Clinical trial NCT02117713
Conditions: Alagille Syndrome
Sponsor: Mirum Pharmaceuticals, Inc.
Start date: 2015-03-16; Completion date: 2020-06-01
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicentre, extension study of LUM001 in children diagnosed with Alagille Syndrome who have completed participation in a core LUM001 treatment protocol. The primary objective is to evaluate long-term safety and tolerability of LUM001. Efficacy will be assessed by evaluating the effect of LUM001 on the biochemical markers and pruritus associated with Alagille Syndrome.

Detailed description:

Arms: arm 1: Participant will receive LUM001 also known as Maralixibat (MRX) administered orally once per day.
Interventions: intervention 1: LUM001 (Maralixibat)
Intervention descriptions: intervention 1: Dosing of LUM001 also known as Maralixibat (MRX) with the objective of achieving optimal control of pruritus at a dose level that is tolerated by the participant and up to a maximum daily dose of 280 micrograms per kilogram (mcg/kg).

Protocol documents:
Prot_000.pdf: 
 
+
 
 
CLINICAL PROTOCOL 
PROTOCOL NUMBER: LUM001-305 
 
 
IMAGINE-II STUDY 
 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE LONG-TERM SAFETY AND 
DURABILITY OF THE THERAPEUTIC EFFECT OF LUM001, AN APICAL SODIUM-
DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT OF 
CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS WITH ALAGILLE 
SYNDROME 
Protocol Amendment 6.2: 13 May 2019 
 
Protocol History 
Original Protocol: 14 Apr 2014 
Protocol Amendment 1: 29 Jan 2015 
Protocol Amendment 2: 12 Feb 2015 
Protocol Amendment 3: 27 Apr 2016 (not published) 
Protocol Amendment 4: 27 Apr 2016* 
Protocol Amendment 5: 13 Nov 2017* 
Protocol Amendment 6: 25 Jun 2018 
Protocol Amenment 6.1 08 Feb 2019 
Developed in Collaboration with ChiLDReN 
*NIDDK DSMB Approval Date: 13 May 2019 
 
 
 
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unpublished information contained herein will be published or disclosed without prior approval from the 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 Pharmauticals, Inc. 
CONFIDENTIAL 
Page 2 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
SPONSOR SIGNATURE PAGE 
 
LUM001-305 
 
 
 
IMAGINE-II STUDY 
 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND DURABILITY OF THE THERAPEUTIC EFFECT OF LUM001, AN APICAL 
SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTI), IN THE 
TREATMENT OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS WITH 
ALAGILLE SYNDROME 
 
Protocol Amendment 6.2: 13 May 2019 
Protocol History 
Original Protocol: 14 Apr 2014 
Protocol Amendment 1: 29 Jan 2015 
Protocol Amendment 2: 12 Feb 2015 
Protocol Amendment 3: 27 Apr 2016  
Protocol Amendment 4: 27 Apr 2016* 
Protocol Amendment 5: 13 Nov 2017* 
Protocol Amendment 6: 25 Jun 2018 
Protocol Amendment 6.1: 08 Feb 2019 
 
 
*NIDDK DSMB Approval Date: 13 May 2019 
 
 
 
 
 
 
 
Sponsor: 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
 
 


Mirum Pharmauticals, Inc. 
CONFIDENTIAL 
Page 3 
LUM001-305 Protocol Amendment 6.2 
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13 May 2019 
 
 
TITLE PAGE 
Study Drug: 
LUM001 
 
Protocol Number: 
LUM001-305 
 
Amendment Number: 
6.2 
 
Date:  
 
 
13 May 2019 
 
 
 
 
 
 
 
IND No: 
119917 
 
Study Phase: 
Phase 2 
 
Protocol Title: 
A Multicenter Extension Study to Evaluate the Long-Term Safety and 
Durability of the Therapeutic Effect of LUM001, an Apical Sodium-
Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment 
of Cholestatic Liver Disease in Pediatric Subjects with Alagille 
Syndrome  
 
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 Pharmauticals, Inc. 
LUMOOl-305 Protocol Amendment 6.2 
SHP625 
CONFIDENTIAL 
PROTOCOL SIGNATURE PAGE 
Sp~nsor's (Mirum) App·[>· ro 
rovv~al
~ 
. . . 
. ... 
Signature: 
/ 
' 
/ . 
,/~ 
Thomas Jaecklin, MD 
Date: 
SVP Clinical Development 
Page4 
13 May 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) 
Clinical Study Title: 
A MULTI CENTER EXTENSION STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND DURABILITY OF THE THERAPEUTIC EFFECT OF LUMOOl , AN APICAL 
SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTI), IN THE 
TREATMENT OF CHO LEST A TIC LIVER DISEASE IN PEDIATRIC SUBJECTS WITH 
ALAGILLE SYNDROME 
Protocol Number: 
Amendment Number: 
Date: 
IND No: 
Sponsor: 
As Agreed: 
Investigator's Signature 
LUMOOl-305 
6.2 
13 May 2019 
119917 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
Date 
Investigator's Name (Please print) 


Mirum Pharmauticals, Inc. 
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LUM001-305 Protocol Amendment 6.2 
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13 May 2019 
 
 
EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or email the Premier 
Research Serious Adverse Event Form within 24 hours to the Premier Research 
Pharmacovigilance Department. Applicable fax numbers and email address can be found on the 
form (sent under separate cover) and below. 
Premier Research SAE Reporting: 
US sites:  
Fax: 215-972-8765, or  
Email: GlobalPV-US@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 sites: 
Central phone number: +1-512-686-1256 (US) 
For non-emergencies, the Premier Research Medical Monitor may be contacted by e-mail: 
medmonitorLUM305@premier-research.com  


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 13 May 2019 
 
PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Mirum within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures. 
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); or a 
product deficiency that relates to identity, quality, durability, reliability, safety and performance 
of the product but did not result in an AE, which include but are not limited to the following: 
• A failure of a product to exhibit its expected pharmacological activity and/or design function 
(eg, reconstitution difficulty) 
• Missing components 
• Damage to the product or unit carton 
• A mislabeled product (eg, potential counterfeiting/tampering) 
• A bacteriological, chemical or physical change or deterioration of the product causing it to 
malfunction or to present a hazard or fail to meet label claims 
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 or Non-
Medical Complaint: 
 
Origin of Product Quality Complaint 
Email 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 .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
PROTOCOL AMENDMENT 6.2 SUMMARY OF CHANGES ..................................................14 
1. 
STUDY SYNOPSIS ...............................................................................................................15 
2. 
LIST OF ABBREVIATIONS AND TERMS.........................................................................33 
3. 
STUDY OBJECTIVES ..........................................................................................................36 
4. 
BACKGROUND AND RATIONALE ...................................................................................37 
4.1 
Therapeutic Rationale ..............................................................................................37 
4.2 
Alagille Syndrome ....................................................................................................38 
4.3 
Pruritus .....................................................................................................................38 
4.4 
LUM001 ...................................................................................................................40 
4.4.1 
Nonclinical Studies ......................................................................................40 
4.4.1.1 
Pharmacology ..........................................................................................40 
4.4.1.2 
Pharmacokinetics .....................................................................................40 
4.4.1.3 
Toxicology ...............................................................................................40 
4.4.2 
Previous Clinical Experience .......................................................................40 
4.5 
Rationale for Dose and Schedule of Administration ................................................42 
5. 
INVESTIGATIONAL PLAN .................................................................................................46 
5.1 
Study Design ............................................................................................................46 
5.2 
Data Monitoring Board ............................................................................................47 
5.3 
Number of Study Centers .........................................................................................48 
5.4 
Number of Subjects ..................................................................................................48 
5.5 
Overall Study Duration and Follow-up ....................................................................48 
5.5.1 
Treatment .....................................................................................................53 
5.5.1.1 
Dose Escalation Period ............................................................................54 
5.5.1.2 
Dose Optimization Period .......................................................................55 
5.5.1.3 
Stable Dosing and Safety Monitoring Periods ........................................55 
5.5.1.4 
Long-term, Optional Follow-up Treatment Period .................................55 
5.5.1.5 
Long-term, Optional Follow-up Treatment Period-2 ..............................56 
5.5.2 
Dosing Interruptions .....................................................................................56 


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5.5.2.1 
Dose Escalation Following Dose Interruption ........................................56 
5.5.2.2 
Visit Schedule Following Dose Interruption for Stable Dosing and 
Safety Monitoring Periods .......................................................................57 
5.5.2.3 
Visit Schedule Following Dose Interruption for Long-term, Optional 
Follow-up Treatment Period ....................................................................58 
5.5.3 
Follow-up .....................................................................................................58 
5.6 
Study Termination ....................................................................................................58 
6. 
SUBJECT ENROLLMENT ...................................................................................................60 
6.1 
Enrollment ................................................................................................................60 
6.2 
Replacement of Subjects ..........................................................................................60 
6.3 
Unblinding of Treatment Assignment ......................................................................60 
7. 
SUBJECT ELIGIBILITY .......................................................................................................62 
7.1 
Inclusion Criteria ......................................................................................................62 
7.2 
Exclusion Criteria .....................................................................................................63 
8. 
STUDY PROCEDURES ........................................................................................................65 
8.1 
Study Schedule .........................................................................................................65 
8.1.1 
Baseline (Day 0) ...........................................................................................65 
8.1.2 
Dose Escalation Treatment Period (Week 0 to Week 4) ..............................65 
8.1.3 
Dose Optimization Period (Week 5 to Week 12) .........................................66 
8.1.4 
Stable Dosing Period (Week 13 to Week 48) ..............................................66 
8.1.5 
Safety Monitoring Period (Week 49 to Week 96) ........................................67 
8.1.6 
Week 96 ........................................................................................................67 
8.1.7 
Follow-up Phone Call (30 days after Last Dose) .........................................68 
8.1.8 
Long-term, Optional Follow-up Treatment Period (Week 96-148) .............68 
8.1.9 
Week 144 ......................................................................................................70 
8.1.10 
Week 148 ......................................................................................................71 
8.1.11 
Long-term, Optional Follow-up Treatment Period-2 (Week 144-220) ........71 
8.1.12 
Week 216 (EOT or ET) ................................................................................72 
8.1.13 
Week 220 (EOS) ..........................................................................................72 
8.2 
Physical Examination, Weight and Height, Vital Signs ...........................................72 
8.3 
Laboratory Assessments ...........................................................................................73 
8.4 
Pruritus and Quality of Life Assessments ................................................................73 
8.4.1 
Itch Reported Outcome (ItchRO™) .............................................................73 
8.4.2 
Clinician Scratch Scale .................................................................................74 
8.4.3 
Clinician Xanthoma Scale ............................................................................75 
8.4.4 
Pediatric Quality of Life Inventory (PedsQL) ..............................................75 
8.4.5 
Caregiver Impression of Change ..................................................................76 
8.5 
Restriction on the Lifestyle of Subjects ...................................................................76 


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8.5.1 
Contraception Requirements ........................................................................76 
8.5.2 
Fasting Requirements ...................................................................................76 
9. 
STUDY DRUG .......................................................................................................................77 
9.1 
Study Drug Description ............................................................................................77 
9.1.1 
LUM001 .......................................................................................................77 
9.2 
Packaging and Labeling ...........................................................................................77 
9.3 
Drug Accountability .................................................................................................77 
10. TREATMENT OF SUBJECTS ..............................................................................................78 
10.1 
Study Drug Administration ......................................................................................78 
10.2 
Treatment Compliance .............................................................................................78 
10.3 
Concomitant Medications ........................................................................................78 
10.4 
Other Protocol-required Drugs .................................................................................79 
10.5 
Safety Monitoring Rules ..........................................................................................79 
10.5.1 
General Monitoring Rules ............................................................................79 
10.5.2 
Safety Monitoring Rules ..............................................................................79 
10.5.2.1 
Safety Monitoring for Liver Chemistry Tests .........................................80 
10.5.2.2 
Stopping Rules for Liver Chemistry Elevations ......................................81 
10.5.2.3 
Safety Monitoring for Triglycerides ........................................................81 
10.5.2.4 
Safety Monitoring for Fat Soluble Vitamins ...........................................82 
10.5.2.5 
Monitoring/Stopping Rules for Coagulation Panel Results ....................82 
10.6 
Adjustment of Dose ..................................................................................................82 
10.7 
Withdrawal of Subjects from the Study ...................................................................82 
11. SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .................................84 
11.1 
Regulatory Requirements .........................................................................................84 
11.2 
Definitions ................................................................................................................84 
11.2.1 
Adverse Event ..............................................................................................84 
11.2.2 
Adverse Reaction and Suspected Adverse Reaction ....................................85 
11.2.3 
Serious Adverse Event (SAE) ......................................................................85 
11.3 
Monitoring and Recording Adverse Events .............................................................86 
11.3.1 
Serious Adverse Events ................................................................................86 
11.3.2 
Non-Serious Adverse Events .......................................................................87 
11.3.3 
Evaluation of Adverse Events (Serious and Non-Serious) ..........................87 
11.3.3.1 
Relationship to the Study Drug ...............................................................87 
11.3.3.2 
Severity ....................................................................................................87 
11.3.3.3 
Action Taken with Study Drug ................................................................88 
11.3.3.4 
Treatment Given for Adverse Event ........................................................88 
11.3.3.5 
Outcome of the Adverse Event ................................................................88 


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11.4 
Procedures for Handling Special Situations .............................................................89 
11.4.1 
Pregnancy Reporting ....................................................................................89 
11.4.2 
Dosing Errors ...............................................................................................89 
11.4.3 
Abnormalities of Laboratory Tests...............................................................90 
12. STATISTICAL CONSIDERATIONS ...................................................................................91 
12.1 
Sample Size Considerations .....................................................................................92 
12.2 
Population .................................................................................................................92 
12.2.1 
Safety Population .........................................................................................92 
12.2.2 
Siblings .........................................................................................................92 
12.2.3 
Demographic and Baseline Characteristics ..................................................92 
12.2.3.1 
Subject Disposition ..................................................................................92 
12.2.3.2 
Baseline Data ...........................................................................................93 
12.2.4 
Efficacy Analyses .........................................................................................93 
12.2.4.1 
Efficacy Variables ...................................................................................93 
12.2.4.2 
Primary Efficacy Analysis .......................................................................94 
12.2.4.3 
Secondary, Exploratory and Other Efficacy Analyses ............................94 
12.2.5 
Safety Analyses ............................................................................................95 
12.2.5.1 
Safety Assessments .................................................................................95 
12.2.6 
Safety Analysis .............................................................................................95 
12.2.6.1 
Adverse Events ........................................................................................95 
12.2.6.2 
Laboratory Tests ......................................................................................96 
12.2.6.3 
Physical Exams, Vital Signs and Weight/Height Measurements ............96 
12.2.6.4 
Concomitant Medications ........................................................................96 
12.2.6.5 
Study Drug Exposure ..............................................................................96 
12.2.7 
Additional Analyses .....................................................................................97 
13. INVESTIGATOR’S REGULATORY OBLIGATIONS .......................................................98 
13.1 
Informed Consent .....................................................................................................98 
13.2 
Ethical Conduct of the Study ...................................................................................98 
13.3 
Independent Ethics Committee/Institutional Review Board ....................................99 
13.4 
Confidentiality ..........................................................................................................99 
14. ADMINISTRATIVE AND LEGAL OBLIGATIONS ........................................................101 
14.1 
Study Personnel ......................................................................................................101 
14.2 
Pre-study Documentation Required .......................................................................101 
14.3 
Protocol Amendments ............................................................................................101 
14.4 
Study Termination ..................................................................................................102 
14.5 
Study Documentation and Storage .........................................................................102 
14.5.1 
Parent Report for Teenagers (ages 13-18 years) ........................................103 


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14.6 
Study Monitoring ...................................................................................................105 
14.7 
Language ................................................................................................................105 
14.8 
Compensation for Injury ........................................................................................105 
15. REFERENCES .....................................................................................................................106 
16. APPENDICES ......................................................................................................................107 
16.1 
Schedule of Procedures ..........................................................................................108 
16.2 
List of Laboratory Analytes ...................................................................................121 
16.3 
Itch Reported Outcome Instrument (ItchRO™) .....................................................122 
16.3.1 
Patient Itch Reported Outcome Instrument, ItchRO(Pt)™ ........................123 
16.3.2 
Observer Itch Reported Outcome Instrument, ItchRO(Obs)™ ..................126 
16.4 
Clinician Scratch Scale ...........................................................................................129 
16.5 
Clinician Xanthoma Scale ......................................................................................130 
16.6 
Pediatric Quality of Life Inventory (PedsQL™) ....................................................131 
16.6.1 
Parent Report for Infants (ages 1-12 months) ............................................132 
16.6.2 
Parent Report for Infants (ages 13 to 24 months) ......................................135 
16.6.3 
Parent Report for Toddlers (ages 2-4 years) ..............................................138 
16.6.4 
Parent Report for Young Children (ages 5-7 years) ...................................140 
16.6.5 
Parent Report for Children (ages 8-12 years) .............................................142 
16.6.6 
Pediatric Quality of Life Inventory v 4.0 for Young Children (ages 5-
7 years) .......................................................................................................144 
16.6.7 
Pediatric Quality of Life Inventory for Children (ages 8-12 years) ...........147 
16.6.8 
Pediatric Quality of Life Inventory for Teenagers (ages 13-18 years).......149 
16.6.9 
Multidimensional Fatigue Scale Parent Report for Toddlers (ages 2-4 
years) ..........................................................................................................151 
16.6.10 
Multidimensional Fatigue Scale Parent Report for Young Children 
(ages 5-7 years) ..........................................................................................153 
16.6.11 
Multidimensional Fatigue Scale Parent Report for Children (ages 8-12 
years) ..........................................................................................................155 
16.6.12 
Multidimensional Fatigue Scale Parent Report for Teenagers (ages 
13-18 years) ................................................................................................157 
16.6.13 
Multidimensional Fatigue Scale Young Child Report (ages 5-7 years) .....159 
16.6.14 
Multidimensional Fatigue Scale Child Report (ages 8-12 years) ..............162 
16.6.15 
Multidimensional Fatigue Scale Teen Report (ages 13-18 years) .............164 
16.6.16 
Family Impact Module v 2.0 ......................................................................166 
16.7 
Caregiver Impression of Change (CIC) .................................................................169 
16.8 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 ..........170 
16.9 
Protocol History .....................................................................................................171 
16.9.1 
Protocol Amendment 6.1 Summary of Changes ........................................172 


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16.9.2 
Protocol Amendment 6 Summary of Changes ...........................................174 
16.9.3 
Protocol Amendment 5 Summary of Changes ...........................................180 
16.9.4 
Protocol Amendment 4 Summary of Changes ...........................................186 
16.9.5 
Protocol Amendment 2 Summary of Changes ...........................................195 
16.9.6 
Protocol Amendment 1 Summary of Changes ...........................................196 


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LIST OF TABLES 
 
Table 1: 
Improvement in Biochemical Markers and Pruritus After Partial 
External Biliary Diversion in PFIC Disease and Alagille Syndrome 
Subjects ..........................................................................................................39 
Table 2: 
Sample Daily Exposure (mg/day) in Pediatric Subjects ................................43 
Table 3: 
GI-associated Adverse Events in Study 003 .................................................44 
Table 4: 
Dose Escalation Regimens ............................................................................54 
Table 5: 
Dose Escalation Regimen for Re-initiation of LUM001 Dosing When 
Dosing Interruption is Greater than 7 Consecutive Days ..............................57 
Table 6: 
Dosing Interruptions: Reintegration to Study Visit Schedule .......................58 
Table 7: 
Composition of LUM001 1.0 mL Oral Solution ...........................................77 
Table 8: 
Composition of LUM001 0.5 mL Oral Solution ...........................................77 
 
LIST OF FIGURES 
 
Figure 1: 
Interruption of Enterohepatic Circulation with an ASBT/IBAT 
Inhibitor .........................................................................................................37 
Figure 2: 
Serum Bile Salt Concentration and Degree of Itch .......................................39 
Figure 3: 
Study Design for LUM001-305 (Day 0-Week 48) ........................................49 
Figure 4: 
Safety Monitoring Period (Week 49-Week 96) .............................................50 
Figure 5: 
Long-term Optional Follow-up Treatment Period (Week 96-
Week 148) .....................................................................................................51 
Figure 6: 
Long-term Optional Follow-up Treatment Period (Week 96-
Week 148) .....................................................................................................52 
Figure 7: 
Long-term Optional Follow-up Treatment Period-2 (Week 144-
Week 220) .....................................................................................................53 
Figure 8: 
Visit Schedule for Re-initiation of LUM001 when Dosing Interruption 
is Greater than 7 Consecutive Days ...............................................................57 
 


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PROTOCOL AMENDMENT 6.2 SUMMARY OF CHANGES 
 
Protocol Number: 
LUM001-305 
Protocol Title: 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
6.2 
Date: 
13 May 2019 
 
The LUM001-305 protocol is being amended to reflect the date of the DSMB approval 
(13May2019)  of changes made per Amendment 6.1 which was never operationalized. 


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1. 
STUDY SYNOPSIS 
Sponsor 
Mirum Pharmaceuticals, Inc 
Protocol 
Number 
LUM001-305 
Protocol Title 
A Multicenter Extension Study to Evaluate the Long-Term Safety and Durability of the 
Therapeutic Effect of LUM001, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor 
(ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Subjects with Alagille 
Syndrome  
Study Phase 
2 
Indication 
Treatment of cholestatic liver disease in Alagille syndrome (ALGS)  
Objectives 
The primary objective of the study is to:  
• Evaluate the long-term safety and tolerability of LUM001 in pediatric subjects with ALGS. 
Secondary objectives of the study are to: 
• Evaluate the long-term effect of LUM001 on serum bile acid levels associated with ALGS. 
• Evaluate the long-term effect of LUM001 on pruritus associated with ALGS. 
• Explore the long-term effect of LUM001 on other biochemical markers of cholestasis and 
liver disease. 
• Evaluate the long-term effect of LUM001 on xanthomas associated with ALGS. 
• Explore an expanded dosing range to identify the doses necessary to achieve the optimal 
benefit-to-risk ratio for this patient population. 
Exploratory objective of the study is to: 
• Evaluate the long term effect of LUM001 on weight in pediatric subjects with ALGS. 
Study Design 
This is a multicenter, double-blind study of LUM001 in children >12 months of age diagnosed 
with ALGS who have completed participation in the LUM001-301 protocol. All subjects will 
receive active drug (LUM001) in the study. The study is divided into 6 parts: a dose escalation 
period, a dose optimization period, a stable dosing period, a safety monitoring period, and 2 
long-term optional follow-up treatment periods.  
Dose Escalation Period 
All subjects entering the extension study will participate in a 4-week double-blind dose 
escalation period during which: 
• Subjects randomized to receive placebo during the LUM001-301 protocol will receive 
weekly dose increases of LUM001 up to a target dose of 140 μg/kg/day. 
• Subjects randomized to active drug during the LUM001-301 protocol will continue to 
receive the dose of LUM001 that they were taking at Week 13 of the LUM001-301 study. 
The LUM001 doses for these subjects will remain blinded and will not be altered during the 
dose-escalation period. 
A minimum period of 7 days must elapse between increases in dose. 
 
Dose Optimization Period 
Following completion of the 4-week dose escalation period, subjects will enter an 8-week dose-
optimization period. During this period, the investigator will have the option to adjust LUM001 
dosing with the objective of achieving optimal control of pruritus at a dose level that is 


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tolerated by the subject and up to a maximum daily dose of 280 μg/kg LUM001 or 20 mg total 
dose. Study drug dose will be increased or decreased in a double-blind manner. Increases in 
dose will be based on effect on pruritus. Reductions in dose will be based on tolerability. At the 
investigator’s discretion, the doses for subjects who were previously down-titrated may be 
re-challenged during the dose optimization period. Each subject will receive one of the 
following dose levels:  
• LUM001 35 μg/kg/day. 
• LUM001 70 μg/kg/day. 
• LUM001 140 μg/kg/day. 
• LUM001 280 μg/kg/day. 
A minimum period of 7 days must elapse between increases in dose.  
Stable Dosing and Safety Monitoring Periods 
Following completion of the 8-week dose optimization period, all subjects will enter the stable 
dosing period lasting 36 weeks followed by a safety monitoring period lasting up to 48 weeks. 
During the stable dosing and safety monitoring periods, subjects will be dosed with the Week 
12 dose, or the highest tolerated dose below the Week 12 dose. However, if a subject 
experiences intolerance due to gastrointestinal symptoms, the investigator, in consultation with 
the ChiLDReN protocol chair and Medical Monitor, may lower the dose to a previously 
tolerated dose for the rest of the study. 
 
Long-term Optional Follow-up Treatment Period: 
The long-term optional follow-up treatment period is for eligible subjects who choose to remain 
on treatment with LUM001 following the initial 96 weeks of treatment. During this long-term 
optional follow-up treatment period, subjects with LUM001 dosing interruptions ≤7 days will 
remain on the same dose they were taking at Week 96. Subjects with LUM001 dosing 
interruptions >7 consecutive days will require dose escalation upon resumption of study drug. 
The dose of LUM001 will be increased at weekly intervals up to the subject’s previously 
achieved highest tolerated dose. Study drug for each subject will remain blinded and will be 
prepared by the unblinded central pharmacist according to the protocol’s specified dose-
escalation regimen. Subjects’ participation in the long-term optional follow-up treatment period 
will continue until the first of the following occur: (i) subjects complete 48 weeks of additional 
treatment (after Week 96 [safety monitoring period]), or (ii) the subjects are eligible to enter 
another LUM001 study. 
 
Long-term Optional Follow-up Treatment Period-2: 
The long-term optional follow-up treatment period-2 is for eligible subjects who choose to 
remain on treatment with LUM001 for an additional 72 weeks. During this long-term optional 
follow-up treatment period-2, subjects will remain on the same dose they were taking at 
Week 144. Study drug for each subject will remain blinded and will be prepared by the 
unblinded central pharmacist according to the protocol’s specified dose-escalation regimen. 
Subjects’ participation in the long-term optional follow-up treatment period will continue until 
the first of the following occur: (i) subjects complete 72 weeks of additional treatment (after 
Week 144 [Long-term Optional Follow-up Treatment Period]), or (ii) the subjects are eligible 
to enter another LUM001 (SHP625) study. 
Number of 
Subjects 
Approximately 36 subjects meeting the study’s inclusion and exclusion criteria will be enrolled 
in the study. 
Study 
Population 
Original Inclusion and Exclusion Criteria (through Protocol Amendment 4) 
Inclusion Criteria 


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To participate in this study, subjects must meet all of the following criteria: 
1. Male or female, 12 months to 18 years of age. 
2. Competent to provide informed consent and assent (per IRB/EC), as appropriate. 
3. Completed participation in the LUM001-301 protocol. 
4. Females of childbearing potential must have a negative urine pregnancy test [β human 
chorionic gonadotropin (β-hCG)] at the Baseline Visit. 
5. Sexually active females must be prepared to use an effective method (≤ 1% failure rate) of 
contraception during the trial. Effective methods of contraception are considered to be: 
a. 
Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection); or 
b. Barrier method, eg, (a) condom with spermicide, or (b) diaphragm, with 
spermicide; or 
c. 
Intrauterine device (IUD). 
6. Subjects above the age of assent and caregivers and children must be able to read and 
understand English or Spanish. 
7. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls 
from study site. 
8. Caregivers (and age appropriate subjects) must be willing and able to complete a daily 
electronic diary (ItchRO) during the first consecutive 12 weeks of the study and then for 4 
consecutive weeks following the Week 24 and Week 44 visits. 
9. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement in 
the ItchRO electronic diary software at the outset of the study. 
10. Eligible subjects must be able to adhere to local Ethics Committee (EC)or Institutional 
Review Board (IRB) blood volume limits for laboratory testing. 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Experienced an adverse event (AE) or serious adverse event (SAE) related to the study 
drug during the LUM001-301 protocol that led to the discontinuation of the subject from 
the LUM001-301 treatment study. 
2. Any conditions or abnormalities (including laboratory abnormalities) which, in the opinion 
of the Investigator or Medical Monitor or ChiLDReN Protocol Chair, may compromise the 
safety of the subject, or interfere with the subject participating in or completing the study. 
3. History or known presence of gallstones or kidney stones. 
4. History of non-adherence during the subject’s participation in the LUM001-301 protocol. 
Non-adherence is defined by dosing compliance of less than 80% in the LUM001-301 
protocol. 
5. Unlikely to comply with the study protocol, or unsuitable for any other reason, as judged 
by the investigator. 
Protocol Amendment 5 Inclusion and Exclusion Criteria: Eligible subjects for the long-term 
optional follow-up treatment period 
Inclusion Criteria: 


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1. The subject has completed the protocol either through Week 96, or the ET visit, or has 
received permission from the sponsor and the ChiLDReN protocol chair to re-enter the 
study in the long-term, optional, follow-up treatment period. 
2. Female subjects of child-bearing potential must have a negative urine or serum pregnancy 
test (β-human chorionic gonadotropin [β-HCG]) at the time of entry into the long-term 
optional, follow-up treatment period. 
3. Male and female subjects of child-bearing potential who are sexually active, or are not 
currently sexually active, but become sexually active during the study or for 30 days 
following the last dose of study drug, must agree to use acceptable contraception during the 
study. 
4. Informed consent and assent (per IRB/EC) as appropriate. 
5. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls 
from study site. 
6. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device 
during the study. 
Exclusion Criteria: 
All exclusion criteria for the original LUM001-305 study apply upon re-entry into the long-
term, optional follow-up treatment period. 
Protocol Amendment 6 Inclusion and Exclusion Criteria: Eligible subjects for the long-term 
optional follow-up treatment period-2 
Inclusion Criteria: 
1. The subject has completed the protocol through either Week 144, or the ET visit, or has 
received permission from the sponsor and the ChiLDReN protocol chair to re-enter the 
study in the long-term optional follow-up period-2.  
2. Females of child-bearing potential must have a negative urine or serum pregnancy test (β-
human chorionic gonadotropin [β-HCG]) at the time of entry into the long-term optional 
follow-up treatment period-2. 
3. Males and females of child-bearing potential who are sexually active, or are not currently 
sexually active, but become sexually active during the study or for 30 days following the 
last dose of study drug, must agree to use acceptable contraception during the study. 
4. Informed consent and assent (per IRB/EC) as appropriate. 
5. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls 
from study site. 
6. Caregivers (and age appropriate subjects) must be willing to follow the rules of eDiary 
completion. 
Exclusion Criteria: 
All exclusion criteria for the original LUM001-305 study apply upon re-entry into the long-
term optional follow-up treatment period-2. 
Treatment 
Groups 
Based on tolerability and effect on pruritus each subject will receive one of the following dose 
levels during the stable dosing, safety monitoring, and long-term, optional, follow-up treatment 
periods:  
• 
LUM001 35 μg/kg/day (up to a maximum daily dose of 2.5 mg). 
• 
LUM001 70 μg/kg/day (up to a maximum daily dose of 5 mg). 
• 
LUM001 140 μg/kg/day (up to a maximum daily dose of 10 mg). 


