
Subjects with normal sBA level AND ItchRO score <1.5 will be maintained at the 
same dose level and will continue morning dosing only. 
• 
Subjects with sBA level above normal AND/OR ItchRO score ≥1.5 will start BID 
dosing (afternoon dose escalation; ADE) as follows: 
− 
The morning dose will be continued at the same dose level, but the volume 
of the morning dose will be reduced by half at the same time that the 
afternoon dose is initiated. 
− 
The afternoon dose will be initiated at half the maximum tolerated morning 
dose and will continue at this dose for a period of 4 weeks.  If this dose 
level is tolerated, the afternoon dose then will be doubled, to a maximum 
dose of 280 µg/kg (or up to the maximum tolerated dose). 
− 
The maximum daily dose will be 280 µg/kg BID, i.e. 560 µg/kg/day(max. 
25 mg BID). 
Subjects who enter the optional follow-up treatment period with a LUM001 dosing 
interruption of ≥7 days initially will receive morning dosing only and will undergo dose 
escalation (DE) in the following manner: 
• 
The morning dose will be initiated at Dose Level 2 (35 µg/kg) and doubled in 
weekly intervals to a maximum dose of 280 µg/kg, or up to the maximum 
tolerated dose. 
• 
Once the morning dose of 280 µg/kg or maximum tolerated dose is achieved, sBA 
and ItchRO score will be evaluated. 
• 
Subjects with normal sBA AND ItchRO score <1.5 after morning dose escalation 
will be maintained at the same dose level and will continue morning dosing only. 
• 
Subjects with sBA above normal AND/OR ItchRO score ≥1.5 will begin BID 
dosing (afternoon dose escalation) as outlined above. 
Subjects will continue to receive study drug until they are eligible to enter another LUM001 
study or until LUM001 is available commercially, whichever occurs first. 
The maximum daily dose will be 280 µg/kg BID, i.e. 560 µg/kg/day (maximum 25 mg).  If 
a subject experiences intolerance (eg, gastrointestinal symptoms such as diarrhea, 
abdominal pain, cramping) at any time during the study, the physician Investigator in 
consultation with the Medical Monitor may lower the dose for the remainder of the study. If 
the subject is on a BID dosing regimen, dose lowering should first be attempted with the 
afternoon dose. 
The sBA value used for determination of ADE eligibility will be the most recent available 
value.  The ItchRO score used for ADE eligibility will be derived from the most recent 
2-week electronic diary collection period.   
Rationale for 
Dose and 
Schedule 
Selection  
The dosage of LUM001 is based upon prior experience with this investigational product in 
healthy volunteers and adult and pediatric subjects with hypercholesterolemia.  In these 
subjects, with normal bile flow and without liver disease, tolerability was limited above 10 
mg daily by an increase in gastrointestinal (GI) adverse events (AEs).  These signs and 
symptoms are believed to be related to increased bile acid excretion and a concomitant 
increase in the concentration of free bile acids in the lower colon.  Patients with cholestatic 


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liver disease have reduced bile flow compared to healthy volunteers and 
hypercholesterolemic patients and LUM001 is likely to produce a correspondingly smaller 
increase in free bile acids in the lower colon.  There is also evidence in patients with 
cholestasis to suggest that ASBT expression may be upregulated and higher ASBTi 
concentrations may be required to achieve the desired target inhibition. 
Dosing in pediatric subjects will be based on subject weight.  The appropriate efficacious 
dose of LUM001 for the lowering of bile acid concentrations and the reduction of pruritus 
in cholestatic populations is not known.  Earlier studies in healthy volunteers and 
hypercholesterolemic patients demonstrated that doses of 10 mg to 20 mg daily (equivalent 
to 140 µg/kg/day to 280 µg/kg/day for a 70 kg subject) led to a decrease in serum bile acids 
by >50% following 2 weeks of treatment.   
In previous studies with LUM001, GI AEs were generally recorded in the first weeks of 
LUM001 dosing and then observed at levels similar to those in the placebo group after 2 or 
3 weeks of continuous dosing.  In a 4-week dose finding study in healthy volunteers, a dose 
escalation regimen was evaluated to mitigate the risk of loose stools, diarrhea and 
abdominal pain/cramps.  When the LUM001 dose was increased after each 7-day dosing 
period, to a maximum of 5 mg daily, the incidence of GI-associated AEs in the LUM001 
treated arm was reduced to rates comparable to those reported in the placebo group.    
To reduce the risk of loose stools, diarrhea and abdominal pain/cramps LUM001 doses will 
be escalated over a period of 4-8 weeks up to a maximum dose of 280 µg/kg BID (or 
maximum tolerated dose).  The morning dose is initiated and escalated first; the afternoon 
dose is only initiated and escalated in patients with elevated sBA level and/or ItchRO ≥1.5 
on the maximum (or maximum tolerated) morning dose. 
This escalation regimen is supported by the safety profile observed in completed and 
ongoing clinical studies of LUM001.  
Twice daily dosing is used in this study based on the findings of a healthy volunteers study 
in adult males (Study SHP625-101), which demonstrated that bile acid levels in feces 
increase with escalating doses and twice-daily regimen of LUM001 (up to 100 mg QD and 
50 mg BID).  In this study, subjects who were randomized to LUM001 treatment received 1 
of 4 doses of LUM001 (10, 20, 50, 100 mg) during 7 days.  No titration was used in this 
study. There was a dose-dependent increase in total fecal BA excretion. In addition, BID 
dosing (i.e. 50 mg BID) led to a further increase in fecal BA excretion as compared to QD 
dosing (i.e. 100 mg QD).  It is therefore hypothesized that twice-daily dosing has the 
potential to allow for more complete target engagement throughout the day at the level of 
the distal ileum. 
The higher dosing level is also supported by favorable results from a juvenile toxicity study 
conducted in rats administered LUM001 for 43 days (PND21 through PND63).  As 
expected for a drug intentionally designed to be minimally absorbed, systemic LUM001 
exposure was very low and consistent with levels that were previously determined in 
several oral gavage studies in adult rats. No adverse effects were observed on postnatal 
growth and development of offspring at the highest doses tested (200 mg/kg/day in males, 
1000 mg/kg/day in females).  This study was initiated in juvenile animals at PND21, which 
from a whole animal development perspective is typically representative of a 2-year old 
child.  However, given the fact that LUM001 is a minimally absorbed drug, of particular 
importance is the age at which the GI tract is considered functionally mature.  In humans 
this is considered to have occurred by 12 months of age; likewise, postnatal maturation of 
the GI tract in rats occurs during the first 3 weeks of life.  Therefore, results from this study 
can be used to support the dosing levels proposed here for children 12 months of age and 
older. 
During the long-term exposure period and the optional follow-up treatment period, the dose 
may be adjusted to account for a change of ≥10% in weight since the screening visit (e.g. 


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the amount of drug dosed may be increased to reflect the subject’s weight increase). The 
dose may also be down-titrated, at the investigator’s discretion and in consultation with the 
Medical Monitor, for subjects experiencing intolerance to a given dose.  If the subject is on 
a twice daily dosing regimen, dose reduction should first be attempted with the afternoon 
dose.  Subjects who were previously down-titrated may be re-challenged during the long-
term exposure period. 


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Study Visit 
Schedule and 
Procedures 
For an individual subject, the study participation period will consist of a screening period of 
up to 6 weeks, a 13-week treatment period (including a dose escalation period followed by 
two stable dose periods), and a 59-week long-term exposure period.  Subjects who 
complete 72 weeks of treatment (Figure 1) may be eligible to receive further treatment 
during the Optional Follow-up Treatment Period. Study activities will be conducted as 
described in the Schedule of Procedures (Section 16.1).  
 
Figure 1: Study Design for LUM001-501 (Up to and including Week 72) 
 
Screening Period (Day -42 to Day -1):  After obtaining informed consent (and/or assent 
when appropriate), demographic data (gender, age, and race) will be collected and subjects 
will undergo a medical history and physical examination including body weight, height, 
and vital signs, and determination of concomitant medications. Blood and urine samples 
will be taken for clinical laboratory testing.  An ultrasound will be performed to determine 
if any mass can be seen in the liver.  Note: A screening ultrasound is not required if the 
results of an ultrasound completed within 6 months are available, provided that the clinical 
status of the subject has not changed significantly since the time of the test. In the absence 
of documented ATP8B1 or ABCB11 mutation prior to screening, genetic testing will be 
performed (refer to Section 8.2). The appropriate genetic counseling will be provided to 
subjects and their legal caregivers at a study visit following the receipt of results of genetic 
testing. Results of genetic screen will not impact continued participation in the study, but 
are done to provide complete and uniform characterization of the subjects’ liver disease.   
The eDiary for assessing pruritus, as measured using an ItchRO instrument, will be 
dispensed and subjects and caregivers will receive training during the screening visit.  The 
patient/caregiver ItchRO will be administered twice daily.  The physician will also provide 
an assessment of itch severity using the clinician administered scratch scale during 
screening.  Females who are of childbearing potential will have a serum or urine pregnancy 
test.  Enrollment will occur after eligibility criteria have been met, 4-7 days prior to the 
baseline visit; this will not require a separate visit and will initiate preparation of study 
drug. 
 
Dose Escalation Treatment Period (Day 0 to Week 4):  At the baseline visit (Day 0), study 
eligibility will be confirmed and body weight, height, and vital signs will be evaluated and 
recorded.  Blood and urine samples will be taken for clinical laboratory testing, including 
fasting lipid panel.  Baseline levels of bile acids and other cholestasis biochemical markers 


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will be determined from blood and urine; blood will also be collected for determination of 
baseline fat-soluble vitamins and for a baseline PK sample.  Compliance with the ItchRO 
will be assessed. A clinician administered scratch scale will be determined and the Pediatric 
Quality of Life Inventory (PedsQL) questionnaire, a measure of quality of life, will be 
administered.  Female subjects who are of childbearing potential will have a urine 
pregnancy test prior to dispensing study drug.  Study drug for Weeks 1 (Dose Level 1) and 
2 (Dose Level 2) will be supplied at the baseline visit to eligible subjects.  Caregivers and 
age appropriate subjects will continue twice daily (morning and evening) completion of 
their eDiary (ItchRO) throughout the dose escalation treatment period.  Subjects will return 
to the clinic at Weeks 2 and 4 and will receive a follow-up phone call at Weeks 1, 3 and 5. 
On clinic visit days, safety and clinical laboratory evaluations will be performed. Clinician 
scratch scale will be administered, adherence to study drug will be assessed. At the Week 2 
visit study drug and additional dosing instructions for Weeks 3 (Dose Level 3) and 4 (Dose 
Level 4) will be supplied.  ItchRO compliance will be assessed and concomitant 
medications and any AEs will be recorded at clinic visits and from phone calls.   
140 µg/kg/day Stable Dosing Treatment Period (Week 5 to Week 8):  Subjects will 
continue to receive LUM001 for another 4 weeks using Dose Level 4, or the highest 
tolerated dose below Dose Level 4. Subjects and caregivers will continue daily completion 
of their eDiary (ItchRO).  Subjects will receive a follow-up phone call at Week 5 and return 
to the clinic at Week 8.  At the Week 8 clinic visit, safety and clinical laboratory 
evaluations will be performed. Clinician scratch scale will be administered, and adherence 
to study drug will be assessed.  For those subjects who tolerated Dose Level 4, at the Week 
8 visit the dose will be increased to Dose Level 5. Additional dosing instructions and study 
drug will be supplied. ItchRO compliance will be assessed and concomitant medications 
and any AEs will be recorded at clinic visits and from phone calls.  
280 µg/kg/day Stable Dosing Treatment Period (Week 9 to Week 13):  Subjects will 
continue to receive LUM001 through Week 13 using Dose Level 5 or the highest tolerated 
dose below this dose. Subjects and caregivers will continue daily completion of their 
eDiary (ItchRO).  Subjects will receive a follow-up phone call at Week 9 and return to the 
clinic at Week 13.  At this clinic visit, safety and clinical laboratory evaluations will be 
performed. Clinician scratch scale will be administered, and adherence to study drug will 
be assessed. The PedsQL, the Patient Impression of Change, the Caregiver Impression of 
Change, and the Caregiver Global Therapeutic Benefit assessments will be administered. 
The eDiary will be collected.  Females who are of childbearing potential will have a urine 
pregnancy test at Week 13.  ItchRO compliance will be assessed and concomitant 
medications and any AEs will be recorded at clinic visits and from phone calls.  Additional 
dosing instructions and study drug will be supplied for the next phase of the study. 
Long-Term Exposure Period (Week 14 to Week 72): Subjects will continue to receive 
study drug for an additional 59 weeks according to the dose achieved during the stable 
dosing treatment period. However, if a subject experiences intolerance due to 
gastrointestinal symptoms, the investigator in consultation with the Medical Monitor may 
lower the dose to a previously tolerated dose. At the Investigator’s discretion and in 
consultation with the Medical Monitor, subjects who were previously down titrated may be 
re-challenged during the long-term exposure period. 
During the long-term exposure period, subjects will return to the clinic at Weeks 24, 36, 44, 
48, 60 and 72. With the exception of the Week 44 visit, safety and clinical laboratory 
evaluations and a physical exam (including collection of vital signs, height and weight 
measurements) will be completed at each clinic visit. In addition, the clinician scratch scale 
will be administered and study drug compliance will be assessed. The PedsQL will be 
completed at Weeks 24, 48 and 72. The Patient and Caregiver Impression of Change (PIC 
& CIC), and the Caregiver Global Therapeutic Benefit assessments will be completed at 
Weeks 48 and 72. At the Week 24 and Week 44 visits, electronic diaries will be issued and 
AEs and concomitant medications will be assessed and recorded. Subjects/caregivers will 


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receive follow-up phone calls at Weeks 16, 20, 28, 32 and 40. Concomitant medications 
and any AEs will be evaluated and recorded at all clinic visits and at scheduled telephone 
contacts.  
Twice daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects during the 4 weeks that follow the Week 24 and Week 44 clinic visits. 
Electronic diaries will be provided to subjects and caregivers at Weeks 24 and 44, and re-
training on the use of the diary will occur, as appropriate, at these 2 visits.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for 
the treatment of pruritus may occur during the long-term exposure period.  
With the exception of the Week 44 visit, additional study drug will be supplied at each 
clinic visit during the long-term exposure dosing period. 
Week 72: Subjects will be evaluated by the investigator to determine whether they are 
eligible to roll over into the optional follow-up treatment period. Eligible subjects must 
have documented consents in order to continue in the optional follow-up treatment period. 
A physical exam (including collection of vital signs, height and weight measurements) will 
be performed. Blood and urine samples will be taken for clinical laboratory testing, 
including a fasting lipid panel and determination of fat-soluble vitamins, bile acids and 
other cholestasis biochemical markers.  Blood will also be collected for study drug 
determination.  The clinician scratch scale and PedsQL will be administered.  Females who 
are of childbearing potential will have a urine pregnancy test, and concomitant medications 
and any AEs will be recorded. Study drug compliance will also be assessed and all used 
and unused study drug and study supplies will be collected. Study drug will be discontinued 
at this visit if the subject chooses not to participate in the optional follow-up treatment 
period.  
Subjects will be encouraged to complete all study activities and visits. Any subject who 
withdraws from the study prior to completion of all treatment period clinic visits should 
undergo the procedures specified for the Week 72 visit.  For safety reasons, efforts must be 
made to follow subjects for at least 30 days following their last dose of study drug.   
Follow-up Phone Call:  For subjects who do not roll over into the optional follow-up 
treatment period, a safety follow-up phone call will be made 30 days after the last dose of 
study drug.  This call will be made for all subjects who complete the study, as well as any 
subject who terminates from the study early.  Concomitant medications and any AEs noted 
during this phone call will be recorded.  
Optional Follow-up Treatment Period (post-Week 72):   
Subjects who are eligible to enter to the follow-up treatment period will continue to receive 
study drug after Week 72 until the first of the following occurs:  (i) the subjects are eligible 
to enter another LUM001 study or (ii) LUM001 is available commercially.  Included below 
are schematics describing the flow of study visits within the optional follow-up treatment 
period. 
Figure 2:  Optional Follow-up Treatment Period (<7 days from last LUM001 dose 
between Protocol Amendment 2 and Amendment 3) 
Applies to the following subject population: 
• 
Subjects who experienced no interruption in LUM001 dosing, or interruption 
<7 days between Protocol Amendment 2 and Protocol Amendment 3.  


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Subjects who are eligible to roll over into the follow-up treatment period with no LUM001 
dosing interruption or an interruption of <7 days will initially receive study drug at the dose 
they were receiving at Week 72.  Once Protocol Amendment 4 is implemented at the site, a 
determination about Afternoon Dose Escalation (ADE) will be made.  The subject then 
will move to Figure 5 or 6, depending on whether they meet criteria for initiating 
Afternoon Dose Escalation.   
Figure 3: Optional Follow-up Treatment (≥7 days from last LUM001 dose between 
Protocol Amendment 2 and Protocol Amendment 3) 
Applies to the following subject population: 
• 
Subjects who experienced an interruption in LUM001 dosing ≥7 days between 
Protocol Amendment 2 and Protocol Amendment 3.  
 
 
Subjects with ≥7 days since last dose of LUM001 (Figure 3) will be dose escalated up to 
280 µg/kg/day or to the maximum tolerated dose starting at Dose Level 2 (35 µg/kg/day). 
This escalation regimen is supported by the safety profile observed in completed and 
ongoing clinical studies of LUM001 and allows for subjects to reach 280 µg/kg/day or a 
maximum tolerated dose within a 4-week period. The dose escalation (DE) period will 
proceed as follows: 
= Clinic Visit
= Phone Contact
70 µg/kg/day
140 µg/kg/day
280 µg/kg/day
35 µg/kg/day
LUM001 280 µg/kg/day or 
maximum tolerated dose –
given as morning dose
Long-Term Exposure
At or after Week 84, assess subject for eligibility for Afternoon Dose Escalation (ADE). 
If ineligible, move to Figure 5.  If eligible, move to Figure 6.
Study
Week
84
96
108
88
92
100
120
116
112
104
FTP 
Dose Escalation (DE)
Week
72
Delayed Rollover -
Dose interruption
>7 days
DE
-2
DE 
Day 0
DE 
73
DE 
76
DE 
75
DE 
74
80


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• 
DE Week -2 Clinic Visit: obtain consent, obtain weight and draw labs.   
• 
DE Day 0 Clinic Visit: Investigator evaluates laboratory results, study drug is 
dispensed and subject begins at 35 µg/kg/day dose level. 
• 
DE Week 73 Telephone Contact: subject escalates to 70 µg/kg/day dose level if 
prior dose level was tolerated.  
• 
DE Week 74 Clinic Visit: subject escalates to 140 µg/kg/day dose level if prior 
dose level was tolerated. 
• 
DE Week 75 Telephone Contact: subject escalates to 280 µg/kg/day dose, if prior 
dose level was tolerated. 
• 
DE Week 76 Clinic Visit: subject continues in Follow-up Treatment Period at 280 
µg/kg/day, or maximum tolerated dose.  
Once Protocol Amendment 4 is implemented at the site, a determination about Afternoon 
Dose Escalation (ADE) will be made.  The subject then will move to Figure 5 or 6, 
depending on whether they meet criteria for initiating Afternoon Dose Escalation.   
Figure 4: Optional Follow-up Treatment (≥7 days from last LUM001 dose between 
Protocol Amendment 3 and Protocol Amendment 4) 
Applies to the following subject population: 
• 
Subjects who experienced an interruption in LUM001 dosing ≥7 days between 
Protocol Amendment 3 and Protocol Amendment 4.  
 
 
Subjects with ≥7 days since last dose of LUM001 prior to site implementation of Protocol 
Amendment 4 will be dose escalated up to 280 µg/kg/day or to the highest tolerated dose 
starting at Dose Level 2 (35 μg/kg/day).  
The dose escalation (DE) period will proceed as follows: 
• 
Protocol Amendment 4 DE Week -2 Clinic Visit: obtain consent for Protocol 
Amendment 4, obtain weight and draw labs.   
• 
Protocol Amendment 4 DE Day 0 Clinic Visit: Investigator evaluates laboratory 
results, study drug is dispensed and subject begins at 35 μg/kg/day dose level. 
• 
Protocol Amendment 4 DE Week 1 Telephone Contact: subject escalates to 70 
μg/kg/day dose level if prior dose level was tolerated. 
= Clinic Visit
= Phone Contact
70 µg/kg/day
140 µg/kg/day
280 µg/kg/day
35 µg/kg/day
LUM001 280 µg/kg/day or 
maximum tolerated dose
PA4 Dose 
Escalation 
Study Week 
PA4 DE 
Wk 8
PA4
Dose Escalation (DE)
Delayed Rollover -
Dose interruption
>7 days
PA4 
DE -2
PA4 DE 
Day 0
PA4 DE 
Wk 4
PA4 DE 
Wk 3
PA4 DE 
Wk 2
PA4 DE 
Wk 1
ADE eligibility 
assessed.  
If ineligible, move 
to Figure 5.  If 
eligible, move to 
Figure 6.


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LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
 
• 
Protocol Amendment 4 DE Week 2 Clinic Visit: subject escalates to 140 
μg/kg/day dose level if prior dose level was tolerated. 
• 
Protocol Amendment 4 DE Week 3 Telephone Contact: subject escalates to 280 
μg/kg/day dose, if prior dose level was tolerated. 


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• 
Protocol Amendment 4 DE Week 4 Clinic Visit: subject continues in follow-up 
treatment period at 280 μg/kg/day, or maximum tolerated dose. 
• 
At Protocol Amendment 4 DE Week 8 Telephone Contact:  eligibility for ADE 
will be assessed.  The subject then will move to Figure 5 or 6, depending on 
whether they meet criteria for initiating Afternoon Dose Escalation.  
Figure 5: Optional Follow-up Treatment under Protocol Amendment 4, without 
Afternoon Dose Escalation (ADE) 
Applies to the following subject population: 
• 
Subjects deemed ineligible for ADE. 
 
Subjects Deemed Ineligible for ADE: 
Subjects with normal sBA level AND ItchRO score <1.5 will be deemed ineligible for 
ADE; such patients will be maintained at the same dose level and will continue morning 
dosing only.  Subjects will have study activities then repeated in recurring 12-week periods 
as follows, until study completion or termination: 
• 
Recurring Period Week 4 (i.e., beginning Week 88 or 4 weeks after consent to 
Protocol Amendment 4) Telephone Contact:  Collection of concomitant 
medications and any adverse events. 
• 
Recurring Period Week 8 Telephone Contact: Collection of concomitant 
medications and any adverse events.  
• 
Recurring Period Week 12 Clinic Visit:  Physical exam, body weight and height, 
vital signs, and blood samples for clinical laboratory testing, including fasting 
lipid panel.  Blood will also be collected for determination of fat-soluble vitamins.  
Urine samples for clinical laboratory testing will be collected at every visit.  
ItchRO compliance will be assessed, the electronic diary will be issued, the 
clinician scratch scale will be administered, and the PedsQL questionnaire will be 
administered.  Additionally, a palatability questionnaire will be completed.  
Female subjects who are of childbearing potential will have a urine pregnancy test 
prior to dispensing study drug.  Study drug compliance will be assessed and study 
drug will be dispensed upon completion of other study procedures. 
 
Figure 6: Optional Follow-up Treatment under Protocol Amendment 4, with 
Afternoon Dose Escalation (ADE) 
= Clinic Visit
= Phone Contact
LUM001 280 µg/kg/day or 
maximum tolerated dose
Morning dosing of 280 
µg/kg/day or MTD 
continues
Repeating 
Period Wk 4 
Repeating 
Period Wk 8 
Repeating 
Period Wk 12 
Study activities repeat 
in recurring 12 week periods
(until study completion or termination) 
EOT/ET
30 Day
Safety 
Follow-U


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Applies to the following subject population:  
• 
Subjects whose sBA levels have not normalized and/or whose ItchRO score is 
≥1.5 and therefore qualify for introduction of afternoon dosing. 
Subjects deemed eligible for ADE, i.e., who have sBA level above normal AND/OR 
ItchRO score ≥1.5, will begin BID dosing (afternoon dose escalation; ADE) as follows: 
• 
On ADE Day 0, morning dosing will continue at 280 µg/kg or the maximum 
tolerated dose; however, the volume of the morning dose will be reduced by  
half  Dosing must have been stable for ≥4 weeks prior to initiation of ADE.  
• 
On ADE Day 0, the afternoon dose will be initiated at half the maximum 
tolerated morning dose and will continue at this dose level for a period of 
4 weeks.  If this dose level is tolerated, the afternoon dose then will be doubled 
(i.e., at ADE Week 4) to a maximum dose of 280 µg/kg (i.e., up to a maximum 
560 µg/kg/day or maximum tolerated dose). 
 
The following procedures will occur during the ADE period: 
• 
ADE Day 0 Clinic Visit:   Physical exam, body weight and height, vital signs, 
and blood and urine samples for clinical laboratory testing, including fasting 
lipid panel.  Blood will also be collected for determination of fat-soluble 
vitamins.  Plasma sample will be obtained for LUM001 PK.  The clinician 
scratch scale and the PedsQL questionnaire will be administered.  Female 
subjects who are of childbearing potential will have a urine pregnancy test prior 
to dispensing study drug.  Study drug compliance will be assessed and study 
drug will be dispensed upon completion of other study procedures. Concomitant 
medications and any adverse events will be collected. 
• 
ADE Week 1 and Week 2 Telephone Contact:  Collection of concomitant 
medications and any adverse events.  Subject/caregiver will be reminded of 
dosing instructions. 
• 
ADE Week 4 Clinic Visit:  Physical exam, body weight and height, vital signs, 
and blood and urine samples for clinical laboratory testing, including fasting 
lipid panel.  Blood will also be collected for determination of fat-soluble 
vitamins.  Plasma sample will be obtained for LUM001 PK.  The clinician 
scratch scale and the PedsQL questionnaire will be administered.  Female 
= Clinic Visit
= Phone Contact
Afternoon dose 
is doubled
Initial 
afternoon dose 
= ½ maximum 
tolerated 
morning dose
LUM001 560 µg/kg/day or 
maximum tolerated dose
Afternoon Dose Escalation (ADE) 
Period
ADE1
Day 0
ADE
Wk 2
ADE 
Wk 8
ADE 
Wk 6
ADE 
Wk 4
1 – Afternoon Dose Escalation (ADE) will be initiated for 
eligible subjects following site implementation of 
Protocol Amendment 4 and signature of appropriate 
consent.  
Of note:  Morning dosing of 280 µg/kg/day or MTD must 
be stable for  ≥ 4 weeks prior to initiation of ADE.
Morning dosing of 280 
µg/kg/day or MTD 
continues at initiation 
of ADE, with an 
adjustment to 
morning dose volume
ADE
Wk 1
ADE 
Wk 5
Repeating 
Period Wk 4 
Repeating 
Period Wk 8 
Repeating 
Period Wk 12 
Study activities repeat in 
recurring 12 week periods 
after completion of ADE
(repeats until study completion or termination)
EOT/ET
30 Day 
Safety 
Follow-Up


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subjects who are of childbearing potential will have a urine pregnancy test prior 
to dispensing study drug.  Study drug compliance will be assessed and study 
drug will be dispensed upon completion of other study procedures. Concomitant 
medications and any adverse events will be collected. 
• 
ADE Week 5 and Week 6 Telephone Contact:  Collection of concomitant 
medications and any adverse events.  Subject/caregiver will be reminded of 
dosing instructions. 
• 
ADE Week 8 Clinic Visit:  Physical exam, body weight and height, vital signs, 
and blood and urine samples for clinical laboratory testing, including fasting 
lipid panel.  Blood will also be collected for determination of fat-soluble 
vitamins.  Plasma sample will be obtained for LUM001 PK.  The clinician 
scratch scale and the PedsQL questionnaire will be administered.  Female 
subjects who are of childbearing potential will have a urine pregnancy test prior 
to dispensing study drug.  Study drug compliance will be assessed and study 
drug will be dispensed upon completion of other study procedures. Concomitant 
medications and any adverse events will be collected. 
Thereafter, subjects will have study activities repeated in recurring 12-week periods as 
described within Figure 5, until study completion or termination. 
If any subject experiences intolerance, the Investigator, in consultation with the Medical 
Monitor, may lower the dose at any time during the entire follow-up treatment period. If the 
subject is on a twice daily dosing regimen, dose lowering should first be attempted with the 
afternoon dose. 


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At the Investigator’s discretion and in consultation with the Medical Monitor, subjects who 
were previously down titrated may be re-challenged during the follow-up treatment period. 
During the follow-up treatment period, subjects will return to the clinic every 3 months.  
Safety and clinical laboratory evaluations and a physical exam (including collection of vital 
signs, height and weight measurements) will be completed at each clinic visit.  In addition, 
the clinician scratch scale will be administered and study drug compliance will be assessed. 
The PedsQL will be administered at DE Day 0 (for subjects requiring dose escalation) and 
at Weeks 84, 96, 108, 120, every clinic visit within each recurring 12-week period, and at 
the EOT visit. Additionally, it will be collected at Protocol Amendment 4 DE Day 0, ADE 
Day 0, ADE Week 4, and ADE Week 8. The Patient and Caregiver Impression of Change 
(PIC & CIC), and the Caregiver Global Therapeutic Benefit assessments will be completed 
at Weeks 108, 120, and the EOT visit. Subjects/caregivers will receive follow-up phone 
calls at Weeks 80, 88, 92, 100, 104, 112, and 116, and twice within each recurring 12-week 
period, and every 3 months hence for the subsequent visits. Concomitant medications and 
any AEs will be evaluated and recorded at all clinic visits and at scheduled telephone 
contacts. 
Twice daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects during the 2 weeks following the Week 84, 96, 108, and 120 clinic 
visits, at Protocol Amendment 4 DE Week 4, and every clinic visit within each recurring 
12-week period.  Electronic diaries will be provided to subjects and caregivers at these 
visits and re-training on the use of the diary will occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for 
the treatment of pruritus may occur during the long-term exposure period.  
With the exception of the EOT visit, additional study drug will be supplied at each clinic visit 
during the follow-up treatment period.  Used and unused study drug will be collected at every 
visit. 
Subjects will be encouraged to complete all study activities and visits. Any subject who 
withdraws from the study prior to completion of all treatment period clinic visits should 
undergo the following assessments as outlined for the End of Treatment/Early Termination 
visit:  Physical exam, body weight and height, vital signs, and blood and urine samples for 
clinical laboratory testing, including fasting lipid panel.  Blood will also be collected for 
determination of fat-soluble vitamins and AFP.  Female subjects who are of childbearing 
potential will have a urine pregnancy test.  Study drug compliance will be assessed.  
Concomitant medications and adverse events will be collected.  The ItchRO, the clinician 
administered pruritus scale, the PedsQL, the Patient Impression of Change, the Caregiver 
Impression of Change, and the Caregiver Global Therapeutic Benefit assessments, and 
palatability questionnaire also will be completed.   
At completion of the Follow-up Treatment Period or early discontinuation: a safety follow-
up phone call will be made 30 days after the last dose of study drug. This call will be made 
for all subjects who complete the study, as well as any subject who terminates from the 
study early. Concomitant medications and adverse events noted during this phone call will 
be recorded. 
Safety and 
Tolerability 
Evaluations 
The safety and tolerability of LUM001 will be assessed by determining the incidence, 
relationship to study drug, and severity of treatment-emergent AEs, withdrawals due to 
AEs, and changes in vital signs, laboratory and other safety parameters.   
A Data Safety Monitoring Board (DSMB) will review serious AE data, other key subject 
safety and study data at specified intervals for the duration of the study.   


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Drug Level 
Evaluations 
United States: At sites in the United States, plasma levels of LUM001 will be evaluated at 
Baseline / Day 0 and Weeks 2, 4, 8, 13, 24, 36, 48, 60 and 72. At Week 4, blood will be 
drawn approximately 2 hours post-dosing for drug level analysis. At all other blood draws, 
blood will be drawn approximately 4 hours post morning dosing for drug level analysis.  
Additionally, for subjects in which afternoon dose escalation is initiated, samples will also 
be drawn at ADE Day 0, ADE Week 4, ADE Week 8, and at the three scheduled clinic 
visits following completion of the ADE period.  
United Kingdom, Europe and Australia: At sites in the United Kingdom, Europe and 
Australia, plasma levels of LUM001 will be evaluated at Baseline / Day 0 and Weeks 4, 13, 
24, 36, 48, 60 and 72. Blood will be drawn approximately 4 hours post-morning dosing for 
drug level analysis.  Additionally, for subjects in which afternoon dose escalation is 
initiated, samples will also be drawn at ADE Day 0, ADE Week 4, ADE Week 8, and at the 
three scheduled clinic visits following completion of the ADE period.   
Safety 
Evaluations 
The following assessments will be used to evaluate safety: 
• 
Adverse events (AEs) and serious adverse events (SAEs). 
• 
Clinical laboratory results, including alpha-fetoprotein (AFP) as a screening for 
hepatocellular carcinoma. 
• 
Vital signs. 
• 
Physical exam findings, including body weight and height. 
• 
Concomitant medication usage. 
Efficacy 
Evaluations 
The main focus for the analyses of efficacy is the period from Baseline (Day 0) to Week 13. 
The period from Baseline (Day 0) to EOT will be analyzed.  
Primary efficacy endpoint:  
• 
Fasting serum bile acid level change from Baseline (Day 0) to Week 13. 
Secondary efficacy endpoints: 
• 
Alanine aminotransferase (ALT) and bilirubin (total and direct) change from 
Baseline (Day 0) to Week 13. 
• 
Pruritus as measured by ItchRO (Observer ItchRO/patient ItchRO) change from 
Baseline (Day 0) to Week 13.  (For each subject, the average daily score will be 
calculated using the 7 days pre-treatment for Baseline / Day 0, and the last 7 days 
of treatment for Week 13.) 
Exploratory efficacy endpoints: 
• 
Change from Baseline (Day 0) in fasting serum bile acid level at Weeks 4, 8, 24, 
36, 48 60, 72, 84, 96, 108, 120, every three months thereafter, and at the End of 
Treatment (EOT) visit. 
• 
Change from Baseline (Day 0) in pruritus as measured by the average daily 
ItchRO (Observer ItchRO/patient ItchRO) at Weeks 4, 8, 28, 48, 86, 98, 110, 122, 
and every three months thereafter. 
• 
Change from Baseline (Day 0) for ALT, and bilirubin (total and direct) at Weeks 
4, 8, 24, 36, 48, 60, 72, 84, 96, 108, 120, every three months thereafter, and at the 
EOT visit. 
• 
Change from Baseline (Day 0) for other biochemical markers of cholestasis [total 
cholesterol, low-density lipoprotein cholesterol (LDL-C)] at Weeks 4, 8, 13, 24, 
36, 48, 60, 72, 84, 96, 108, 120, every three months thereafter, and at the EOT 
visit. 
• 
Responder analysis: pruritus response rates as measured by ItchRO (Observer 
ItchRO/patient ItchRO) at Weeks 4, 8, 13, 28, 48, 86, 98, 110, 122, and every 
three months thereafter, up to but not including the EOT visit. 


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• 
Change from Baseline (Day 0) in the Clinician Scratch Scale, at Weeks 2, 4, 8, 13, 
24, 36, 48, 60, 72, 84, 96, 108, 120, every three months thereafter, and at the EOT 
visit. 
• 
Change from Baseline (Day 0) in bile acid synthesis [serum 7α-hydroxy-4-
cholesten-3-one (7αC4)] at Weeks 4, 8, 13, 24, 36, 48, 60, 72, 84, 96, 108, 120, 
every three months thereafter, and at the EOT visit. 
• 
Change from Baseline (Day 0) for PedsQL at Weeks 13, 24, 48, 72, 84, 96, 108, 
120, every three months thereafter, and at the EOT visit. 
• 
Patient Impression of Change (PIC) at Weeks 13, 48, 72, 108, 120, and the EOT 
visit. 
• 
Caregiver Impression of Change (CIC) at Weeks 13, 48, 72, 108, 120, and the 
EOT visit. 
• 
Caregiver Global Therapeutic Benefit (CGTB) assessment at Weeks 13, 48, 72, 
108, 120, and at the EOT visit. 
• 
Change from Baseline (Day 0) for other biochemical markers [autotaxin and 
lysophosphatidic acid (LPA)] at Weeks 4, 8, 13, 36, 48, 60, 72, 84, 96, 108, 120, 
every three months thereafter, and at the EOT visit. 
• 
Change from Baseline (Day 0) for measures of bile acid synthesis (FGF-19 and 
FGF-21) at Weeks 4, 8, 13, 36, 48, 60, 72, 84, 96, 108, 120, every three months 
thereafter, and at the EOT visit. 
 
Additional evaluations of safety and efficacy surrogates will be specified in the Statistical 
Analysis Plan. 
For subjects entering the optional follow-up treatment period with ≥7 days since last dose 
of LUM001, any of the above evaluations may also occur at clinic visits during the DE 
period.  
Interim Analyses 
The following interim analyses are planned. The first interim analysis of key safety and 
efficacy parameters will be performed after the first 12 subjects who meet the Per Protocol 
population definition have completed the Week 13 study visit.  This analysis will provide 
initial information about the activity of LUM001 in the study population. A second interim 
analysis will be performed after all enrolled subjects have completed the Week 48 (or Early 
Termination) study visit. This analysis will provide an assessment of the long-term safety 
and efficacy of LUM001.  A third interim analysis will be performed after all enrolled 
subjects have completed at least 6 months of treatment under Protocol Amendment 4 (or 
the Early Termination visit). This analysis will provide an assessment of the long-term 
safety and efficacy of LUM001.  Subsequent interim analyses will be performed in yearly 
intervals. 
Exploratory 
Genetic Analyses 
To better understand the role of genetics in treatment response, an additional blood sample 
will be taken for exome sequencing.  The data analysis will focus initially on genetic 
variation in candidate genes that may have a role in treatment response, such as 
ASBT/SLC10A2 and genes in its pathway (ie upstream or downstream of 
ASBT/SLC10A2) and genes implicated in PFIC (ATP8B1, ABCB11 and ABCB4) with the 
goal of identifying genetic variation that may discriminate treatment responders from non-
responders. Following examination of candidate genes, the data analysis may be expanded 
to evaluate genetic variation in additional regions of the exome.  This genetic analysis is 
more comprehensive and may provide valuable information beyond the ATP8B1 and 
ABCB11 genes. The submission of this blood sample is voluntary. The results of this 
analysis may identify relevant genetic variants, only some of which will be of known 
clinical benefit.   
Exploratory 
Responder 
Analyses – 
As part of a comprehensive approach to identify serum markers in PFIC patients that 
respond well to treatment, previously collected serum samples will be analyzed using both 
metabolomic and proteomic biomarker discovery approaches. Metabolomics addresses the 


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Metabolomic and 
Proteomic 
Investigations 
activity of small molecules (<10 kDa) produced by active and living cells during their life 
cycle. These molecules are not accessible by genomic, transcriptomic or proteomic 
approaches. Metabolomics monitors the chemical transformations in metabolic cascades 
and can be used to identify observable differences between patient populations. A targeted 
mass spectrometry proteomic approach will allow for the identification and quantitation of 
greater than 150 unique proteins in each serum sample. Serum samples from both 
responding and non-responding patients will be analyzed in both biomarker discovery 
platforms and the data will be evaluated for potential markers that can significantly 
delineate responders from non-responders. 
Palatability Data 
Palatability data will be collected at each clinic visit in the follow up treatment period, with 
the exception of the DE and ADE visits.  A palatability questionnaire will be completed by 
the subject and/or caregiver (dependent on age). 
Statistical 
Considerations 
Sample Size 
PFIC is a very rare disease.  The planned sample size of approximately 24 evaluable 
subjects was based on practical considerations, rather than on statistical considerations and 
desired power for a pre-specified difference. 
Statistical Analysis Plan 
A statistical analysis plan (SAP) will be written for the study that contains detailed 
descriptions of the analyses to be performed.   
Safety 
All safety analyses will be performed on the Safety Population, defined as all subjects who 
were assigned and received at least one dose of the study drug.  Subjects will be analyzed 
by the treatment received.  
Safety measures including AEs, clinical laboratory tests, vital signs, physical exams, and 
concomitant medication usage will be summarized descriptively by study phase (Weeks 0-
13, 14-48, 49-72, 73-124) and over the entire study duration (Weeks 0-72, 0-EOT Visit).  
For quantitative variables, descriptive statistics including number of observations, mean, 
median, standard deviation, minimum, and maximum will be given for the values 
themselves as well as for change from Baseline (Day 0) at each study visit.  Qualitative 
variables will be summarized using counts and percentages at each study visit.   
Drug Level Analysis 
Plasma concentrations of LUM001 will be examined descriptively by visit.  
Efficacy 
The main population for efficacy will be the modified intention-to-treat population (MITT), 
defined as all subjects assigned, receiving at least one dose of treatment, and having at least 
one post-baseline efficacy assessment. Subjects will be analyzed by assigned treatment.  
The Per Protocol population (PP) will consist of all subjects in the MITT population who 
did not have a major protocol violation, inclusive of violation of entry criteria. Subjects in 
this population will be referenced as evaluable. 
Efficacy endpoints will be displayed by study visit, using summary statistics including the 
number of observations, the mean, median, standard deviation, minimum, and maximum 
for continuous measures and counts and percentages for categorical measures.  Actual 
values as well as change from baseline will be presented. For continuous measures the 
change from baseline will be tested using the paired t-test, or comparable nonparametric 
measures if appropriate.  
Examination of potential treatment effects by dose will be done if the sample sizes in the 
dose groups during the stable dosing phase of the study permit. 


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In addition to absolute change from baseline, a responder analysis will be considered.  The 
response definition and its appropriate analysis methodology will be outlined in the SAP 
for the study.  
Supportive and exploratory efficacy measures will be analyzed similarly as above.  Details 
of the analysis methods will be outlined in the SAP.  
All data will be included in data listings. 
 


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2 
LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
7αC4, C4 
7α-hydroxy-4-cholesten-3-one; an indirect method of bile acid 
synthesis 
Ac 
before meals 
ADE 
afternoon dose escalation 
AFP 
alpha-feto protein 
ALGS 
Alagille syndrome 
ADME 
absorption, distribution, metabolism, excretion 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
aPTT 
activated partial thromboplastin time 
ASBT 
apical sodium-dependent bile acid transporter 
ASBTi 
apical sodium-dependent bile acid transporter inhibitor 
AST 
aspartate aminotransferase (SGOT) 
ATC 
Anatomic Therapeutic Chemical; classification for drugs 
ATX 
Autotaxin 
BA 
bile acid 
BID 
twice a day 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CGTB 
caregiver global therapeutic benefit questionnaire 
cholesterol 7α-
hydroxylase 
rate-limiting enzyme in the synthesis of bile acid from cholesterol 
CIC 
caregiver impression of change questionnaire 
CRF 
case report form 
CS 
clinically significant 
CV 
curriculum vitae 
DE 
dose escalation 
dL 
Deciliter 


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Abbreviation 
Definition 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
EOT 
End of Treatment 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor 19; regulates carbohydrate, lipid and bile 
acid metabolism 
FGF-21 
fibroblast growth factor 21; modulates hepatic metabolism 
FIC1 
familial intrahepatic cholestasis 1 
FXR 
farnesoid X receptor; bile acid receptor 
g 
Gram 
GCP 
good clinical practices 
GGTP (γGTP) 
gamma-glutamyl transpeptidase 
GI 
Gastrointestinal 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HMG-CoA reductase 
 
3-hydroxy-3-methyl-glutaryl-CoA reductase; rate-controlling 
enzyme of the pathway that produces cholesterol 
HR 
heart rate 
HRQoL 
health related quality of life 
IAF 
informed assent form 
IB 
Investigator’s Brochure 
IBAT 
ileal bile acid transporter 
IBATi 
ileal bile acid transporter inhibitor 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethic committee 
INR 
international normalized ratio 
IRB 
institutional review board 


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Abbreviation 
Definition 
ItchRO™ 
Itch Reported Outcome 
ITT 
intention-to-treat 
IU 
international unit(s) 
IUD 
intrauterine device 
kDA 
kilodalton 
kg 
Kilogram 
L 
Litre 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
LPA 
lysophosphatidic acid 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MITT 
modified intention-to-treat 
mL 
Milliliter 
mmol 
Millimole 
NBD 
nasobiliary drainage 
NCS 
not clinically significant 
ng 
Nanogram 
ObsRO 
observer reported outcome 
PBC 
primary biliary cirrhosis 
PEBD 
partial external biliary diversion 
PedsQL 
Pediatric Quality of Life Inventory 
PFIC 
progressive familial intrahepatic cholestasis 
PI 
principal investigator 
PIC 
patient impression of change questionnaire 
PND 
post-natal day 
PRO 
patient reported outcome  
PSC 
primary sclerosing cholangitis 


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Abbreviation 
Definition 
Pt 
patient 
PT 
prothrombin time 
QD 
once daily 
q.s. 
quantity sufficient 
qAM 
every morning 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acid 
SD-5613 
original designation for LUM001 
sec 
Second 
SLC10A2 
solute carrier family 10 member 2; gene that encodes ASBT 
protein  
SUSAR 
suspected unexpected serious adverse reaction 
TG 
Triglycerides 
TGR5 
a G protein-coupled receptor for bile acids 
TPN 
total parenteral nutrition 
UDCA 
ursodeoxycholic acid, ursodiol 
ULN 
upper limit of normal 
US, USA 
United States of America 
WBC 
White blood cell 
WHO 
World Health Organization 
WMA 
World Medical Association 
yr(s) 
year(s) 
β-hCG 
beta-sub-unit of human chorionic gonadotropin; pregnancy test 
μg 
Microgram 
μM 
Micromolar 
 


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3 
STUDY OBJECTIVES 
Objectives of study (Up to and including Week 72): 
• To evaluate the long-term safety and tolerability of LUM001 in pediatric subjects with 
PFIC. 
• To evaluate the effect of LUM001 on serum bile acids in pediatric subjects with PFIC at 
13 weeks of treatment. 
• To evaluate the effect of LUM001 on biochemical markers of cholestasis and liver 
disease at 13 weeks of treatment. 
• To evaluate the effect of LUM001 on pruritus in pediatric subjects with PFIC at 13 weeks 
of treatment. 
Objectives of Optional Follow-up Treatment Period (After Week 72): 
• To offer eligible subjects in the LUM001-501 study continued study treatment beyond 
Week 72 until the first of the following occurs:  (i) the subjects are eligible to enter 
another LUM001 study or (ii) LUM001 is available commercially.  
• To obtain safety and efficacy data in subjects treated long-term on LUM001. 
• To explore a twice a day (BID) dosing regimen and higher daily dosing of LUM001. 
• To identify genetic indicators of treatment response, including use of exome sequencing. 
• To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma. 
• To assess palatability of the LUM001 formulation. 
Exploratory Objective:  
• To allow the possibility of analysis of serum markers of treatment response using 
metabolomic and proteomic analysis on previously collected serum samples. 
 


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4 
BACKGROUND AND RATIONALE 
LUM001 (previously known as SD-5613) is an inhibitor of the ileal bile acid transporter/apical 
sodium-dependent bile acid transporter/soluble carrier family 10 member 2 
(IBAT/ASBT/SLC10A2), initially developed as a lipid lowering agent.  At this time, further 
development for this indication is not planned.  By virtue of its ability to inhibit bile acid 
absorption, LUM001 is being developed as a therapeutic agent for signs and symptoms of 
cholestatic liver disease associated with progressive familial intrahepatic cholestasis (PFIC) and 
other diseases.  
4.1 
Therapeutic Rationale 
In patients with PFIC, impairment of the egress of bile acids from the liver leads to cholestasis, 
hepatocellular injury and damage, and progressive liver disease that may ultimately lead to the 
need for liver transplantation.   Itch is a common symptom associated with cholestasis, it can 
occur at all stages of cholestatic liver disease, with or without jaundice.  
Surgical interruption of the enterohepatic circulation in patients with PFIC has been shown to be 
beneficial. However, complications do occur and many patients and their families are reluctant to 
accept a permanent external ostomy in spite of the expected benefits.  Pharmacological diversion 
of bile acids to the distal gut with an ASBTi/IBATi could be an attractive alternative to surgical 
intervention for patients with PFIC.   
LUM001 is a potent inhibitor of ASBT/IBAT.  The ASBT/IBAT is present in the terminal 25% 
of the small intestine.  This transporter mediates the uptake of conjugated bile acids across the 
brush border membrane of the enterocyte.  Additional proteins and transporters carry bile acids 
from the enterocyte through the intestinal wall into the blood stream, where they are circulated to 
the liver via the portal vein and then re-secreted into the intestine in a system known as the 
enterohepatic circulation.  Approximately, ninety-five percent of bile acids that enter the gut 
lumen are recycled to the gallbladder where they are stored for future release to the duodenum.  
Figure 1: 
Interruption of Enterohepatic Circulation with an ASBT/IBAT Inhibitor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASBT 
 
Reduction of recycling, 
lowers BA levels in liver, 
preventing liver damage 
X 


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ASBT/IBAT expression is under negative feedback regulation by bile acids; thus in the setting of 
cholestasis, ASBT/IBAT is maladaptively upregulated (Neimark et al. 2004; Hofmann 2003). 
Inhibiting the reuptake of bile acids may represent an ideal treatment for cholestatic disease. In 
cholestasis secondary to defects in FIC1 (ATP8B1) bile acid signaling may be deranged leading 
to an even more pronounced up-regulation of ASBT, which may be a key part of the 
pathophysiology of the disease.  By blocking the intestinal reabsorption of bile acids, LUM001 
could interrupt the enterohepatic circulation and mimic the effects of partial external biliary 
diversion or ileal exclusion.  The current study will test this hypothesis.   
4.2 
Progressive Familial Intrahepatic Cholestasis 
Progressive familial intrahepatic cholestasis (PFIC) refers to a group of autosomal recessive 
disorders of childhood that disrupt bile formation and present with cholestasis (Alissa et al. 
2008). The exact prevalence remains unknown, but the estimated prevalence at birth is between 
1/50,000 and 1/100,000.  Three types of PFIC have been identified and related to mutations in 
hepatocellular transport system genes involved in bile formation.  Figure 2, taken from 
Davit-Spraul et al. (2009), shows these three types together with their associated genes and 
transport defects. This protocol will focus on the PFIC subjects with normal serum 
gamma-glutamyl transpeptidase (GGTP) activity, namely PFIC1 and PFIC2. 
 
Figure 2: 
Types of Progressive Familial Intrahepatic Cholestasis 
 
 
BA: bile acid; PC: phosphatidylcholine. 
 
Progressive familial intrahepatic cholestasis type 1 (FIC1) is thought to comprise ~25-35% of the 
PFIC population. Cell line based studies and examination of ileal tissue from children with FIC1 
disease reveals abnormal homeostatic responses to bile acids (Chen et al. 2004; Frankenberg et 
al. 2008; Chen et al. 2010; Chen et al. 2013). As such, there is a marked up-regulation of ASBT 


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in the ileum of individuals with FIC1 disease.  Patients with FIC1 usually present with features 
of neonatal cholestasis.  Serum bilirubin is not necessarily increased in FIC1, but elevation in 
serum bile acids is a nearly uniform feature of the disease.  The most prominent and problematic 
on-going manifestation of FIC1 is pruritus.  In the absence of surgical treatment, progression to 
cirrhosis and end-stage liver disease is expected in the first or second decade of life.  Partial 
external biliary diversion or partial ileal exclusion, can produce rapid and profound improvement 
in pruritus and biochemical markers of cholestasis, and may slow the progression to cirrhosis 
(Whitington and Whitington 1988; Emond and Whitington 1995; Hollands et al. 1998; Ng et al. 
2000). Liver transplantation in FIC1 disease has been complicated by a number of unique post-
transplant problems, including severe diarrhea and progressive steatohepatitis (Lykavieris et al. 
2003; Miyagawa-Hayashino et al. 2009). 
PFIC2 is caused by mutations in the ABCB11 gene (also designated BSEP). This gene encodes 
the ATP-dependent canalicular bile salt export pump (BSEP) of human liver and is located on 
human chromosome 2. BSEP protein, expressed at the hepatocyte canalicular membrane, is the 
major exporter of primary bile acids against extreme concentration gradients. Mutations in this 
protein are responsible for the decreased biliary bile salt secretion described in affected patients, 
leading to decreased bile flow and accumulation of bile salts inside the hepatocyte with ongoing 
severe hepatocellular damage. 
Patients with PFIC2, like those with PFIC1, have normal serum gamma-glutamyl transpeptidase 
(GGTP) activity, normal serum cholesterol level and very high serum bile acid concentration, but 
PFIC2 patients have higher transaminase and alpha-fetoprotein serum levels at diagnosis. The 
liver histology is also similar between the two types but the liver architecture is more perturbed 
in PFIC2, with more pronounced lobular and portal fibrosis and inflammation. Hepatocellular 
necrosis and giant cell transformation is also much more pronounced and may persist with time. 
These differences between PFIC1 and PFIC2 likely reflect the severe lobular injury present in 
PFIC2. 
4.3 
Pruritus 
Intractable and pharmacologically recalcitrant pruritus is one of the major morbidities afflicting 
children with PFIC.  Treatment with anti-pruritics and bile salt binding resins may provide 
partial relief of itching for children with PFIC, but currently available pharmacologic approaches 
are of limited value.  It has been shown that removing bile with surgical procedures such as 
partial external biliary diversion (PEBD) and nasobiliary drainage (NBD) substantially reduces 
pruritus in PFIC (Whitington and Whitington 1988; Emerick and Whitington 2002), and other 
cholestatic liver diseases including Alagille syndrome and primary biliary cirrhosis.  Almost 
complete resolution of pruritus has been observed in children with PFIC disease in a period of as 
little as two to four weeks following the procedure.  The rapid resolution of itch in response to 
therapy can be seen in Figure 3 extracted from the original description of this procedure by 
Whitington and Whitington (1988). Rapid lowering of bile acids, bilirubin and ALT has also 
been observed (Table 1). 