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• 
LUM001 280 μg/kg/day (up to a maximum daily dose of 20 mg). 
Study Drug 
Dosage and 
Administration 
Study drug will be prepared by a central pharmacy based on the subject’s weight. During the 
study, weight will be monitored at each visit. A change from baseline in a subject’s weight that 
is greater than 10% will require a dose adjustment. Each subsequent 10% increase in weight 
will be considered the new baseline for determination of future dose adjustments. Weight-based 
dose adjustments will be made by the central pharmacy at the time of the subject’s next 
LUM001 preparation.  
Study drug will be dispensed to subjects/caregivers at the study site. The appropriate amount of 
study drug will be dispensed at the Study Day 0 visit and daily dosing will begin on Study 
Day 1. Subjects who weigh 10 kg or more will receive a 1.0 mL grape-flavored solution 
containing LUM001. Subjects who weigh less than 10 kg will receive 0.5 mL grape flavored 
solution containing LUM001. The volume, either 1.0 mL or 0.5 mL administered will not 
change during the course of the study. Dosing will occur up to 216 weeks of treatment. 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.  
Dose Escalation Period 
For subjects randomized to placebo in the LUM001-301 protocol, or those who complete the 
core study more than 7 days prior enrollment into this study, the LUM001 dose during the first 
4 weeks of the study will be increased at weekly intervals to 140 μg/kg/day, or to a maximum 
tolerated dose below 140 μg/kg/day (10 mg maximum total dose). For subjects who were 
randomized to receive active drug in the LUM001-301 protocol. LUM001 doses will remain 
the same as the dose being taken at Week 13 of the core study. Study treatment for each subject 
will remain blinded and will be prepared by the unblinded central pharmacist according to a 
specified dose-escalation regimen. This regimen will represent a real dose escalation for 
subjects previously randomized to placebo and a mock dose escalation for subjects previously 
randomized to active study treatment.  
The dosing regimen for each treatment group during the dose escalation period is summarized 
in the following table. 
 
 
LUM001-301 
Protocol 
Extension Study Protocol LUM001-305 
Dose Escalation Period 
Week 13 
(μg/kg/day) 
Week 1 
Days 1 - 7 
(μg/kg/day) 
Week 2 
Days 8 - 14 
(μg/kg/day) 
Week 3 
Days 15 - 21 
(μg/kg/day) 
Week 4 
Days 22 - 28 
(μg/kg/day) 
Placebo 1 
14 
35 
70 
140 
35 2 
35 
35 
35 
35 
70 3 
70 
70 
70 
70 
140 4 
140 
140 
140 
140 
280 5 
280 
280 
280 
280 
1 
For subjects randomized to placebo in the LUM001-301 protocol, or those who complete the core 
study more than 7 days prior enrollment into this study, the LUM001 dose during the first 4 weeks 
of the study will be increased at weekly intervals to 140 μg/kg/day, or to a maximum tolerated 
dose below 140 μg/kg/day (10 mg maximum total dose). 
2 
LUM001 doses for subjects whose stable dose upon completion of the LUM001-301 protocol was 
35 μg/kg/day will remain stable at 35 μg/kg/day, or to a maximum daily dose of 2.5 mg/day.  
3 
LUM001 doses for subjects whose stable dose upon completion of the LUM001-301 protocol was 
70 μg/kg/day will remain stable at 70 μg/kg/day, or to a maximum daily dose of 5 mg/day.  
4 
LUM001 doses for subjects whose stable dose upon completion of the LUM001-301 protocol was 
140 μg/kg/day will remain stable at 140 μg/kg/day, or to a maximum daily dose of 10 mg/day.  


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5 
LUM001 doses for subjects whose stable dose upon completion of the LUM001-301 protocol was 
280 μg/kg/day will remain stable at 280 μg/kg/day, or to a maximum daily dose of 20 mg/day.  
 
The primary anticipated adverse reaction or intolerance is gastrointestinal in nature (eg, 
diarrhea, abdominal pain, cramping, etc.). In the absence of GI intolerance, escalation to the 
next dose level for an individual patient may occur at the investigator’s discretion, following a 
scheduled phone call or visit (see Schedule of Procedures, Section 16.1). 
If a subject experiences intolerance due to gastrointestinal symptoms, the investigator, in 
consultation with the ChiLDReN protocol chair and Medical Monitor, may lower the dose to a 
previously tolerated dose for the remainder of the study. 
Dose Optimization Period 
Following the dose escalation period, the LUM001 dose for each subject may be increased and 
decreased by the investigator as clinically indicated for the control of pruritus at a dose level 
that is tolerated by the subject. Dose optimization will occur in a blinded, titrated manner with 
four dose levels available as treatment options: 35, 70, 140 or 280 μg/kg/day. Adjustments may 
occur at weekly intervals. Once an optimal LUM001 dose is achieved, the dose will be fixed for 
the duration of the study.  
 
The maximum daily dose of LUM001 in this study is 280 μg/kg/day, up to a maximum daily 
dose of 20 mg. Blinded investigators may request dose adjustment for any subject based on an 
assessment of tolerability and effect on pruritus. Caregivers and age-appropriate subjects will 
be asked whether they wish to take a higher dose of the study medication to achieve greater 
relief of itching. If so, the dose may be adjusted upward, within the permitted dose range. 
However, the patient, caregiver, physician investigator, or the Medical Monitor may 
recommend against further escalation if there are safety or tolerability concerns. Doses of 
LUM001 will not be increased above 280 μg/kg/day or 20 mg per day at any time.  
Stable Dosing and Safety Monitoring Periods 
At the end of the dose optimization period, subjects will continue dosing to complete the stable 
dosing and safety monitoring periods for up to 96 weeks of cumulative LUM001 exposure in 
this study.  
 
Subjects who completed the 48-week study prior to the implementation of Protocol Amendment 
#4 may be re-contacted and re-consented for participation in the safety monitoring period of the 
study. 
 
If, at any time during the study, a subject experiences intolerance due to gastrointestinal 
symptoms, the physician investigator may lower the dose to a previously tolerated dose.  
Long-term Optional Follow-up Treatment Period: 
At Week 96, all subjects will be assessed by the investigator to determine their willingness and 
eligibility to roll over into the long-term optional follow-up treatment period. Following the 
completion of the Week 96 study visit, subjects who choose to participate in the long-term 
optional follow-up treatment period will be maintained at the same Week 96 dose level. 
Subjects with dose interruptions >7 consecutive days prior to implementation of Protocol 
Amendment 5 will be rescreened and require dose escalation upon resumption of study drug. 
The dose of LUM001 will be increased at weekly intervals up to the subject’s previously 
tolerated dose under Protocol Amendment 4. Subjects who do not wish to enter the long-term, 
optional follow-up treatment period will be contacted via telephone by the study site 
approximately 30 days after the last dose of the study drug. 


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Subjects who either completed the 96-week study prior to the implementation of Protocol 
Amendment 5, or have received permission from the ChiLDReN protocol chair and the 
Medical Monitor, may be recontacted and reconsented for participation in the long-term, 
optional follow-up treatment period of the study.  
Study drug administration under Protocol Amendment 5 will not change from Protocol 
Amendment 4. 
Long-term Optional Follow-up Treatment Period-2: 
At Week 144, all subjects will be assessed by the investigator to determine their willingness 
and eligibility to roll over into the long-term optional follow-up treatment period-2. Following 
the completion of the Week 144 study visit, subjects who choose to participate in the long term 
optional follow-up treatment period-2 will be maintained at the same Week 144 dose level. 
Subjects who do not wish to enter the long term optional follow up treatment period-2 should 
complete the in-clinic Week 148 Visit 30 days after the last dose of study drug.  
Subjects who either completed the 144-week study prior to the implementation of Protocol 
Amendment 6, or have received permission from the ChiLDReN protocol chair and the 
Medical Monitor, may be recontacted and reconsented for participation in the long-term, 
optional follow-up treatment period-2 of the study. 
Study Drug Administration under Protocol Amendment 6 will not change from Protocol 
Amendment 5. 
Dose Escalation Following Dose Interruptions 
Subjects with interruptions in LUM001 dosing of more than 7 consecutive days during the 
stable dosing, safety monitoring, and long-term optional follow-up treatment periods, will 
require dose escalation upon resumption of the study drug. The dose of LUM001 will be 
increased at weekly intervals up to the subject’s previously achieved highest tolerated dose. 
Study drug for each subject will remain blinded and will be prepared by the unblinded central 
pharmacist according to the protocol’s specified dose-escalation regimen.  
 
Dose Escalation Regimen for Resumption of LUM001 Dosing When Dosing Interruption 
is Greater Than 7 Consecutive Days 
Week 1 
 (μg/kg/day) 
Week 2 
 (μg/kg/day) 
Week 3 
 (μg/kg/day) 
Week 4 
 (μg/kg/day) 
35 
70 1 
140 1 
280 1 
1 Weekly dose escalations will end once the highest tolerated dose achieved prior to the 
subject’s LUM001 dosing interruption is reached. 
 


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Rationale for 
Dose and 
Schedule 
Selection  
The dosage of LUM001 for the first studies in pediatric cholestatic subjects was based upon 
prior experience with this investigational 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 gastrointestinal (GI) 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. Subjects with 
cholestatic liver disease have reduced bile flow compared to healthy volunteers and 
hypercholesterolemic subjects. LUM001 is likely to produce a smaller increase in free bile 
acids in the lower colon. There is also evidence in subjects with cholestasis to suggest that 
ASBT expression may be upregulated and higher LUM001 concentrations may be required to 
achieve the desired target inhibition of ASBT. 
Dosing in pediatric subjects will be based on subject weight. Earlier studies in healthy 
volunteers and hypercholesterolemic subjects 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 by >50% 
following 2 weeks of treatment.  
In previous studies with LUM001, GI AEs were generally recorded in the first week of 
LUM001 dosing. After 2 to 3 weeks of continuous dosing the observed rates of events was 
similar to those in the placebo group. In a 4-week dose finding study in healthy volunteers, a 
dose escalation regimen was evaluated to mitigate the risk of loose stools and diarrhea. 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.  
The starting dose in this clinical trial may be as low as 14 µg/kg/day, is equivalent to less than 
the well-tolerated 1 mg dose (~17 µg/kg, 60 kg body weight) used in a previous study (Study 
014), where LUM001 was tested at doses up to 5 mg/day for 14 days in 40 hyperlipidemic 
pediatric subjects (n=5, children ages 10-11; n=35, adolescents ages 12-17), At the 1 mg dose 
in Study 014, only two out of eight subjects reported moderate or severe GI-associated AEs 
during 14 days. On a weight basis, 23 subjects received a dose ≥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 the current study, escalation of LUM001 
doses for LUM001-naïve subjects will occur at 7-day intervals starting at 14 µg/kg/day and 
increasing to 35 µg/kg/day, 70 µg/kg/day, and 140 µg/kg/day. Thereafter, the dose of LUM001 
may be adjusted for all study subjects during the dose-optimization period. A minimum period 
of 7-days must elapse between increases in dose. Dose adjustments will be made at the 
investigator’s discretion with the goal of reaching a dose optimized for maximum efficacy and 
tolerability of 35, 70, 140 or 280 μg/kg/day.  
The dose may also be down-titrated, at the investigator’s discretion and in consultation with the 
ChiLDReN protocol chair and the Medical Monitor, for subjects experiencing intolerance to a 
given dose. 
Study Visit 
Schedule and 
Procedures 
For an individual subject, the study participation period will consist of a 4-week dose escalation 
period, followed by 8-weeks of dose optimization, a 36-week stable dosing period, a 48-week 
safety monitoring period, a 48-week long-term optional, follow-up treatment period, and a 72-
week long-term optional, follow-up treatment period-2. Planned participation for each subject 
enrolled in the extension study is a maximum of 220 weeks, inclusive of the safety follow-up 
contact approximately 30 days after the last dose of LUM001. Study activities will be 
conducted as described in the Schedule of Procedures (Section 16.1). 


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Study Scheme (as described below):  
Day 0-Week 48 
 
 
Week 49 – Week 96  
 
 
Week 96 – Week 148 
(no interruption in LUM001 dosing, or interruption ≤7 days between Week 96 and Week 100) 
 
 
 


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Week 96 – Week 148 
(interruption >7 days between Week 96 and Week 100)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Week 144 – Week 220 
 
 
Baseline (Day 0): Evaluations and procedures completed for the Week 13 Visit of the 
LUM001-301 study will also serve as the evaluations for the Baseline Visit for the extension 
study. Informed consent and/or assent for participation in the extension study must be obtained 
for all participating subjects and their parents or legal guardians, as appropriate. At the Baseline 
visit (Week 0), subjects will be assessed to confirm continued study eligibility including a 
review of medical history and will undergo a physical examination including body weight, 
height, and vital signs. 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 as well as for PK analysis (plasma levels of LUM001). The 
clinician scratch scale will be administered, as well as the PedsQL. Female subjects of 
childbearing potential will have a urine pregnancy test and concomitant medications and any 
AEs will be recorded. The degree and severity of xanthomatosis will be evaluated for all 
subjects by the clinician xanthoma scale. Study drug for Weeks 1 and 2 will be supplied at the 
Baseline visit to eligible subjects. 
Dose Escalation Period (Week 0 to Week 4): Double-blind dosing in the dose escalation period 
will be initiated on the morning after the Baseline Visit. Caregivers and age appropriate 
subjects will be instructed to complete their ItchRO electronic diary twice daily (morning and 
evening). Subjects will return to the clinic at Weeks 2, and 4, and will receive follow-up phone 
calls at Weeks 1 and 3. 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 and additional dosing instructions will be supplied. Study diary compliance will be 
assessed and concomitant medications and any AEs will be recorded at clinic visits and at 
scheduled telephone contacts. Additional study drug will be supplied at Weeks 2 and 4. 
Dose Optimization Period (Week 5 to Week 12): During the dose optimization period, the dose 
for each subject may be increased or decreased at the investigator’s discretion in a double-blind 
manner. The purpose of the dose optimization period is to allow the investigator to adjust the 
subject’s LUM001 dose to a level that is both tolerable to the subject and maximizes the 
potential effect of LUM001 on pruritus. Once an optimal dose is achieved, the dose will be 
fixed for the duration of the study.  
Electronic diaries will be completed twice daily by age-appropriate subjects and caregivers 
through Week 12 and then collected. Subjects will return to the clinic at Weeks 8 and 12 and 
will receive follow-up telephone calls at Weeks 6 and 10. At the clinic visits, safety and clinical 


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laboratory evaluations will be performed and vital signs, height and weight measurements will 
be collected. The clinician scratch scale will be administered and a review of study diary and 
medication compliance will be completed. Concomitant medications and any AEs will be 
assessed and recorded at each visit and at scheduled telephone contacts. Additional study drug 
will be supplied at Weeks 8 and 12.  
Stable Dosing Treatment Period (Week 13 to Week 48): Subjects will continue to receive study 
drug during the stable dosing treatment period according to the dose achieved during the dose 
optimization period. However, if a subject experiences intolerance due to gastrointestinal 
symptoms, the investigator, in consultation with the ChiLDReN protocol chair and Medical 
Monitor, may lower the dose to a previously tolerated dose for the remainder of the study.  
During the stable dosing period, subjects will return to the clinic at Weeks 24, 36, 44 and 48. 
Subjects who undergo a dose change at the Week 12 visit will also return to the clinic at Week 
16 (see below). 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 and clinician xanthoma scale will be administered and study drug 
compliance will be assessed. The PedsQL will be completed at Weeks 24 and 48 the Caregiver 
Impression of Change (CIC) will be completed at Week 48. Subjects/caregivers will 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.  
Subjects who undergo a dose change at the Week 12 visit will complete an on-site clinic visit at 
Week 16. Subjects who do not undergo a dose change at Week 12 will receive a follow-up 
phone call at Week 16. The study activities that will be conducted at the Week 16 clinic visit 
are described in the Schedule of Procedures (Section 16.1). 
Electronic diaries will be completed by age-appropriate subjects and caregivers following the 
Week 24 and Week 44 visits. The diaries will be redistributed at Week 24 and completed twice 
daily for 4 weeks before being collected at Week 28. The diaries will then be redistributed at 
Week 44 and completed twice daily until the end of the study (Week 48). Re-training on the use 
of the diary will occur as appropriate at the Week 24 and Week 44 visits. 
At the physician investigator’s discretion, tapering or withdrawal of concomitant medications 
used for the treatment of pruritus may occur during the stable dosing period.  
With the exception of Week 44, additional study drug will be supplied at each clinic visit 
during the stable dosing period.  


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Safety Monitoring Period (Week 49 to Week 96): During the safety monitoring period, subjects 
will return to the clinic every 3 months, at Weeks 60, 72, 84, and 96.  
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. The clinician scratch 
scale will also be completed at each clinic visit and study drug compliance will be assessed. The 
PedsQL, CIC, and the Clinician Xanthoma scale will also be administered at Weeks 60, 72, 84, and 
96. Subjects/caregivers will receive follow-up phone calls at Weeks 52, 56, 64, 68, 76, 80, 88, 
and 92. Concomitant medications and any AEs will be evaluated and recorded at all clinic visits 
and at scheduled telephone contacts.  
Twice daily completion of the ItchRO electronic diary will be required by caregivers and age 
appropriate subjects during the 2 weeks following the Week 60, 72, 84, and 96 clinic visits. 
Review of electronic diary data and assessment of compliance will occur during scheduled 
telephone contacts at Week 64, 76, and 88 and during the Week 96 clinic visit. 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 safety monitoring period.  
Additional study drug will be supplied at each clinic visit during the follow-up treatment 
period. 
Week 96: Subjects will be evaluated by the investigator to determine whether they are eligible 
to roll over into the long-term, optional follow-up treatment period. This will include a formal 
reassessment of the Protocol Amendment 5 inclusion and exclusion criteria and consenting of 
the subject at Week 96 per Schedule C. Eligible subjects must have documented consents in 
order to continue in the long-term, 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, 
as well as for PK analysis (plasma levels of LUM001). The clinician scratch scale and PedsQL 
will be administered and the degree and severity of xanthomatosis will be evaluated for all 
subjects using the clinician xanthoma scale. Review of the ItchRO electronic diary data and 
assessment of compliance will occur during the Week 96 clinic visit. The electronic diaries will 
be provided to subjects and caregivers and retraining on the use of the diary will occur, as 
appropriate. Twice daily completion of the diary will be required during the 2 weeks following 
the Week 96 clinic visit. Female subjects 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 long-term, 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 96 visit, with the exception of the ItchRO assessment. 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 (30 days after Last Dose): For subjects who do not roll over into the 
long-term, optional follow-up treatment period, a safety follow-up phone call will be made 
30 days after the last dose of study drug for subjects participating in all versions of the protocol 
up through Protocol Amendment 4. 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. For subjects who participate in the 


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long-term, optional follow-up treatment period, this phone call will be replaced by the Week 
148 end of study (EOS) clinic visit. For subjects who participate in the long-term, optional 
follow-up treatment period-2, this phone call will be replaced by the Week 220 (EOS) clinic 
visit. 
Long-term, Optional Follow-up Treatment Period (Week 96-148): Once Protocol Amendment 
5 is implemented at the site, subjects who are eligible and consent for entry into the long-term, 
optional follow-up treatment period will continue to receive study drug until the first of the 
following occurs: 
(i) 
The subjects complete 48 weeks of additional treatment after Week 96 (safety 
monitoring period) 
(ii) 
The subjects are eligible and consent to enter another LUM001 study 
Subjects with no LUM001 dosing interruptions or interruptions ≤7 days will continue to 
receive the same LUM001 dose they last received during LUM001-305 (Week 96 dose). Study 
activities will proceed as outlined in Schedule D.  
Subjects with LUM001 dosing interruptions >7 days will be rescreened and dose escalated 
up to 280 µg/kg/day or the highest tolerated dose over 4 weeks beginning at 35 µg/kg/day (see 
Figure 6). Study activities will proceed as outlined below and in Schedule E. 
• 
Protocol Amendment (PA) 5 Re-initiating (RI) Day -2 Clinic Visit: Consent (and/or 
assent as applicable) are obtained; eligibility criteria are confirmed. Physical 
examination (body weight, height, vital signs) is performed; blood and urine samples 
collected for clinical laboratory testing. Female subjects of childbearing potential will 
have a serum pregnancy test. Concomitant medications and AEs will be recorded. 
• 
PA5 RI Day 0 Clinic Visit: Eligibility criteria are confirmed. Physical examination 
(body weight, height, vital signs) is performed; blood and urine samples collected for 
clinical laboratory testing. Female subjects of childbearing potential will have a serum 
pregnancy test. Clinician scratch scale, clinician xanthoma scale, and PedsQL are 
completed. Concomitant medications and AEs will be recorded. Study drug is 
dispensed and subject begins dosing at 35 μg/kg/day dose level. 
• 
PA5 RI Week 1 Telephone Contact: Concomitant medications and AEs will be 
recorded. Subject escalates to 70 μg/kg/day dose level if prior dose level was tolerated. 
• 
PA5 RI Week 2 Clinic Visit: Physical examination (body weight, height, vital signs) is 
performed; blood and urine samples collected for clinical laboratory testing. Female 
subjects of childbearing potential will have a serum pregnancy test. Clinician scratch 
scale, clinician xanthoma scale, and PedsQL are completed. Concomitant medications 
and AEs will be recorded. Study drug is dispensed and subject escalates to 
140 μg/kg/day dose, if prior dose level was tolerated. 
• 
PA5 RI Week 3 Telephone Contact: Concomitant medications and AEs will be 
recorded. Subject escalates to 280 µg/kg/day dose level or previous maximum 
tolerated dose, if prior dose level was tolerated. 
• 
PA5 RI Week 4 Clinic Visit: Physical examination (body weight, height, vital signs) is 
performed; blood and urine samples collected for clinical laboratory testing. Female 
subjects of childbearing potential will have a serum pregnancy test. Clinician scratch 
scale, clinician xanthoma scale, and PedsQL are completed. The ItchRO electronic 
diaries will be provided to subjects and caregivers and re-training on the use of the 
diary will occur, as appropriate. Twice daily completion of the electronic diary will be 
required during the 2 weeks following this visit. Concomitant medications and AEs 
will be recorded. Study drug is dispensed and subject continues dosing at 
280 µg/kg/day dose level or on maximum tolerated dose. 


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• 
PA5 Schedule D Week 104 Telephone Contact (4 weeks after PA5 RI Week 4 Clinic 
Visit): Concomitant medications and AEs will be recorded. Subjects will then follow 
study activities as outlined in Schedule D. 
Per Schedule D, subjects will return to the clinic every 12 weeks at Weeks 108, 120, 132, 144, 
(end of treatment/early termination [EOT/ET]), and at Week 148 (EOS). During the clinic 
visits, physical exam, body weight and height, vital signs, urine samples, and blood samples for 
clinical laboratory testing including fasting lipid panel and fat soluble vitamins, bile acids, and 
other cholestasis biochemical markers will be collected. ItchRO compliance will be assessed, 
the electronic diary will be issued, the clinician scratch scale and the clinician xanthoma scale 
will be assessed at every clinic visit. The PedsQL questionnaire and CIC will be administered at 
Weeks 108, 144 and 148. Review of the ItchRO electronic diary data and assessment of 
compliance will occur during the Week 112, 124, and 136 telephone contacts. The ItchRO 
electronic diaries will be provided to subjects and caregivers and retraining on the use of the 
diary will occur, as appropriate. Twice daily completion of the electronic diary will be required 
during the 2 weeks following the Week 96, 108, 120, and 132 clinic visits and during the 
4 weeks following the Week 144 visit. Subjects rolling over into the long-term optional follow-
up treatment period-2 will complete the electronic diary for 2 weeks following the Week 144 
visit. Female subjects of childbearing potential will have a urine pregnancy test at each clinic 
visit prior to dispensing study drug. Study drug compliance will be assessed and study drug will 
be dispensed. Concomitant medications and AEs will be collected. 
Telephone Contact will occur at Weeks 100, 104, 112, 116, 124, 128, 136, and 140 where 
collection of concomitant medications and any AEs will be recorded. 
Week 144: Subjects will be evaluated by the investigator to determine whether they are eligible 
to roll over into the long-term, optional follow-up treatment period-2. This will include a formal 
reassessment of the Protocol Amendment 6 inclusion and exclusion criteria and consenting of 
the subject at Week 144, per Schedule D. Eligible subjects must have documented consents in 
order to continue in the long-term, optional follow-up treatment period-2. Subjects who 
withdraw from the study prior to completion of the long-term, optional follow-up treatment 
period, should also undergo the procedures specified for the EOT/ET visit (Week 144). These 
procedures include a physical exam (including collection of vital signs, height and weight 
measurements), blood and urine sampling for safety and clinical laboratory evaluations 
(including a fasting lipid panel, determination of fat-soluble vitamins, bile acids and other 
cholestasis biochemical markers, as well as for PK analysis plasma levels of LUM001). In 
addition, the following assessments should be completed: the clinician scratch scale, the 
PedsQL and the clinician xanthoma scale. The CIC assessment will be completed. Female 
subjects of childbearing potential will have a urine pregnancy test. 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 long-term, optional treatment period-2. 
Review of the ItchRO electronic diary data and assessment of compliance will occur during the 
Week 144 clinic visit. The electronic diaries will be provided to subjects and caregivers and 
retraining on the use of the diary will occur, as appropriate. Twice daily completion of the diary 
will be required for 2 weeks following the Week 144 clinic visit for subjects rolling over into 
the long-term, optional follow-up treatment period-2. Subjects not rolling over into long-term, 
optional follow-up treatment period-2 will be asked to complete the diary for 4 weeks following 
Week 144.  
Week 148: Subjects who either elect not to participate in, or who are not eligible to participate 
in the long-term, optional, follow-up treatment period-2 will return to the study site 30 days 
after the last dose of study drug and undergo the procedures specified for the EOS visit 
(Week 148). These procedures include a physical exam (including collection of vital signs, 
height and weight measurements), blood and urine sampling for safety and clinical laboratory 
evaluations (including a fasting lipid panel, determination of fat-soluble vitamins, bile acids and 


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other cholestasis biochemical markers, as well as for PK analysis plasma levels of LUM001). In 
addition, the following assessments should be completed: the clinician scratch scale, the 
PedsQL, the clinician xanthoma scale, and the CIC. Female subjects of childbearing potential 
will have a urine pregnancy test. Concomitant medications and any AEs will be recorded. 
Long-term Optional Follow-up Treatment Period-2 (Week 144 - 220): Once Protocol 
Amendment 6 is implemented at the site, subjects who are eligible and consent for entry into 
the long-term, optional follow-up treatment period-2 will continue to receive study drug until 
the first of the following occurs: 
(i) 
The subjects complete 72 weeks of additional treatment after Week 144 (long-term, 
optional follow-up treatment period) 
(ii) 
The subjects are eligible and consent to enter another LUM001 (SHP625) study 
Subjects rolling over into the long-term optional follow-up treatment period-2 will continue to 
receive the same LUM001 dose they last received during LUM001-305 (Week 144 dose) (refer 
to Figure 7). Study activities will proceed as outlined in Schedule of Procedures F. Subjects 
with dose interruptions after Week 48 and prior to Week 96, or who early terminated, may re-
enter the study with the permission from the sponsor and the ChiLDReN protocol chair. These 
subjects will initiate dose escalation at visit PA5 RI -2 (per Schedule of Procedures E) and then 
will follow study activities beginning at Week 104 (per Schedule of Procedures D). 
Per Schedule of Procedures F, subjects will return to the clinic every 12 weeks at Weeks 156, 
168, 180, 192, 204, 216 (EOT/ET visit) and at Week 220 (EOS visit). During the clinic visits, 
physical exam, body weight and height, vital signs, urine samples, and blood samples for 
clinical laboratory testing including fasting lipid panel and fat soluble vitamins, bile acids, and 
other cholestasis biochemical markers will be collected. The clinician scratch scale and 
clinician xanthoma scale will be assessed at every clinic visit. The PedsQL questionnaire and 
the CIC will be administered at Weeks 156, 216 and 220 clinic visits. The ItchRO electronic 
diaries will be provided to subjects and caregivers and retraining on the use of the diary will 
occur, as appropriate. Caregivers are not required to complete the eDiary (ItchRO[Obs]) if the 
subject is living separately from the ItchRO observer; however, subjects ≥9 years of age will be 
required to complete ItchRO(Pt). Twice daily completion of the electronic diary will be 
required during the 2 weeks following the Week 144, 156, 168, 180, 192, and 204 clinic visits 
and during the 4 weeks following the Week 216 (EOT/ET) visit. Review of the ItchRO 
electronic diary data and assessment of compliance will occur during scheduled telephone 
contacts at Week 148, 160, 172, 184, 196, 208 and during the Week 220 clinic visit. Female 
subjects of childbearing potential will have a urine pregnancy test at each clinic visit prior to 
dispensing study drug. Study drug compliance will be assessed and study drug will be 
dispensed. Concomitant medications and AEs will be collected. 
Telephone Contact will occur at Weeks 148, 152, 160, 164, 172, 176, 184, 188, 196, 200, 208 
and 212 where collection of concomitant medications and any AEs will be recorded. 
Week 216 (EOT/ET): Subjects who either complete the long-term optional follow-up treatment 
period-2 or who withdraw from the study prior to completion should undergo the procedures 
specified for the EOT/ET visit (Week 216). These procedures include a physical exam 
(including collection of vital signs, height and weight measurements), blood and urine sampling 
for safety and clinical laboratory evaluations (including a fasting lipid panel, determination of 
fat-soluble vitamins, bile acids and other cholestasis biochemical markers, as well as for PK 
analysis of LUM001 plasma levels In addition, the following assessments should be completed: 
the clinician scratch scale, the PedsQL, the clinician xanthoma scale, and the CIC. Female 
subjects of childbearing potential will have a urine pregnancy test. 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. 