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Figure 3: 
Serum Bile Salt Concentration and Degree of Itch 
 
Patient SR- serum bile salt concentration and degree of itch over a 4-yr course.  Nasoduodenal drainage (D) resulted 
in reduced serum bile salt concentration and itch.  When medical management failed, a cholecystostomy tube was 
placed (S1), resulting in a reduction in serum bile salt concentration to normal and the disappearance of itching.  
When the cholecystostomy tube was accidentally pulled out (A), the serum bile salt concentration and itching 
increased rapidly.  The construction of a permanent cholecystostomy (S2), resulted in a quick return to normal, a 
state that has been maintained since (Whitington and Whitington 1988).  
Table 1: 
Improvement in Biochemical Markers and Pruritus After Partial External 
Biliary Diversion in PFIC Disease and Alagille Syndrome Subjects 
Diagnosis 
Age at 
Surgery 
(yrs) 
Pruritus Score 
(0-4 Scale)* 
Serum Bile 
Acids 
(µM) 
Conjugated 
Bilirubin 
(µM) 
Alanine 
Aminotransferase 
(IU/L) 
Pre 
Post 
Pre 
Post 
Pre 
Post 
Pre 
Post 
PFIC 
3 
4 
0 
226 
2 
24 
0 
140 
30 
PFIC 
9 
4 
0 
225 
3 
80 
0 
193 
13 
PFIC 
3 
4 
0 
275 
9 
17 
0 
155 
69 
PFIC 
3 
4 
0 
218 
5 
68 
10 
141 
64 
Alagille 
12 
4 
1 - 2 
153 
37 
164 
77 
198 
168 
Alagille 
6 
4 
1 
317 
25 
50 
15 
248 
305 
*0 = no itching; 4 = itching with cutaneous mutilation and bleeding (Whitington and Whitington 1988) 
A retrospective analysis of PFIC patients following PEBD indicated that normalization of serum 
bile acids within 1 year of surgery was associated with clinical improvement and an excellent 
long-term outcome (Schukfeh et al. 2012). 
 
4.4 
LUM001 
 
Nonclinical Studies 
4.4.1.1 
Pharmacology 
LUM001 is a potent selective inhibitor of the ileal apical sodium dependent bile transporter, a 
transmembrane protein localized on the luminal surface of ileal enterocytes, commonly referred 


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to as ASBT/IBAT.  The drug is a competitive inhibitor for bile acid substrate with a high affinity 
for the transporter.  Nonclinical studies indicate that selective inhibition of ASBT by LUM001 
results in increased fecal bile acid excretion, inhibition of the postprandial rise in serum bile 
acids, and decrease in serum total cholesterol.  It also increases the activity of hepatic cholesterol 
7α-hydroxylase and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, consistent with 
inhibition of bile acid reabsorption as the mechanism of action. 
4.4.1.2 
Pharmacokinetics 
Because of its large molecular weight and the presence of a quaternary nitrogen atom, LUM001 
is poorly absorbed from the gut.  In rats and dogs, oral bioavailability was < 0.4% at all doses 
tested.  LUM001 is metabolically stable after oral administration. After intravenous 
administration, the majority of drug is excreted in the feces, with approximately 5% excretion in 
the urine. 
4.4.1.3 
Toxicology 
A comprehensive assessment of LUM001 has been conducted in vitro and in animals.  LUM001 
is not toxic at doses far higher than those that are pharmacologically active in mice, rats, dogs, 
and monkeys.  The most significant effect observed in rodents is a prolongation of coagulation 
time considered secondary to malabsorption of vitamin K, which in turn is related to inhibition of 
bile acid absorption, the pharmacologic effect of LUM001.  Reversible prolongation of 
coagulation times was observed primarily in male rats that are especially sensitive to agents that 
alter vitamin K absorption and may not be an appropriate model for predicting vitamin K 
malabsorption in humans.  Acute oral doses up to 200 mg/kg LUM001 were well tolerated in 
dogs, with emesis as the primary dose-limiting toxicity.  There was no evidence of mutagenic 
activity in vitro and no clastogenic activity in vitro or in vivo.  Results from rat and rabbit 
embryo/fetal development studies with doses up to 1000 and 250 mg/kg/day, respectively, 
showed no adverse effects on fetal growth and development.  
To support the use of LUM001 in young children, a toxicity study in juvenile animals was 
completed.  As expected for a drug intentionally designed to be minimally absorbed, LUM001 
exposure was very low and consistent with levels observed in adult rats. No adverse effects were 
observed on postnatal growth and development of offspring at a dose of 200 mg/kg/day in males 
and 1000 mg/kg/day in females, the highest doses tested. This study was initiated in juvenile 
animals at PND21, which from a whole animal development perspective is typically 
representative of a 2 year old child. However given the fact that LUM001 is a minimally 
absorbed drug, as evidenced by this and multiple other studies, of particular importance is the 
age at which the GI tract is considered functionally mature. In humans this occurs by 12 months 
of age; likewise, postnatal maturation of the GI tract in rats occurs during the first three weeks of 
birth. Therefore this study presented evidence to support the safety of LUM001 in future clinical 
trials in children 12 months of age and older. These trials have the promise to address a life-
threatening clinical need in this patient population. 
The higher dosing level implemented with Protocol Amendment 4 is supported by favorable 
results from a juvenile toxicity study conducted in rats administered LUM001 for 43 days 
(PND21 through PND63).  As expected for a drug intentionally designed to be minimally 


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absorbed, systemic LUM001 exposure was very low and consistent with levels that were 
previously determined in several oral gavage studies in adult rats. No adverse effects were 
observed on postnatal growth and development of offspring at the highest doses tested (200 
mg/kg/day in males, 1000 mg/kg/day in females).  This study was initiated in juvenile animals at 
PND21, which from a whole animal development perspective is typically representative of a 2-
year old child.  However, given the fact that LUM001 is a minimally absorbed drug, of particular 
importance is the age at which the GI tract is considered functionally mature.  In humans this is 
considered to have occurred by 12 months of age; likewise, postnatal maturation of the GI tract 
in rats occurs during the first 3 weeks of life.  Therefore, results from this study can be used to 
support the dosing levels proposed here for children 12 months of age and older. 
Additional toxicology information can be found in the Investigator’s Brochure. 
 
Previous Clinical Experience 
Detailed information concerning the clinical studies conducted with LUM001 can be found in 
the Investigator’s Brochure.  A summary is included below. 
The overall objective of the initial clinical development plan was to evaluate the safety and 
efficacy of chronic, oral administration of LUM001 (tablet and capsule formulations) for the 
reduction of serum LDL-C in subjects with hypercholesterolemia.  The efficacy, 
pharmacokinetics, tolerability, and safety of LUM001 in humans have been evaluated in a total 
of 12 clinical studies, including 2 studies that also tested sustained release formulations.  Phase 1 
studies included a single and two multiple dose tolerability studies, an absorption, distribution, 
metabolism, and excretion (ADME) study, a statin co-administration study, a statin interaction 
study, and a food composition study.  Phase 2 studies included two dose-ranging studies in adult 
subjects, a tolerability study in adolescents and children, and a multiple dose tolerability and 
efficacy study of three sustained release formulations, compared with the immediate release 
formulation.  More than 1,400 human subjects have been exposed to LUM001 (immediate 
release) for up to 10 weeks. 
In previous clinical studies, LUM001 inhibited the postprandial increase in serum total bile acids 
concentrations and increased fecal total bile acids excretion, consistent with the mechanism of 
action of inhibiting ASBT.  LUM001 administration resulted in reductions of serum LDL-C in 
healthy volunteers and subjects with elevated cholesterol.  These findings confirm that LUM001, 
a minimally absorbed inhibitor of ASBT, is effective in blocking enterohepatic recirculation of 
bile acids with the expected consequences on bile acid and cholesterol metabolism.  With 
LUM001 administration, there was also a trend toward increases in high-density lipoprotein 
cholesterol (HDL-C) and total triglycerides relative to placebo.   
Administration of LUM001 at doses up to 100 mg once daily over a four-week period was 
generally safe in healthy volunteers and at does up to 40 mg once daily for up to 10 weeks in 
subjects with hypercholesterolemia.  The most commonly reported adverse drug reactions in 
LUM001-treated subjects were abdominal cramping (pain) and diarrhea and loose stools.  These 
GI AEs are also observed in subjects who undergo biliary diversion, are believed to be 
mechanism-based, due to elevated bile acid concentrations in the colon.  With the exception of a 


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single serious adverse event (SAE) of cholecystitis no other SAEs possibly related or related to 
LUM001 have been reported in the 12 studies conducted to date, (over 1,400 subjects exposed). 
 
The majority of orally administered LUM001 was excreted intact in the feces along with a few 
minor metabolites.  LUM001 exposure in adolescents and children (Study 014) was low and 
consistent with a drug that is minimally absorbed.  Pharmacokinetic parameters in adolescent and 
children subjects did not significantly differ from those seen in adult subjects.   
No clinically significant laboratory abnormalities were documented in LUM001-treated subjects.  
LUM001 was associated with mild, often transient elevations of serum ALT in a small 
percentage of subjects.  Clinically significant reductions of serum fat-soluble vitamin levels were 
not observed with LUM001 treatment in humans; however, levels of the carotenoid β-carotene 
were mildly reduced.  No alterations in coagulation parameters were observed, indicating no 
functional changes in vitamin K status.  Fecal fat excretion was not increased compared to 
placebo after four weeks of LUM001 treatment at doses up to 100 mg. 
4.5 
Rationale for Dose and Schedule of Administration  
The dosage of LUM001 chosen for the first studies in cholestatic subjects is based upon prior 
experience with this product in healthy volunteers and subjects with hypercholesterolemia.  In 
these subjects, with normal bile flow and without liver disease, tolerability was limited above 10 
mg daily by an increase in GI AEs.  These signs and symptoms were believed to be related to 
increased bile acid excretion and an increased concentration of free bile acids in the lower colon.  
In patients with cholestatic liver disease it is likely that bile flow is reduced compared to healthy 
volunteers and hypercholesterolemic patients and LUM001 will produce a correspondingly 
smaller increase in free bile acids in the lower colon, and could potentially lead to the drug being 
better tolerated at the same dose level.   
Ideally, dosing in pediatric subjects should be scaled from that in adults based on intestinal 
length, i.e. mg of drug per cm of intestine.  Differing relationships between intestinal mucosal 
surface area, age, and body weight have been reported in the literature. Weaver et al.(1991) 
provided 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.  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 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 pediatric subjects from those in adults based using a direct mg/kg scaling.  For 
reference in an average adult subject, weighing 70 kg, a 10 mg daily dose is equivalent to 
140 µg/kg/day. 


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Sample daily exposure (mg/day) across proposed dose levels for subjects ranging in weight from 
10-30 kg is depicted in Table 2. 
Table 2: 
Sample Daily Exposure (mg/day) in Pediatric Subjects 
 
In a previous study (Study 014), LUM001 was administered to 40 hyperlipidemic pediatric 
subjects (n=5, children ages 10-11; n=35 adolescents ages 12-17), up to a maximum tested dose 
of 5 mg/day for 14 days.  The average subject weight in Study 014 was 60 kg and a 5 mg/day 
dose of LUM001 was approximately equivalent to 83 µg/kg/day.  Plasma LUM001 exposure in 
adolescents and children was low (non-detectable <0.25 ng/mL to 1.13 ng/mL) and consistent 
with a drug that is minimally absorbed.  Detection of LUM001 in plasma samples was sporadic, 
both within and among subjects. In addition there does not appear to be a relationship with either 
subject age or gender.  These data do not differ from the extensive pharmacokinetic data 
collected in adults to date. Although the bioavailability of LUM001 has not yet been 
characterized in children younger than 10 years of age, the GI systems are functionally mature in 
children by about 1 year of age (Walthall et al. 2005; van den Anker et al. 2011). This study will 
enroll children ages 12 months and older. 
In Study 014, as with all other studies of LUM001, no drug related serious AEs were observed.  
The most frequently reported AEs in all treatment groups (LUM001 and placebo) were diarrhea, 
abdominal pain, loose stools and nausea.  All subjects completed 14 days of treatment.  Most 
AEs were assessed with a probable or uncertain relationship to study medication and were 
generally characterized as mild or moderate in severity, except for those in six subjects who 
experienced severe nausea, diarrhea or abdominal pain.  These GI events usually resolved during 
continued treatment.  It is noteworthy that the AEs were generally recorded in the first seven 
days of LUM001 dosing, and observed at a four-fold lower frequency from Day 8 to 14.  This is 
consistent with the extensive adult dosing experience, where GI events were observed at levels 
similar to those in the placebo group after two weeks of continuous dosing.   
To assess the effects of dose titration to mitigate dose-limiting adverse effects, LUM001 was 
evaluated in a 28-day once-daily dosing study in healthy volunteers (Study 003).  In one arm, the 
dose was increased after each 7-day dosing period, to a maximum of 5 mg daily (equivalent to a 
dose of 67 µg/kg/day, using the average subject weight).  Using this dosing regimen, the 
incidence of GI-associated AEs was lower than those observed in the placebo group (Table 3) 
and in other treatment arms with constant dosing above and below 5 mg daily. 
Sample Daily Exposure (mg/day) in Pediatric Subjects   
Weight  
(kg) 
Dose Level 1 
(14µg/kg/day) 
Dose Level 2 
(35µg/kg/day) 
Dose Level 3 
(70µg/kg/day) 
Dose Level 4 
(140µg/kg/day) 
Dose Level 5 
(280µg/kg/day) 
Dose Level 6 
(560µg/kg/day) 
10 
0.14 
0.35 
0.70 
1.40 
2.80 
5.60 
15 
0.21 
0.53 
1.05 
2.10 
4.20 
8.40 
20 
0.28 
0.70 
1.40 
2.80 
5.60 
11.20 
25 
0.35 
0.88 
1.75 
3.50 
7.00 
14.00 
30 
0.42 
1.05 
2.10 
4.20 
8.40 
16.80 
 


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Table 3: 
GI-associated Adverse Events in Study 003 
GI Adverse Events 
Placebo 
(n=20) 
1 mg qAM 
(n=8) 
2.5 mg qAM 
(n=25) 
5 mg qAM 
(n=26) 
0.5-5 mg qAM* 
(n=16) 
Abdominal pain 
2 (10%) 
3 (37%) 
4 (16%) 
5 (17%) 
1 (6.3%) 
Constipation 
2 (10%) 
0 
3 (12%) 
0 
0 
Diarrhea  
1 (5%) 
1 (12%) 
5 (20%) 
2 (7%) 
0 
Nausea 
0 
0 
1 (4%) 
1 (4%) 
0 
Pruritus Ani 
0 
0 
6 (24%) 
4 (15%) 
0 
*Escalation regimen: 0.5 mg qAM (7 µg/kg/day) on Days 1-7, 1 mg qAM (13 µg/kg/day) on Days 8-14, 2.5 mg 
qAM (33 µg/kg/day) on Days 15-21, 5 mg qAM (67 µg/kg/day) on Days 22-28.  Average body weight 75 kg. 
The appropriate efficacious dose of LUM001 for the lowering of bile acid concentrations and the 
reduction of pruritus in cholestatic populations is not known.  However, earlier studies 
demonstrated that doses of 10 mg daily (equivalent to 140 µg/kg/day for a 70 kg subject) led to a 
decrease in serum bile acids in healthy volunteers by >50%.  In the PFIC population, there is 
some evidence that ASBT is upregulated, suggesting that higher doses may be required to 
saturate transporters and reach the desired effect in PFIC disease.  
In the current study, safety and efficacy of LUM001 will be assessed for the first time in children 
with PFIC and cholestatic liver disease, 1 year of age and older, starting at a dose of 14 
µg/kg/day.  The starting dose is equivalent to less than the well tolerated 1 mg dose used in 
Study 014 (~17 µg/kg, 60 kg body weight), where only two subjects reported moderate or severe 
GI-associated AEs during 14 days.  On a weight basis, 23 subjects received a dose approximately 
≥14 µg/kg/day.  The highest starting dose in Study 014 was 168 µg/kg/day.   
To reduce the risk of loose stools and diarrhea in subjects in study LUM001-501, the LUM001 
doses will be escalated over a period of 4-8 weeks up to a maximum dose of 280 µg/kg BID (or 
maximum tolerated dose).  For BID dosing, the morning dose is initiated and escalated first; the 
afternoon dose is only initiated and escalated in patients with elevated sBA and/or ItchRO ≥1.5 
on the maximum (or maximum tolerated) morning dose. This escalation regimen is supported by 
the safety profile observed in completed and ongoing clinical studies of LUM001. 
Twice-daily dosing is used in this study based on the findings of a healthy volunteers study in 
adult males (Study SHP625-101), which demonstrated that bile acid levels in feces increase with 
escalating doses and twice-daily regimen of LUM001 (up to 100 mg QD and 50 mg BID).  In 
this study, subjects who were randomized to LUM001 treatment, received 1 of 4 doses of 
LUM001 (10, 20, 50, 100 mg) during 7 days.  No titration was used in this study. There was a 
dose-dependent increase in total fecal BA excretion.  In addition, BID dosing (i.e. 50 mg BID) 
led to a further increase in fecal BA excretion as compared to QD dosing (i.e. 100 mg QD).  It is 
therefore hypothesized that twice-daily dosing has the potential to allow for more complete 
target engagement throughout the day at the level of the distal ileum. 
The higher dosing level is also supported by favorable results from a juvenile toxicity study 
conducted in rats administered LUM001 for 43 days (PND21 through PND63).  As expected for 


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a drug intentionally designed to be minimally absorbed, systemic LUM001 exposure was very 
low and consistent with levels that were previously determined in several oral gavage studies in 
adult rats.  No adverse effects were observed on postnatal growth and development of offspring 
at the highest doses tested (200 mg/kg/day in males, 1000 mg/kg/day in females).  This study 
was initiated in juvenile animals at PND21, which from a whole animal development 
perspective, is typically representative of a 2-year old child.  However, given the fact that 
LUM001 is a minimally absorbed drug, of particular importance is the age at which the GI tract 
is considered functionally mature.  In humans this is considered to have occurred by 12 months 
of age; likewise, postnatal maturation of the GI tract in rats occurs during the first 3 weeks of 
life.  Therefore, results from this study can be used to support the dosing levels proposed here for 
children 12 months of age and older. 


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5 
INVESTIGATIONAL PLAN 
5.1 
Study Design 
This is an open label study in children with PFIC (GGTP <100 IU/L) designed to evaluate the 
safety and efficacy of LUM001. The study is divided into 5 parts: a 4-week dose escalation 
period, a 4-week stable dosing period at 140 μg/kg/day, a 5-week stable dosing period at 
280 μg/kg/day, a 59-week long-term exposure period, and an optional follow-up treatment period 
for eligible subjects who choose to stay on treatment with LUM001.  During the optional follow-
up treatment period, subjects may be eligible for BID dosing based on efficacy as measured by 
sBA level and ItchRO score, and may have their dose of LUM001 increased to a maximum of 
560 μg/kg/day (280 μg/kg BID).  Subjects’ participation in the optional follow-up treatment 
period will continue until the first of the following occurs: (i) subjects are eligible to enter 
another LUM001 study or (ii) LUM001 is available commercially. 
An interim analysis of key safety and efficacy parameters will be performed after the first 12 
subjects who meet the Per Protocol population definition have completed the Week 13 study 
visit.  A second interim analysis will be performed after all evaluable subjects have completed 
the Week 48 (or Early Termination) study visit.  A third interim analysis will be performed after 
all enrolled subjects have completed at least 6 months of treatment under Protocol Amendment 4 
(or the Early Termination visit).  Subsequent interim analyses will be performed in yearly 
intervals.  See Section 12.2.7 for additional information. 
5.2 
Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will review SAE data, other key subject safety 
and study data at specified intervals for the duration of the study.  The DSMB will be composed 
of at least 2 members who are otherwise independent from the conduct of the study and one 
biostatistician.  The DSMB’s primary responsibility is to review the progress of the study, 
particularly with regard to safety and risk/benefit, and make recommendations to Sponsor to stop 
or modify the trial if safety concerns are identified.  Further details regarding the structure, 
function and operation of the DSMB will be detailed in the DSMB charter.   
5.3 
Number of Study Centers 
This will be a multicenter study at approximately 13 clinical centers. 
5.4 
Number of Subjects 
Approximately 24 evaluable subjects are planned for treatment in this study. Of these, a 
minimum of 8 enrolled will be PFIC1 subjects in light of the potential specific role that ASBT 
plays in the pathophysiology of FIC1 disease. 
5.5 
Overall Study Duration and Follow-up 
For an individual subject, the duration of the study, including subject screening, treatment and 
safety follow-up, is expected to be approximately 76 weeks.  Following the screening visit, 


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subjects who meet all eligibility criteria will return to the clinic for 11 visits and will receive 10 
telephone contacts from the study staff (see Figure 4).  Subjects who complete 72 weeks of 
treatment may be eligible to receive further treatment during the optional follow-up treatment 
period.  Eligible subjects may continue study treatment beyond Week 72 until the first of the 
following occurs:  (i) the subject is eligible to enter another LUM001 study or (ii) LUM001 is 
available commercially.  
Study activities will be conducted as described in the Schedule of Procedures (Section 16.1).  
Figure 4: 
Study Design for LUM001-501 (Up to and including Week 72) 
 
Optional Follow-up Treatment Period (post-Week 72; < 7 days from last LUM001 dose 
between Protocol Amendment 2 and Protocol Amendment 3) 
Applies to the following subject population: 
• Subjects who experienced no interruption in LUM001 dosing, or interruption <7 days 
between Protocol Amendment 2 and Protocol Amendment 3.  


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= Clinic Visit
= Phone Contact
LUM001 70 µg/kg/day
LUM001 140 µg/kg/day
LUM001 280 µg/kg/day
LUM001 35 µg/kg/day
Optional Follow-Up Treatment Period
Assess subject for eligibility for Afternoon Dose Escalation (ADE).  
If ineligible, move to Figure 5.  If eligible, move to Figure 6.
Study
Week
84
96
108
120
72
76
80
88
92
100
116
112
104
LUM001 280 µg/kg/day or 
maximum tolerated dose –
given as morning dose
**In consultation with Medical Monitor, the dose may be lowered to a previously well-tolerated dose to address tolerability issues at any time during the study**
**At the Investigator’s discretion, subjects who were previously down-titrated may be re-challenged during the follow-up period**


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Optional Follow-up Treatment Period (post-Week 72; ≥ 7 days from last LUM001 dose 
between Protocol Amendment 2 and Protocol Amendment 3) 
Applies to the following subject population: 
• Subjects who experienced an interruption in LUM001 dosing ≥7 days between Protocol 
Amendment 2 and Protocol Amendment 3.  
 
Optional Follow-up Treatment Period (post-Week 72; ≥ 7 days from last LUM001 dose 
between Protocol Amendment 3 and Protocol Amendment 4)   
Applies to the following subject population: 
• Subjects who experienced an interruption in LUM001 dosing ≥7 days between Protocol 
Amendment 3 and Protocol Amendment 4.  
 
 
Screening 
Each subject who provides informed consent/assent will complete all screening activities in ≤ 6 
weeks.   
= Clinic Visit
= Phone Contact
70 µg/kg/day
140 µg/kg/day
280 µg/kg/day
35 µg/kg/day
LUM001 280 µg/kg/day or 
maximum tolerated dose –
given as morning dose
Long-Term Exposure
At or after Week 84, assess subject for eligibility for Afternoon Dose Escalation (ADE). 
If ineligible, move to Figure 5.  If eligible, move to Figure 6.
Study
Week
84
96
108
88
92
100
120
116
112
104
FTP 
Dose Escalation (DE)
Week
72
Delayed Rollover -
Dose interruption
>7 days
DE
-2
DE 
Day 0
DE 
73
DE 
76
DE 
75
DE 
74
80
= Clinic Visit
= Phone Contact
70 µg/kg/day
140 µg/kg/day
280 µg/kg/day
35 µg/kg/day
LUM001 280 µg/kg/day or 
maximum tolerated dose
PA4 Dose 
Escalation 
Study Week 
PA4 DE 
Wk 8
PA4
Dose Escalation (DE)
Delayed Rollover -
Dose interruption
>7 days
PA4 
DE -2
PA4 DE 
Day 0
PA4 DE 
Wk 4
PA4 DE 
Wk 3
PA4 DE 
Wk 2
PA4 DE 
Wk 1
ADE eligibility 
assessed.  
If ineligible, move 
to Figure 5.  If 
eligible, move to 
Figure 6.


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Treatment 
The appropriate amount of study drug will be dispensed at the Study Day 0 visit and daily dosing 
will begin on Study Day 1.  
All subjects will receive LUM001, up to 560 μg/kg/day (given as twice-daily [BID] doses of 
280 μg/kg) or up to a maximum daily dose of 25 mg BID.  Dosing will occur over a 13-week 
treatment period (comprised of 4-weeks dose escalation [Dose Level 1-4], 4-weeks stable dosing 
at 140 µg/kg/day, and 5-weeks stable dosing at 280 µg/kg/day), followed by a 59-week long-
term exposure period.  
For the first 72 weeks of the study, each subject will receive either 1.0 mL (subjects weighing 
≥10 kg) or 0.5 mL (subjects weighing <10 kg) of solution containing LUM001 orally as follows, 
administered as a daily morning dose: 
• Dose Level 1: 14 µg/kg/day. 
• Dose Level 2: 35 µg/kg/day. 
• Dose Level 3: 70 µg/kg/day. 
• Dose Level 4: 140 µg/kg/day. 
• Dose Level 5: 280 µg/kg/day. 
At Week 72, all subjects will be assessed by the investigator to determine their willingness and 
eligibility to roll over into the optional follow-up treatment period.  Subjects eligible for the 
optional follow-up treatment period will continue treatment under dosing scenarios based on 
whether their LUM001 dosing will continue without interruption or interruption of <7 
continuous days, or with interruption ≥7 days.  Eligibility for BID dosing will be determined 
based on efficacy as measured by sBA level and ItchRO score. 
The sBA value used for determination of ADE eligibility will be the most recent available value.  
The ItchRO score used for ADE eligibility will be derived from the most recent 2-week 
electronic diary collection period. 
If a subject experiences intolerance (eg, gastrointestinal symptoms such as diarrhea, abdominal 
pain, cramping) at any time during the study, the physician investigator in consultation with the 
Medical Monitor may lower the dose for the remainder of the study.  If the subject is on twice 
daily dosing regimen, dose lowering should first be attempted with the afternoon dose.  Subjects 
who were previously down-titrated may be re-challenged during the long-term exposure period. 
5.5.2.1 
Dose Escalation Period 
During the first 4 weeks of the study, the dose escalation period, the dose will be increased at 
weekly intervals starting with Dose Level 1, up to Dose Level 4, to acclimate the subject to the 
study drug.  


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If a subject experiences intolerance (eg, gastrointestinal symptoms such as diarrhea, abdominal 
pain, cramping) at any time during the study, the physician investigator in consultation with the 
Medical Monitor may lower the dose for the remainder of the study. In these circumstances an 
unscheduled visit will occur and the appropriate replacement study medication will be issued to 
the subject as quickly as possible. 
5.5.2.2 
Stable Dosing Period 
Following the dose escalation period (Day 0 – 4) subjects will continue LUM001 dosing through 
Week 8 using Dose Level 4, or the highest tolerated dose below Dose Level 4. For those subjects 
who tolerated Dose Level 4, at Week 8, the dose will be increased to Dose Level 5 until Week 
13.  
5.5.2.3 
Long-term Exposure Period  
Subjects will continue to receive LUM001 during the long-term exposure dosing treatment 
period according to the highest dose achieved during the stable dosing treatment period. 
However, if a subject experiences intolerance due to gastrointestinal symptoms, the investigator, 
in consultation with the Medical Monitor, may lower the dose for the remainder of the study.  At 
the investigator’s discretion and in consultation with the Medical Monitor, subjects who were 
previously down-titrated may be re-challenged during the long-term exposure period. 
During the long-term exposure period, the dose may be adjusted to account for a change of 
≥10% in weight since the screening visit (e.g. the amount of drug dosed may be increased to 
reflect the subject’s weight increase).  
During the long-term exposure period, subjects will return to the clinic at Weeks 24, 36, 44, 48, 
60 and 72. With the exception of Week 44, safety and clinical laboratory evaluations, blood 
sampling for study drug determination, and a physical exam (including collection of vital signs, 
height and weight measurements) will be completed at each clinic visit. In addition, the clinician 
scratch scale will be administered and study drug compliance will be assessed. The PedsQL will 
be completed at Weeks 24, 48, and 72, and the Patient and Caregiver Impression of Change (PIC 
& CIC), and the Caregiver Global Therapeutic Benefit assessments will be completed at Weeks 
48 and 72. At the Week 24 and Week 44 visits, electronic diaries will be issued and AEs and 
concomitant medications will be assessed and recorded.  
Subjects/caregivers will receive follow-up phone calls at Weeks 16, 20, 28, 32 and 40. 
Concomitant medications and any adverse events (AEs) will be evaluated and recorded at all 
clinic visits and at scheduled telephone contacts.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for the 
treatment of pruritus may occur during the long-term exposure period.  
With the exception of Week 44, additional study drug will be supplied at each clinic visit during 
the long-term exposure period. 


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5.5.2.4 
Optional Follow-up Treatment Period (Post-Week 72) 
Optional Follow-up Treatment Period (Post-Week 72): 
Subjects eligible for the optional follow-up treatment period will continue treatment under 
dosing scenarios based on whether: 
-Their LUM001 dosing will continue without interruption or interruption of <7 continuous days,  
or  
-Their LUM001 dosing will continue with interruption ≥7 days.   
Eligibility for BID dosing will be determined based on efficacy as measured by sBA level and 
ItchRO score. 
Subjects who enter the optional follow-up treatment period without LUM001 dosing interruption 
or with an interruption of <7 continuous days will be dosed in the following manner: 
• Subjects with normal sBA level AND ItchRO score <1.5 will be maintained at the same 
dose level and will continue morning dosing only. 
• Subjects with sBA level above normal AND/OR ItchRO score ≥1.5 will start BID dosing 
(afternoon dose escalation; ADE) as follows: 
− The morning dose will be continued at the same dose level, but the volume of the 
morning dose will be reduced by half at the same time that the afternoon dose is 
initiated. 
− The afternoon dose will be initiated at half the maximum tolerated morning dose 
and will continue at this dose for a period of 4 weeks.  If this dose level is tolerated, 
the afternoon dose then will be doubled, to a maximum dose of 280 µg/kg (or up to 
the maximum tolerated dose). 
− The maximum daily dose will be 280 µg/kg BID, i.e. 560 µg/kg/day (max. 25 mg 
BID). 
Subjects who enter the optional follow-up treatment period with a LUM001 dosing interruption 
of ≥7 days initially will receive morning dosing only and will undergo dose escalation (DE) in 
the following manner: 
• The morning dose will be initiated at Dose Level 2 (35 µg/kg) and doubled in weekly 
intervals to a maximum dose of 280 µg/kg , or up to the maximum tolerated dose. 
• Once the morning dose of 280 µg/kg or maximum tolerated dose is achieved, sBA and 
ItchRO score will be evaluated. 
• Subjects with normal sBA AND ItchRO score <1.5 after morning dose escalation will be 
maintained at the same dose level and will continue morning dosing only. 


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• Subjects with sBA above normal AND/OR ItchRO score ≥1.5 will begin BID dosing 
(afternoon dose escalation) as outlined above. 
Subjects will continue to receive study drug until they are eligible to enter another LUM001 
study or until LUM001 is available commercially, whichever occurs first. 
The maximum daily dose will be 280 µg/kg BID, i.e. 560 µg/kg/day (maximum 25 mg).  If a 
subject experiences intolerance (eg, gastrointestinal symptoms such as diarrhea, abdominal pain, 
cramping) at any time during the study, the physician Investigator in consultation with the 
Medical Monitor may lower the dose for the remainder of the study. If the subject is on a BID 
dosing regimen, dose lowering should first be attempted with the afternoon dose. 
The sBA value used for determination of ADE eligibility will be the most recent available value.  
The ItchRO score used for ADE eligibility will be derived from the most recent 2-week 
electronic diary collection period.   
5.5.2.5 
Safety Follow-up Period   
A safety follow-up phone call will be made by the study site 30 days after the last dose of study 
drug.  This call will be made for all subjects who complete the study, as well as any subject who 
terminates from the study early.  Concomitant medications and any AEs noted during this phone 
call will be recorded.  Subjects who complete the study or who discontinued early due to reasons 
other than safety may be eligible for participation in the optional follow-up treatment period 
under Protocol Amendment 4.  
Additional study drug will be supplied at each clinic visit during the follow-up treatment period. 
Used study drug will be collected at each clinic visit and dosing compliance assessed.  
 
Electronic Diary 
Twice daily completion of the electronic diary will be required by caregivers and age appropriate 
subjects beginning at the screening visit through the end of the Week 13 visit and again during 
the 4 weeks that follow the Week 24 and Week 44 clinic visits.  For subjects who enter the 
optional follow-up treatment period, twice daily completion of the electronic diary will occur 
during the 2 weeks that follow the Week 84, 96, 108, and 120 visits, Protocol Amendment 4 DE 
Week 4, and every clinic visit within each recurring 12-week period2 . Electronic diaries will be 
provided to subjects and caregivers and re-training on the use of the diary will occur, as 
appropriate, at these visits.  
5.6 
End of Study 
For subjects who did not consent to the optional follow-up treatment period, a subject is 
considered to have completed treatment if treatment was not permanently discontinued prior to 
the Week 72 visit.  A follow-up phone contact is required for all subjects should the final visit 
occur earlier than 30 days from the final dose.  
For subjects who consented to the follow-up treatment period, an additional follow-up period 
disposition is collected in the eCRF.  The subject is considered to have completed treatment 


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during the follow-up treatment period if study treatment was not permanently discontinued prior 
to the subject completing the EOT visit as defined in the most recent consent signed by the 
subject. A follow-up contact is required for all subjects should the final visit occur earlier than 30 
days from the final dose.  
The end of study for the purposes of regulatory reporting is the point at which the last contact 
with the last subject during the protocol-specified scheduled follow-up treatment period is made. 


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6 
SUBJECT ENROLLMENT 
6.1 
Screening 
Before subjects may be screened for eligibility to participate in the study, the Sponsor, or 
designee, requires a copy of the appropriate written Independent Ethic Committee (IEC) 
approval of the protocol, informed consent/assent form(s) (ICF), and all other applicable subject 
information and/or recruitment material. 
Following informed consent/assent, the subject will be entered into the study and will be 
assigned a unique subject identification number before any study procedures, including screening 
procedures, are performed.  This number will be used to identify the subject throughout the study 
and must be used on all study documentation related to that subject.  The Subject identification 
number must remain constant throughout the entire study.  In the event the subject is re-
consented and rescreened, the subject must be given a new subject identification number.  
Subject identification numbers, once assigned, will not be reused. 
6.2 
Enrollment 
Subjects will be enrolled after all screening assessments have been completed and the 
Investigator has verified that eligibility criteria have been met.  
Subjects will be enrolled into the optional follow-up treatment period based on the eligibility 
criteria outlined in Section 7.3. 
6.3 
Replacement of Subjects 
A subject who withdraws from the study prior to completion of the Week 13 treatment period 
may be replaced at the discretion of the Sponsor. Subjects who substantially violate the protocol 
may also be replaced, if required, in order to provide 24 evaluable subjects. Subjects who are 
determined to be screen failures may be replaced after consultation with the sponsor. 


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7 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
before being assigned to study drug treatment. 
7.1 
Inclusion Criteria 
To participate in this study subjects must meet the following criteria: 
1. Male or female subjects between the ages of 12 months and 18 years inclusive. 
2. Diagnosis of PFIC based on: 
a. Intrahepatic cholestasis manifest by total serum bile acid >3x upper limit of normal 
(ULN) for age. 
and, b or c: 
b. Two documented mutant alleles in ATP8B1, or ABCB11. 
c. Evidence of chronic liver disease, excluding those listed in (see Section 16.3), with 
one or more of the following criteria:  
1. 
Duration of biochemical or clinical abnormalities of >6 months, or 
2. 
Pathologic evidence of progressive liver disease, or  
3. 
Sibling of known individual affected by PFIC (predicted to be chronic). 
3. GGTP <100 IU/L at screening. 
4. Females of childbearing potential must have a negative urine or serum pregnancy test [β 
human chorionic gonadotropin (β-hCG)] during screening and a negative urine pregnancy 
test at the Baseline (Day 0) visit. 
5. Males and females of child-bearing potential who are sexually active, or are not currently 
sexually active during the study, but become sexually active during the period of the study 
and 30 days following the last dose of study drug, must agree and use acceptable 
contraception during the trial, as described in Section 8.7.1. 
6. Informed consent and assent (per IRB/EC) as appropriate. 
7. Access to phone for scheduled calls from study site. 
8. Caregivers and children above the age of assent must have the ability to read and understand 
one of the following languages: English, Spanish, US Spanish, French, German or Polish. 
9. Subjects expected to have a consistent caregiver(s) for the duration of the first 13 weeks of 
the study. 
10. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device as 
required by the study. To accommodate potential cultural restrictions within the FIC1 
affected population a paper version of the ItchRO diary will be made available. 
11. Caregivers (and age appropriate subjects) using the eDiary must digitally accept the licensing 
agreement in the eDiary software at the outset of the study. 
12. Caregivers (and age appropriate subjects) must complete at least 10 eDiary reports (morning 
or evening) during each of two consecutive weeks of the screening period, prior to 


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assignment (maximum possible reports = 14 per week). Subjects using a paper diary must 
complete the same number of reports within the same timeframe. 
7.2 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Chronic diarrhea requiring specific intravenous fluid or nutritional intervention for the 
diarrhea and/or its sequelae. 
2. Surgical disruption of the enterohepatic circulation at the time at screening.  Subjects who 
have undergone reversal of a prior surgical procedure intended to disrupt enterohepatic 
circulation and who and have a permanently restored flow of bile acids from the liver to the 
terminal ileum may be eligible for the study upon consultation with the Medical Monitor.  
3. Liver transplant. 
4. Decompensated cirrhosis [international normalized ratio (INR) > 1.5, albumin < 30 g/L, 
history or presence of clinically significant ascites, variceal hemorrhage, and/or 
encephalopathy]. 
5. ALT >15×ULN at screening. 
6. History or presence of other liver disease (see Section 16.3). 
7. History or presence of any other disease or condition known to interfere with the absorption, 
distribution, metabolism or excretion of drugs, including bile salt metabolism in the intestine 
(e.g., inflammatory bowel disease). 
8. Liver mass on imaging. 
9. Known diagnosis of human immunodeficiency virus (HIV) infection. 
10. Cancers except for in situ carcinoma, or cancers treated at least 5 years prior to screening 
with no evidence of recurrence. 
11. Any female who is pregnant or lactating or who is planning to become pregnant within 20 
weeks of assignment. 
12. Any known history of alcohol or substance abuse. 
13. Administration of bile acid or lipid binding resins within 30 days prior to  
Baseline / Day 0 and throughout the trial. 
14. Administration of sodium phenylbutyrate within 30 days prior to  
Baseline / Day 0 and throughout the trial. 
15. Investigational drug, biologic, or medical device within 30 days prior to screening, or 5 half-
lives of the study agent, whichever is longer. 
16. History of non-adherence to medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to 
non-adherence with the study protocol based on Investigator judgment. 
17. Any other conditions or abnormalities which, in the opinion of the Investigator or Medical 
monitor, may compromise the safety of the subject, or interfere with the subject participating 
in or completing the study. 


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7.3 
Eligibility for Optional Follow-up Treatment Period 
 
Inclusion Criteria 
To participate in optional follow-up treatment period subjects must meet the following criteria: 
1. The subject has either:  
• completed the protocol through the Week 72 visit with no major safety concerns. 
OR 
• discontinued due to safety reasons judged unrelated to the study drug, and blood tests 
have returned to levels acceptable for this patient population/individual and subject does 
not meet any of the protocol’s stopping rules at re-entry.  The decision will be made by 
the investigator in consultation with the Medical Monitor.  [Subjects who were 
discontinued for other reasons will be considered on an individual basis.]  
2. Females of childbearing potential must have a negative urine or serum pregnancy test 
(β-hCG) at the time of entry into the optional follow-up treatment period. 
3. Informed consent and assent (per IRB/EC) as appropriate. 
 
Exclusion Criteria 
Subjects will be excluded from the optional follow-up treatment period if they meet the 
following criteria: 
1. Surgical disruption of the enterohepatic circulation. 
 
2. Investigational drug other than LUM001, biologic, or medical device within 30 
days prior to re-entry, or 5 half-lives of the study agent, whichever is longer. 


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8 
STUDY PROCEDURES 
8.1 
Study Schedule 
The schedule of assessments for this study is provided in the Schedule of Procedures, Section 
16.1. Subject-related events and activities including specific instructions, procedures, 
concomitant medications, dispensing of study drug, and descriptions of AEs should be recorded 
in the appropriate source documents and CRFs. 
 
Screening Period (Day -42 to Day -1) 
Screening evaluations will be performed from Day -42 to Day -1. Subjects and caregivers who 
give written informed consent/assent will provide demographic data (gender, age, and race) and 
undergo a complete medical history (including ongoing medical conditions and symptoms and 
assessment of inclusion/exclusion criteria). A physical examination will be conducted including 
body weight, height, and vital signs, determination of concomitant medications, and blood and 
urine samples will be taken for clinical laboratory testing. An ultrasound will be performed to 
determine if any masses are present in the liver. Note: A screening ultrasound is not required if 
the results of an ultrasound completed within 6 months are available and the clinical status of the 
subject has not changed significantly since the time of the test. 
In the absence of documented ATP8B1 or ABCB11 mutation prior to screening, genetic testing 
will be performed. The appropriate genetic counseling will be provided to subjects and their 
legal caregivers at a study visit following the receipt of results of genetic testing. Results of 
genetic screen will not impact continued participation in the study, but are done to provide 
complete and uniform characterization of the subjects’ liver disease.    
The eDiary for assessing pruritus, as measured using an Itch Reported Outcome (ItchRO) 
instrument, will be dispensed and subjects and caregivers will receive training during the 
screening visit.  The patient/caregiver ItchRO will be administered twice daily during the 
screening period to determine study eligibility and baseline score.  The physician will provide an 
assessment of itch severity using the clinician administered scratch scale during screening.   
Females who are of childbearing potential will have a serum pregnancy test.  Enrollment will 
occur after eligibility criteria have been met, 4-7 days prior to the baseline visit.  
Rescreening:  If a subject is unable to complete the screening procedures and meet eligibility 
criteria within the 42-day screening period, consideration may be given to rescreening at a later 
date.  Screening procedures should be repeated at that time. 
 
Dose Escalation Treatment Period (Day 0 to Week 4) 
At the baseline visit (Day 0), study eligibility will be confirmed and body weight, height, and 
vital signs will be evaluated and recorded.  Blood and urine samples will be taken for clinical 
laboratory testing, including fasting lipid panel.  Baseline levels of bile acids and other 
cholestasis biochemical markers will be determined from blood and urine (for a complete list of 
analytes see Section 16.2).  Blood will also be collected for determination of baseline fat-soluble 
vitamins.  Also during the baseline visit, ItchRO compliance will be assessed, the clinician 


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scratch scale will be administered, and the PedsQL questionnaire, a measure of quality of life 
will be administered.  Female subjects who are of childbearing potential will have a urine 
pregnancy test at all study visits prior to dispensing study drug. Study drug for Weeks 1 (Dose 
Level 1) and 2 (Dose Level 2) will be supplied at the baseline visit to eligible 
subjects.  Caregivers and age appropriate subjects will continue twice daily (morning and 
evening) completion of their eDiary (ItchRO) throughout the dose escalation treatment period.   
Subjects will return to the clinic at Weeks 2 and 4 and will receive a follow-up phone call at 
Weeks 1, 3 and 5. On clinic visit days, safety and clinical laboratory evaluations will be 
performed.  The clinician scratch scale will be administered, adherence to study drug will be 
assessed. At the Week 2 visit study drug and additional dosing instructions for Weeks 3 (Dose 
Level 3) and 4 (Dose Level 4) will be supplied.  Follow-up phone calls will review dosing 
instructions for the following week.  ItchRO compliance will be assessed and concomitant 
medications and any AEs will be recorded at clinic visits and from phone calls.  Phone contact at 
Weeks 1 and 3 and clinic visits at Weeks 2 and 4 have a ±2 day window. 
Blood sampling for study drug level determination:  
• US: At sites in the United States, blood sampling for plasma levels of LUM001 will be 
collected at Baseline (Day 0) and Weeks 2 and 4.  At Week 2, blood will be drawn 
approximately 4 hours post dosing for drug level analysis. At Week 4, blood will be 
drawn approximately 2 hours post-dosing.   
• UK, EU, and Australia: At sites in the United Kingdom, Europe and Australia, blood 
sampling for plasma levels of LUM001 will be collected at Week 4.  Blood will be drawn 
approximately 4 hours post-dosing.   
 
140 µg/kg/day Stable Dosing Treatment Period (Week 5 to Week 8) 
Each subject will continue to receive LUM001 during the stable dosing treatment period using 
Dose Level 4, or the highest tolerated dose below Dose Level 4. Subjects and caregivers will 
continue daily completion of their eDiary (ItchRO).  Subjects/caregivers will receive a follow-up 
phone call at Week 5 and return to the clinic at Week 8.   
At the Week 8 clinic visit, safety and clinical laboratory evaluations as well as blood sampling 
for study drug determination will be performed, approximately 4 hours post study drug 
administration.  The clinician scratch scale will be administered and adherence to study drug will 
be assessed. For those subjects who tolerated Dose Level 4, at the Week 8 visit the dose will be 
increased to Dose Level 5, subjects will continue dosing for another 5 weeks using Dose Level 5 
or the highest tolerated dose below this dose. Additional dosing instructions and study drug will 
be supplied. ItchRO compliance will be assessed and concomitant medications and any AEs will 
be recorded at clinic visits and from phone calls. 
Females who are of childbearing potential will have a urine pregnancy test at all clinic visits. 
Concomitant medications and any AEs will be recorded at clinic visits and from phone calls.  
Phone contact at Week 5, and the clinic visit at Week 8 will have a ±5 day window. 


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Blood sampling for study drug level determination:  
• US: At sites in the United States, blood sampling for plasma levels of LUM001 will be 
collected at Week 8.  Blood will be drawn approximately 4 hours post morning dosing.  
• UK, EU, and Australia: At sites in the United Kingdom, Europe and Australia, blood 
sampling for plasma levels of LUM001 will not be collected between Weeks 5 and 8. 
 
280 µg/kg/day Stable Dosing Treatment Period (Week 9 to Week 13) 
Each subject will continue to receive LUM001 during the stable dosing treatment period using 
Dose Level 5 or the highest tolerated dose below this dose. Subjects and caregivers will continue 
daily completion of their eDiary (ItchRO). Subjects/caregivers will receive a follow-up phone 
call at Week 9 and return to the clinic at Week 13.   
At the Week 13 clinic visit, safety and clinical laboratory evaluations as well as blood sampling 
for study drug determination will be performed, approximately 4 hours post study drug 
administration.  The clinician scratch scale will be administered and adherence to study drug will 
be assessed.  Additional dosing instructions and study drug will be supplied at Week 13.  At the 
Week 13 visit, the PedsQL will be administered and the eDiary will be collected.   
Females who are of childbearing potential will have a urine pregnancy test at all clinic visits. 
Additional dosing instructions and study drug will be supplied for the next phase of the study. 
Concomitant medications and any AEs will be recorded at clinic visits and from phone calls.  
Phone contact at Week 9 and the Week 13 clinic visit will have a ±5 day window. 
Blood sampling for study drug level determination:  
• At all sites (US, UK, EU and Australia), blood sampling for plasma levels of LUM001 
will be collected at Week 13.  Blood will be drawn approximately 4 hours post morning 
dosing for drug level analysis.   
 
Long-Term Exposure Period (Week 14 to Week 72) 
Subjects will continue to receive LUM001 during the long-term exposure dosing treatment 
period according to the dose achieved during the stable dosing treatment period. However, if a 
subject experiences intolerance due to gastrointestinal symptoms, the investigator in consultation 
with the Medical Monitor may lower the dose for the remainder of the study.  At the 
investigator’s discretion and in consultation with the Medical Monitor, subjects who were 
previously down-titrated may be re-challenged during the long-term exposure period. 
During the long-term exposure period, subjects will return to the clinic at Weeks 24, 36 44, 48, 
60 and 72. With the exception of Week 44, safety and clinical laboratory evaluations, and a 
physical exam (including collection of vital signs, height and weight measurements) will be 
completed at each clinic visit. In addition, the clinician scratch scale will be administered and 
study drug compliance will be assessed. The PedsQL will be completed at Weeks 24, 48 and 72, 
and the Patient and Caregiver Impression of Change (PIC & CIC) and the Caregiver Global 
Therapeutic Benefit assessments will be completed at Weeks 48 and 72. Subjects/caregivers will 


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receive follow-up phone calls at Weeks 16, 20, 28, 32 and 40. Concomitant medications and any 
AEs will be evaluated and recorded at all clinic visits and at scheduled telephone contacts.  
Twice daily completion of the electronic diary will be required by caregivers and age appropriate 
subjects during the 4 weeks that follow the Week 24 and Week 44 clinic visits. Electronic diaries 
will be provided to subjects and caregivers at Weeks 24 and 44, and re-training on the use of the 
diary will occur, as appropriate, at these 2 visits.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for the 
treatment of pruritus may occur during the long-term exposure period and will be documented on 
the appropriate case report form.  
With the exception of the Week 44 visit, additional study drug will be supplied at each clinic 
visit during the long-term exposure period.  Used study drug will be collected at each clinic visit, 
and dosing compliance will be assessed. Clinic visits and telephone contacts during the long-
term exposure period have a ±14 day window. 
Blood sampling for study drug level determination:  
• At all sites (US, UK, EU and Australia), blood sampling for plasma levels of LUM001 
will be collected at Weeks 24, 36, 48, 60 and 72.  Blood will be drawn approximately 4 
hours post dosing.  
At Week 72, all subjects will be assessed by the investigator to determine their willingness and 
eligibility to roll-over into the optional follow-up treatment period. Following completion of the 
Week 72 study visit, subjects who do not wish to enter the optional follow-up treatment period 
will be contacted via telephone by the study site approximately 30 days after the last dose of 
study drug.   
 
Early Termination for Subjects without Participation in the Optional 
Follow-up Treatment Period 
Any subject who withdraws from the study prior to completion of all treatment period clinic 
visits should undergo all procedures specified for the Week 72 study termination visit. In 
addition the following assessments should be completed; the ItchRO (if prior to the Week 48 
visit), the clinician administered pruritus scale, the PedsQL, the Patient Impression of Change, 
the Caregiver Impression of Change, and the Caregiver Global Therapeutic Benefit assessments, 
as defined for Early Termination (see Section 16.1; Schedule J). For safety reasons, efforts must 
be made to follow subjects for at least 30 days following their last dose of study drug. 
 
Optional Follow-up Treatment Period (Post-Week 72) 
Subjects who are eligible to enter the follow-up treatment period will continue to receive study 
drug after Week 72 until the first of the following occurs:  (i) the subjects are eligible to enter 
another LUM001 study or (ii) LUM001 is available commercially.  
 Included below are schematics describing the flow of study visits within the optional follow-up 
treatment period. 


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Subjects who experienced no interruption in LUM001 dosing, or interruption <7 days between 
Protocol Amendment 2 and Protocol Amendment 3:  
Subjects who are eligible to enter the follow-up treatment period with no LUM001 dosing 
interruption or an interruption of <7 days will initially receive study drug at the dose they were 
receiving at Week 72.  Once Protocol Amendment 4 is implemented at the site, a determination 
about Afternoon Dose Escalation (ADE) will be made.  The subject then will move to Figure 5 
or Figure 6, depending on whether they meet criteria for initiating Afternoon Dose 
Escalation.   
Subjects who experienced an interruption in LUM001 dosing ≥7 days between Protocol 
Amendment 2 and Protocol Amendment 3: 
 
Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 280 µg/kg/day or 
to the maximum tolerated dose starting at Dose Level 2 (35 µg/kg/day). This escalation regimen 
is supported by the safety profile observed in completed and ongoing clinical studies of LUM001 
and allows for subjects to reach 280 µg/kg/day or a maximum tolerated dose within a 4-week 
period. The dose escalation (DE) period will proceed as follows: 
• DE Week -2 Clinic Visit: obtain consent, obtain weight and draw labs.   
• DE Day 0 Clinic Visit: Investigator evaluates laboratory results, study drug is dispensed 
and subject begins at 35 µg/kg/day dose level. 
• DE Week 73 Telephone Contact: subject escalates to 70 µg/kg/day dose level if prior 
dose level was tolerated.  
• DE Week 74 Clinic Visit: subject escalates to 140 µg/kg/day dose level if prior dose level 
was tolerated. 
• DE Week 75 Telephone Contact: subject escalates to 280 µg/kg/day dose, if prior dose 
level was tolerated. 
• DE Week 76 Clinic Visit: subject continues in Follow-up Treatment Period at 280 
µg/kg/day, or maximum tolerated dose.  