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Week 220 (EOS): All subjects will return to the study site 30 days after the last dose of study 
drug and undergo the procedures specified for the EOS visit (Week 220). These procedures 
include a physical exam (including collection of vital signs, height and weight measurements), 
blood and urine sampling for safety and clinical laboratory evaluations (including a fasting lipid 
panel, determination of fat-soluble vitamins, bile acids and other cholestasis biochemical 
markers, as well as for PK analysis plasma levels of LUM001). In addition, the following 
assessments should be completed: the clinician scratch scale, the PedsQL, the clinician 
xanthoma scale, and the CIC. Female subjects of childbearing potential will have a urine 
pregnancy test. Concomitant medications and any AEs will be recorded. 
Drug Level 
Evaluations 
Plasma levels of LUM001 will be evaluated at Baseline and Weeks 2, 4, 8, 12, 24, 36, 48, 96, 
216 (EOT/ET) and 220 (EOS). Blood will be drawn approximately 4 hours post-dosing for 
drug level analysis.  
Safety and 
Tolerability 
Evaluations 
The safety and tolerability of LUM001 will be assessed by determining the incidence, 
relationship to study drug, severity and seriousness of treatment-emergent AEs, withdrawals 
due to AEs, and changes in vital signs, laboratory and other safety parameters.  
Alterations in liver parameters assessed for the purposes of safety monitoring will be relative to 
the baseline (Day 0) of the LUM001-301 protocol in which the subject was enrolled. 
A Data Safety Monitoring Board (DSMB) will review SAE data, other key subject safety and 
study data at specified intervals for the duration of the study.  
Efficacy 
Evaluations 
The primary evaluation will be the mean change from baseline (Day 0) of LUM001-301 and 
baseline (Day 0) of LUM001-305 to Week 48 in:  
• 
Fasting serum bile acid level. 
Secondary evaluations will be the mean change from baseline (Day 0) of LUM001-301 and 
baseline (Day 0) of LUM001-305 through Week 216/EOT in: 
• 
Biochemical markers of cholestasis and liver disease (eg, alanine aminotransferase [ALT], 
alkaline phosphate [ALP], gamma-glutamyltransferase [GGT] and bilirubin [total and 
direct]). 
• 
Pruritus as measured by the electronic diary ItchRO instruments (ItchRO(Obs)TM, caregiver 
instrument/ItchRO(Pt) TM patient instrument). 
• 
During the first 12 weeks of the study, the electronic diary (ItchRO) will be completed 
twice daily (AM & PM). During the stable dosing period (Weeks 13-48), twice daily 
completion of the electronic diary (ItchRO) for 4 consecutive weeks will be required 
following the Week 24 and Week 44 clinic visits. For subjects who continue in the 
safety monitoring period, twice daily completion of the ItchRO will be required for 2 
consecutive weeks following the Week 60, 72, and 84 clinic visits. For subjects who 
continue in the long-term optional follow-up treatment period, twice daily completion 
of the ItchRO will be required for 2 consecutive weeks following the Week 96, 108, 
120 and 132 clinic visits and for 4 weeks following the Week 144 visit. For subjects 
who continue in the long-term optional follow-up treatment period-2, twice daily 
completion of the ItchRO will be required for 2 consecutive weeks following the 
Week 144, 156, 168, 180, 192, and 204 clinic visits, and for 4 weeks following the 
Week 216 visit. 
• 
Xanthomas as measured by clinician xanthoma scale. 
• 
Clinician scratch scale 
• 
Fasting serum bile acid levels 
The exploratory evaluation will be the mean change in weight z-score from baseline (Day 0) of 
LUM001-301 and baseline (Day 0) of LUM001-305 through Week 216 (EOT/ET). 


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Exploratory evaluations will include the mean change from baseline in ItchRO, fasting sBA, 
and biochemical markers of cholestasis and liver disease at Week 144, Week 216 (EOT/ET), 
and at Week 220 (EOS).  
Additional exploratory evaluations will be specified in the statistical analysis plan and may 
include analyses between Week 144 (EOT/ET) and Week 148 (EOS) for subjects who 
complete Protocol Amendment 5 and between Week 216 (EOT/ET) and Week 220 (EOS) for 
subjects who complete Protocol Amendment 6.  
Statistical 
Considerations 
Sample Size 
Approximately 36 subjects meeting the study’s inclusion and exclusion criteria will be enrolled 
in the study. The number of subjects enrolled in this study will be determined by the number of 
subjects who roll-over from the LUM001-301 protocol. Because this is an extension study for 
the LUM001-301 protocol, the sample size is not based on statistical considerations.  
Safety 
All safety analyses will be performed on the Safety Population, defined as all subjects who 
received at least one dose of the study drug during the extension study.  
Adverse Events will be examined over the entire treatment period, and for the dose escalation 
and optimization periods. Adverse events for each study period will be summarized overall by 
treatment group based on the treatment group at enrollment in the extension study at baseline 
(Study Day 0). Adverse events for the stable dosing period will also be summarized overall and 
by treatment group based on the stable dosing group. 
 
Other safety measures including clinical laboratory tests, vital signs, physical exams, and 
concomitant medication usage will be summarized descriptively. For quantitative variables, 
descriptive statistics including number of observations, mean, median, standard deviation and 
range will be given for the values themselves and by their mean changes from pre-defined 
reference points (see below) at each visit. Qualitative variables will be summarized using 
counts and percentages by baseline treatment group at each study visit.  
Drug Level Analysis 
Descriptive statistics analysis of LUM001 concentrations will be carried out on the plasma 
concentration data. 
Efficacy 
All efficacy analyses will also be performed on the Safety Population, defined as all subjects 
who received at least one dose of the study drug during the extension study. 
Secondary 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 
μg 
microgram 
μM 
micromolar 
7αC4, C4 
7α-hydroxy-4-cholesten-3-one; an indirect method of bile acid synthesis 
AE 
adverse event 
ALGS 
Alagille syndrome 
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 
β-hCG 
beta-subunit of human chorionic gonadotropin; pregnancy test 
BA 
bile acid 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cholesterol 7α-hydroxylase 
rate-limiting enzyme in the synthesis of bile acid from cholesterol 
CIC 
Caregiver Impression of Change 
CMV IgM 
cytomegalovirus IgM antibody 
CRF 
case report form 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
curriculum vitae 
dL 
deciliter 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
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 


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Abbreviation 
Definition 
G 
gram 
GCP 
good clinical practices 
GGT  
gamma-glutamyltransferase 
GGTP (γGTP) 
gamma-glutamyl transpeptidase 
GI 
gastrointestinal 
HAV IgM 
Hepatitis A virus IgM antibody 
HbsAg 
surface antigen of the hepatitis B virus 
HCV 
Hepatitis C virus 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein 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 Harmonization 
INR 
international normalized ratio 
IRB 
institutional review board 
ItchRO™ 
Itch Reported Outcome 
ItchRO(Obs)™ 
Itch Reported Outcome observer instrument 
ItchRO(Pt)™ 
Itch Reported Outcome patient instrument 
IUD 
intrauterine device 
Kg 
kilogram 
L 
liter 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
LPA 
lysophosphatidic acid 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
mmol 
millimole 
MRI 
magnetic resonance imaging 


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Abbreviation 
Definition 
NBD 
nasobiliary drainage 
NCS 
not clinically significant 
ObsRO 
observer reported outcome 
PA 
Protocol amendment 
PBC 
primary biliary cirrhosis 
PEBD 
partial external biliary diversion 
PedsQL 
Pediatric Quality of Life Inventory 
PFIC 
progressive familial intrahepatic cholestasis 
PI 
principal investigator 
PK 
pharmacokinetic 
PROM 
patient reported outcome measure 
Pt 
patient 
PT 
prothrombin time 
q.s. 
quantity sufficient 
qAM 
every morning 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
US, USA 
United States of America 
WBC 
white blood cell 
WHO 
World Health Organization 
WMA 
World Medical Association 


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3. 
STUDY OBJECTIVES 
The primary objective of the study is to:  
• Evaluate the long-term safety and tolerability of LUM001 in pediatric subjects with 
Alagille syndrome (ALGS). 
Secondary objectives of the study are to: 
• Evaluate the long-term effect of LUM001 on serum bile acid levels associated with 
ALGS. 
• Evaluate the long-term effect of LUM001 on pruritus associated with ALGS. 
• Explore the long-term effect of LUM001 on other biochemical markers of cholestasis and 
liver disease. 
• Evaluate the long-term effect of LUM001 on xanthomas associated with ALGS. 
• Explore an expanded dosing range to identify the doses necessary to achieve the optimal 
benefit-to-risk ratio for this patient population. 
Exploratory objective of the study is to: 
• Evaluate the long-term effect of LUM001 on weight in pediatric subjects with ALGS. 


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4. 
BACKGROUND AND RATIONALE 
LUM001 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 (SD-5613). 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.  
4.1 
Therapeutic Rationale 
Alagille syndrome (ALGS) is an example of cholestatic liver disease in children. In patients with 
ALGS, impairment of the egress of bile acids from the liver leads to cholestasis, hepatocellular 
injury and damage, and progressive liver disease that may ultimately lead to the need for liver 
transplantation. Itch is the archetypal symptom of cholestasis, occurring at all stages of 
cholestatic liver disease, with or without jaundice.  
Surgical interruption of the enterohepatic circulation in patients with cholestatic liver disease 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 in ALGS.  
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. 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 
 
Preventing recycling, 
lowers bile acid (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). 
Therefore, inhibiting the reuptake of bile acids may represent an ideal treatment for cholestatic 
disease. In the current study, ALGS will serve as models for generalized cholestasis. By 
inhibiting the intestinal reabsorption of bile acids, LUM001 could interrupt the enterohepatic 
circulation and mimic the effects of partial external biliary diversion (PEBD) or ileal exclusion. 
The current extension study will test this hypothesis.  
4.2 
Alagille Syndrome 
Alagille syndrome (ALGS) is an autosomal dominant with variable penetration multisystem 
disorder. The clinical diagnosis is based on the presence of intrahepatic bile duct paucity on liver 
biopsy in association with at least three of the major clinical features: chronic cholestasis, cardiac 
disease, skeletal abnormalities, ocular abnormalities and characteristic facial features. Fewer than 
200 patients with ALGS are born each year in the United States. The estimated prevalence in 
Europe is 1.4/100,000 (Orphanet: The portal for rare diseases and orphan drugs). Elevations of 
serum bilirubin up to 30 times normal and serum bile salts up to 100 times normal are not 
uncommon. Levels of markers of bile duct damage, including gamma-glutamyltransferase 
(GGTP or GGT) and alkaline phosphatase (ALP), usually are significantly elevated. Cholesterol 
levels may exceed 25.9–51.7 mmol/L. Multiple xanthomas are common sequelae of severe 
cholestasis. The pruritus seen in patients with this condition is among the most severe of any 
chronic liver disease and it is present in most children by the third year of life. Although surgical 
interruption of the enterohepatic circulation has been successfully employed in the treatment of 
cholestasis and hypercholesterolemia in ALGS (Emerick and Whitington, 2002) (Modi et al., 
2007), the management of cholestasis in ALGS remains largely supportive at this time. As 
cholestasis tends to improve over the first 5 to 10 years of life, therapies that ameliorate the 
complications of cholestasis, without a commitment to liver transplantation, are particularly 
attractive (Emerick et al., 1999).  
4.3 
Pruritus 
Patients with cholestatic liver disease frequently present with pruritus, which can be severe, even 
in the absence of jaundice. Elevation of serum bile acids is frequently accompanied by pruritus, 
and a causal association between pruritus and bile acids is suggested by the following: (1) 
pruritus can been induced in volunteers by applying topical unconjugated bile acids, 
deoxycholate and chenodeoxycholate to the skin; and (2) pruritus can be relieved by surgical 
interruption of the enterohepatic circulation, which dramatically lowers serum bile acids. 
Nevertheless, the correlation between the levels of serum and skin bile acids and the degree of 
pruritus is poor.  
Intractable and pharmacologically recalcitrant pruritus is one of the major morbidities afflicting 
children with ALGS or progressive familial intrahepatic cholestasis (PFIC). Treatment with 
antipruritics and bile salt resins may provide partial relief of itching for children with ALGS, but 


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currently available pharmacologic approaches are of limited value. It has been shown that 
removing bile with surgical procedures such as partial external biliary diversion and nasal biliary 
drainage (NBD) substantially reduces pruritus in ALGS (Emerick and Whitington, 2002), PFIC, 
and primary biliary cirrhosis (PBC). 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 2 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). 
Figure 2: 
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) 
 


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4.4 
LUM001 
4.4.1 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 
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. Additional toxicology information 
can be found in the Investigator’s Brochure (IB). 
4.4.2 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 


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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 adsorption, 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 doses 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. With 
the exception of a single serious adverse event (SAE) of cholecystitis no other SAEs possibly 
related or related to LUM001 have been reported, (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 (CS) reductions of serum fat-soluble vitamin levels 
were not observed with LUM001 treatment in humans; however, levels of the carotenoid 
-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. 
One Phase 2 randomized, double-blind, placebo-controlled study has been completed in pediatric 
subjects from 12 months to 18 years with ALGS (LUM001-302 – IMAGO). This study 
evaluated the safety and efficacy of maralixibat in the treatment of cholestatic liver disease. All 


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subjects suffered from intractable pruritus explainable only by liver disease. The primary 
efficacy endpoint for this study, the change from baseline to Week 13/ET in fasting serum bile 
acid levels for maralixibat treatment in comparison with placebo treatment, was not met. Despite 
nominal improvements at some time point assessments, there were no significant differences in 
the serum bile acid level from baseline values to Week 13/ET in either the 140 μg/kg/day or the 
280 μg/kg/day treatment groups. Nominally significant improvements in Observer ItchRO 
average daily itch scores from baseline values to the Week 13/ET visit were noted in the  
140 μg/kg/day treatment group and in the overall maralixibat treatment group. Additionally, the 
Peds QL Scale (Parent) score compared with placebo treatment showed a significant 
improvement at Week 13/ET in the maralixibat 140 ug/kg/day and in the overall maralixibat 
treatment groups. There were no SAEs or deaths reported during the conduct of the study. 
Generally similar percentages of subjects experienced TEAEs in the active treatment groups (in 
the maralixibat 140 μg/kg/day treatment group, 6/6 subjects [100.0%] and in the maralixibat  
280 μg/kg/day treatment group, 7/8 subjects [87.5%]) versus 4/6 subjects (66.7%) who 
experienced a TEAE in the placebo group. The majority of TEAEs reported in the overall 
maralixibat group were mild or moderate in severity (9/14 subjects [64.3%] and 4/14 subjects 
[28.6%], respectively). Reported events were generally consistent with the expected TEAEs 
including GI events and conditions associated with liver deterioration. 
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 and in 
the completed Phase 2 study completed in pediatric subjects with ALGS (LUM001-302, see 
Section 4.4.2). 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 a concomitant increase in the concentration of free 
bile acids in the lower colon. In subjects with cholestatic liver disease it is likely that bile flow is 
reduced compared to healthy volunteers and hypercholesterolemic subjects and that 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, ie, 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, Austin, & Cole 
(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, Destrieux, Desme, 
Bertrand, & Velut (2002). Their analysis demonstrated that age had a negative and body weight a 


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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. 
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 
Weight 
(kg) 
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) 
10 
0.1 
0.4 
0.7 
1.4 
2.8 
15 
0.2 
0.5 
1.1 
2.1 
4.2 
20 
0.3 
0.7 
1.4 
2.8 
5.6 
25 
0.4 
0.9 
1.8 
3.5 
7.0 
30 
0.4 
1.1 
2.1 
4.2 
8.4 
 
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 <0.25cng/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 to 18 years. 
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. 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. Thirty-nine (39) out of 40 
subjects randomized to receive LUM001 completed the 14-day treatment period. One subject in 
the 0.3 mg group experienced severe diarrhea and abdominal pain that resulted in withdrawal 
from the study after 4 days of treatment. It is noteworthy that the AEs in Study 014 were 
generally recorded in the first seven days of LUM001 dosing, and observed at a four-fold lower 
frequency from Days 8 to 14. This is consistent with the extensive adult dosing experience, 


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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. 
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 LUM001 development program, the safety, tolerability and efficacy of LUM001 is 
being assessed for the first time in children with cholestatic liver disease associated with ALGS, 
12 months to 18 years. The starting dose in these clinical trials, 14 µg/kg/day, is equivalent to 
less than the well-tolerated 1 mg dose (~17 µg/kg, 60 kg body weight) used in Study 014, where 
LUM001 was tested at doses up to 5 mg/day for 14 days in 39 hyperlipidemic pediatric subjects. 
At the 1 mg dose in Study014, only two out of eight subjects reported moderate or severe GI-
associated AEs during 14 days. On a weight basis, 23 subjects received a dose ≥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 the current study, escalation of LUM001 doses 
for LUM001-naïve subjects will occur at 7-day intervals starting at 14 µg/kg/day and increasing 
to 35 µg/kg/day, 70 µg/kg/day, and 140 µg/kg/day. Thereafter, the dose of LUM001 may be 
adjusted for all study subjects during the dose-optimization period. A minimum period of 7-days 


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must elapse between increases in dose. Dose adjustments will be made at the investigator’s 
discretion with the goal of reaching a dose optimized for maximum efficacy and tolerability of 
either 35, 70, 140 or 280 μg/kg/day. 
The dose may also be down-titrated, at the investigator’s discretion and in consultation with the 
ChiLDReN protocol chair and the Medical Monitor, for subjects experiencing intolerance to a 
given dose. 


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5. 
INVESTIGATIONAL PLAN 
5.1 
Study Design 
This is a multicenter, double-blind study of LUM001 in children >12 months of age diagnosed 
with ALGS who have completed participation in the LUM001-301 protocol. All subjects will 
receive active drug (LUM001) in the study. The study is divided into 6 parts: a dose escalation 
period, a dose optimization period, a stable dosing period, a safety monitoring period, and 2 long 
term, optional treatment periods. 
Dose Escalation Period 
All subjects entering the extension study will participate in a 4-week double-blind dose 
escalation period during which: 
• Subjects randomized to receive placebo during the LUM001-301 protocol will receive 
weekly dose increases of LUM001 up to a target dose of 140 μg/kg/day. 
• Subjects randomized to active drug during the LUM001-301 protocol will continue to 
receive the dose of LUM001 that they were taking at Week 13 of their core study. The 
LUM001 doses for these subjects will remain blinded and will not be altered during the 
dose-escalation period.  
A minimum period of 7 days must elapse between increases in dose. 
Dose Optimization Period 
Following completion of the 4-week dose escalation period, subjects will enter an 8-week dose-
optimization period. During this period, the investigator will have the option to adjust LUM001 
dosing with the objective of achieving optimal control of pruritus at a dose level that is tolerated 
by the subject and up to a maximum daily dose of 280 μg/kg LUM001 or 20 mg total dose. 
Study drug dose will be increased or decreased in a double-blind manner. Increases in dose will 
be based on effect on pruritus. Reductions in dose will be based on tolerability. At the 
investigator’s discretion, the doses for subjects who were previously down-titrated may be 
re-challenged during the dose optimization period. Each subject will receive one of the following 
dose levels:  
• LUM001 35 μg/kg/day. 
• LUM001 70 μg/kg/day. 
• LUM001 140 μg/kg/day. 
• LUM001 280 μg/kg/day. 


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A minimum period of 7 days must elapse between increases in dose.  
Stable Dosing and Safety Monitoring Periods 
Following completion of the 8-week dose optimization period, all subjects will enter the stable 
dosing period lasting 36 weeks followed by a safety monitoring period lasting up to 48 weeks. 
During the stable dosing and safety monitoring periods, subjects will be dosed with the Week 12 
dose, or the highest tolerated dose below the Week 12 dose. However, if a subject experiences 
intolerance due to gastrointestinal symptoms, the investigator, in consultation with the 
ChiLDReN protocol chair and Medical Monitor, may lower the dose to a previously tolerated 
dose for the rest of the study. 
Long-term Optional Follow-up Treatment Period 
The long-term, optional follow-up treatment period is for eligible subjects who choose to remain 
on treatment with LUM001 following the initial 96 weeks. During this long-term, optional 
follow-up treatment period, subjects with dosing interruptions ≤7 days will remain on the same 
dose they were taking at Week 96. Subjects with LUM001 dosing interruptions >7 consecutive 
days will require dose escalation upon resumption of study drug. The dose of LUM001 will be 
increased at weekly intervals up to the subject’s previously achieved highest tolerated dose. 
Study drug for each subject will remain blinded and will be prepared by the unblinded central 
pharmacist according to the protocol’s specified dose-escalation regimen. Subjects’ participation 
in the long-term, optional follow-up treatment period will continue until the first of the following 
occur: (i) subjects complete 48 weeks of additional treatment (after Week 96 [safety monitoring 
period]), or (ii) the subjects are eligible to enter another LUM001 study.  
Long-term Optional Follow-up Treatment Period-2 
The long-term optional follow-up treatment period-2 is for eligible subjects who choose to 
remain on treatment with LUM001 for an additional 72 weeks. During this long-term optional 
follow-up treatment period-2, subjects will remain on the same dose they were taking at 
Week 144. Study drug for each subject will remain blinded and will be prepared by the 
unblinded central pharmacist according to the protocol’s specified dose-escalation regimen. 
Subjects’ participation in the long-term optional follow-up treatment period will continue until 
the first of the following occur: (i) subjects complete 72 weeks of additional treatment (after 
Week 144 [Long-term Optional Follow-up Treatment Period]), or (ii) the subjects are eligible to 
enter another LUM001 (SHP625) study. 
5.2 
Data Monitoring Board 
A Data Monitoring Board (DMB) will review adverse event (AE) data, other key subject safety 
and study data at specified intervals for the duration of the study. The DMB will be composed of 
at least 2 members who are otherwise independent from the conduct of the study: one or more 


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physicians and at least one biostatistician. The DMB’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 DMB will be detailed in the DMB 
charter.  
5.3 
Number of Study Centers 
This will be a multicenter study in approximately 12 clinical centers that participated in Study 
LUM001-301. 
5.4 
Number of Subjects 
Approximately 36 subjects meeting the study’s inclusion and exclusion criteria may be enrolled 
in the study.  
5.5 
Overall Study Duration and Follow-up 
For an individual subject, the study participation period will consist of a 4-week dose escalation 
period, followed by 8-weeks of dose optimization, a 36-week stable dosing period, a 48-week 
safety monitoring period, a 48-week long-term, optional follow-up treatment period, and a 
72-week long-term, optional follow-up treatment period-2. Planned participation for each subject 
enrolled in the long-term, optional follow-up treatment period-2 is a maximum of 220 weeks, 
inclusive of the safety follow-up contact approximately 30 days after the last dose of LUM001.  
Study activities will be conducted as described in the Schedule of Procedures (Section 16.1).  


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Figure 3: 
Study Design for LUM001-305 (Day 0-Week 48) 
 
 
 


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Figure 4: 
Safety Monitoring Period (Week 49-Week 96)  
*for subjects not rolling over into Protocol Amendment 5 
 
 


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Figure 5: 
Long-term Optional Follow-up Treatment Period (Week 96-Week 148)  
Applies to the following population: 
• Subjects with no interruption in LUM001 dosing or interruption ≤7 days between Week 
96 and Week 100) 
 


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Figure 6: 
Long-term Optional Follow-up Treatment Period (Week 96-Week 148)  
Applies to the following population: 
• Subjects who experienced an interruption in LUM001 dosing >7 consecutive days 
between Week 96 and Week 100 


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Figure 7: 
Long-term Optional Follow-up Treatment Period-2 (Week 144-Week 220)  
 
 
5.5.1 Treatment 
The Week 13 Visit from the LUM001-301 protocol will also serve as the Baseline Visit for the 
extension protocol. Eligible subjects will be enrolled in the extension study at the Baseline Visit 
(Day 0). Dosing with study drug will begin on Day 1, following the Baseline Visit on (Day 0). 
Study drug will be prepared by a central pharmacy based on the subject’s weight. During the 
study, weight will be monitored at each visit. A change from Baseline in a subject’s weight that 
is greater than 10% will require a dose adjustment. Each subsequent 10% increase in weight will 
be considered the new baseline for determination of future dose adjustments. The central 
pharmacy will make weight-based dose adjustments at the time of the subject’s next LUM001 
preparation.  
Diluent will be added by the central pharmacy pharmacist prior to shipping study drug to the site. 
Study drug will be dispensed to subjects/caregivers at the study site. The appropriate amount of 
study drug will be dispensed at the Study Day 0 visit and daily dosing will begin on Study Day 1. 
Subjects who weigh 10 kg or more will receive a 1.0 mL grape-flavored solution containing 
LUM001. Subjects who weigh less than 10 kg will receive a 0.5 mL grape-flavored solution 
containing LUM001. The volume administered will not change during the course of the study. 
Dosing will occur up to 216 weeks of treatment. 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.  


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5.5.1.1 
Dose Escalation Period 
For subjects randomized to placebo in the LUM001-301 protocol, or those who complete the 
core study more than 7 days prior enrollment into this study, the LUM001 dose during the first 
4 weeks of the study will be increased at weekly intervals to 140 μg/kg/day, or to a maximum 
tolerated dose below 140 μg/kg/day (10 mg maximum total dose). For subjects who were 
randomized to receive active drug in the LUM001-301 protocol LUM001 doses will remain the 
same as the dose being taken at Week 13 of the core study. Study treatment for each subject will 
remain blinded and will be prepared by the unblinded central pharmacist according to a specified 
dose-escalation regimen. This regimen will represent a real dose escalation for subjects 
previously randomized to placebo and a mock dose escalation for subjects previously 
randomized to active study treatment.  
The dosing regimen for each treatment group during the dose escalation period is summarized in 
Table 4.  
 
Table 4: 
Dose Escalation Regimens 
LUM001-301 
Protocol 
Extension Study Protocol LUM001-305 
Dose Escalation Period 
Week 13 
(μg/kg/day) 
Week 1 
Days 1 - 7 
(μg/kg/day) 
Week 2 
Days 8 - 14 
(μg/kg/day) 
Week 3 
Days 15 - 21 
(μg/kg/day) 
Week 4 
Days 22 - 28 
(μg/kg/day) 
Placebo 1 
14 
35 
70 
140 
35 2 
35 
35 
35 
35 
70 3 
70 
70 
70 
70 
140 4 
140 
140 
140 
140 
280 5 
280 
280 
280 
280 
1 
For subjects randomized to placebo in the LUM001-301 protocol, or those who complete the core study more than 7 days 
prior enrollment into this study, the LUM001 dose during the first 4 weeks of the study will be increased at weekly 
intervals to 140 μg/kg/day, or to a maximum tolerated dose below 140 μg/kg/day (10 mg maximum total dose). 
2 
LUM001 doses for subjects whose stable dose upon completion of the LUM001-301 protocol was 35 μg/kg/day will 
remain stable at 35 μg/kg/day, or to a maximum daily dose of 2.5 mg/day.  
3 
LUM001 doses for subjects whose stable dose upon completion of the LUM001-301 protocol was 70 μg/kg/day will 
remain stable at 70 μg/kg/day, or to a maximum daily dose of 5 mg/day.  
4 
LUM001 doses for subjects whose stable dose upon completion of the LUM001-301 protocol was 140 μg/kg/day will 
remain stable at 140 μg/kg/day, or to a maximum daily dose of 10 mg/day.  
5 
LUM001 doses for subjects whose stable dose upon completion of the LUM001-301 protocol was 280 μg/kg/day will 
remain stable at 280 μg/kg/day, or to a maximum daily dose of 20 mg/day.  
The primary anticipated adverse reaction or intolerance is gastrointestinal in nature (eg, diarrhea, 
abdominal pain, cramping, etc.). In the absence of GI intolerance, escalation to the next dose 
level for an individual subject may occur at the investigator’s discretion, following a scheduled 
phone call or visit (see Schedule of Procedures, Section 16.1). 


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If a subject experiences intolerance due to gastrointestinal symptoms, the investigator, in 
consultation with the ChiLDReN protocol chair and Medical Monitor, may lower the dose to a 
previously tolerated dose for the remainder of the study. In these circumstances, an unscheduled 
visit will occur and the appropriate replacement study medication will be provided to the 
subject/caregiver. 
5.5.1.2 
Dose Optimization Period 
Following the dose escalation period, the LUM001 dose for each subject may be increased or 
decreased by the investigator as clinically indicated with the objective of achieving control of 
pruritus at a dose level that is tolerated by the subject. Dose optimization will occur in a blinded, 
titrated manner with four dose levels available as treatment options: 35, 70, 140 or 280 
μg/kg/day. Adjustments may occur at weekly intervals. Once an optimal LUM001 dose is 
achieved, the dose will be fixed for the duration of the study.  
The maximum daily dose of LUM001 in this study is 280 μg/kg/day, up to a maximum daily 
dose of 20 mg. Blinded investigators may request dose adjustment for any subject based on an 
assessment of tolerability and effect on pruritus. Caregivers and age-appropriate subjects will be 
asked whether they wish to take a higher dose of the study medication to achieve greater relief of 
itching. If so, the dose may be adjusted upward, within the permitted dose range. However, the 
patient, caregiver, physician investigator, or the Medical Monitor may recommend against 
further escalation if there are safety or tolerability concerns. Doses of LUM001 will not be 
increased above 280 μg/kg/day or 20 mg per day at any time.  
5.5.1.3 
Stable Dosing and Safety Monitoring Periods 
At the end of the Dose Optimization Period, subjects will continue dosing to complete the stable 
dosing and safety monitoring periods for up to 96 weeks of cumulative LUM001 exposure in this 
study.  
Subjects who completed the 48-week study prior to the implementation of Protocol 
Amendment #4 may be re-contacted and re-consented for participation in the safety monitoring 
period of the study. 
If, at any time during the study, a subject experiences intolerance due to gastrointestinal 
symptoms, the physician investigator may lower the dose to a previously tolerated dose. 
To ensure the safety of subjects participating in this study, a Data Monitoring Board (DMB) will 
review SAE data, other key subject safety and study data at specified intervals for the duration of 
the study. 
5.5.1.4 
Long-term, Optional Follow-up Treatment Period 
At Week 96, all subjects will be assessed by the investigator to determine their willingness and 
eligibility to roll over into the long-term, optional follow-up treatment period. Following the 


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completion of the Week 96 study visit, subjects who choose to participate in the long-term, 
optional follow-up treatment period will be maintained at the same Week 96 dose level. Subjects 
with dose interruptions >7 consecutive days prior to implementation of Protocol Amendment 5 
will be rescreened and require dose escalation upon resumption of study drug. The dose of 
LUM001 will be increased at weekly intervals up to the subject’s previously tolerated dose under 
Protocol Amendment 4. Subjects who do not wish to enter the long term, optional follow-up 
treatment period will be contacted via telephone by the study site approximately 30 days after the 
last dose of the study drug.  
Subjects who either completed the 96-week study prior to the implementation of Protocol 
Amendment 5, or have received permission from the ChiLDReN protocol chair and the Medical 
monitor, may be recontacted and reconsented for participation in the long-term optional follow-
up treatment period of the study. 
Study drug administration under Protocol Amendment 5 will not change from Protocol 
Amendment 4. 
5.5.1.5 
Long-term, Optional Follow-up Treatment Period-2 
At Week 144, all subjects will be assessed by the investigator to determine their willingness and 
eligibility to roll over into the long-term, optional follow-up treatment period-2. Following the 
completion of the Week 144 study visit, subjects who choose to participate in the long-term, 
optional follow-up treatment period-2 will be maintained at the same Week 144 dose level. 
Subjects who do not wish to enter the long term optional follow up treatment period-2 should 
complete the in-clinic Week 148 Visit 30 days after the last dose of study drug. 
Subjects who either completed the 144-week study prior to the implementation of Protocol 
Amendment 6, or have received permission from the ChiLDReN protocol chair and the Medical 
Monitor, may be recontacted and reconsented for participation in the long-term, optional follow-
up treatment period-2 of the study. 
Study Drug Administration under Protocol Amendment 6 will not change from Protocol 
Amendment 5. 
5.5.2 Dosing Interruptions 
5.5.2.1 
Dose Escalation Following Dose Interruption 
Subjects with interruptions in LUM001 dosing of more than 7 consecutive days during the stable 
dosing, safety monitoring, and long-term, optional follow-up treatment periods will require dose 
escalation upon re-initiation of the study drug. The dose of LUM001 will be increased at weekly 
intervals up to the subject’s previously achieved highest tolerated dose. Study drug for each 
subject will remain blinded and will be prepared by the unblinded central pharmacist according 
to the protocol’s specified dose-escalation regimen (Table 5).  