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Once Protocol Amendment 4 is implemented at the site, a determination about Afternoon Dose 
Escalation (ADE) will be made.  The subject then will move to Figure 5 or Figure 6, 
depending on whether they meet criteria for initiating Afternoon Dose Escalation.   
Subjects who experienced an interruption in LUM001 dosing ≥7 days between Protocol 
Amendment 3 and Protocol Amendment 4:  
Subjects with ≥7 days since last dose of LUM001 prior to site implementation of Protocol 
Amendment 4 will be dose escalated up to 280 µg/kg/day or to the highest tolerated dose starting 
at Dose Level 2 (35 μg/kg/day).  
The dose escalation (DE) period will proceed as follows: 
• Protocol Amendment 4 DE Week -2 Clinic Visit: obtain consent for Protocol 
Amendment 4, obtain weight and draw labs.   
• Protocol Amendment 4 DE Day 0 Clinic Visit: Investigator evaluates laboratory results, 
study drug is dispensed and subject begins at 35 μg/kg/day dose level. 
• Protocol Amendment 4 DE Week 1 Telephone Contact: subject escalates to 70 μg/kg/day 
dose level if prior dose level was tolerated. 
• Protocol Amendment 4 DE Week 2 Clinic Visit: subject escalates to 140 μg/kg/day dose 
level if prior dose level was tolerated. 
• Protocol Amendment 4 DE Week 3 Telephone Contact: subject escalates to 280 
μg/kg/day dose, if prior dose level was tolerated. 
• Protocol Amendment 4 DE Week 4 Clinic Visit: subject continues in follow-up treatment 
period at 280 μg/kg/day, or maximum tolerated dose. 
• At Protocol Amendment 4 DE Week 8 Telephone Contact:  eligibility for ADE will be 
assessed.  The subject will then move to Figure 5 or Figure 6, depending on whether they 
meet criteria for initiating Afternoon Dose Escalation.   


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Figure 5: Optional Follow-up Treatment under Protocol Amendment 4, without Afternoon 
Dose Escalation (ADE) 
Applies to the following subject population: 
• Subjects deemed ineligible for ADE. 
 
Subjects Deemed Ineligible for ADE: 
Subjects with normal sBA level AND ItchRO score <1.5 will be deemed ineligible for ADE; 
such patients will be maintained at the same dose level and will continue morning dosing only.  
Subjects will have study activities then repeated in recurring 12-week periods as follows, until 
study completion or termination: 
• Recurring Period Week 4 (i.e., beginning Week 88 or 4 weeks after consent to Protocol 
Amendment 4) Telephone Contact:  Collection of concomitant medications and any 
adverse events. 
• Recurring Period Week 8 Telephone Contact: Collection of concomitant medications and 
any adverse events.  
• Recurring Period Week 12 Clinic Visit:  Physical exam, body weight and height, vital 
signs, and blood samples for clinical laboratory testing, including fasting lipid 
panel.  Blood will also be collected for determination of fat-soluble vitamins.  Urine 
samples for clinical laboratory testing will be collected at every visit.  ItchRO compliance 
will be assessed, the electronic diary will be issued, the clinician scratch scale will be 
administered, and the PedsQL questionnaire will be administered.  Additionally, a 
palatability questionnaire will be completed.  Female subjects who are of childbearing 
potential will have a urine pregnancy test prior to dispensing study drug.  Study drug 
compliance will be assessed and study drug will be dispensed upon completion of other 
study procedures. 
= Clinic Visit
= Phone Contact
LUM001 280 µg/kg/day or 
maximum tolerated dose
Morning dosing of 280 
µg/kg/day or MTD 
continues
Repeating 
Period Wk 4 
Repeating 
Period Wk 8 
Repeating 
Period Wk 12 
Study activities repeat 
in recurring 12 week periods
(until study completion or termination) 
EOT/ET
30 Day 
Safety 
Follow-Up


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Figure 6: Optional Follow-up Treatment under Protocol Amendment 4, with Afternoon 
Dose Escalation (ADE) 
Applies to the following subject population:  
• Subjects whose sBA levels have not normalized and/or whose ItchRO score is ≥1.5 and 
therefore qualify for introduction of afternoon dosing. 
 
Subjects deemed eligible for ADE, i.e., who have sBA level above normal AND/OR ItchRO 
score ≥1.5, will begin BID dosing (afternoon dose escalation; ADE) as follows: 
• On ADE Day 0, morning dosing will continue at 280 µg/kg or the maximum tolerated 
dose; however, the volume of the morning dose will be reduced by half.  Dosing must 
have been stable for ≥4 weeks prior to initiation of ADE.  
• On ADE Day 0, the afternoon dose will be initiated at half the maximum tolerated 
morning dose and will continue at this dose level for a period of 4 weeks.  If this dose 
level is tolerated, the afternoon dose then will be doubled (i.e., at ADE Week 4) to a 
maximum dose of 280 µg/kg (i.e., up to a maximum 560 µg/kg/day or maximum 
tolerated dose). 
The following procedures will occur during the ADE period: 
• ADE Day 0 Clinic Visit:   Physical exam, body weight and height, vital signs, and blood 
and urine samples for clinical laboratory testing, including fasting lipid panel.  Blood will 
also be collected for determination of fat-soluble vitamins.  Plasma sample will be 
= Clinic Visit
= Phone Contact
Afternoon dose 
is doubled
Initial 
afternoon dose 
= ½ maximum 
tolerated 
morning dose
LUM001 560 µg/kg/day or 
maximum tolerated dose
Afternoon Dose Escalation (ADE) 
Period
ADE1
Day 0
ADE
Wk 2
ADE 
Wk 8
ADE 
Wk 6
ADE 
Wk 4
1 – Afternoon Dose Escalation (ADE) will be initiated for 
eligible subjects following site implementation of 
Protocol Amendment 4 and signature of appropriate 
consent.  
Of note:  Morning dosing of 280 µg/kg/day or MTD must 
be stable for  ≥ 4 weeks prior to initiation of ADE.
Morning dosing of 280 
µg/kg/day or MTD 
continues at initiation 
of ADE, with an 
adjustment to 
morning dose volume
ADE
Wk 1
ADE 
Wk 5
Repeating 
Period Wk 4 
Repeating 
Period Wk 8 
Repeating 
Period Wk 12 
Study activities repeat in 
recurring 12 week periods 
after completion of ADE
(repeats until study completion or termination)
EOT/ET
30 Day 
Safety 
Follow-Up


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obtained for LUM001 PK.  The clinician scratch scale and the PedsQL questionnaire will 
be administered.  Female subjects who are of childbearing potential will have a urine 
pregnancy test prior to dispensing study drug.  Study drug compliance will be assessed 
and study drug will be dispensed upon completion of other study procedures. 
Concomitant medications and any adverse events will be collected. 
• ADE Week 1 and Week 2 Telephone Contact:  Collection of concomitant medications 
and any adverse events.  Subject/caregiver will be reminded of dosing instructions. 
• ADE Week 4 Clinic Visit:  Physical exam, body weight and height, vital signs, and blood 
and urine samples for clinical laboratory testing, including fasting lipid panel.  Blood will 
also be collected for determination of fat-soluble vitamins.  Plasma sample will be 
obtained for LUM001 PK.  The clinician scratch scale and the PedsQL questionnaire will 
be administered.  Female subjects who are of childbearing potential will have a urine 
pregnancy test prior to dispensing study drug.  Study drug compliance will be assessed 
and study drug will be dispensed upon completion of other study procedures. 
Concomitant medications and any adverse events will be collected. 
• ADE Week 5 and Week 6 Telephone Contact:  Collection of concomitant medications 
and any adverse events.  Subject/caregiver will be reminded of dosing instructions. 
• ADE Week 8 Clinic Visit:  Physical exam, body weight and height, vital signs, and blood 
and urine samples for clinical laboratory testing, including fasting lipid panel.  Blood will 
also be collected for determination of fat-soluble vitamins.  Plasma sample will be 
obtained for LUM001 PK.  The clinician scratch scale and the PedsQL questionnaire will 
be administered.  Female subjects who are of childbearing potential will have a urine 
pregnancy test prior to dispensing study drug.  Study drug compliance will be assessed 
and study drug will be dispensed upon completion of other study procedures. 
Concomitant medications and any adverse events will be collected. 
Thereafter, subjects will have study activities repeated in recurring 12-week periods as described 
within Figure 5, until study completion or termination. 
If any subject experiences intolerance, the Investigator, in consultation with the Medical 
Monitor, may lower the dose at any time during the entire follow-up treatment period. If the 
subject is on a twice daily dosing regimen, dose lowering should first be attempted with the 
afternoon dose. 
At the Investigator’s discretion and in consultation with the Medical Monitor, subjects who were 
previously down titrated may be re-challenged during the follow-up treatment period. During the 
follow-up treatment period, subjects will return to the clinic every 3 months.  
Safety and clinical laboratory evaluations and a physical exam (including collection of vital 
signs, height and weight measurements) will be completed at each clinic visit.  In addition, the 
clinician scratch scale will be administered and study drug compliance will be assessed. The 
PedsQL will be administered at DE Day 0 (for subjects requiring dose escalation) and at Weeks 
84, 96, 108, 120, every clinic visit within each recurring 12-week period, and at the EOT visit. 


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Additionally, it will be collected at Protocol Amendment 4 DE Day 0, ADE Day 0, ADE Week 
4, and ADE Week 8. The Patient and Caregiver Impression of Change (PIC & CIC), and the 
Caregiver Global Therapeutic Benefit assessments will be completed at Weeks 108, 120, and the 
EOT visit. Subjects/caregivers will receive follow-up phone calls at Weeks 80, 88, 92, 100, 104, 
112, and 116, and twice within each recurring 12-week period, and every 3 months hence for the 
subsequent visits. Concomitant medications and any AEs will be evaluated and recorded at all 
clinic visits and at scheduled telephone contacts. 
Twice daily completion of the electronic diary will be required by caregivers and age appropriate 
subjects during the 2 weeks following the Week 84, 96, 108, and 120 clinic visits, at Protocol 
Amendment 4 DE Week 4, and every clinic visit (not including the EOT visit) within each 
recurring 12-week period.  Electronic diaries will be provided to subjects and caregivers at these 
visits and re-training on the use of the diary will occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for the 
treatment of pruritus may occur during the long-term exposure period.  
Blood sampling will be performed for study drug level determination as follows:  
• US: At sites in the United States, for subjects in which afternoon dose escalation is 
initiated in the optional follow-up treatment period, samples will be drawn at ADE Day 0, 
ADE Week 4, ADE Week 8, and at the three scheduled clinic visits following completion 
of the ADE period. Blood will be drawn approximately 4 hours post morning dosing for 
drug level analysis.   
• UK, EU, and Australia: At sites in the United Kingdom, Europe and Australia, for 
subjects in which afternoon dose escalation is initiated in the optional follow-up 
treatment period, samples will be drawn at ADE Day 0, ADE Week 4, ADE Week 8, and 
at the three scheduled clinic visits following completion of the ADE period. Blood will 
be drawn approximately 4 hours post morning dosing for drug level analysis.   
With the exception of the EOT visit, additional study drug will be supplied at each clinic visit 
during the follow-up treatment period.  Used and unused study drug will be collected at every 
visit. 
At completion of the Follow-up Treatment Period or early discontinuation: a safety follow-up 
phone call will be made 30 days after the last dose of study drug. This call will be made for all 
subjects who complete the study, as well as any subject who terminates from the study early. 
Concomitant medications and adverse events noted during this phone call will be recorded. 
 
End of Treatment or Early Termination 
Any subject who completes or withdraws from the study should undergo all procedures specified 
for the EOT/ET visit (see Schedule J).  The following assessments are to be completed at the 
EOT/ET visit:  Physical exam, body weight and height, vital signs, and blood and urine samples 
for clinical laboratory testing, including fasting lipid panel.  Blood will also be collected for 
determination of fat-soluble vitamins and AFP.  Female subjects who are of childbearing 
potential will have a urine pregnancy test.  Study drug compliance will be assessed.  
Concomitant medications and adverse events will be collected.  The ItchRO, the clinician 


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administered pruritus scale, the PedsQL, the Patient Impression of Change, the Caregiver 
Impression of Change, and the Caregiver Global Therapeutic Benefit assessments, and 
palatability questionnaire also will be completed, as defined for Early Termination (see Section 
16.1).   
 
Safety Follow-up Period   
A safety follow-up phone call will be made by the study site 30 days after the last dose of study 
drug.  This call will be made for all subjects who complete the study, as well as any subject who 
terminates from the study early.  Concomitant medications and any AEs noted during this phone 
call will be recorded.  
Subjects who complete the study or who discontinued early due to reasons other than safety may 
be eligible for participation in the optional follow-up treatment period. 
8.2 
Genetic Testing 
ATP8B1 or ABCB11 mutations are predictive of PFIC. For subjects who do not have 
documentation of an ATP8B1 or ABCB11 mutation, blood samples for genotyping will be 
collected at the screening visit. The appropriate genetic counseling in accordance with local laws 
will be provided to any subject and their legal caregivers at a study visit following the receipt of 
results of genetic testing, at no cost to the subject. Subjects for whom prior genotyping was 
performed may need to have an optional repeat analysis performed if the original information 
collected at screening was insufficient for complete documentation of the diagnosis of PFIC 
including the type of mutation recorded. For those participants for which the type of the mutation 
cannot be documented, genetic testing may be conducted and the results recorded. 
In addition, to better understand the role of genetics in treatment response, an additional blood 
sample will be taken for exome sequencing. The data analysis will focus initially on genetic 
variation in candidate genes that may have a role in treatment response, such as ASBT/SLC10A2 
and genes in its pathway (ie upstream or downstream of ASBT/SLC10A2) and genes implicated 
in PFIC (ATP8B1, ABCB11 and ABCB4) with the goal of identifying genetic variation that may 
discriminate treatment responders from non-responders. Following examination of candidate 
genes, the data analysis may be expanded to evaluate genetic variation in additional regions of 
the exome. This genetic analysis is more comprehensive and may provide valuable information 
beyond the ATP8B1 and ABCB11 genes. The submission of this blood sample is voluntary. The 
results of this analysis may identify relevant genetic variants, only some of which will be of 
known clinical benefit. A blood sample for exome sequencing will be drawn once, at the time of 
consent under Protocol Amendment 4. 
8.3 
Physical Examination, Weight and Height, Vital Signs 
A physician Investigator (or designee) will conduct a physical examination on each subject at 
screening and at the Week 24, Week 36, Week 48, Week 60 and Week 72 clinic visits. For 
subjects who enter into the optional follow-up treatment period, physical examinations will also 
be conducted at every clinic visit as outlined in the Schedules of Procedures in Section 16.1. 


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In addition, body weight, height (length), and vital signs, including body temperature, blood 
pressure, respiration and pulse, will be determined at every study clinic visit. 
8.4 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of planned tests is 
compiled in Section 16.2. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The clinical 
significance of each value outside of the reference range will be assessed and documented as 
either not clinically significant (NCS) or clinically significant (CS).  See Section 11.4.1 
regarding laboratory abnormalities. 
8.5 
Pruritus and Quality of Life Assessments 
All assessments completed by the subject and caregiver will be provided as validated translations 
in the following languages; English, Spanish, US Spanish, French, German or Polish. 
 
Itch Reported Outcome (ItchRO™) 
Pruritus will be assessed using a newly developed Itch caregiver/patient reported outcome 
measure (ItchRO) administered as a twice daily electronic diary.  To accommodate potential 
cultural restrictions within the FIC1 affected population a paper version of the ItchRO diary will 
be made available. 
Caregivers for all subjects will complete the Observer instrument: ItchRO(Obs)™.  Children ≥9 
years of age will complete the patient instrument: ItchRO(Pt)™.  Children between the ages of 5 
and 8 years of age will complete the patient instrument with the assistance of their caregiver: 
ItchRO(Pt) 
Subjects and caregivers will be trained in the use of the electronic (or paper) diary during the 
screening visit.  Beginning with the screening period, pruritus will be assessed and recorded 
twice daily by caregivers and subjects (ItchRO), as described in Section 16.4.   
To be eligible for enrollment, caregivers must complete at least 10 eDiary (or paper) reports 
(morning and/or evening) during each of two consecutive weeks of the screening period. In 
addition, subjects ≥9 years of age must complete at least 10 eDiary reports (morning and/or 
evening) during each of two consecutive weeks of the screening period.  
Following enrollment, subjects/caregivers will be required to submit twice daily assessments 
using the electronic (or paper) diary during Day 0-13 of the study.  Electronic diaries will be 
returned to the study site at the Week 13 clinic visit (or sooner if the subject has withdrawn from 
the study before then). 
During the long-term exposure period, daily completion of the diary will be required by subjects 
and caregivers only during the 4 consecutive weeks that follow the Week 24 and Week 44 clinic 
visits.  At Week 24 and Week 44, subjects/caregivers will be provided with the electronic diary 
and re-trained on its use, as needed.  At the Week 24 visit, subjects/caregivers will also be 


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provided with prepaid/pre-labeled mailing supplies that should be used to return the electronic 
diary to the study center immediately after they have completed the 4 weeks of diary entries.  At 
the Week 44 visit, subjects/caregivers will be instructed to bring their electronic diary with them 
when they return for the Week 48 clinic visit. For subjects who enter the optional follow-up 
treatment period, completion of the diary will occur as outlined in the Schedules of Procedures in 
Section 16.1.  
Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score 
of 4, with 4 representing very severe itching. The highest score between the morning and 
evening reports will represent the daily score: a measure of the worst itching over the previous 
24-hour period. In the event that either the morning or evening reports are not completed within 
the allowed reporting window the completed report will represent the daily score. In the event 
that a subject/caregiver failed to complete both the morning and evening report, the daily score 
for that day will be treated as missing data. Missing data on the daily ItchRO score will be 
imputed using the average daily ItchRO score from that study week. When possible the caregiver 
completing the questions should be a caregiver with whom the child lives with most of the time. 
 
Clinician Scratch Scale 
A clinician’s assessment of pruritus made by the principal investigator or sub-investigator using 
the clinician scratch scale (Section 16.5) will be recorded at screening, Day 0 (baseline), Weeks 
2, 4, 8, 13, 24, 36, 48, 60, and 72.  
For subjects who enter the optional follow-up treatment period, the clinician scratch scale will 
also be administered at clinic visits as outlined in the Schedules of Procedures in Section 16.1.  
The clinician’s assessment of the subject’s pruritus is focused on scratching and visible damage 
to the skin as a result of scratching as observed by the physician.  The clinician scratch scale uses 
a 5-point scale, in which 0 designates no evidence of scratching and 4 designates cutaneous 
mutilation with bleeding, hemorrhage and scarring.  Whenever possible, the same individual 
should make the assessments for a subject visits. 
 
Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL™ is a one-page questionnaire that will be administered to subjects and or caregivers 
at the Day 0 (baseline) and Weeks 13, 24, 48 and 72 visits using the age-appropriate PedsQL 
module (Section 16.6).  
For subjects who enter the optional follow-up treatment period, the PedsQL will also be 
administered at clinic visits as outlined in the Schedules of Procedures in Section 16.1. For 
subjects with interruptions in LUM001 dosing of ≥7 days, the PedsQL will also be administered 
at DE Day 0. 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 at the Day 0 (baseline) and Weeks 13, 24, 48 and 72 visits using the 
age-appropriate module, see Section 16.6.   


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For subjects who enter the optional follow-up treatment period, the multidimensional fatigue and 
family impact questionnaires will also be administered at clinic visits as outlined in the 
Schedules of Procedures in Section 16.1. For subjects with interruptions in LUM001 dosing of 
≥7 days, the multidimensional fatigue and family impact questionnaires will also be administered 
at DE Day 0.  Age at the baseline visit will be used as the age for the determination of the 
appropriate questionnaire to be used throughout the study.  This same module will be used for 
the duration of the study regardless of subsequent birthdays during the study. 
 
Patient Impression of Change 
The Patient Impression of Change (PIC) is designed to assess the subject’s perception of his/her 
itching at the end of study drug treatment compared to his/her itching prior to the start of 
treatment with study drug.  The PIC will be completed by subjects who were 9 years of age or 
older at the Week 13, Week 48, and Week 72 visits, see Section 16.7. For subjects who enter the 
optional follow-up treatment period, the PIC will be completed by subjects who were 9 years of 
age or older at clinic visits as outlined in the Schedules of Procedures in Section 16.1.  
 
Caregiver Impression of Change 
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s perception of 
the subject’s itching at the end of study drug treatment compared to his/her itching prior to the 
start of treatment with study drug.  The CIC will be completed by all caregivers at the Weeks 13, 
48, and 72 visits, see Section 16.8.  For subjects who enter the optional follow-up treatment 
period, the CIC will also be administered at will occur at clinic visits as outlined in the Schedules 
of Procedures in Section 16.1. 
 
Caregiver Global Therapeutic Benefit 
The Caregiver Global Therapeutic Benefit (CGTB) questionnaire is designed to assess the 
caregiver’s perception of the treatment benefits on the subject’s itching compared to the side 
effects experienced with study drug.  The CGTB will be completed by all caregivers at the Week 
13, 48 and 72 visits, see Section 16.9. For subjects who enter the optional follow-up treatment 
period, the CGTB will also be administered at clinic visits as outlined in the Schedules of 
Procedures in Section 16.1. 
 
Palatability 
A palatability questionnaire (see Section 16.11) will be completed by the subject and/or 
caregiver (dependent on age) at clinic visits at time points as outlined in the Schedules of 
Procedures in Section 16.1.  
8.6 
Metabolomic and Proteomic Investigations 
As part of a comprehensive approach to identify serum markers in PFIC patients that respond 
well to treatment, previously collected serum samples will be analyzed using both metabolomic 
and proteomic biomarker discovery approaches.  Metabolomics addresses the activity of small 
molecules (<10 kDa) produced by active and living cells during their life cycle. These molecules 
are not accessible by genomic, transcriptomic or proteomic approaches. Metabolomics monitors 
the chemical transformations in metabolic cascades and can be used to identify observable 


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differences between patient populations. A targeted mass spectrometry proteomic approach will 
allow for the identification and quantitation of greater than 150 unique proteins in each serum 
sample.  
Previously collected serum samples from both responding and non-responding patients will be 
analyzed in both biomarker discovery platforms and the data will be evaluated for potential 
markers that can significantly delineate responders from non-responders.   No additional sample 
collection will be required for this exploratory analysis. 
8.7 
Restriction on the Lifestyle of Subjects 
 
Contraception Requirements 
Sexually active female subjects of childbearing potential must continue to use acceptable 
contraception with their partners, or refrain from sexual activity, from the time of screening, 
throughout the study period and for 30 days following the last dose of the IP. 
If hormonal contraceptives are used they should be administered according to the package insert. 
Females of child-bearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days following the last dose of the IP. 
Acceptable methods of contraception are: 
a. Hormonal contraceptives (e.g., oral contraceptive pill, depot, patch, intramuscular 
implant or injection, or vaginal ring), stabilized for at least 30 days if first use, plus 
condoms; and/or 
b. Barrier method, e.g., (i) condom (male or female) or (ii) diaphragm, with spermicide; 
or 
c. Intrauterine device (IUD). 
d. or a sexual partner who is surgically sterilized.  
Male Contraception: 
Contraception is required for all sexually-active male subjects and their partners. All male 
subjects agree not to donate sperm, and to use 1 of the following approved methods of 
contraception until 30 days following study discharge: 
a. Male condom with spermicide 
b. Intrauterine device with spermicide (use by female sexual partner) 
c. Female condom with spermicide (use by female sexual partner) 
d. Contraceptive sponge with spermicide (use by female sexual partner) 
e. Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with spermicide, 
or a cervical cap with spermicide) (use by female sexual partner) 
f. Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner). 


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Fasting Requirements 
On study days in which blood samples are collected for the lipid panel and/or cholestasis 
biomarkers, all subjects will be required to fast for at least 4 hours (only water is permitted) 
before blood sample collection. On these visit days study drug should be administered as usual (1 
mL or 0.5 mL qAM, ac), in the morning 30 minutes before breakfast. After breakfast only water 
should be consumed until the scheduled clinic visit.  


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9 
STUDY DRUG 
9.1 
Study Drug Description 
 
LUM001 
The composition of LUM001 study drug 1.0 mL oral solution is described in Table 4. The 
composition of LUM001 study drug 0.5 mL oral solution is described in Table 5.  
Table 4: 
Composition of LUM001 1.0 mL Oral Solution 
Component 
Function 
Quantity per 1.0 mL 
LUM001 
Active Ingredient 
up to 50.0 mg 
Propylene Glycol 
Co-solvent 
250.0 mg 
Sucralose 
Sweetener 
7.5 mg 
Grape Flavoring Agent 
Taste Masking Agent 
5.0 mg 
Water 
Vehicle 
q.s. to 1.0 mL 
q.s = quantity sufficient 
Table 5: 
Composition of LUM001 0.5 mL Oral Solution 
Component 
Function 
Quantity per 0.5 mL 
LUM001 
Active Ingredient 
up to 25.0 mg 
Propylene Glycol 
Co-solvent 
125.0 mg 
Sucralose 
Sweetener 
3.75 mg 
Grape Flavoring Agent 
Taste Masking Agent 
2.5 mg 
Water 
Vehicle 
q.s. to 0.5 mL 
q.s = quantity sufficient 
9.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged study drug labeled in accordance with 
specific country regulatory requirements. Standard syringes will be provided for oral 
administration of study drug. 
9.3 
Drug Accountability 
Study staff are required to document the receipt, dispensing and return/destruction of study drug 
supplies provided by the Sponsor.   
At the conclusion of the study, any unused drug, as well as original containers (even if empty), 
will be returned to the Sponsor or handled according to written instructions from the Sponsor, 
following approval by the Sponsor.   


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10 
TREATMENT OF SUBJECTS 
10.1 
Study Drug Administration 
The dose of study drug (LUM001) in this study is based on weight.  All subjects will receive 
LUM001, up to 560 μg/kg/day (given as twice-daily doses of 280 μg/kg) or a maximum daily 
dose of 25 mg BID.  During the long-term exposure period (Week 14 to Week 72) of the study 
and during the optional follow-up treatment period (Week 76 to EOT), the dose may be adjusted 
if there is a change of ≥10% in weight since the screening visit (e.g. the amount of drug dosed 
may be increased to reflect the subject’s weight increase).  The dose may also be down-titrated, 
at the investigator’s discretion and in consultation with the Medical Monitor, for subjects 
experiencing intolerance (eg, gastrointestinal symptoms such as diarrhea, abdominal pain, 
cramping) to a given dose.  If the subject is on twice daily dosing regimen, dose reduction should 
first be attempted with the afternoon dose.  Subjects who were previously down-titrated may be 
re-challenged during the long-term exposure period. 
Study drug (LUM001) will be prepared by a central pharmacy based on the subject’s weight at 
screening. Diluent will be added by the central pharmacy pharmacist prior to shipping study drug 
to the site.   
Subjects will receive a grape-flavored solution containing LUM001.  Each subject dose will be 
administered orally once a day (QD) or twice a day (BID) using the syringe provided.  The first 
dose should be taken at least 30 minutes prior to the first meal of the day and the second dose, 
where applicable, should be taken at least 30 minutes prior to dinner (evening meal).  The doses 
will not be administered q12h in order to better cover the luminal bile acid release associated 
with dinner and to minimize the risk of disturbing sleep due to the potential for abdominal pain 
and diarrhea at night.  It is recommended that the dose should be taken approximately at the 
same time each day for the duration of the treatment period. 
QD Dosing Regimen 
In case of QD dosing, the required dose will be delivered in 0.5 mL volume for subjects who 
weigh less than 10 kg and in 1.0 mL for subjects who weigh 10 kg or more. 
BID Dosing Regimen 
In case of BID dosing, the required dose is delivered in half the dosing volume:  0.25 mL BID 
for subjects who weigh less than 10 kg) or 0.50 mL BID for subjects who weigh 10 kg or more. 
For subjects weighing less than 10 kg at study entry, once a weight of 10 kg is reached while in 
the study, the subject will be moved from 0.5 mL total daily dosing volume (0.25 mL BID) to 
1.0 mL total daily dosing volume (0.50 mL BID). 
See Sections 5.5.2, 5.5.2.1, and 5.5.2.2 for information regarding dosing during the dose 
escalation and stable dosing periods, respectively. 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
study drug preparation, administration and storage.   


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10.2 
Treatment Compliance 
Compliance with treatment dosing will be monitored and recorded by the study center staff.  
Subjects and/or caregivers will be asked to complete a paper diary indicating when they took 
their study medication and when they ate breakfast and, for subjects who receive a BID regimen, 
when they ate dinner (evening meal). 
10.3 
Concomitant Medications 
A concomitant medication is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered during 
participation in the study (the period from the first day of screening through the last contact).  
All subjects will have fat soluble vitamin levels monitored; blood samples for fat soluble 
vitamins should be obtained before the daily dose of vitamins is administered, and approximately 
4 hours after any food or formula. 
All medications (other than study drug) taken by subjects during the course of the study will be 
recorded and reviewed by the Principal Investigator (PI)/Investigator’s designee.  Concomitant 
medication will be coded using the World Health Organization (WHO) Drug Dictionary (release 
date 01 September 2008, or more recent version if available).  AEs related to administration of 
these medications must also be documented. 
The dosage and dosing regimen of concomitant drug therapy other than that specified by the 
protocol should not change during the course of the study, with the exception of weight-based 
dose adjustments and vitamin supplementation. All modifications to a subject’s concomitant 
drug therapy, including weight-based dose adjustments and vitamin supplementation regimen 
must be carefully documented in the relevant case report forms.  No new medications used to 
treat pruritus may be added during the period from Baseline (Day 0) until Week 13 (timepoint 
for primary analysis).  If drug therapy other than that specified by the protocol is taken, a joint 
decision will be made by the Investigator or Investigator’s designee and Sponsor to continue or 
discontinue the subject.   
10.4 
Other Protocol-required Drugs 
There are no other protocol required drugs. Subjects are expected to maintain a stable dose and 
administration schedule for all permitted concomitant medications throughout the course of the 
study. 
10.5 
Safety Monitoring Rules 
 
General Monitoring Rules 
In the evaluation of AEs and the potential relationship to study drug it is important to note that 
due to their liver disease many subjects with PFIC will have abnormal liver enzyme levels (e.g. 
AST, ALT, ALP) and bilirubin at baseline. If an individual subject exhibits a CTCAE Grade 3 
treatment emergent toxicity, with the exception of the specific rules outlined below (Section 
10.5) dosing will be suspended. Continued dosing with study drug (LUM001) may be considered 


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following discussion with the Medical Monitor.  The Investigator and Medical Monitor will 
evaluate the subject’s safety data and make a decision to either restart dosing at the same level, 
restart dosing at a lower dose level, or discontinue dosing.   
To ensure subject safety, dosing up to 140 μg/kg/day or 10 mg maximum dose, will first occur in 
one subject. If the subject is able to tolerate the 140 μg/kg/day dose, 3 additional subjects will be 
dosed. If at least 3 of the 4 subjects are able to tolerate the dose then dosing will be open to the 
rest of the subjects. The same staggered enrollment process will be followed specifically for 
subjects under 2 years of age. 
To ensure subject safety, dosing up to 280 μg/kg/day or 25 mg maximum dose, will first occur in 
one subject. If the subject is able to tolerate the 280 μg/kg/day dose, 3 additional subjects will be 
dosed. If at least 3 of the 4 subjects are able to tolerate the dose then dosing will be open to the 
rest of the subjects. The same staggered enrollment process will be followed specifically for 
subjects under 2 years of age. 
In addition, if 4 or more subjects at a dose level lower, suspend or stop study medication or 
exhibit treatment emergent toxicity of CTCAE Grade 3 or greater in the same system organ class 
(SOC), further dosing of subjects at that dose level and any higher dose levels will be halted until 
a safety assessment is completed. Study visits and completion of the ItchRO diaries, for all 
assigned subjects, will continue during the assessment period. After review a decision will be 
made whether to restart dosing at the same dose level, restart dosing at a lower dose level, or 
discontinue the subjects from the study. The Data and Safety Monitoring Board (DSMB) will be 
notified of any SAE as specified in the DSMB charter. 
 
Safety Monitoring Rules 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations.   
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 (in the central laboratory that performed the initial measurement) on new 
specimens.  Of note: the INR re-test should be conducted by the central laboratory, but may also 
be conducted at a local laboratory on an as needed basis.  All new specimen collections should 
take place within 48 to 72 hours of the availability of the initial report.  The results from the 
retest must be available prior to the next scheduled clinic visit or phone follow-up.   
 
Stopping Rule Guidance:  Subject dosing must be suspended until the retest results are available.  
If any of the stopping criteria described below (refer to Sections 10.5.2.2 and 10.5.2.5) are 
confirmed, the Investigator in consultation with the Medical Monitor or appropriately qualified 
designee, will permanently discontinue the subject from further treatment with study drug 
(LUM001). The subject will be evaluated as outlined below and will be encouraged to complete 
the early termination study procedures (Week 48 visit).  Subjects who do not meet the stopping 
rules based on retest may continue dosing and the Investigator and the Medical Monitor (or 


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appropriately qualified designee) should confer as to whether additional close monitoring of the 
subject is appropriate. 
10.5.2.1 
Safety Monitoring for Liver Chemistry Tests 
Safety monitoring criteria take into consideration the subject’s baseline ALT and total bilirubin 
levels.  The baseline will be defined as the last evaluation before dosing with study drug (Day 0).   
If at any time in the study an ALT or total bilirubin result meets the criteria shown in the table 
below, in relation to the subject’s baseline level, the initial measurement(s) should be confirmed 
within 48 to 72 hours of the availability of the initial report.   
Baseline ALT 
ALT 
< ULN 
> 5 x ULN 
> ULN 
> 3 x baseline and > 5 x ULN 
 
Baseline Total Bilirubin 
Total Bilirubin 
Total Bilirubin ≤10 mg/dL (or ≤171.04 μmol/L) 
3 mg/dl (or 51 μmol/L) increase 
Total Bilirubin >10 mg/dL  (or >171.04 μmol/L) 
5 mg/dl (or 85 μmol/L)  increase  
 
Frequency of Repeat Measurements: Subjects with a confirmed ALT or total bilirubin level that 
is continuing to rise should have their liver chemistry tests (ALT, ALP, INR and total bilirubin) 
retested as clinically indicated, until levels stabilize or begin to recover. 
Further Investigation into Liver Chemistry Elevations: Based on the inclusion criteria for this 
study the population to be enrolled will have pre-existing baseline liver disease and will be 
closely monitored by the investigators with experience in the management of pediatric hepatic 
diseases. For subjects with a confirmed elevation in ALT or total bilirubin level, as described 
above, the following evaluations should be performed as clinically indicated: 
• Close and frequent monitoring of liver enzyme and serum bilirubin tests as clinically 
indicated.  Frequency of retesting can decrease if abnormalities stabilize or the trial drug 
has been discontinued and the subject is asymptomatic. If the appropriate frequency of 
monitoring is not feasible study drug administration will be suspended. 
• Obtain a detailed history of symptoms and prior and concurrent diseases. 
• Obtain comprehensive history for concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational drug 
use, and special diets. 
• Obtain a history for exposure to environmental chemical agents and travel. 
• Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel). 
• Serology for autoimmune hepatitis [e.g., antinuclear antibody (ANA)]. 


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Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Medical Monitor.  
10.5.2.2 
Stopping Rules for Liver Chemistry Elevations 
In the event of confirmed laboratory results exceeding the following criteria and the event is 
without an alternative explanation as discussed with the Medical Monitor, discontinuation 
of dosing of a subject with study drug (LUM001) will be considered if: 
  
Baseline Tests 
Change Observed 
ALT (any level) 
ALT ≥ 20 x ULN 
Total Bilirubin ≤10 mg/dL (or  ≤171.04 μmol/L) 
5 mg/dl (or 85 μmol/L) increase and a 2 x increase 
over baseline level 
Total Bilirubin >10 mg/dL (>171.04 μmol/L) 
2 x increase over baseline level 
 
10.5.2.3 
Safety Monitoring for Triglycerides 
In the event of a confirmed laboratory result for fasting total triglyceride >500 mg/dL (>5.65 
mmol/L), the Investigator and the Medical Monitor may consider a temporary interruption of 
study drug (LUM001).  Dosing may resume when the triglyceride level returns to <300 mg/dL 
(3.39 mmol/L) or to the subject’s baseline level. 
10.5.2.4 
Safety Monitoring for Fat Soluble Vitamins 
Vitamin status will be assessed per the schedule of procedures (see Section 16.1), blood samples 
will be obtained at the study visits before the daily dose of vitamins is administered. In the event 
of a confirmed laboratory result that falls either below or above the normal range for a vitamin 
(25-hydroxy vitamin D, retinol, retinol binding protein, tocopherol (α), total lipids), or for an 
elevated INR (as a proxy for vitamin K status), the investigator should make the appropriate 
modification to the subject’s vitamin supplementation regimen.  
The response to the change in regimen will be assessed by relevant follow up blood work one 
month later.  Changes will continue to be made until the levels are in the desired range.  
Adjustments may be discontinued outside of the desired range if there is agreement between the 
Investigator and Medical Monitor that vitamin sufficiency cannot be reasonably expected. 
10.5.2.5 
Monitoring/Stopping Rules for Coagulation Panel Results 
In the event of a confirmed laboratory result for INR >1.5, the Investigator and the Medical 
Monitor may consider a temporary interruption of study drug (LUM001).  Dosing may resume 
when the INR falls below 1.5 or returns to the subject’s baseline level.  
10.6 
Adjustment of Dose 
Gastrointestinal intolerance, as evidenced by diarrhea/loose stools, abdominal pain/cramping and 
nausea, is expected to be the most frequent manifestation of a lack of tolerability to study drug.  
If an individual subject exhibits a treatment emergent CTCAE Grade 2 or greater drug-related GI 


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toxicity, study drug dose may be lowered to a previously well tolerated dose.  If the subject is on 
twice daily dosing regimen, dose lowering should first be attempted with the afternoon dose.  
This decision should be made in consultation with the Medical Monitor. A requirement for 
intravenous fluids as treatment for diarrhea will lead to discontinuation of study drug. At the 
investigator’s discretion and in consultation with the Medical Monitor, subjects who were 
previously down-titrated may be re-challenged during the long-term exposure period.  
10.7 
Withdrawal of Subjects from the Study 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution.  Any subject 
and/or legal guardian who withdraws consent to continued participation in the study will be 
removed from further treatment and/or study observation immediately upon the date of the 
request.   
Any investigator decision to withdraw a subject from the study must first be discussed with the 
Medical Monitor prior to withdrawal. The Investigator will provide the reason for withdrawal on 
the appropriate eCRF.  
For any subject who requests to stop study treatment or has withdrawn from study treatment at 
the request of the legal caregiver, Investigator or Sponsor before completion of the protocol-
specified treatment period, and has received >1 dose of study drug (LUM001), every effort 
should be made to complete the assessments scheduled for the Early Termination visit (see 
Schedule of Procedures, Section 16.1), provided the subject has not withdrawn full consent.  The 
Early Termination visit should be scheduled within 7 days of the last study drug dose.  The 
eDiary, unused study drug, and all other study supplies must also be retrieved. 
For safety reasons, efforts must be made to follow subjects for at least 30 days following their 
last dose of study drug.  If a subject withdraws due to an AE, the Investigator should arrange for 
the subject to have follow-up visit(s) until the AE has resolved or stabilized.   
Subjects must be withdrawn from the study for any of the following reasons: 
• Withdrawal of consent/assent by the subject or legal caregiver. 
• Pregnancy. 
• An AE (including disease progression) that leads the Investigator to decide that the 
subject should be withdrawn.  If a subject suffers an AE that, in the judgment of the 
Investigator or the Sponsor, presents an unacceptable consequence or risk to the subject, 
the subject must be discontinued from the study. 
• Significant protocol deviation (e.g., medication or treatment that is prohibited by the 
protocol). 
• At the discretion of the Investigator if deemed not medically acceptable to continue study 
treatment. 


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• Noncompliance, including failure to adhere to the study requirements as stated in the 
study protocol. 
• Administrative decision by the Investigator or Sponsor. 


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11 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
All AEs, whether observed by the Investigator, reported by the subject, the subject’s caregiver, 
from laboratory findings, or other means, will be recorded on the AE eCRF and medical record. 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee 
throughout the conduct of the study. 
11.1 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of SAEs including suspected unexpected serious adverse reactions (SUSARs) per 
the International Conference on Harmonisation (ICH) guidelines E2A and ICH E6.  Country-
specific regulatory requirements will be followed in accordance with local country regulations 
and guidelines. 
The Investigator should immediately report all SAEs to the Sponsor or designee.  It is essential 
to report SAEs in a timely manner to the Sponsor, or designee, along with completed 
documentation of AEs to allow the Sponsor, or designee, to identify potential study-related, 
study drug- or dose-related AEs.   
The Sponsor is responsible for reporting any suspected adverse reaction that is both serious and 
unexpected to the applicable regulatory authorities.  The Sponsor or designee will evaluate the 
available information and decide if there is a reasonable possibility that the study drug caused the 
AE and, therefore, meets the definition of a SUSAR.   
Additionally, Independent Ethics Committees (IEC)/Institutional Review Boards (IRB) will be 
notified of any SAE according to applicable regulations.  The Data and Safety Monitoring Board 
(DSMB) will be notified of any SAE as specified in the DSMB charter.  
The Sponsor or designee will submit SUSARs to regulatory agencies in according to local law.  
The Sponsor or designee will submit SUSARs to Investigators. 
11.2 
Definitions 
 
Adverse Event 
An AE is any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the study or 
use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
An AE does not include the following: 
• Continuous persistent disease/symptom present before the start of study drug, which does 
not unexpectedly progress, or change in severity following drug administration. 


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• Disease being studied and/or signs and symptoms associated with the disease, such as 
jaundice or itching, or abnormalities in liver enzymes already present during the 
screening period or at the baseline visit. 
• Treatment failure or lack of efficacy. 
 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any AE caused by the study drug. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the adverse event.  A suspected adverse reaction implies a lesser degree of certainty about 
causality than an adverse reaction. 
 
Serious Adverse Event (SAE) 
An SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death. 
• Is life threatening: that is, poses an immediate risk of death at the time of the event. 
• An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death.  It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE.  Hospitalization for elective treatment or a pre-
existing condition that did not worsen during the clinical investigation is not considered 
an AE.  Hospitalization or nursing home admission for the purpose of caregiver respite is 
not considered an AE.   
• Complications that occur during hospitalization are AEs, and if a complication prolongs 
hospitalization, the event is considered serious.  Treatment in a hospital emergency room 
is not a hospitalization.  Admission to the hospital is the criterion that defines “serious”, 
not the duration of hospital stay. 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Results in congenital anomaly or birth defect in the offspring of the subject (whether the 
subject is male or female).   


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• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one 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. 
11.3 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  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, 
significant worsening of the symptoms should be recorded as an AE. The Investigator should 
always group signs and symptoms into a single term that constitutes a single unifying diagnosis 
if possible.  
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom.  Following questioning and evaluation, all AEs, whether believed by the 
Investigator to be related or unrelated to the study drug, must be documented in the subject’s 
medical records, in accordance with the Investigator’s normal clinical practice, and on the AE 
eCRF.  Each AE is to be evaluated for seriousness, causal relationship to the study drug, 
intensity, action taken, any treatment given, outcome, and duration.  It should be noted that the 
term “severe” used to grade intensity is not synonymous with the term “serious.” 
 
Serious Adverse Events 
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to study drug) should be reported to the Sponsor or designee 
within 24 hours of the study center’s first knowledge of the event.  The collection of SAEs will 
begin after the subject signs the informed consent/assent form and stop 30 days after the last dose 
of study drug.    
When the Investigator is reporting by telephone, it is important to speak to someone in person 
versus leaving a message.  An initial report of the SAE should be completed and a copy should 
be transmitted to the Sponsor or designee.   
Detailed information should be actively sought and provided to the Sponsor or designee as soon 
as additional information becomes available.  All SAEs will be followed until resolution.  SAEs 
that remain ongoing past the subject’s last protocol-specified follow-up visit will be evaluated by 
the Investigator and Sponsor.  If the Investigator and Sponsor agree the subject’s condition is 
unlikely to resolve, the Investigator and Sponsor will determine the follow-up requirement.  


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Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed consent/assent 
form and will stop 30 days after the last dose of study drug.  The Investigator will monitor each 
subject closely and record all observed or volunteered AEs on the Adverse Event Case Report 
Form.  
 
Evaluation of Adverse Events (Serious and Non-Serious) 
The following should be documented on the Adverse Event Case Report Form: 
11.3.3.1 
Relationship to the Study Drug 
The Investigator will document his/her opinion of the relationship of the AE to treatment with 
study drug using the following criteria:  
• Related:  There is clear evidence that the event is related to the use of study drug (e.g., 
confirmation by positive re-challenge test). 
• Possible:  The event cannot be explained by the subject’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and study drug administration. 
• Unlikely/Remote:  An event for which an alternative explanation is more likely 
(e.g., concomitant medications or ongoing medical conditions) or the temporal 
relationship to study drug administration and/or exposure suggests that a causal 
relationship is unlikely (For reporting purposes, Unlikely/Remote will be grouped 
together with Not Related). 
• Not Related:  The event can be readily explained by the subject’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and study drug. 
11.3.3.2 
Severity 
The Common Terminology Criteria for Adverse Events (CTCAE) grade of the event should be 
reported according to CTCAE Version 4.0 (Section 16.10).  If the CTCAE does not have a 
grading for a particular AE, the severity of the event should be reported based on the following: 
• Mild (Grade 1):  The event is easily tolerated by the subject and does not affect the 
subject’s usual daily activities. 
• Moderate (Grade 2):  The event causes the subject more discomfort and interrupts the 
subject’s usual daily activities. 
• Severe (Grade 3):  The event is incapacitating and causes considerable interference with 
the subject’s usual daily activities. 


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Specific definitions will be provided for designated GI events expected to occur in this study, in 
order to aid Investigators with determination of event severity. 
Please also refer to Section 10.5.2 regarding specific safety monitoring for liver chemistry tests 
given that subjects with PFIC may have abnormal liver enzyme levels at baseline. 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 11.2.3).  
11.3.3.3 
Action Taken with Study Drug 
Action taken with study drug due to the event is characterized by one of the following; 
• None:  No changes were made to study drug administration and dose. 
• Permanently Discontinued:  Study drug was discontinued and not restarted. 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted or 
delayed due to the AE and restarted at the same dose. 
• Reduced dose:  Dosing was reduced, temporarily interrupted or delayed due to the AE 
and restarted at the next lower dose. 
11.3.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g. medications or procedures) given for the AE should be recorded on the AE 
eCRF (treatment should also be recorded on the concomitant treatment or ancillary procedures 
CRF as appropriate). 
11.3.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by one of the 
following: 
• AE Persists:  Subject terminates from the trial and the AE continues. 
• Recovered:  Subject recovered completely from the AE. 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE). 
• Change in Severity (if applicable):  AE severity changed. 
If the event is a SAE then the event’s outcome is characterized by one of the following: 
• Ongoing:  SAE continuing. 


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• Persists (as non-serious AE):  Subject has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE). 
• Recovered:  Subject recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date). 
• Fatal:  Subject died (the date of death should be entered as the SAE resolution date). 
11.4 
Procedures for Handling Special Situations 
The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours. 
• Serious adverse event (SAE, see Section 11.3.1). 
• Pregnancy. 
• Dosing errors. 
 
Pregnancy Reporting 
If a subject becomes pregnant or a pregnancy is suspected during the study, the study center staff 
must be informed immediately.  The Sponsor or designee should be notified within 24 hours of 
first learning of the occurrence of pregnancy.  Follow-up information including delivery or 
termination should be reported within 24 hours. 
If pregnancy is suspected during the study (including follow-up), a pregnancy test will be 
performed.  The subject with a confirmed pregnancy will be immediately withdrawn from 
treatment with study drug.  However, the subject will be encouraged to complete the 
Early Termination procedures to the extent that study procedures do not interfere with the 
pregnancy.  Regardless of continued study participation, the study physician will assist the 
subject in getting obstetrical care and the progress of the pregnancy will be followed until the 
outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the study center and Sponsor may 
require access to the mother and infant’s medical records for an additional follow-up after birth. 
Payment for all aspects of obstetrical care, child or related care will be the subject’s 
responsibility.   
 
Dosing Errors 
Study drug dosing errors should be documented as protocol deviations.  A brief description 
should be provided in the deviation, including whether the subject was symptomatic 
(list symptoms) or asymptomatic, and if the event was accidental or intentional.   


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Dosing details should be captured on the appropriate eCRF.  If the subject takes a dose of study 
drug that exceeds protocol specifications and the subject is symptomatic, then the symptom(s) 
should be documented as an AE and be reported per Section 11.3. 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours.    
 
Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment (e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia).  Whenever possible, 
the underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Medical 
Monitor.  Laboratory abnormalities deemed not clinically significant (NCS) by the Investigator 
should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs by the 
Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents. 


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12 
STATISTICAL CONSIDERATIONS 
This section presents a summary of the planned statistical analyses.  A Statistical Analysis Plan 
(SAP) will be written for the study that contains detailed descriptions of the analyses to be 
performed.   
The main focus for the analyses of efficacy is the period from Baseline (Day 0) to Week 13. The 
period from Baseline (Day 0) to EOT will be analyzed and the period from Weeks 48-72 and 73-
EOT have been added to obtain additional safety data and to monitor biochemical markers of 
cholestasis. 
Continuous variables will be summarized using descriptive statistics including n, mean, median, 
standard deviation, and range (i.e., minimum and maximum).  Qualitative variables will be 
summarized using counts and percentages.  Summaries will be provided by study phase (Weeks 
0-13, 14-48, 49-72, 73-124) and over the entire study duration (Weeks 0-72 and 0-EOT Visit), 
by visit and by stable dosing dose group (if appropriate). Unless otherwise specified, statistical 
analyses will be performed using SAS Version 9 or higher.   All statistical tests will be 
conducted at the 0.05 significance level using two-tailed tests and p-values will be reported, if 
applicable. Given the rare nature of PFIC, the statistical power of any comparison is limited. As 
such the analysis will be largely descriptive in nature.  
12.1 
Sample Size Considerations 
PFIC is a rare disease.  The planned sample size of approximately 24 evaluable PFIC subjects is 
based on practical considerations, rather than determined by statistical considerations and desired 
power for a pre-specified difference.  As such, this study is designed to provide important 
information for this patient population that is needed for planning future studies.   
12.2 
Populations 
 
Safety Population 
The Safety Population is defined as all subjects who were assigned and received at least one dose 
of the study drug.  The Safety Population will be used for all safety analyses.  Subjects will be 
analyzed by the treatment received.   
 
Efficacy Populations 
There will be two analysis populations for efficacy.  
The main population for efficacy analysis will use a modified intention-to-treat population 
(MITT), which will include all subjects who were assigned, received at least one dose of 
treatment, and have at least one post-baseline efficacy assessment.  Subjects will be analyzed by 
assigned treatment.    
The Per Protocol population (PP) will consist of all subjects in the MITT population who did not 
have a major protocol violation, inclusive of violation of entry the criteria. Subjects in this 
population will be referenced as evaluable. 


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Demographic and Baseline Characteristics 
12.2.3.1 
Subject Disposition 
Subject disposition will be summarized descriptively.  The number and percentage of subjects 
assigned, completed, and withdrawing, along with reasons for withdrawal, will be tabulated.   
The number and percentage of subjects receiving each study drug dose following the protocol 
specified dose escalation procedure and stable dosing regimen will be tabulated.   
Line listings will be prepared for all subjects not following the planned dosing schedule, showing 
all doses and dose changes occurring.  
Other disposition and study conduct information, including major protocol violations will be 
listed.  Duration of the follow-up period will be tabulated. 
12.2.3.2 
Baseline Data 
The following baseline data will be used to describe the study population: 
• Demographic variables, including age, gender and race/ethnicity. 
• Medical history. 
• Baseline disease characteristics (e.g., genotyping results, pruritus scores, liver 
biochemistries). 
• Prior medications of interest [e.g., ursodiol (UDCA), rifampicin] and concomitant 
medications. 
• Growth parameters including height and weight at baseline. 
Demographic and baseline characteristics will be summarized.  
Medical history information will be presented in listings. 
 
Safety Analyses 
Safety analyses will be performed on the Safety Population.   
12.2.4.1 
Safety Assessments 
The following assessments will be used to monitor safety: 
• Adverse events (AEs) and serious adverse events (SAEs). 
• Clinical laboratory results. 
• Vital signs. 


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• Physical exam findings, including body weight and height. 
• Concomitant medication usage. 
• Serum alpha-fetoprotein (AFP). 
 
Planned Method of Analysis 
 
Safety Analysis 
Safety analyses will be performed on the Safety Population.  Safety data, including AEs, clinical 
laboratory tests, vital signs, physical examinations, and concomitant medication usage will be 
summarized descriptively by study phase (Weeks 0-13, 14-48, 49-72, and 73-120) and over the 
entire study duration (Weeks 0-EOT Visit).  Individual subject listings will be prepared for all 
safety data. 
12.2.6.1 
Adverse Events 
Frequencies (number and percentage) of subjects with one or more treatment emergent AEs will 
be summarized, by system organ class and preferred term according to the Medical Dictionary 
for Regulatory Activities (MedDRA™) terminology.  All treatment emergent AEs, all treatment 
emergent AEs potentially related to study drug, all treatment emergent SAEs and all treatment 
emergent SAEs potentially related to study drug will be summarized.  Specific AEs of special 
interest, particularly GI related AEs, will be outlined in the SAP and summarized.  AEs will be 
summarized overall and then separately for each of the study phases.  
The incidence of AEs, and their severity, as well as the incidence of subjects who withdraw due 
to an AE will be tabulated.  A subject listing of all treatment emergent AEs, and AEs causing 
study discontinuation will be presented.  
12.2.6.2 
Laboratory Tests 
Clinical laboratory (chemistry panel, complete blood count (CBC) with differential, coagulation, 
lipid panel, cholestasis biomarkers, fat soluble vitamins, and urinalysis parameters) test 
parameters will be listed for individual subjects and summarized using descriptive statistics by 
study visit.  Change and percent change from baseline for the safety variables will also be 
presented over time after study drug administration, as appropriate.  Percent change from 
baseline will be added for laboratory values as outlined in the SAP.  Baseline for clinical 
laboratory parameters will be defined as the last evaluation before dosing with study drug (Day 
0).   
A separate listing will present laboratory values of all subjects who change from normal to 
abnormal or from abnormal to normal during the course of the study using methods to be 
specified in the SAP. 
The effect of LUM001 on fat soluble vitamin levels will be assessed.  These laboratory values 
will be listed for individual subjects.  A separate subject listing presenting shifts in levels of fat 
soluble vitamins will also be prepared.   


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12.2.6.3 
Physical Exams, Vital Signs and Weight/Height Measurements 
Changes in physical exam findings after baseline will be listed for individual subjects. 
Vital signs, weight and height (both weight and height are to be measured as an absolute number 
and as a z-score for age and gender) will be listed for individual subjects and summarized using 
descriptive statistics by clinical visit.  Changes from baseline for all visits after the baseline visit 
will be included in the summary table.  Baseline for vital signs will be defined as the last 
evaluation before dosing with study drug.  In general this will be the Day 0 visit.   
12.2.6.4 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary and summarized descriptively by Anatomic Therapeutic Chemical (ATC) class, using 
counts and percentages.  Medications started prior to the first dose of study medication will be 
indicated in the data listing. 
12.2.6.5 
Study Drug Exposure 
Due to poor absorption of LUM001 very low systemic exposure and plasma drug levels are 
expected.  The key measurement will be the pharmacodynamic effect on fasting serum bile acid 
levels. However, exposure to study drug will be measured approximately 2-4 hours post dose and 
data will be summarized and listed across the treatment period by treatment group.  Average 
daily dose, total drug exposure, and total subject days of exposure to study medication will be 
summarized descriptively. 
12.2.6.6 
Serum Alpha-fetoprotein 
Assessments of serum alpha-fetoprotein (AFP) will be listed for individual subjects and 
summarized using descriptive statistics by study visit.  
 
Interim Analyses 
The following interim analyses are planned. The first interim analysis of key safety and efficacy 
parameters will be performed after the first 12 subjects who meet the Per Protocol population 
definition have completed the Week 13 study visit.  This analysis will provide initial information 
about the activity of LUM001 in the study population. A second interim analysis will be 
performed after all enrolled subjects have completed the Week 48  
(or Early Termination) study visit. This analysis will provide an assessment of the long-term 
safety and efficacy of LUM001.  A third interim analysis will be performed after all enrolled 
subjects have completed at least 6 months of treatment under Protocol Amendment 4 (or the 
Early Termination visit).  This analysis will provide an assessment of the long-term safety and 
efficacy of LUM001.  Subsequent interim analyses will be performed in yearly intervals. 
The statistical analysis plan will specify the safety and efficacy parameters to be included in 
these analyses and describe the procedures for executing the interim analyses. 
The results of the interim analyses may lead to changes in the study design.  Staff directly 
involved in the conduct of the trial, including the DSMB, will review the results of the interim 


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analyses.  Interim study information may be shared with trial investigators, investigator staff, 
study monitors, or sponsor employees or other personnel. 
 
Additional Analyses 
Additional analyses may be performed to explore both safety and efficacy measures collected in 
this study.  The precise methods and analyses will be determined after the database is locked.  
Thus, all such analyses will be interpreted cautiously and not used for formal inference. 
 
Efficacy Analyses 
The primary analysis population for the efficacy analysis will be the MITT population defined in 
Section 12.2.2.   
12.2.9.1 
Efficacy Variables 
Primary efficacy endpoint:  
• Fasting serum bile acid level change from Baseline (Day 0) to Week 13. 
Secondary efficacy endpoints: 
• Alanine aminotransferase (ALT) and bilirubin (total and direct) change from Baseline 
(Day 0) to Week 13. 
• Pruritus as measured by ItchRO (Observer ItchRO/patient ItchRO) change from Baseline 
(Day 0) to Week 13.  (For each subject, the average daily score will be calculated using 
the 7 days pre-treatment for Baseline (Day 0), and the last 7 days of treatment for Week 
13.) 
Exploratory efficacy endpoints: 
• Change from Baseline (Day 0) in fasting serum bile acid level at Weeks 4, 8, 24, 36, 48 
60, 72, 84, 96, 108, 120, every three months thereafter, and at the End of Treatment 
(EOT) visit. 
• Change from Baseline (Day 0) in pruritus as measured by the average daily ItchRO 
(Observer ItchRO/patient ItchRO) at Weeks 4, 8, 28, 48, 86, 98, 110, 122, and every 
three months thereafter.  
• Change from Baseline (Day 0) for ALT, and bilirubin (total and direct) at Weeks 4, 8, 24, 
36, 48, 60, 72, 84, 96, 108, 120, every three months thereafter, and at the EOT visit. 
• Change from Baseline (Day 0) for other biochemical markers of cholestasis [total 
cholesterol, low-density lipoprotein cholesterol (LDL-C)] at Weeks 4, 8, 13, 24, 36, 48, 
60, 72, 84, 96, 108, 120, every three months thereafter, and at the EOT visit. 


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• Responder analysis: pruritus response rates as measured by ItchRO (Observer 
ItchRO/patient ItchRO) at Weeks 4, 8, 13, 28, 48, 86, 98, 110, 122, and every three 
months thereafter, up to but not including the EOT visit. 
• Change from Baseline (Day 0) in the Clinician Scratch Scale, at Weeks 2, 4, 8, 13, 24, 
36, 48, 60, 72, 84, 96, 108, 120, every three months thereafter, and at the EOT visit. 
• Change from Baseline (Day 0) in bile acid synthesis [serum 7α-hydroxy-4-cholesten-3-
one (7αC4)] at Weeks 4, 8, 13, 24, 36, 48, 60, 72, 84, 96, 108, 120, every three months 
thereafter, and at the EOT visit. 
• Change from Baseline (Day 0) for PedsQL at Weeks 13, 24, 48, 72, 84, 96, 108, 120, 
every three months thereafter, and at the EOT visit. 
• Patient Impression of Change (PIC) at Weeks 13, 48, 72, 108, 120, and the EOT visit. 
• Caregiver Impression of Change (CIC) at Weeks 13, 48, 72, 108, 120, and the EOT visit. 
• Caregiver Global Therapeutic Benefit (CGTB) assessment at Weeks 13, 48, 72, 108, 120, 
and at the EOT visit. 
• Change from Baseline (Day 0) for other biochemical markers [autotaxin and 
lysophosphatidic acid (LPA)] at Weeks 4, 8, 13, 36, 48, 60, 72, 84, 96, 108, 120, every 
three months thereafter, and at the EOT visit. 
• Change from Baseline (Day 0) for measures of bile acid synthesis (FGF-19 and FGF-21) 
at Weeks 4, 8, 13, 36, 48, 60, 72, 84, 96, 108, 120, every three months thereafter, and at 
the EOT visit. 
Pattern of change in serum bile acids from Baseline (Day 0) to EOT will be evaluated and its 
appropriate analysis methodology will be outlined in the Statistical Analysis Plan (SAP) for the 
study. 
Secondary evaluations will be the mean change from Baseline (Day 0) compared to Week 48 in: 
• Biochemical markers of cholestasis and liver disease including alanine aminotransferase 
(ALT), and bilirubin (total and direct). 
• Pruritus as measured by the ItchRO instruments (ItchRO(Obs)TM, caregiver 
instrument/ItchRO(Pt) TM patient instrument). 
Additional evaluations of safety and efficacy surrogates will be specified in the Statistical 
Analysis Plan. 
For subjects entering the optional treatment period with ≥7 continuous days since last dose of 
LUM001, any of the above evaluations may also occur at clinic visits during the DE and 


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Protocol Amendment 4 DE periods.  Additionally, these evaluations may also occur during the 
ADE period 
The primary assessment of pruritus in this study will be composed of the ItchRO assessment 
from the diary. Given the age range of this population and the small sample size, the primary 
ItchRO score will be derived from the ItchRO(Obs) instrument.  The itch score from the 
ItchRO(Pt) will be analyzed separately. Subjects 9 years of age or older will complete the 
ItchRO(Pt) independently. Subjects between the ages of 5 and 8 years of age or where the 
investigator has expressed concern about the subjects ability to reliably complete the data (e.g. 
due to developmental delay) will complete the ItchRO(Pt) with the help of the caregiver. There 
will be no ItchRO(Pt) report for subjects under the age of 5.   
For this instrument the caregiver and/or subject indicate the itch severity in the morning and in 
the evening each day during screening and during the designated study periods [Day 0 – 13, 
Week 24-28, Week 44-48, Week 84-86, Week 96-98, Week 108-110, Week 120-122, and Week 
0-2 of each recurring 12-week period]. The daily score will be assessed as outlined in Section 
16.4 and will have a range from 0-4, with the higher score indicating increasing itch severity.  
The daily score will be taken as the highest score of the morning and evening scores, 
representing the most severe itch over the 24 hour period. The average daily score will be the 
average of the daily scores over a defined study week consisting of the 7 days prior to the visit. 
For the change from baseline calculation in average daily ItchRO score, baseline is defined as the 
average daily ItchRO score in the week consisting of the 7 days immediately prior to Day 0. The 
average daily ItchRO score for each post-baseline study visit (e.g., Weeks 4, 8, 13, 28, 48, 86, 
98, 110, and 122) is defined as the average daily ItchRO score in the week consisting of the 
7 days immediately prior to the scheduled visit. In addition to change from baseline, a responder 
analysis will be considered.  The response definition and its appropriate analysis methodology 
will be outlined in the SAP for the study.  
The additional questions included in the ItchRO that are not scored, will be tabulated. 
If a caregiver is not compliant with the ItchRO (Obs) at Weeks 13, 28, 48, 86, 98, 110, and 122, 
the average daily score from the most recent, previous compliant week will be used in an LOCF 
format.  On study compliance for the ItchRO will be defined as having at least 4 of the 7 daily 
ItchRO scores for a 7-day period. Similar methods will be used for the ItchRO (Pt). Missing data 
imputation will not be done for other efficacy endpoints. 
A number of sensitivity analyses will be performed to assess the robustness of the results. Details 
of these analyses will be outlined in the SAP for the study. 
12.2.9.2 
Primary Efficacy Analysis 
The change from baseline in the serum bile acid levels will be displayed by study visit, using 
summary statistics including the number of observations, mean, median, standard deviation, 
minimum and maximum.  Differences from baseline will be calculated and summarized as 
above, with a 95% confidence interval for the mean.  The change from baseline will be tested 
using the paired t-test, or comparable nonparametric measures as appropriate.  


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Where sample size allows, treatment effects over time will be examined using methods 
appropriate for repeated observations. Examination of potential dose effects will be done if the 
sample sizes in the dose groups during the stable dosing phase of the study permit. 
12.2.9.3 
Secondary, Exploratory and Other Efficacy Analyses 
Secondary and exploratory efficacy variables that are continuous measures will be analyzed 
similarly to the primary efficacy analyses.  
Exploratory efficacy measures that are categorical will be summarized by frequencies and 
percents. P-values from the secondary and exploratory efficacy analyses will be considered 
nominal. 
The sensitivity of the results for pruritus to missing data assumptions will be explored as outlined 
in the SAP for the study. The sensitivity analyses may include analyses using observed cases as 
well as various assumptions for missing data from subjects who terminate from the study early. 
Additional exploratory analyses may be performed and will be defined and outlined in the SAP 
for the study. Inferential statistics may be used as part of the data summary.   
 Exploratory Genetic Analyses 
To identify genetic indicators of treatment response using exome sequencing, an additional blood 
sample will be taken.  The data analysis will focus initially on genetic variation in candidate 
genes that may have a role in treatment response, such as ASBT/SLC10A2 and genes in its 
pathway (ie upstream or downstream of ASBT/SLC10A2) and genes implicated in PFIC 
(ATP8B1, ABCB11 and ABCB4) with the goal of identifying genetic variation that may 
discriminate treatment responders from non-responders.  Following examination of candidate 
genes, the data analysis may be expanded to evaluate genetic variation in additional regions of 
the exome.  This genetic analysis is more comprehensive and may provide valuable information 
beyond the ATP8B1 and ABCB11 genes.  The submission of this blood sample is voluntary.  
The results of this analysis may identify relevant genetic variants, only some of which will be of 
known clinical benefit. 
 Exploratory Responder Analyses (Metabolomic and Proteomic 
Investigations) 
As part of a comprehensive approach to identify serum markers in PFIC patients that respond 
well to treatment, previously collected serum samples will be analyzed using both metabolomic 
and proteomic analysis.  Metabolomics addresses the activity of small molecules (<10 kDa) 
produced by active and living cells during their life cycle. These molecules are not accessible by 
genomic, transcriptomic or proteomic approaches. Metabolomics monitors the chemical 
transformations in metabolic cascades and can be used to identify observable differences 
between patient populations. A targeted mass spectrometry proteomic approach will allow for 
the identification and quantitation of greater than 150 unique proteins in each serum sample. 
Serum samples from both responding and non-responding patients will be analyzed in both 
biomarker discovery platforms and the data will be evaluated for potential markers that can 
significantly delineate responders from non-responders. 


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 Palatability Analyses 
Palatability data will be collected at each clinic visit in the follow-up treatment period, with the 
exception of the DE and ADE visits.  A palatability questionnaire will be completed by the 
subject and/or caregiver, dependent on age (see Section 16.11).  Data will be listed for individual 
subjects and summarized using descriptive statistics by study visit. Change over time will also be 
presented over time, as appropriate. Baseline will be defined as the first recorded evaluation. 
 


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13 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
13.1 
Informed Consent 
The written informed consent/assent document(s) should be prepared in the language(s) of the 
potential patient population, based on an English version provided by the Sponsor or designee. 
The Investigator is responsible for obtaining written informed consent/assent from the subject 
and/or their legally acceptable representative(s).  Before any screening tests or assessments are 
performed, an adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study will be provided to the subject and/or legally acceptable representative.  The 
subject and/or legally acceptable representative must be given sufficient time to consider whether 
to participate in the study and be assured that withdrawal from the study may be requested at any 
time without jeopardizing medical care related to or required as a result of study participation.   
Subjects and/or their legally acceptable representative(s) will be required to read, sign, and date 
an IEC approved informed consent/assent form (ICF/IAF) summarizing the discussion at 
screening.  Since this is a pediatric study, in addition to the written informed consent, the assent 
of the child must also be obtained.  The person who conducted the informed consent discussion 
(not necessarily an Investigator) should also sign and date the ICF/IAF.  The original signed 
ICF/IAF should be retained in accordance with institutional policy.  Subjects and/or their legally 
acceptable representative(s) will be given a copy of their ICF, and IAF.   
The subject’s and/or legal representative’s agreement and the acquisition of informed consent 
should be documented in the subject’s medical record.  When the study is completed and the 
CRF has been monitored, the ICF will be kept in the Investigator’s central study file.  Regulatory 
authorities may check the existence of the signed ICF in this central study folder if not having 
done so during the performance of the study. 
Over the course of the study, the ICF/IAF may be modified, as appropriate (e.g., due to protocol 
amendment or significant new safety information).  The resulting IEC-approved ICF/IAF will be 
used for all subjects subsequently entering the study or those already enrolled and still actively 
participating in the trial.  
13.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated October 
2008, the applicable regulations and guidelines of current Good Clinical Practice (GCP) as well 
as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed.  
13.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent/assent forms, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB for written 
approval.  A copy of the written approval of the protocol and informed consent form must be 
received by the Sponsor or designee before recruitment of subjects into the study and shipment 


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of study drug.  A copy of the written approval of any other items/materials that must be approved 
by the study center or IEC/IRB must also be received by the Sponsor or designee before 
recruitment of subjects into the study and shipment of study drug.  The Investigator’s Brochure 
must be submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit and, where necessary, obtain approval from the IEC/IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH 
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of SAEs occurring at the 
study center and other AE reports received from the Sponsor or designee, in accordance with 
local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor or designee. 
13.4 
Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor or designee, subjects should be identified by 
unique initials and a subject study number only.  Documents that are not for submission to the 
Sponsor or designee (e.g., signed informed consent/assent forms) should be kept in strict 
confidence by the Investigator. 
In compliance with federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, regulatory 
agency(ies), and the IEC/IRB direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the subject to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the subject. 
All information concerning this study and which was not previously published is considered 
confidential information.  This confidential information shall remain the sole property of Mirum 
Pharmaceuticals, Inc.; it shall not be disclosed to others without written consent of Mirum 
Pharmaceuticals, Inc. and shall not be used except in the performance of this study. 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by Mirum Pharmaceuticals, Inc., as they 
deem necessary.  To allow the use of the information derived from this clinical study and to 
ensure compliance to current federal regulations, the Investigator is obliged to furnish Mirum 
Pharmaceuticals, Inc., with the complete test results and all data compiled in this study. 


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14 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
14.1 
Study Personnel 
Prior to the start of this study, the Investigator must supply the Sponsor or designee with a list of 
the names of the Investigator(s) for the study and other possible participants, their professional 
background (e.g., Investigator, coordinator, technician) and their role in the study.  The 
Investigator should ensure that all appropriately qualified persons to whom he/she has delegated 
trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities Form. 
14.2 
Pre-study Documentation Required 
The Investigator must provide the Sponsor or designee with the following documents (copies 
should be kept by the Investigator in the clinical site’s regulatory document binder): 
• Signed and dated Protocol Signature Page.   
• Completed and signed statement of Investigator (Form FDA 1572/financial disclosure 
form) (where applicable).   
• Curriculum vitae (CV) of the Investigator and sub-investigators (where applicable, all 
persons listed on Form FDA 1572). 
• Letter of approval from the IEC/IRB for both protocol and consent/assent forms. 
• Copy of the IEC/IRB-approved written informed consent/assent forms, and any other 
written information and/or advertisement to be used. 
• IEC/IRB membership list or compliance certification letter. 
• Name and location of the laboratory utilized for laboratory assays, and other facilities 
conducting tests, including a copy of the laboratory certificate (where applicable).   
• In case a laboratory certification is not available, a written statement as to how the 
laboratory complies with quality assurance should be provided.  The Sponsor's monitor 
must be notified if the laboratory is changed. 
• List of normal laboratory values (where applicable).   
In addition, in advance of enrollment of subjects, study staff are required to complete all required 
training. 
14.3 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
Agreement from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent document.  The regulatory authority and IEC/IRB must be informed of 


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all amendments and give approval for any amendments likely to affect the safety of the subjects 
or the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor or designee.  Amendments to the protocol will not be implemented until 
written IEC/IRB approval has been received. 
14.4 
Study Termination 
Both the Sponsor or designee and the Investigator reserve the right to terminate the study the 
Investigator’s site, according to the terms of the study contract.  The Investigator/ Sponsor or 
designee should notify the IEC/IRB in writing of the trial’s completion or early termination and 
send a copy of the notification to the Sponsor or designee. 
The Sponsor or designee reserves the right to terminate the study overall. 
14.5 
Study Documentation and Storage 
Source documents are original documents, data, and records from which the subject’s case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, imaging, and correspondence.  All original 
source documents supporting entries in the case report forms must be maintained and be readily 
available. 
The Investigator and the study center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor or designee and/or applicable regulatory authorities.  The clinical site’s regulatory 
document binder essential elements should include: 
• Subject files containing completed case report forms (eCRFs), informed consents/assents, 
and supporting copies of source documentation. 
• Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor or designee. 
• If drug supplies are maintained at the study center, documentation for proof of receipt, 
study drug accountability records, return of study drug for destruction, final study drug 
product reconciliation statement, and all drug-related correspondence. 
No study document should be destroyed without prior written agreement between the Sponsor or 
designee and the Investigator.  Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify the Sponsor or designee. 
14.6 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 


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the various records of the trial (e.g., case report forms and other pertinent data) provided that 
subject confidentiality is respected.  Quality control audits may be performed at the Sponsor’s 
discretion. 
Throughout the course of the study, a study monitor will make frequent contacts with the 
Investigator and/or study staff.  This will include telephone calls and on-site visits.  During the 
on-site visits, the CRFs will be reviewed for completeness and adherence to the protocol, 
accuracy, consistency of the data, and adherence to local regulations on the conduct of clinical 
research.  The monitor will need access to subject medical records and other study-related 
records needed to verify the entries on the case report forms.  The study monitor will also 
perform drug accountability checks and review the clinical site’s regulatory document binder to 
assure completeness of documentation in all respects of clinical study conduct.  On completion 
of the study, the study monitor will arrange for a final review of the study files after which the 
files should be secured for the appropriate time period. 
The Investigator or appointed delegate will receive the study monitor during these on-site visits 
and will cooperate in providing the documents for inspection and respond to inquiries.  In 
addition, the Investigator will permit inspection of the study files by authorized representatives 
of the regulatory agencies. 
14.7 
Language 
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
14.8 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Subjects will be treated and/or compensated for any study-
related illness/injury in accordance with the information provided in the Informed Consent 
document. 
 


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15 
REFERENCES 
Alissa, F. T., Jaffe, R. & Shneider, B. L. 2008. Update on progressive familial intrahepatic 
cholestasis. J Pediatr Gastroenterol Nutr, 46, 241-52. 
Chen, F., Ananthanarayanan, M., Emre, S., Neimark, E., Bull, L. N., Knisely, A. S., Strautnieks, 
S. S., Thompson, R. J., Magid, M. S., Gordon, R., Balasubramanian, N., Suchy, F. J. & Shneider, 
B. L. 2004. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased 
farnesoid X receptor activity. Gastroenterology, 126, 756-64. 
Chen, F., Ellis, E., Strom, S. C. & Shneider, B. L. 2010. ATPase Class I Type 8B Member 1 and 
protein kinase C zeta induce the expression of the canalicular bile salt export pump in human 
hepatocytes. Pediatr Res, 67, 183-7. 
Chen, F., Ghosh, A. & Shneider, B. L. 2013. Phospholipase D2 mediates signaling by ATPase 
class I type 8B membrane 1. J Lipid Res, 54, 379-85. 
Davit-Spraul, A., Gonzales, E., Baussan, C. & Jacquemin, E. 2009. Progressive familial 
intrahepatic cholestasis. Orphanet J Rare Dis, 4, 1. 
Emerick, K. M. & Whitington, P. F. 2002. Partial external biliary diversion for intractable 
pruritus and xanthomas in Alagille syndrome. Hepatology, 35, 1501-6. 
Emond, J. C. & Whitington, P. F. 1995. Selective surgical management of progressive familial 
intrahepatic cholestasis (Byler's disease). J Pediatr Surg, 30, 1635-41. 
Frankenberg, T., Miloh, T., Chen, F. Y., Ananthanarayanan, M., Sun, A. Q., Balasubramaniyan, 
N., Arias, I., Setchell, K. D., Suchy, F. J. & Shneider, B. L. 2008. The membrane protein ATPase 
class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X 
receptor. Hepatology, 48, 1896-905. 
Hofmann, A. F. 2003. Inappropriate ileal conservation of bile acids in cholestatic liver disease: 
homeostasis gone awry. Gut, 52, 1239-41. 
Hollands, C. M., Rivera-Pedrogo, F. J., Gonzalez-Vallina, R., Loret-de-Mola, O., Nahmad, M. & 
Burnweit, C. A. 1998. Ileal exclusion for Byler's disease: an alternative surgical approach with 
promising early results for pruritus. J Pediatr Surg, 33, 220-4. 
Hounnou, G., Destrieux, C., Desme, J., Bertrand, P. & Velut, S. 2002. Anatomical study of the 
length of the human intestine. Surg Radiol Anat, 24, 290-4. 
Lykavieris, P., van Mil, S., Cresteil, D., Fabre, M., Hadchouel, M., Klomp, L., Bernard, O. & 
Jacquemin, E. 2003. Progressive familial intrahepatic cholestasis type 1 and extrahepatic 
features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver 
steatosis after liver transplantation. J Hepatol, 39, 447-52. 


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Miyagawa-Hayashino, A., Egawa, H., Yorifuji, T., Hasegawa, M., Haga, H., Tsuruyama, T., 
Wen, M. C., Sumazaki, R., Manabe, T. & Uemoto, S. 2009. Allograft steatohepatitis in 
progressive familial intrahepatic cholestasis type 1 after living donor liver transplantation. Liver 
Transpl, 15, 610-8. 
Neimark, E., Chen, F., Li, X. & Shneider, B. L. 2004. Bile acid-induced negative feedback 
regulation of the human ileal bile acid transporter. Hepatology, 40, 149-56. 
Ng, V. L., Ryckman, F. C., Porta, G., Miura, I. K., de Carvalho, E., Servidoni, M. F., Bezerra, J. 
A. & Balistreri, W. F. 2000. Long-term outcome after partial external biliary diversion for 
intractable pruritus in patients with intrahepatic cholestasis. J Pediatr Gastroenterol Nutr, 30, 
152-6. 
Schukfeh, N., Metzelder, M. L., Petersen, C., Reismann, M., Pfister, E. D., Ure, B. M. & 
Kuebler, J. F. 2012. 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, 47, 501-5. 
van den Anker, J., Schwab, M. & Kearns, G. 2011. Developmental Pharmacokinetics. In: 
Seyberth, H., Rane, A. & Schwab, M. (eds.) Pediatric Clinical Pharmacology  
Varni, J. W., Seid, M. & Kurtin, P. S. 2001. 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, 39, 800-12. 
Walthall, K., Cappon, G. D., Hurtt, M. E. & Zoetis, T. 2005. Postnatal development of the 
gastrointestinal system: a species comparison. Birth Defects Res B Dev Reprod Toxicol, 74, 132-
56. 
Weaver, L. T., Austin, S. & Cole, T. J. 1991. Small intestinal length: a factor essential for gut 
adaptation. Gut, 32, 1321-3. 
Whitington, P. F. & Whitington, G. L. 1988. Partial external diversion of bile for the treatment of 
intractable pruritus associated with intrahepatic cholestasis. Gastroenterology, 95, 130-6. 
 


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16 
APPENDICES 
 


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16.1 
Schedule of Procedures 
Overall Scheme and Corresponding Schedule of Procedures 
 
The following schematic shows the study flow and corresponding Schedule of Procedures (A – I).   
Study Termination and End of Treatment Procedures are outlined in Schedule J. 
 
 
 
A
BL - W13
Dose escalation
Stable dosing
W14 – W72
Stable dosing
<7 days
interruption
≥7 days
interruption
Optional
follow-up 
W72 – W120
q12W
No gap or <7 
days
interruption
≥7 days
interruption
ADE 0 - q12W
B
C
D
Core Study & Optional Follow-Up (PA3)
ADE ineligible
ADE eligible
E
F
H
I
Extension & Afternoon
Dose Escalation (PA4)
W72 – W120
Treatment
gap 
before
PA4 
consent?
G
ADE ineligible
ADE eligible
PA4 DE-2 –
PA4 DE W8
q12W
ADE 0 - q12W


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Schedule of Procedures A-D: Study Entry – Week 120 
Schedule of Procedures A (Baseline – Week 13) 
Study Period 
Screening 
Treatment Period 
Dose Escalation 
Stable Dosing Period 
Study Week 
 
 
1 
2 
3 
4 
5 
8 
9 
13 
Study Day 
Day -42 
 
Day 0 
7 
14 
21 
28 
35 
56 
63 
91 
Window (in days) 
 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
Eligibility Assessment (Inclusion/Exclusion) 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Body Weight & Height 
X 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signs 1 
X 
X 
 
X 
 
X 
 
X 
 
X 
Liver imaging (ultrasound) 2 
X 
 
 
 
 
 
 
 
 
 
Serum or Urine Pregnancy Test (if indicated)3 
X 
X 
 
X 
 
X 
 
X 
 
X 
CBC with Differential 4 
X 
X 
 
X 
 
X 
 
X 
 
X 
Coagulation4 
X 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry Panel 4 
X 
X 
 
X 
 
X 
 
X 
 
X 
Lipid Panel 4,5, 
 
X 
 
X 
 
X 
 
X 
 
X 
Cholestasis Biomarkers 4,5 
X 
X 
 
X 
 
X 
 
X 
 
X 
Fat Soluble Vitamins 4,5,6 
 
X 
 
 
 
 
 
X 
 
X 
Plasma Sample for LUM001: US 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
Plasma Sample for LUM001: UK, EU, Australia 
 
Xb 
 
 
 
Xb 
 
 
 
Xb 
PFIC Genotyping7 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 4 
X 
Xc 
 
Xc 
 
X 
 
X 
 
X 
Caregiver ItchRO/Patient ItchRO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinician Scratch Scale 
X 
X 
 
X 
 
X 
 
X 
 
X 
PedsQL 
 
X 
 
 
 
 
 
 
 
X 
Patient/ Caregiver Impression of Change 
 
 
 
 
 
 
 
 
 
X 
Caregiver Global Therapeutic Benefit 
 
 
 
 
 
 
 
 
 
X 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
Study Drug Supplied 
 
X 
 
X 
 
X 
 
X 
 
X 
Review Study Diaries & Assess Compliance 
 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contact 
 
 
X 
 
X 
 
X 
 
X 
 


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Schedule of Procedures A (Baseline – Week 13) 
Study Period 
Screening 
Treatment Period 
Dose Escalation 
Stable Dosing Period 
Study Week 
 
 
1 
2 
3 
4 
5 
8 
9 
13 
Study Day 
Day -42 
 
Day 0 
7 
14 
21 
28 
35 
56 
63 
91 
Window (in days) 
 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
2 
Screening ultrasound not required if an ultrasound completed < 6 months is available. 
3 
Females of childbearing potential, result must be reviewed prior to dispensing study drug.
 
 
4 
See Section 16.2 for detailed list of laboratory analytes. 
5 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
6 
Blood samples must be drawn before administration of vitamin supplementation. 
7 
Genotyping will be performed to provide a full characterization and documentation of the mutation type in 
support of the diagnosis of PFIC. 
a In the US, , blood will be drawn ~4 hours post dosing for drug level analysis 
at Weeks 2, 8, and 13,. At Week 4, blood will be drawn ~2 hours post-
dosing (fasting <4 hrs will be allowed to accommodate 2-hr post dose draw). 
b In the UK, EU and AUS, , blood will be drawn ~4 hours post dosing for 
drug level analysis at Weeks 4 and 13. 
c At indicated visits during the treatment period, oxalate will be part of UA. 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 


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Schedule of Procedures B - Stable Dosing Treatment Period: Week 14 – Week 72 
Study Period 
Treatment Period (continued) 
Study 
Termination 
Safety 
Follow 
Up 
59 Week Long-term exposure 
Study Week 
16 
20 
24 
28 
32 
36 
40 
44 
48 
60 
Week 72 
(or Early 
Term7) 
30 days 
after 
final 
dose 
Study Day 
112 
140 
168 
196 
224 
252 
280 
308 
336 
420 
504 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
Physical Exam 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Body Weight & Height 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Vital Signs1 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
CBC with Differential2 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Coagulation2 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Chemistry Panel2 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Lipid Panel2,3 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Cholestasis Biomarkers2,3 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Fat Soluble Vitamins2,3,4 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Plasma Sample for LUM001: All 
 
 
Xa 
 
 
Xa 
 
 
Xa 
Xa 
Xa 
 
Urinalysis2 
 
 
X 
 
 
X 
 
 
Xb 
X 
Xb 
 
Urine Pregnancy Test 5 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Clinician Scratch Scale 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Caregiver ItchRO/Patient ItchRO 
 
 
Xc 
Xc 
to Week 
28 
 
 
 
Xc 
X to 
Week 48 
 
 
 
PedsQL 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Patient/Caregiver Impression of 
Change  
 
 
 
 
 
 
 
 
X 
 
X 
 
Caregiver Global Therapeutic 
Benefit 
 
 
 
 
 
 
 
 
X 
 
X 
 
Study Drug Supplied 
 
 
X 
 
 
X 
 
 
X 
X 
Xd 
 
Assess Compliance 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone Contact6 
X 
X 
 
X 
X 
 
X 
 
 
 
 
X 


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Schedule of Procedures B - Stable Dosing Treatment Period: Week 14 – Week 72 
Study Period 
Treatment Period (continued) 
Study 
Termination 
Safety 
Follow 
Up 
59 Week Long-term exposure 
Study Week 
16 
20 
24 
28 
32 
36 
40 
44 
48 
60 
Week 72 
(or Early 
Term7) 
30 days 
after 
final 
dose 
Study Day 
112 
140 
168 
196 
224 
252 
280 
308 
336 
420 
504 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.
 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7   
Subjects who withdraw early should complete all evaluations at this visit. 
a 
At Weeks 24, 36, 48, 60 and 72 blood will be drawn approximately 4 hours post 
dosing for drug level analysis. 
b 
At indicated visits during treatment period, oxalate will be part of the UA. 
c  
During the long-term exposure period, daily completion of the study diary for 4 
consecutive weeks will be required following the Week 24 & Week 44 clinic 
visits. 
d       For subjects entering optional Follow-up Treatment Period, once   
         corresponding consent is signed. 
 
 
Clinic Visit 
 
Phone Contact 


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Schedule of Procedures C – Optional Follow-Up Treatment Period: Week 72- Week 120 For Subjects 
With No Interruption in LUM001 Dosing or Interruption <7 Days.  Includes Evaluation of Eligibility 
for BID Dosing Regimen.   
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
FTP Study Week 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Study Day 
532 
560 
588 
616 
644 
672 
700 
728 
756 
784 
812 
840 
Window (in days) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Informed Consent/Assent 
for PA48 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Afternoon dose escalation 
(ADE) eligibility 
assessment followed by 
shift in visit schedule9  
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
Physical Exam 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & Height 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signs1 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC with Differential2 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Coagulation2 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Chemistry Panel2 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Lipid Panel2,3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Cholestasis Biomarkers2,3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Fat Soluble Vitamins2,3,4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Optional Genotyping5 
 
 
X 
 
 
 
 
 
 
 
 
 
Exome Sequencing 
Sample10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
Urinalysis2 
 
 
X 
 
 
X 
 
 
Xa 
 
 
Xa 
Serum or Urine Pregnancy 
Test (if indicated)6 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician Scratch Scale 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
Xb 
Xb 
to Week 
86 
 
Xb 
Xb 
to Week 
98 
 
Xb 
Xb 
to Week 
110 
 
Xb 
PedsQL 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Patient/Caregiver 
Impression of Change  
 
 
 
 
 
 
 
 
X 
 
 
X 
Caregiver Global 
Therapeutic Benefit 
 
 
 
 
 
 
 
 
X 
 
 
X 
Study Drug Supplied 
 
 
X 
 
 
X 
 
 
X 
 
 
 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 160 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
 
Schedule of Procedures C – Optional Follow-Up Treatment Period: Week 72- Week 120 For Subjects 
With No Interruption in LUM001 Dosing or Interruption <7 Days.  Includes Evaluation of Eligibility 
for BID Dosing Regimen.   
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
FTP Study Week 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Study Day 
532 
560 
588 
616 
644 
672 
700 
728 
756 
784 
812 
840 
Window (in days) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Assess Study Drug 
Compliance 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone Contact7 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.
 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Genotyping sample will be drawn at Week 84 or at the time of re-consent for the optional follow-up 
treatment period; sample will be used to provide a full characterization and documentation of the 
mutation type in support of the diagnosis of PFIC. 
6 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
7 
Subjects must be available to receive a phone call from study staff. 
8   
Once necessary approvals are received for Protocol Amendment 4 and associated  
          consent/assent documents are available, site will consent/assent patient for Protocol  
          Amendment 4 at next clinic visit. 
9        Once necessary approvals are received for Protocol Amendment 4 and associated  
          consent/assent has been signed, site will assess patient eligibility for Protocol Amendment 4.   
          Depending on outcome of ADE eligibility assessment, patient will move into either Schedule of  
          Procedures E or F.  Of note: It is possible that subject will not necessarily complete up     
          through Week 120 before they move to Schedule of Procedures E or F.   
10     Sample will require consenting under PA4 and will be drawn once, at the time of such re- 
           consent. 
  
 
a 
At indicated visits during treatment period, oxalate will be part of the UA. 
b  
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 84, Week 96, Week 108,  and Week 120 visits. 
 
 
Clinic Visit 
 
Phone Contact 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 161 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Schedule of Procedures D – Optional Follow-Up Treatment Period: Week 72-Week 120 for Subjects 
With Interruption in LUM001 Dosing ≥7days.  Includes Evaluation of Eligibility for BID Dosing 
Regimen. 
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
Dose Escalation (DE) 
Continuation of Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 DE 
73 
DE 
74 
DE 
75 
DE 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Study Day 
-14 
0 
511* 518* 525* 532* 560* 
588* 
616* 
644* 
672* 
700* 
728* 
756* 
784* 
812* 
840* 
Window (in days) 
(±14) 
(±2) 
(±2) (±2) 
(±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Informed 
Consent/Assent for 
study re-entry under 
PA311 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess Eligibility 
for study re-entry 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent/Assent for 
PA4 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Afternoon dose 
escalation (ADE) 
eligibility 
assessment followed 
by shift in visit 
schedule9 
 
 
 
 
 
 
 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
Physical Exam 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & 
Height 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signs1 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC with 
Differential2 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Coagulation2 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Chemistry Panel2 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Lipid Panel2,3 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Cholestasis 
Biomarkers2,3 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Fat Soluble 
Vitamins2,3,4 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Optional 
Genotyping5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis2 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Xa 
 
 
Xa 
Exome Sequencing 
Sample10 
 
 
 
 
 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 162 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Schedule of Procedures D – Optional Follow-Up Treatment Period: Week 72-Week 120 for Subjects 
With Interruption in LUM001 Dosing ≥7days.  Includes Evaluation of Eligibility for BID Dosing 
Regimen. 
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
Dose Escalation (DE) 
Continuation of Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 DE 
73 
DE 
74 
DE 
75 
DE 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Study Day 
-14 
0 
511* 518* 525* 532* 560* 
588* 
616* 
644* 
672* 
700* 
728* 
756* 
784* 
812* 
840* 
Window (in days) 
(±14) 
(±2) 
(±2) (±2) 
(±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Serum or Urine 
Pregnancy Test (if 
indicated)6 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician Scratch 
Scale 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
 
 
 
 
 
Xb 
Xb 
to 
Week 
86 
 
Xb 
Xb 
to 
Week 
98 
 
Xb 
Xb 
to 
Week 
110 
 
Xb 
PedsQL 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Patient/Caregiver 
Impression of 
Change  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Caregiver Global 
Therapeutic Benefit 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Study Drug 
Supplied 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Assess Compliance 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone 
Contact7 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.
 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Optional genotype sample will be performed to provide a full characterization and the associated 
documentation of the mutation type in support of the diagnosis of PFIC. 
6 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
7 
Subjects must be available to receive a phone call from study staff. 
8   
Once necessary approvals are received for Protocol Amendment 4 and associated  
          consent/assent documents are available, site will consent/assent patient for Protocol  
          Amendment 4 at next clinic visit. 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 163 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Schedule of Procedures D – Optional Follow-Up Treatment Period: Week 72-Week 120 for Subjects 
With Interruption in LUM001 Dosing ≥7days.  Includes Evaluation of Eligibility for BID Dosing 
Regimen. 
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
Dose Escalation (DE) 
Continuation of Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 DE 
73 
DE 
74 
DE 
75 
DE 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Study Day 
-14 
0 
511* 518* 525* 532* 560* 
588* 
616* 
644* 
672* 
700* 
728* 
756* 
784* 
812* 
840* 
Window (in days) 
(±14) 
(±2) 
(±2) (±2) 
(±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
9        Once necessary approvals are received for Protocol Amendment 4 and associated  
          consent/assent has been signed, site will assess patient eligibility for Protocol Amendment 4.   
          Depending on outcome of ADE eligibility assessment, patient will move into either Schedule of  
          Procedures E or F.  Of note: It is possible that subject will not necessarily complete up     
          through Week 120 before they move to Schedule of Procedures E or F.   
10     Sample will require re-consenting under PA4 and will be drawn once, at the time of such re- 
          consent. 
11     For participants re-entering under Protocol Amendment 3, Baseline laboratory values are  
considered those collected at re-entry visit DE-2 weeksCalculation of Study Day includes subject’s 
participation through the first 72 weeks. 
 
a 
At indicated visits during treatment period, oxalate will be part of the UA. 
b  
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 84, Week 96, Week 108,  and Week 120 visits. 
 
 
 
 
Clinic Visit 
 
Phone Contact 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 164 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
 
Schedule of Procedures E-F: Rollover under Protocol Amendment 4 
Schedule of Procedures E – Extension of Optional Follow-Up Treatment Period, for subjects ineligible for ADE, applicable as 
follows:  
• Subject did not yet complete the optional follow up treatment period as outlined under Protocol Amendment 3 and is 
able to consent to Protocol Amendment 4 activities without an interruption in  LUM001 dosing, OR 
• Subject completed optional follow up treatment period as outlined under PA3 and dosing interruption was <7 days. 
• Subject deemed ineligible for ADE.   
 
 
Below study activities repeat in recurring 12 week periods7 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
4 weeks after consent 
under PA4 
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Physical Exam 
 
 
X 
Body Weight & Height 
 
 
X 
Vital Signs1 
 
 
X 
CBC with Differential2 
 
 
X 
Coagulation2 
 
 
X 
Chemistry Panel2 
 
 
X 
Lipid Panel2,3 
 
 
X 
Cholestasis Biomarkers2,3 
 
 
X 
Fat Soluble Vitamins2,3,4 
 
 
X 
Urinalysis2 
 
 
Xa 
AFP Sample 
 
 
X8 
Serum or Urine Pregnancy Test 
(if indicated)5 
 
 
X 
Clinician Scratch Scale 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
X  
(collected for 2 
week period 
following this 
visit) 
PedsQL 
 
 
X 
Palatability Questionnaire 
 
 
X 
Study Drug Supplied 
 
 
X 
Assess Compliance 
 
 
X 
Concomitant Medications  
X 
X 
X 
Adverse Events 
X 
X 
X 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 165 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
 
Below study activities repeat in recurring 12 week periods7 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
4 weeks after consent 
under PA4 
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Follow-up Phone Contact6 
X 
X 
 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.
 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7        Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible 
to enter another LUM001 study or (ii) LUM001 is available commercially.  
8        Sample will be drawn at every other clinic visit.   
 
a 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 166 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Schedule of Procedures F – Extension of Optional Follow-Up Treatment Period, for subjects eligible for ADE, applicable as 
follows:  
• Subject did not yet complete the optional follow up treatment period as outlined under Protocol Amendment 3 (PA3) 
and is able to consent to Protocol Amendment 4 activities without an interruption in  LUM001 dosing OR 
• Subject completed the optional follow up treatment period as outlined under PA3 and dosing interruption was <7 days. 
• Subject deemed eligible for ADE. 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in recurring 12 week periods 
after completion of the ADE period7 
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Physical Exam 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & 
Height 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signs1 
X 
 
 
X 
 
 
X 
 
 
X 
CBC with 
Differential2 
X 
 
 
X 
 
 
X 
 
 
X 
Coagulation2 
X 
 
 
X 
 
 
X 
 
 
X 
Chemistry 
Panel2 
X 
 
 
X 
 
 
X 
 
 
X 
Lipid Panel2,3 
X 
 
 
X 
 
 
X 
 
 
X 
Cholestasis 
Biomarkers2,3 
X 
 
 
X 
 
 
X 
 
 
X 
Fat Soluble 
Vitamins2,3,4 
X 
 
 
X 
 
 
X 
 
 
X 
Urinalysis2 
X 
 
 
X 
 
 
X 
 
 
Xa 
AFP Sample 
 
 
 
 
 
 
 
 
 
X8 
Plasma Sample 
for LUM0019 
X 
 
 
X 
 
 
X 
 
 
X9 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 167 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in recurring 12 week periods 
after completion of the ADE period7 
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Serum or Urine 
Pregnancy Test 
(if indicated)5 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician 
Scratch Scale 
X 
 
 
X 
 
 
X 
 
 
X 
Caregiver 
ItchRO/ 
Patient ItchRO 
 
 
 
 
 
 
 
 
 
X 
(collected for 2 
week period 
following this 
visit) 
PedsQL 
X 
 
 
X 
 
 
X 
 
 
X 
Palatability 
Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Supplied 
X 
 
 
X 
 
 
X 
 
 
X 
Assess 
Compliance 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up 
Phone Contact6 
 
X 
X 
 
X 
X 
 
X 
X 
 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 168 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in recurring 12 week periods 
after completion of the ADE period7 
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7        Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another LUM001 study or (ii) LUM001 is available commercially. 
8        Sample will be drawn at every other clinic visit.   
9        PK sample will additionally be collected at the three scheduled clinic visits following  completion of the afternoon dose escalation period.   
 
a 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 
 
 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 169 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
 
Schedule of Procedures G-I: Subject Re-Entry under Protocol Amendment 4 
Schedule of Procedures G – Optional Follow-Up Treatment Period: Re-Entry Under Protocol Amendment 4 applicable as 
follows: 
• Subject previously completed (or early terminated from ) the optional follow up treatment period as defined under 
Protocol Amendment 3 and has subsequently experienced an interruption in LUM001 dosing ≥7days 
• Subject is considered eligible for study re-entry under Protocol Amendment 4 
• Subject eligibility will be assessed for afternoon dose escalation at Protocol Amendment 4 DE Week 8 shown in the 
table below.   
o If subject is found to be ineligible for ADE, subject will move from Schedule G to Schedule H. 
o If subject is found to be eligible for ADE, subject will move from Schedule G to Schedule I. 
 
 
Study Period 
Protocol Amendment 4 Follow-up Treatment Period  
Dose Escalation (DE) 
PA4 DE Study 
Week 
PA4 
DE -2 
PA4 
DE 
Day 0 
PA4 
DE  
Week 1 
PA4 
DE 
Week 2 
PA4 
DE  
Week 3 
PA4 
DE  
Week 4 
PA4  
DE  
Week 8 
Scheduling 
Considerations 
-14 
0 
 
 
 
 
 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
Assess Eligibility 
for study re-entry 
X 
X 
 
 
 
 
 
Assess Eligibility 
for ADE 
 
 
 
 
 
 
X 
Physical Exam 
X 
X 
 
X 
 
X 
 
Body Weight & 
Height 
X 
X 
 
X 
 
X 
 
Vital Signs1 
X 
X 
 
X 
 
X 
 
CBC with 
Differential2 
X 
X 
 
X 
 
X 
 
Coagulation2 
X 
X 
 
X 
 
X 
 
Chemistry Panel2 
X 
X 
 
X 
 
X 
 
Lipid Panel2,3 
X 
X 
 
X 
 
X 
 
Cholestasis 
Biomarkers2,3 
X 
X 
 
X 
 
X 
 
Fat Soluble 
Vitamins2,3,4 
X 
X 
 
X 
 
X 
 
Urinalysis2 
X 
X 
 
X 
 
X 
 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 170 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Study Period 
Protocol Amendment 4 Follow-up Treatment Period  
Dose Escalation (DE) 
PA4 DE Study 
Week 
PA4 
DE -2 
PA4 
DE 
Day 0 
PA4 
DE  
Week 1 
PA4 
DE 
Week 2 
PA4 
DE  
Week 3 
PA4 
DE  
Week 4 
PA4  
DE  
Week 8 
Scheduling 
Considerations 
-14 
0 
 
 
 
 
 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
Exome Sequencing 
Sample7 
X 
 
 
 
 
 
 
Serum or Urine 
Pregnancy Test (if 
indicated)5 
X 
X 
 
X 
 
X 
 
Clinician Scratch 
Scale 
X 
X 
 
X 
 
X 
 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
 
 
 
X  
(collected for 2 
week period 
following this visit) 
 
PedsQL 
 
X 
 
 
 
 
 
Study Drug 
Supplied 
 
X 
 
X 
 
X 
 
Assess Compliance 
 
 
 
X 
 
X 
 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone 
Contact6 
 
 
X 
 
X 
 
X 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7       Sample will be drawn once, at the time of consent under PA4. 
8     For participants re-entering under Protocol Amendment 4, Baseline laboratory values are considered those collected at re-entry visit PA4 DE-2 weeks 
 
 
 
 
Clinic Visit 
 
Phone Contact 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 171 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Schedule of Procedures H – Optional Follow-Up Treatment Period: 
Re-Entry Under Protocol Amendment 4, Subject Ineligible for ADE 
 
Below study activities repeat in recurring 12 week periods7 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
The Week 4 visit of 
the first repeating 
period will take place 
4 weeks after PA4 DE 
Week 8  
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Physical Exam 
 
 
X 
Body Weight & Height 
 
 
X 
Vital Signs1 
 
 
X 
CBC with Differential2 
 
 
X 
Coagulation2 
 
 
X 
Chemistry Panel2 
 
 
X 
Lipid Panel2,3 
 
 
X 
Cholestasis Biomarkers2,3 
 
 
X 
Fat Soluble Vitamins2,3,4 
 
 
X 
Urinalysis2 
 
 
Xa 
AFP Sample 
 
 
X8 
Serum or Urine Pregnancy Test 
(if indicated)5 
 
 
X 
Clinician Scratch Scale 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
X  
(collected for 2 
week period 
following this 
visit) 
PedsQL 
 
 
X 
Palatability Questionnaire 
 
 
X 
Study Drug Supplied 
 
 
X 
Assess Compliance 
 
 
X 
Concomitant Medications  
X 
X 
X 
Adverse Events 
X 
X 
X 
Follow-up Phone Contact6 
X 
X 
 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL 
Page 172 
LUM001-501 Protocol Amendment 4.1 
 
08 February 2019 
 
 
Schedule of Procedures H – Optional Follow-Up Treatment Period: 
Re-Entry Under Protocol Amendment 4, Subject Ineligible for ADE 
 
Below study activities repeat in recurring 12 week periods7 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
The Week 4 visit of 
the first repeating 
period will take place 
4 weeks after PA4 DE 
Week 8  
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.
 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7        Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible 
to enter another LUM001 study or (ii) LUM001 is available commercially. 
8        Sample will be drawn at every other clinic visit.   
 
a 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 
 
 
 
 


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Schedule Of Procedures I – Optional Follow-Up Treatment Period: Re-Entry Under Protocol Amendment 4, Subject 
Eligible For ADE 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeating in recurring 12 week periods 
after completion of the ADE period7 
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Physical Exam 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & 
Height 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signs1 
X 
 
 
X 
 
 
X 
 
 
X 
CBC with 
Differential2 
X 
 
 
X 
 
 
X 
 
 
X 
Coagulation2 
X 
 
 
X 
 
 
X 
 
 
X 
Chemistry 
Panel2 
X 
 
 
X 
 
 
X 
 
 
X 
Lipid Panel2,3 
X 
 
 
X 
 
 
X 
 
 
X 
Cholestasis 
Biomarkers2,3 
X 
 
 
X 
 
 
X 
 
 
X 
Fat Soluble 
Vitamins2,3,4 
X 
 
 
X 
 
 
X 
 
 
X 
Urinalysis2 
X 
 
 
X 
 
 
X 
 
 
Xa 
AFP Sample 
 
 
 
 
 
 
 
 
 
X8 
Plasma Sample 
for LUM0019 
X 
 
 
X 
 
 
X 
 
 
X9 
Serum or Urine 
Pregnancy Test 
(if indicated)5 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician 
Scratch Scale 
X 
 
 
X 
 
 
X 
 
 
X 


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Schedule Of Procedures I – Optional Follow-Up Treatment Period: Re-Entry Under Protocol Amendment 4, Subject 
Eligible For ADE 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeating in recurring 12 week periods 
after completion of the ADE period7 
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Caregiver 
ItchRO/ 
Patient ItchRO 
 
 
 
 
 
 
 
 
 
X 
(collected for 2 
week period 
following this 
visit) 
PedsQL 
X 
 
 
X 
 
 
X 
 
 
X 
Palatability 
Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Supplied 
X 
 
 
X 
 
 
X 
 
 
X 
Assess 
Compliance 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up 
Phone Contact6 
 
X 
X 
 
X 
X 
 
X 
X 
 


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Schedule Of Procedures I – Optional Follow-Up Treatment Period: Re-Entry Under Protocol Amendment 4, Subject 
Eligible For ADE 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeating in recurring 12 week periods 
after completion of the ADE period7 
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7        Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another LUM001 study or (ii) LUM001 is available commercially. 
8        Sample will be drawn at every other clinic visit.   
9        PK sample will additionally be collected at the three scheduled clinic visits following  completion of the afternoon dose escalation period.   
 
a 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 
 
 


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Schedule of Procedures J – Study Termination and End of Treatment Procedures 
Schedule of Procedures J – End of Treatment (EOT) / Early 
Termination (ET) Visit and Post-Treatment Safety Follow-Up 
 
EOT  / ET 
Safety Follow Up 
Scheduling 
Considerations 
To take place upon 
completion of study7 or at 
the time of early 
withdrawal 
Minimum of 30 days 
after final dose 
Physical Exam 
X 
 
Body Weight & Height 
X 
 
Vital Signs1 
X 
 
CBC with Differential2 
X 
 
Coagulation2 
X 
 
Chemistry Panel2 
X 
 
Lipid Panel2,3 
X 
 
Cholestasis Biomarkers2,3 
X 
 
Fat Soluble Vitamins2,3,4 
X 
 
Urinalysis2 
Xa 
 
AFP Sample 
X 
 
Serum or Urine Pregnancy 
Test (if indicated)5 
X 
 
Clinician Scratch Scale 
X 
 
PedsQL 
X 
 
Patient/Caregiver 
Impression of Change 
X 
 
Caregiver Global 
Therapeutic Benefit 
X 
 
Palatability Questionnaire 
X 
 
Assess Compliance 
X 
 
Concomitant Medications  
X 
X 
Adverse Events 
X 
X 
Follow-up Phone Contact6 
 
X 


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Schedule of Procedures J – End of Treatment (EOT) / Early 
Termination (ET) Visit and Post-Treatment Safety Follow-Up 
 
EOT  / ET 
Safety Follow Up 
Scheduling 
Considerations 
To take place upon 
completion of study7 or at 
the time of early 
withdrawal 
Minimum of 30 days 
after final dose 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.
 