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Table 5: 
Dose Escalation Regimen for Re-initiation of LUM001 Dosing When 
Dosing Interruption is Greater than 7 Consecutive Days 
 
Study Week 
Week 1 
(μg/kg/day) 
Week 2 
(μg/kg/day) 
Week 3 
(μg/kg/day) 
Week 4 
(μg/kg/day) 
LUM001 Dose 
35 
70 1 
140 1 
280 1 
1 Weekly dose escalations will end once the highest tolerated dose achieved prior to the subject’s LUM001 dosing interruption 
is reached. 
 
5.5.2.2 
Visit Schedule Following Dose Interruption for Stable Dosing and Safety 
Monitoring Periods 
Upon re-initiation of study drug, subjects who undergo a dosing interruption of greater than 7 
consecutive days will follow the same visit schedule and procedures that are specified for the 
Baseline Day 0 Visit (Section 8.1.1) and during Dose Escalation Treatment Period (Section 
8.1.2). Completion of the ItchRO electronic diary, however, will not be required during this time. 
The visit schedule upon re-initiation of LUM001 dosing is shown in Figure 8. 
Figure 8: 
Visit Schedule for Re-initiation of LUM001 when Dosing Interruption is 
Greater than 7 Consecutive Days 
 
 
 
Subjects with dosing interruptions of greater than 7 consecutive days will require reintegration in 
the study to ensure that 1) their resumed visit schedule aligns with the protocol, and 2) their total 
LUM001 exposure during the study does not exceed 216 weeks.  
If the decision to interrupt dosing occurred at the time of a Clinic Visit, the first visit upon dose 
re-initiation (“RI Day 0” in Figure 8) should be assigned to that same Clinic Visit. If the decision 


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to interrupt dosing occurred between Clinic Visits, the first visit upon dose re-initiation (“RI Day 
0”) should be assigned to the next Clinic Visit. Table 6 provides the assignment of the first study 
visit upon dose re-initiation based on when the dosing interruption occurred.  
Table 6: 
Dosing Interruptions: Reintegration to Study Visit Schedule 
Dosing Interruption 
Assignment of 
First Dose Re-initiation Study Visit 
Between Weeks 13 - 24 
Week 24 
Between Weeks 25 - 36 
Week 36 
Between Weeks 37 - 48 
Week 48 
Between Weeks 49 - 60 
Week 60 
Between Weeks 61 - 72 
Week 72 
Between Weeks 73 - 84 
Week 84 
 
After Week 84 
To be managed on a case-by-case basis in consultation with 
the Medical Monitor and ChiLDReN Protocol Chair 
 
5.5.2.3 
Visit Schedule Following Dose Interruption for Long-term, Optional 
Follow-up Treatment Period 
Upon re-initiation of study drug into the long-term optional follow-up treatment periods, subjects 
who undergo a dosing interruption of greater than 7 consecutive days will follow the re-entry 
dose escalation schedule as outlined in Figure 6 and in Study Schedule of Procedures E  after 
receiving permission from the Sponsor and ChiLDReN protocol chair. 
Dose interruptions greater than 7 consecutive days that occur between Week 104 and Week 216, 
should also be discussed with the ChiLDReN protocol chair and the Medical Monitor to 
determine how to reintegrate the subject into Study Schedule of Procedures D  
5.5.3 Follow-up 
A safety follow-up phone call will be made by the study site 30 days after the last dose of study 
drug for subjects participating in all versions of the protocol up through Protocol Amendment 4. 
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. For subjects who participate in the long-term, optional follow-up treatment 
period, this phone call will be replaced by the Week 148 end of study (EOS) clinic visit. For 
subjects who participate in the long-term, optional follow-up treatment period-2, this phone call 
will be replaced by the Week 220 (EOS) clinic visit. 
5.6 
Study Termination 
A subject is considered to have completed the study period(s) based on the version of the 
protocol they participated under. For subjects who consent to the long-term, optional follow-up 
treatment period or the long-term, optional follow-up treatment period-2, the subject is 


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considered to have completed the study if they participated in the Week 144 end of treatment 
(EOT) or Week 216 (EOT) visit, respectively. 
The end of study for the purposes of regulatory reporting and EDC entry is the point of last 
contact with the last subject during the protocol-specified scheduled follow-up period or the EOS 
visit as specified in Schedule of Procedures F . 


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6. 
SUBJECT ENROLLMENT 
6.1 
Enrollment 
Before subjects may be enrolled to participate in the study, the Sponsor, or designee, requires a 
copy of the appropriate written Independent Ethic Committee (IEC) or Institutional Review 
Board (IRB) approval of the protocol, informed consent/assent form(s) (ICF), and all other 
applicable subject information. 
Following informed consent/assent, the subject will be considered enrolled into the study. The 
unique 6-digit subject identification number assigned to the subject upon screening in the 
LUM001-301 protocol will be used to identify the subject in the LUM001-305 extension study. 
This number will be used to identify the subject throughout the study. The subject’s 
identification number must remain constant and must be used on all study documentation related 
to that subject.  
Subjects will be enrolled in the long-term, optional follow-up treatment period based on the 
investigator’s determination of meeting eligibility criteria outlined in Section 7. A subject will be 
considered enrolled in either the long-term, optional follow-up period under Protocol 
Amendment 5 or the long-term, optional follow-up period-2 under Protocol Amendment 6, 
respectively, after the subject consents and the investigator has determined the subject meets 
study entry eligibility criteria per Protocol Amendment 5 or 6, as appropriate . However, any 
subject who consents to Protocol Amendment 5 or 6 and does not meet criteria per the 
investigator is considered a screen failure for the long-term, optional follow-up period under 
Protocol Amendment 5 or 6, as appropriate. Final consent and eligibility determined for subjects 
rescreened will be collected in the case report form (CRF). 
6.2 
Replacement of Subjects 
There will be no replacement of subjects who withdraw from the study. 
6.3 
Unblinding of Treatment Assignment 
All subjects, investigators, and study center personnel, except for the central pharmacist who 
prepares the study drug and the pharmacy monitor who monitors the pharmacy records and 
procedures, will remain blinded to all subjects’ treatment assignments until after the study 
database for Mirum’s LUM001-305 protocol has been locked. Sponsor personnel and CRO 
personnel will remain blinded to all subjects’ dose levels until after the study databases for the 
LUM001-301 protocol have been locked. Once the treatment assignments for these core studies 
have been unblinded, access to the unblinded treatment assignments for subjects participating in 
LUM001-305 will be provided to Sponsor and CRO personnel on a need-to-know basis only, 
with such access being restricted to the maximum extent feasible, consistent with their 
performing a comprehensive and timely analysis of the data from the LUM001-301 study. 


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If in the event of an emergency situation when knowledge of the treatment assignment will 
impact the clinical management of the subject, the investigator will have the ability to unblind 
the treatment assignment for that subject at any time by contacting the study’s central 
pharmacy. If a subject is unblinded by the investigator, the Sponsor must be informed of the 
unblinding within 24 hrs. If the blinding is prematurely broken, it is the responsibility of the 
investigator to promptly document and explain any unblinding to the Sponsor. 
Breaking of the blind should not occur except in the event of a medical emergency where the 
identity of the drug must be known in order to properly treat the subject, or when causality must 
be determined prior to submitting a regulatory safety report for a SAE (as defined in 
Section 11.2.3). 
Any unblinding event carried out in connection with submission of a regulatory safety report will 
be conducted by the Sponsor (see Section 11.1). 
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Schedule of Procedures, Section 16.1) prior to unblinding, as knowledge of the 
treatment arm could influence subject assessment. 


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7. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
before being dispensed study drug treatment. 
Original Inclusion and Exclusion Criteria (through Protocol Amendment 4) 
7.1 
Inclusion Criteria 
To participate in this study, subjects must meet all of the following criteria: 
1. Male or female, 12 months to 18 years of age. 
2. Competent to provide informed consent and assent (per IRB/EC), as appropriate. 
3. Completed participation in the LUM001-301 protocol. 
4. Females of childbearing potential must have a negative urine pregnancy test [β human 
chorionic gonadotropin (β-hCG)] at the Baseline Visit. 
5. Sexually active females must be prepared to use an effective method (≤ 1% failure rate) of 
contraception during the trial. Effective methods of contraception are considered to be: 
6. Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection); or 
7. Barrier method, eg, (a) condom with spermicide, or (b) diaphragm, with spermicide; or 
8. Intrauterine device (IUD). 
9. Subjects above the age of assent and caregivers and children must be able to read and 
understand English or Spanish. 
10. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls from 
study site. 
11. Caregivers (and age appropriate subjects) must be willing and able to complete a daily 
electronic diary (ItchRO) during the first consecutive 12 weeks of the study and then for 4 
consecutive weeks following the Week 24 and Week 44 visits.  
12. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement in the 
ItchRO electronic diary software at the outset of the study. 
13. Eligible subjects must be able to adhere to local Ethics Committee or Institutional Review 
Board (IRB) blood volume limits for laboratory testing. 
Protocol Amendment 5 Inclusion Criteria: Eligible subjects for the long-term optional 
follow-up treatment period 
Subjects will be considered eligible for the long-term optional follow-up treatment period if they 
meet the following criteria: 
1. The subject has completed the protocol either through Week 96, or the ET visit, or has 
received permission from the sponsor and the ChiLDReN protocol chair to re-enter the study 
in the long-term, optional follow-up treatment period. 


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2. Females of child-bearing potential must have a negative urine or serum pregnancy test 
(β-human chorionic gonadotropin [β-HCG]) at the time of entry into the long-term optional 
follow-up treatment period. 
3. Male and female subjects of child-bearing potential who are sexually active, or are not 
currently sexually active, but become sexually active during the study or for 30 days 
following the last dose of study drug, must agree to use acceptable contraception during the 
study. 
4. Informed consent and assent (per IRB/EC) as appropriate. 
5. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls from 
study site. 
6. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device 
during the study. 
Protocol Amendment 6 Inclusion Criteria: Eligible subjects for the long-term optional 
follow-up treatment period-2 
1. The subject has completed the protocol through either Week 144, or the ET visit, or has 
received permission from the sponsor and the ChiLDReN protocol chair to re-enter the study 
in the long-term optional follow-up period-2.  
2. Females of child-bearing potential must have a negative urine or serum pregnancy test (β-
human chorionic gonadotropin [β-HCG]) at the time of entry into the long-term optional 
follow-up treatment period-2. 
3. Males and females of child-bearing potential who are sexually active, or are not currently 
sexually active, but become sexually active during the study or for 30 days following the last 
dose of study drug, must agree to use acceptable contraception during the study. 
4. Informed consent and assent (per IRB/EC) as appropriate. 
5. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls from 
study site. 
6. Caregivers (and age appropriate subjects) must be willing to follow the rules of eDiary 
completion (see Section 8.4.1). 
7.2 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Experienced an AE or SAE related to the study drug during the LUM001-301 protocol that 
led to the discontinuation of the subject from the core study. 
2. Any conditions or abnormalities (including laboratory abnormalities) which, in the opinion of 
the Investigator, Medical Monitor or ChiLDReN Protocol Chair, may compromise the safety 
of the subject, or interfere with the subject participating in or completing the study. 
3. History or known presence of gallstones or kidney stones. 


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4. History of non-adherence during the subject’s participation in the LUM001-301 protocol. 
Non-adherence is defined by dosing compliance1 of less than 80% in the LUM001-301 
protocol.  
5. Unlikely to comply with the study protocol, or unsuitable for any other reason, as judged by 
the investigator. 
Protocol Amendment 5 Exclusion Criteria: Eligible subjects for the long-term optional 
follow-up treatment period 
All exclusion criteria for the original LUM001-305 study apply upon re-entry into the long-term, 
optional follow-up treatment period. 
Protocol Amendment 6 Exclusion Criteria: Eligible subjects for the long-term optional 
follow-up treatment period-2 
All exclusion criteria for the original LUM001-305 study apply upon re-entry into the long-term 
optional follow-up treatment period-2. 
                                                 
 
1. 
Dosing compliance is calculated by [the total number of doses that were actually taken by the subject] divided by [the 
total number of doses that should have been taken by the subject] multiplied by 100.  


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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. 
8.1.1 Baseline (Day 0) 
Evaluations and procedures completed for the Week 13 Visit of the LUM001-301 study will also 
serve as the evaluations for the Baseline Visit for the extension study. Informed consent (and/or 
assent when appropriate) for participation in the extension study must be obtained for all 
participating subjects and their parents or legal guardians, as appropriate. At the Baseline visit 
(Week 0), subjects will be assessed to confirm continued study eligibility including a review of 
medical history and will undergo a physical examination including body weight, height, and vital 
signs. Blood and urine samples will be taken for clinical laboratory testing, including a fasting 
lipid panel and determination of bile acids and other cholestasis biochemical markers as well as 
for PK analysis (plasma levels of LUM001). The clinician scratch scale will be administered, as 
will the PedsQL. Female subjects of childbearing potential will have a urine pregnancy test and 
concomitant medications and any AEs will be recorded. The degree and severity of 
xanthomatosis will be evaluated for all subjects by the clinician xanthoma scale. Study drug for 
Weeks 1, and 2 will be supplied at the Baseline visit to eligible subjects.  
8.1.2 Dose Escalation Treatment Period (Week 0 to Week 4) 
Double-blind dosing in the dose escalation period will be initiated on the morning after the 
Baseline Visit. Caregivers and age appropriate subjects will be instructed to complete their 
ItchRO electronic diary (eDiary) twice daily (morning and evening). Subjects will return to the 
clinic at Weeks 2, and 4, and will receive follow-up phone calls at Weeks 1 and 3. On clinic visit 
days, vital signs (including height and weight measurements) will be collected and 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. The 
clinician scratch scale will be administered, adherence to study drug will be assessed and 
additional dosing instructions will be supplied. Study diary compliance will be assessed and 
concomitant medications and any AEs will be recorded at clinic visits and at scheduled telephone 
contacts. Additional study drug will be supplied at Week 2 and Week 4. 
Clinic visits and follow-up phone calls during the dose escalation period are allowed a ±2 day 
scheduling window. 


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8.1.3 Dose Optimization Period (Week 5 to Week 12) 
During the dose optimization period, the dose for each subject may be increased or decreased at 
the investigator’s discretion in a double-blind manner. The purpose of the dose optimization 
period is to allow the investigator to adjust the subject’s LUM001 dose to a level that is both 
tolerable to the subject and maximizes the potential effect of LUM001 on pruritus. Once an 
optimal dose is achieved, the dose will be fixed for the duration of the study.  
Electronic diaries will be completed twice daily by age-appropriate subjects and caregivers 
through Week 12 and then collected. Subjects will return to the clinic at Weeks 8 and 12 and will 
receive follow-up telephone calls at Weeks 6 and 10. At the clinic visits, vital signs (including 
height and weight measurements) will be collected and 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. The clinician scratch scale will 
be administered and a review of study diary and medication compliance will be completed. 
Concomitant medications and any AEs will be assessed and recorded at each visit and at 
scheduled telephone contacts. Additional study drug will be supplied at Weeks 8 and 12.  
Clinic visits and follow-up phone calls during the dose optimization period are allowed a ±5 day 
scheduling window. 
8.1.4 Stable Dosing Period (Week 13 to Week 48) 
Subjects will continue to receive study drug during the stable dosing treatment period according 
to the dose achieved during the dose optimization period. However, if a subject experiences 
intolerance due to gastrointestinal symptoms the investigator, in consultation with the 
ChiLDReN protocol chair and Medical Monitor, may lower the dose to a previously tolerated 
dose for the remainder of the study.  
During the stable dosing period, subjects will return to the clinic at Weeks 24, 36, 44 and 48. 
Subjects who undergo a dose change at the Week 12 visit will also return to the clinic at Week 
16 (see below). 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 and clinician xanthoma scale will be administered and study drug compliance will 
be assessed. The PedsQL will be completed at Weeks 24 and 48 and the Caregiver Impression of 
Change (CIC) will be completed at Week 48. Subjects/caregivers will 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.  
Subjects who undergo a dose change at the Week 12 visit will complete an on-site clinic visit at 
Week 16. Subjects who do not undergo a dose change at Week 12 will receive a follow-up phone 
call at Week 16. The study activities that will be conducted at the Week 16 clinic visit are 
described in the Schedule of Procedures (Section 16.1). 


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Electronic diaries will be completed by age-appropriate subjects and caregivers following the 
Week 24 and Week 44 visits. The diaries will be redistributed at Week 24 and completed twice 
daily for 4 weeks before being collected at Week 28. The diaries will then be redistributed at 
Week 44 and completed twice daily until the end of the study (Week 48). Re-training on the use 
of the diary will occur as appropriate at the Week 24 and Week 44 visits. 
At the physician investigator’s discretion, tapering or withdrawal of concomitant medications 
used for the treatment of pruritus may occur during the stable dosing period.  
With the exception of Week 44, additional study drug will be supplied at each clinic visit during 
the stable dosing period. 
Clinic visits and follow-up phone calls during the stable dosing period are allowed a ±14 day 
scheduling window. 
8.1.5 Safety Monitoring Period (Week 49 to Week 96) 
During the safety monitoring period, subjects will return to the clinic every 3 months, at Weeks 
60, 72, 84, and 96.  
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. The clinician 
scratch scale will also be completed at each clinic visit and study drug compliance will be 
assessed. The PedsQL, CIC, and the Clinician Xanthoma scale will also be administered at 
Weeks 60, 72, 84, and 96. Subjects/caregivers will receive follow-up phone calls at Weeks 52, 
56, 64, 68, 76, 80, 88, and 92. Concomitant medications and any AEs will be evaluated and 
recorded at all clinic visits and at scheduled telephone contacts.  
Twice daily completion of the ItchRO electronic diary will be required by caregivers and age 
appropriate subjects during the 2 weeks following the Week 60, 72, 84, and 96 clinic visits. 
Review of electronic diary data and assessment of compliance will occur during scheduled 
telephone contacts at Week 64, 76, and 88 and during the Week 96 clinic visit. 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 safety monitoring period.  
Additional study drug will be supplied at each clinic visit during the follow-up treatment period. 
8.1.6 Week 96 
Subjects will be evaluated by the investigator to determine whether they are eligible to roll over 
into the long-term, optional follow-up treatment period. This will include a formal re-assessment 
of the Protocol Amendment 5 inclusion and exclusion criteria and consenting of the subject at 


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Week 96 per Schedule C. Eligible subjects must have documented consents in order to continue 
in the long-term, 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 as well as for PK analysis 
(plasma levels of LUM001). The clinician scratch scale and PedsQL will be administered and the 
degree and severity of xanthomatosis will be evaluated using the clinician xanthoma scale. 
Review of the ItchRO electronic diary data and assessment of compliance will occur during the 
Week 96 clinic visit. The electronic diaries will be provided to subjects and caregivers and 
retraining on the use of the diary will occur, as appropriate. Twice daily completion of the diary 
will be required during the 2 weeks following the Week 96 clinic visit. Female subjects 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 long-term 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 96 visit, with the exception of the ItchRO assessment. For safety reasons, efforts must be 
made to follow subjects for at least 30 days following their last dose of study drug. 
8.1.7 Follow-up Phone Call (30 days after Last Dose) 
For subjects who do not roll over into the long-term, 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. 
For subjects who participate in the long-term optional follow-up treatment period, this phone call 
will be replaced by the Week 148 (EOS) clinic visit. 
8.1.8 Long-term, Optional Follow-up Treatment Period (Week 96-148) 
Once Protocol Amendment 5 is implemented at the site, subjects who are eligible and consent for 
entry into the long-term, optional follow-up treatment period will continue to receive study drug 
until the first of the following occurs:  
i.The subjects complete 48 weeks of additional treatment after Week 96 (safety monitoring 
 
period) 
ii.The subjects are eligible and consent to enter another LUM001 study 
 
Subjects with no LUM001 dosing interruptions or interruptions ≤7 days will continue to 
receive the same LUM001 dose they last received during LUM001-305 (Week 96 dose) (refer to 
Figure 5). Study activities will proceed as outlined in Schedule of Procedures D .  


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Subjects with LUM001 dosing interruptions >7 days will be rescreened and require dose 
escalation upon resumption of study drug. The dose of LUM001 will be increased at weekly 
intervals up to 280 µg/kg/day or the subject’s previously tolerated dose under Protocol 
Amendment 4 (refer to Figure 6). Study activities will proceed as outlined below and in Schedule 
of Procedures E . 
• Protocol Amendment (PA) 5 Re-initiating (RI) Day -2 Clinic Visit: Consent (and/or assent as 
applicable) are obtained; eligibility criteria are confirmed. Physical examination (body 
weight, height, vital signs) is performed; blood and urine samples collected for clinical 
laboratory testing. Female subjects of childbearing potential will have a serum pregnancy 
test. Concomitant medications and AEs will be recorded. 
• PA5 RI Day 0 Clinic Visit: Eligibility criteria are confirmed. Physical examination (body 
weight, height, vital signs) is performed; blood and urine samples collected for clinical 
laboratory testing. Female subjects of childbearing potential will have a serum pregnancy 
test. Clinician scratch scale, clinician xanthoma scale, and PedsQL are completed. 
Concomitant medications and AEs will be recorded. Study drug is dispensed and subject 
begins dosing at 35 μg/kg/day dose level. 
• PA5 RI Week 1 Telephone Contact: Concomitant medications and AEs will be recorded. 
Subject escalates to 70 μg/kg/day dose level or previous maximum tolerated dose as 
established under Protocol Amendment 4. 
• PA5 RI Week 2 Clinic Visit: Physical examination (body weight, height, vital signs) is 
performed; blood and urine samples collected for clinical laboratory testing. Female subjects 
of childbearing potential will have a serum pregnancy test. Clinician scratch scale, clinician 
xanthoma scale, and PedsQL are completed. Concomitant medications and AEs will be 
recorded. Study drug is dispensed and subject escalates to 140 μg/kg/day dose or previous 
maximum tolerated dose as established under Protocol Amendment 4. 
• PA5 RI Week 3 Telephone Contact: Concomitant medications and AEs will be recorded. 
Subject escalates to 280 µg/kg/day dose level or previous maximum tolerated dose as 
established under Protocol Amendment 4. 
• PA5 RI Week 4 Clinic Visit: Physical examination (body weight, height, vital signs) is 
performed; blood and urine samples collected for clinical laboratory testing. Female subjects 
of childbearing potential will have a serum pregnancy test. Clinician scratch scale, clinician 
xanthoma scale, and PedsQL are completed. The ItchRO electronic diaries will be provided 
to subjects and caregivers and retraining on the use of the diary will occur, as appropriate. 
Twice daily completion of the electronic diary will be required during the 2 weeks following 
this visit. Concomitant medications and AEs will be recorded. Study drug is dispensed and 
subject continues dosing at 280 µg/kg/day dose level or previous maximum tolerated dose as 
established under Protocol Amendment 4. 
• PA5 Schedule D Week 104 Telephone Contact (4 weeks after PA5 RI Week 4 Clinic Visit): 
Concomitant medications and AEs will be recorded. Subjects will then follow study activities 
as outlined in Schedule of Procedures D , Week 104. 


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Per Schedule of Procedures D , subjects will return to the clinic every 12 weeks at Weeks 108, 
120, 132, 144 (EOT/ET visit) and at Week 148 (EOS visit). During the clinic visits, physical 
exam, body weight and height, vital signs, urine samples, and blood samples for clinical 
laboratory testing including fasting lipid panel and fat soluble vitamins, bile acids, and other 
cholestasis biochemical markers will be collected. ItchRO compliance will be assessed, the 
electronic diary will be issued, and the clinician scratch scale and clinician xanthoma scale will 
be assessed at every clinic visit. The PedsQL questionnaire and the CIC will be administered at 
Weeks 108, 144 and 148. Review of the ItchRO electronic diary data and assessment of 
compliance will occur during the Week 112, 124, and 136 telephone contacts. The ItchRO 
electronic diaries will be provided to subjects and caregivers and retraining on the use of the 
diary will occur, as appropriate. Twice daily completion of the electronic diary will be required 
during the 2 weeks following the Week 96, 108, 120, and 132 clinic visits and during the 
4 weeks following the Week 144 visit. Subjects rolling over into the long-term optional follow-
up treatment period-2 will complete the electronic diary for 2 weeks following the Week 144 
visit. Female subjects of childbearing potential will have a urine pregnancy test at each clinic 
visit prior to dispensing study drug. Study drug compliance will be assessed and study drug will 
be dispensed. Concomitant medications and AEs will be collected. 
Telephone Contact will occur at Weeks 100, 104, 112, 116, 124, 128, 136, and 140 where 
collection of concomitant medications and any AEs will be recorded. 
8.1.9 Week 144 
Subjects will be evaluated by the investigator to determine whether they are eligible to roll over 
into the long-term, optional follow-up treatment period-2. This will include a formal 
reassessment of the Protocol Amendment 6 inclusion and exclusion criteria and consenting of the 
subject at Week 144, per Schedule of Procedures D . Eligible subjects must have documented 
consents in order to continue in the long-term, optional follow-up treatment period-2. Subjects 
who withdraw from the study prior to completion of the long-term, optional follow-up treatment 
period, should also undergo the procedures specified for the EOT/ET visit (Week 144). These 
procedures include a physical exam (including collection of vital signs, height and weight 
measurements), blood and urine sampling for safety and clinical laboratory evaluations 
(including a fasting lipid panel, determination of fat-soluble vitamins, bile acids and other 
cholestasis biochemical markers, as well as for PK analysis plasma levels of LUM001). In 
addition, the following assessments should be completed: the clinician scratch scale, the PedsQL 
and the clinician xanthoma scale. The CIC assessment will be completed. Female subjects of 
childbearing potential will have a urine pregnancy test. 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 long-term, optional treatment period-2. Review of the 
ItchRO electronic diary data and assessment of compliance will occur during the Week 144 
clinic visit. The electronic diaries will be provided to subjects and caregivers and retraining on 
the use of the diary will occur, as appropriate. Twice daily completion of the diary will be 


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required for 2 weeks following the Week 144 clinic visit for subjects rolling over into the long-
term, optional follow-up treatment period-2. Subjects not rolling over into long-term, optional 
follow-up treatment period-2 will be asked to complete the diary for 4 weeks following 
Week 144. 
8.1.10 Week 148 
Subjects who either elect not to participate in, or who are not eligible to participate in the long-
term, optional, follow-up treatment period-2 will return to the study site 30 days after the last 
dose of study drug and undergo the procedures specified for the EOS visit (Week 148). These 
procedures include a physical exam (including collection of vital signs, height and weight 
measurements), blood and urine sampling for safety and clinical laboratory evaluations 
(including a fasting lipid panel, determination of fat-soluble vitamins, bile acids and other 
cholestasis biochemical markers, as well as for PK analysis plasma levels of LUM001). In 
addition, the following assessments should be completed: the clinician scratch scale, the PedsQL, 
the clinician xanthoma scale, and the CIC. Female subjects of childbearing potential will have a 
urine pregnancy test. Concomitant medications and any AEs will be recorded. 
8.1.11 Long-term, Optional Follow-up Treatment Period-2 (Week 144-220) 
Once Protocol Amendment 6 is implemented at the site, subjects who are eligible and consent for 
entry into the long-term, optional follow-up treatment period-2 will continue to receive study 
drug until the first of the following occurs:  
i.The subjects complete 72 weeks of additional treatment after Week 144 (long-term, 
 
optional follow-up treatment period 
ii.The subjects are eligible and consent to enter another LUM001 (SHP625) study 
 
Subjects rolling over into the long-term optional follow-up treatment period-2 will continue to 
receive the same LUM001 dose they last received during LUM001-305 (Week 144 dose) (refer 
to Figure 7). Study activities will proceed as outlined in Schedule of Procedures F . Subjects with 
dose interruptions after Week 48 and prior to Week 96, or who early terminated, may re-enter the 
study with the permission from the sponsor and the ChiLDReN protocol chair. These subjects 
will initiate dose escalation at visit PA5 RI -2 (per Schedule of Procedures E ) and then will 
follow study activities beginning at Week 104 (per Schedule of Procedures D). 
Per Schedule of Procedures F , subjects will return to the clinic every 12 weeks at Weeks 156, 
168, 180, 192, 204, 216 (EOT/ET visit) and at Week 220 (EOS visit). During the clinic visits, 
physical exam, body weight and height, vital signs, urine samples, and blood samples for clinical 
laboratory testing including fasting lipid panel and fat soluble vitamins, bile acids, and other 
cholestasis biochemical markers will be collected. The clinician scratch scale and clinician 
xanthoma scale will be assessed at every clinic visit. The PedsQL questionnaire and the CIC will 
be administered at Weeks 156, 216 and 220 clinic visits. The ItchRO electronic diaries will be 
provided to subjects and caregivers and retraining on the use of the diary will occur, as 


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appropriate. Caregivers are not required to complete the eDiary (ItchRO[Obs]) if the subject is 
living separately from the ItchRO observer; however, subjects ≥9 years of age will be required to 
complete ItchRO(Pt). Twice daily completion of the electronic diary will be required during the 
2 weeks following the Week 144, 156, 168, 180, 192, and 204 clinic visits and during the 
4 weeks following the Week 216 (EOT/ET) visit. Review of the ItchRO electronic diary data and 
assessment of compliance will occur during scheduled telephone contacts at Week 148, 160, 172, 
184, 196, 208 and during the Week 220 clinic visit. Female subjects of childbearing potential 
will have a urine pregnancy test at each clinic visit prior to dispensing study drug. Study drug 
compliance will be assessed and study drug will be dispensed. Concomitant medications and 
AEs will be collected. 
Telephone Contact will occur at Weeks 148, 152, 160, 164, 172, 176, 184, 188, 196, 200, 208 
and 212 where collection of concomitant medications and any AEs will be recorded. 
8.1.12 Week 216 (EOT or ET) 
Subjects who either complete the long-term, optional follow-up treatment period-2 or who 
withdraw from the study prior to completion should undergo the procedures specified for the 
EOT/early termination (ET) visit (Week 216). These procedures include a physical exam 
(including collection of vital signs, height and weight measurements), blood and urine sampling 
for safety and clinical laboratory evaluations (including a fasting lipid panel, determination of 
fat-soluble vitamins, bile acids and other cholestasis biochemical markers, as well as for PK 
analysis plasma levels of LUM001). In addition, the following assessments should be completed: 
the clinician scratch scale, the PedsQL, the clinician xanthoma scale, and the CIC. Female 
subjects of childbearing potential will have a urine pregnancy test. 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.  
8.1.13 Week 220 (EOS) 
All subjects will return to the study site 30 days after the last dose of study drug and undergo the 
procedures specified for the EOS visit (Week 220). These procedures include a physical exam 
(including collection of vital signs, height and weight measurements), blood and urine sampling 
for safety and clinical laboratory evaluations (including a fasting lipid panel, determination of 
fat-soluble vitamins, bile acids and other cholestasis biochemical markers, as well as for PK 
analysis plasma levels of LUM001). In addition, the following assessments should be completed: 
the clinician scratch scale, the PedsQL, the clinician xanthoma scale, and the CIC. Female 
subjects of childbearing potential will have a urine pregnancy test. Concomitant medications and 
any AEs will be recorded. 
8.2 
Physical Examination, Weight and Height, Vital Signs 
A physician Investigator will conduct a physical examination on each subject at Baseline, at 
Weeks 24, 36, and 48, and at Week 16 on subjects who undergo a change in dose at their 