 
2 
See Section 16.2 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential. 
6 
Subjects must be available to receive a phone call from study staff. 
7       Will take place when the first of the following occur: (i) subjects are eligible to enter another     
LUM001 study or (ii) LUM001 is available commercially.   
 
a 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 
 


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16.2 
List of Laboratory Analytes 
Screening Tests 
Genotyping  
(if indicated) 
ATP8B1/ 
ABCB11 
ABCB4 
Serum βhCG  
(if indicated) 
 
CBC with 
Differential 
Red blood cells 
Hemoglobin 
Hematocrit 
MCV, MCH, 
MCHC 
Platelets 
White blood cells 
WBC Differential 
(% and absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Clinical Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Phosphate 
Glucose 
Blood urea                     
nitrogen (BUN) 
Creatinine 
Uric Acid 
Total bilirubin 
Direct bilirubin  
Alkaline 
phosphatase (ALP) 
AST (SGOT) 
ALT (SGPT) 
GGTP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel1 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Triglycerides (TG) 
 
Cholestasis Biomarkers1 
Serum bile acids 
7α hydroxy-4-colesten-3-
one (C4) 
 
Fat Soluble Vitamins1 
25-hydroxy vitamin D 
Retinol 
Retinol binding protein  
Tocopherol (α) 
 
Marker of 
hepatocellular 
carcinoma 
alpha-fetoprotein (AFP) 
Urinalysis 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Occult blood and 
cells 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic 
examination2 
Oxalate3 
 
LUM001 Drug 
Levels 
LUM001 in plasma 
 
 
Coagulation 
Activated partial thromboplastin time (aPTT) (sec) 
Prothrombin time (PT) (sec) 
INR 
1 
Other biomarkers [e.g., autotaxin, lysophosphatidic acid (LPA), FGF-19, FGF-21] may be measured.   
2 
Will be performed on abnormal findings unless otherwise specified. 
3 
At the specified time points on the Schedule of Procedures (Section 16.1), oxalate will be part of the urinalysis. 
 
 


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16.3 
Liver Disease Diagnoses Excluded from PFIC Definition  
1. 
Confirmed diagnosis of other chronic cholestatic liver disease, such as biliary atresia, cystic 
fibrosis, autoimmune liver disease, extrahepatic biliary obstruction/disease, autosomal 
recessive polycystic kidney disease, hepatic venoocclusive disease, chronic allograft 
rejection, bile acid synthesis defect, alpha-1-antitrypsin deficiency, Alagille syndrome, 
mitochondrial defect, large duct primary sclerosing cholangitis (PSC), or PSC in the setting 
of inflammatory bowel disease or immunodeficiency. 
2. 
Short bowel syndrome/TPN related disease. 
3. 
Chronic known infectious hepatitis (e.g. Hepatitis C, Hepatitis B, etc.). 
4. 
Chronic known or strongly suspected drug toxicity (e.g. Augmentin related cholestasis). 
5. 
Acquired immunodeficiency syndrome. 
6. 
Acute liver failure. 
7. 
Extrahepatic portal vein obstruction, congenital hepatic fibrosis or congenital portosystemic 
shunt. 
8. 
Confirmed diagnosis of bile acid synthesis defect. 
 
 


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16.4 
Itch Reported Outcome Instrument (ItchRO™) 
Many of the PFIC subjects in this study are expected to be between 12 months and 5 years of 
age, necessitating reliance upon an observer-reported outcome instrument (ObsRO) to evaluate a 
pruritus endpoint.   
The ItchRO instrument is being developed both as a patient reported outcome measure (PRO) for 
pediatric subjects (9 years of age and older) and an ObsRO for caregivers/parents.  The ItchRO 
will be completed using an electronic diary (eDiary) twice daily (morning and evening) for both 
the PRO and ObsRO.  
 
 


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Patient Itch Reported Outcome Instrument, ItchRO(Pt)™ 
A screen shot from the ItchRO(Pt) morning report is show below. The score associated with 
each response option is indicated in red text (these will not be shown on the eDiary). The 
minimum ItchRO(Pt) morning report score is 0 and the maximum score is 4.  
 
 
 
If the patient selects “I didn’t feel  itchy at all” the diary is complete, if not the following screens 
will be shown on the eDiary: 
 
0 
1 
2 
3 
4 


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A screen shot from the ItchRO (Pt) evening report is shown below. The score associated with 
each response option is indicated in red text (these will not be shown on the eDiary). The 
minimum ItchRO(Pt) evening report score is 0 and the maximum score is 4.  
 
 
If the patient selects “I didn’t feel itchy” the diary is complete, if not the following screen will be 
shown on the eDiary: 
 
0 
1 
2 
3 
4 


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Observer Itch Reported Outcome Instrument, ItchRO(Obs)™ 
A screen shot from the ItchRO(Obs) morning report is shown below. The score associated with 
each response option is indicated in red text (these will not be shown on the eDiary). The 
minimum ItchRO(Obs) morning report score is 0 and the maximum score is 4.  
 
 
 
If the caregiver selects “None observed or reported” the diary is complete, if not the following 
screen will be shown on the eDiary: 
0 
1 
2 
3 
4 


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All caregivers will also be required to answer the following question on the ItchRO(Obs) 
morning report: 
 
 
 
The score associated with each response option is indicated in red text (these will not be shown 
on the eDiary). The minimum ItchRO(Obs) evening report score is 0 and the maximum score is 
4. A screen shot from the ItchRO(Obs) evening report is shown below: 
 


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If the caregiver selects “None observed or reported” the diary is complete, if not the following 
screen will be shown on the eDiary: 
 
 
 
All caregivers will also answer the following question on the ItchRO(Obs) evening report: 
 
0 
1 
2 
3 
4 


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16.5 
Clinician Scratch Scale  
This scoring scale was originally developed to assess pruritus before and after surgical 
intervention in children with ALGS and PFIC (Whitington and Whitington 1988).   
The clinician will rate the subject’s pruritus, as evidenced by scratching, according to the 
following scale: 
Score 
Description 
0 
None 
1 
Rubbing or mild scratching when undistracted 
2 
Active scratching without evident skin abrasions 
3 
Abrasion evident 
4 
Cutaneous mutilation, haemorrhage and scarring evident 
 
 
 


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16.6 
Pediatric Quality of Life Inventory (PedsQL™) 
The PedsQL Generic Cores Scale is composed of 23 items to assess pediatric HRQoL 
measurements across 4 domains:  Physical Functioning (8 items), Emotional Functioning 
(5 items), Social Functioning (5 items), and School Functioning (5 items).  Each item consists of 
a 5-level Likert item survey (0-4).  Each PedsQL™ age-appropriate form should take less than 
four minutes to complete.   
Pediatric HRQoL measurement instruments must be sensitive to cognitive development and must 
include both child self-report and parent proxy-report.  Accordingly, the PedsQL consists of 
developmentally appropriate forms for children ages 1-12 months and 13-24 months, 2-4, 5-7, 
8-12, and 13-18 years.  Pediatric self-report is measured in children and adolescents ages 5-18 
years, and parent proxy-report of child HRQOL is measured for children and adolescents ages 
2-18 years.   
Quality of life will be assessed using the appropriate PedsQLTM module(s) provided below. 
 
 


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Parent Report for Infants (ages 1-12 months) 
 
 
 


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Parent Report for Infants (ages 13-24 months) 
 
 
 
 


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Parent Report for Toddlers (ages 2–4 years) 
 


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Parent Report for Young Children (ages 5-7 years) 
 


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Parent Report for Children (ages 8-12 years) 
 


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Parent Report for Teenagers (ages 13-18 years) 
 
 
 


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Pediatric Quality of Life Inventory v 4.0 for Young Children (ages 5-7 years) 
 
 
 


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Pediatric Quality of Life Inventory for Children (ages 8-12 years) 
 
 
 


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Pediatric Quality of Life Inventory for Teenagers (ages 13-18 years) 
 


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 Multidimensional Fatigue Scale Parent Report for Toddlers (ages 2-4 years) 
 


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 Multidimensional Fatigue Scale Parent Report for Young Children  
(ages 5-7 years) 
 


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 Multidimensional Fatigue Scale Parent Report for Children (ages 8-12 
years) 
 


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 Multidimensional Fatigue Scale Parent Report for Teenagers  
(ages 13-18 years) 
 
 
 


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 Multidimensional Fatigue Scale Young Child Report (ages 5-7 years) 
 


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 Multidimensional Fatigue Scale Child Report (ages 8-12 years) 
 


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 Multidimensional Fatigue Scale Teen Report (ages 13-18 years) 
 


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 Family Impact Module v 2.0 
 
 
 
 


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16.7 
Patient Impression of Change (PIC) 
The Patient Impression of Change (PIC) is designed to assess the subject’s perception of his/her 
itching at the end of study drug treatment compared to his/her itching prior to the start of 
treatment with study drug.  The PIC will be completed, by subjects who were 9 years of age or 
older at the Week 13, Week 48, Week 72, Week 108, Week 120, and EOT visits. 
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.   
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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16.8 
Caregiver Impression of Change (CIC)  
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s perception of 
the subject’s itching at the end of study drug treatment compared to his/her itching prior to the 
start of treatment with study drug.  The CIC will be completed by all caregivers at the Week 13, 
Week 48, Week 72, Week 108, Week 120, and EOT visits.   
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 (rubbing, scratching, skin 
damage, sleep disturbances or irritability) 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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16.9 
Caregiver Global Therapeutic Benefit (CGTB) 
The Caregiver Global Therapeutic Benefit (CGTB) questionnaire is designed to assess the 
caregiver’s perception of the treatment benefits on the subject’s itching compared to the side 
effects experienced with study drug.  The CGTB will be completed by all caregivers at the Week 
13, Week 48, Week 72, Week 108, Week 120, and EOT visits.   
The questionnaire is designed for self-administration and uses a 5-point scale in which 
1 designates the best outcome and 5 designates the worst outcome.   
CGTB 
 
Considering all aspects of your child’s treatment, do you feel that the benefits of this treatment 
outweigh the side-effects? 
 
 
Definitely (1) 
Somewhat (2) 
About the same (3) 
Maybe not (4) 
Definitely not (5) 
 
 
 


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16.10 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Adverse events should be graded by severity based using CTCAE Version 4.0 [Published: May 
28, 2009 (v4.03: June 14, 2010)]. 
 


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16.11 Palatability Questionnaire 
 
 


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SAP_001.pdf: 
 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 1 of 108 
   Statistical Analysis Plan 
Sponsor 
Mirum Pharmaceuticals, Inc. 
Protocol Title: 
Open Label Study of the Efficacy and Long Term Safety of LUM001, 
an Apical Sodium-Dependent Bile Acid Transporter Inhibitor 
(ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric 
Patients with Progressive Familial Intrahepatic Cholestasis 
Protocol Number: 
LUM001-501 
Premier Research PCN: 
LUME2940 
Document Version: 
Amendment 3 (Final Version 1.0) 
Document Date:  
30-Jun-2020 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 2 of 108 
Approvals 
Role 
Signatures 
Date (dd-Mmm-yyyy) 
Biostatistician 
Print Name: Jana Steinmetz, MS 
 
Sign Name:
 
 
 
 
 
 
Mirum 
Pharmaceuticals, 
Inc. 
Representatives 
Print Name: Thomas Jaecklin, MD 
 
Sign Name:
 
 
 
 
 
 
Print Name: Will Garner, PhD 
 
Sign Name:  
 
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Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 3 of 108 
Document History 
Statistical Analysis Plan (SAP) Amendment 3 
Date: 30-Jun-2020 
The primary reasons for this analysis plan amendment are to make updates per changes made in 
Protocol Amendment 4.1 (dated 08-Feb-2019), and to make clarifications and changes to 
planned analyses for the addendum to the final clinical study report (CSR). The final CSR was 
produced using the 3rd planned IA focused on data through Week 72.  Analyses described in SAP 
Amendment 3 will be followed for the final analyses. 
The following changes have been made to SAP Amendment 2:   
x Reflect the change of sponsorship from Lumena Pharmaceuticals LLC (Lumena 
Pharmaceuticals LLC is an indirect wholly-owned subsidiary of Shire North American 
Group, Inc) to Mirum Pharmaceuticals, Inc. 
x Reflect re-naming of LUM001 as maralixibat chloride (MRX). 
x An intent-to-treat (ITT) analysis population has been added for the final analysis. Each 
sibling pair is included in the ITT analysis population. The ITT population will be used as 
the analysis set for all final efficacy analyses, as described in this SAP (amendment 3). 
x The per-protocol (PP) analysis population was used in the 1st interim analysis to examine 
efficacy outcomes. No summaries using the PP Population are planned for the final 
analyses. 
x Efficacy analysis performed on the modified intent-to-treat (mITT) analysis population 
for the 3rd planned IA is considered as a sibling sensitivity analysis, and will not be 
repeated for the final analysis. For the 3rd planned IA, all subjects either withdrew early 
(prior to Week 72) or completed the study through Week 72. The LUM001-501 CSR 
dated 07May2020 focused on data collected or assessed through Week 72. 
x Visit-based assessments have been mapped to analysis visits based on study day, where 
study day is relative to the date of first dose of study drug (see Section 6.1.6).   
x Visit-based analyses will be performed by analysis visit, rather than clinic visit. 
Applicable efficacy and safety endpoints have been updated to reflect this change. 
Analyses of all efficacy variables, regardless of drug interruptions, will be performed 
using the analysis visits. For subjects with an extended drug interruption, efficacy 
assessments after the interruption are essentially treated as if the subject was on study 
drug during the period of time that the subject was off study drug. The analysis visit 
windows will also be used for all visit-based safety assessments that occurred before an 
extended (>28-day) drug interruption (due to a protocol amendment), including those 
subjects without such a drug interruption. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 4 of 108 
x Visit-based safety data collected or assessed after a > 28-day drug interruption period 
(between protocol amendments) will not be included in analysis summaries, but will be 
included within listings. 
x The assumption of normality for primary and secondary efficacy variables will be tested 
using the Shapiro-Wilk test, rather than by a visual inspection of a normal Q-Q plot. 
x For each primary and secondary efficacy variable (except ItchRO (Obs) 4-week morning 
average score), and select exploratory variables (i.e., alkaline phosphatase [ALP], total 
cholesterol, ĮK\GUR[\O-4-cholesten-3-one [C4], gamma-glutamyl transferase [GGT], 
and low-density lipoprotein cholesterol [LDL-C]) an analysis by PFIC2 subtype 
(truncating PFIC2, non-truncating PFIC2) has been added. 
x A summary of ItchRO (Obs) morning scores has been added as an exploratory analysis 
WKDWSUHVHQWVWKHQXPEHUDQGSHUFHQWRIGD\VWKHGDLO\PRUQLQJVFRUHLV 1 point by time 
period and PFIC type. Time periods include Screening/Baseline, Day 1 - Week 8, Weeks 
> 8 - 13, Weeks > 13 - 24, Weeks > 24 - 36, Weeks > 36 - 48, Weeks > 48 - 72, Weeks 
> 72 – 124, Weeks > 124 – 204, and Weeks > 204. 
x Last-observation-carried-forward (LOCF) records at Week 72 and Week 124 (Week 48 
and Week 122 for ItchRO variables) have been added for visit-based assessments. 
Applicable efficacy and safety endpoints have been updated to reflect this change. 
x “Endpoint” time points (i.e., Week 13/early termination [E]T, Week 48/ET, Week 
72/LOCF, Week 122/ET, Week 124/LOCF, and end of treatment [EOT]/ET) have been 
replaced with the LOCF analysis time points.  
x ItchRO 2-week morning and evening average scores are replaced with weekly morning 
and evening average scores.  
x Secondary efficacy variables have been updated to include: ALP, aspartate 
aminotransferase [AST], bilirubin (total and direct), ItchRO (Obs) weekly average score, 
ItchRO (Obs) 4-week morning average score, and ItchRO (Obs) weekly morning average 
score. ItchRO (Pt) average scores and ALP are now considered as exploratory efficacy 
variables. 
x Exploratory efficacy variables have been updated. 
x Change from Baseline to Week 13 in ItchRO weekly morning average score and alanine 
aminotransferase (ALT) are considered as secondary efficacy endpoints. 
x ItchRO 4-week morning and evening average scores are only derived through Week 48 
(i.e., Baseline, and Weeks 4, 8, 13, 28, and 48). After Week 48 ItchRO was only 
collected in 2-week time periods. Change from Baseline in ItchRO (Obs) 4-week 
morning average score is summarized at Weeks 13, 48, and 48/LOCF. 
x ItFK52UHVSRQGHUGHILQLWLRQEDVHGRQDFKDQJHIURPEDVHOLQHRI-0.5 has been replaced 
ZLWKDFKDQJHIURPEDVHOLQHRI-1.75. Thus, ItchRO responder definitions include 
FKDQJHIURPEDVHOLQHRI---DQG-1.75. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 5 of 108 
x Pruritus response rates as measured by ItchRO (Obs) and ItchRO (Pt) weekly morning 
morning average scores have been added. Pruritus response rates as measured by these 
weekly morning average scores will be summarized at Weeks 13, 48, 48/LOCF, 98, 122, 
122/LOCF, and every 12 weeks (where applicable) through the end of treatment.  
x Serum bile acid (sBA) responder definitions have been updated to include (a) % change 
IURPEDVHOLQHRI -EV%$ 102 μmol/L, (c) FKDQJHIURPEDVHOLQHRI -75 or 
V%$ 102 μmol/L, and (dV%$5 μmol/L (normalization). sBA response rates will 
be summarized at Weeks 13, 48, 72, 72/LOCF, 96, 120, 124/LOCF, and every 12 weeks 
(where applicable) through the end of treatment. 
x Response rates for liver function lab tests (C4, AST, ALT, and total bilirubin) will be 
summarized at Weeks 13, 48, 72, 72/LOCF, 96, 120, 124/LOCF, and every 12 weeks 
(where applicable) through the end of treatment. 
x Efficacy analysis by MRX dose has been removed, as it is no longer believed to be 
relevant. 
x Efficacy analysis by PFIC2 subtypes (non-truncated and truncated) have been added for 
select efficacy variables.  
x z-scores for body mass index (BMI) have been added. 
x z-scores for body height, body weight, and BMI are considered as exploratory efficacy 
endpoints rather than safety. 
x Adverse events of special interest (AESI) groups have been changed for consistency with 
other MRX Phase 2 analysis plans (see Section 9.2.1). 
x The coding dictionary versions used to code adverse events (AEs) and medications have 
been changed to a more recent version, for consistency with other MRX Phase 2 studies. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1; previously v16.0. Concomitant medications will be coded using World 
Health Organization-Drug Dictionary (WHO-DD) (Enhanced version Sept 2019); 
previously Enhanced version March 1, 2013. 
x $(VDQGH[SRVXUHZLOOEHDQDO\]HGE\05;GRVHg/kg QD, 280 BID 
including 2-week dose-escalation dose of 280 plus 140 μg/kg). 
x For subjects with >14 days of study drug interruption/withdrawal, the definition of a 
concomitant medication has been described. 
x ItchRO reliability based on itch severity assessments by the patient and those by the 
observer/caregiver have been removed, because the ItchRO instrument has been validated 
under a separate analysis plan.  
x Schedule of Procedures D and G: clarifying footnote added to indicate that baseline 
reference laboratory value for subjects re-entering in protocol amendment 3 (PA3) and 
protocol amendment 4 (PA4), DIWHUDGRVHLQWHUUXSWLRQRIGD\VLVEDVHGRQODERUDWRU\
assessments collected at the re-entry visit Dose-escalation -2 Weeks. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 6 of 108 
x Analyses will be based on data pooled across investigative sites. Demographic and 
baseline characteristics, and disease history and baseline disease characteristics will not 
be presented descriptively by investigative site, as previously planned, for those sites that 
assigned at least 6 subjects to study drug (i.e., 25% of the total planned number of 
subjects assigned study drug).  
x Due to a misinterpretation of the automatic dose-escalation protocol by the drug supplier, 
3 of the 7 subjects enrolled and administered study drug at Site 001 were not titrated up 
to the 280 ug/kg/day dose per the protocol.  This dosing error resulted in a “Serious 
Breach of GCP or the Trial Protocol”, according to UK’s Regulations. Subjects 001-051, 
001-053, and 001-054 were dosed on 140 ug/kg/day until Week 24 at which time they 
were dose-escalated to 280 ug/kg/day.  A sensitivity analysis excluding all Site 001 
subjects was described in SAP Amendment 2. This sensitivity analysis has been removed. 
The study drug exposure listing (Listing 16.6.2) includes the dosing information for these 
subjects. 
x A mixed-effects model for repeated measures analysis on each ItchRO (Obs) efficacy 
variable was added in SAP Amendment 2 as a sensitivity analysis. This sensitivity 
analysis has been removed.  
x Treatment compliance overall and by PFIC type will be presented; a separate analysis 
presentation for treatment compliance during BID dosing has been removed. 
x Figures of mean change from baseline over time are changed to present the mean ±SE, 
instead of mean ±SD. 
x Update list of planned summary tables for 3rd planned interim analyses (see 
Section 14.1). 
x Update list of planned summary tables, figures and listings for final analyses (see 
Section 14). 
x Administrative/formatting changes. 
x Addition of Will Garner, PhD, as a signatory. 
x Format SAP according to the most recent Premier Research (Premier) SAP template. 
The amended SAP (SAP Amendment 3) will be finalized and submitted to file after database 
lock but before final analyses are produced. As LUM001-501 is an open-label study and various 
interim analyses have been completed prior to database lock, based on previous finalized SAPs, 
the integrity of the final analysis is maintained.  
 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 7 of 108 
Statistical Analysis Plan (SAP) Amendment 2 
Date: 14-May-2018 
The primary reasons for this analysis plan amendment are to make updates per changes made in 
PA3 (dated 02-Nov-2015) and PA4 (dated 20-Dec-2016) that include changes to study 
objectives, study design, inclusion/exclusion criteria, procedures/assessments, study drug 
administration (including twice daily dosing regimen), optional follow-up treatment periods, and 
subject re-entry.   
The following changes have been made to SAP Amendment 1:   
x Addition of study objectives specific to the Optional Follow-up Treatment Periods (After 
Week 72) described in Protocol Amendment 3 and Protocol Amendment 4. 
x Addition of an exploratory study objective. 
x The study design has been adapted to include an optional follow-up treatment period for 
eligible subjects who choose to stay on treatment with MRX. The optional follow-up 
treatment period occurs after the 4-week dose-escalation period, the 4-week stable dosing 
period at 140 μg/kg/day, the 5-week stable dosing period at 280 μg/kg/day, and the 59-
week long-term exposure period. During the optional follow-up treatment period, 
subjects may have their dose of MRX increased to a maximum of 560 μg/kg/day (280 
μg/kg twice-daily [BID] doses), based on ongoing efficacy as measured by sBA level and 
ItchRO score and safety assessment. 
x Updates were made that reflect the increase in the study’s duration and the addition of 
study visits, including endpoint time points Week 124/ET and EOT/ET and updating the 
Schedule of Procedures table(s). 
x Addition of a planned third interim analysis, along with subsequent periodic interim 
analyses. 
x A given subject may have been off study drug for a lengthy period of time (i.e., GD\V
during the course of their study treatment. The reasons for being off study drug include 
drug interruption (e.g., as directed by an investigator due to an AE), study drug 
compliance issues (e.g., missed consecutive doses), and dosing gaps due to being off 
study between protocol amendments 2 and 3, or 3 and 4 (e.g., a subject completing study 
drug under protocol amendment 2 (PA2), but before implementation of PA3 for which 
they subsequently provide informed consent and are reinitiated on study drug). If any 
visit occurs more than 7 days after the date of last dose on protocol amendments 2, 3, or 4 
(referred to as “last dose”), or the date of last dose before the dose interruption, the 
assessments performed during that visit will not be used in analysis summaries. In this 
case, assessments performed at the last visit that occurred before or within 7 days of the 
date of “last dose” will be assigned to the appropriate endpoint or ET analysis visit (e.g., 
Week 13/ET and Week 72/ET).  


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 8 of 108 
x Similarly, ItchRO assessments that occur during non-dosing days that are more than 7 
days after the date of the “last dose” will not be used for deriving ItchRO average scores. 
In this event, the appropriate ET average score will be based on ItchRO assessments 
made on the last 7 days (for weekly average scores), or last 14 days (for 2-week average 
scores), or last 28 days (for 4-week average scores), immediately following the date of 
the “last dose”. 
x Handling and/or derivation of analysis visits, treatment-emergent AEs (TEAEs), 
treatment compliance, and treatment exposure affected by subjects being off study drug 
during the course of their study treatment are addressed. 
x Addition of clarity to definition of Per-Protocol Population. 
x The subject disposition summary has been updated to include the number and percentage 
of subjects that consented to PA3 and completed at least 1 post-Week 72 assessment, 
consented to PA4 and completed at least 1 post-Week 124 assessment, completed study 
treatment through varying study phases (i.e., Week 72, Week 124, and EOT), and 
discontinued early from the study at each study phase (along with reasons for 
withdrawal). The number and percentage of subjects that were initiated on BID dosing 
and discontinued early during BID dosing (along with reasons for withdrawal) will also 
be summarized. The number of screen failures under the original protocol, the number of 
screen failures under a protocol amendment, the number of families with siblings 
enrolled in the study, and the total number of siblings have also been added to the subject 
disposition summary. 
x Treatment compliance during BID dosing summary statistics have been added for 
subjects that initiated afternoon dose-escalation (ADE). Treatment compliance derivation 
for this analysis summary has been added. 
x BMI has been added as a baseline characteristic to the demographics summary table, and 
is summarized by visit as a safety variable. 
x For the baseline disease characteristics summary table, ItchRO (ItchRO Observer and 
ItchRO Patient) 4-week morning average and 4-week evening average scores have been 
added. 
x All by investigative site efficacy analysis have been removed. 
x At least one of the investigative sites are located in a country that does not permit the 
reporting of complete dates of birth. These sites only report the birth year. Complete date 
of birth is required, however, to derive a subject’s weight and height z-scores and 
determine vital signs that are out-of-normal range, at each scheduled study visit. For 
partial birth dates, the convention for imputing missing dates for the purpose of statistical 
analysis has been added. 
x For the secondary efficacy variable(s), ItchRO weekly average score has been replaced 
with 3 ItchRO average scores:  weekly average score, 4-week morning average score, and 
4-week-evening average score. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 9 of 108 
x Secondary evaluations will include the mean change from Baseline to Week 48/ET for 
ItchRO endpoints and mean change from Baseline to Week 72/ET for other efficacy 
endpoints. 
x ItchRO 2-week morning average scores and 2-week evening average scores have been 
added as secondary efficacy variables for those time points during the follow-up 
treatment period for which the electronic diary (eDiary) was only to be completed by 
subjects for 2 consecutive weeks following Weeks 84, 96, 108, 120, and after each of the 
recurring 12-week period clinic visits. ItchRO 2-week average scores for these post-
Week 48 time points will be presented in all tables, figures, and listings along with 4-
week averages (rather than separately).  Footnotes will be added, as applicable, to 
distinguish the derivations/time periods.  
x For subjects enrolled in the ADE phase, analysis has been added for primary and 
secondary efficacy variables that include a paired t-test for change from baseline to 
EOT/ET (with the exception of ItchRO variables) and change from baseline by study 
visit summary statistics. Summary statistics for sBA levels by study visit and dose of 
MRX have also been added for those subjects enrolled in the ADE phase. 
x For efficacy analyses, the PP Population will only be used to examine change from 
baseline to Week 13/ET and Week 72/ET in sBA levels and change from baseline to 
Week 13/ET and Week 48/ET in each ItchRO (Obs) efficacy variable. 
x For each ItchRO (Obs) efficacy variable, a Mixed-effects Model for Repeated Measures 
(MMRM) analysis has been added as a sensitivity analysis, using the mITT Population. 
x Further information with respects to the statistical model used for the MMRM analysis 
has been added. 
x An additional ItchRO responder definition has been added using a decrease from baseline 
RISRLQW 
x 7KH,WFK52UHVSRQGHUGHILQLWLRQEDVHGRQDFKDQJHIURPEDVHOLQHRIKDVEHHQ
UHSODFHGZLWKDFKDQJHIURPEDVHOLQHRI 
x Responder definitions based on ItchRO weekly average scores have been changed to use 
4-week morning average scores. Where applicable (i.e., for post-Week 48 time points), 
2-week morning average scores will be used. 
x The Crossover Population has been removed, along with the exploratory analysis 
comparing the efficacy of 140 μg/kg/day versus 280 μg/kg/day for which this analysis 
population was used. 
x Fat-soluble vitamin tests have been excluded as exploratory efficacy variables. Fat-
soluble vitamins are presented as safety endpoints. 
x For select fat-soluble vitamins (FSVs), abnormalities and clinically-meaningful shifts 
from baseline summaries at each scheduled visit (as appropriate) have been added. For 
these select fat-soluble vitamins, categories may include normal, sufficient, insufficient, 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 10 of 108 
possibly insufficient, indeterminate, and excess (see Section 6.1.9 for specific 
definitions). 
x
For study drug exposure summaries, the units for average daily dose have been changed 
from mg/day to μg/kg/day, and the units for total drug exposure has been changed from 
mg to μg/kg. 
x The cumulative time interval categories used to summarize study drug exposure have 
been revised (see Section 9.1). 
x A new category of AESI group has been added that combines gastrointestinal (GI)-
related events and conditions associated with liver deterioration. 
x Palatability questionnaire data have been added in a listing and summary shift tables. 
x Due to a misinterpretation of the automatic dose-escalation protocol by the drug supplier, 
3 of the 7 subjects enrolled and administered study drug at Site 001 were not titrated up 
to the 280 ug/kg/day dose per the protocol.  This dosing error resulted 3 subjects on a 
dose of 140 ug/kg/day until Week 24 at which time they were dose-escalated to the 280 
ug/kg/day dose.  A sensitivity analysis, excluding all Site 001 subjects, has been added in 
the analysis of primary and secondary efficacy endpoints. Additionally, a summary of 
incidence of TEAEs by study phase with the exclusion of Site 001 subjects has been 
added, along with a listing of all AEs reported by subjects at Site 001. 
x List of abbreviations have been updated. 
x The Sponsor’s address has been changed from “12531 High Bluff Drive, Suite 110, San 
Diego, CA 92130” to “300 Shire Way, Lexington, MA 02421”. The following footnote 
has been added, “Lumena Pharmaceuticals LLC is an indirect wholly-owned subsidiary 
of Shire North American Group, Inc.”. 
x The Shire Biostatistics Team Lead has been changed from Tom Tang, Ph.D. to Yi Chen, 
M.S. 
x The Shire Medical Lead has been changed from Beatriz Caballero, MD to Thomas 
Jaecklin, MD. 
The amended SAP will be finalized and submitted to file before the final database lock 
pertaining to Lumena Pharmaceuticals LLC study protocol LUM001-501.  
 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 11 of 108 
Statistical Analysis Plan (SAP) Amendment 1 
Date: 09-Aug-2016 
The primary reasons for this amendment are to add secondary and exploratory efficacy variables 
(including new responder variables), add analyses summarizing data for Progressive Familial 
Intrahepatic Cholestasis (PFIC)1 and PFIC2 subjects, change the derivation of average daily 
ItchRO score, add 3 AE categories of special interest, redefine the timing and overall plan for the 
second planned interim analysis, change label of ItchRO average daily score, and make updates 
per changes made in Protocol Amendment 3.  
This SAP amendment will not cover those changes to Protocol Amendment 3 that were impacted 
by the addition of the optional follow-up treatment period (after Week 72). A second amendment 
to the SAP will be developed, before database lock, which will cover changes impacted by this 
optional follow-up treatment period.    
The following changes have been made to the original SAP (v1.0):   
x ALP and AST have been added as secondary efficacy variables. 
x High-density lipoprotein (HDL) cholesterol, triglycerides, GGT, activated partial 
thromboplastin time (aPTT), prothrombin time, international normalized ratio (INR), 
25-hydroxyvitamin D, vitamin A, alpha tocopherol, retinol binding protein (RBP), the 
15 sBA subspecies, and the ratio of cholic acid and chenodeoxycholic acid have been 
added as exploratory efficacy variables. 
x Responder analysis based on sBA, ItchRO (Obs) scores, and liver function lab tests 
(ĮK\GUR[\O-4-cholesten-3-one [C4], AST, ALT, and total bilirubin) have been 
defined and added as exploratory efficacy variables. 
x Autotaxin, fibroblast growth factor 19 (FGF-19), and fibroblast growth factor 21 
(FGF-21) have been added as exploratory efficacy variables. The clinical protocol and 
original SAP (v1.0) specified these tests as exploratory evaluations that may be 
conducted as a post hoc analysis. 
x Data summaries will be presented for PFIC1 and PFIC2 subjects independently and 
for all subjectss combined. 
x The derivation of ItchRO daily score has been changed to the average of morning and 
evening scores. The clinical protocol and original SAP (v1.0) define ItchRO daily 
score as the maximum of the morning and evening scores. 
x If a Week 72/ET visit occurs more than 7 days after the date of last dose, assessments 
performed at the last visit that occurs before or within 7 days of the date of last dose 
will be assigned to the Week 72/ET analysis visit. The original SAP specified that, in 
this case, assessments performed at the last visit that occurs on or before the day of the 
date of last dose would be assigned to the Week 72/ET analysis visit.  


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 12 of 108 
x For early discontinued subjects whose Week 72/ET visit occurs before or within 7 
days of the date of last dose, the post-baseline analysis visit windowing conventions 
for the ET visit will be used (see Section 6.1.6). The original SAP specified that these 
analysis visit windowing conventions would apply if the Week 72/ET visit occurs on 
or before the day of the date of last dose. 
x If ItchRO assessments occur more than 7 days after the date of the Week 48 visit or 
last dose (if discontinuation is beforeWeek 48), the Endpoint (Week 48/ET) weekly 
average score will be based on assessments made on the last 7 days immediately 
following the date of the Week 48 visit or last dose (if discontinuation is before Week 
48). The original SAP specified that, in this case, assessments made on the last 7 days 
immediately preceding (but not including) the Week 48 visit date or last dose (if 
discontinuation is before Week 48) would be the basis for the Endpoint (Week 48/ET) 
weekly average score. 
x An algorithm for determining each scheduled visit date used in deriving weekly 
average ItchRO scores has been added. 
x For subjects with >14 days of study drug interruption/withdrawal, the definition of a 
TEAE has been described. 
x For demographics summaries, a subject’s age at baseline will be presented. The 
original SAP specified age at enrollment.
x Secondary efficacy evaluations will include mean change from baseline to Week 48. 
The original SAP included this Week 48 analysis as a durability of effect analysis. 
x TEAE presentations by study phase (i.e., Weeks 0-13, Weeks 14-48, > Week 48, and 
Overall) have been clarified, including the use of study day to determine each study 
phase (e.g., Week 0-13 represents study days 0-91). 
x 3 additional AESIs (thyroid function abnormality, fat-soluble vitamin deficiency 
events, and growth retardation events) have been defined and added to the safety 
analysis. 
x The second planned interim analysis has been changed to include subject activity up 
through Week 72 that has occurred on or before 14Jun2016. Over 90% of the enrolled 
subjects are expected to have completed the Week 48 assessments for this interim 
analysis. The clinical protocol and SAP (v1.0) described the second planned interim 
analysis as taking place after all enrolled subjects had completed the Week 48 (or 
early termination) study visit. Further, safety and efficacy analyses will be performed 
in the Safety Population. The original SAP (v1.0) specified the mITT and Per-
Protocol populations for efficacy analyses. Details have been added to describe the 
analyses for the second planned interim analysis.    
x For the ItchRO efficacy variable, the terminology has been changed to “ItchRO 
weekly average score”. The terminology for this variable in the clinical protocol and 
original SAP (v1.0) is “ItchRO average daily score”. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 13 of 108 
x The objective evaluating durability of effect of MRX was removed, along with 
associated analyses. Per PA3, durability of effect cannot be assessed in this study 
since it is not a placebo controlled trial and a treatment effect has not yet been 
established. 
x Graphical displays are described in greater detail. 
x The timing of data monitoring committee (DMC) meetings has been updated from 
“quarterly” to “at specified intervals” for the duration of the study. 
x The Sponsor’s name has been changed from “Lumena Pharmaceuticals, Inc.” to 
“Lumena Pharmaceuticals LLC”. 
x The Shire Biostatistics Team Lead has been changed from Aparna Raychaudhuri, 
Ph.D. to Tom Tang, Ph.D. 
x Jana Steinmetz, M.S. has been added as a co-author to the SAP. 
The amended SAP will be finalized and submitted to file before the final database lock 
pertaining to Lumena Pharmaceuticals LLC study protocol LUM001-501. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 14 of 108 
Table of Contents 
Approvals ........................................................................................................................................ 2 
Document History ........................................................................................................................... 3 
Statistical Analysis Plan (SAP) Amendment 3 ............................................................................... 3 
Statistical Analysis Plan (SAP) Amendment 2 ............................................................................... 7 
Statistical Analysis Plan (SAP) Amendment 1 ............................................................................. 11 
Table of Contents .......................................................................................................................... 14 
List of Tables ................................................................................................................................ 17 
1.
Overview ........................................................................................................................... 18 
2.
Study Objectives and Endpoints ....................................................................................... 19 
2.1.
Study Objectives ......................................................................................................... 19 
2.1.1. Objectives up to and Including Week 72 .................................................................... 19 
2.1.2. Objectives of the Optional Follow-up Treatment Period (After Week 72) ................ 20 
2.1.3. Exploratory Objective ................................................................................................. 20 
2.2.
Study Endpoints .......................................................................................................... 20 
2.2.1. Safety Endpoints ......................................................................................................... 20 
2.2.2. Efficacy Endpoints ...................................................................................................... 21 
2.2.3. Other Endpoints .......................................................................................................... 28 
3.
Overall Study Design and Plan ......................................................................................... 28 
3.1.
Overall Design ............................................................................................................ 28 
3.2.
Sample Size and Power ............................................................................................... 28 
3.3.
Study Population ......................................................................................................... 29 
3.4.
Treatments Administered ............................................................................................ 29 
3.4.1. Dose-Escalation Period ............................................................................................... 29 
3.4.2. Stable Dosing Period................................................................................................... 30 
3.4.3. Long-term Exposure Period ........................................................................................ 30 
3.4.4. Optional Follow-up Treatment Period (Post-Week 72) .............................................. 30 
3.4.5. End of Treatment ........................................................................................................ 31 
3.5.
Method of Assigning Subjects to Treatment Groups .................................................. 32 
3.6.
Study Period and Schedule of Procedures .................................................................. 32 
3.6.1. Schedule of Procedures A – Dose-escalation and Stable Dosing Period: 
Baseline – Week 13 .................................................................................................... 33 
3.6.2. Schedule of Procedures B – Stable Dosing Treatment Period: Week 14 – 
Week 72 ...................................................................................................................... 35 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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3.6.3. Schedule of Procedures C – Optional Follow-Up Treatment Period: Week 72 – 
Week 120 .................................................................................................................... 37 
3.6.4. Schedule of Procedures D – Optional Follow-Up Treatment Period: Week 72 – 
Week 120 .................................................................................................................... 39 
3.6.5. Schedule of Procedures E – Extension of Optional Follow-Up Treatment 
Period, Subject Ineligible for ADE ............................................................................. 42 
3.6.6. ParticipantSchedule of Procedures G – Optional Follow-Up Treatment Period: 
Re-Entry Under Protocol Amendment 4 ..................................................................... 47 
3.6.7. Schedule of Procedures H – Optional Follow-Up Treatment Period: Re-Entry 
Under Protocol Amendment 4, Subject Ineligible for ADE ....................................... 49 
3.6.8. Schedule of Procedures I – Optional Follow-Up Treatment Period: Re-Entry 
Under Protocol Amendment 4, Subject Eligible For ADE ......................................... 51 
3.6.9. Schedule of Procedures J – End of Treatment (EOT) / Early Termination (ET) 
Visit and Post-Treatment Safety Follow-Up ............................................................... 54 
4.
Statistical Analysis and Reporting .................................................................................... 56 
4.1.
Introduction ................................................................................................................. 56 
4.2.
Data Monitoring .......................................................................................................... 57 
4.3.
Interim and Final Analyses ......................................................................................... 57 
4.3.1. First Interim Analyses ................................................................................................. 57 
4.3.2. Second Interim Analyses ............................................................................................ 58 
4.3.3. Third Interim Analyses ............................................................................................... 59 
4.3.4. Final Analysis ............................................................................................................. 60 
4.3.5. Posthoc Analyses ........................................................................................................ 60 
5.
Analysis Populations ......................................................................................................... 60 
6.
General Issues for Statistical Analysis .............................................................................. 60 
6.1.
Statistical Definitions and Algorithms ........................................................................ 60 
6.1.1. Baseline ....................................................................................................................... 60 
6.1.2. Study Day.................................................................................................................... 61 
6.1.3. Adjustments for Covariates......................................................................................... 61 
6.1.4. Multiple Comparisons ................................................................................................. 61 
6.1.5. Handling of Dropouts or Missing Data ....................................................................... 61 
6.1.6. Analysis Visit Windows ............................................................................................. 63 
6.1.7. Investigative Sites ....................................................................................................... 66 
6.1.8. Variable Definitions .................................................................................................... 66 
6.1.9. Derived Variables ....................................................................................................... 66 
6.1.10. PedsQL Scoring Algorithm......................................................................................... 71 
6.1.11. Data Adjustments/Handling/Conventions .................................................................. 72 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 16 of 108 
7.
Study Subjects and Demographics.................................................................................... 76 
7.1.
Disposition of Subjects and Withdrawals ................................................................... 76 
7.2.
Protocol Violations and Deviations ............................................................................ 76 
7.3.
Demographics and Other Baseline Characteristics ..................................................... 77 
7.4.
Disease History and Baseline Disease Characteristics ............................................... 77 
7.5.
Treatment Compliance ................................................................................................ 78 
8.
Efficacy Analysis .............................................................................................................. 78 
8.1.
Primary Efficacy Variable Analysis ........................................................................... 79 
8.2.
Secondary Efficacy Variable Analysis ....................................................................... 79 
8.3.
Exploratory Efficacy Variable Analysis ..................................................................... 80 
8.4.
Sensitivity Analysis .................................................................................................... 80 
9.
Safety and Tolerability Analysis ....................................................................................... 80 
9.1.
Exposure to Treatment ................................................................................................ 81 
9.2.
Adverse Events ........................................................................................................... 81 
9.2.1. Adverse Events of Special Interest ............................................................................. 82 
9.2.2. Deaths and Serious Adverse Events ........................................................................... 82 
9.2.3. Life Threatening Adverse Events ............................................................................... 82 
9.2.4. Adverse Events Leading to Withdrawal ..................................................................... 83 
9.3.
Clinical Laboratory Evaluations ................................................................................. 83 
9.4.
Vital Signs ................................................................................................................... 83 
9.5.
Physical Examination.................................................................................................. 83 
9.6.
Concomitant Medications ........................................................................................... 84 
9.7.
Pharmacokinetic Analysis ........................................................................................... 84 
10.
Other Planned Analysis..................................................................................................... 84 
10.1.
Quality of Life............................................................................................................. 84 
10.2.
Palatability Analysis ................................................................................................... 85 
10.3.
Genetic Endpoints ....................................................................................................... 85 
10.4.
Additional Analyses .................................................................................................... 85 
11.
Changes from Protocol Planned Analyses ........................................................................ 85 
12.
Additional Exploratory Analyses ...................................................................................... 86 
13.
References ......................................................................................................................... 87 
14.
Planned Tables, Figures, and Listings .............................................................................. 87 
14.1.
Planned Table Descriptions ........................................................................................ 87 
14.2.
Planned Figure Descriptions ....................................................................................... 94 
14.3.
Planned Listing Descriptions ...................................................................................... 96 
15.
Tables, Listings, and Listing Shells ................................................................................ 100 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 17 of 108 
15.1.
Standard Layout for all Tables, Listings, and Figures .............................................. 100 
Appendix 1: Premier Research Library of Abbreviations .......................................................... 101 
Appendix 2: Laboratory Tests for % Change from Baseline Presentation ................................. 105 
Appendix 3: Listing of Fat-Soluble Vitamin Deficiency Events ................................................ 106 
List of Tables 
Table 1 
Analysis Visit Windows – Visit-Based Analysis........................................................ 65 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 18 of 108 
1.
Overview 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Mirum 
Pharmaceuticals Inc. (Mirum) protocol LUM001-501, Open Label Study of the Efficacy and 
Long Term Safety of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor 
(ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Patients with Progressive 
Familial Intrahepatic Cholestasis, dated 08-Feb-2019 (Amendment 4.1).  
The original LUM001-501 protocol, dated 23-Oct-2013, planned for a 48-week treatment period. 
This treatment period included 4 parts: a 4-week dose-escalation (DE) period at doses up to 140 
μg/kg/day; a 4-week stable dosing period at 140 μg/kg/day; a 5-week stable dosing period at 280 
μg/kg/day, and a 35-week long-term exposure period. 
There have been 5 protocol amendments to date. The summary list of changes to each of the 
protocol amendments are described in the final amendment, Protocol Amendment 4.1. Several of 
the protocol amendments included optional long-term treatment extensions and one of the later 
amendments added a twice-a-day (BID) dosing regimen.  
Protocol Amendment 2, dated 05-Nov-2014, increased the number of subjects from 12 to 
approximately 24 evaluable subjects, increased the treatment period to 72 weeks, and added a 2nd 
interim analysis when all enrolled subjects reached the Week 48 visit. 
Protocol Amendment 3, dated 02-Nov-2015, added an optional follow-up treatment period 
intended to offer the opportunity to eligible subjects to continue on treatment after Week 72 until 
the first to occur of the following: (i) up to 52 weeks of additional treatment (Week 124), or (ii) 
in the event that a new study opens to enrollment.  
Protocol Amendment 4, dated 20-Dec-2016, allow continued participation in the Optional 
Follow-Up Treatment Period, beyond what was previously described in Protocol Amendment 
3.  Study treatment in the Optional Follow-up Treatment Period will continue until the first of the 
following occurs: (i) the subjects are eligible to enter another LUM001 study or (ii) LUM001 is 
available commercially. This amendment also described the way in which eligible subjects who 
had previously discontinued from the study may re-enter and receive study treatment in the 
optional follow-up treatment period (After Week 72). Additional objectives for the Optional 
Follow-up Treatment Period were added, including the exploration of a twice daily (BID) dosing 
regimen (280 μg/kg BID) and higher daily dosing of LUM001.  
The final protocol amendment, Amendment 4.1, dated 08Feb2019, primarily amended Protocol 
Amendment 4 to reflect the change of sponsorship from Lumena Pharmaceuticals LLC (Lumena 
Pharmaceuticals LLC is an indirect wholly-owned subsidiary of Shire North American Group, 
Inc.) to Mirum Pharmaceuticals, Inc. 
A subject may have been off study drug for an extended period of time during the course of their 
study treatment. The reasons for being off study drug include drug interruption (e.g., as directed 
by an investigator due to an AE), study drug compliance issues (e.g., missed consecutive doses), 
and dose interruptions due to being off study between protocol amendments. For example, a 
subject could complete study drug treatment through Week 72 under the Protocol Amendment 2 
before implementation of Protocol Amendment 3 that extended treatment through Week 124. 
The subject could subsequently provide informed consent under the new amendment and be 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 19 of 108 
re-initiated on study drug. Subjects with a drug interruption of at least 7 days had their study 
drug dose re-escalated. 
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 Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice. 
The planned analysis identified in this SAP may be included in CSRs, regulatory submissions, or 
future manuscripts. Also, post-hoc exploratory analysis 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 addendum to the final CSR, and the 
results of these post-hoc analyses may be referred in the CSR and will be available for review in 
CSR Section 14.2. 
Reference materials for this statistical analysis plan include the study protocol and accompanying 
sample data collection documents. 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
The amended SAP (Amendment 3) will be finalized and submitted to file before final analyses 
are produced. 
The active study drug LUM001 is now named maralixibat chloride (MRX) and that label will be 
used hereinafter within this document. 
2. 
Study Objectives and Endpoints
2.1.
Study Objectives
2.1.1. Objectives up to and Including Week 72 
The objectives of this study (up to and including Week 72) are: 
x To evaluate the long-term safety and tolerability of MRX in pediatric subjects with 
progressive familial intrahepatic cholestasis (PFIC). 
x To evaluate the effect of MRX on serum bile acids in pediatric subjects with PFIC at 13 
weeks of treatment. 
x To evaluate the effect of MRX on biochemical markers of cholestasis and liver disease at 
13 weeks of treatment. 
x To evaluate the effect of MRX on pruritus in pediatric subjects with PFIC at 13 weeks of 
treatment. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 20 of 108 
2.1.2. Objectives of the Optional Follow-up Treatment Period (After Week 72) 
Objectives of the Optional Follow-up Treatment Period (After Week 72) are: 
x To offer eligible subjects in the LUM001-501 study continued study treatment beyond 
Week 72 until the first of the following occurs:  (i) the subjects are eligible to enter 
another MRX study or (ii) MRX is available commercially. 
x To obtain safety and efficacy data in subjects treated long-term on MRX. 
x To explore a twice a day (BID) dosing regimen and higher daily dosing of MRX. 
x To identify genetic indicators of treatment response, including use of exome sequencing. 
x To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma. 
x To assess palatability of the MRX formulation. 
2.1.3. Exploratory Objective 
An exploratory objective is: 
x To allow the possibility of analysis of serum markers of treatment response using 
metabolomic and proteomic analysis on previously collected serum samples. 
2.2.
Study Endpoints 
In addition to the time points specified in the protocol, efficacy and visit-based safety endpoints 
will also be analyzed in a LOCF approach at Week 72 (Week 48 for ItchRO endpoints) and 
Week 124 (Week 122 for ItchRO endpoints).  
Subjects that did not complete at least 1 post-Week 72 assessment (Week 48 for ItchRO) will be 
excluded from all post-Week 72 (Week  48 for ItchRO) analyses. Subjects that did not complete 
at least 1 post-Week 124 assessment will be excluded from all post-Week 124 analyses. 
2.2.1. Safety Endpoints 
The safety and tolerability endpoints for this study include the following: 
x Incidence of TEAEs including serious adverse events (SAEs), related to study drug, 
leading to withdrawal, special interest TEAEs, along with TEAEs by severity 
x Change from baseline in clinical safety laboratory values at each analysis visit (where 
applicable) 
x Observed serum AFP values at each analysis visit (where applicable) 
x Physical examination findings, including body height, weight, and BMI at each analysis 
visit 
x Vital signs at each analysis visit 
x
Concomitant medication usage