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Week 12 visit. A physical examination will also be conducted for any subject who terminates 
from the study early at the Early Termination Visit. For subjects who enter into the safety 
monitoring period, physical examinations will be conducted at Weeks 60, 72, 84, and 96. For 
subjects who enter into the long-term, optional follow-up treatment period, physical 
examinations will be conducted at Weeks 108, 120, 132, 144 (EOT/ET) and Week 148 (EOS). 
For subjects who enter into the long-term, optional follow-up treatment period-2, physical 
examinations will be conducted at Weeks 156, 168, 180, 192, 204, 216 (EOT/ET) and Week 220 
(EOS). 
Body weight, height, and vital signs, including body temperature, blood pressure (BP), 
respiration and pulse, will be determined at every study clinic visit. A change in weight greater 
than 10% of the weight used to calculate the subject’s current LUM001 dose will result in a dose 
adjustment. Each subsequent 10% increase in weight will be considered the new baseline for 
determination of future dose adjustments. This dose adjustment will be made by the central 
pharmacy when they make the subject’s next LUM001 preparation. 
8.3 
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. 
8.4 
Pruritus and Quality of Life Assessments 
8.4.1 Itch Reported Outcome (ItchRO™) 
Pruritus will be assessed using a newly developed Itch caregiver/patient reported outcome 
measure (ItchROTM) administered as a twice daily electronic diary as described in Section 16.3. 
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 on the use of the electronic diary during their 
participation in LUM001-301 protocol.  
During the dose escalation and dose optimization periods (Week 0 - Week 12), 
subjects/caregivers will be required to submit twice daily assessments using the electronic diary.  
During the stable dosing 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 


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and re-trained on its use, as needed. At the Week 24 visit, subjects/caregivers will also be 
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.  
During the safety monitoring periods, twice daily completion of the diary will be required by 
subjects and caregivers only during the 2 consecutive weeks that follow the Week 60, Week 72, 
and Week 84 clinic visits. During the long-term, optional follow-up treatment period, twice daily 
completion of the ItchRO will be required for 2 consecutive weeks following the Week 96, Week 
108, Week 120, and 132 clinic visits. Subjects who elect not to participate in the long-term, 
optional follow-up treatment period-2 (Protocol Amendment 6) will also be asked to complete 
the ItchRO during the 4 weeks that follow the Week 144 (EOT) visit. During the long-term, 
optional follow-up treatment period-2, twice daily completion of the ItchRO will be required for 
2 consecutive weeks following the Week 144, Week 156, Week 168, Week 180, Week 192, and 
Week 204 clinic visits and during the 4 weeks that follow the Week 216 (EOT) visit. At these 
visits, subjects/caregivers will be provided with the electronic diary and re-trained on its use, as 
needed. In cases where an ItchRO observer can no longer observe the subject (eg, no longer 
living with the subject), the ItchRO(Obs) will not need to be completed; however, ItchRO(Pt) 
will need to be completed by subjects aged ≥9 years of age. Subjects/caregivers will be 
instructed to bring their electronic diary with them when they return for their next clinic visit. 
The electronic diary will be collected at Week 148 for subjects who do not participate in the 
long-term, optional follow-up treatment period-2 (Protocol Amendment 6), and at Week 220 for 
subjects who do participate in the long-term, optional follow-up treatment period-2. 
8.4.2 Clinician Scratch Scale 
A clinician’s assessment of pruritus will be made by the principal investigator or sub-investigator 
using the clinician scratch scale (Section 16.4). This assessment will be completed at Baseline 
(Day 0) and at all clinic visits thereafter (Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96). For 
subjects who enter into the long-term, optional follow-up treatment period, the clinician scratch 
scale will be administered at Weeks 108, 120, 132, 144 (EOT/ET). Subjects who elect not to 
participate in the long-term, optional follow-up treatment period-2 (Protocol Amendment 6) will 
also have the clinician scratch scale administered at Week 148 (EOS). For subjects who enter 
into the long-term, optional follow-up treatment period-2, the clinician scratch scale will be 
administered at Weeks 156, 168, 180, 192, 204, 216 (EOT/ET) and Week 220 (EOS). 
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. 


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8.4.3 Clinician Xanthoma Scale 
A clinician’s assessment of xanthomatosis will be made by the principal investigator or 
appropriate designee using the clinician xanthoma scale (Section 16.5). This assessment will be 
completed at Baseline (Day 0) and at Weeks 24, 36, 48, 60, 72, 84, and 96. For subjects who 
enter into the long-term, optional follow-up treatment period, the clinician’s assessment of 
xanthomatosis will be administered at Weeks 108, 120, 132, 144 (EOT/ET). Subjects who elect 
not to participate in the long-term, optional follow-up treatment period-2 (Protocol Amendment 
6) will also have the clinician’s assessment of xanthomatosis administered at Week 148 (EOS). 
For subjects who enter into the long-term, optional follow-up treatment period-2, the clinician’s 
assessment of xanthomatosis will be administered at Weeks 156, 168, 180, 192, 204, 216 
(EOT/ET) and Week 220 (EOS). 
The clinician’s assessment of the subject’s xanthomatosis is focused on the number of lesions 
present and the degree to which the subject’s lesions interfere or limit his or her activities. The 
clinician xanthoma scale uses a 5-point scale, in which 0 represents no evidence of 
xanthomatosis, 1 represents fewer than 20 scattered individual lesions, 2 represents more than 20 
lesions that do not interfere with or limit activities, 3 represents large numbers of lesions that by 
their large numbers or size cause distortion of the face or extremities, and 4 represents 
xanthomas that interfere with function (such as hand use or ability to walk) because of excess 
size or number (Emerick and Whitington, 2002). 
8.4.4 Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL™ is a one-page questionnaire that will be administered to subjects and or caregivers 
at the Baseline (Day 0) and Week 24 and Week 48 clinical visits using the age-appropriate 
PedsQL module (Section 16.6). For subjects who enter into the long-term, optional follow-up 
treatment period, the PedsQL will be administered at Weeks 108, 144 (EOT/ET). Subjects who 
elect not to participate in the long-term, optional follow-up treatment period-2 (Protocol 
Amendment 6) will also have the PedsQL administered at Week 148 (EOS). For subjects who 
enter into the long-term, optional follow-up treatment period-2, the PedsQL will be administered 
at Weeks 156, 216 (EOT/ET) and Week 220 (EOS). 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 Baseline (Day 0) and Weeks 24, 48, 60, 72, 84, 
and 96 clinical visits using the age-appropriate module, see Section 16.6. For subjects who enter 
into the long-term, optional follow-up treatment period, the multidimensional fatigue and family 
impact questionnaires will be administered at Weeks 108 and 144 (EOT/ET). Subjects who elect 
not to participate in the long-term, optional follow-up treatment period-2 (Protocol 
Amendment 6) will also have the multidimensional fatigue and family impact questionnaires 
administered at Week 148 (EOS). For subjects who enter into the long-term, optional follow-up 
treatment period-2, the multidimensional fatigue and family impact questionnaires will be 


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administered at Weeks 156, 216 (EOT/ET) and Week 220 (EOS). Age at the LUM001-301 
baseline visit will be used as the age for the determination of the appropriate questionnaire to be 
used for the study. This same module will be used for the duration of the study regardless of 
subsequent birthdays throughout the study. 
8.4.5 Caregiver Impression of Change 
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s perception of 
the subject’s xanthoma severity at the end of study drug treatment compared to his/her xanthoma 
severity prior to the start of treatment with study drug. The CIC will be completed by all 
caregivers at the Weeks 48, 60, 72, 84, and 96 visits, see Section 16.1. For subjects who enter 
into the long-term, optional follow-up treatment period, the CIC will be administered at Weeks 
108, 144 (EOT/ET). Subjects who elect not to participate in the long-term, optional follow-up 
treatment period-2 (Protocol Amendment 6) will also have the CIC administered at Week 148 
(EOS). For subjects who enter into the long-term, optional follow-up treatment period-2, the CIC 
will be administered at Weeks 156, 168, 180, 192, 204, 216 (EOT/ET) and Week 220 (EOS). 
8.5 
Restriction on the Lifestyle of Subjects 
8.5.1 Contraception Requirements 
Sexually active female subjects of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, from the time of enrollment 
until the end of the study. 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. 
8.5.2 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.  
All subjects will have fat soluble vitamin levels monitored; blood samples for the analysis of fat 
soluble vitamins should be obtained before the daily dose of vitamins is administered, and 
approximately 4 hours after any food or formula. 


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9. 
STUDY DRUG 
9.1 
Study Drug Description 
9.1.1 LUM001 
LUM001 is a powder that is to be dissolved with an appropriate diluent in order to administer the 
study drug as an oral solution. The composition of LUM001 study drug oral solution is described 
in Table 7. The composition of LUM001 study drug 0.5 mL oral solution is described in Table 8. 
Table 7: 
Composition of LUM001 1.0 mL Oral Solution 
Component 
Function 
Quantity per 1.0 mL 
LUM001 
Active Ingredient 
0.02 to 20 mg 
Propylene Glycol 
Co-solvent 
250 mg 
Sucralose 
Sweetener 
7.5 mg 
Grape Flavoring Agent 
Taste Masking Agent 
5 mg 
Water, q.s. to 
Vehicle 
1.0 mL 
 
Table 8: 
Composition of LUM001 0.5 mL Oral Solution 
Component 
Function 
Quantity per 0.5 mL 
LUM001 
Active Ingredient 
0.02 to 20 mg 
Propylene Glycol 
Co-solvent 
125 mg 
Sucralose 
Sweetener 
3.75 mg 
Grape Flavoring Agent 
Taste Masking Agent 
2.5 mg 
Water 
Vehicle 
q.s. to 0.5 mL 
 
9.2 
Packaging and Labeling 
The Sponsor will provide the central pharmacy with packaged study drug labeled in accordance 
with specific country regulatory requirements. Standard syringes will be provided by the sponsor 
for administration of study drug. 
9.3 
Drug Accountability 
The central pharmacy and all 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 drugs, 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 in this study is based on weight. During the study, the subject’s weight 
will be monitored at each visit. A change in weight greater than 10% of the weight used to 
calculate the subject’s current LUM001 dose will result in a dose adjustment. Each subsequent 
10% increase in weight will be considered the new baseline for determination of future dose 
adjustments. This dose adjustment will be made by the central pharmacy when they make the 
subject’s next LUM001 preparation. 
Study drug (LUM001 with diluent) will be prepared by a central pharmacy based on the 
subject’s last recorded weight from the LUM001-301 study. Diluent will be added by the central 
pharmacy pharmacist prior to shipping study drug to the site. Study drug will be dispensed to 
subjects/caregivers at the study site.  
Each subject dose for subjects who weigh 10 kg or more will be administered orally as a 1.0 mL 
solution containing study drug (LUM001) using the syringe provided. Each subject dose for 
subjects who weigh less than 10 kg will be administered orally as a 0.5 mL solution containing 
study drug (LUM001)using the syringe provided. Study drug should be taken at least 30 minutes 
prior to the first meal of the day (qAM, ac) and should be administered approximately at the 
same time each day for the duration of the treatment period. See Sections 5.5.1.1, 5.5.1.2, and 
5.5.1.3 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.  
10.2 
Treatment Compliance 
Compliance with treatment dosing will be monitored and recorded by the study site staff. 
Subjects and/or guardians will be asked to complete a paper diary indicating when they took 
their study medication and when they ate breakfast. 
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 (from baseline/Day 0 until the 30-day post-treatment follow-up visit). 
Concomitant medications should not be recorded prior to informed consent, or during gap 
periods when the subject is not participating in the study. 
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 


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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. 
At the physician investigator’s discretion, tapering or withdrawal of concomitant medications 
used for the treatment of pruritus may occur during stable dosing period. With the exception of 
vitamin supplementation and anti-pruritic medications, the dosage and dosing regimen of other 
concomitant medications should not change during the course of the study except for dose 
adjustments due to weight increase. All modifications to concomitant medications must be 
carefully documented in the relevant CRFs. 
Concomitant use of bile acid or lipid binding resins or any investigational drug product other 
than LUM001 is not allowed during the study.  
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 
10.5.1 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 Alagille syndrome will have abnormal liver enzyme 
levels (eg, ALT, ALP) total bilirubin, cholesterol and serum bile acids prior to their exposure to 
study drug in the lead-in study. If an individual subject exhibits a Common Terminology Criteria 
for Adverse Events (CTCAE) Grade 3 treatment emergent laboratory abnormality, with the 
exception of the specific rules outlined below (Sections 10.5) dosing can be suspended or 
continued as per the investigator’s judgement and following discussion with the ChiLDReN 
protocol chair and the medical monitor. If suspended, the investigator, the ChiLDReN protocol 
chair, and the 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.  
10.5.2 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 
exceeding 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 retest should be conducted by the central laboratory but may also be 


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conducted at a local laboratory if needed. All new specimen collection for retesting should take 
place within 48-72 hours 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: If any of the stopping criteria described below (refer to Section 10.5.1) 
are confirmed, the physician investigator in consultation with the ChiLDReN protocol chair and 
the medical monitor or appropriately qualified designee(s), will permanently discontinue the 
subject from further treatment with study drug. The subject will be evaluated as outlined below 
and will be encouraged to complete the early termination study procedures. Subjects who do not 
meet the stopping rules based on retest may continue dosing and the Investigator, the ChiLDReN 
protocol chair, and the medical monitor (or appropriately qualified designee) should confer as to 
whether additional close monitoring of the subject is appropriate. The investigator should also 
assess the need to capture an AE, its severity according to the CTCAE directives and potential 
causality. These assessments should also include an evaluation of whether criteria for an SAE are 
fulfilled (see Section 11.2.3). 
10.5.2.1 
Safety Monitoring for Liver Chemistry Tests 
Safety monitoring criteria take into consideration the subject’s historical baseline ALT and total 
bilirubin levels. Historical baseline levels will be defined as the values reported for each subject 
at their baseline visit for the LUM001-301 protocol.  
If at any time in the study an ALT or total bilirubin result exceeds the criteria shown in the table 
below, in relation to the subject’s historical baseline level, the initial measurement(s) should be 
confirmed within 48 to 72 hours of the initial report.  
Historical Baseline1 ALT 
ALT 
< ULN 
> 5 x ULN  
> ULN 
> 3 x historical baseline and > 5 x ULN 
 
Historical Baseline1 Total Bilirubin 
Total Bilirubin 
Total Bilirubin 1-10 mg/dL  
(17.10 – 171.04 μmol/L) 
3 mg increase over historical baseline level 
Total Bilirubin >10 mg/dL  
(>171.04 μmol/L) 
5 mg increase over historical baseline level 
1 Historical baseline values are those reported at baseline of the LUM001-301 protocol. 
 
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/exclusion 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 


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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 nonprescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets. 
• Obtain a history for exposure to environmental chemical agents and travel  
• Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, CMV IgM, and EBV 
antibody panel). 
• Serology for autoimmune hepatitis (eg, 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 
ChiLDReN protocol chair and the Medical monitor.  
10.5.2.2 
Stopping Rules for Liver Chemistry Elevations 
In the event of confirmed laboratory results meeting the following criteria, and the event is 
without an alternative explanation as discussed with the ChiLDReN protocol chair, and 
medical monitor, discontinuation of dosing of a subject with study drug will be considered if: 
 
Historical Baseline Tests 
Change Observed 
ALT (any level) 
ALT  20 x ULN 
Total Bilirubin 1-10 mg/dL (17.10 – 171.04 μmol/L) 
5 mg increased and a 2 x increase over historical 
baseline level 
Total Bilirubin >10 mg/dL (>171.04 μmol/L) 
2 x increase over historical baseline level 
1 Historical Baseline values are those reported at baseline of the LUM001-301 protocol.  
 
 
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, the ChiLDReN protocol chair, and the medical monitor may consider 
a temporary interruption of study drug. Dosing may resume when the triglyceride level returns to 
<300 mg/dL (3.39 mmol/L) or to the subject’s baseline level. 


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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, the ChiLDReN protocol chair, 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 (unresponsive to vitamin K therapy), 
the Investigator, the ChiLDReN protocol chair, and the medical monitor may consider a 
temporary interruption of study drug. 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 
toxicity, study drug dose may be lowered to a previously well tolerated dose. This decision 
should be made in consultation with the ChiLDReN protocol chair and medical monitor. A 
requirement for intravenous fluids as treatment for diarrhea (without an alternative explanation) 
will lead to discontinuation of study drug.  
If a subject experiences an acute illness requiring temporary discontinuation of study drug, they 
may continue their participation in the study and resume study treatment as long as the period of 
discontinuation does not exceed 7 days.  
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 who 
withdraws consent to participate in the study will be removed from further treatment and/or 
study observation immediately upon the date of the request.  


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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 guardian, Investigator or Sponsor before completion of the protocol-
specified treatment period, and has received >1 dose of study drug, 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 electronic 
diary 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 guardian. 
• 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 (eg, medication or treatment that is prohibited by the 
protocol). 
• At the discretion of the Investigator if deemed not medically acceptable to continue 
study treatment. 
• 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 Harmonization (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 Monitoring Board (DMB) will 
be notified of any SAE as specified in the DMB charter.  
Appropriate personnel at the Sponsor or designee will unblind SUSARs for the purposes of 
regulatory reporting. The Sponsor or designee will submit SUSARs to regulatory agencies in 
blinded or unblinded fashion according to local law. The Sponsor or designee will submit 
SUSARs to Investigators in a blinded fashion. 
11.2 
Definitions 
11.2.1 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: 


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• Continuous persistent disease/symptom present before the start of study drug, which 
does not unexpectedly progress, or change in severity following drug administration. 
• Disease being studied and/or signs and symptoms associated with the disease, such as 
jaundice or itching, or abnormalities in liver enzymes already present at the baseline 
visit. 
• Treatment failure or lack of efficacy. 
 
11.2.2 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 AE. A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction. 
11.2.3 Serious Adverse Event (SAE) 
A serious AE 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 (ie, before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened. In addition, AEs that occur while the subject is 
not enrolled in the study during a gap period (ie, prior to enrollment in Protocol Amendment 5), 
will be collected as medical history unless the AE started within 30 days of last dose. 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.” 
11.3.1 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 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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11.3.2 Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the ICF 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.  
11.3.3 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 (eg, 
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 
(eg, 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 CTCAE grade of the event should be reported according to CTCAE Version 4.0 
(Section 16.8). 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. 
 
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. 


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Please also refer to Section 10.5.2 regarding specific safety monitoring for liver chemistry tests 
given that subjects with ALGS may have abnormal liver enzymes 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 (eg, 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. 
• 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). 


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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. 
• SAE (see Section 11.3.1). 
• Pregnancy. 
• Dosing errors. 
• Treatment unblinding for any reason (see Section 6.3). 
 
11.4.1 Pregnancy Reporting 
If a subject becomes pregnant or a pregnancy is suspected in either a subject or in the partner of a 
male study participant 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 (ie, 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.  
11.4.2 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 the event accidental or intentional.  
Dosing details should be captured on the appropriate eCRF and paper subject diaries. 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. 


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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.  
11.4.3 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 (eg, 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, the 
ChiLDReN protocol chair, and the 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 SAP will be written prior to database lock. 
Approximately 36 subjects meeting the study’s inclusion and exclusion criteria will be enrolled 
in the study. The number of subjects enrolled in this study will be determined by the number of 
subjects who roll-over from the LUM001-301 protocol. Because this is an extension study for 
LUM001-301 protocol, the sample size is not based on statistical considerations.  
Safety 
All safety analyses will be performed on the Safety Population, defined as all subjects who 
received at least one dose of the study drug during the extension study.  
Adverse Events will be examined over the entire treatment period, and for the dose escalation 
and optimization periods. Adverse events for each study period will be summarized overall by 
treatment group based on the treatment group at enrollment in the extension study at baseline 
(Study Day 0). Adverse events for the stable dosing period will also be summarized overall and 
by treatment group based on the stable dosing group. 
Other safety measures including clinical laboratory tests, vital signs, physical exams, and 
concomitant medication usage will be summarized descriptively. For quantitative variables, 
descriptive statistics including number of observations, mean, median, standard deviation and 
range will be given for the values themselves and by their mean changes from pre-defined 
reference points (see below) at each visit. Qualitative variables will be summarized using counts 
and percentages by baseline treatment group at each study visit.  
Drug Level Analysis 
Descriptive statistics analysis of LUM001 concentrations will be carried out on the plasma 
concentration data. 
Efficacy 
All efficacy analyses will also be performed on the Safety Population, defined as all subjects 
who received at least one dose of the study drug during the extension study. 
Secondary 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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12.1 
Sample Size Considerations 
Approximately 36 subjects meeting the study’s inclusion and exclusion criteria may be enrolled 
in the study. Because this is an extension study for subjects who participated in the LUM001-301 
protocol, the sample size is not based on statistical considerations. 
12.2 
Population 
12.2.1 Safety Population 
Because of the design of the study, there will be only one analysis population for the study. The 
Safety Population is defined as all subjects who were enrolled 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 treatment received.  
12.2.2 Siblings 
At the start of the LUM001-301 study, siblings enrolled in the study will be assigned in a blinded 
manner to the same treatment arm. The data from all enrolled participants (including siblings) 
will be used for the safety analysis. For the efficacy analysis, data from only one of the siblings 
will be used. The choice of which subject’s data to use in the efficacy analysis will be done in a 
random fashion before the LUM001-301 study is unblinded. Additionally, a sensitivity analysis 
will be conducted using the data from the siblings that were not randomly chosen in order to 
assess the potential impact on the results. Additional methodological detail will be included in 
the protocol’s SAP.  
12.2.3 Demographic and Baseline Characteristics 
12.2.3.1 
Subject Disposition 
Subject disposition will be summarized descriptively. The number and percentage of subjects 
enrolled, completed, and withdrawn, along with reasons for withdrawal, will be tabulated 
overall, and by treatment group assigned at LUM001-305 study entry.  
The number and percentage of subjects receiving study drug following the protocol specified 
dose escalation procedure, stable dosing, safety monitoring, and long-term optional follow-up 
dosing regimens will be tabulated overall and by treatment group assigned in the core study 
(LUM001-301). 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. In addition, for subjects who had dose gaps or re-initiated to all protocol amendments, the 
number of days of the off-drug period will be summarized. Duration of the follow-up period will 
be tabulated. 


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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 (eg, pruritus scores, liver biochemistries). 
• Prior medications of interest (eg, ursodiol [UDCA], rifampicin) and concomitant 
medications. 
Demographic and baseline characteristics will be summarized overall and descriptively by 
treatment group assigned in the core study (LUM001-301).  
Baseline for this study will be considered Day 0 in the study. 
Medical history information will be presented in listings. 
12.2.4 Efficacy Analyses 
12.2.4.1 
Efficacy Variables 
The primary evaluation will be the mean change from baseline (Day 0) of LUM001-301 and 
baseline (Day 0) of LUM001-305 baseline to Week 48 in:  
• Fasting serum bile acid level. 
Secondary evaluations will be the mean change from baseline (Day 0) of LUM001 301 and 
baseline (Day 0) of LUM001-305 through Week 216/EOT in: 
• Biochemical markers of cholestasis and liver disease (eg, ALT, ALP, GGT and bilirubin 
[total and direct]). 
• Pruritus as measured by the ItchRO instruments (ItchRO(Obs)TM, caregiver 
instrument/ItchRO(Pt) TM patient instrument). 
• During the first 12 weeks of the study, the electronic diary (ItchRO) will be 
completed twice daily (AM & PM). During the stable dosing period (Weeks 13-48), 
twice daily completion of the electronic diary (ItchRO) for 4 consecutive weeks will 
be required following the Week 24 and Week 44 clinic visits. For subjects who 
continue in the safety monitoring period, twice daily completion of the ItchRO will be 
required for 2 consecutive weeks following the Week 60, 72, and 84 clinic visits. For 
subjects who continue in the long-term, optional follow-up treatment period, twice 
daily completion of the ItchRO will be required for 2 consecutive weeks following 
the Week 96, 108, 120, and 132 clinic visits, and for 4 weeks following the Week 144 
visit. For subjects who continue in the long-term optional follow-up treatment period-


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2, twice daily completion of the ItchRO will be required for 2 consecutive weeks 
following the Week 144, 156, 168, 180, 192, 204 clinic visits, and for 4 weeks 
following the Week 216 visit. 
• Xanthomas as measured by clinician xanthoma scale. 
• Clinician scratch scale 
• Fasting serum bile acid level 
The exploratory evaluation will be the mean change in weight z-score from baseline Day 0 of 
LUM001-301 and baseline (Day 0) of LUM001-305 through Week 216 (EOT/ET). 
Exploratory evaluations will include the mean change from baseline in ItchRO, fasting sBA, and 
biochemical markers of cholestasis and liver disease at Week 144, Week 216, (EOT/ET) and at 
Week 220 (EOS). The exploratory evaluation will be the mean change in weight z-score from 
baseline (Day 0) of LUM001-301 and baseline (Day 0) of LUM001-305 through Week 216 
(EOT/ET).  
Additional exploratory evaluations will be specified in the SAP and may include analyses 
between Week 144 (EOT/ET) and Week 148 (EOS) for subjects who complete Protocol 
Amendment 5 and between Week 216 (EOT/ET) and Week 220 (EOS) for subjects who 
complete Protocol Amendment 6. 
12.2.4.2 
Primary Efficacy Analysis 
The change from baseline to Week 48 in the serum bile acid will be tabulated overall and by 
treatment group assigned in the core study (LUM001-301), using summary statistics including 
the number of observations, the 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. 
12.2.4.3 
Secondary, Exploratory and Other Efficacy Analyses 
Secondary Analyses 
Secondary efficacy variables that are continuous measures will be analyzed similarly to the 
primary efficacy analyses.  
Change from baseline in Xanthoma scale will be categorized as improved, stable or worsened. 
Exploratory Analyses 
Exploratory efficacy variables that are continuous measures will be analyzed similarly to the 
primary efficacy analyses.  
Additional exploratory analyses may be performed and will be defined in the SAP. 


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Other Analyses 
Analyses of PedsQL and the CIC will be performed and will be defined in the SAP. 
12.2.5 Safety Analyses 
Safety analyses will be performed on the Safety Population.  
12.2.5.1 
Safety Assessments 
The following assessments will be used to monitor safety: 
• AEs and SAEs. 
• Clinical laboratory results. 
• Vital signs. 
• Physical exam findings, including body weight and height. 
• Concomitant medication usage. 
 
12.2.6 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 overall for the safety 
population. 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 overall, and by treatment group assigned in the core study (LUM001-301), 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 the dose escalation/optimization, stable dose, safety 
monitoring and long-term, optional follow-up treatment periods of the study.  
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.  


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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 overall, and by treatment group 
assigned in the core study (LUM001-301) for each study visit. Change from baseline will also be 
presented over time, as appropriate. Percent change from baseline will be added for laboratory 
values as outlined in the SAP.  
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. Changes within a treatment 
group for selected safety measures will be assessed at Weeks 8, 12, 24, 36, 48, 96, and at 
additional time points during the long-term, optional follow-up treatment periods. 
The effect of LUM001 on fat soluble vitamin levels will be assessed. These laboratory values 
will be summarized as above and listed for individual subjects. A separate listing will present 
laboratory values of all subjects who change from sufficient to insufficient or from insufficient to 
sufficient during the course of the study.  
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 
overall, and by treatment group assigned in the core study (LUM001-301) for each study 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. This 
will include the LUM001-301 baseline visit (Day 0) and the LUM001-305 baseline (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.  
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 serum bile acid levels. 
However, exposure to study drug will be measured at specified study visits approximately 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 by treatment group. 
 


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12.2.7 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 and 
the blind is broken. 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.  


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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, 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 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/ascent form (ICF/IAF) summarizing the discussion prior to 
enrollment. Since this is a pediatric study, in addition to the written informed consent, the assent 
of the child must also be obtained, as required by each study center’s governing IRB. 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 (eg, 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.  


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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/assents form(s) 
must be received by the Sponsor or designee before recruitment of subjects into the study and 
shipment 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/assent documents. 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 serious AEs 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 CRFs 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 (eg, 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. 


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The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only 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 (eg, 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 enrolment of subjects, study staff is 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/assent documents. The regulatory authority and IEC/IRB must be 
informed of 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 


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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 CRF 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 CRFs 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 CRFs (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. 


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14.5.1 Parent Report for Teenagers (ages 13-18 years) 
 
 


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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 
the various records of the trial (eg, CRFs 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 CRFs. 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 
Orphanet [Online]. Available: www.orpha.net [Accessed]. 
Emerick, K. M., Rand, E. B., Goldmuntz, E., Krantz, I. D., Spinner, N. B. & Piccoli, D. A. 1999. 
Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. 
Hepatology, 29, 822-9. 
Emerick, K. M. & Whitington, P. F. 2002. Partial external biliary diversion for intractable 
pruritus and xanthomas in Alagille syndrome. Hepatology, 35, 1501-6. 
Hofmann, A. F. 2003. Inappropriate ileal conservation of bile acids in cholestatic liver disease: 
homeostasis gone awry. Gut, 52, 1239-41. 
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. 
Modi, B. P., Suh, M. Y., Jonas, M. M., Lillehei, C. & Kim, H. B. 2007. Ileal exclusion for 
refractory symptomatic cholestasis in Alagille syndrome. J Pediatr Surg, 42, 800-5. 
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. 
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  
Schedule of Procedures A: Baseline – Week 12 
Study Period 
Baseline 
Treatment Period 
Dose Escalationc 
Dose Optimization 
Study Week 
 
1 
2 
3 
4 
6 
8 
10 
12 
Study Day 
Day 01 
7 
14 
21 
28 
42 
56 
70 
84 
Window (in days) 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Assessment / Medical History 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
Body Weight & Height 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signs2 
X 
 
X 
 
X 
 
X 
 
X 
CBC with Differential3 
X 
 
X 
 
X 
 
X 
 
X 
Coagulation3 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry Panel3 
X 
 
X 
 
X 
 
X 
 
X 
Lipid Panel3,4 
X 
 
X 
 
X 
 
X 
 
X 
Cholestasis Biomarkers3,4 
X 
 
X 
 
X 
 
X 
 
X 
Fat Soluble Vitamins3,4 
X 
 
 
 
 
 
X 
 
X 
Plasma Sample for LUM001d 
X 
 
X 
 
X 
 
X 
 
X 
Urinalysis3 
Xa 
 
Xa 
 
Xa 
 
X 
 
X 
Urine Pregnancy Test 5 
X 
 
X 
 
X 
 
X 
 
X 
Subject eDiary / Caregiver eDiary (ItchRO) 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Clinician Scratch Scale 
X 
 
X 
 
X 
 
X 
 
X 
Clinician Xanthoma Scale 
X 
 
 
 
 
 
 
 
 
PedsQL 
X 
 
 
 
 
 
 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
Study Drug Supplied 
X 
 
X 
 
X 
 
X 
 
X 
Assess Study Drug Compliance 
 
 
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 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contact6 
 
X 
 
X 
 
X 
 
X 
 


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Schedule of Procedures A: Baseline – Week 12 
Study Period 
Baseline 
Treatment Period 
Dose Escalationc 
Dose Optimization 
Study Week 
 
1 
2 
3 
4 
6 
8 
10 
12 
Study Day 
Day 01 
7 
14 
21 
28 
42 
56 
70 
84 
Window (in days) 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
1 
Evaluations and procedures completed for the Week 13 Visit of the LUM001-301 protocol will also serve as 
the evaluations for the Baseline Visit for this extension study.  
2 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
3 
See Section 16.2 for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins 
should be drawn prior to administration of vitamin supplementation. 
4 
Subjects are required to fast at least 4 hrs. (only water permitted prior to collection). 
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. 
a At the indicated visits, oxalate will be part of the 
urinalysis. 
b During the first 12 weeks of the study, the eDiary 
(ItchRO) will be completed twice daily (AM & PM). 
Compliance will be assessed at each visit/phone contact. 
c Subjects should be dosed for at least 7 days at each dose 
level. 
d At Weeks 2, 8, 12, 24, 36 and 48, 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 for drug level analysis. 
 