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 21 of 108 
x
Study drug exposure, including weekly average dose, total drug exposure, and treatment 
duration 
x Plasma sample MRX concentrations at each analysis visit (where applicable) 
Vital signs include heart rate (HR), respiratory rate, body temperature, and blood pressure (BP). 
Note that the z-scores for body weight, height and BMI are considered as efficacy but are 
derived from safety variables. Z-scores are derived as described in Section 6.1.9. 
Adverse events and study drug exposure will be summarized by PFIC type (PFIC1, PFIC2, and 
overall) and MRX dose (280 μg/kg QD and 280 μg/kg BID). Concomitant medications will be 
summarized overall and by PFIC type. 
Laboratory results (with the exception of AFP) will be summarized by analysis visit as observed 
and change from baseline values.  Percent change from baseline summaries will be included for 
select laboratory tests as described in Section 9.3. 
For select fat-soluble vitamins, including 25-hydroxyvitamin D, alpha tocopherol / total lipids 
ratio, INR, retinol:RBP molar ratio, and vitamin A, abnormalities and clinically-meaningful 
shifts from baseline summaries will be presented for each analysis visit (as appropriate). For 
these FSVs, categories may include sufficient, insufficient, possibly insufficient, indeterminate, 
and excess (see Section 6.1.9 for specific definitions). A summary of corrected sodium 
abnormalities will also be presented. 
Serum samples for AFP, a marker of hepatocellular carcinoma, are only drawn during the 
optional follow-up treatment period at every other 12-week repeating period clinic visit and at 
the EOT visit. 
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study includes the following: 
x Fasting sBA level change from Baseline (Day 0) to Week 13. 
2.2.2.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study include the following: 
x ALT, AST, and bilirubin (total and direct) change from Baseline (Day 0) to Week 13. 
x Pruritus as measured by ItchRO (Obs) change from Baseline (Day 0) to Week 13. 
ItchRO (Obs) secondary efficacy variables include: weekly average scores, 4-week morning 
average scores, and weekly morning average scores. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 22 of 108 
2.2.2.3.
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints of this study include the following:  
x Change from Baseline in fasting sBA level at Weeks 4, 8, 24, 36, 48, 60, 72, 72/LOCF, 
84, 96, 108, 120, 124/LOCF, and every 12 weeks (where applicable) through the end of 
treatment. 
x Change from Baseline in pruritus as measured by ItchRO (Obs) weekly average score 
and weekly morning average score at Weeks 4, 8, 28, 48, 48/LOCF, 86, 98, 110, 122, 
122/LOCF, and every 12 weeks (where applicable) through the end of treatment. 
x Change from Baseline in pruritus as measured by ItchRO (Obs) 4-week morning average 
score at Weeks 13, 48, and 48/LOCF. 
x Change from Baseline in ALT, AST, and bilirubin (total and direct) levels at Weeks 4, 8, 
24, 36, 48, 60, 72, 72/LOCF, 84, 96, 108, 120, 124/LOCF, and every 12 weeks (where 
applicable) through the end of treatment. 
x Change from Baseline in pruritus as measured by ItchRO (Obs) weekly evening average 
score at Weeks 4, 8, 13, 28, 48, 48/LOCF, 86, 98, 110, 122, 122/LOCF, and every 12 
weeks (where applicable) through the end of treatment. 
x
Change from Baseline in pruritus as measured by ItchRO (Pt) weekly average score, 
weekly morning average score, and weekly evening average score at Weeks 4, 8, 13, 28, 
48, 48/LOCF, 86, 98, 110, 122, 122/LOCF, and every 12 weeks (where applicable) 
through the end of treatment. 
x Change from Baseline for ALP, ĮK\GUR[\O-4-cholesten-3-one (C4), total cholesterol, 
LDL-C, and GGT at Weeks 4, 8, 13, 24, 36, 48, 60, 72, 72/LOCF, 84, 96, 108, 120, 
124/LOCF, and every 12 weeks (where applicable) through the end of treatment 
x Responder analysis: pruritus response rates as measured by ItchRO (Obs and Pt) weekly 
morning average scores at Weeks 13, 48, 48/LOCF, 98, 122, 122/LOCF, and every 12 
weeks (where applicable) through the end of treatment; Responder definitions include 
FKDQJHIURPEDVHOLQHRI---DQG-1.75. 
x Responder analysis: sBA response rates at Weeks 13, 48, 72, 72/LOCF, 96, 120, 
124/LOCF, and every 12 weeks (where applicable) through the end of treatment. 
Responder definitions include FKDQJHIURPEDVHOLQHRI-V%$ 102 μmol/L, % 
FKDQJHIURPEDVHOLQHRI-75 or V%$ PRO/DQGV%$PRO/
(normalization). 
x Responder analysis:  sBA and ItchRO (Obs) weekly morning average scores at Weeks 
13, 48, 72 (sBA only), 96 (Week 98 for ItchRO data), 120 (Week 122 for ItchRO data), 
124/LOCF (Week 122/LOCF for ItchRO data), and every 12 weeks (where applicable) 
through the end of treatment. Responder definitions include each of the sBA responder 
definitions combined with an ItchRO (Obs) weekly morning average change from 
EDVHOLQHVFRUHRI-1.0 point. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 23 of 108 
x
Responder analysis: liver function lab tests (C4, AST, ALT, and total bilirubin) at Weeks 
13, 48, 72, 72/LOCF, 96, 120, 124/LOCF, and every 12 weeks (where applicable) 
through the end of treatment. 5HVSRQGHUGHILQLWLRQVLQFOXGH&FKDQJHIURPEDVHOLQH
100, shift from >ULN (upper limit of normal) at baseline to normal in AST, shift from 
>ULN at baseline to normal in ALT, and shift from >ULN at baseline to normal in total 
bilirubin. 
x Change from Baseline in the Clinician Scratch Scale (CSS) score at Weeks 2, 4, 8, 13, 
24, 36, 48, 60, 72, 72/LOCF, 84, 96, 108, 120, 124/LOCF, and every 12 weeks (where 
applicable) through the end of treatment. 
x Change from Baseline in height, weight, and BMI z-scores at Weeks 2, 4, 8, 12, 24, 36, 
48, 60, 72, 72/LOCF, 84, 96, 108, 120, 124/LOCF, and every 12 week (where applicable) 
through the end of treatment. 
x Change from Baseline for Pediatric Quality of Life Inventory (PedsQL) Total Scale Score 
(parent), Multidimensional Fatigue Scale Score (parent), and Family Impact Total Scale 
Score at Weeks 13, 13/ET, 24, 48, 72, 72/LOCF, 84, 96, 108, 120, 124, 124/LOCF, and 
every 12 weeks (where applicable) through the end of treatment. 
The following exploratory efficacy variables will only be presented in subject listings:  
• 
patient impression of change (PIC) 
• 
caregiver impression of change (CIC) 
• 
caregiver global therapeutic benefit (CGTB) 
• 
autotaxin 
• 
aPTT 
• 
prothrombin time 
• 
INR 
• 
triglycerides 
• 
high-density lipoprotein cholesterol (HDL-C)
• 
FGF-19 
• 
FGF-21 
• 
sBA sub-species (taurocholic acid, taurochenodeoxycholic acid, 
tauroursodeoxycholic acid, taurodeoxycholic acid, taurolithocholic acid, glycocholic 
acid, glycoursodeoxycholic acid, glycochenodeoxycholic acid, glycodeoxycholic 
acid, glycolithocholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, 
deoxycholic acid, and lithocholic acid) and the ratio of cholic acid and 
chenodeoxycholic acid 
2.2.2.4. 
Efficacy Parameter Descriptions 
Itch Reported Outcome (ItchRO™) 
The primary assessment of pruritus in this study will be evaluated using a newly developed Itch 
caregiver/patient reported outcome measure (ItchRO) administered as a twice daily eDiary. To 
accommodate potential cultural restrictions within the familial intrahepatic cholestasis 1 (FIC1) 
affected population a paper version of the ItchRO diary will be made available. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 24 of 108 
Caregivers for all subjects will complete the observer instrument: ItchRO (Obs). Children at least 
9 years of age will complete the patient instrument: ItchRO (Pt). Children between the ages of 5 
and 8 years of age or where the investigator has expressed concern about the subject’s ability to 
reliably complete the data (e.g., due to developmental delay) will complete the patient instrument 
with the assistance of their caregiver. There will be no ItchRO (Pt) report for subjects under the 
age of 5. The itch score from the ItchRO (Obs) and the ItchRO (Pt) will be analyzed separately. 
Given the age range of the study population and the small sample size, the primary ItchRO score 
will be derived from the ItchRO (Obs) instrument. 
For this instrument, the caregiver and/or subject indicate the itch severity in the morning and in 
the evening each day during the following periods: 
x Screening through first 13 weeks of the treatment period 
x 4 consecutive weeks that follow the Week 24 clinic visit 
x 4 consecutive weeks including and preceding the Week 48 clinic visit 
x 2 consecutive weeks that follow the Week 84, Week 96, Week 108, and Week 120 
clinic visits 
x 2-week periods following each recurring 12-week clinic visit during the optional 
extension follow-up treatment period.  
ItchRO scores have a range of 0–4, with the higher score indicating increasing itch severity. For 
both the ItchRO (Obs) and the ItchRO (Pt), the average score between the morning and evening 
ItchRO reports represent the daily score: a measure of itching over the previous 24-hour period 
(see Section 6.1.9).  
Pruritus scores as measured by the ItchRO instrument (observer and patient) include: weekly 
average score, weekly morning average score, weekly evening average score, 4-week average 
score, and 4-week evening average score. ItchRO scores will be calculated as described in 
Section 6.1.9. 
Weekly average scores are calculated as the average of the daily scores over a defined study 
week consisting of the 7 days before the scheduled visit (i.e., Baseline [Day 0], Weeks 4, 8, 28, 
48, 86, 98, 110, 122, and every 12 weeks thereafter). For the change from baseline calculation in 
weekly average ItchRO scores, baseline is defined as the weekly average ItchRO score in the 
week consisting of the 7 days immediately before the baseline visit date. Post-baseline weekly 
average ItchRO scores are only computed if at least 4 of the 7 daily ItchRO scores for the 7-day 
period are available. 
Weekly morning and weekly evening average scores are calculated as the average of the 
morning/evening scores over a defined study week consisting of the 7 days before the scheduled 
visit (i.e., Baseline [Day 0], Week 4, 8, 28, 48, 86, 98, 110, 122, and every 12 weeks thereafter). 
For the change from baseline calculation in weekly morning and weekly evening average ItchRO 
scores, baseline is defined as the weekly morning/evening average ItchRO score in the period 
consisting of the 7 days immediately before the baseline visit date. Post-baseline weekly 
morning/evening average ItchRO scores are only computed if at least 4 of the 7 morning/evening 
ItchRO scores for the 7-day period are available. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
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4-week average scores are calculated as the average of the evening/morning scores over a 
defined period consisting of the 28 days before the scheduled visit (i.e., Baseline [Day 0], Weeks 
4, 8, 28, and 48). For the change from baseline calculation in 4-week average ItchRO scores, 
baseline is defined as the weekly average ItchRO score in the period consisting of the 28 days 
immediately before the baseline visit date. Post-baseline 4-week average ItchRO scores are only 
computed if at least 20 of the 28 evening/morning ItchRO scores for the 28-day period are 
available. 
In deriving weekly or 4-week average post-baseline ItchRO scores, each scheduled visit date will 
be determined based on the varying eDiary collection periods (as applicable):  (A) Week 4, 8, 13, 
and 48, (B) Week 28, 86, 98, 110, and 122, and (C) recurring 12-week periods during the 
optional extension follow-up treatment period.   
A. Week 4, 8, 13, and 48:  The scheduled visit date is used. 
B. Week 28, 86, 98, 110, and 122:  Each scheduled visit date will be determined based on 
the date of the associated scheduled visit (i.e., Week 24, 84, 96, 108, and 120) plus 28 
days for Week 28, and plus 14 days for Week 86, 98, 110, and 122. 
C. Recurring 12-week periods:  Each scheduled visit date will be determined based on the 
date of the associated scheduled visit plus 14 days.   
In general, scheduled visit dates will be determined based on the date of the vital signs 
assessment. If the date of vital signs is missing, then the date of the physical examination will be 
used. If both of these dates are missing for a specific scheduled visit then the start date from the 
subject visits derived dataset will be used.  Further, for missing but expected dates (where ItchRO 
data exists), the last visit past the missing date is used and the appropriate amount of days is 
subtracted. 
Clinician Scratch Scale (CSS) 
The CSS provides an assessment of itch severity. The clinician’s assessment of the subject’s 
pruritus is focused on scratching and visible damage to the skin as a result of scratching as 
observed by the physician. The clinician scratch scale uses a 5-point scale, in which 0 designates no 
evidence of scratching, and 4 designates cutaneous mutilation with bleeding, haemorrhage and 
scarring. 
Caregiver Impression of Change (CIC) 
The CIC is designed to assess the caregiver’s perception of the subject’s itching after various 
points of study drug treatment compared to his/her itching before the start of treatment with 
study drug. 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: 1=Much better, 
2=Better, 3=A little better, 4=No change, 5=A little worse, 6=Worse, 7=Much worse. 
Patient Impression of Change (PIC) 
The PIC is designed to assess the subject’s perception of his/her itching after various points of 
study drug treatment compared to his/her itching before the start of treatment with study drug. 
The PIC is completed, by subjects who were 9 years of age or older. The questionnaire is 
designed for self-administration and uses a 7-point scale in which 1 designates the best outcome 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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and 7 designates the worst outcome: 1=Much better, 2=Better, 3=A little better, 4=No change, 
5=A little worse, 6=Worse, and 7=Much worse. 
Caregiver Global Therapeutic Benefit (CGTB) 
The CGTB questionnaire is designed to assess the caregiver’s perception of the treatment 
benefits on the subject’s itching compared to the side effects experienced with study drug. The 
questionnaire is designed for self-administration and uses a 5-point scale in which 1 designates 
the best outcome and 5 designates the worst outcome: 1=Definitely, 2=Somewhat, 3=About the 
same, 4=Maybe not, 5=Definitely not. 
Pediatric Quality of Life Inventory (PedsQL) 
The PedsQLTM 6 is a validated, modular instrument designed to measure health-related quality of 
life (HRQoL) in infants, children and adolescents. The PedsQL questionnaire is administered to 
subjects and/or caregivers depending on age using age-appropriate PedsQL modules. The 
PedsQL consists of developmentally appropriate forms for infants/children ages 1-12 months, 
13-24 months, 2-4, 5-7, 8-12, and 13-18 years. Pediatric self-report is measured in children and 
adolescents ages 5-18 years, and parent proxy-report of child HRQoL is measured for children 
and adolescents ages 12 months to 18 years.  
In addition to the core generic PedsQL module, the multidimensional fatigue and family impact 
questionnaires are also administered using the age-appropriate module.   
Age at baseline will be used as the age for the determination of the appropriate module to be 
used for the study, and this same module will be used for the duration of the study (regardless of 
subsequent birthdays after the baseline visit).  
With the exception of the 5-7 year age group (Young Child) subject report, each item of the 
PedsQL consists of a 5-level Likert-type item survey (0-4), where 0=Never, 1=Almost never, 
2=Sometimes, 3=Often, and 4=Almost always. Items of the PedsQL Young Child subject report 
are scored on a 3-point scale, where 0=Not at all, 2=Sometimes, and 4=A lot.  
The PedsQL Generic Core Scale is composed of items to assess pediatric HRQoL measurements 
across 6 subscales: Physical Functioning, Physical Symptoms (only applicable for infants, 1-24 
months), Emotional Functioning, Social Functioning, Cognitive Functioning [only applicable for 
infants, 1-24 months], and School Functioning (only applicable for children, 2 18 years).  
The Total Scale Score, Physical Health Summary Score and Psychosocial Health Summary 
Score are computed individually for both the parent and subject reports of the PedsQL Generic 
Core Scale. The Total Scale Score is computed from all items. The Physical Health Summary 
Score is computed from the items of the Physical Functioning domain, and the Physical 
Symptoms domain (infants only). The Psychosocial Health Summary Score is computed from 
items of the Emotional, Social, and School Functioning domains, and the Cognitive Functioning 
domain (infants only). 
The PedsQL Multidimensional Fatigue Scale is composed of items across 3 subscales: General 
Fatigue, Sleep/Rest Fatigue, and Mental Fatigue. Respondents use the scale to indicate how 
frequently certain fatigue-related symptoms and complaints trouble them. The Multidimensional 
Fatigue Scale Score is computed from all items of the PedsQL Multidimensional Fatigue Scale. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 27 of 108 
The PedsQL Family Impact Scale is composed of items encompassing 6 subscales measuring 
parent self-reported functioning: Physical Functioning, Emotional Functioning, Social 
Functioning, Cognitive Functioning, Communication, and Worry, and 2 subscales measuring 
parent-reported family functioning: Daily Activities and Family Relationships. The Family 
Impact module assesses the impact of pediatric chronic health conditions on parents and the 
family. The Family Impact Total Scale Score is computed from all items of the PedsQL Family 
Impact Scale. The Parent Functioning Summary Score is computed from the items of the 
Physical, Emotional, Social, and Cognitive Functioning domains. The Family Impact Summary 
Score is computed from the items of the Daily Activities and Family Relationships domains.
PedsQL scoring algorithms for scale scores are presented in Section 6.1.10.  
Responder Definitions 
Pruritus responder rates as measured by ItchRO (Obs) and ItchRO (Pt) weekly morning average 
scores are defined as: 
• 
FKDQJHIURPEDVHOLQHDYHUDJHVFRUH-1.0 point 
• 
FKDQJHIURPEDVHOLQHDYHUDJHVFRUH-1.33 points 
• 
FKDQJHIURPEDVHOLQHDYHUDJHVFRUH-1.5 points 
• 
change from baseline average VFRUH-1.75 points 
Serum bile acid response rate endpoints are defined as: 
• 
% FKDQJHIURPEDVHOLQHLQV%$-75 
• 
V%$XPRO/ 
• 
FKDQJHIURPEDVHOLQHLQV%$-75 or sBA XPRO/ 
• 
V%$XPRO/(normalized)  
Serum bile acid and ItchRO (Observer) response rate endpoints are defined as: 
• 
ItchRO (Observer) weekly morning average sFRUH-1.0 point and 
- 
FKDQJHIURPEDVHOLQHLQV%$-75 
- 
V%$XPRO/ 
- 
FKDQJHIURPEDVHOLQHLQV%$-75 or V%$XPRO/ 
- 
V%$XPRO/QRUPDOL]HG 
The sBA and ItchRO (Obs) response rates are summarized at Weeks 13, 48, 72 (sBA only), 
96/98, and 120/122, as applicable. In general, responder definitions that are based on both sBA 
and ItchRO require matching visit data. The exception is for Week 96/98, where Week 96 sBA 
data and Week 98 ItchRO data will be used, and for Week 120/122, where Week 120 sBA data 
and Week 122 ItchRO data will be used. 
Liver function lab test response rate endpoints are defined as: 
• 
FKDQJHIURPEDVHOLQHLQ&i.e., at least 2 times the baseline C4 level) 
• 
shift in AST level from > ULN at baseline to normal 
• 
shift in ALT level from > ULN at baseline to normal 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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• 
shift in total bilirubin level from > ULN at baseline to normal 
2.2.3. Other Endpoints 
2.2.3.1.
Genetic Endpoints 
For the purpose of this analysis plan, exploratory genetic analyses will be limited to the 
presentation of genotype data in a listing. 
2.2.3.2.
Metabolomic and Proteomic Endpoints
Exploratory responder analyses (metabolomics and proteomic investigation) is outside the scope 
of this analysis plan. 
2.2.3.3.
Palatability Endpoints 
Palatability of the MRX formulation is assessed in all patients, by-proxy in patients <4 years old 
DQGE\SDWLHQWTXHVWLRQQDLUHLQFKLOGUHQ\HDUVROGDWHDFKFOLQLFYLVLWLQWKHRSWLRQDOIROORZ-
up treatment period, with the exception of the DE and ADE visits. 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is an open-label study in children with PFIC designed to evaluate the safety and efficacy of 
MRX. The study is divided into 5 parts: a 4-week dose-escalation period, a 4-week stable dosing 
period at 140 μg/kg/day, a 5-week stable dosing period at 280 μg/kg/day, a 59-week long-term 
exposure period, and an optional follow-up treatment period for eligible participants who choose 
to stay on treatment with MRX. During the optional follow-up treatment period, subjects may be 
eligible for twice daily (BID) dosing based on efficacy as measured by sBA level and ItchRO 
score, and may have their dose of MRX increased to a maximum of 560 μg/kg/day (280 μg/kg 
BID). Subjects’ participation in the optional follow-up treatment period will continue until the 
first of the following occurs: (i) subjects are eligible to enter another MRX study or (ii) MRX is 
available commercially.  
A minimum of three interim analyses of key safety and/or efficacy parameters will be performed. 
The first interim analyses will occur after the first 12 subjects who meet the Per-Protocol (PP) 
population definition have completed the Week 13 study visit. The second interim analyses will 
occur after all enrolled subjects have completed the Week 48 (or Early Termination) study visit. 
The third interim analyses will be performed after all enrolled subjects have completed at least 6 
months of treatment under PA4 (or the Early Termination visit). Subsequent interim analyses 
may be performed at periodic intervals. 
3.2. 
Sample Size and Power 
PFIC is a rare disease. The planned sample size of approximately 24 evaluable subjects with 
PFIC is based on practical considerations, rather than statistical considerations and desired power 
for a prespecified difference. As such, this study is designed to provide important information for 
this patient population that is needed for planning future studies. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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3.3.
Study Population 
The study population is males and females between the ages of 12 months and 18 years, 
inclusive, diagnosed with PFIC and who have a gamma-glutamyl transpeptidase blood level less 
than 100 IU/L at screening. 
3.4.
Treatments Administered 
All subjects will receive MRXXSWRȝJNJGD\JLYHQDV%,'GRVHVRIȝJNg) or up to a 
maximum daily dose of 25 mg BID. Dosing will occur over a 13-week treatment period 
(comprised of 4-weeks dose-escalation [Dose Level 1-4], 4-weeks stable dosing at 140 
μg/kg/day, and 5-weeks stable dosing at 280 μg/kg/day), followed by a 59-week long-term 
exposure period.  
For the first 72 weeks of the study, each subject will receive either 1.0 mL (subjects weighing 
 kg) or 0.5 mL (subjects weighing <10 kg) of solution containing MRX orally as follows, 
administered as a daily morning dose: 
x Dose Level 1: 14 μg/kg/day. 
x Dose Level 2: 35 μg/kg/day. 
x Dose Level 3: 70 μg/kg/day. 
x Dose Level 4: 140 μg/kg/day. 
x Dose Level 5: 280 μg/kg/day. 
At Week 72, all subjects will be assessed by the investigator to determine their willingness and 
eligibility to roll over into the optional follow-up treatment period. Subjects eligible for the 
optional follow-up treatment period will continue treatment under dosing scenarios based on 
whether their MRX dosing will continue without interruption or interruption of <7 continuous 
GD\VRUZLWKLQWHUUXSWLRQGD\V(OLJLELOLW\IRU%,'GRVLQJZLOOEHGHWHUPLQHGEDVHGRQ
efficacy as measured by sBA level and ItchRO score. 
The sBA value used for determination of ADE eligibility will be the most recent available value. 
The ItchRO score used for ADE eligibility will be derived from the most recent 2-week 
electronic diary collection period. 
If a subject experiences intolerance (e.g., GI symptoms such as diarrhea, abdominal pain, 
cramping) at any time during the study, the physician investigator in consultation with the 
Sponsor Medical Monitor may lower the dose for the remainder of the study. If the subject is on 
the BID dosing regimen, dose lowering will first be attempted with the afternoon dose. Subjects 
who were previously down-titrated may be re-challenged during the long-term exposure period. 
3.4.1. Dose-Escalation Period 
During the first 4 weeks of the study, the dose-escalation period, the dose will be increased at 
weekly intervals starting with Dose Level 1, up to Dose Level 4, to acclimate the subject to the 
study drug. 
If a subject experiences intolerance (e.g., GI symptoms such as diarrhea, abdominal pain, 
cramping) at any time during the study, the physician investigator in consultation with the 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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Sponsor Medical Monitor may lower the dose for the remainder of the study. In these 
circumstances an unscheduled visit will occur and the appropriate replacement study medication 
will be issued to the subject as quickly as possible. 
3.4.2. Stable Dosing Period 
Following the dose-escalation period (Day 0 – Week 4) subjects will continue MRX dosing 
through Week 8 using Dose Level 4, or the highest tolerated dose below Dose Level 4. For those 
subjects who tolerated Dose Level 4, at Week 8, the dose will be increased to Dose Level 5 until 
Week 13. 
3.4.3. Long-term Exposure Period
Subjects will continue to receive MRX during the long-term exposure dosing treatment period at 
the highest dose achieved during the stable dosing treatment period. However, if a subject 
experiences intolerance due to GI symptoms, the investigator in consultation with the Sponsor 
Medical Monitor, may lower the dose for the remainder of the study. At the investigator’s 
discretion and in consultation with the Sponsor Medical Monitor, subjects who were previously 
down-titrated may be re-challenged during the long-term exposure period. 
During the long-term exposure period, the dose may be adjusted to account for a change of 
LQZHLJKWVLQFHWKHVFUHHQLQJYLVLWe.g., the amount of drug dosed may be increased to 
reflect the subject’s weight increase). 
3.4.4. Optional Follow-up Treatment Period (Post-Week 72) 
Subjects eligible for the optional follow-up treatment period will continue treatment under 
dosing scenarios based on whether their MRX dosing will (1) continue without interruption or 
interruption of <7 continuous days, OR, (2) FRQWLQXHZLWKLQWHUUXSWLRQGD\V 
Eligibility for BID dosing will be determined based on efficacy as measured by sBA level and 
ItchRO score. 
Subjects who enter the optional follow-up treatment period without MRX dosing interruption or 
with an interruption of <7 continuous days will be dosed in the following manner: 
x Subjects with normal sBA level AND ItchRO score <1.5 will be maintained at the same 
dose level and will continue morning dosing only. 
x SubjHFWVZLWKV%$OHYHODERYHQRUPDO$1'25,WFK52VFRUHZLOOVWDUW%,'GRVLQJ
(afternoon dose-escalation) as follows: 
 The morning dose will be continued at the same dose level, but the volume of 
the morning dose will be reduced by half at the same time that the afternoon 
dose is initiated. 
 The afternoon dose will be initiated at half the maximum tolerated morning 
dose and will continue at this dose for a period of 4 weeks. If this dose level is 
tolerated, the afternoon dose then will be doubled, to a maximum dose of 
280 μg/kg (or up to the maximum tolerated dose). 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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
The maximum daily dose will be 280 μg/kg BID, ie 560 μg/kg/day (max. 
25 mg BID). 
Subjects who enter the optional follow-up treatment period with a MRX dosing interruption of 
 days initially will receive morning dosing only and will undergo DE in the following manner: 
x The morning dose will be initiated at Dose Level 2 (35 μg/kg) and doubled in weekly 
intervals to a maximum dose of 280 μg/kg, or up to the maximum tolerated dose. 
x Once the morning dose of 280 μg/kg or maximum tolerated dose is achieved, sBA and 
ItchRO score will be evaluated. 
x Subjects with normal sBA AND ItchRO score <1.5 after morning dose-escalation will be 
maintained at the same dose level and will continue morning dosing only. 
x SuEMHFWVZLWKV%$DERYHQRUPDO$1'25,WFK52VFRUHZLOOEHJLQ%,'GRVLQJ
(afternoon dose-escalation) as outlined above. 
Subjects will continue to receive study drug until they are eligible to enter another MRX study or 
until MRX is available commercially, whichever occurs first. 
The maximum daily dose will be 280 μg/kg BID, ie 560 μg/kg/day (maximum 25 mg). If a 
subject experiences intolerance (e.g., GI symptoms such as diarrhea, abdominal pain, cramping) 
at any time during the study, the physician Investigator in consultation with the Sponsor Medical 
Monitor may lower the dose for the remainder of the study. If the subject is on a BID dosing 
regimen, dose lowering should first be attempted with the afternoon dose. 
The sBA value used for determination of ADE eligibility will be the most recent available value. 
The ItchRO score used for ADE eligibility will be derived from the most recent 2-week 
electronic diary collection period. 
Subjects who complete the study or who discontinued early due to reasons other than safety may 
be eligible for participation in the optional follow-up treatment period under Protocol 
Amendment 4. 
3.4.5. End of Treatment 
For subjects who did not consent to the optional follow-up treatment period, a subject is 
considered to have completed treatment if treatment was not permanently discontinued before 
the Week 72 visit. A follow-up phone contact is required for all subjects should the final visit 
occur earlier than 30 days from the final dose.  
For subjects who consented to the follow-up treatment period, an additional follow-up period 
disposition is collected in the electronic case report form (eCRF). The subject is considered to 
have completed treatment during the follow-up treatment period if study treatment was not 
permanently discontinued before the subject completing the EOT visit as defined in the most 
recent consent signed by the subject. A follow-up contact is required for all subjects should the 
final visit occur earlier than 30 days from the final dose.  
The end of study for the purposes of regulatory reporting is the point at which the last contact 
with the last subject during the protocol-specified scheduled follow-up treatment period is made. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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3.5.
Method of Assigning Subjects to Treatment Groups 
This is an open-label study, and therefore all subjects will be assigned to treatment with MRX. 
3.6.
Study Period and Schedule of Procedures 
For an individual subject, the study participation period will consist of a screening period of up 
to 6 weeks, a 13-week treatment period (including a dose-escalation period followed by two 
stable dose periods), and a 59-week long-term exposure period.  Subjects who complete 72 
weeks of treatment may be eligible to receive further treatment during the Optional Follow-up 
Treatment Period.  
Overall Scheme and Corresponding Schedule of Procedures 
The following schematic shows the study flow and corresponding Schedule of Procedures 
(A - I).   
Study Termination and End of Treatment Procedures are outlined in Schedule J (Section 3.6.9). 
Any subject who completes or withdraws from the study should undergo all procedures specified 
for the EOT/ET visit (see Section 3.6.9).  
 
The below sections show the schedule of procedures and the data to be collected on each study 
day or week. 

BL - W13
Dose escalation
Stable dosing
W14 – W72
Stable dosing
<7 days
interruption
days
interruption
Optional
follow-up 
W72 – W120
q12W
No gap or <7 
days
interruption
days
interruption
ADE 0 - q12W



Core Study & Optional Follow-Up (PA3)
ADE ineligible
ADE eligible
	



Extension & Afternoon
Dose Escalation (PA4)
W72 – W120
Treatment
gap 
before
PA4 
consent?

ADE ineligible
ADE eligible
PA4 DE-2 –
PA4 DE W8
q12W
ADE 0 - q12W


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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3.6.1. Schedule of Procedures A – Dose-escalation and Stable Dosing Period: Baseline – Week 13 
Study Period 
Screening 
Treatment Period 
Dose-escalation 
Stable Dosing Period 
Study Week 
 
 
1 
2 
3 
4
5 
8 
9 
13 
Study Day 
Day -42 
 
Day 0 
7 
14 
21 
28 
35 
56 
63 
91 
Window (in days) 
 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
Eligibility Assessment (Inclusion/Exclusion) 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
Body Weight & Height 
X 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signs 1 
X 
X 
 
X 
 
X 
 
X 
 
X 
Liver imaging (ultrasound) 2 
X 
 
 
 
 
 
 
 
 
 
Serum or Urine Pregnancy Test (if indicated)3 
X 
X 
 
X 
 
X 
 
X 
 
X 
CBC with Differential 4 
X 
X 
 
X 
 
X 
 
X 
 
X 
Coagulation4 
X 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry Panel 4 
X 
X 
 
X 
 
X 
 
X 
 
X 
Lipid Panel 4,5, 
 
X 
 
X 
 
X 
 
X 
 
X 
Cholestasis Biomarkers 4,5 
X 
X 
 
X 
 
X 
 
X 
 
X 
Fat-Soluble Vitamins 4,5,6 
 
X 
 
 
 
 
 
X 
 
X 
Plasma Sample for MRX: US 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
 
Xa 
Plasma Sample for MRX: UK, EU, Australia 
 
Xb 
 
 
 
Xb 
 
 
 
Xb 
PFIC Genotyping7 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 4 
X 
Xc 
 
Xc 
 
X 
 
X 
 
X 
Caregiver ItchRO/Patient ItchRO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinician Scratch Scale 
X 
X 
 
X 
 
X 
 
X 
 
X 
PedsQL 
 
X 
 
 
 
 
 
 
 
X 
Patient/ Caregiver Impression of Change 
 
 
 
 
 
 
 
 
 
X 
Caregiver Global Therapeutic Benefit 
 
 
 
 
 
 
 
 
 
X 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
Study Drug Supplied 
 
X 
 
X 
 
X 
 
X 
 
X 
Review Study Diaries & Assess Compliance 
 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 34 of 108 
Study Period 
Screening 
Treatment Period 
Dose-escalation 
Stable Dosing Period 
Study Week 
 
 
1 
2 
3 
4
5 
8 
9 
13 
Study Day 
Day -42 
 
Day 0 
7 
14 
21 
28 
35 
56 
63 
91 
Window (in days) 
 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
Phone Contact 
 
 
X 
 
X 
 
X 
 
X 
 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
2 
Screening ultrasound not required if an ultrasound completed < 6 months is available. 
3 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
4 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
5 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
6 
Blood samples must be drawn before administration of vitamin supplementation. 
7 
Genotyping will be performed to provide a full characterization and documentation of the mutation type in 
support of the diagnosis of PFIC. 
A In the US, , blood will be drawn ~4 hours post dosing for drug level analysis 
at Weeks 2, 8, and 13,. At Week 4, blood will be drawn ~2 hours post-
dosing (fasting <4 hrs will be allowed to accommodate 2-hr post dose 
draw). 
B In the UK, EU and AUS, , blood will be drawn ~4 hours post dosing for 
drug level analysis at Weeks 4 and 13. 
c At indicated visits during the treatment period, oxalate will be part of UA. 
 
 
 
Clinic Visit 
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 35 of 108 
3.6.2. Schedule of Procedures B – Stable Dosing Treatment Period: Week 14 – Week 72 
Study Period 
Treatment Period (continued) 
Study 
Termination 
Safety 
Follow 
Up 
59 Week Long-term exposure 
Study Week 
16 
20 
24 
28 
32 
36 
40 
44
48 
60 
Week 72 
(or Early 
Term7) 
30 days 
after 
final 
dose 
Study Day 
112 
140 
168 
196 
224 
252 
280 
308 
336 
420 
504 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14)
(±14) 
(±14) 
(±5) 
Physical Exam 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Body Weight & Height 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Vital Signs1 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
CBC with Differential2 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Coagulation2 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Chemistry Panel2 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Lipid Panel2,3 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Cholestasis Biomarkers2,3 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
FAT-Soluble Vitamins2,3,4 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Plasma Sample for MRX: All 
 
 
Xa 
 
 
Xa 
 
 
Xa 
Xa 
Xa 
 
Urinalysis2 
 
 
X 
 
 
X 
 
 
Xb 
X 
Xb 
 
Urine Pregnancy Test 5 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Clinician Scratch Scale 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Caregiver ItchRO/Patient ItchRO 
 
 
Xc 
Xc 
to Week 
28 
 
 
 
Xc 
X to 
Week 48 
 
 
 
PedsQL 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Patient/Caregiver Impression of 
Change  
 
 
 
 
 
 
 
 
X 
 
X 
 
Caregiver Global Therapeutic 
Benefit 
 
 
 
 
 
 
 
 
X 
 
X 
 
Study Drug Supplied 
 
 
X 
 
 
X 
 
 
X 
X 
Xd 
 
Assess Compliance 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone Contact6 
X 
X 
 
X 
X 
 
X 
 
 
 
 
X 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 36 of 108 
Study Period 
Treatment Period (continued) 
Study 
Termination 
Safety 
Follow 
Up 
59 Week Long-term exposure 
Study Week 
16 
20 
24 
28 
32 
36 
40 
44
48 
60 
Week 72 
(or Early 
Term7) 
30 days 
after 
final 
dose 
Study Day 
112 
140 
168 
196 
224 
252 
280 
308 
336 
420 
504 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14)
(±14) 
(±14) 
(±5) 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
2 
See Section16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7   
Subjects who withdraw early should complete all evaluations at this visit. 
A 
At Weeks 24, 36, 48, 60 and 72 blood will be drawn approximately 4 hours post 
dosing for drug level analysis. 
B 
At indicated visits during treatment period, oxalate will be part of the UA. 
C  
During the long-term exposure period, daily completion of the study diary for 4 
consecutive weeks will be required following the Week 24 & Week 44 clinic 
visits. 
D       For subjects entering optional Follow-up Treatment Period, once corresponding 
consent is signed. 
 
 
 
Clinic Visit
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 37 of 108 
3.6.3. Schedule of Procedures C – Optional Follow-Up Treatment Period: Week 72 – Week 120  
For Subjects With No Interruption in MRX Dosing or Interruption <7 Days. Includes Evaluation of Eligibility for BID Dosing 
Regimen.   
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
FTP Study Week 
76 
80
84 
88 
92 
96 
100 
104 
108 
112 
116 
120c 
Study Day 
532 
560 
588 
616 
644 
672 
700 
728 
756 
784 
812 
840 
Window (in days) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Informed Consent/Assent 
for PA48 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Afternoon dose-escalation 
(ADE) eligibility 
assessment followed by 
shift in visit schedule9  
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
Physical Exam 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Body Weight & Height 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Vital Signs1 
 
 
X 
 
 
X
 
 
X 
 
 
X 
CBC with Differential2 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Coagulation2 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Chemistry Panel2 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Lipid Panel2,3 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Cholestasis Biomarkers2,3 
 
 
X 
 
 
X
 
 
X 
 
 
X 
FAT-Soluble Vitamins2,3,4 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Optional Genotyping5 
 
 
X 
 
 
 
 
 
 
 
 
 
Exome Sequencing 
Sample10 
 
 
X10 
 
 
X10
 
 
X10 
 
 
X10 
Urinalysis2 
 
 
X 
 
 
X
 
 
Xa
 
 
Xa 
Serum or Urine Pregnancy 
Test (if indicated)6 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician Scratch Scale 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
Xb 
Xb 
to Week 
86 
 
Xb 
Xb 
to Week 
98 
 
Xb 
Xb 
to Week 
110 
 
Xb 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 38 of 108 
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
FTP Study Week 
76 
80
84 
88 
92 
96 
100 
104 
108 
112 
116 
120c 
Study Day 
532 
560 
588 
616 
644 
672 
700 
728 
756 
784 
812 
840 
Window (in days) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
PedsQL 
 
 
X 
 
 
X
 
 
X 
 
 
X 
Patient/Caregiver 
Impression of Change  
 
 
 
 
 
 
 
 
X 
 
 
X 
Caregiver Global 
Therapeutic Benefit 
 
 
 
 
 
 
 
 
X 
 
 
X 
Study Drug Supplied 
 
 
X 
 
 
X
 
 
X 
 
 
 
Assess Study Drug 
Compliance 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant Medications  
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
Follow-up Phone Contact7 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
2 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Genotyping sample will be drawn at Week 84 or at the time of re-consent for the optional follow-up treatment period; sample will be used to provide a full 
characterization and documentation of the mutation type in support of the diagnosis of PFIC. 
6 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
7 
Subjects must be available to receive a phone call from study staff. 
8 
Once necessary approvals are received for Protocol Amendment 4 and associated consent/assent documents are available, site will consent/assent patient for 
Protocol Amendment 4 at next clinic visit. 
9 
Once necessary approvals are received for Protocol Amendment 4 and associated consent/assent has been signed, site will assess patient eligibility for 
Protocol Amendment 4.  Depending on outcome of ADE eligibility assessment, patient will move into either Schedule of Procedures E or F.  Of note: It is 
possible that subject will not necessarily complete up through Week 120 before they move to Schedule of Procedures E or F.   
10 
Sample will require consenting under PA4 and will be drawn once, at the time of such re-consent. 
  
 
A 
At indicated visits during treatment period, oxalate will be part of the UA. 
B  
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 84, Week 96, Week 108,  and Week 120 visits. 
C 
A Week 124 (or ET) visit (Study Day 868 ± 14 days) was included in Protocol Amendment 3. 
 
 
 
Clinic Visit 
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 39 of 108 
3.6.4. Schedule of Procedures D – Optional Follow-Up Treatment Period: Week 72 – Week 120  
For Subjects With Interruption in MRX 'RVLQJGD\V,QFOXGHV(YDOXDWLRQRI(OLJLELOLW\IRU%,''RVLQJ5HJLPHQ 
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
Dose-escalation (DE) 
Continuation of Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 DE 
73 
DE 
74 
DE 
75
DE 
76 
80
84 
88 
92 
96 
100 
104 
108 
112 
116 
120c 
Study Day 
-14 
0 
511* 518* 525* 532* 560* 
588* 
616* 
644* 
672* 
700*
728* 
756* 
784* 
812* 
840* 
Window (in days)
(±14) 
(±2) 
(±2) (±2) (±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Informed 
Consent/Assent for 
study re-entry under 
PA311 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess Eligibility 
for study re-entry 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent/Assent for 
PA4 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
Afternoon dose-
escalation (ADE) 
eligibility 
assessment followed 
by shift in visit 
schedule9 
 
 
 
 
 
 
 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
Physical Exam 
X 
X
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Body Weight & 
Height 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Vital Signs1 
X 
X
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
CBC with 
Differential2 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Coagulation2 
X 
X
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Chemistry Panel2 
X 
X
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Lipid Panel2,3 
X 
X
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Cholestasis 
Biomarkers2,3 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
FAT-Soluble 
Vitamins2,3,4 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 40 of 108 
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
Dose-escalation (DE) 
Continuation of Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 DE 
73 
DE 
74 
DE 
75
DE 
76 
80
84 
88 
92 
96 
100 
104 
108 
112 
116 
120c 
Study Day 
-14 
0 
511* 518* 525* 532* 560* 
588* 
616* 
644* 
672* 
700*
728* 
756* 
784* 
812* 
840* 
Window (in days)
(±14) 
(±2) 
(±2) (±2) (±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Optional 
Genotyping5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis2 
X 
X
 
X 
 
X 
 
X 
 
 
X 
 
Xa 
 
 
Xa 
Exome Sequencing 
Sample10 
 
 
 
 
 
 
 
X10 
 
 
X10 
 
X10 
 
 
X10 
Serum or Urine 
Pregnancy Test (if 
indicated)6 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Clinician Scratch 
Scale 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
 
 
 
 
 
Xb 
Xb 
to 
Week 
86 
 
Xb 
Xb 
to 
Week 
98 
 
Xb 
Xb 
to 
Week 
110 
 
Xb 
PedsQL 
 
X
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
Patient/Caregiver 
Impression of 
Change  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Caregiver Global 
Therapeutic Benefit 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Study Drug 
Supplied 
 
X
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
Assess Compliance 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Concomitant 
Medications  
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X 
Adverse Events 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X 
Follow-up Phone 
Contact7 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X
X 
 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
2 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Optional genotype sample will be performed to provide a full characterization and the associated documentation of the mutation type in support of the diagnosis of 
PFIC. 
6 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
7 
Subjects must be available to receive a phone call from study staff. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 41 of 108 
Study Period 
Treatment Period (continued) 
Follow-up Treatment Period  
Dose-escalation (DE) 
Continuation of Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 DE 
73 
DE 
74 
DE 
75
DE 
76 
80
84 
88 
92 
96 
100 
104 
108 
112 
116 
120c 
Study Day 
-14 
0 
511* 518* 525* 532* 560* 
588* 
616* 
644* 
672* 
700*
728* 
756* 
784* 
812* 
840* 
Window (in days)
(±14) 
(±2) 
(±2) (±2) (±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
8   
Once necessary approvals are received for Protocol Amendment 4 and associated consent/assent documents are available, site will consent/assent patient for 
Protocol Amendment 4 at next clinic visit. 
9   
Once necessary approvals are received for Protocol Amendment 4 and associated consent/assent has been signed, site will assess patient eligibility for Protocol 
Amendment 4.  Depending on outcome of ADE eligibility assessment, patient will move into either Schedule of Procedures E or F.  Of note: It is possible that 
subject will not necessarily complete up through Week 120 before they move to Schedule of Procedures E or F.   
10     Sample will require re-consenting under PA4 and will be drawn once, at the time of such re-consent. 
11 
For subjects re-entering under Protocol Amendment 3, Baseline laboratory values are considered those collected at re-entry visit DE-2 weeks 
 
* 
Calculation of Study Day includes subject’s participation through the first 72 weeks. 
 
A 
At indicated visits during treatment period, oxalate will be part of the UA. 
B  
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 84, Week 96, Week 108,  and Week 120 visits. 
C 
A Week 124 (or ET) visit (Study Day 868 ± 14 days) was included in Protocol Amendment 3. 
 
 
 
 
Clinic Visit 
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 42 of 108 
3.6.5. Schedule of Procedures E – Extension of Optional Follow-Up Treatment Period, Subject Ineligible for ADE
Applicable as follows:  
x Subject did not yet complete the optional follow up treatment period as outlined under Protocol Amendment 3 and is 
able to consent to Protocol Amendment 4 activities without an interruption in  MRX dosing, OR 
x Subject completed optional follow up treatment period as outlined under PA3 and dosing interruption was <7 days. 
x Subject deemed ineligible for ADE.   
 
Below study activities repeat in recurring 12 week periods7 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
4 weeks after consent 
under PA4 
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Physical Exam 
 
 
X 
Body Weight & Height 
 
 
X 
Vital Signs1 
 
 
X 
CBC with Differential2 
 
 
X 
Coagulation2 
 
 
X 
Chemistry Panel2 
 
 
X 
Lipid Panel2,3 
 
 
X 
Cholestasis Biomarkers2,3 
 
 
X 
FAT-Soluble Vitamins2,3,4 
 
 
X 
Urinalysis2 
 
 
Xa 
AFP Sample 
 
 
X8 
Serum or Urine Pregnancy Test 
(if indicated)5 
 
 
X 
Clinician Scratch Scale 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
X 
(collected for 2 
week period 
following this 
visit) 
PedsQL 
 
 
X 
Palatability Questionnaire 
 
 
X 
Study Drug Supplied 
 
 
X 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 43 of 108 
 
Below study activities repeat in recurring 12 week periods7 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
4 weeks after consent 
under PA4 
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Assess Compliance 
 
 
X 
Concomitant Medications  
X 
X
X 
Adverse Events 
X 
X
X 
Follow-up Phone Contact6 
X 
X
 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
2 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7 
Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible 
to enter another MRX study or (ii) MRX is available commercially.  
8       Sample will be drawn at every other clinic visit.   
 
A 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
 
 
Clinic Visit 
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 44 of 108 
Schedule of Procedures F – Extension of Optional Follow-Up Treatment Period, Subjects eligible for ADE 
Applicable as follows:  
x Subject did not yet complete the optional follow up treatment period as outlined under Protocol Amendment 3 (PA3) 
and is able to consent to Protocol Amendment 4 activities without an interruption in  MRX dosing OR 
x Subject completed the optional follow up treatment period as outlined under PA3 and dosing interruption was <7 days. 
x Subject deemed eligible for ADE. 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose-escalation (ADE) 
 
Study activities repeat in recurring 12 week periods 
after completion of the ADE period7 
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Physical Exam 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & 
Height 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signs1 
X 
 
 
X 
 
 
X 
 
 
X 
CBC with 
Differential2 
X 
X 
X 
X 
Coagulation2 
X 
 
 
X 
 
 
X 
 
 
X 
Chemistry 
Panel2 
X 
X 
X 
X 
Lipid Panel2,3 
X 
 
 
X 
 
 
X 
 
 
X 
Cholestasis 
Biomarkers2,3 
X 
X 
X 
X 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 45 of 108 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose-escalation (ADE)
 
Study activities repeat in recurring 12 week periods 
after completion of the ADE period7
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
FAT-Soluble 
Vitamins2,3,4 
X 
 
 
X 
 
 
X 
 
 
X 
Urinalysis2 
X 
 
 
X 
 
 
X 
 
 
Xa 
AFP Sample 
 
 
 
 
 
 
 
 
 
X8 
Plasma Sample 
for MRX9 
X 
 
 
X 
 
 
X 
 
 
X9 
Serum or Urine 
Pregnancy Test 
(if indicated)5 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician 
Scratch Scale 
X 
 
 
X 
 
 
X 
 
 
X 
Caregiver 
ItchRO/ 
Patient ItchRO 
 
 
 
 
 
 
 
 
 
X 
(collected for 2 
week period 
following this 
visit) 
PedsQL 
X
X
X
X 
Palatability 
Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Supplied
X 
 
 
X 
 
 
X 
 
 
X 
Assess 
Compliance 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 46 of 108 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose-escalation (ADE)
 
Study activities repeat in recurring 12 week periods 
after completion of the ADE period7
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up 
Phone Contact6 
 
X 
X 
 
X 
X 
 
X 
X 
 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
2 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7       Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another MRX study or (ii) MRX is available commercially. 
8       Sample will be drawn at every other clinic visit.   
9       PK sample will additionally be collected at the three scheduled clinic visits following completion of the afternoon dose-escalation period.   
 
A 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
Clinic Visit 
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 47 of 108 
3.6.6. ParticipantSchedule of Procedures G – Optional Follow-Up Treatment Period: Re-Entry Under Protocol Amendment 4 
Applicable as follows: 
x Subject previously completed (or early terminated from ) the optional follow up treatment period as defined under 
Protocol Amendment 3 and has subsequently experienced an interruption in MRX GRVLQJGD\V 
x Subject is considered eligible for study re-entry under Protocol Amendment 4 
x Subject eligibility will be assessed for afternoon dose-escalation at Protocol Amendment 4 DE Week 8 shown in the 
table below.   
o If subject is found to be ineligible for ADE, subject will move from Schedule G to Schedule H. 
o If subject is found to be eligible for ADE, subject will move from Schedule G to Schedule I. 
Study Period 
Protocol Amendment 4 Follow-up Treatment Period  
Dose-escalation (DE) 
PA4 DE Study 
Week 
PA4 
DE -2 
PA4 
DE 
Day 0 
PA4 
DE  
Week 1 
PA4 
DE 
Week 2 
PA4
DE  
Week 3 
PA4 
DE  
Week 4 
PA4  
DE  
Week 8 
Scheduling 
Considerations 
-14
0 
 
 
 
 
 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
Informed 
Consent/Assent8 
X 
 
 
 
 
 
 
Assess Eligibility 
for study re-entry 
X 
X 
 
 
 
 
 
Assess Eligibility 
for ADE 
 
 
 
 
 
X 
Physical Exam 
X 
X 
 
X 
 
X 
 
Body Weight & 
Height 
X 
X 
 
X 
 
X 
 
Vital Signs1 
X 
X 
 
X 
 
X 
 
CBC with 
Differential2 
X 
X 
 
X 
 
X 
 
Coagulation2 
X 
X 
 
X 
 
X 
 
Chemistry Panel2 
X 
X 
 
X 
 
X 
 
Lipid Panel2,3 
X 
X 
 
X 
 
X 
 
Cholestasis 
Biomarkers2,3 
X 
X 
 
X 
 
X 
 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 48 of 108 
Study Period 
Protocol Amendment 4 Follow-up Treatment Period  
Dose-escalation (DE) 
PA4 DE Study 
Week 
PA4 
DE -2 
PA4 
DE 
Day 0 
PA4 
DE  
Week 1 
PA4 
DE 
Week 2 
PA4
DE  
Week 3 
PA4 
DE  
Week 4 
PA4  
DE  
Week 8 
Scheduling 
Considerations 
-14
0 
 
 
 
 
 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
FAT-Soluble 
Vitamins2,3,4 
X 
X 
 
X 
 
X 
 
Urinalysis2 
X 
X 
 
X 
 
X 
 
Exome Sequencing 
Sample7 
X 
 
 
 
 
 
 
Serum or Urine 
Pregnancy Test (if 
indicated)5 
X 
X 
 
X 
 
X 
 
Clinician Scratch 
Scale 
X 
X 
 
X 
 
X 
 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
 
 
X  
(collected for 2 
week period 
following this visit) 
 
PedsQL 
X 
 
 
 
 
 
Study Drug 
Supplied 
X 
 
X 
 
X 
 
Assess Compliance 
 
 
X 
 
X 
 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone 
Contact6 
 
X 
 
X 
 
X 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
2 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7       Sample will be drawn once, at the time of consent under PA4. 
8 
For subjects re-entering under Protocol Amendment 4, Baseline laboratory values are considered those collected at re-entry visit PA4 DE-2 weeks. 
 
 
 
 
Clinic Visit 
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 49 of 108 
3.6.7. Schedule of Procedures H – Optional Follow-Up Treatment Period: Re-Entry Under Protocol Amendment 4, Subject 
Ineligible for ADE 
 
Below study activities repeat in recurring 12 week periods7 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
The Week 4 visit of 
the first repeating 
period will take place 
4 weeks after PA4 DE 
Week 8  
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Physical Exam 
 
 
X 
Body Weight & Height 
 
 
X 
Vital Signs1 
 
 
X 
CBC with Differential2 
 
 
X 
Coagulation2 
 
 
X 
Chemistry Panel2 
 
 
X 
Lipid Panel2,3 
 
 
X 
Cholestasis Biomarkers2,3 
 
 
X 
FAT-Soluble Vitamins2,3,4 
 
 
X 
Urinalysis2 
 
 
Xa 
AFP Sample 
 
 
X8 
Serum or Urine Pregnancy Test 
(if indicated)5 
 
 
X 
Clinician Scratch Scale 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
X 
(collected for 2 
week period 
following this 
visit) 
PedsQL 
 
 
X 
Palatability Questionnaire 
 
 
X 
Study Drug Supplied 
 
 
X 
Assess Compliance
 
 
X 
Concomitant Medications  
X 
X
X 
Adverse Events 
X 
X
X 
Follow-up Phone Contact6 
X 
X
 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 50 of 108 
 
Below study activities repeat in recurring 12 week periods7 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
The Week 4 visit of 
the first repeating 
period will take place 
4 weeks after PA4 DE 
Week 8  
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
2 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes.
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7       Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible 
to enter another MRX study or (ii) MRX is available commercially. 
8       Sample will be drawn at every other clinic visit.   
 
A 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
Clinic Visit 
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 51 of 108 
3.6.8. Schedule of Procedures I – Optional Follow-Up Treatment Period: Re-Entry Under Protocol Amendment 4, Subject 
Eligible For ADE 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose-escalation (ADE) 
 
Study activities repeating in recurring 12 week periods 
after completion of the ADE period7 
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE 
Week 4 
ADE 
Week 5 
ADE 
Week 6 
ADE 
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Physical Exam 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & 
Height 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signs1 
X 
 
 
X 
 
 
X 
 
 
X 
CBC with 
Differential2 
X 
 
 
X 
 
 
X 
 
 
X 
Coagulation2 
X 
 
 
X 
 
 
X 
 
 
X 
Chemistry 
Panel2 
X 
 
 
X 
 
 
X 
 
 
X 
Lipid Panel2,3 
X 
 
 
X 
 
 
X 
 
 
X 
Cholestasis 
Biomarkers2,3 
X 
 
 
X 
 
 
X 
 
 
X 
FAT-Soluble 
Vitamins2,3,4 
X 
 
 
X 
 
 
X 
 
 
X 
Urinalysis2 
X 
 
 
X 
 
 
X 
 
 
Xa 
AFP Sample 
 
 
 
 
 
 
 
 
 
X8 
Plasma Sample 
for MRX9 
X 
 
 
X 
 
 
X 
 
 
X9 
Serum or Urine 
Pregnancy Test 
(if indicated)5 
X 
 
 
X 
 
 
X 
 
 
X 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 52 of 108 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose-escalation (ADE)
 
Study activities repeating in recurring 12 week periods 
after completion of the ADE period7
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above
(±2) 
(±2) 
(±2) 
 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Clinician 
Scratch Scale 
X 
 
 
X 
 
 
X 
 
 
X 
Caregiver 
ItchRO/ 
Patient ItchRO 
 
 
 
 
 
 
 
 
 
X 
(collected for 2 
week period 
following this 
visit) 
PedsQL 
X 
 
 
X 
 
 
X 
 
 
X 
Palatability 
Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Supplied 
X 
 
 
X 
 
 
X 
 
 
X 
Assess 
Compliance 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up 
Phone Contact6 
 
X 
X 
 
X 
X 
 
X 
X 
 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 53 of 108 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose-escalation (ADE)
 
Study activities repeating in recurring 12 week periods 
after completion of the ADE period7
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above
(±2) 
(±2) 
(±2) 
 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
2 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
6 
Subjects must be available to receive a phone call from study staff. 
7       Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another MRX study or (ii) MRX is available commercially. 
8       Sample will be drawn at every other clinic visit.   
9       PK sample will additionally be collected at the three scheduled clinic visits following completion of the afternoon dose-escalation period.   
 