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Schedule of Procedures B - Stable Dosing: Week 16 – Week 48 
Study Period 
Treatment Period (cont’d) 
Stable Dosing 
Study Week 
166 
20 
24 
28 
32 
36 
40 
44 
Week 48 
 
Study Day 
112 
140 
168 
196 
224 
252 
280 
308 
336 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
Physical Exam 
X6 
 
X 
 
 
X 
 
 
X 
Body Weight & Height 
X6 
 
X 
 
 
X 
 
 
X 
Vital Signs1 
X6 
 
X 
 
 
X 
 
 
X 
CBC with Differential2 
X6 
 
X 
 
 
X 
 
 
X 
Coagulation2 
X6 
 
X 
 
 
X 
 
 
X 
Chemistry Panel2 
X6 
 
X 
 
 
X 
 
 
X 
Lipid Panel2,3 
X6 
 
X 
 
 
X 
 
 
X 
Cholestasis Biomarkers2,3 
X6 
 
X 
 
 
X 
 
 
X 
Fat Soluble Vitamins2,3  
 
 
X 
 
 
X 
 
 
X 
Plasma Sample for LUM001c 
 
 
X 
 
 
X 
 
 
X 
Urinalysis2 
X6 
 
X 
 
 
X 
 
 
Xa 
Urine Pregnancy Test 4 
X6 
 
X 
 
 
X 
 
 
X 
Clinician Scratch Scale 
 
 
X 
 
 
X 
 
 
X 
Clinician Xanthoma Scale 
 
 
X 
 
 
X 
 
 
X 
Subject eDiary/Caregiver eDiary 
(ItchRO) 
 
 
Xb 
Xb 
to Week 28 
 
 
 
Xb 
Xb 
to Week 48 
PedsQL 
 
 
X 
 
 
 
 
 
X 
Caregiver Impression of Change 
(CIC) 
 
 
 
 
 
 
 
 
X 
Study Drug Supplied 
 
 
X 
 
 
X 
 
 
X 
Assess Study Drug Compliance 
 
 
X 
 
 
X 
 
X 
X 
Review Study Diaries & Assess 
Compliance 
 
 
X 
 
 
X 
 
X 
X 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contact5 
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. Blood samples for analysis of fat soluble vitamins 
should be drawn prior to administration of vitamin supplementation. 
3 
Subjects are required to fast at least 4 hrs. (only water permitted prior to collection). 
4 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
5 
Subjects must be available to receive a phone call from study staff. 
6  A Week 16 Clinic Visit will be completed for all subjects who undergo a change in dose at Week 12; 
Subjects who do not undergo a dose change at Week 12 will be contacted by phone at Week 16. 
a At the indicated visits, oxalate will be part of the urinalysis. 
b During the stable dosing period, twice daily completion of 
the eDiary (ItchRO) for 4 consecutive weeks will be required 
following the Week 24 and Week 44 clinic visits.  
c At Weeks 2, 8, 13, 24, 36 and 48, 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 for drug level analysis 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 111 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures B - Stable Dosing: Week 16 – Week 48 
Study Period 
Treatment Period (cont’d) 
Stable Dosing 
Study Week 
166 
20 
24 
28 
32 
36 
40 
44 
Week 48 
 
Study Day 
112 
140 
168 
196 
224 
252 
280 
308 
336 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
 
  
Clinic Visit 
 
Phone Contact 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 112 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
 
Schedule of Procedures C - Safety Monitoring Period: Week 52 – Week 96/Early Termination Schedule of Procedures  
Study Period 
Treatment Period (cont’d) 
Study Termination 
Follow-Up 
Safety Monitoring Period 
Study Week 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
Week 96 
(or Early Term7) 
30 days after 
final dose8 
Study Day 
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
Informed Consent / 
Eligibility Assessment 
for PA51 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical Exam 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Body Weight & Height 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Vital Signs2 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
CBC with Differential3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Coagulation3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Chemistry Panel3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Lipid Panel3,4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Cholestasis 
Biomarkers3,4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Fat Soluble Vitamins3,4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Plasma Sample for 
LUM001 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis3 
 
 
X 
 
 
X 
 
 
X 
 
 
Xa 
 
Urine Pregnancy Test5 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Clinician Scratch Scale  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Clinician Xanthoma 
Scale 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Subject 
eDiary/Caregiver eDiary 
(ItchRO) 
 
 
Xb 
Xb 
to 
Week 
62 
 
Xb 
Xb 
to 
Week 
74 
 
Xb 
Xb 
to 
Week 
86 
 
Xb 
Xb 
to Week 98 
PedsQL 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Caregiver Impression of 
Change (CIC) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Supplied 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Assess Study Drug 
Compliance 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Review Study Diaries & 
Assess Compliance 
 
 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
Concomitant 
Medications  
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 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 113 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures C - Safety Monitoring Period: Week 52 – Week 96/Early Termination Schedule of Procedures  
Study Period 
Treatment Period (cont’d) 
Study Termination 
Follow-Up 
Safety Monitoring Period 
Study Week 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
Week 96 
(or Early Term7) 
30 days after 
final dose8 
Study Day 
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
Phone Contact6 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
1 
Subjects can consent to roll over into the long-term optional follow-up treatment period, per Schedule D. 
2 
Blood pressure (BP), heart rate (HR), temperature, respiration rate 
3 
See Section 16.2 for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins 
should be drawn prior to administration of vitamin supplementation. 
4 
Subjects are required to fast at least 4 hrs. (only water permitted prior to collection). 
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 during the follow-up treatment period should complete all evaluations at this 
visit. 
8 
Visit not required for subjects with ≤7 days LUM001 dose interruption who roll over into the long-term 
optional follow-up treatment period (Schedule D) or for subjects with >7 days but less than 30 days 
LUM001 dose interruption who roll over into the long-term optional follow-up treatment period (Schedule 
E). 
a At the indicated visits, oxalate will be part of the 
urinalysis. 
b During the follow-up period, twice daily completion of 
the eDiary (ItchRO) for 2 consecutive weeks will be 
required following the Week 60, 72, 84, and 96 clinic 
visits. 
c Study staff will review ItchRO diary data from the 
prior period and assess compliance. 
  
Clinic Visit 
 
Phone Contact 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 114 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures D – Long-term, Optional Treatment Period: Week 96 – Week 148  
for those subjects with ≤7 days from the last dose of LUM001 applicable as follows: 
• 
If another study becomes available for subjects prior to completion of Protocol Amendment 5, the subject will complete EOT 
assessments as outlined for Week 144. 
• 
Subjects who complete 48 weeks of additional treatment and who are not eligible for another study will complete EOS assessments as 
outlined for Week 148. 
Schedule of Procedures D – Long-term, Optional Treatment Period: Week 96 – Week 148 
Study Period 
Treatment Period (cont’d) 
EOT Visit/ET 
EOS Visit9 
Long-term, Optional Follow-up Treatment Period 
Study Week 
100 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
 
 Week 1448 
Week 148 
Study Day 
700 
728 
756 
784 
812 
840 
868 
896 
924 
952 
980 
1008 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
Informed Consent / 
Eligibility Assessment 
for PA61,10 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical Exam 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Body Weight2 & Height 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital Signs3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CBC with Differential4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Coagulation4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Chemistry Panel4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Lipid Panel4,5 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Cholestasis 
Biomarkers4,5 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Fat Soluble Vitamins4,5 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Plasma Sample for 
LUM001 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urinalysis4 
 
 
X 
 
 
X 
 
 
X 
 
 
Xa 
Xa 
Urine Pregnancy Test6 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Clinician Scratch Scale  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Clinician Xanthoma 
Scale 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Subject 
eDiary/Caregiver eDiary 
(ItchRO) 
Xb 
to 
Week 
98 
 
Xb 
Xb 
to 
Week 
110 
 
Xb 
Xb 
to 
Week 
122 
 
Xb 
Xb 
to 
Week 
134 
 
Xb 
Xb 
to Week 148 
PedsQL 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Caregiver Impression of 
Change (CIC) 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 115 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures D – Long-term, Optional Treatment Period: Week 96 – Week 148 
Study Period 
Treatment Period (cont’d) 
EOT Visit/ET 
EOS Visit9 
Long-term, Optional Follow-up Treatment Period 
Study Week 
100 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
 
 Week 1448 
Week 148 
Study Day 
700 
728 
756 
784 
812 
840 
868 
896 
924 
952 
980 
1008 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
Study Drug Supplied 
 
 
X 
 
 
X 
 
 
X 
 
 
X11 
 
Assess Study Drug 
Compliance 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Review Study Diaries & 
Assess Compliance 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xc 
 
Xc 
Xc 
Concomitant 
Medications  
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 
Phone Contact7 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
  
1 
Subjects can consent to roll over into the long-term optional follow-up treatment period-2, per Schedule 
F. 
2 
Increases of 10% or more in a subject’s weight from baseline will require a dose adjustment, per 
Section 10.1. 
3 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.
 
 
4 
See Section 16.2 for detailed list of laboratory analytes. Blood samples for analysis of fat soluble 
vitamins should be drawn prior to administration of vitamin supplementation. 
5 
Subjects are required to fast at least 4 hrs. (only water permitted prior to collection). 
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 
Subjects who withdraw early during the follow-up treatment period should complete all evaluations at 
this visit.  
9 
Subjects who elect not to participate in the long-term, optional follow-up treatment period-2 (Protocol 
Amendment 6) should return to the study site 30 days after the last dose of study drug and complete all 
evaluations at this visit 
10 Eligibiility should only be assessed at Week 144 for subjects that complete PA5 (Week 144) and rollover 
directly to PA6. Subjects who did not consent to PA5 and who re-enter in PA6 from IPA5 or earlier will 
not be re-assessed for eligibility at Week 144 
11. Subjects should continue dosing at Week 144 if entering PA6 
 
a At the indicated visits, oxalate will be part of the 
urinalysis. 
b During the follow-up period, twice daily completion of 
the eDiary (ItchRO) for 2 consecutive weeks will be 
required following the Week 108, 120, and 132 visits and 
for 4 consecutive weeks following the Week 144 clinic 
visit. 
c Study staff will review ItchRO diary data from the prior 
period and assess compliance. 
  
Clinic Visit 
 
Phone Contact 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 116 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures E – Re-Entry into Long-term Optional Treatment Period/Long-term Optional Treatment Period-2: applicable as 
follows: 
• 
Subjects either previously completed the follow-up period up to Week 96, or has received permission from the sponsor and the 
ChiLDReN protocol chair to re-enter the study.  
Schedule of Procedures E – Re-entry into Long-term, Optional Treatment Period/ Long-term, Optional Treatment Period-2 
Study Period 
Dose Escalation Treatment Period 
PA5 DE Study 
Week 
PA5 
RI -2h 
PA5 
RI 
Day 0 
PA5 
RI 
Week 1 
PA5 
RI 
Week 2 
PA5 
RI 
Week 3 
PA5 
RI 
Week 4 
PA5 
 Schedule D - Week 
104 
Scheduling 
Considerations 
 
0 
 
 
 
 
 
Window (in 
days) 
 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
 
(±2) 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
Assess Eligibility 
for study re-entry 
X 
X 
 
 
 
 
 
Physical Exam 
X 
X 
 
X 
 
X 
 
Body Weight & 
Height 
X 
X 
 
X 
 
X 
 
Vital Signsa 
X 
X 
 
X 
 
X 
 
CBC with 
Differentialb 
X 
X 
 
X 
 
X 
 
Coagulationb 
X 
X 
 
X 
 
X 
 
Chemistry Panelb 
X 
X 
 
X 
 
X 
 
Lipid Panelb,c 
 
X 
 
X 
 
X 
 
Cholestasis 
Biomarkersb,c 
 
X 
 
X 
 
X 
 
Fat Soluble 
Vitaminsb,c,d 
 
X 
 
X 
 
X 
 
Urinalysisb 
 
X 
 
X 
 
X 
 
Serum Pregnancy 
Test (if 
indicated)e 
X 
X 
 
X 
 
X 
 
Clinician Scratch 
Scale 
 
X 
 
X 
 
X 
 
Clinician 
Xanthoma Scale 
 
X 
 
X 
 
X 
 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 117 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures E – Re-entry into Long-term, Optional Treatment Period/ Long-term, Optional Treatment Period-2 
Study Period 
Dose Escalation Treatment Period 
PA5 DE Study 
Week 
PA5 
RI -2h 
PA5 
RI 
Day 0 
PA5 
RI 
Week 1 
PA5 
RI 
Week 2 
PA5 
RI 
Week 3 
PA5 
RI 
Week 4 
PA5 
 Schedule D - Week 
104 
Scheduling 
Considerations 
 
0 
 
 
 
 
 
Window (in 
days) 
 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
 
(±2) 
Caregiver 
ItchRO/ 
Patient ItchRO 
 
 
 
 
 
X  
(collected for 2-week 
period following this 
visit) 
 
PedsQL 
 
X 
 
 
 
 
 
Study Drug 
Suppliedf 
 
X 
 
X 
 
X 
 
Caregiver 
ItchRO/ 
Patient ItchRO 
Device Supplied 
 
 
 
 
 
X 
 
Assess Study 
Drug Compliance 
 
 
 
X 
 
X 
 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone 
Contactg 
 
 
X 
 
X 
 
X 
a 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
b 
See Section 16.2 for detailed list of laboratory analytes. 
c 
Subjects are required to fast at least 4 hrs (only water permitted) prior to collection. 
d 
Blood samples must be drawn before administration of vitamin supplementation. 
e 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
f 
Study drug may be dispensed at unscheduled clinic visits. 
g 
Subjects must be available to receive a phone call from study staff. 
h 
Subjects with dose interruptions prior to Week 96 or who early terminated may re-enter the study under Protocol Amendment 6. These subjects will initiate dose 
escalation at visit PA5 RI -2. 
 
 
Clinic Visit 
 
Phone Contact 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 118 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures F – Long-term, Optional Treatment Period-2: Week 144 – 220 (Study Completion/Termination), applicable as 
follows: 
• 
If another study becomes available for subjects prior to completion of Protocol Amendment 6, the subject will complete EOT 
assessments as outlined for Week 216. 
• 
Subjects who complete 72 weeks of additional treatment and who are not eligible for another study will complete EOS assessments as 
outlined for Week 220. 
Schedule of Procedures F – Long-term, Optional Treatment Period-2: Week 144 – Week 220 (Study Completion/Termination) 
Study Period 
 
Long-term, Optional Follow-up Treatment Period-2 
EOT/ET 
Visit 
EOS 
Visit 
Study Week 
148 
152 
156 
160 
164 
168 
172 
176 
180 
184 
188 
192 
196 
200 
204 
208 
212 
 
 Week 
2167 
Week 
220 
Study Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Window  
(in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
Physical Exam 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Body Weight1 
& Height 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital Signs2 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
CBC with 
Differential3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Coagulation3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Chemistry 
Panel3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Lipid Panel3,4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Cholestasis 
Biomarkers3,4 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Fat Soluble 
Vitamins3,4  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Plasma 
Sample for 
LUM001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urinalysis3 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xa 
Xa 
Urine 
Pregnancy 
Test5 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Clinician 
Scratch Scale  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Clinician 
Xanthoma 
Scale 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 119 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures F – Long-term, Optional Treatment Period-2: Week 144 – Week 220 (Study Completion/Termination) 
Study Period 
 
Long-term, Optional Follow-up Treatment Period-2 
EOT/ET 
Visit 
EOS 
Visit 
Study Week 
148 
152 
156 
160 
164 
168 
172 
176 
180 
184 
188 
192 
196 
200 
204 
208 
212 
 
 Week 
2167 
Week 
220 
Study Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Window  
(in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
Subject 
eDiary/ 
Caregiver 
eDiary 
(ItchRO) 
Xb 
to 
Week 
146 
 
Xb 
Xb 
to 
Week 
158 
 
Xb 
Xb 
to 
Week 
170 
 
Xb 
Xb 
to 
Week 
182 
 
Xb 
Xb 
to 
Week 
194 
 
Xb 
Xb 
to 
Week206 
 
Xb 
Xb 
to Week 
220 
PedsQL 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Caregiver 
Impression of 
Change (CIC) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Study Drug 
Supplied 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Assess Study 
Drug 
Compliance 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Review Study 
Diaries & 
Assess 
Compliance 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
ItchRO/Patient 
ItchRO 
Device 
Returned 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant 
Medications  
X 
X 
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 
X 
X 
Phone 
Contact6 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
1 
Increases of 10% or more in a subject’s weight from baseline will require a dose 
adjustment, per Section 10.1. 
2 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.
 
 
3 
See Section 16.2 for detailed list of laboratory analytes. Blood samples for analysis of 
fat soluble vitamins should be drawn prior to administration of vitamin 
supplementation. 
4 
Subjects are required to fast at least 4 hrs. (only water permitted prior to collection). 
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. 
a At the indicated visits, oxalate will be part of the urinalysis. 
b During the follow-up period, twice daily completion of the eDiary (ItchRO) for 2 
consecutive weeks will be required following the Week 144, 156, 168, 180, 192, 
and 204 visits and for 4 consecutive weeks following the Week 216 clinic visit. In 
cases where the the subject no longer lives with an ItchRO observer, the 
ItchRO(Obs) will not need to be completed; however, ItchRO(Pt) will need to be 
completed by subjects aged ≥9 years of age 
c Study staff will review ItchRO diary data from the prior period and assess 
compliance. 
 
Clinic Visit 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
Page 120 
LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
Schedule of Procedures F – Long-term, Optional Treatment Period-2: Week 144 – Week 220 (Study Completion/Termination) 
Study Period 
 
Long-term, Optional Follow-up Treatment Period-2 
EOT/ET 
Visit 
EOS 
Visit 
Study Week 
148 
152 
156 
160 
164 
168 
172 
176 
180 
184 
188 
192 
196 
200 
204 
208 
212 
 
 Week 
2167 
Week 
220 
Study Day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Window  
(in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
7 
Subjects who withdraw early during the follow-up treatment period-2 should complete 
all evaluations at this visit. 
 
Phone Contact 


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16.2 
List of Laboratory Analytes 
 
CBC with Differential 
Red blood cells 
Hemoglobin 
Hematocrit 
MCV, MCH, MCHC 
Platelets 
White blood cells 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Coagulation 
Activated partial 
thromboplastin time (aPTT) 
(sec) 
Prothrombin time (PT) (sec) 
INR 
Clinical Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Phosphate 
Glucose 
Blood urea nitrogen 
(BUN) 
Creatinine 
Uric Acid 
Total bilirubin 
Direct bilirubin 
(conjugated) 
Indirect bilirubin 
(unconjugated) 
Alkaline 
phosphatase (ALP) 
AST (SGOT) 
ALT (SGPT) 
GGT 
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) 
Total lipids 
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 
1 Blood samples for the analysis of fat soluble vitamins should be drawn prior to administration of vitamin 
supplementation and approximately 4 hours after food or formula. Other biomarkers [eg, autotaxin, 
lysophosphatidic acid (LPA), FGF-19, FGF-21] may be measured. At the discretion of the Sponsor, samples 
will be collected and appropriately stored for subsequent analysis, as needed. 
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 
Itch Reported Outcome Instrument (ItchRO™) 
Many of the ALGS subjects in this study are expected to be between the ages of 12 months and 
10 years, 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 (PROM) 
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 PROM and ObsRO.  


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16.3.1 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.  
 
 
 
0 
1 
2 
3 
4 


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If the patient selects “I didn’t feel itchy at all” the morning diary is complete, if not the following 
screens will be shown on the eDiary: 
 
 
 
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.  
 
 
0 
1 
2 
3 
4 


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If the patient selects “I didn’t feel itchy” the evening diary is complete, if not the following 
screen will be shown on the eDiary: 
 


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16.3.2 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 morning 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: 
 
 
A screen shot from the ItchRO(Obs) 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(Obs) evening report score is 0 and the maximum score is 4.  
 
 
0 
1 
2 
3 
4 


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If the caregiver selects “None observed or reported” the evening 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: 
 
 
 


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16.4 
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, hemorrhage and scarring evident 


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16.5 
Clinician Xanthoma Scale 
The Clinician Xanthoma scoring scale was originally developed to assess xanthomas before and 
after surgical intervention in children with ALGS (Emerick and Whitington, 2002)  
The clinician will rate the subject’s degree of xanthomatosis according to the following scale: 
Score 
Description 
0 
None 
1 
Minimal 
2 
Moderate 
3 
Disﬁguring 
4 
Disabling 
 
In the study in which this scale was used to assess xanthomas before and after surgical 
intervention in children with ALGS, “minimal” xanthomas represented fewer than 20 scattered 
individual lesions, “moderate” represented more than 20 lesions that did not interfere with or 
limit activities, “disﬁguring” represented large numbers of lesions that by their large numbers or 
size caused distortion of the face or extremities, and “disabling” represented xanthomas that 
interfered with function (such as hand use or ability to walk) because of excess size or number. 


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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, 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.  
Quality of life will be assessed using the appropriate PedsQLTM module(s) provided below. 


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16.6.1 Parent Report for Infants (ages 1-12 months) 
 


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16.6.2 Parent Report for Infants (ages 13 to 24 months) 
 
 
 


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16.6.3 Parent Report for Toddlers (ages 2-4 years) 
 


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


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16.6.5 Parent Report for Children (ages 8-12 years) 
 


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


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


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


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


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


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


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


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


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


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


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16.6.16 Family Impact Module v 2.0 
 
 


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16.7 
Caregiver Impression of Change (CIC) 
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s perception of 
the subject’s xanthoma severity at the end of study drug treatment compared to his/her xanthoma 
severity prior to the start of treatment with study drug. The CIC will be completed by all 
caregivers at the Week 48, 60, 72, 84, and 96 visits. For subjects who enter into the long-term, 
optional follow-up treatment period, the CIC will be administered at Weeks 108, 144. Subjects 
who elect not to participate in the long-term, optional follow-up treatment period-2 (Protocol 
Amendment 6) will also have the CIC administered at Week 148 (EOS). For subjects who enter 
into the long-term, optional follow-up treatment period-2, the CIC will be administered at Weeks 
156, 168, 180, 192, 204, 216 (EOT/ET) and Week 220 (EOS). 
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 xanthoma severity since the start of the study? 
 
 
Much better (1) 
Better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Worse (6) 
Much worse (7) 


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16.8 
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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16.9 
Protocol History 
Document 
Date 
Global/Country/Site Specific 
Original Protocol 
14 Apr 2014 
 
Amendment 1 
29 Jan 2015 
Global 
Amendment 2 
12 Feb 2015 
Global 
Amendment 3 
Note: no summary of 
changes included for 
Protocol Amendment 3 as 
this protocol version was 
never operationalized. 
27 Apr 2016 
Global 
Amendment 4 
27 Apr 2016 
Global 
Amendment 5 
13 Nov 2017 
Global 
Amendment 6 
25 Jun 2018 
Global 
Amendment 6.1 
08 Feb 2019 
Global 
 


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16.9.1 
Protocol Amendment 6.1 Summary of Changes 
 
Protocol Number: 
LUM001-305 
Protocol Title: 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
6.1 
Date: 
08 February 2019 
 
The LUM001-305 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 6 (25 Jun 2018). 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. 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Section(s) Affected 
by Change 
Description of Change 
Rationale 
Cover page, Sponsor; 
Title Page, Sponsor; 
Sponsor Signature 
Page, Sponsor; 
Protocol Signature 
page, Sponsor  
Replaced Shire’s address with the new sponsor’s 
address.  
To provide new Sponsor’s 
(Mirum) address 
Title Page, Medical 
Lead and Premier 
Medical Monitor; 
Protocol Signature 
page, Sponsor 
(Mirum) Approval 
Updated the Medical Lead and add Premier medical 
monitor information. 
To provide updated and correct 
information. 
Product Quality 
Complaints 
Replaced Shire’s contact with the new sponsor’s 
contact. 
To provide new Sponsor’s 
contact information. 


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Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Schedule D 
 
Footnote added to eligibility assessment at Week 
144 
 
To clarify subjects that 
completed PA5 rolling over from 
PA5 to PA6 will be assessed for 
eligibility.  Subjects who did not 
consent to PA5 and re-enter into 
PA6 will not have eligibility re-
assessed 
Added drug dispensation at Week 144 
To claritfy for subjects entering 
PA6 
Schedule E 
Added Drug Compliance to be done at Weeks 2 and 
4 
To ensure compliance is assessed 
 


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16.9.2 Protocol Amendment 6 Summary of Changes 
 
Protocol Number: 
LUM001-305 
Protocol Title: 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
6 
Date: 
25 Jun 2018 
 
The LUM001-305 protocol is being amended to allow continued participation in the long-term 
optional follow-up treatment period-2, beyond what was previously described in Protocol 
Amendment 5. Study treatment in the long-term optional follow-up treatment period-2 will 
continue until the first of the following occurs: (i) the subjects complete 72 weeks of additional 
treatment (after Week 144 [long-term, optional follow-up treatment period]), or (ii) the subjects 
are eligible to enter another LUM001 study. 
The following changes have been made to the Protocol Amendment 6 (25 Jun 2018). 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. 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment 
Number 6 
Amendment Date 
25 Jun 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected 
by Change 
Description of Change 
Rationale 
Title Page, Medical 
Lead 
Updated phone number for Shire Medical Lead. 
To provide updated contact 
information. 
Emergency Contact 
Information, Premier 
Medical Monitor 
Updated the Premier medical monitor information. 
To provide updated and correct 
information. 
Section 1, Study 
Design; Section 5.1, 
Study Design; 
Section 5.5, Overall 
Study Duration and 
Follow-up 
Updated study design text to reflect addition of new 
long-term optional follow-up treatment period-2 of 
72 weeks. Stated that eligible subjects will remain 
on treatment until either of the following occur: (i) 
subjects complete 72 weeks of additional treatment 
(after Week 144 [long-term optional follow-up 
To extend the treatment period to 
allow continued participation in 
the study. 


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Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment 
Number 6 
Amendment Date 
25 Jun 2018 
Global/Country/Site Specific 
Global 
treatment period]), or (ii) the subjects are eligible to 
enter another LUM001 study. 
Section 7.1, Inclusion 
Criteria 
Moved inclusion criteria from Section 7.2 in 
Protocol Amendment 5 to Section 7.1 in Protocol 
Amendment 6. 
To correct misplacement of 
Protocol Amendment 5 inclusion 
criteria as these were erroneously 
included in Section 7.2 in prior 
protocol version. 
Section 1, Inclusion 
Criteria; Section 7.1, 
Inclusion Criteria 
Updated inclusion criteria for Protocol Amendment 
5 to clarify that eligible subjects either completed 
Week 96 or received permission from the sponsor 
and ChiLDReN protocol chair, not the Premier 
medical monitor. 
To clarify that permission for re-
entry into the study should come 
from the ChiLDReN protocol 
chair, not the Premier medical 
monitor. 
Section 1, Inclusion 
Criteria; Section 7.1, 
Inclusion Criteria 
Added inclusion criteria for Protocol Amendment 
6:  
1. The subject has completed the protocol through 
either Week 144, or the ET visit, or has received 
permission from the sponsor and the ChiLDReN 
protocol chair to re-enter the study in the long-
term optional follow-up period-2.  
2. Females of child-bearing potential must have a 
negative urine or serum pregnancy test (β-
human chorionic gonadotropin [β-HCG]) at the 
time of entry into the long-term optional follow-
up treatment period-2. 
3. Males and females of child-bearing potential 
who are sexually active, or are not currently 
sexually active, but become sexually active 
during the study or for 30 days following the last 
dose of study drug, must agree to use acceptable 
contraception during the study. 
4. Informed consent and assent (per IRB/EC) as 
appropriate. 
5. Caregivers (and age appropriate subjects) must 
have access to phone for scheduled calls from 
study site. 
6. Caregivers (and age appropriate subjects) must 
be willing to follow the rules of eDiary 
completion. 
To specify inclusion criteria for 
Protocol Amendment 6. 
Section 1, Exclusion 
Criteria; Section 7.2, 
Exclusion Criteria 
Exclusion Criteria: 
All exclusion criteria for the original LUM001-305 
study apply upon re-entry into the long-term 
optional follow-up treatment period-2. 
To specify exclusion criteria for 
Protocol Amendment 6. 


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Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment 
Number 6 
Amendment Date 
25 Jun 2018 
Global/Country/Site Specific 
Global 
Section 1, Study Drug 
Dosage and 
Administration; 
Section 5.5.1, 
Treatment 
Updated text to indicate that dosing will occur up to 
216 weeks of treatment. 
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 1, Study Drug 
Dosage and 
Administration; 
Section 5.5.1.5, Long-
term Optional Follow-
up Treatment Period-
2; Section 8.1.11, 
Long-term Optional 
Follow-up Treatment 
Period-2 
Added text describing enrollment of subjects into 
the long-term optional follow-up treatment period-
2. 
 
Added new sections 5.5.1.5 and 8.1.11, Long-term 
Optional Follow-up Treatment Period-2.  
 