A 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
Clinic Visit 
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 54 of 108 
3.6.9. Schedule of Procedures J – End of Treatment (EOT) / Early Termination (ET) Visit and Post-Treatment Safety Follow-
Up  
 
EOT  / ET 
Safety Follow Up 
Scheduling 
Considerations
To take place upon 
completion of study7 or at 
the time of early 
withdrawal 
Minimum of 30 days 
after final dose 
Physical Exam 
X 
 
Body Weight & Height 
X 
 
Vital Signs1 
X 
 
CBC with Differential2 
X 
 
Coagulation2 
X 
 
Chemistry Panel2 
X 
 
Lipid Panel2,3 
X 
 
Cholestasis Biomarkers2,3 
X 
 
FAT-Soluble Vitamins2,3,4 
X 
 
Urinalysis2 
Xa 
 
AFP Sample 
X 
 
Serum or Urine Pregnancy 
Test (if indicated)5 
X 
 
Clinician Scratch Scale 
X 
 
PedsQL 
X 
 
Patient/Caregiver 
Impression of Change 
X 
 
Caregiver Global 
Therapeutic Benefit 
X 
 
Palatability Questionnaire 
X 
 
Assess Compliance 
X 
 
Concomitant Medications  
X 
X 
Adverse Events 
X 
X 
Follow-up Phone Contact6 
 
X 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 55 of 108 
 
EOT  / ET 
Safety Follow Up 
Scheduling 
Considerations
To take place upon 
completion of study7 or at 
the time of early 
withdrawal 
Minimum of 30 days 
after final dose 
1 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
2 
See Section 16.2 of Protocol Amendment 4 for detailed list of laboratory analytes. 
3 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
4 
Blood samples must be drawn before administration of vitamin supplementation. 
5 
Females of childbearing potential. 
6 
Subjects must be available to receive a phone call from study staff. 
7       Will take place when the first of the following occur: (i) subjects are eligible to enter another     
MRX study or (ii) MRX is available commercially.   
 
A 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
Clinic Visit
 
Phone Contact 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 56 of 108 
4.
Statistical Analysis and Reporting 
Statistical analysis will be performed following Premier Research’s Standard Operating 
Procedures (SOPs). 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed using SAS (release 9.4 or higher). 
Data summaries will be presented for PFIC1 and PFIC2 subjects independently and for all 
subjects combined. Select efficacy variables will also be presented by PFIC2 subtype (truncating 
and non-truncating). 
Continuous (quantitative) variables will be summarized using descriptive statistics including 
number of subjects (n) with non-missing values, mean, 2-sided 95% confidence interval (CI) for 
the mean, standard deviation (SD), and/or standard error of the mean (SE), median, minimum, 
and maximum.  
Categorical (qualitative) variable summaries will include the number and percentage of subjects 
who are in each particular category. In general, the denominator for the percentage calculation 
will be based upon the total number of subjects in the analysis population for the PFIC 
type/subtype, and/or treatment phase, 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, unless otherwise specified. Measures of location 
(mean and median) will be reported to 1 degree of precision more than the observed data and 
measures of spread (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, along with select laboratory values of autotaxin, FGF-19, and FGF-21, will be 
presented as integers. Derived values for BMI, PedsQL summary and total scale scores, along 
with select laboratory values of sBA, 25-hydroxyvitamin D, vitamin A, and pH, will be 
presented to 1 decimal place. Derived values of height, weight, and BMI z-scores, and ItchRO 
DYHUDJHYDOXHVDORQJZLWKVHOHFWODERUDWRU\YDOXHVRIFUHDWLQLQHĮ-tocopherol, RBP, retinol:RBP 
molar ratio, and alpha tocopherol/total lipids will be reported to 2 decimal places.  
Percentages will be presented to 1 decimal place, unless otherwise specified. Where the number 
of subjects in a particular category is 0, a percentage (i.e., 0.0%) will not be displayed. 
All statistical tests will be conducted using 2-tailed tests at the 0.05 significance level, with 
corresponding 95% CIs and p-values presented. A p-value of d 0.10 but > 0.05 will be 
considered evidence of a trend. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 57 of 108 
All final, planned analyses identified in this SAP will be performed after all relevant study data 
have been processed and integrated into the analysis database, and the database has been locked. 
Any post-hoc, exploratory analysis completed to support planned study analyses, which were not 
identified in this SAP, will be documented and reported in Section 9.8 of the CSR. Any results 
from these unplanned analyses (post-hoc) will also be clearly identified as such in the text of the 
CSR. 
4.2.
Data Monitoring 
A data monitoring committee (DMC) will review SAE data and other key subject safety and 
study data at specified intervals for the duration of the study. The DMC will be composed of at 
least 2 members who are otherwise independent from the conduct of the study and 1 
biostatistician. The DMC’s primary responsibility is to review the progress of the study, 
particularly with regard to safety and risk/benefit, and make recommendations to the sponsor to 
stop or modify the trial if safety concerns are identified. Further details regarding the structure, 
function, and operation of the DMC are detailed in the DMC charter. 
4.3. 
Interim and Final Analyses 
A minimum of 4 analyses of the data are planned: at least 3 planned interim analyses and a final 
analysis. The first planned interim analysis of safety and efficacy parameters will be performed 
after the first 12 subjects who met the PP Population definition have completed the Week 13 
study visit. This analysis will provide initial information about the safety and potential 
therapeutic activity of MRX in the study population. A second planned interim analysis will be 
performed after all enrolled subjects have completed the Week 48 (or Early Termination) study 
visit. This analysis includes subject activity up through Week 72 that has occurred on or before 
14Jun2016 and will provide an assessment of the long-term safety and efficacy of MRX. A third 
planned interim analysis will be performed after all enrolled subjects have completed at least 6 
months of treatment under Protocol Amendment 4 (or the Early Termination visit). This analysis 
will provide an assessment of the long-term safety and efficacy of MRX. A final analysis of the 
data will be performed after all enrolled subjects have completed their final (or Early 
Termination) study visit. Details of these analyses are specified below. 
The results of the interim analyses may lead to changes in the study design. Staff directly 
involved in the conduct of the study, including the DMC, will review the results of the interim 
analyses. Interim study information may be shared with study investigators, investigator staff, 
study monitors, or sponsor employees or other personnel. 
4.3.1. First Interim Analyses 
The first planned interim analyses will take place after the first 12 subjects who meet the PP 
Population criteria have completed the Week 13 study visit. This analysis will present data on 
key safety and efficacy variables, and is intended to provide initial information about the 
potential therapeutic activity of MRX in the study population.  


Statistical Analysis Plan,  
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Protocol Number LUM001-501  
 
PCN Number LUME2940 
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Safety analyses will include all available AE data from all subjects in the Safety Population. 
Efficacy analyses will include all available primary and secondary efficacy data through the first 
interim analysis cut-off (March 23, 2015) in the mITT and PP populations.  
The following data will be presented for the first interim analysis: 
x Demographic data  (PP and Safety populations) 
x Disease history and baseline disease characteristics  (PP and Safety populations) 
x Treatment compliance  (Safety Population) 
x Fasting sBA  (PP and mITT populations) 
x ALT  (PP and mITT populations) 
x Total bilirubin  (PP and mITT populations) 
x Direct bilirubin  (PP and mITT populations) 
x C4 (PP and mITT populations) 
x ItchRO weekly average score (observer and patient)  (PP and mITT populations) 
x PedsQL Total Scale Score (Parent) (PP and mITT populations) 
x AEs  (Safety Population) 
Data will be presented with descriptive statistics only. Efficacy variables will be tabulated by all 
available visits (including Week 13/ET) with changes from baseline. 
Treatment compliance for ongoing subjects will be based on the date of the latest visit to have 
accountability data at the time of the cut. For efficacy outputs, if a subject is ongoing, the cut-off 
for determining if a visit is on-treatment for the Week 13/ET summaries is based on the latest 
visit from all domains. 
See Section 14.1 for details of the tables to be included in the first interim analysis. 
For the first interim analysis, subject listings will be generated for AEs, SAEs, and efficacy data, 
including efficacy laboratory tests, ItchRO (Pt and Obs) reported outcomes, PIC, CIC, CGTB, 
and CSS scores. A figure depicting individual subject exposure to study drug over the treatment 
period will also be provided. 
4.3.2. Second Interim Analyses 
The second planned interim analyses will be performed after all enrolled subjects have 
completed the Week 48 (or Early Termination) study visit and will include subject activity up 
through Week 72 that has occurred on or before 14Jun2016. This analysis will present data on 
key safety and efficacy variables, and is intended to provide initial information about the 
potential long-term therapeutic activity of MRX in the study population. For this interim 
analysis, over 90% of the enrolled subjects are expected to have completed the Week 48 
assessments.  


Statistical Analysis Plan,  
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Safety analyses will include any AE that started on or before the 14Jun2016 analysis cut-off date. 
Efficacy analyses will include all available efficacy data through the second interim analysis cut-
off. Safety and efficacy analyses will be performed in the Safety Population.  
For this interim analysis, the last dose date will be set to 14Jun2016 for subjects that are ongoing 
in the study and on treatment after the cut-off date. For the interim analysis, any AE that started 
after the cut-off date will be excluded from the safety analyses. 
Section 14 provides a complete list of tables and listings, along with a description of the figures, 
to be included in the second planned interim analysis. All subject listings will be sorted by PFIC 
type (i.e., PFIC1, PFIC2). 
Analyses described in SAP Amendment 1 will be followed for the second planned interim 
analyses.  
4.3.3. Third Interim Analyses 
The third planned interim analyses will be performed after all enrolled subjects have completed 
at least 6 months of treatment under PA4 (or the Early Termination visit) and will thus include 
subject activity that has occurred on or before 20Feb2018. This analysis will provide an 
assessment of the long-term safety and efficacy of MRX. 
Safety analyses will include any AE that started on or before the 20Feb2018 analysis cut-off 
date. Efficacy analyses will include all available efficacy data through the analysis cut-off date. 
Efficacy analyses will be performed in the mITT Population. Safety and all other analyses will 
be performed in the Safety Population.  
For this interim analysis, the last dose date will be set to 20Feb2018 for subjects that are ongoing 
in the study and on treatment after the cut-off date. For the interim analysis, any AE that started 
after the cut-off date will be excluded from the safety analyses. 
Section 14.1 provides a complete list of tables to be included in the third planned interim 
analysis. The following figures will also be included in this interim analysis (see Section 14.2):  
change from baseline in sBA levels over time (Figure 14.2.4.1), change from baseline in ItchRO 
(Obs) 4-week morning average score over time (Figure 14.2.9.1.2), change from baseline in CSS 
over time (Figure 14.2.14), study drug exposure by subject (Figure 14.3.1), and TEAEs over time 
and individual subject (Figure 14.3.2). A subject profile listing that includes select labs and 
pruritus (itch/scratch) scores (Listing 16.1.1) will also be included for this analysis (see Section 
14.3). 
Analyses described in SAP Amendment 2 will be followed for the third planned interim 
analyses. At the time of the analysis cut-off date (20Feb2018), all subjects had either withdrawn 
early or completed the study through Week 72. The LUM001-501 CSR, dated 07May2020, 
focused on data collected or assessed through Week 72. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
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4.3.4. Final Analysis 
Safety analyses will include all subjects in the Safety Population. Efficacy analyses will include 
all subjects in the ITT analysis population. Analyses described in SAP Amendment 3 will be 
followed for the final analyses. 
4.3.5. Posthoc Analyses 
Additional analyses may be performed to explore both safety and efficacy measures collected 
during this study. The precise methods and analyses will be determined after the final analyses 
are performed. Thus, all such analyses will be interpreted cautiously and not used for formal 
inference. 
5.
Analysis Populations 
The following analysis populations are planned for this study:  
x Safety Population (SAF): The Safety Population is defined as all subjects who were 
assigned to receive and received at least 1 dose of the study drug. The Safety Population 
will be used for all safety analyses. 
x Modified Intent-To-Treat Population (mITT): The mITT Population is defined as all 
subjects who were assigned, received at least 1 dose of treatment, and have at least 1 
post-baseline primary efficacy assessment (i.e., serum bile acid laboratory value). The 
mITT Population is the main population for efficacy analysis for the 3rd planned interim 
analysis. 
x Intent-To-Treat Population (ITT): The ITT Population is defined as all subjects who 
were assigned, and received at least 1 dose of treatment. For the final analyses, the ITT 
Population is the analysis set used for efficacy analyses. 
x Per-Protocol Population (PP): The PP Population consists of all subjects in the mITT 
Population who do not have a major, non-evaluable protocol deviation (see Section 7.2). 
The PP Population was used in the 1st planned interim analysis. No summaries are 
planned for the final analyses using this analysis population. 
Because PFIC is a rare disease, siblings were allowed to enroll in the study. The use of siblings 
in each analysis population is discussed in Section 6.1.11. 
6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
For all visit-based efficacy analyses, and for visit-based safety data that is collected or assessed 
before an extended (> 28-day) drug interruption period (between protocol amendments), the 
following baseline definition will be used for change from baseline values: 


Statistical Analysis Plan,  
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• 
Baseline (Day 0): The observation obtained at Study Day 0 (before first dose of 
study drug) will be used as the baseline (Day 0) observation for all calculations of 
change from baseline (Day 0). If Study Day 0 is not available/missing, the last value 
obtained during the screening period is used as the baseline (Day 0) observation.  
For ItchRO weekly average scores, baseline is defined as the average of daily scores in the week 
consisting of the 7 days immediately before the baseline visit (Study Day 0). For ItchRO weekly 
morning/evening average scores, baseline is defined as the average of morning/evening scores 
consisting of the 7 days immediately before the baseline visit. For the ItchRO 4-week 
morning/evening average scores, baseline is defined as the average of morning/evening scores in 
the 4-week period consisting of the 28 days immediately before the baseline visit (Study Day 0). 
The derivation of weekly and 4-week baseline ItchRO average scores will use up to 7 and 28 
daily scores, respectively, with no minimum daily requirement applied. 
Visit-based safety data collected or assessed after a > 28-day drug interruption period (between 
protocol amendments) will not be included in analysis summaries.    
6.1.2. Study Day 
Day 1 is defined as the date of first study drug administration. Study day is calculated relative to 
the date of Day 1. 
6.1.3. Adjustments for Covariates 
No adjustments will be made for covariates. 
6.1.4. Multiple Comparisons 
No adjustments will be made for multiple comparisons. 
6.1.5. Handling of Dropouts or Missing Data 
General 
In addition to the time points specified in the protocol, efficacy and visit-based safety endpoints 
will also be analyzed in a LOCF approach at Week 72 (Week 48 for ItchRO endpoints) and 
Week 124 (Week 122 for ItchRO endpoints).  
If any assessment/visit occurs more than 7 days after the date of last dose on PA2, PA3, or PA4 
(i.e., “last dose”), and before dose re-initiation, the assessments performed during that visit will 
not be used in analysis summaries (see Section 6.1.6). 
Rules for handling missing or partial AE, concomitant medication, date of birth, or original PFIC 
diagnosis dates are described in Section 6.1.11. 
The sensitivity of efficacy and safety results to missing data assumptions are discussed in 
Section 8.4. 


Statistical Analysis Plan,  
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Protocol Number LUM001-501  
 
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Primary and Secondary Efficacy Endpoints 
Based on the intent-to-treat principle, all subjects included in the ITT Population will be included 
in the primary analysis of primary and secondary efficacy endpoints. 
LOCF Imputation 
In addition to the time points specified in the protocol, efficacy and visit-based safety variables 
will also be analyzed (as a sensitivity analysis) at the following LOCF time points: 
Week 48/LOCF (ItchRO variables only), Week 72/LOCF (non-ItchRO variables), 
Week 122/LOCF (ItchRO variables only), and Week 124/LOCF (non-ItchRO variables), where 
appropriate. 
Subjects that did not complete at least 1 post-Week 72 assessment (Week 48 for ItchRO) will be 
excluded from all post-Week 72 (Week  48 for ItchRO) analyses. Subjects that did not complete 
at least 1 post-Week 124 assessment will be excluded from all post-Week 124 analyses. 
Each LOCF time point is defined as the last post-baseline value obtained on or before the date of 
“last dose” plus 7 days within the defined study period (i.e., Week 48, 72, 122, or 124). For 
ItchRO measurements, averages scores at LOCF time points will use the last average score prior 
to the designated LOCF time point (i.e., Week 48 or Week 122) carried forward.  
ItchRO Assessments 
In the event that either the morning or evening ItchRO reports are not completed within the 
allowed reporting window, the completed report will represent the daily score. In the event that a 
subject/caregiver failed to complete both the morning and evening report, the daily score for that 
day will be treated as missing data. 
If a subject/caregiver is not compliant with reporting ItchRO assessments during the 7-day 
period before a study visit, the weekly average score from the most recent, previous compliant 7-
day period will be used in a LOCF format. For non-compliant 4-week ItchRO assessments (i.e., 
morning and evening scores), the most recent compliant 28-day period will be used, where the 
28 days minus the 7 days immediately before the study visit will be used. This process will be 
repeated as necessary. For example, if the 28-day period before the Week 8 visit (e.g., Study 
Days 28-55) is non-compliant, then Study Days 21-48 would be used. If that 4-week period is 
non-compliant then the 4-week ItchRO morning/evening score would be missing. Additionally, 
the same ItchRO assessment day (morning/evening/daily score) will not be used across different 
weekly/4-week time periods (i.e., no overlap). 
For post-baseline average ItchRO scores, on-study compliance is defined as having at least 4 of 
the 7 daily scores for a 7-day period, and at least 20 of the 28 daily morning/evening scores for a 
28-day period. The derivation of weekly and 4-week baseline ItchRO average scores will use up 
to 7 and 28 daily scores, respectively, with no minimum daily requirement applied. 
ItchRO assessments that occur during non-dosing days that are more than 7 days after the date of 
the “last dose”, and before dose re-initiation, will not be used for deriving ItchRO average 
scores. 


Statistical Analysis Plan,  
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PedsQL Assessments 
For PedsQL scale scores, if more than 50% of the items in the scale are missing, the scale score 
is not computed (see Section 6.1.10). 
Responder Definitions 
If a subject has a missing sBA or ItchRO value at a week required in determining responder 
status, then the missing change from baseline value will be considered as not meeting the criteria 
for a responder. 
Adverse Event Severity and Relationship 
For analysis purposes, only the following rules will be applied for missing AE severity or 
relationship to study drug. An AE that does not have a reported relationship to study drug value 
will be considered as “potentially related” to study drug. If the severity of an AE is missing, the 
severity will be reported as “severe”. 
Fat Soluble Vitamin (FSV) Data
For analysis purposes, missing FSV lab values will be reported in a “Missing” category in 
summarizing FSV level abnormalities. 
6.1.6. Analysis Visit Windows 
Analyses of all visit-based efficacy and safety variables will be performed using the analysis visit 
windows as defined in this section. Table 1 addresses scheduled post-baseline assessments; 
baseline assessments are described in Section 6.1.1. Scheduled visits will be selected over 
unscheduled visits. 
Analyses of all efficacy variables, regardless of drug interruptions, will be performed using 
analysis visits. For subjects with an extended drug interruption, efficacy assessments after the 
interruption are essentially treated as if the subject was on study drug during the period of time 
that the subject was off study drug.  
The analysis visit windows in Table 1 will also be used for all visit-based safety assessments that 
occurred before an extended (>28-day) drug interruption (due to a protocol amendment), 
including those subjects without such a drug interruption. Visit-based safety data collected or 
assessed after a > 28-day drug interruption period (between protocol amendments) will not be 
included in analysis summaries. 
For those subjects who discontinue early from the study, Table 1 will also be used to assign the 
appropriate analysis visit to the ET visit. For subjects that were dose-escalated after a drug 
interruption of > 28 days (between protocol amendments), the data collected/assessed during the 
dose-escalation period (i.e., DE Week -2 and DE Day 0 for both PA3 and PA4) will not be 
assigned to a post-dose analysis visit.  


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
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The study day will be calculated for each scheduled or ET post-baseline visit (and/or assessment) 
relative to the date of first dose of study drug, and compared to the assessment window presented 
in Table 1, as appropriate, 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 60 but a specific assessment 
(e.g., PedsQL or CGTB score) was not scheduled at that visit (see Section 3.6, Study Period and 
Schedule of Procedures), then that assessment will not be used for analyses. 
Average ItchRO scores, which are derived by anchoring on scheduled in-clinic visit dates, will 
also be assigned to a study week for analysis according to Table 1. For analysis visits past 
Week 48, ItchRO average weekly scores are based on the 2-week period following the scheduled 
in-clinic visit, rather than the week before the scheduled in-clinic visit. Thus, the “Analysis 
Visit” and “Analysis Visit Name” will be adjusted accordingly (e.g., “Week 86” rather than 
“Week 84”).  
If more than 1 visit falls within the same visit window, the data from the visit closest to the target 
day will be used for the analysis visit. If 2 visits within the same visit window are equidistant 
from the target day, the data from the later visit will be used for the analysis visit. 
Adverse events and concomitant medications are exceptions to the above rules.  The treatment of 
AEs and concomitant medications that start during periods of dosing gaps are discussed in 
Section 6.1.11. 
 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
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Table 1 
Analysis Visit Windows – Visit-Based Analysis 
Analysis 
Visit 
Analysis Visit 
Name 
Target Day of 
Planned Visit 
Assessment Window 
(Study Days1) 
2 
Week 2 
14 
Post-GRVHņ 
4 
Week 4 
28 
2ņ42 
8 
Week 8 
56 
43 ņ 
13 
Week 13
91
75 – 130 
24 
Week 24 
168 
131 – 210 
36 
Week 36 
252 
211 – 294 
48 
Week 48 
336 
295 – 378 
60 
Week 60 
420 
379 – 461 
72 
Week 72
504
462 – 546 
84 
Week 84 
588 
547 – 630 
96 
Week 96 
672 
631 – 704 
108 
Week 108 
756 
705 – 788 
120 
Week 120 
840 
789 – 872 
132 
Week 132
924
873 – 956
144 
Week 144 
1008 
957 – 1040 
156 
Week 156 
1092 
1041 – 1124 
168 
Week 168 
1176 
1125 – 1203 
180 
Week 180 
1260 
1204 – 1287 
192 
Week 192 
1344 
1288 – 1371
204 
Week 204 
1428 
1372 – 1450 
216 
Week 216 
1512 
1451 – 1534 
228 
Week 228 
1596 
1535 – 1618 
240 
Week 240 
1680 
1619 – 1702 
252 
Week 252 
1764 
1703 – 1792
264 
Week 264 
1848 
1793 – 1876 
276 
Week 276 
1932 
1877 – 1950 
288 
Week 288 
2016 
1951 – 2034 
300 
Week 300 
2100 
2035 – 2118 
312 
Week 312 
2184 
2119 – 2202
324 
Week 324 
2268 
2203 – 2286 
336 
Week 336 
2352 
2287 – 2370 
348 
Week 348 
2436 
2371 – 2454 
360 
Week 360 
2520 
2455 – 2538 
1 Study day relative to the date of first dose of study drug. 
As a result of the study design, treatment extensions, and drug interruptions, study days are 
staggered within and between subjects across the study. To minimize the loss of data used for 
analysis, the assessment windows are not always equally spaced.


Statistical Analysis Plan,  
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6.1.7. Investigative Sites 
An investigative site is defined as a single principal investigator (including subinvestigators) who 
enroll subjects for the study. If an investigator has multiple practice locations, these locations are 
considered a single investigative site. 
Analyses will be based on data pooled across investigative sites.  
There is the potential that a subject could be transferred to a principal investigator that did not 
enrol the subject. Unless otherwise specified, the investigative site of the enrolling investigator 
will be used for the unique subject ID. 
6.1.8. Variable Definitions 
x “First dose” represents the first dose of study drug. 
x “Last dose” represents the last dose on PA2 (i.e., through Week 72), PA3 (i.e., 
through Week 124), and/or PA4 (i.e., through the end of treatment). 
x “End of Study” is the point at which the last contact with the last subject during the 
protocol-specified scheduled follow-up period is made. 
x “Screen Failure” is a subject who has signed the informed consent (e.g., original or 
protocol amendment) but does not meet the associated eligibility criteria, or otherwise 
chose not to participate in the study/extension, before receiving the “first dose” of 
study drug. 
x “Study Phase” used in compliance summaries (i.e., Weeks 0-13, Weeks 14-72, Weeks 
73-124, Week >124, and Weeks 0-EOT) will be visit-based. 
x “Week xx/LOCF” where xx=48 (ItchRO only), 72 (non-ItchRO variables), 122 
(ItchRO only), and 124 (non-ItchRO variables). See Section 6.1.5.  
6.1.9. Derived Variables 
x PFIC2 Subtype: 
Non-truncating if genotypic severity is ‘mild’ or ‘moderate’ 
 
Truncating if genotypic severity is ‘severe’ 
Only applicable for subjects with PFIC type = ‘PFIC2’. 
x Age (years) at Baseline 
For subjects in which only the partial date of birth (i.e., year of birth) is reported, the 
reported age in years at baseline will be used.  
Otherwise,  
    Age (years) at baseline = Integer of [ (baseline visit date – date of birth) / 365.25 ] 


Statistical Analysis Plan,  
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Protocol Number LUM001-501  
 
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x Age (months) at Baseline 
For subjects under 2 years of age, and in which only the year of birth is reported, the 
reported age in years and months at baseline will be used:  
Age (months) at baseline = (12 x Age (years) at baseline) + # of months at baseline 
Otherwise,  
    Age (months) at baseline = Integer of [(baseline visit date – date of birth) / 30.4375] 
Partial birth dates are imputed for analysis purposes as described in Section 6.1.11. 
x Age Group at Baseline: 
1 if age (full years) at baseline < 2 years 
2 if age (full years) at baseline is 2 to 4 years 
3 if age (full years) at baseline is 5 to 8 years 
4 if age (full years) at baseline is 9 to 12 years 
5 if age (full years) at baseline is 13 to 18 years 
x Body Mass Index (kg/m2) = Weight (kg) / [Height (cm)/100]2 
x Time Since Original Diagnosis of PFIC (months) = (date of first dose – date of 
original diagnosis of PFIC) / 30.4375 
x Baseline Value = value obtained at baseline visit (before first dose of study drug)  
If baseline visit is not available, the last value obtained during screening is used as 
the baseline value. 
For weekly average ItchRO scores, baseline is defined as the weekly average 
ItchRO score in the week consisting of the 7 days immediately before the baseline 
visit date. For 4-week average ItchRO scores, baseline is defined as the 4-week 
average ItchRO score in the period consisting of the 28 days immediately before the 
baseline visit date. 
Change from Baseline = post-baseline value at time point – value at baseline 
For weekly and 4-week average ItchRO scores, “value” is the average score over a 
7-day and 28-day period, respectively, as defined below. 
% Change from Baseline = 100 x change from baseline / value at baseline 
x Body Weight, Height and BMI z-Scores: 
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 charts4 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 
charts5 will be used to derive z-scores. 


Statistical Analysis Plan,  
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x ItchRO Daily Score = Average of morning and evening scores  
If either the morning or evening reports are not completed, the available score is 
used as the daily score. If both morning and evening reports are not completed, the 
daily score for that day is treated as missing data. 
x ItchRO Weekly Average Score = Sum of ItchRO Daily Scores (over a 7-day period) 
divided by the number of days ItchRO is completed 
The baseline weekly average score is calculated using the 7 days immediately before 
the baseline (Day 0) visit date. Post-baseline weekly average scores are calculated 
using the 7 days immediately before each select scheduled visit date. Post-baseline 
weekly average scores are only computed if at least 4 of the 7 ItchRO scores for the 
7-day period are available. 
x ItchRO Weekly Morning Average Score = Sum of ItchRO daily morning scores 
(over a 7-day period) divided by the number of days ItchRO is completed 
ItchRO Weekly Evening Average Score = Sum of ItchRO daily evening scores 
(over a 7-day period) divided by the number of days ItchRO is completed  
The baseline weekly average score is calculated using the 7 days immediately before 
the baseline (Day 0) visit date. Post-baseline weekly average scores are calculated 
using the 7 days immediately before each select scheduled visit date. Post-baseline 
weekly morning/evening average scores are only computed if at least 4 of the 7 
morning/evening ItchRO scores for the 7-day period are available. 
x ItchRO 4-Week Morning Average Score = Sum of ItchRO daily morning scores 
(over a 28-day period) divided by the number of days ItchRO is completed 
ItchRO 4-Week Evening Average Score = Sum of ItchRO daily evening scores 
(over a 28-day period) divided by the number of days ItchRO is completed  
The baseline 4-week average score is calculated using the 28 days immediately 
before the baseline (Day 0) visit date. Post-baseline 4-week average scores are 
calculated using the 28 days immediately before each select scheduled visit date. 
Post-baseline 4-week morning/evening average scores are only computed if at least 
20 of the 28 morning/evening ItchRO scores for the 28-day period are available.  
x Alpha Tocopherol / Total Lipids Ratio (mg/g) = 1000 x alpha tocopherol (mg/dL) / 
total lipids (mg/dL) 
For alpha tocopherol concentrations reported as below the minimum quantitation 
limit (i.e., 0.1 mg/dL), half of the minimum quantitation limit is used in the 
calculation. 


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PCN Number LUME2940 
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x Corrected Sodium (mmol/L) = sodium (mmol/L) + [ 0.216 x total serum lipids (g/L) ] 
x Retinol:RBP Molar Ratio (mol/mol) = 0.0734 x serum retinol (μg/dL) / serum RBP 
(mg/dL) 
x Fat-Soluble Vitamin Level Abnormality Definitions 
25-Hydroxyvitamin D: 
6XIILFLHQWLIOHYHOto 96 ng/mL 
 
Insufficient if level < 20 ng/mL 
 
Excess if level > 96 ng/mL 
 
Alpha Tocopherol / Total Lipids Ratio: Sufficient if ratio > 0.8 to < 3.5 mg/g 
 
,QVXIILFLHQWLIUDWLRPJJ 
 
([FHVVLIUDWLRPJJ 
 
Corrected Sodium: 
Sufficient LIOHYHO 135 to 148 mmol/L 
 
Insufficient if level < 135 mmol/L 
 
Excess if level > 148 mmol/L 
 
Intl. Normalized Ratio: 
Sufficient if ratio < 1.2 
 
,QGHWHUPLQDWHLIUDWLRWR 
 
Possibly Insufficient if ratio > 1.5 
 
Retinol:RBP Molar Ratio: 
Sufficient if ratio PROPRO 
 
Insufficient if ratio < 0.8 mol/mol 
Vitamin A: 
Sufficient if level 20 to 77 μg/dL 
 
Insufficient if level < 20 μg/dL 
 
Excess if level > 77 μg/dL  
x Overall Treatment Duration (days) = LASTDAY – FIRSTDAY + 1 day – GAP 
Where, LASTDAY = date of last dose, FIRSTDAY = date of first dose, and GAP = total 
# of days subject was off study between PA2 and PA3 and/or PA3 and PA4. 
280 QD Treatment Duration (days) =  
Date of last dose on QD dosing regimen – FIRSTDAY + 1 day – GAP   
280 BID Treatment Duration (days) =  
Date of last dose on BID dosing regimen – Date of first dose on BID dosing 
regimen + 1 day   
The 280 BID treatment duration is only derived for subjects that dose-escalated 
to a BID dosing regimen, and that GAP=0 during the BID dosing period. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 70 of 108 
x Expected Treatment Duration (days) = EXPLASTDAY – FIRSTDAY + 1 day – GAP 
Expected treatment duration is used in deriving treatment compliance (see below), 
overall and by study phase. For each study phase, EXPLASTDAY = date of the last 
visit in the study phase (i.e., Week 13, 72, 124, or EOT) for subjects that complete 
study treatment for the specific study phase OR the date of last dose for subjects that 
ET during the specific study phase. For ET subjects, the date of last dose is 
considered, rather than the last visit date during the study phase in which the subject 
early terminated. 
For the Week 0-13 study phase, FIRSTDAY = date of first dose, and GAP = 0;  
For the Week 14-72 study phase, FIRSTDAY = date of the Week 13 visit plus 1 day, 
and GAP = 0; 
For the Week 73-124 study phase, FIRSTDAY = date of the Week 72 visit plus 1 day, 
and GAP = # days subject was off study between PA2 and PA3 (i.e., between Week 72 
visit and first dose under PA3); Subjects that did not complete at least 1 post-Week 72 
assessment are not included in the Week 73-124 study phase; 
For the Week >124 study phase, FIRSTDAY = date of the Week 124 visit plus 1 day, 
and GAP = # days subject was off study between PA3 and PA4 (i.e., between Week 
124 visit and first dose under PA4); Subjects that did not complete at least 1 post-
Week 124 assessment are not included in the >Week 124 study phase; 
Overall expected treatment duration is derived by summing over the expected 
treatment duration for each of the 4 individual study phases (Weeks 0-13, 14-72, 73-
124, and >124). 
x % Compliance = 100 x Number of days at least 1 dose is taken / Expected Treatment 
Duration (days) 
where,  
Number of days at least 1 dose is taken = Expected Treatment Duration (days) – 
Number of days a dose was missed [during the specified time period, not 
including dosing gaps due to the subject being off study between protocol 
amendments] 
Compliance is determined for the following study phases: Weeks 0-13, Weeks 
14-72, Weeks 73-124, Weeks >124, and Overall (Weeks 0-EOT).  
x Total Dose Received (μg/kg) = Dose (μg/kg/day) x Treatment Duration (days), for a 
given constant dose level  
Total dose received does not account for dose deviations (e.g., missed dose, 
overdose, or underdose). 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 71 of 108 
x Total Drug Exposure (μg/kg)  >7UHDWPHQWGXUDWLRQGD\VI x Total dose 
received (μg/kg)i ) ] 
where,  
i = 1 to k, (k = number of days subject is receiving a constant dose) 
Total drug exposure is determined separately overall, during QD dosing, and 
during BID dosing. Time periods for which no study drug was administered due 
to dosing gaps while a subject is off study (between protocol amendments) are 
not included. 
x Average Daily Dose (μg/kg/day)  =  Total Drug Exposure (μg/kg) / Treatment 
Duration (days) 
Average daily dose is determined separately overall, during QD dosing, and 
during BID dosing. Time periods for which no study drug was administered 
due to dosing gaps while a subject is off study (between protocol amendments) 
are not included. 
x Clinically-Meaningful Shift from Baseline [applicable for ALT and total bilirubin 
laboratory tests] 
For total bilirubin, a clinically-meaningful shift is dependent upon the baseline level: 
LIWKHEDVHOLQHOHYHOLVPJG/DFOLQLFDOO\-meaningful shift is defined as a post-
EDVHOLQHOHYHOWKDWLVDPJLQFUHDVHIURPEDVHOLQHOHYHOLIWKHEDVHOLQHOHvel is > 10 
mg/dL, a clinically-meaningful shift is defined as a post-EDVHOLQHOHYHOWKDWLVDPJ
increase from baseline level. 
For ALT, a clinically-meaningful shift is dependent upon the baseline level: if the 
EDVHOLQHOHYHOLV8/1WKHQDFOLQLFDlly-meaningful shift is defined as a post-baseline 
OHYHO![8/1LIWKHEDVHOLQHOHYHOLV!8/1WKHQDFOLQLFDOO\-meaningful shift is 
defined as a post-EDVHOLQHOHYHO![EDVHOLQHOHYHODQG![8/1 
6.1.10. PedsQL Scoring Algorithm 
For each item of the PedsQL instrument (parent and subject), 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 ĺ 100, 1 ĺ 75, 2 ĺ 50, 3 ĺ 25, 4 ĺ 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 Reference 6 in Section 
13 for scoring instructions on the PedsQL. 
PedsQL scale scores are computed for the following: 
x 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) 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 72 of 108 
x 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) 
x 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 age 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) 
x 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)
x 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) 
x 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) 
x 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 subject reports. 
6.1.11. Data Adjustments/Handling/Conventions 
Data not subject to analysis according to this plan will not appear in any tables or graphs but will 
be included only in the data listings. 
Subject Age 
The age of a subject at Study Day 0 (baseline) will be used to determine the appropriate age 
category for the ItchRO and PedsQL instruments, unless specified otherwise. 
Siblings 
Because PFIC is a rare disease, siblings were allowed to enroll in the study. Each sibling will be 
included in the Safety and ITT analysis populations. The data for only 1 sibling will be 
considered for the mITT and PP populations because of the potential for lack of independence of 
the observer reports. The choice of sibling to use in the efficacy analysis will be made at random, 
unless only 1 sibling is evaluable PP and the other sibling is not. In this case, the evaluable 
sibling will be considered for use in the efficacy analyses. Sibling selection for the purposes of 
efficacy analysis will be completed before data lock.  
The efficacy analysis performed on the mITT analysis population for the planned 3rd IA (see 
Section 4.3.3) is considered as a sensitivity analysis. For the final analysis, no additional 
sensitivity analysis based on the inclusion or exclusion of sibling data will be performed.  


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 73 of 108 
Adverse Event and Concomitant Medication Coding 
Adverse events will be coded using the MedDRA version 22.1. Concomitant medications will be 
coded using WHO-DD (Enhanced version Sept 2019), Anatomical Therapeutic Chemical (ATC) 
level 2 for ATC class and Clinical Substance for preferred term. 
Prior and Concomitant Medication Definition and Handling of Data 
A concomitant medication is any non-protocol specified drug or substance administered during 
participation in the study. This period of participation is from the first day of screening through 
the date of last contact.  For subjects re-entering the study under PA3 and PA4 study extensions 
and experienced a study drug administration interruption, investigators were instructed not to 
enter concomitant medications that started and stopped during the period of time that the subject 
was off study since the subject was not enrolled in the study. 
Medications that started before the first dose of study drug are considered prior medications 
whether or not they were stopped prior to the first dose of study drug. Any medication 
continuing or starting after the first dose of study drug will be considered to be concomitant. If a 
medication 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. 
For subjects with study drug interruptions (for any reason), any concomitant medication that 
starts > 14 days after the last dose before the drug interruption and ended before the study drug 
was re-initiated will not be considered (for analysis purposes) as a concomitant medication. 
Treatment-Emergent Adverse Event Definition and Handling of Data 
In general, TEAEs are defined as AEs with a start date on or after the date of the first dose of study 
drug and started before the “last dose” of study drug plus 14 days. For subjects with >14 days of 
study drug interruption/withdrawal, for any reason including the subject is off the study in between 
protocol amendments, the definition of a TEAE will consider both the date of the last dose before 
drug interruption/withdrawal and the “last dose”. For these subjects, AEs that start >14 days after the 
last dose (before study drug interruption) and ended before the drug is re-initiated will not be 
considered as treatment-emergent.
Any AE that started before the first dose and worsens in severity or changes from nonserious to 
serious on or after the first dose date will also be designated as a TEAE. 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 reported on the AE CRF 
with a start date that matches the end date, and the term reported includes “Worsened” (e.g., 
“Worsened Headaches”). If an event becomes serious, the date that the event became serious is 
reported on the AE CRF as the End Date of that AE and the Start Date of the corresponding 
SAE. 
Adverse event severity grades are reported according to the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0. If the CTCAE does not have a grading for a particular 
AE, the severity of the event is reported by the investigator as mild, moderate, or severe. If 
CTCAE is not used and the event is reported as life-threatening then the severity of the event is 
considered as “Life-Threatening (CTCAE Grade 4)” for analysis purposes. Similarly, if CTCAE 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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is not used and the event results in death then, for analysis purposes, the severity of the event is 
considered as “Fatal (CTCAE Grade 5)”. 
A treatment-related AE is any AE with a relationship to the study drug of related or possibly 
related. 
An AE that does not have a reported relationship to study drug value will be considered as 
“Possibly Related” to study drug. If the severity of an AE is missing, the severity will be 
considered as “Severe”. 
Adverse Events of Special Interest 
The following events have been defined as AESIs due to the nature of the disease under study as 
well as due to the mechanism of action of MRX: 
x Diarrhoea events 
x FSV deficiency events 
x Elevated transaminases events 
x Elevated bilirubin events 
The list of preferred terms (PTs) used to identify FSV deficiency events are provided in 
Appendix 3. Diarrhoea events include PTs of ‘Diarrhoea’, ‘Diarrhoea haemorrhagic’, and 
‘Gastroenteritis’. Elevated transaminases events include PTs of ‘Alanine aminotransferase 
increased’, ‘Aspartate aminotransferase increased’, Alanine aminotransferase abnormal’, and 
‘Aspartate aminotransferase abnormal’. Elevated bilirubin events include the PTs of ‘Blood 
bilirubin increased’, ‘Blood bilirubin abnormal’, ‘Bilirubin conjugated abnormal’, ‘Bilirubin 
conjugated increased’, and ‘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 Prior/Concomitant Medication Dates 
AEs or medications with entirely missing start dates will be classified as treatment-emergent or 
concomitant, as appropriate. 
For partial AE or concomitant medication 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 before the first dose date, then the day is assigned the first day of the month (01); (b) 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 75 of 108 
if both the day and month are missing, and the year matches the first dose date and the end date 
is on or after the first dose date, then the date is assigned the first dose date; if the year does not 
match the first dose date or the end date is before the first dose date, then the day/month are 
assigned the first day of the year (01 Jan). 
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 (31 Dec). 
Partial Dates of Birth 
At least one of the investigative sites are located in a country that does not permit the reporting 
of complete dates of birth. These sites only report the birth year. Complete date of birth is 
required, however, to derive a subject’s weight and height z-scores and determine vital signs that 
are out-of-normal range, at each scheduled study visit. For partial birth dates, the convention for 
imputing missing dates for the purpose of statistical analysis is as follows:  
Where available, the age in years and months at baseline will be used. If only age in years (at 
baseline) is reported, then 6 months will be used. 
Date of Birth = Baseline Visit Date – [ 365.25 x ( Age in yrs + (months/12) ) ] 
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 medication start date, 
then set the derived date of birth to the earliest of the 3 dates. 
Lower and Upper Limit of Quantitation 
,QJHQHUDOIRUTXDQWLWDWLYHODERUDWRU\YDOXHVUHSRUWHGDV³´RU³´WKHORZHUOLPLWRI
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 MRX concentrations that are reported as <LLOQ, 
where a value of zero will be used in calculating summary statistics. 
)RUTXDQWLWDWLYHODERUDWRU\YDOXHVUHSRUWHGDV³!´RU³´WKHXSSHUOLPLWRI quantitation (ULOQ), 
the reported value (i.e., ULOQ) will be used for analysis. 
Repeat 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. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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7.
Study Subjects and Demographics 
7.1.
Disposition of Subjects and Withdrawals 
Subject disposition for all subjects will include tabulations of the number and percentage of 
subjects in each of the ITT, mITT and PP analysis populations, down-titrated during the study, 
consented to PA3 and completed at least 1 post-Week 72 assessment, consented to PA4 and 
completed at least 1 post-Week 124 assessment. The number and percentage of subjects that 
completed study treatment through varying study phases (i.e., Week 72, Week 124, and EOT), 
and discontinued early from the study at each study phase (along with reasons for withdrawal) 
will also be presented. The number and percentage of subjects that were initiated on BID dosing 
and discontinued early during BID dosing (along with reasons for withdrawal) will also be 
summarized. Percentages will be based on the number of subjects in the Safety Population.  
The subject disposition tabulation will also include the number of subjects screened for 
eligibility, the number of screen failures under the original protocol, the number of screen 
failures under a protocol amendment, the number of subjects assigned to study treatment, the 
number of families with siblings enrolled in the study, the total number of siblings, and the 
number of subjects in the Safety Population. 
The number and percentage of assigned subjects by investigative site will also be tabulated. 
Percentages will be based on the number of subjects assigned to study treatment. 
Study drug accountability and compliance listings will be prepared for all subjects, 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 major protocol deviations 
will be listed. 
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be tracked, recorded, and reviewed before database lock, following the 
Protocol Deviation Guidance Plan for the MRX program, including:  
x Informed consent form process or signature/version issue 
x Violation of inclusion/exclusion criteria 
x Study/protocol procedures 
x Dosing error 
x Excluded medication 
x Visit window deviation 
x Other deviation from study procedures 
Other protocol deviations may be identified during the study. 
Protocol deviations will be classified as “Major” or “Minor”. A major deviation poses a possible 
safety issue to the subject, or it has a potential impact on the statistical analysis of the protocol. A 
minor deviation is identified as any protocol deviation that does not meet the criteria for a major 
deviation. Major deviations will be reviewed by the Sponsor and Premier to determine the final 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
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classification. Protocol deviations which are deemed to be “Major” and “Non-Evaluable” (i.e., a 
deviation that has a potential impact on the efficacy analysis), will be classified as “Major Non-
Evaluable”. Subjects with at least 1 deviation classified as “Major Non-Evaluable” will be 
excluded from the PP analysis population (see Section 5). 
Major protocol deviations will be presented in a subject listing. Major protocol deviations 
include: 
x Significant and/or persistent dosing error 
x Subject did not meet criteria for assignment and does not have a waiver or dispensation 
by medical monitor 
x Use of bile acid or lipid binding resins during participation in the trial 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age at baseline, gender, race, ethnicity, country, height z-score, weight z-
score, and BMI z-score will be presented. 
Tabulations for age group categories, defined as <2, 2–4, 5–8, 9–12, and 13–18 years of age at 
baseline, will also be presented. Unless otherwise noted, age is the subject’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. A category of “Not Reported” is included for 
race and ethnicity. 
These analyses will be conducted on the Safety Population. 
7.4. 
Disease History and Baseline Disease Characteristics 
Summary statistics will be presented for the following baseline variables by PFIC type and by 
PFIC2 subtype: 
x time since original diagnosis of PFIC 
x number of subjects having a family history of PFIC 
x number of subjects using anything to treat itch in the past 
x number of subjects using topical, oral, or other therapies to treat itch in the past 
x number of subjects using each specific therapy to treat itch in the past 
x number of subjects with a liver ultrasound 
x number of subjects with liver masses detected on ultrasound 
x baseline pruritus scores: 
- 
clinician scratch scale score 
- 
ItchRO (Obs) weekly morning average score 
- 
ItchRO (Obs) weekly evening average score 
- 
ItchRO (Obs) weekly average score 
- 
ItchRO (Pt) weekly average score 
- 
ItchRO (Obs) 4-week morning average score 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 78 of 108 
- 
ItchRO (Pt) 4-week morning average score 
- 
ItchRO (Obs) 4-week evening average score 
- 
ItchRO (Pt) 4-week evening average score 
x baseline levels of biochemical markers of cholestasis and liver disease and other 
important baseline laboratory tests: 
- 
sBA 
- 
ALP 
- 
AST 
- 
ALT 
- 
GGT 
- 
FGF-19 
- 
bilirubin (total and direct) 
- 
total cholesterol 
- 
triglycerides 
- 
C4 
- 
retinol (Vitamin A) 
- 
25-hydroxyvitamin D 
- 
tocopherol alpha (Vitamin E) 
- 
INR 
Tabulations of pruritus therapy medications will also be presented for categories of 1 medication, 
2 medications, and at least 3 medications. 
These analyses will be conducted on the Safety Population. 
Medical history information and prior medications will be presented in subject listings. 
7.5. 
Treatment Compliance 
Treatment compliance will be calculated for each subject and summarized descriptively. This 
analysis will be completed using the Safety Population for each of the following study phases:  
Weeks 0-13, Weeks 14-72, Weeks 73-124, Weeks >124, and overall (Weeks 0-EOT). Subjects 
terminated before any given study phase are not included in the analysis of that study phase. 
For a given day, a subject is considered compliant with treatment if any amount of study drug 
was administered. 
Study drug accountability will be presented in a subject listing. 
8. 
Efficacy Analysis 
The primary analysis population for efficacy analysis will be the ITT Population.  
Subjects that did not complete at least 1 post-Week 72 assessment will be excluded from all post-
Week 72 analyses. Subjects that did not complete at least 1 post-Week 124 assessment will be 
excluded from all post-Week 124 analyses. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 79 of 108 
No adjustment for multiplicity will be made. All efficacy data will be included in subject data 
listings. 
8.1.
Primary Efficacy Variable Analysis 
The primary analysis of the primary efficacy endpoint, sBA change from Baseline to Week 13, 
will be based on a paired t-test. The null hypothesis that the sBA mean change from baseline to 
Week 13 is zero will be tested. The mean change from baseline to Week 13 will be presented, 
along with its associated 95% confidence interval and p-value.  
Secondary efficacy evaluations on sBA levels will include mean change from baseline to 
Week 48, Week 72, Week 72/LOCF, Week 120, and Week 124/LOCF. 
The assumption of normality of the changes from baseline will be tested using the Shapiro-Wilk 
test. If the p-YDOXHRIWKHWHVWLVWKHQthe data suggests non-normality, and the null 
hypothesis that the median change from baseline is zero will be tested with the Wilcoxon signed 
rank test. 
Observed and change from baseline in sBA level will also be summarized by analysis visit, using 
summary statistics including the number of observations, the mean and associated 95% 
confidence interval, median, standard deviation, standard error of the mean, minimum and 
maximum, and the p-value for testing if the mean change from baseline is zero (based on a 
paired t-test). 
The above-described analysis will be performed overall and by PFIC type.  The analysis on 
observed and change from baseline values by analysis visit, will also be performed by PFIC2 
subtype. 
8.2. 
Secondary Efficacy Variable Analysis 
Secondary efficacy variables include ALT, AST, bilirubin (total and direct), ItchRO (Obs) 
weekly average score, ItchRO (Obs) weekly morning average score, and ItchRO (Obs) 4-week 
morning average score. Secondary efficacy variables will be analyzed similar to the primary 
efficacy variable, as described in the previous section. 
The paired t-test analysis will be performed on mean change from baseline to Week 13, 
Week 48, Week 48/LOCF (for ItchRO variables only), Week 72 (for non-ItchRO variables only), 
Week 72/LOCF (for non-ItchRO variables only), Week 120 (Week 122 for ItchRO variables), 
and Week 124/LOCF (Week 122/LOCF for ItchRO variables) for each secondary efficacy 
variable. 
With the exception of ItchRO (Obs) 4-week morning average score, the analysis on observed and 
change from baseline values by analysis visit will also be performed by PFIC2 subtype. 
ItchRO (Obs) morning scores will also be summarized by time period and PFIC type, as the 
number and percent of days the daLO\PRUQLQJVFRUHLVSRLQW7LPHSHULRGVLQFOXGH
Screening/Baseline, Day 1 - Week 8, Weeks > 8 - 13, Weeks > 13 - 24, Weeks > 24 - 36, 
Weeks > 36 - 48, Weeks > 48 - 72,  Weeks > 72 – 124, Weeks > 124 – 204, and Weeks > 204. 
No inferential statistical tests will be performed. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 80 of 108 
8.3.
Exploratory Efficacy Variable Analysis 
The following exploratory efficacy variables will be presented by analysis visit with descriptive 
statistics: ALP, total cholesterol, C4, GGT, LDL-C, ItchRO (Obs) weekly evening average score, 
CSS score, height z-score, weight z-score, BMI z-score, PedsQL total scale score (parent), 
PedsQL multidimensional fatigue scale score (parent), PedsQL family impact total scale score, 
and ItchRO (Pt) weekly, weekly morning, and weekly evening average scores.  
For ALP, total cholesterol, C4, GGT, and LDL-C, an analysis on observed and change from 
baseline values by PFIC2 subtype and analysis visit will also be included. 
The above-described summaries will also include the p-value for paired t-tests. 
8.4. 
Sensitivity Analysis 
For post-baseline sBA levels, ItchRO (Obs and Pt) weekly morning average scores, and liver 
function lab test responder analyses, using various responder definitions (see Section 2.2.2.4), 
will be conducted as sensitivity analyses.  
Analyses of efficacy data will include LOCF analysis values (see Section 6.1.5). 
Data summaries will be presented for PFIC1 and PFIC2 subjects independently and for all 
subjects combined. Select efficacy variables will also be presented by PFIC2 subtype (truncating 
and non-truncating). 
For subjects who discontinue early from the study, either before Week 72 (i.e., PA2), Week 124 
(i.e., PA3), or PA4, the reason for withdrawal and effect on safety and efficacy results will be 
discussed in the CSR. 
9. 
Safety and Tolerability Analysis 
All safety analyses will be performed on the Safety Population. 
Safety measures of MRX including study drug exposure, AEs and SAEs, clinical laboratory 
values, concomitant medication usage, and plasma levels of MRX will be summarized 
descriptively. TEAEs of special interest (see Section 9.2.1) will be summarized separately. Vital 
signs and physical examination findings will be provided in subject listings. 
Study drug exposure and AEs will be summarized descriptively by MRX dose (280 QD vs. 280 
BID) and PFIC type (PFIC1, PFIC2, and overall).  
For the AE and study drug exposure summaries, MRX dose is based on the dose at the onset of 
the event. 7KH4'GRVHLQFOXGHVDOO4'GRVHVJNJ7KH%,'GRVHLQFOXGHVWKH
dose of 420 μg/kg daily for 2 weeks as part of a dose-escalation. 
For visit-based safety data (i.e., safety labs and plasma levels of MRX), analysis will exclude any 
data collected or assessed after a drug interruption > 28 days due to a subject being off study 
(between protocol amendments). Visit-based data collected after the drug interruption, at the 
point of study drug re-initiation, will be included in subject listings.  
Concomitant medications will be summarized descriptively overall and by PFIC type. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 81 of 108 
9.1.
Exposure to Treatment 
The average daily dose (μg/kg/day), total drug exposure (μg/kg), and treatment duration (days) 
will be summarized overall and by PFIC type and MRX dose (280 QD, 280 BID). Study drug 
exposure estimates exclude dosing gaps due to subject being off study (between protocol 
amendments). 
For the overall treatment period, the number of days on study drug for the entire study (date of 
last dose – date of first dose + 1 day - # days subject was off study between PAs) will also be 
summarized categorically, overall and by PFIC type and MRX dose, using the following 
cumulative time intervals:  
ZHHNVGD\V 
> 13 weeks (> 86 days) 
> 48 weeks (> 322 days) 
> 72 weeks (> 490 days) 
ZHHNVGD\V 
Note these categories are not mutually exclusive. The number of days may not be exactly 7 x the 
number of weeks to allow for permitted visit windows. 
9.2.
Adverse Events 
In general, TEAEs are AEs with a start date on or after the first dose date of study drug and a 
start date before the last dose of study drug plus 14 days. For subjects with >14 days of study 
drug interruption/withdrawal, the definition of a TEAE considers both the date of the last dose 
before drug interruption and the actual last dose (see Section 6.1.11).  
A summary of TEAEs will be presented overall, by PFIC type (PFIC1, PFIC2), and by MRX 
dose group (280 μg/kg QD, 280 μg/kg BID). The summary will include the total number and 
percent of subjects reporting: 
x 
Any TEAEs 
x 
Any treatment-related TEAE 
x 
Any serious TEAE 
x 
Any serious treatment-related TEAE  
x 
Any TEAE leading to study discontinuation 
x 
TEAEs resulting in death 
For each MRX dose group, the percent of subjects will be derived using a denominator based on 
the number of subjects that received the given dose. For example, overall there are 10 subjects 
that were dose-escalated to BID dosing, while all 33 subjects received a QD dose. 
The number and percent of subjects with reported TEAEs, grouped by MedDRA system organ 
class (SOC) and PT, will be tabulated overall and by maximum severity. These AE summaries 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 82 of 108 
will be repeated for treatment-related AEs. In the case of multiple occurrences of the same TEAE 
within the same subject, each subject will only be counted once for each preferred term.  
Adverse events will be summarized overall and by PFIC type and MRX dose (280 QD, 280 
BID).  In presenting AEs by MRX dose, events will only be counted in the MRX dose group in 
which the start of the event occurred. For example, if an event starts while a subject is 
administered a 280 μg/kg QD dose and continues into the dose-escalation period of the BID 
dosing period, the event will only be counted in the ‘280 QD’ dose group. 
All AEs will be coded using MedDRA version 22.1. All TEAEs summarized by SOC and PT 
will be sorted in alphabetical order of the SOC and by descending frequency order of the PT 
within each SOC. 
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 6.1.11. 
In the AE data listings, events that are treatment-emergent will be flagged. AEs will be presented 
in by-subject listings, detailing the treatment phase, MRX dose (μg/kg/day) received at the start 
of the event (or the last dose received if the AE started after the last dose or during dose 
interruption), 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.  
9.2.1. Adverse Events of Special Interest 
Due to the nature of the disease under study, as well as due to the mechanism of action of MRX, 
the following events have been defined as AESIs: diarrhoea events, FSV deficiency events, 
elevated transaminases, and elevated bilirubin. For each of the AESI events, the PTs are 
described in Section 6.1.11. 
The incidence of TEAEs of special interest for FSV deficiency events will be summarized 
separately in the same manner as AEs that lead to permanent discontinuation of study drug. Each 
group of AESIs will be presented in subject listings.  
9.2.2. Deaths and Serious Adverse Events 
Treatment-emergent SAEs, and treatment-emergent SAEs potentially related to study drug, will 
be tabulated by SOC and PT. 
All deaths that occur during the study, including the post treatment follow-up period, will be 
presented in a subject listing. Subject listings of SAEs and SAEs related to study drug will also 
be presented. 
9.2.3. Life Threatening Adverse Events 
Life threatening AEs and severe or life-threatening AEs will be provided in separate subject 
listings in the same manner as SAEs. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 83 of 108 
9.2.4. Adverse Events Leading to Withdrawal 
Treatment-emergent AEs that lead to permanent discontinuation of study drug will be 
summarized and provided in subject listings in the same manner as SAEs. 
9.3.
Clinical Laboratory Evaluations 
Clinical laboratory variables (chemistry panel, hematology, coagulation, lipid panel, cholestasis 
biomarkers, and fat-soluble vitamins) will be summarized using descriptive statistics by analysis 
visit as both observed values and change from baseline values. For analysis, all laboratory values 
will be presented in conventional (US) units, with the exception of serum bile acid which will be 
reported in units of μmol/L.  
Percent change from baseline will be added for the laboratory parameters listed in Appendix 2: 
Laboratory Tests for % Change from Baseline Presentation. 
Laboratory values of all subjects who change (baseline to post-baseline) from normal to 
abnormal (low/high) or from abnormal (low/high) to normal during the course of the study will 
be presented in a listing. A subject listing of fat-soluble vitamin levels that demonstrate 
significant shifts from baseline will be presented separately. These listings will include all 
analysis visits for a given subject and lab test if there is a shift from baseline at any time over the 
course of the study.  
For select FSVs (i.e., 25-hydroxyvitamin D, alpha tocopherol/total lipids ratio, INR, retinol:RBP 
molar ratio, and vitamin A), abnormalities and clinically-meaningful shifts from baseline 
summaries will be presented at each analysis visit (as appropriate). For these fat-soluble 
vitamins, categories may include sufficient, insufficient, possibly insufficient, indeterminate, and 
excess (see Section 6.1.9 for specific definitions). A summary of corrected sodium abnormalities 
will also be presented. 
A tabulation of the number of subjects with clinically meaningful shifts (see Section 6.1.9 for 
definition) in bilirubin and ALT will be presented by visit. Clinically meaningful shifts in those 
variables will also be listed. 
All laboratory variables will be presented by panel, including urinalysis, in subject listings. A 
separate subject listing for efficacy laboratory variables will also be presented.  
9.4.
Vital Signs 
Vital signs (BP, HR, body temperature, and respiration rate) will be presented in subject listings. 
9.5. 
Physical Examination 
Abnormal physical examination findings at screening and indications of clinically significant 
abnormal findings that were newly diagnosed or worsened since the screening visit will be 
provided in a subject listing. Body height, body weight, and BMI, along with associated z-scores 
for each, will also be included in subject listings. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 84 of 108 
9.6.
Concomitant Medications 
A concomitant medication is any non-protocol specified drug or substance administered after the 
first dose of study drug. For subjects with study drug interruptions (for any reason), any 
concomitant medication that starts > 14 days after the last dose before the drug interruption and 
ended before the study drug was re-initiated will not be considered (for analysis purposes) as a 
concomitant medication. 
Concomitant medications will be summarized descriptively overall and by PFIC type, using the 
number and percentage of subjects by ATC class and preferred term. 
Concomitant medications will also be presented in subject listings. Medications that are ongoing 
at time of informed consent will be indicated in the data listing. 
9.7.
Pharmacokinetic Analysis 
Due to poor absorption of MRX very low systemic exposure and plasma drug levels are 
expected. Blood sampling for plasma levels of MRX are collected periodically throughout the 
study period. Sampling at United States sites and those at non-US sites (i.e., United Kingdom, 
Europe, and Australia) follow a somewhat different schedule (see Section 3.6). Additionally, 
blood samples are taken approximately 4 hours post-dose, except at week 4 for US sites, when 
they are taken approximately 2 hours post-dose. 
MRX plasma concentrations will be summarized using descriptive statistics by analysis visit and 
dose of MRX received at the specified analysis visit. Week 4 plasma levels will be presented 
separately for US and non-US sites because of the difference in timing of blood sampling post-
dose.  
Plasma MRX concentrations will also be presented in subject listings. 
10.
Other Planned Analysis 
10.1.
Quality of Life 
Quality of life will be assessed on Total Scale Score (Parent), Multidimensional Fatigue Scale 
Score (Parent), and Family Impact Total Scale Score as efficacy parameters using the appropriate 
PedsQL module(s). The change from baseline to each post-baseline analysis visit (i.e., Week 13, 
24, 48, 72, 72/LOCF, 84, 96, 108, 120, 124/LOCF, 132, and every 12 weeks thereafter) will be 
presented with descriptive statistics. 
Analyses for the quality of life variables are performed on the ITT Population. 
PedsQL scoring algorithms for scale scores are provided in Section 6.1.10. All individual item 
and total/summary scale scores will be presented in subject listings. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 85 of 108 
10.2.
Palatability Analysis 
Palatability data, which is collected at each clinic visit in the follow-up treatment period, will be 
listed for individual subjects and summarized by analysis visit. For each palatability question, the 
number and percentage of subjects will be presented for each answer given.  
10.3.
Genetic Endpoints 
For the purpose of this analysis plan, exploratory genetic analyses will be limited to the 
presentation of genotype data in a listing. 
10.4. Additional Analyses 
Additional analyses may be performed to explore both safety and efficacy measures collected in 
this study. The precise methods and analyses will be determined after the database is locked. 
Thus all such analyses will be interpreted cautiously and not used for formal inference, although 
inferential statistics may be used as part of the data summary. 
11.
Changes from Protocol Planned Analyses 
The protocol states that missing data imputation will not be done for efficacy endpoints. 
However, based on the intent-to-treat principle, visit-based efficacy and safety endpoints will 
include Week 72/LOCF (Week 48/LOCF for ItchRO variables) and Week 124/LOCF (Week 
122/LOCF for ItchRO variables) analysis time points. 
The protocol states that the subject disposition summary will include a tabulation of the duration 
of the follow-up period. This tabulation will not be included. 
The protocol states that safety data will be summarized by study phase (Weeks 0-13, 14-48, 49-
72, and 73-120) and over the entire study duration (Weeks 0-EOT Visit). However, AEs and 
study drug exposure will be summarized by PFIC type (PFIC1, PFIC2, and overall) and MRX 
dose (280 QD and 280 BID). Laboratory results (including AFP) will be summarized by analysis 
visit. Vital signs will only be presented in subject listings.  
In general, subjects that did not complete at least 1 post-Week 72 assessment will be excluded 
from all post-Week 72 analyses. Subjects that did not complete at least 1 post-Week 124 
assessment will be excluded from all post-Week 124 analyses. 
Body height, body weight, and BMI z-scores have been moved from safety variables to 
exploratory efficacy variables. 
AST have been added as a secondary efficacy variable. 
For the secondary efficacy variable(s), ItchRO weekly average score has been replaced with 3 
ItchRO (Obs) average scores:  weekly average score, weekly morning average score, and 4-week 
morning average score. 
The protocol defines the ItchRO daily score as the maximum of the morning and evening scores. 
The definition of the daily score has been changed to the average of morning and evening scores. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 86 of 108 
The protocol specifies that exploratory efficacy variables will be analyzed similarly to the 
primary efficacy variables. However, owing to the small sample size and the limitations of the 
uncontrolled design of the study, only descriptive statistics will be presented for: ALP, GGT, C4, 
total cholesterol, LDL-C, select PedsQL variables (total scale score [parent], multidimensional 
fatigue scale score [parent], and family impact total scale score), and select exploratory ItchRO 
variables. For CSS, PIC, CIC, CGTB, HDL-C, triglycerides, INR, aPTT, prothrombin time, 
select ItchRO and PedsQL variables, and the sBA sub-species, will only be presented in subject 
listings. 
The protocol also specifies that exploratory evaluations may be conducted on the change from 
baseline in lysophosphatidic acid (LPA) at Weeks 4, 8, 13, 36, 48, 60, and 72. The method for 
assaying LPA has not been validated, thus LPA data will not be available for this analysis. 
The protocol specifies that pattern of change in serum bile acids from baseline (Day 0) to EOT 
will be evaluated and its appropriate analysis methodology will be outlined in the SAP. This 
“pattern of change” endpoint will not be pursued as described in the protocol.  
The protocol states that the additional questions included in the ItchRO instrument that are not 
scored will be tabulated. This data consists of morning and evening daily records, and will not be 
tabulated but rather presented in a subject listing. 
The protocol states that the definition for the PP Population “will consist of all subjects in the 
MITT population who did not have a major protocol violation, inclusive of violation of entry the 
criteria”; however, this has been changed to all subjects in the mITT Population who did not 
have a major, non-evaluable protocol deviation. 
The protocol includes a PP Population for efficacy analysis. The PP analysis population was 
used in the 1st interim analysis to examine efficacy outcomes. No summaries using the PP 
Population are planned for the final analyses. 
The protocol states that “where sample size allows, treatment effects over time will be examined 
using methods appropriate for repeated observations”. A repeated-measures analysis has not 
been included for the final analyses.  
12. 
Additional Exploratory Analyses 
Additional exploratory analyses generally referred to but not specifically described in the 
protocol, include:  
x For ALT and total bilirubin, the number and percentage of subjects demonstrating a 
clinically-meaningful shift from their baseline level will be presented at each post-baseline 
analysis visit. 
x For select fat-soluble vitamins, abnormalities and clinically-meaningful shifts from baseline 
will be presented at each analysis visit (as appropriate). For these select fat-soluble vitamins, 
categories may include sufficient, insufficient, possibly insufficient, indeterminate, and 
excess (see Section 6.1.9 for specific definitions). 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 87 of 108 
x Quality of life will be assessed by examining changes from baseline in select summary and 
total scale scores using the appropriate PedsQL module(s). 
Additional exploratory analyses may or may not be included in the clinical study report. 
 