Added text stating that subjects who choose to 
participate in the long-term optional follow-up 
treatment period-2 will be maintained at the same 
Week 144 dose level and that subjects who choose 
not to participate will be contacted by the study site 
30 days after the last dose of study drug. 
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 1, Study Visit 
Schedule and 
Procedures; 
Section 5.5, Overall 
Study Duration and 
Follow-up 
Updated text under schematic describing study 
procedures for Week 96 – Week 148 to indicate 
that subjects with dose interruptions >7 days 
between Week 96 and Week 100 should use this 
schedule to dose escalate. 
To clarify for study sites that 
subjects with dose interruptions 
>7 days between Week 96 and 
Week 100 should re-enter the 
study at PA5 RI-2 and dose 
escalate. 
Section 1, Study Visit 
Schedule and 
Procedures; 
Section 5.5, Overall 
Study Duration and 
Follow-up; 
Section 8.1.11, Long-
term Optional Follow-
up Treatment Period-
2; Section 8.1.12, End 
of Treatment or Early 
Termination Visit; 
Section 8.1.13, End of 
Study Visit 
Updated descriptions of study design text to reflect 
the addition of the long-term optional follow-up 
treatment period-2, including the addition of 2 new 
sections: 8.1.12, End of Treatment or Early 
Termination Visit; and Section 8.1.13, End of Study 
Visit.  
 
Added new text describing the study activities that 
will occur during the end of treatment (EOT)/early 
termination (ET), and end of study (EOS) visits.  
 
Added new study schematic showing study 
activities for subjects who roll over into the long-
term, optional follow-up treatment period-2. 
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 1, Drug Level 
Evaluations 
Plasma levels of LUM001 will be evaluated at 
Baseline and Weeks 2, 4, 8, 12, 24, 36, 48, 96, 144 
216 (EOT/ET) and 148 220 (EOS). 
To update the timing of PK 
sample collections, per the 
addition of the long-term 
optional treatment period-2. 
Section 1, Safety and 
Tolerability 
Evaluations 
Added text to indicate that SAEs would also be 
evaluated. 
To clarify the scope of the safety 
analysis. 


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Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment 
Number 6 
Amendment Date 
25 Jun 2018 
Global/Country/Site Specific 
Global 
Section 1, Efficacy 
Evaluations; Section 
12.2.4.1, Efficacy 
Variables 
Updated text to indicate that secondary and 
exploratory endpoints would be evaluated from 
baseline to Week 216 (EOT). 
 
Added text updating the electronic diary (ItchRO) 
requirements to reflect the addition of the long-term 
optional treatment period-2. 
 
Added text indicating that additional exploratory 
evaluations will be specified in the SAP and may 
include evaluations between Week 144 (EOT/ET) 
and Week 148 (EOS) and between Week 216 
(EOT/ET) and Week 220 (EOS) for subjects who 
complete Protocol Amendment 5 and 6, 
respectively. 
To update the scope of the 
efficacy analysis. 
 
Section 8.1.8; Long-
term Optional Follow-
up Treatment Period 
Added text indicating that dose of LUM001 may be 
increased during the dose escalation period up to 
280 µg/kg/day. 
Added text indicating that PA5 Schedule D 
Week 104 telephone contact would occur 4 weeks 
after PA5 RI Week 4 Clinic Visit. 
Added text stating that subjects rolling over into the 
long-term optional treatment period-2 will complete 
the electronic diary for additional 2 weeks 
following the Week 144 visit. 
To clarify the maximum dose 
level of LUM001. 
To clarify timing of Week 104 
telephone contact. 
To clarify requirement of 
electronic diary for subjects 
rolling over into Protocol 
Amendment 6. 
Section 8.1.9; Week 
144 
Updated section title and added text to reflect the 
potential roll-over of subjects from Protocol 
Amendment 5 to Amendment 6 and the electronic 
diary completion requirements for all subjects. 
To reflect extended treatment 
period under Protocol 
Amendment 6 and to clarify the 
electronic diary completion 
requirements. 
Section 5.5.2.2, Visit 
Schedule Following 
Dose Interruption for 
Stable Dosing and 
Safety Monitoring 
Periods 
Updated text to indicate that total LUM001 
exposure should not exceed 216 weeks. 
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 5.5.2.3, Visit 
Schedule Following 
Dose Interruption for 
Long-term, Optional 
Follow-up Treatment 
Periods 
Updated text to indicate that subjects with dose-
interruptions greater than 7 consecutive days should 
receive permission from the Sponsor and 
ChiLDReN protocol chair when following the re-
entry dose escalation schedule. 
Clarified timing of dosing interruptions. 
To clarify that permission should 
be obtained from both the 
Sponsor and ChiLDReN protocol 
chair. 
To specify timing of permitted 
dose interruptions. 


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Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment 
Number 6 
Amendment Date 
25 Jun 2018 
Global/Country/Site Specific 
Global 
Section 5.5.3, Follow-
up 
Added text indicating that for subjects who 
participate in the long-term optional follow-up 
treatment period-2, the follow-up safety phone call 
will be replaced by the Week 220 (EOS) clinic 
visit.  
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 5.6, Study 
Termination 
Updated text to indicate that subjects who 
participate in the long-term, optional, follow-up 
treatment period-2, will be considered completed if 
they participate in the Week 216 (EOT) visit. 
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 6.1, 
Enrollment 
Added text describing the assessment of eligibility 
and enrollment process for subjects rolling over 
into the long-term optional follow-up treatment 
period-2.  
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 8.2, Physical 
Examination, Weight 
and Height, Vital 
Signs; Section 8.4.1, 
Itch Reported 
Outcome (ItchRO™); 
Section 8.4.2, 
Clinician Scratch 
Scale; Section 8.4.3, 
Clinician Xanthoma 
Scale; Section 8.4.4, 
Pediatric Quality of 
Life Inventory 
(PedsQL); Section 
8.4.5, Caregiver 
Impression of Change 
Edited text to reflect additional time points for these 
assessments that will occur during the long-term 
optional follow-up treatment period-2.  
 
In section 8.4.1, ItchRO, added text: 
 
In cases where an observer can no longer 
observe the subject (eg, no longer living with the 
subject), the ItchRO(Obs) will not need to be 
completed; however, ItchRO(Pt) will need to be 
completed by subjects aged ≥9 years of age. 
To reflect the addition of the 
long-term optional treatment 
period-2. 
To update the ItchRO 
requirement to reflect the fact 
that some subjects may be living 
away from home (eg, at college); 
therefore, the daily completion of 
the ItchRO(Obs) may no longer 
be feasible. 
Section 12.2.4.3, 
Secondary, 
Exploratory and Other 
Efficacy Analyses 
Removed text: 
Change from baseline in Xanthoma scale will be 
categorized as improved, stable or worsened and 
will be compared between treatment groups using 
the chi-square test. 
P-values from the secondary and exploratory 
efficacy analyses will be interpreted as hypothesis 
generating and not definitive. 
To correct erroneous text; the chi 
square test is not relevant for this 
extension study. 
Section 16.1, 
Schedule of 
Procedures C 
Added a footnote to ItchRO assessment at Week 96 
and at follow-up visit to indicate that the electronic 
diary should be completed for 2 weeks following 
the Week 96 visit. 
To correct an oversight in the 
prior protocol amendment. 
Section 16.1, 
Schedule of 
Procedures D 
Added a new row for informed consent/eligibility 
assessment for Protocol Amendment 6 with the 
following footnote: 
1. Subjects can consent to roll over into the long-
term optional follow-up treatment period-2, per 
Schedule F. 
To reflect the addition of the 
long-term optional treatment 
period-2. 


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Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment 
Number 6 
Amendment Date 
25 Jun 2018 
Global/Country/Site Specific 
Global 
Section 16.1, 
Schedule of 
Procedures D 
Added a footnote to the EOS visit: 
9. Subjects who elect not to participate in the 
long-term, optional follow-up treatment period-2 
(Protocol Amendment 6) should return to the 
study site 30 days after the last dose of study 
drug and complete all evaluations at this visit. 
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 16.1, 
Schedule of 
Procedures E 
Updated table title to clarify that subjects who 
either previously completed up to Week 96, or has 
received permission from the sponsor and the 
ChiLDReN protocol chair (not the Premier medical 
monitor) may re-enter the study using Scheduled E. 
 
Added a footnote to the PA5 RI -2 visit: 
h. Subjects with dose interruptions prior to 
Week 96 or who early terminated may re-enter 
the study under Protocol Amendment 6. These 
subjects will initiate dose escalation at visit PA5 
RI -2.  
To reflect the addition of the 
long-term optional treatment 
period-2. 
To clarify for study sites that 
subjects with dose interruptions 
>7 days prior to Week 96 or who 
early terminated should re-enter 
the study at PA5 RI -2 and dose 
escalate. 
Section 16.1, 
Schedule of 
Procedures F 
Added Schedule of Procedures F - Long-term, 
Optional Follow-up Treatment Period-2: Week 144 
– Study Completion/Termination, applicable as 
follows: 
• 
If another study becomes available for 
subjects prior to completion of Protocol 
Amendment 6, the subject will complete 
EOT assessments as outlined for Week 216. 
• 
Subjects who complete 72 weeks of 
additional treatment and who are not 
eligible for another study will complete 
EOS assessments as outlined for Week 220. 
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 16.7; 
Caregiver Impression 
of Change (C) 
Edited text to reflect additional time points for CIC 
assessments that will occur during the long-term 
optional follow-up treatment period-2.  
To reflect the addition of the 
long-term optional treatment 
period-2. 
Section 16.9, Protocol 
History; 16.9.1, 
Protocol Amendment 
5 Summary of 
Changes  
Updated protocol history to reflect sections to 
reflect Protocol Amendments 5 and 6. 
 
Moved Protocol Amendment 5 Summary of 
Changes from beginning of protocol to Section 
16.9.1. 
To reflect Protocol Amendments 
5 and 6. 
 
 


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16.9.3 
Protocol Amendment 5 Summary of Changes 
 
Protocol Number: 
LUM001-305 
Protocol Title: 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
5 
Date: 
13 Nov 2017* 
 
*NIDDK DSMB Approval Date: 13 Nov 2017 
 
The LUM001-305 protocol is being amended to allow continued participation in the long-term 
optional follow-up treatment period, beyond what was previously described in Protocol 
Amendment 4. Study treatment in the long-term optional follow-up treatment period will 
continue until the first of the following occurs: (i) the subjects complete 48 weeks of additional 
treatment (after Week 96 [safety monitoring period]), or (ii) the subjects are eligible to enter 
another LUM001 study. 
The following changes have been made to the Protocol Amendment 5 (13 Nov 2017). 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 
Title Page, Medical 
Lead;  
Protocol 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: 
Nirav Desai, MD 
 
Shire 
 
300 Shire Way 
Lexington, MA 02451 
Phone: (781) 869-7756 
Email: nirav.desai@shire.com 
  
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. 
Section 1, Objectives; 
Section 3, Study 
Objectives 
Added new exploratory objective to evaluate the long-term effect of LUM001 on 
weight in pediatric subjects with ALGS. 
Section 1, Study Design; 
Section 5.1, Study 
Design; Section 5.5, 
Overall Study Duration 
and Follow-up 
Updated study design text to reflect addition of new long-term optional follow-up 
treatment period of 48 weeks. Stated that eligible subjects will remain on treatment 
until either of the following occur: (i) subjects complete 48 weeks of additional 
treatment (after Week 96 [safety monitoring period]), or (ii) the subjects are eligible 
to enter another LUM001 study. 
Section 1, Inclusion 
Criteria; Section 7.2, 
Inclusion Criteria 
Inclusion Criteria: 
1. The subject has completed the protocol either through Week 96, or the 
ET visit, or has received permission from the sponsor and the Premier 
Medical monitor to re-enter the study in the long-term, optional follow-
up treatment period. 
2. Female subjects of child-bearing potential must have a negative urine or 
serum pregnancy test (β-human chorionic gonadotropin [β-HCG]) at 
the time of entry into the long-term optional follow-up treatment 
period. 
3. Male and female subjects of child-bearing potential who are sexually 
active, or are not currently sexually active, but become sexually active 
during the study or for 30 days following the last dose of study drug, 
must agree to use acceptable contraception during the study. 
4. Informed consent and assent (per IRB/EC) as appropriate. 
5. Caregivers (and age appropriate subjects) must have access to phone 
for scheduled calls from study site. 
6. Caregivers (and age appropriate subjects) must be willing and able to 
use an eDiary device during the study. 
Exclusion Criteria: 


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Section 
Description of Change 
1. All exclusion criteria for the original LUM001-305 study apply upon re-
entry into the long-term, optional follow-up treatment period. 
Section 1, Treatment 
Groups 
Updated study design text to reflect addition of new long-term optional follow-up 
treatment period of 48 weeks. 
Section 1, Study Drug 
Dosage and 
Administration; 
Section 5.5.1, Treatment; 
Section 8.2, Physical 
Examination, Weight 
and Height, Vital Signs; 
Section 10.1, Study 
Drug Administration 
Updated text describing weight-based dosing adjustments to indicate that each 
subsequent 10% increase in weight will be considered the new baseline for 
determination of future dose adjustments 
 
Updated text to indicate that dosing will occur up to 144 weeks of treatment. 
Section 1, Study Drug 
Dosage and 
Administration; Section 
5.5.1.5, Long-term 
Optional Follow-up 
Treatment Period-2 
Section 8.1.11, Long-
term Optional Follow-up 
Treatment Period-2 
Added text describing enrollment of subjects into the long-term optional follow-up 
treatment period-2. 
 
Added new sections 5.5.1.5 and 8.1.11, Long-term Optional Follow-up Treatment 
Period-2 describing study activities that will occur during this treatment period.  
 
Added text stating that subjects who choose to participate in the long-term optional 
follow-up treatment period-2 will be maintained at the same Week 144 dose level and 
that subjects who choose not to participate should complete the in-clinic Week 148 
visit that will occur 30 days after the last dose of study drug. 
Section 1, Study Visit 
Schedule and 
Procedures; 
Section 8.1.8, Long-term 
Optional Follow-up 
Treatment Period; 
Section 8.1.9, Week 144; 
Section 8.1.10, Week 
148; Section 8.1.12, End 
of Treatment (EOT) or 
Early Termination (ET) 
visit; Section 8.1.13., 
End of Study Visit 
Updated descriptions of study design text to reflect the addition of the long-term 
optional follow-up treatment period-2, including updates to study activities during the 
long-term optional treatment period, Week 144/ET visit, Week 148 visit (EOS). 
Added new text describing the study activities that will occur during the long-term 
optional follow-up treatment period, the end of treatment (EOT)/early termination 
(ET), and end of study (EOS) visits.  
 
Added new study schematics showing study activities for subjects who roll over into 
the long-term, optional follow-up treatment period-2. 
 
Added new sections 8.19, End of Treatment or Early Termination Visit and 8.1.10, 
End of Study Visit. 
Section 1, Drug Level 
Evaluations 
Plasma levels of LUM001 will be evaluated at Baseline and Weeks 2, 4, 8, 12, 24, 36, 
48, 96, 144 (EOT/ET) and 148 (EOS). 
 
Section 1, Efficacy 
Evaluations; 
Section 12.2.4.1, 
Efficacy Variables 
The primary evaluation will be the mean change from baseline (Day 0) of LUM001-
301 and baseline (Day 0) of LUM001-305 baseline to Week 48 in:  
• 
Fasting serum bile acid level. 
 
Secondary evaluations will be the mean change from baseline (Day 0) of LUM001-
301 and baseline (Day 0) of LUM001-305 through baseline to Weeks 12, 48, 96 
and Week 144/ET in: 
• 
Biochemical markers of cholestasis and liver disease (eg, alanine 
aminotransferase [ALT], alkaline phosphate [ALP], gamma-
glutamyltransferase [GGT] and bilirubin [total and direct]). 
• 
Pruritus as measured by the ItchRO instruments (ItchRO(Obs)TM, caregiver 
instrument/ItchRO(Pt)TM patient instrument). 


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Section 
Description of Change 
o 
During the first 12 weeks of the study, the electronic diary (ItchRO) 
will be completed twice daily (AM & PM). During the stable 
dosing period (Weeks 13-48), twice daily completion of the 
electronic diary (ItchRO) for 4 consecutive weeks will be required 
following the Week 24 and Week 44 clinic visits. For subjects who 
continue in the safety monitoring period, twice daily completion of 
the electronic diary (ItchRO) will be required for 2 consecutive 
weeks will be required following the Week 60, 72, and 84 clinic 
visits. For subjects who continue in the long-term optional 
follow-up treatment period, twice daily completion of the 
ItchRO will be required for 2 consecutive weeks following the 
Week 96, 108, 120, and 132 clinic visits and for 4 weeks 
following the 144/ET clinic visit.  
• 
Xanthomas as measured by clinician xanthoma scale. 
• 
Clinician scratch scale 
• 
Fasting serum bile acid levels 
 
The exploratory evaluation will be the mean change in weight z-score from 
Baseline (Day 0) of LUM001-301 and baseline (Day 0) of LUM001-305 through 
Week 144/ET. 
Section 1, Statistical 
Considerations; 
Section 12.2.6.1, 
Adverse Events 
Updated safety analysis text to indicate that AEs will be summarized overall and by 
treatment group assigned in the core study (LUM001-301). 
Section 4.4.2, Previous 
Clinical Experience 
Added text describing safety and efficacy results for the completed Phase 2 
randomized, double-blind, placebo-controlled study has been completed in pediatric 
subjects from 12 months to 18 years with ALGS (LUM001-302 – IMAGO). 
Section 4.5, Rationale 
for Dose and Schedule 
of Administration 
Added reference to completed Phase 2 study LUM001-301. 
Section 5.5.2.3 Visit 
Schedule Following 
Dose Interruption for 
Long-term Optional 
Follow-up Treatment 
Period 
Added new section 5.5.2.3, Visit Schedule Following Dose Interruption for Long-
term, Optional Follow-up Treatment Period 
 
Added text and study schematic describing study procedures to be followed for 
subject with LUM001 dosing interruptions >7 consecutive days prior to entry into 
Protocol Amendment 5. 
 
Added “Dosing Interruptions: Reintegration to Study Visit Schedule during Protocol 
Amendment 5” table to show study visit assignments for subjects with LUM001 
dosing interruptions >7 consecutive days. 
Section 5.5.3, Follow-up 
Added text indicating that the 30-day safety phone call will apply for subjects who 
participate in all version of the protocol up through Protocol Amendment 4.  
Added text indicating that for subjects who participate in the long-term optional 
follow-up treatment period, this phone call will be replaced by the Week 148 (EOS) 
clinic visit.  
Section 5.6, Study 
Termination 
Updated text to indicate that a subject will be considered to have completed the study 
based on the version of the protocol they participated under. For subjects who 
participate in the long-term, optional, follow-up treatment period, they will be 
considered completed if they participate in the Week 144 (EOT) visit. 
Section 6.1, Enrollment 
Added text describing the assessment of eligibility and enrollment process for 
subjects rolling over into the long-term optional follow-up treatment period.  


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Section 
Description of Change 
Section 8.2, Physical 
Examination, Weight 
and Height, Vital Signs; 
Section 8.4.1, Itch 
Reported Outcome 
(ItchRO™); 
Section8.4.2, Clinician 
Scratch Scale; Section 
8.4.3, Clinician 
Xanthoma Scale; Section 
8.4.4, Pediatric Quality 
of Life Inventory 
(PedsQL); Section 8.4.5, 
Caregiver Impression of 
Change 
Edited text to reflect additional time points for these assessments that will occur 
during the long-term optional follow-up treatment period.  
Section 10.3, 
Concomitant 
Medications 
Added text indicating that concomitant medications should not be collected prior to 
informed consent or during gap periods when the subject is not participating in the 
study. 
Section 10.5.1, General 
Monitoring Rules 
If an individual subject exhibits a CTCAE Grade 3 treatment emergent toxicity 
laboratory abnormality, with the exception of the specific rules outlined below 
(Section 10.5) dosing will can be suspended. Continued dosing with study drug may 
be considered or continued as per the investigator’s judgment and following 
discussion with the ChiLDReN protocol chair and the Sponsor Medical Monitor. 
The Investigator and Sponsor Medical Monitor sponsor medical monitor. If 
suspended, the investigator, the ChiLDReN protocol chair, and sponsor 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.  
Section 10.5.2, Safety 
Monitoring Rules 
Of note: the INR retest should be conducted by the central laboratory, but may 
also be conducted at a local laboratory on an as needed basis. 
 
Subjects who do not meet the stopping rules based on retest may continue dosing 
and the Investigator, the ChiLDReN protocol chair, and the sponsor medical 
monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the subject is appropriate. 
 
The investigator should also assess the need to capture an AE, its severity 
according to the CTEAE directives and potential causality. These assessments 
should also include an evaluation of whether criteria for an SAE are fulfilled 
(see Section 11.2.3). 
Section 10.5.2.2, 
Stopping Rules for Liver 
Chemistry Elevations; 
Section 10.5.2.3, Safety 
Monitoring for 
Triglycerides; Section 
10.5.2.4, Safety 
Monitoring for Fat 
Soluble Vitamins 
Section 10.5.2.5, 
Monitoring/Stopping 
Rules for Coagulation 
Panel Results 
Added language indicating that all dose adjustments or drug interruptions would be 
conducted in coordination with the ChiLDReN protocol chair, in addition to the 
investigator and sponsor medical monitor.  


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Section 
Description of Change 
Section 11.3, Monitoring 
and 
Recording 
of 
Adverse Events 
In addition, AEs that occur while the subject is not enrolled in the study during 
a gap period (ie, prior to enrollment in Protocol Amendment 5) will be collected 
as medical history unless the AE started within 30 days of last dose. 
Section 11.3.1, Serious 
Adverse Events 
Updated to indicate that 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. 
Section 11.3.2, Non-
serious Adverse Events 
Updated to indicate that collection of non-serious AEs will begin after the subject 
signs the informed consent/assent form and stop 30 days after the last dose of study 
drug. 
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 ALGS may have abnormal liver enzyme 
levels at baseline. 
Section11.4.1, 
Pregnancy Reporting 
If a subject becomes pregnant or a pregnancy is suspected in either a subject or in 
the partner of a male study participant during the study… 
Section 11.4.3; 
Abnormalities of 
Laboratory Tests 
Added language indicating that all clinically significant abnormalities will be 
monitored by the investigator, sponsor medical monitor, and ChiLDReN protocol 
chair. 
Section 12.2.3.1, Subject 
Disposition 
The number and percentage of subjects enrolled, completed, and withdrawn, along 
with reasons for withdrawal, will be tabulated overall, and by treatment group when 
entering the study as well as after the dose optimization period. assigned at 
LUM001-305 study entry. 
In addition, for subjects who had dose gaps or re-initiated to all protocol 
amendments, the number of days of the off-drug period will be summarized. 
Section 12.2.6.2, 
Laboratory Tests 
Changes within a treatment group for selected safety measures will be assessed at 
Weeks 8, 12, 24, 36 and at the final study evaluation visit (Week 48) using methods 
to be specified in the SAP, 48, 96, and at additional time points during the long-
term optional follow-up treatment period. 
Section 16.1, Schedule 
of Procedures D-E 
Added Schedule of Procedures D - Long-term, Optional Follow-up Treatment Period: 
Week 96 – Study Completion/Termination for those subjects with ≤7 days from the 
last dose of LUM001 applicable as follows: 
• 
If another study becomes available for subjects prior to completion of Protocol 
Amendment 5, the subject will complete EOT assessments as outlined for 
Week 144. 
• 
Subjects who complete 48 weeks of additional treatment and who are not 
eligible for another study will complete EOS assessments as outlined for 
Week 148. 
Added Schedule of Procedures E - Long-term, Optional Treatment Period: Subject 
Re-entry under Protocol Amendment 5, applicable as follows: 
• 
Subject either previously completed the follow-up period as defined under 
Protocol Amendment 4, or has received permission from the sponsor and the 
Premier medical monitor to re-enter the study under Protocol Amendment 5 
and has subsequently experienced an interruption in LUM001 dosing >7days. 
• 
Subject is considered eligible for study re-entry under Protocol Amendment 
5. 


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16.9.4 
Protocol Amendment 4 Summary of Changes 
 
Protocol Number: 
LUM001-305 
Protocol Title: 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
4* 
Date: 
27 April 2016* 
 
*NIDDK DSMB Approval Date: 24 June 2016 
 
Note: Original NIDDK DSMB approval for Amendment 3 was obtained on 21 March 2016. 
However, following this approval, additional edits were made to correct previously unidentified 
inconsistencies within the protocol. Shire then approved the corrected version of Amendment 3 
on 27 April 2016. Because edits were made after the NIDDK DSMB approved Amendment 3, the 
revised protocol (version date 27 April 2016) was up-versioned to Amendment 4 (version date 27 
April 2016). Amendment 4 was approved by the NIDDK DSMB on 24 June2016 and by Shire on 
28 June 2016. Amendment 3 was never operationalized.  
Protocol Amendment 2 (12 February 2015) was amended to extend the duration of the study to 
100 weeks. Additional edits, as captured in the below table, were made to Protocol Amendment 
2 and Amendment 3 to improve the clarity of the protocol and/or correct minor inconsistencies. 
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 
Title page; Medical Lead  
Changed from: 
 
Sponsor Contact:  
Ciara Kennedy, PhD 
 
Lumena Pharmaceuticals, Inc. 
 
Phone: +1-858-337-7922 
 
Email: ckennedy@lumenapharma.com 
 
To:  
 
Medical Lead: 
Beatriz Caballero, MD 
 
Shire, Inc. 
 
Zahlerweg 10 
6300 Zug 
Switzerland 
 
Phone: +41(0) 41 288 42 30   
 
Email: bcaballero@shire.com 
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 
Study Synopsis; Study 
Design 
Section 5.1; Study 
Design 
Section 8.1.4; Stable 
Dosing Period 
The study is divided into 3 4parts: a dose escalation period, a dose optimization 
period, and a stable dosing period, and a safety monitoring period. Planned 
participation for each subject enrolled in the study is 48 approximately 100 
weeks (inclusive of the safety follow-up contact approximately 30 days 
after the last dose of LUM001). 
Stable Dosing Period and Safety Monitoring Periods 
Following completion of the 8-week dose optimization period, all subjects will 
enter the stable dosing period lasting 36 weeks. During the remainder of the 
study followed by a safety monitoring period lasting up to 48 weeks. During 
the stable dosing and safety monitoring periods, subjects will be dosed with 
the Week 12 dose, or the highest tolerated dose below the Week 12 dose. However, if 
a subject experiences intolerance due to gastrointestinal symptoms, the investigator, 
in consultation with the ChiLDReN protocol chair and Sponsor Medical Monitor, 
may lower the dose to a previously tolerated dose for the rest of the study. 


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Study Synopsis; 
Exclusion Criteria 
Section 7.2; Exclusion 
Criteria 
 
2. 
Any conditions or abnormalities (including laboratory abnormalities) 
which, in the opinion of the Investigator or Medical Monitor or ChiLDReN 
Protocol Chair, may compromise the safety of the subject, or interfere with the 
subject participating in or completing the study. 
Study Synopsis; Study 
Drug Dosage and 
Administration 
Section 5.5.1; Treatment 
Section 5.5.1.1; Dose 
Escalation Period 
Section 5.5.1.3; Stable 
Dosing and Safety 
Monitoring Periods 
Section 5.5.2; Dosing 
Interruptions (new 
section) 
Section 10.6; Adjustment 
of Dose 
Dosing will occur over a 48 96-week treatment period. 
 
If a subject experiences intolerance due to gastrointestinal symptoms, the investigator, 
in consultation with the ChiLDReN protocol chair and Sponsor Medical Monitor, 
may lower the dose to a previously tolerated dose for the rest of the study. 
 
Stable Dosing Period and Safety Monitoring Periods 
At the end of the Dose Optimization Period, subjects will continue dosing to complete 
48 the stable dosing and safety monitoring periods for up to 96 weeks of 
cumulative LUM001 exposure in this study.  
 
Subjects who completed the 48-week study prior to the implementation of 
Protocol Amendment #4 may be re-contacted and re-consented for participation 
in the safety monitoring period of the study. 
 
Dosing Interruptions 
 
Dose Escalation Following Dose Interruption 
 
Subjects with interruptions in LUM001 dosing of more than 7 consecutive days 
during the stable dosing or safety monitoring periods will require dose escalation 
upon re-initiation of the study drug. The dose of LUM001 will be increased at 
weekly intervals up to the subject’s previously achieved highest tolerated dose. 
Study drug for each subject will remain blinded and will be prepared by the 
unblinded central pharmacist according to the protocol’s specified dose-
escalation regimen (Table 5).  
 
Table 5: 
Dose Escalation Regimen for Re-initiation of LUM001 when 
Dosing Interruption is Greater than 7 Consecutive Days 
 
Study Week 
Week 1 
(μg/kg/day) 
Week 2 
(μg/kg/day) 
Week 3 
(μg/kg/day) 
Week 4 
(μg/kg/day) 
LUM001 
Dose 
35 
70 1 
140 1 
280 1 
1 Weekly dose escalations will end once the highest tolerated dose achieved prior to the subject’s LUM001 dosing 
interruption is reached. 
 
Visit Schedule Following Dose Interruption 
Upon re-initiation of study drug, subjects who undergo a dosing interruption of 
greater than 7 consecutive days will follow the same visit schedule and 
procedures that are specified for the Baseline Day 0 Visit (Section 8.1.1) and 
during Dose Escalation Treatment Period (Section 8.1.2). Completion of the 
ItchRO electronic diary, however, will not be required during this time. The visit 
schedule upon re-initiation of LUM001 dosing is shown in Figure 4. 
 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
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LUM001-305 Protocol Amendment 6.2 
SHP625 
13 May 2019 
 
 
 
 
Figure 4: 
Visit Schedule for Re-initiation of LUM001 Dosing When 
Dosing Interruption is Greater than 7 Consecutive Days 
 
 
 
Subjects with dosing interruptions of greater than 7 consecutive days will 
require reintegration in the study to ensure that 1) their resumed visit schedule 
aligns with the protocol, and 2) their total LUM001 exposure during the study 
does not exceed 96 weeks.  
 
If the decision to interrupt dosing occurred at the time of a Clinic Visit, the first 
visit upon dose re-initiation (“RI Day 0” in Figure 4) should be assigned to that 
same Clinic Visit. If the decision to interrupt dosing occurred between Clinic 
Visits, the first visit upon dose re-initiation (“RI Day 0”) should be assigned to 
the next Clinic Visit. Table 6 provides the assignment of the first study visit upon 
dose re-initiation based on when the dosing interruption occurred.  
 
 
Table 6: 
Dosing Interruptions: Reintegration to Study Visit Schedule 
Dosing Interruption 
Assignment of 
First Dose Re-initiation Study Visit 
Between Weeks 13 - 24 
Week 24 
Between Weeks 25 - 36 
Week 36 
Between Weeks 37 - 48 
Week 48 
Between Weeks 49 - 60 
Week 60 
Between Weeks 61 - 72 
Week 72 
Between Weeks 73 - 84 
Week 84 
 
After Week 84 
To be managed on a case-by-case basis in 
consultation with the Medical Monitor and 
ChiLDReN Protocol Chair 


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LUM001-305 Protocol Amendment 6.2 
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Study Synopsis; 
Rationale for Dose and 
Schedule Selection  
Section 4.5; Rationale for 
Dose and Schedule of 
Administration 
The dose may also be down-titrated, at the investigator’s discretion and in 
consultation with the ChiLDReN protocol chair and the Sponsor Medical 
Monitor, for subjects experiencing intolerance to a given dose. 