13. 
References 
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food 
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016.w.amstat.org/about/ethicalguidelines.cfm 
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 
2014.w.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
4. World Health Organization (WHO) 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) 
5. Centers for Disease Control (CDC) 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) 
6. The PedsQL Measurement Model for the Pediatric Quality of Life Inventory – Scoring 
Instructions (www.pedsql.org) 
14.
Planned Tables, Figures, and Listings  
All tables, figures, and listings will have a header showing the sponsor company name, protocol 
number, and output version, and a footer showing the filename and path, and date of output 
generation. All tables and figures will have a “SOURCE: Listing(s) XXXX” line that indicates 
which data listing(s) contains the underlying data. 
14.1.
Planned Table Descriptions 
The following are planned summary tables for protocol number LUM001-501. The table 
numbers and page numbers are place holders only and will be determined when the tables are 
produced. All the tables listed below will be presented for the final analyses, but only a subset 
will be presented for each interim analyses. The table below indicates which tables will appear in 
the first, second, and third planned interim analyses. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 88 of 108 
Table 
Number 
Table Title for Final Analysis 
Include 
in 1st IA 
Include 
in 2nd IA 
Include 
in 3rd IA 
Final 
Analysis 
14.1.1 
Subject Disposition (All Subjects) 
 
A 
9 
14.1.2 
Number of Enrolled Subjects by Investigative Site
 
9 
14.1.3 
Demographics and Baseline Characteristics (Safety 
Population) 
9 
9 
9 
9 
     --- 
Demographics and Baseline Characteristics (Per-
Protocol Population) 
9 
 
 
 
14.1.4 
Disease History and Baseline Disease Characteristics 
(Safety Population) 
9 
9 
9 
9 
     --- 
Disease History and Baseline Disease Characteristics 
(Per-Protocol Population) 
9 
 
 
 
14.1.5 
Summary of Prior Pruritus Therapy Medications (Safety 
Population) 
 
 
 
9 
14.1.6 
Treatment Compliance (Safety Population) 
9
9 
9 
9 
     --- 
Treatment Compliance During BID Dosing for Subjects 
that Initiated Afternoon Dose-escalation (ADE) (Safety 
Population) 
 
 
9 
 
14.2.1 
Primary and Secondary Efficacy Variables:  Change 
from Baseline by PFIC Type and Select Analysis Visits  
(Intent-to-Treat Population) 
 
 
 
9 
     --- 
Primary and Secondary Efficacy Endpoints:  Change 
from Baseline to EOT/ET for Subjects Enrolled in the 
ADE Phase - Paired t-tests (Modified Intent-to-Treat 
Population) 
 
 
9 
 
     --- 
Primary and Secondary Efficacy Variables:  Change 
from Baseline by Study Visit for Subjects Enrolled in 
the ADE Phase (Modified Intent-to-Treat Population) 
 
 
9 
 
     --- 
Change from Baseline Serum Bile Acid Level (umol/L) 
by Study Visit – QD Dosing Only (Modified Intent-to-
Treat Population) 
 
 
A 
 
     --- 
Change from Baseline Serum Bile Acid Level (umol/L) 
by Study Visit – BID Dosing Only (Modified Intent-to-
Treat Population) 
 
 
A 
 
14.2.2.1 
Change from Baseline sBA (umol/L) by PFIC Type and 
Analysis Visit (Intent-to-Treat Population) 
9 
9 (SP) 
S 
9 
14.2.2.2 
Change from Baseline sBA (umol/L) by PFIC2 Subtype 
and Analysis Visit (Intent-to-Treat Population) 
 
 
 
9 
14.2.3.1.1 
Change from Baseline ItchRO (Observer) Weekly 
Average Score by PFIC Type and Analysis Visit (Intent-
to-Treat Population) 
 
 
 
9 
14.2.3.1.2 
Change from Baseline ItchRO (Observer) Weekly 
Average Score by PFIC2 Subtype and Analysis Visit 
(Intent-to-Treat Population)
 
 
 
9 
14.2.3.2.1
Change from Baseline ItchRO (Observer) Weekly 
Morning Average Score by PFIC Type and Analysis 
Visit (Intent-to-Treat Population) 
 
 
 
9 
14.2.3.2.2 
Change from Baseline ItchRO (Observer) Weekly 
Morning Average Score by PFIC2 Subtype and Analysis 
Visit (Intent-to-Treat Population) 
 
 
 
9 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 89 of 108 
Table 
Number 
Table Title for Final Analysis 
Include 
in 1st IA 
Include 
in 2nd IA 
Include 
in 3rd IA 
Final 
Analysis 
14.2.3.2.3 
Percent of Days ItchRO (Observer) Morning Score is 
 1 Point by PFIC Type and Time Period (Intent-to-
Treat Population) 
 
 
 
9 
14.2.3.3 
Change from Baseline ItchRO (Observer) Weekly 
Evening Average Score by PFIC Type and Analysis 
Visit (Intent-to-Treat Population) 
 
 
 
9 
14.2.4.1 
Change from Baseline ItchRO (Patient) Weekly 
Average Score by PFIC Type and Analysis Visit (Intent-
to-Treat Population) 
 
 
 
9 
14.2.4.2 
Change from Baseline ItchRO (Patient) Weekly 
Morning Average Score by PFIC Type and Analysis 
Visit (Intent-to-Treat Population) 
 
 
 
9 
14.2.4.3 
Change from Baseline ItchRO (Patient) Weekly 
Evening Average Score by PFIC Type and Analysis 
Visit (Intent-to-Treat Population) 
 
 
 
9 
     --- 
Change from Baseline ItchRO (Patient) Pruritus 
Average Score by Study Visit (Modified Intent-to-Treat 
Population) 
9 
9 (SP) 
S 
 
     --- 
Change from Baseline ItchRO (Observer) Pruritus 
Average Scores by Study Visit (Modified Intent-to-
Treat Population) 
9 
9 (SP) 
S 
 
14.2.5.1 
Change from Baseline ALT (U/L) by PFIC Type and 
Analysis Visit (Intent-to-Treat Population) 
9 
9 (SP) 
S 
9 
14.2.5.2 
Change from Baseline ALT (U/L) by PFIC2 Subtype 
and Analysis Visit (Intent-to-Treat Population) 
 
 
 
9 
14.2.6.1 
Change from Baseline Total Bilirubin (mg/dL) by PFIC 
Type and Analysis Visit (Intent-to-Treat Population) 
9 
9 (SP) 
S 
9 
14.2.6.2 
Change from Baseline Total Bilirubin (mg/dL) by 
PFIC2 Subtype and Analysis Visit (Intent-to-Treat 
Population) 
 
 
 
9 
14.2.7.1 
Change from Baseline Direct Bilirubin (mg/dL) by PFIC 
Type and Analysis Visit (Intent-to-Treat Population) 
9 
9 (SP) 
S 
9 
14.2.7.2 
Change from Baseline Direct Bilirubin (mg/dL) by 
PFIC2 Subtype and Analysis Visit (Intent-to-Treat 
Population) 
 
 
 
9 
14.2.8.1 
Change from Baseline ALP (U/L) by PFIC Type and 
Analysis Visit (Intent-to-Treat Population) 
 
9 (SP) 
 
9 
14.2.8.2 
Change from Baseline ALP (U/L) by PFIC2 Subtype 
and Analysis Visit (Intent-to-Treat Population)
 
 
 
9 
14.2.9.1
Change from Baseline AST (U/L) by PFIC Type and 
Analysis Visit (Intent-to-Treat Population) 
 
9 (SP) 
 
9 
14.2.9.2 
Change from Baseline AST (U/L) by PFIC2 Subtype 
and Analysis Visit (Intent-to-Treat Population) 
 
 
 
9 
14.2.10.1 
Change from Baseline Total Cholesterol (mg/dL) by 
PFIC Type and Analysis Visit (Intent-to-Treat 
Population) 
 
9 (SP) 
S 
9 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 90 of 108 
Table 
Number 
Table Title for Final Analysis 
Include 
in 1st IA 
Include 
in 2nd IA 
Include 
in 3rd IA 
Final 
Analysis 
14.2.10.2 
Change from Baseline Total Cholesterol (mg/dL) by 
PFIC2 Subtype and Analysis Visit (Intent-to-Treat 
Population) 
 
 
 
9 
14.2.11.1 
Change from Baseline C4 (ng/mL) by PFIC Type and 
Analysis Visit (Intent-to-Treat Population) 
9 
9 (SP) 
S 
9 
14.2.11.2 
Change from Baseline C4 (ng/mL) by PFIC2 Subtype 
and Analysis Visit (Intent-to-Treat Population)
 
 
 
9 
14.2.12.1 
Change from Baseline GGT (U/L) by PFIC Type and 
Analysis Visit (Intent-to-Treat Population) 
 
9 (SP) 
 
9 
14.2.12.2 
Change from Baseline GGT (U/L) by PFIC2 Subtype 
and Analysis Visit (Intent-to-Treat Population) 
 
 
 
9 
14.2.13.1 
Change from Baseline LDL-C (mg/dL) by PFIC Type 
and Analysis Visit (Intent-to-Treat Population) 
 
9 (SP) 
S 
9 
14.2.13.2 
Change from Baseline LDL-C (mg/dL) by PFIC2 
Subtype and Analysis Visit (Intent-to-Treat Population) 
9 
14.2.14.1 
Pruritus Responder Rates as Measured by ItchRO 
(Observer) Morning Average Scores by PFIC Type and 
Analysis Visit Using Various Responder Definitions 
(Intent-to-Treat Population) 
 
 
9 
9 
14.2.14.2 
Pruritus Responder Rates as Measured by ItchRO 
(Patient) Morning Average Scores by PFIC Type and 
Analysis Visit Using Various Responder Definitions 
(Intent-to-Treat Population) 
 
 
9 
9 
14.2.14.3 
Serum Bile Acid and ItchRO (Observer) Responder 
Analysis by PFIC Type and Analysis Visit (Intent-to-
Treat Population) 
 
9 (SP) 
9 
9 
14.2.14.4 
Liver Function Lab Test Responder Analysis by PFIC 
Type and Analysis Visit (Intent-to-Treat Population) 
 
9 (SP) 
9 
9 
14.2.15 
Change from Baseline Clinician Scratch Scale Score by 
PFIC Type and Analysis Visit (Intent-to-Treat 
Population) 
 
9 (SP) 
S 
9 
14.2.16.1 
Change from Baseline in Height Measurement z-Scores 
by PFIC Type and Analysis Visit (Intent-to-Treat 
Population) 
 
 
 
9 
14.2.16.2 
Change from Baseline in Weight Measurement z-Scores 
by PFIC Type and Analysis Visit (Intent-to-Treat 
Population) 
 
 
 
9 
14.2.16.3 
Change from Baseline in BMI z-Scores by PFIC Type 
and Analysis Visit (Intent-to-Treat Population) 
 
 
 
9 
14.2.17.1 
Change from Baseline PedsQL Total Scale Score 
(Parent) by PFIC Type and Analysis Visit (Intent-to-
Treat Population) 
9 
9 (SP) 
S 
9 
14.2.17.2 
Change from Baseline PedsQL Multidimensional 
Fatigue Scale Score (Parent) by PFIC Type and 
Analysis Visit (Intent-to-Treat Population) 
 
9 (SP) 
S 
9 
14.2.17.3 
Change from Baseline PedsQL Family Impact Total 
Scale Score by PFIC Type and Analysis Visit (Intent-to-
Treat Population) 
 
9 (SP) 
 
9 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 91 of 108 
Table 
Number 
Table Title for Final Analysis 
Include 
in 1st IA 
Include 
in 2nd IA 
Include 
in 3rd IA 
Final 
Analysis 
     --- 
Change from Baseline PedsQL Psychosocial Health 
Summary Score (Parent) by Study Visit (Modified 
Intent-to-Treat Population) 
 
9 (SP) 
 
 
     --- 
Change from Baseline PedsQL Total Scale Score 
(Child) by Study Visit (Modified Intent-to-Treat 
Population) 
 
9 (SP) 
S 
 
     --- 
Change from Baseline PedsQL Multidimensional 
Fatigue Scale Score (Child) by Study Visit (Modified 
Intent-to-Treat Population) 
 
9 (SP) 
S 
 
     --- 
Change from Baseline PedsQL Physical Health 
Summary Score (Parent) by Study Visit (Modified 
Intent-to-Treat Population) 
 
9 (SP) 
 
 
     --- 
Change from Baseline PedsQL Physical Health 
Summary Score (Child) by Study Visit (Modified 
Intent-to-Treat Population) 
 
9 (SP) 
 
 
     --- 
Change from Baseline PedsQL Psychosocial Health 
Summary Score (Child) by Study Visit (Modified 
Intent-to-Treat Population) 
 
9 (SP) 
 
 
     --- 
Change from Baseline PedsQL Parent Functioning 
Summary Score by Study Visit (Modified Intent-to-
Treat Population) 
 
9 (SP) 
 
 
     --- 
Change from Baseline PedsQL Family Impact Summary 
Score by Study Visit (Modified Intent-to-Treat 
Population) 
 
9 (SP) 
S 
 
     --- 
Patient Impression of Change (PIC) Score by Study 
Visit (Modified Intent-to-Treat Population) 
 
9 (SP) 
9 
 
     --- 
Caregiver Impression of Change (CIC) Score by Study 
Visit (Modified Intent-to-Treat Population) 
 
9 (SP) 
9 
 
     --- 
Caregiver Global Therapeutic Benefit (CGTB) Score by 
Study Visit (Modified Intent-to-Treat Population) 
 
9 (SP) 
9 
 
     --- 
Change from Baseline Autotaxin Level (ng/mL) by 
Study Visit (Modified Intent-to-Treat Population) 
 
9 (SP) 
S 
 
     --- 
Change from Baseline Fibroblast Growth Factor 19 
(FGF-19) Level (pg/mL) by Study Visit (Modified 
Intent-to-Treat Population) 
 
9 (SP) 
S 
 
     --- 
Change from Baseline Fibroblast Growth Factor 21 
(FGF-21) Level (pg/mL) by Study Visit (Modified 
Intent-to-Treat Population)
 
9 (SP) 
 
 
---
Change from Baseline HDL Cholesterol Level (mg/dL) 
by Study Visit (Modified Intent-to-Treat Population) 
 
9 (SP) 
S 
 
     --- 
Change from Baseline Triglycerides Level (mg/dL) by 
Study Visit (Modified Intent-to-Treat Population) 
 
9 (SP) 
S 
 
     --- 
Change from Baseline International Normalized Ratio 
(INR) by Study Visit (Modified Intent-to-Treat 
Population) 
 
9 (SP) 
S 
 
     --- 
Change from Baseline Activated Partial Thromboplastin 
Time (aPTT) (sec) by Study Visit (Modified Intent-to-
Treat Population)
 
9 (SP) 
S 
 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 92 of 108 
Table 
Number 
Table Title for Final Analysis 
Include 
in 1st IA 
Include 
in 2nd IA 
Include 
in 3rd IA 
Final 
Analysis 
     --- 
Change from Baseline Prothrombin Time (PT) (sec) by 
Study Visit (Modified Intent-to-Treat Population) 
 
9 (SP) 
S 
 
     --- 
Change from Baseline Serum Bile Acid Subspecies by 
Study Visit (Modified Intent-to-Treat Population) 
 
9 (SP) 
 
 
     --- 
Pruritus Responder Rates as Measured by ItchRO 
(Observer) by Study Visit (Modified Intent-to-Treat 
Population) 
 
 
9 
 
     --- 
Pruritus Responder Rates as Measured by ItchRO 
(Patient) by Study Visit (Modified Intent-to-Treat 
Population) 
 
 
9 
 
14.3.1 
Study Drug Exposure by PFIC Type and MRX Dose 
(Safety Population) 
 
 
9 
9 
14.3.2.1 
Summary of Treatment-Emergent Adverse Events by 
PFIC Type and MRX Dose (Safety Population) 
9 
9 (SP) 
9 
9 
14.3.2.2 
Incidence of Treatment-Emergent Adverse Events by 
PFIC Type and MRX Dose (Safety Population) 
9 
9 (SP) 
9 
9 
14.3.2.3 
Incidence of Treatment-Emergent Adverse Events by 
Maximum Severity, PFIC Type and MRX Dose (Safety 
Population) 
9 
9 (SP) 
9 
9 
14.3.2.4 
Incidence of Treatment Related Adverse Events by 
PFIC Type and MRX Dose (Safety Population) 
9 
9 (SP) 
9 
9 
14.3.2.5 
Incidence of Treatment Related Adverse Events by 
Maximum Severity, PFIC Type and MRX Dose (Safety 
Population) 
9 
9 (SP) 
9 
9 
14.3.2.6 
Incidence of Treatment-Emergent Serious Adverse 
Events by PFIC Type and MRX Dose (Safety 
Population) 
9 
9 (SP) 
9 
9 
14.3.2.7 
Incidence of Treatment Related Serious Adverse Events 
by PFIC Type and MRX Dose (Safety Population) 
9 
9 (SP) 
9 
9 
14.3.2.8 
Incidence of Adverse Events Leading to Permanent 
Treatment Discontinuation by PFIC Type and MRX 
Dose (Safety Population) 
9 
9 (SP) 
9 
9 
14.3.2.9 
Incidence of Treatment-Emergent Adverse Events of 
Special Interest - Fat-Soluble Vitamin Deficiency 
Events by PFIC Type and MRX Dose 
 
9 (SP) 
9 
9 
14.3.2.10 
Listing of Deaths 
9
9 (SP)
9 
9 
     --- 
Incidence of Treatment-Emergent Adverse Events of 
Special Interest - Gastrointestinal Related Events by 
Study Phase (Safety Population) 
9 
9 (SP) 
9 
 
     --- 
Incidence of Treatment-Emergent Adverse Events of 
Special Interest – Conditions Associated with Liver 
Deterioration by Study Phase (Safety Population) 
9
9 (SP) 
9
 
     --- 
Incidence of Treatment-Emergent Adverse Events of 
Special Interest – GI-Related Events and Conditions 
Associated with Liver Deterioration by Study Phase 
(Safety Population) 
 
 
9 
 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 93 of 108 
Table 
Number 
Table Title for Final Analysis 
Include 
in 1st IA 
Include 
in 2nd IA 
Include 
in 3rd IA 
Final 
Analysis 
     --- 
Incidence of Treatment-Emergent Adverse Events of 
Special Interest - Thyroid Function Events by Study 
Phase (Safety Population) 
 
9 (SP) 
 
 
     --- 
Incidence of Treatment-Emergent Adverse Events of 
Special Interest - Growth Retardation Events by Study 
Phase (Safety Population) 
 
9 (SP) 
 
 
14.3.3.1 
Summary of Clinical Laboratory Data: Clinical 
Chemistry (Safety Population) 
 
 
9 
9 
14.3.3.2 
Summary of Clinical Laboratory Data: Hematology 
(Safety Population) 
 
 
9 
9 
14.3.3.3 
Summary of Clinical Laboratory Data: Fat-Soluble 
Vitamins (Safety Population) 
 
 
9 
9 
14.3.3.4 
Summary of Clinical Laboratory Data: Lipid Panel 
(Safety Population) 
 
 
9 
9 
14.3.3.5 
Summary of Clinical Laboratory Data: Cholestasis 
Biomarkers (Safety Population) 
 
 
9 
9 
14.3.3.6 
Summary of Clinical Laboratory Data: Coagulation 
(Safety Population) 
 
 
9 
9 
14.3.3.7 
Listing of Laboratory Parameter Levels with Significant 
Shifts from Baseline Over the Study (Safety Population) 
 
 
9 
9 
14.3.3.8 
Listing of Fat-Soluble Vitamin Levels with Significant 
Shifts from Baseline Over the Study (Safety Population) 
 
 
9 
9 
14.3.3.9.1 
Summary of Clinically Meaningful Shifts in Bilirubin 
and ALT (Safety Population) 
 
 
9 
9 
14.3.3.9.2 
Listing of Clinically Meaningful Shifts in Bilirubin and 
ALT (Safety Population) 
 
 
9 
9 
14.3.3.10 
Summary of Clinical Laboratory Data: Hepatocellular 
Carcinoma Marker (Safety Population) 
 
 
9 
9 
14.3.3.11 
Summary of Corrected Sodium and Fat-Soluble Vitamin 
Level Abnormalities (Safety Population) 
 
 
9 
9 
14.3.3.12 
Summary of Clinically-Meaningful Shifts from Baseline 
in Fat-Soluble Vitamins (Safety Population) 
 
 
9 
9 
     --- 
Summary of Weight Measurement z-Scores (Safety 
Population) 
 
 
9 
 
     --- 
Summary of Height Measurement z-Scores (Safety 
Population) 
 
 
9 
 
14.3.4 
Summary of Concomitant Medications (Safety 
Population) 
 
 
 
9 
14.3.5 
Summary of Plasma Sample MRX Concentrations 
(ng/mL) by Analysis Visit (Safety Population) 
 
 
 
9 
14.4 
Summary of Palatability Data by Analysis Visit (Safety 
Population) 
 
 
 
9 
Note: The 1st and 3rd interim analysis (IA) use the Modified Intent-to-Treat Population for all efficacy summary tables. The 
2nd IA is performed on the Safety Population. For each IA, TEAEs were summarized by study phase, instead of MRX 
dose.  SP = Safety Population;  A = table was added to the 3rd IA after SAP Amendment 1 was approved;  S = summary 
table was split into 2 tables: QD Dosing Only and BID Dosing Only 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 94 of 108 
14.2.
Planned Figure Descriptions 
Figures for select efficacy variables will depict trends over time for PFIC1 and PFIC2 subjects 
independently and overall using the ITT analysis population. Mean (± SE) observed values 
and/or change from baseline (Day 0) for select efficacy variables will be displayed graphically 
by study week over the treatment period. For these line plots over time, study week will be based 
on the analysis visit mapping described in Table 1. 
Study drug exposure will be displayed as a swimmer plot that includes a horizontal bar showing 
treatment duration for each subject in the study. Each bar will be color coded in a manner that 
displays the time periods in which each subject was on the varying daily doses (i.e., 
14 μg/kg/day, 35 μg/kg/day, 70 μg/kg/day, 140 μg/kg/day, 280 μg/kg/day, 420 μg/kg/day, and 
560 μg/kg/day). Gaps in line segments will indicate a drug interruption or missed dose for any 
reason. Vertical reference lines will be included at study day 336 (Week 48), 504 (Week 72), and 
868 (Week 124) to represent treatment periods associated with the original protocol, and protocol 
amendments 2 and 3. 
TEAEs of special interest will be displayed in swimmer-type plots. A plot will be displayed for 
each individual AESI (as the preferred term) and present the start and stop study day of each 
event over time. The vertical axis will represent each unique subject that reported the respective 
AESI. The horizontal axis will represent time, as study day. The severity of each event will be 
depicted as color-coded lines and symbols. 
The following are planned summary figures for protocol number LUM001-501. The figure 
numbers and page numbers are place holders only and will be determined when the figures are 
produced. Additional graphical displays may be included in the clinical study report. 
Listing of Planned Figures 
14.2.2.1.1 9 Plot of Mean (SE) Change from Baseline in sBA (umol/L) by PFIC Type Over 
Time – Intent-to-Treat Population 
14.2.2.1.2  
Plot of Mean (SE) sBA (umol/L) by PFIC Type Over Time – Intent-to-Treat 
Population 
14.2.3.2.1.1 Plot of Mean (SE) Change from Baseline in ItchRO (Obs) Weekly Average 
Morning Score by PFIC Type Over Time - Intent-to-Treat Population 
14.2.3.2.1.2 Plot of Mean (SE) ItchRO (Obs) Weekly Average Morning Score by PFIC 
Type Over Time - Intent-to-Treat Population 
14.2.5.1 
Plot of Mean (SE) Change from Baseline in ALT (U/L) by PFIC Type Over 
Time – Intent-to-Treat Population 
14.2.6.1 
Plot of Mean (SE) Change from Baseline in Total Bilirubin (mg/dL) Over 
Time - Intent-to-Treat Population 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 95 of 108 
14.2.7.1 
Plot of Mean (SE) Change from Baseline in Direct Bilirubin (mg/dL) Over 
Time - Intent-to-Treat Population 
14.2.9.1 
Plot of Mean (SE) Change from Baseline in AST (U/L) by PFIC Type Over 
Time – Intent-to-Treat Population 
14.2.11.1 
Plot of Mean (SE) Change from Baseline in C4 (ng/mL) by PFIC Type Over 
Time – Intent-to-Treat Population 
14.2.16.1 
Plot of Mean (SE) Change from Baseline in Height z-Score by PFIC Type 
Over Time - Intent-to-Treat Population 
14.2.16.2 
Plot of Mean (SE) Change from Baseline in Weight z-Score by PFIC Type 
Over Time - Intent-to-Treat Population 
14.3.1 9 
Study Drug Exposure Over Time by Subject – Safety Population 
14.3.2 9 
Plot of Treatment-Emergent Adverse Events of Special Interest Over Time by 
Preferred Term and Individual Subject – Safety Population 
For the second planned interim analysis, data presented in all graphical displays will be based on 
the Safety Population. Figures checked (9) are included in the third planned interim analysis 
using the mITT population (refer to SAP Amendment 2). 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 96 of 108 
14.3.
Planned Listing Descriptions 
The following are planned data and patient/subject data listings for protocol number 
LUM001-501.  
In general, listings produced will include the subject data collected on associated CRF pages. All 
listings will be sorted by PFIC type, site and subject number. PFIC type, which will be displayed 
at the top of each page in a listing, includes PFIC1, PFIC2 (non-truncating), and PFIC2 
(truncating). 
The study drug accountability and compliance subject listing will include percent compliance 
estimates for each subject and study phase (Weeks 0-13, Weeks 14-72, Weeks 73-124, >Week 
124, and overall). 
For ItchRO (Obs and Pt) weekly morning and evening average scores, clinical scratch scale 
score, total sBA listings, and efficacy laboratory listings, change from baseline values will be 
included. 
For AE listings, study day relative to the date of first dose of study drug will be provided along 
with stop and start dates. For partial event dates, study day will be derived using an imputed date 
as described in Section 6.1.11. Subject listings of AEs will include the dose level the subject was 
receiving at the start of the event and the duration of the event (days).  
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 medication listing, medications that are ongoing at the time of informed 
consent will be indicated. 
In addition to presenting subject listings of raw scores for each of the PedsQL module items, 
listings with total scale and summary scores will also be presented for 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. 
In all listings a blank line will be placed between subjects. Within a data listing, if an item 
appears line after line (e.g., repetition of subject number), then only the first occurrence will be 
displayed. 
The order of the listings will be as follows: 
16.1.1*9 
Subject Profile: Select Labs and Pruritus Scores 
16.1.2* 
Subject Profile: Serum Bile Acid Subspecies 
16.1.3*9 
Subject Profile: Pediatric Quality of Life Inventory – Total Scale and 
Summary Scores 
16.1.4*9 
Subject Profile: Efficacy and Safety Labs (Serum Bile Acid, Lipids, Fat-
Soluble Vitamins, and Coagulation) 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 97 of 108 
16.1.5 
Subject Profile: Fat-Soluble Vitamin Level Abnormalities 
16.2.19 
Analysis Populations and Treatment 
16.2.2.1 
Subject Disposition:  Screen Failure 
16.2.2.29 
Subject Disposition:  All Subjects Assigned Treatment 
16.3.1 
Inclusion and Exclusion Criteria 
16.3.29 
Major Protocol Deviations 
16.3.3 
Subjects Excluded from Efficacy Analysis 
16.4.19 
Demographics and Informed Consent 
16.4.29 
Medical History 
16.4.39 
PFIC Disease History 
16.4.4*9 
Prior and Concomitant Medications 
16.5 
Liver Imaging
16.6.19 
Study Drug Accountability and Compliance 
16.6.29 
Study Drug Exposure 
16.7.1*9 
Total Serum Bile Acid 
16.7.2*9 
Clinician Scratch Score 
16.7.3.1*9 
Itch Reported Outcomes (Subject and Caregiver) 
16.7.3.2*9 
Itch Reported Outcomes (Subject and Caregiver) Morning and Evening 
Average Scores 
16.7.3.3*9 
Itch Reported Outcomes (Subject and Caregiver) Weekly Average Scores 
16.7.4*9 
PIC, CIC, and CGTB 
 
16.7.5*9 
Efficacy Laboratory Tests 
16.7.6 
Height, Weight, and BMI z-Scores 
16.7.7.1* 
Pediatric Quality of Life Inventory (Parent Report) – Total Scale and 
Summary Scores 
16.7.7.2* 
Pediatric Quality of Life Inventory (Subject Report) – Total Scale and 
Summary Scores 
16.7.8.1.1 
Pediatric Quality of Life Inventory (Parent Report for Infants) – Physical 
Functioning 
16.7.8.1.2 
Pediatric Quality of Life Inventory (Parent Report for Children 2–18 Years) – 
Physical Functioning 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 98 of 108 
16.7.8.2 
Pediatric Quality of Life Inventory (Parent Report for Infants) – Physical 
Symptoms 
16.7.8.3.1 
Pediatric Quality of Life Inventory (Parent Report for Infants) – Emotional 
Functioning 
16.7.8.3.2 
Pediatric Quality of Life Inventory (Parent Report for Children 2–18 Years) – 
Emotional Functioning 
16.7.8.4.1 
Pediatric Quality of Life Inventory (Parent Report for Infants) – Social 
Functioning 
16.7.8.4.2 
Pediatric Quality of Life Inventory (Parent Report for Children 2–18 Years) – 
Social Functioning 
16.7.8.5 
Pediatric Quality of Life Inventory (Parent Report for Infants) – Cognitive 
Functioning 
16.7.8.6 
Pediatric Quality of Life Inventory (Parent Report for Children 2–18 Years) – 
Nursery/Day Care/School Functioning 
16.7.8.7.1 
Pediatric Quality of Life Inventory (Subject Report) – Physical Functioning  
16.7.8.7.2 
Pediatric Quality of Life Inventory (Subject Report) – Emotional Functioning 
16.7.8.7.3 
Pediatric Quality of Life Inventory (Subject Report) – Social Functioning 
16.7.8.7.4 
Pediatric Quality of Life Inventory (Subject Report) – School Functioning 
16.7.8.8.1 
Multidimensional Fatigue Scale (Parent Report) – General Fatigue 
16.7.8.8.2 
Multidimensional Fatigue Scale (Parent Report) – Sleep/Rest Fatigue
16.7.8.8.3 
Multidimensional Fatigue Scale (Parent Report) – Mental Fatigue 
16.7.8.9.1 
Multidimensional Fatigue Scale (Subject Report) – General Fatigue 
16.7.8.9.2 
Multidimensional Fatigue Scale (Subject Report) – Sleep/Rest Fatigue 
16.7.8.9.3 
Multidimensional Fatigue Scale (Subject Report) – Cognitive Fatigue 
16.7.8.10.1 
Family Impact Module (Parent Report) – Physical Functioning 
16.7.8.10.2 
Family Impact Module (Parent Report) – Emotional Functioning 
16.7.8.10.3 
Family Impact Module (Parent Report) – Social Functioning 
16.7.8.10.4 
Family Impact Module (Parent Report) – Cognitive Functioning 
16.7.8.10.5 
Family Impact Module (Parent Report) – Communication 
16.7.8.10.6 
Family Impact Module (Parent Report) – Worry 
16.7.8.10.7 
Family Impact Module (Parent Report) – Daily Activities 
16.7.8.10.8 
Family Impact Module (Parent Report) – Family Relationships 
16.8.1*9 
Adverse Events 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 99 of 108 
16.8.2.1*9 
Adverse Events of Special Interest: Fat-Soluble Vitamin Deficiency Events 
16.8.2.2 
Adverse Events of Special Interest: Diarrhoea Events 
16.8.2.3 
Adverse Events of Special Interest: Elevated Transaminases Events 
16.8.2.4 
Adverse Events of Special Interest: Elevated Bilirubin Events 
16.8.3.1*9 
Serious Adverse Events 
16.8.3.2 
Serious Related Adverse Events 
16.8.4.1*9 
Adverse Events Leading to Study Drug Discontinuation 
16.8.4.2 
Adverse Events Leading to Dose Reduction 
16.8.5.1 
Severe or Life Threatening Adverse Events 
16.8.5.29 
Life Threatening Adverse Events 
16.8.6*9 
Adverse Events Causing Death 
16.9.1*9 
Vital Signs 
16.9.29 
Physical Examination
16.10.19 
Clinical Laboratory Tests: Clinical Chemistry 
16.10.2 
Clinical Laboratory Tests: Hematology 
16.10.3 
Clinical Laboratory Tests: Urinalysis 
16.10.4 
Clinical Laboratory Tests: Fat-Soluble Vitamins 
16.10.5 
Clinical Laboratory Tests: Lipid Panel 
16.10.6 
Clinical Laboratory Tests: Cholestasis Biomarkers 
16.10.79 
Clinical Laboratory Tests: Coagulation 
16.10.8 
Clinical Laboratory Tests: Hepatocellular Carcinoma Marker – Alpha-
Fetoprotein (AFP) 
16.10.9 
Clinical Laboratory Tests: Timing of Sample Collection, Last Dose and Last 
Meal 
16.10.10 
Pregnancy Tests 
16.11 
Telephone Contact Log 
16.12 
Genotype Data 
16.13 
Plasma Sample MRX Concentrations 
16.14 
Palatability Questionnaire 
Listings marked with an asterisk (*) were included in the second planned interim analysis. 
Listings marked with a check mark (9) were included in the third planned interim analysis. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 100 of 108 
AESIs for the final analysis include fat-soluble vitamin deficiency events, diarrhoea events, 
elevated transaminases events, and elevated bilirubin events.  AESIs defined in previous, 
approved SAPs and were presented in interim analyses included fat-soluble vitamin deficiency 
events, GI related events, conditions associated with liver deterioration, GI related events and 
conditions associated with liver deterioration, thyroid function events, and growth retardation 
events.  
15. 
Tables, Listings, and Listing Shells 
15.1. 
Standard Layout for all Tables, Listings, and Figures 
Table and listing shells are provided in a separate document. Programming notes may be added if 
appropriate after each TLF shell. 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 101 of 108 
Appendix 1: Premier Research Library of Abbreviations 
Abbreviation 
Definition 
ADE 
afternoon dose-escalation 
AE 
adverse event
AESI 
adverse event of special interest 
AFP 
alpha-fetoprotein 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
aPTT 
activated partial thromboplastin time 
ASBTi 
apical sodium-dependent bile acid transporter inhibitor 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical; classification for drugs 
BID 
twice a day 
BMI 
body mass index 
C4 
ĮK\GUR[\O-4-cholesten-3-one 
BP 
blood pressure 
CBC 
complete blood count 
CDC 
Center for Disease Control 
CGTB 
caregiver global therapeutic benefit 
CIC 
caregiver impression of change 
CRF 
case report form 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 102 of 108 
Abbreviation 
Definition 
CSR 
clinical study report 
CSS
clinician scratch scale 
CTCAE
Common Terminology Criteria for Adverse Events 
DE 
dose-escalation 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EMA 
European Medicines Agengy 
EOT 
end of treatment 
ET 
early termination 
FGF-19 
fibroblast growth factor 19 
FGF-21 
fibroblast growth factor 21 
FIC1 
familial intrahepatic cholestasis 1 
FDA 
Food and Drug Administration 
FSV 
fat-soluble vitamins
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HDL-C 
high-density lipoprotein cholesterol 
HR 
heart rate 
HRQoL 
health related quality of life 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 103 of 108 
Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
INR 
nternational normalized ratio 
ItchRO™ 
Itch Reported Outcome 
ItchRO (Obs)™ 
Itch Reported Outcome observer instrument 
ItchRO (Pt)™ 
Itch Reported Outcome patient instrument 
ITT 
Intent-to-Treat 
INR 
international normalized ratio 
IU 
international unit(s) 
LDL-C 
low-density lipoprotein cholesterol 
LLOQ 
lower limit of quantitation 
LOCF 
last-observation-carried-forward 
LPA 
lysophosphatidic acid 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified Intent-to-Treat 
MRX
maralixibat chloride 
PA2
protocol amendment 2 
PA3
protocol amendment 3 
PA4
protocol amendment 4 
PedsQL 
Pediatric Quality of Life Inventory 
PFIC 
progressive familial intrahepatic cholestasis 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 104 of 108 
Abbreviation 
Definition 
PIC 
patient impression of change 
PP 
Per-Protocol 
PT 
preferred term  
RBP 
retinol binding protein 
SAE 
serious adverse event 
SAP 
statistical analysis plan
sBA
serum bile acid 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
ULOQ
upper limit of quantitation 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 105 of 108 
Appendix 2: Laboratory Tests for % Change from Baseline Presentation 
CBC with Differential 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells 
WBC Differential  
 
DEVROXWH21/< 
 
• Neutrophils 
 
• Basophils 
• Lymphocytes 
 
• Monocytes 
 
• Eosinophils 
Clinical Chemistry 
Bicarbonate 
Albumin 
Total bilirubin 
Direct bilirubin (conjugated) 
Indirect bilirubin (uncongugated) 
ALP 
AST (SGOT) 
ALT (SGPT) 
GGT 
Lipid Panel 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Triglycerides 
 
Cholestasis Biomarkers 
Serum bile acids 
Įhydroxy-4-colesten-3-one (C4) 
 
Urinalysis 
Oxalate 
Coagulation 
INR 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 106 of 108 
Appendix 3: Listing of Fat-Soluble Vitamin Deficiency Events 
The following MedDRA Preferred Terms associated with fat-soluble vitamin deficiency 
events are included as an AESI: 
- vitamin A deficiency  
- vitamin A abnormal 
- vitamin A decreased 
- vitamin A deficiency related corneal disorders 
- night blindness                     
- ketokomalacia 
- haemorrhagic disorders of the new born  
- xerophthalmia 
- growth retardation 
- nail disorder 
- dry skin 
- eye disorder 
- eye irritation 
- eye pruritus 
- vitamin D deficiency 
- vitamin D abnormal 
- vitamin D decreased 
- rickets 
- osteomalacia 
- osteoporosis 
- osteopenia 
- heartrate abnormal 
- heartrate increased 
- heartrate irregular 
- tachycardia 
- arrhythmia 
- hypocalcemia
- tetany 
- tremor 
- irritability 
- hunger 
- seizure 
- confusional state 
- anxiety 
- fatigue 
- calcium deficiency 
- pallor 
- palpitation 
- hyperhidrosis 


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 107 of 108 
- paraesthesia oral 
- tooth demineralization 
- bone deformity 
- bone density abnormal 
- bone density decreased 
- fractures 
- vitamin E deficiency 
- vitamin E decreased 
- hyporeflexia 
- ataxia 
- nystagmus 
- areflexia 
- ophthalmoplegia 
- visual acuity reduced 
- visual impairment 
- abnormal behavior 
- personality disorder 
- personality change 
- muscular wasting 
- muscle disorder 
- muscle spasms 
- hair disorder 
- alopecia 
- alopecia areata 
- vitamin K deficiency 
- vitamin K decreased 
- mean platelet volume abnormal 
- mean platelet volume decreased 
- platelet count abnormal 
- platelet count decreased 
- cold feet 
- cold hand 
- cold hands & feet 
- coldness of limbs 
- coldness of lower extremities 
- blood glucose increased 
- bleeding time abnormal 
- bleeding time prolonged 
- coagulation time abnormal 
- coagulation time prolonged 
- international normalised ratio increased 
- international normalised ratio abnormal 
- haemorrhage 
- melaena                        


Statistical Analysis Plan,  
Sponsor Mirum Pharmaceuticals, Inc.  
Protocol Number LUM001-501  
 
PCN Number LUME2940 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    30-Jun-2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 108 of 108 
- epistaxis 
- haematochezia 
- haemoptysis