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LUM001-305 Protocol Amendment 6.2 
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13 May 2019 
 
 
Study Synopsis; Study 
Visit Schedule and 
Procedures 
Section 5.5; Overall 
Study Duration and 
Follow-up 
Section 8.1.4; Stable 
Dosing Period 
Section 8.1.5; Safety 
Monitoring Period (Week 
49 to Week 96)  
Section 8.1.6; 
Week 96/Study 
Termination (End of 
Study)  
Section 8.1.8; Early 
Termination 
Changed: 
For an individual subject, the study participation period will consist of a 4-week dose 
escalation period, followed by 8-weeks of dose optimization and a 36-week stable 
dosing period, and a 48-week safety monitoring period. Planned participation for 
each subject enrolled in the extension study is 48 a maximum of 100 weeks, 
inclusive of the safety follow-up contact approximately 30 days after the last dose 
of LUM001. Study activities will be conducted as described in the Schedule of 
Procedures (Section 16.1). 
Study Scheme (as described below):  
Day 0 – Week 48  
 
 
Week 49 – Week 100:  
 
 
 
Stable Dosing Treatment Period (Week 13 to Week 48):  
… However, if a subject experiences intolerance due to gastrointestinal symptoms the 
investigator, in consultation with the ChiLDReN protocol chair and Sponsor 
Medical Monitor… 
 


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With the exception of the Week 44, A additional study drug will be supplied at each 
clinic visit during the stable dosing period.  
 
Safety Monitoring Period (Week 49 to Week 96): During the safety monitoring 
period, subjects will return to the clinic every 3 months, at Weeks 60, 72, 84, and 
96.  
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. The clinician scratch scale will also be completed at each clinic 
visit and study drug compliance will be assessed. The PedsQL, Caregiver 
Impression of Change (CIC), and the Clinician Xanthoma scale will also be 
administered at Weeks 60, 72, 84, and 96. Subjects/caregivers will receive follow-
up phone calls at Weeks 52, 56, 64, 68, 76, 80, 88, 92, and 100. Concomitant 
medications and any adverse events 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 60, 72, and 84 
clinic visits. Review of electronic diary data and assessment of compliance will 
occur during scheduled telephone contacts at Week 64, 76, and 88 and during 
the Week 96 clinic visit. 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 safety 
monitoring period.  
With the exception of the Week 96 visit, additional study drug will be supplied at 
each clinic visit during the follow-up treatment period. 
Week 96 / Study Termination (End of Study): At the Week 48 96/Study Termination 
Visit, a physical exam (including collection of vital signs, height and weight 
measurements)… 
Early Termination: Any subject who withdraws from the study prior to completion of 
all treatment period clinic visits should undergo the procedures specified for the Week 
48 96/Study Termination 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 procedures specified for the Week 48 96/ Study Termination visit 
(Section 16.1). 


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13 May 2019 
 
 
Study Synopsis; Efficacy 
Evaluations 
Section 12.2.4.1; Efficacy 
Variables 
The primary evaluation for the durability of the therapeutic effect will be the mean 
change from Baseline (Day 0) to Week 48 in:  
 
Secondary evaluations for the durability of the therapeutic effect will be the mean 
change from Baseline (Day 0) to Week Weeks 48 and 96 and the change from Week 
12 to Week Weeks 48 and 96 in: 
 
For subjects who continue in the safety monitoring period, twice daily 
completion of the electronic diary (ItchRO) for 2 consecutive weeks will be 
required following the Week 60, 72, and 84 clinic visits. 
 
Secondary evaluations will be the mean change from Baseline to Week 96 and 
the change from Week 12 to Weeks 48 and 96 in serum bile acid. 
 
Additional exploration of evaluations of safety and durability of therapeutic effect, 
will be specified in the statistical analysis plan. 
Study Synopsis; 
Statistical Considerations 
Section 12; Statistical 
Considerations 
Special attention will be paid to change from baseline for those on placebo at baseline 
and to durability of effect during the first 12 weeks for those on active study drug at 
baseline and to durability during the stable dosing period for all subjects at all dose 
levels. 
Section 8.4.1; Safety 
Monitoring Period 
During the safety monitoring periods, daily completion of the diary will be 
required by subjects and caregivers only during the 2 consecutive weeks that 
follow the Week 60, Week 72, and Week 84 clinic visits. At these visits, 
subjects/caregivers will be provided with the electronic diary and re-trained on 
its use, as needed. Subjects/caregivers will be instructed to bring their electronic 
diary with them when they return for their next clinic visit. The electronic diary 
will be collected at Week 96. 
Section 8.4.2; Clinician 
Scratch Scale 
This assessment will be completed at Baseline (Day 0) and at all clinic visits 
thereafter (Weeks 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 4896).  
Section 8.4.3; Clinician 
Xanthoma Scale 
This assessment will be completed at Baseline (Day 0) and at Weeks 24, 36, 48, 60, 
72, 84, and 96).  
Section 8.4.4; Pediatric 
Quality of Life Inventory 
(PedsQL) 
In addition to the core generic PedsQL module, the multidimensional fatigue and 
family impact questionnaires will also be administered at the Baseline (Day 0) and 
Week Weeks 24, 48, 60, 72, 84, and 96 clinical visits using the age-appropriate 
module… 
Section 8.4.5; Caregiver 
Impression of Change 
Section 16.7, Caregiver 
Impression of Change 
(CIC) 
The CIC will be completed by all caregivers at the Week Weeks 48, 60, 72, 84, and 
96 visits. 
Section 10.5.2; Safety 
Monitoring Rules 
 
Stopping Rule Guidance: If any of the stopping criteria described below (refer to 
Section 10.5.1) are confirmed, the physician investigator in consultation with the 
ChiLDReN protocol chair and the Sponsor Medical Monitor or appropriately 
qualified designee(s), will permanently discontinue… 
Section 10.5.2.1; Safety 
Monitoring for Liver 
Chemistry Tests 
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 ChiLDReN protocol chair and the Sponsor Medical Monitor. 
Section 10.6; Adjustment 
of Dose 
This decision should be made in consultation with the ChiLDReN protocol chair 
and Sponsor Medical Monitor. 


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LUM001-305 Protocol Amendment 6.2 
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13 May 2019 
 
 
Section 11.3.1; 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 
form and stop at the end of the subject’s follow-up period which is defined as 
Week 52 100 or 30 days after the last dose of study drug for those subjects that 
terminate the prior to the Week 48 96 visit.  
Section 11.3.2; Non-
Serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed 
consent form and will stop at the end of the subject’s follow-up period, which is 
defined as Week 52 100. The Investigator will monitor each subject closely and 
record all observed or volunteered AEs on the Adverse Event Case Report Form.  
Section 16.1; Schedule of 
Procedures 
Added: 
Removed “ / Study termination” from title and the “follow-up” column from the 
Schedule of Procedure for the Stable Dosing Period (Week 16-Week 48). 
 
Added new Schedule of Procedures for the Safety Monitoring Period (Week 52 – 
Week 96/Study Termination.  
Overall  
Throughout the protocol, reference to evaluating durability of effect of LUM001 was 
removed to better reflect the correspondence of analyses to study objectives which 
characterize the evaluation of long-term LUM001 effects on efficacy, and which do 
not characterize these effects as “durability of effect.” 


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LUM001-305 Protocol Amendment 6.2 
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13 May 2019 
 
 
16.9.5 
Protocol Amendment 2 Summary of Changes 
Protocol Number: 
LUM001-305 
Protocol Title: 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
2 
Date: 
February 12, 2015 
 
The following changes have been made to Protocol Amendment 1: 
• The date of the document has been changed throughout to February 12, 2015. 
• The logo on the protocol’s cover page was updated to reflect the Childhood Liver Disease 
Research Network’s (ChiLDReN) current design.  
The following table provides a summary list of changes to the protocol: 
Section 
Description of Change 
Header 
Date changed to February 12, 2015 
Cover Page 
Date changed to February 12, 2015 
Sponsor Signature Page 
Date changed to February 12, 2015 
Title Page 
Date changed to February 12, 2015 
Protocol Signature Page  
Date changed to February 12, 2015 


Mirum Pharmaceuticals, Inc. 
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LUM001-305 Protocol Amendment 6.2 
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13 May 2019 
 
 
16.9.6 
Protocol Amendment 1 Summary of Changes 
Protocol Number: 
LUM001-305 
Protocol Title: 
A MULTICENTER EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
1 
Date: 
January 29, 2015 
 
The following changes have been made to the original protocol: 
The number of subjects enrolled in the study has been increased from 24 to approximately 36 to 
reflect current number of subjects planned in the LUM001-301 protocol.  
An inclusion criterion has been added indicating that eligible subjects must be able to adhere to 
local Ethics Committee or Institutional Review Board (IRB) blood volume limits for laboratory 
testing. 
The statistical section has been revised to address the statistical management of data generated 
from siblings enrolled in the study and to clarify the interpretation of p-values from secondary 
and exploratory analyses. 
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 
Number of Subjects (Synopsis, Section 5.4), 
Statistical Considerations (Section 12) 
Changed number of subjects from 24 to 
approximately 36 to reflect current number of subjects 
planned in the LUM001-301 protocol 
Inclusion Criteria (Synopsis, Section 7.1) 
Added inclusion criterion requiring the ability of 
eligible subjects to adhere to local Ethics Committee 
or Institutional Review Board (IRB) blood volume 
limits for laboratory testing 
Itch Reported Outcome (Section 8.4.4) 
Clarified that age at the screening visit will be used as 
the age for the determination of the appropriate use of 
the electronic diary for the duration of the study, 
regardless of subsequent birthdays during the study. 


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13 May 2019 
 
 
Section 
Description of Change 
Study Schedule (Section 8.1) 
Clarified that samples for the determination of fat 
soluble vitamins are not collected at Weeks 2 and 4. 
Note: Blood samples for the determination of fat-
soluble vitamins are to be collected at the following: 
Baseline, Week 8, Week 12, Week 24, Week 36 and 
at Week 48 
PedsQL (Section 8.4.4) 
Clarified that the age at the LUM001-301 baseline 
visit will be used as the age for the determination of 
the appropriate questionnaire to be used for the study. 
This same module will be used for the duration of the 
study regardless of subsequent birthdays throughout 
the study. 
LUM001 (Section 9.1.1) 
Tables 5 and 6 have been updated to reflect quantity 
of LUM001 per 1.0 mL and 0.5 mL oral solutions 
Synopsis, Statistical Considerations  
(Section 12.2.2) 
Language was added to address the statistical 
management of data generated from siblings enrolled 
in the study.  
Statistical Considerations (Section 12.2.4.3) 
Clarified that the p-values from the secondary and 
exploratory analyses will be interpreted as hypothesis 
generating and not definitive. 
Section 16.2 
Removed Serum βhCG from list of analytes. Urine 
pregnancy tests, as indicated, are performed during 
this protocol. 
All Sections, as appropriate 
Reference to a ‘core LUM001 treatment protocol’ was 
changed to the ‘LUM001-301 protocol’. Only 
subjects who completed participation in protocol 
LUM001-301 are eligible for participation in this 
study (LUM001-305). 
All Sections, as appropriate 
Sponsor name was changed from Lumena 
Pharmaceuticals, Inc. to Lumena Pharmaceuticals 
LLC 
All Sections 
Minor changes have been made to the text to improve 
the clarity of the protocol and/or correct minor 
inconsistencies and typographical errors. 
 

SAP_001.pdf: 
Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 1 of 83
Sponsor 
Mirum Pharmaceuticals, Inc.
Protocol Title:
A Multicenter Extension Study to Evaluate the Long-Term Safety 
and Durability of the Therapeutic Effect of LUM001, an Apical 
Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the 
Treatment of Cholestatic Liver Disease in Pediatric Patients with 
Alagille Syndrome
Protocol Number:
LUM001-305
Premier Research PCN:
LUME3562
Document Version:
FINAL Version 1.0
Document Date: 
09-Apr-2020


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 2 of 83
Approvals
Role
Signatures
Date (dd-Mmm-yyyy)
Biostatistician
Print Name: Jana Steinmetz
Sign Name:
Mirum
Pharmaceuticals, 
Inc.
Representatives
Print Name: Thomas Jaecklin, MD
Sign Name:
Print Name: Will Garner, PhD
Sign Name: 
Si
S gn Name:
Si
S gn Name: 
Si
S gn Nam
a e:


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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Table of Contents
Approvals........................................................................................................................................ 2 
Table of Contents............................................................................................................................ 3 
List of Tables .................................................................................................................................. 6 
1. 
Overview............................................................................................................................. 7 
2. 
Study Objectives and Endpoints......................................................................................... 8 
2.1. 
Study Objectives ........................................................................................................... 8 
2.2. 
Study Endpoints............................................................................................................ 9 
2.2.1. Safety Endpoints........................................................................................................... 9 
2.2.2. Efficacy Endpoints...................................................................................................... 10 
2.2.3. Other Endpoints .......................................................................................................... 18 
3. 
Overall Study Design and Plan......................................................................................... 18 
3.1. 
Overall Design ............................................................................................................ 18 
3.2. 
Sample Size and Power............................................................................................... 19 
3.3. 
Study Population......................................................................................................... 19 
3.4. 
Treatments Administered............................................................................................ 19 
3.4.1. Dose Escalation Period ............................................................................................... 20 
3.4.2. Dose Optimization Period........................................................................................... 20 
3.4.3. Stable Dosing and Safety Monitoring Period ............................................................. 21 
3.4.4. Long-Term Optional Follow-up Treatment Period..................................................... 22 
3.4.5. Long-Term Optional Follow-up Treatment Period-2 ................................................. 23 
3.5. 
Method of Assigning Participants to Treatment Groups ............................................ 25 
3.6. 
Blinding and Unblinding............................................................................................. 25 
3.7. 
Schedule of Procedures............................................................................................... 26 
3.7.1. Schedule of Procedures A – Baseline – Week 12....................................................... 26 
3.7.2. Schedule of Procedures B – Stable Dosing: Week 16 – Week 48.............................. 28 
3.7.3. Schedule of Procedures C – Safety Monitoring Period: Week 52 – Week 
96/Early Termination Schedule of Procedures ........................................................... 30 
3.7.4. Schedule of Procedures D – Long-term Optional Treatment Period: Week 96 –
Week 148 .................................................................................................................... 32 
3.7.5. Schedule of Procedures E – Re-entry into Long-term, Optional Treatment 
Period/Long-term, Optional Treatment Period-2........................................................ 34 
3.7.6. Schedule of Procedures F – Long-term, Optional Treatment Period-2: Week 
144 – Week 220 (Study Completion / Termination) .................................................. 36 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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4. 
Statistical Analysis and Reporting.................................................................................... 39 
4.1. 
Introduction................................................................................................................. 39 
4.2. 
Interim Analysis.......................................................................................................... 40 
4.3. 
Data Monitoring.......................................................................................................... 40 
5. 
Analysis Populations......................................................................................................... 40 
6. 
General Issues for Statistical Analysis.............................................................................. 41 
6.1. 
Statistical Definitions and Algorithms........................................................................ 41 
6.1.1. Baseline....................................................................................................................... 41 
6.1.2. Study Day.................................................................................................................... 41 
6.1.3. Adjustments for Covariates......................................................................................... 42 
6.1.4. Multiple Comparisons................................................................................................. 42 
6.1.5. Handling of Dropouts or Missing Data....................................................................... 42 
6.1.6. Investigative Sites....................................................................................................... 44 
6.1.7. Analysis Visit Windows ............................................................................................. 44 
6.1.8. Variable Definitions.................................................................................................... 48 
6.1.9. Derived Variables ....................................................................................................... 48 
6.1.10. Data Adjustments/Handling/Conventions .................................................................. 52 
7. 
Study Participants and Demographics .............................................................................. 55 
7.1. 
Disposition of Participants and Withdrawals.............................................................. 55 
7.2. 
Protocol Violations and Deviations ............................................................................ 56 
7.3. 
Demographics and Other Baseline Characteristics..................................................... 57 
7.4. 
Prior Medications........................................................................................................ 57 
7.5. 
Treatment Compliance................................................................................................ 57 
8. 
Efficacy Analysis.............................................................................................................. 58 
8.1. 
Primary Efficacy Analysis .......................................................................................... 58 
8.2. 
Secondary, Exploratory and Other Efficacy Analyses ............................................... 58 
9. 
Safety and Tolerability Analysis....................................................................................... 58 
9.1. 
Treatment Exposure.................................................................................................... 59 
9.2. 
Adverse Events ........................................................................................................... 59 
9.2.1. Adverse Events Leading to Withdrawal ..................................................................... 60 
9.2.2. Deaths and Serious Adverse Events ........................................................................... 60 
9.2.3. Adverse Events of Special Interest ............................................................................. 61 
9.3. 
Clinical Laboratory Evaluations ................................................................................. 61 
9.4. 
Physical Examination.................................................................................................. 62 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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9.5. 
Vital Signs................................................................................................................... 62 
9.6. 
Concomitant Medication............................................................................................. 62 
9.7. 
Safety Data Graphical Presentations........................................................................... 63 
10. 
Other Analysis .................................................................................................................. 63 
10.1. Pharmacokinetic Analysis........................................................................................... 63 
11. 
Changes from Planned Analysis ....................................................................................... 63 
12. 
References......................................................................................................................... 64 
13. 
Tables, Listings, and Figures ............................................................................................ 65 
13.1. Planned Table Descriptions ........................................................................................ 65 
13.2. Planned Listing Descriptions...................................................................................... 69 
13.3. Planned Figure Descriptions....................................................................................... 74 
14. 
Tables, Listings, and Listing Shells .................................................................................. 75 
14.1. Standard Layout for all Tables, Listings, and Figures................................................ 75 
Appendix 1:  Premier Research Library of Abbreviations ........................................................... 76 
Appendix 2: Listing of Safety and Efficacy Laboratory Analytes ............................................... 79 
Appendix 3: Listing Fat Soluble Vitamin Deficiency Events ...................................................... 80 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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List of Tables
Table 1: Secondary Efficacy Endpoints........................................................................................ 11 
Table 2: Analysis of Continuous Efficacy Endpoints (including Sensitivity).............................. 12 
Table 3: Categorical Analyses of Efficacy Endpoints (including Sensitivity) ............................. 14 
Table 4: Analysis Visit Windows – Primary Analysis ................................................................. 46 
Table 5: Analysis Visit Windows – Supporting Subgroup Analysis (Data Assessed after an 
Extended Drug Interruption)................................................................................................. 47 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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1.
Overview 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Mirum
Pharmaceuticals Inc. (Mirum) protocol LUM001-305, A Multicenter Extension Study to 
Evaluate the Long-Term Safety and Durability of the Therapeutic Effect of LUM001, an Apical 
Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic 
Liver Disease in Pediatric Patients with Alagille Syndrome, dated 13-May-2019
(Amendment 6.2).
The original LUM001-305 protocol, dated 14-Apr-2014, planned for a 48-week treatment period. 
This treatment period included 3 parts: a 4-week dose escalation period, at doses up to 280 
μg/kg/day; a 7-week dose optimization period where dosing may be increased or decreased to 
35, 70, 140 or 280 μg/kg/day; and a 35-week stable dosing period where participants continue to 
receive study drug according to the dose achieved in the dose-optimization period.
There have been 8 protocol amendments (PAs) to date. The summary list of changes to each of 
the protocol amendments are describe in the final amendment, Protocol Amendment 6.2. Several 
of the protocol amendments included optional long-term extensions.
Protocol Amendment 1, dated 29-Jan-2015, changed the number of participants from 24 to 36 to 
reflect the number of participants planned in the predecessor protocol, LUM001-301.
Additionally, this amendment clarified that the age at LUM001-301 baseline will be used for 
determinations of the PedsQL among other minor changes to improve the clarity of the protocol 
and/or correct minor inconsistencies and typographical errors.
Protocol Amendment 2, dated 12-Feb-2015, changed the logo on the protocol cover page to 
reflect the Childhood Liver Disease Research Network’s (ChiLDReN) current design.
Protocol Amendment 3, dated 27-Apr-2016, provided for an optional 48-week treatment period. 
At Week 48, all participants were to be assessed by the investigator to determine the participant’s 
willingness and eligibility to roll over into the 48-week (through Week 96/Early Termination 
[ET]), safety monitoring period. Amendment 3 was not operationalized as Protocol Amendment 
4 was finalized on the same day (27-Apr-2016) with additional edits to correct previously 
unidentified inconsistencies within the protocol.
Protocol Amendment 5, dated 13-Nov-2017, primarily changed the study design to allow 
participation in the long-term optional follow-up treatment period, beyond what was previously 
described in earlier amendments. After Week 96, participants are allowed to roll over into this 
additional 48-week treatment (through Week 144/ET) period.
Protocol Amendment 6, dated 25-Jun-2018, provided for an additional 72-week treatment period 
after Week 144/ET. After Week 144, participants are allowed to roll over into this 72-week 
treatment (through Week 216/End of Treatment [EOT]) period.
Protocol Amendment 6.1, dated 08-Feb-2019, was changed to reflect the new sponsorship from 
Lumena Pharmaceuticals to Mirum Pharmaceuticals, Inc. Several edits were made to clarify the 
different treatment periods for each amendment extending the study.


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The final protocol amendment, Amendment 6.2, dated 13-May-2019, had the 6.1 version 
changed to 6.2, to coincide with the data safety monitoring board (DSMB) approval date of 13-
May-2019. No changes were made to the text.
The enrollment of siblings was allowed, however, no siblings enrolled in the study. Thus, the
analysis plan does not address the handling of siblings.
A participant 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 adverse event [AE]), study drug compliance issues (e.g., 
missed consecutive doses), and dosing gaps due to being off study between protocol 
amendments. For example, a participant could complete study drug treatment through Week 48
under the original protocol before implementation of Protocol Amendment 4 that extended 
treatment through Week 96. The participant could subsequently provide informed consent under 
the amendment and be re-initiated on study drug.
Participants with a drug interruption of at least 7 days had their study drug dose re-escalated
beginning at 35 μg/kg/day. Participants were escalated up to a maximum of 280 μg/kg/day or
highest tolerated dose.
The planned analysis identified in this SAP may be included in clinical study reports (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 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 plan include the protocol and the accompanying sample 
data collection documents. Operational aspects related to collection and timing of planned 
clinical assessments are not repeated in this SAP unless relevant to the planned analysis.
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA),
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
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 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 
The objectives of this study are:
x
Evaluate the long-term safety and tolerability of MRX in pediatric participants with


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Alagille Syndrome (ALGS).
x
Evaluate the long-term effect of MRX on serum bile acid levels.
x
Evaluate the long-term effect of LUM001 on pruritus associated with ALGS
x
Explore the long-term effect of MRX on other biochemical markers of cholestasis and liver 
disease.
x
Evaluate the long-term effect of MRX on xanthomas.
x
Explore an expanded dosing range to identify the doses necessary to achieve the optimal 
benefit-to-risk ratio for this patient population.
x
Evaluate the long-term effect of MRX on weight in pediatric participants with ALGS.
2.2.
Study Endpoints 
Safety and efficacy endpoints are examined overall and for each of the 6 treatment phases:
x
Dose Escalation Period (Day 1 – Week 4),
x
Dose Optimization Period (Week 5 – Week 12),
x
Safety Dosing Period (Week 13 – Week 48), 
x
Safety Monitoring Period (Week 49 – Week 96),
x
Long-term Optional Follow-up Treatment Period (Week 97 – Week 144 [148*]),
x
Long-term Optional Follow-up Treatment Period-2 (Week 145 – Week 216; Week 220
assessments will occur 4 weeks after last dose).
* Week 148 is only completed for participants who do not wish to enter the long-term optional 
follow-up treatment period-2.
Unless otherwise specified, summaries will be provided by treatment sequence where applicable
from the LUM001-301 core study (e.g., Placebo [PBO]-MRX), and overall.
2.2.1. Safety Endpoints 
The safety endpoints for this study include the following:
x
Incidence of AEs including serious, related to study medication, leading to withdrawal, 
special interest AEs, along with AEs by severity and by relationship to study medication
x
Change from MRX baseline in clinical safety laboratory values at each clinic visit (if 
applicable).
x
Change from MRX baseline in physical examination findings and vital signs at each 
clinic visit.
x
Concomitant medication usage.


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Physical examination findings include body weight and height, along with body mass index 
(BMI). Vital signs include heart rate, respiratory rate, body temperature, and blood pressure. Z-
scores for height, weight, and BMI will be calculated. Note that the z-scores for body weight and 
height are considered as efficacy but are derived from safety variables.
Safety laboratory tests and units that will be used for reporting are listed in Appendix 2. Note 
that bilirubin (total and direct), alkaline phosphatase (ALP), GGT, alanine aminotransferase 
(ALT), and aspartate aminotransferase (AST) are considered as both safety and efficacy 
laboratory tests.
2.2.2. Efficacy Endpoints 
2.2.2.1.
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is the mean change from MRX baseline to Week 48 in 
fasting serum bile acid (sBA). 
2.2.2.2.
Secondary Endpoints
Secondary efficacy endpoints include mean change from MRX baseline through Week 216/EOT
(as well as Week 220/EOS, which occurs 4 weeks after the last dose of study medication) in:
x
Biochemical markers of cholestasis and liver disease (e.g., ALT, AST, ALP, GGT, and 
bilirubin [total and direct])
x
Pruritus as measured by the ItchRO* instruments (ItchRO[Obs]TM caregiver 
instrument/ItchRO[Pt]TM patient instrument).
x
Xanthomas as measured by clinician xanthoma scale.
x
Clinician scratch scale.
x
Fasting serum bile acid level.
* During the first 12 weeks of the study, the electronic diary (ItchRO) will be completed twice 
daily (AM & PM). During the stable dosing period (Weeks 13-48), twice daily completion of the 
electronic diary (ItchRO) for 4 consecutive weeks will be required following the Week 24 and 
Week 44 clinic visits. For participants who continue in the safety monitoring period, twice daily 
completion of the ItchRO will be required for 2 consecutive weeks following the Week 60, 72, 
and 84 clinic visits. For participants who continue in the long-term, optional follow-up treatment 
period, twice daily completion of the ItchRO will be required for 2 consecutive weeks following 
the Week 96, 108, 120, and 132 clinic visits, and for 4 weeks following the Week 144 visit. For 
participants who continue in the long-term optional follow-up treatment period-2, twice daily 
completion of the ItchRO will be required for 2 consecutive weeks following the Week 144, 156, 
168, 180, 192, 204 clinic visits, and for 4 weeks following the Week 216 visit.
For the secondary ItchRO endpoint, only the weekly average morning severity score will be 
summarized.
The secondary efficacy endpoints for this study are summarized in Table 1.


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Table 1: Secondary Efficacy Endpoints
Efficacy
Parameter(s)
Variable(s)
Mean Change
From MRX BL*
Week
Through Week
(LUM001-305)
ItchRO(Obs)
Weekly average morning severity 
score
0
220/EOS
sBA
Laboratory test level
0
220/EOS
Liver enzymes
(ALP, AST, ALT, GGT, 
total bilirubin, direct 
bilirubin)
Laboratory test level
0
220/EOS
Clinician xanthoma scale
5-point scale
0
220/EOS
Clinician scratch scale
5-point scale
0
220/EOS
* The observation obtained at first dose of MRX (either in LUM001-301 or in LUM001-305)
2.2.2.3.
Additional Efficacy Endpoints
The following additional efficacy evaluations will be assessed from Change from baseline (Day 
0) of LUM001-301 and baseline (Day 0) of LUM001-305 through Week 220/EOS:
x
Pediatric Quality of Life Inventory (PedsQLTM), including 4 domains: Physical 
Functioning, Emotional Functioning, Social Functioning, and School Functioning. In 
addition to these 4 domains, a total score will also be calculated. PedsQL is collected both 
for child and parent and will be summarized accordingly.
x
Caregiver Impression of Change (CIC)
2.2.2.4.
Sensitivity Endpoints
All efficacy endpoints for this study are described in


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Table 2 and Table 3 for continuous and categorical endpoints, respectively. Note that data for 
participants who early terminated from the study prior to Week 216 or are otherwise missing 
Week 48, Week 96, Week 144, and/or Week 216 data will be imputed in a last-observation-
carried-forward (LOCF) sensitivity analysis approach (see Section 6.1.5.2).


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Table 2: Analysis of Continuous Efficacy Endpoints (including Sensitivity)
Efficacy
Parameter(s)
Variable(s)
Mean Change
From MRX BL** Week
Through Week
(LUM001-305)
ItchRO(Obs)
Weekly average 
morning severity 
score
0
2, 4, 8, 12, 28, 46, 46/LOCF, 
62, 74, 86, 98, 98/LOCF, 
110, 122, 134, 146^, 
146/LOCF, 158, 170, 182, 
194, 206, 218, 218/LOCF^
sBA
Laboratory test level
0
2, 4, 8, 12, 16, 24, 36, 48^,
48/LOCF, 60, 72, 84, 96, 
96/LOCF, 108, 120, 132, 
144^, 144/LOCF, 148*, 156, 
168, 180, 192, 204, 216^,
216/LOCF, and 220/EOS^
Liver enzymes
(ALP, ALT, GGT, 
AST, total bilirubin, 
direct bilirubin)
Laboratory test level
0
2, 4, 8, 12, 16, 24, 36, 48, 
48/LOCF, 60, 72, 84, 96, 
96/LOCF, 108, 120, 132, 
144, 144/LOCF, 148*, 156, 
168, 180, 192, 204, 216^,
216/LOCF, and 220/EOS
Lipid panel and 
cholestasis biomarkers
(cholesterol, LDL-C, 
C4)
Laboratory test level
0
2, 4, 8, 12, 16, 24, 36, 48, 
48/LOCF, 60, 72, 84, 96, 
96/LOCF, 108, 120, 132, 
144^, 144/LOCF, 148*, 156, 
168, 180, 192, 204, 216^,
216/LOCF, and 220/EOS^
Clinician Scratch 
Score (CSS)
Score
0
2, 4, 8, 12, 24, 36, 48, 
48/LOCF, 60, 72, 84, 96, 
96/LOCF, 108, 120, 132, 
144, 144/LOCF, 148*, 156, 
168, 180, 192, 204, 216^,
216/LOCF, and 220/EOS
Clinician Xanthoma 
Scale
Score
0
24, 36, 48, 48/LOCF, 60, 72, 
84, 96, 96/LOCF, 108, 120, 
132, 144, 144/LOCF, 148*, 
156, 168, 180, 192, 204, 
216^, 216/LOCF, and 
220/EOS


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PedsQL
Total Scale Score 
(Parent);
Multidimensional 
Fatigue Scale Score 
(Parent);
Family Impact Total 
Scale Score;
Psychosocial Health 
Summary Score 
(Parent);
Total Scale Score 
(Child);
Multidimensional 
Fatigue Scale Score 
(Child)
0
24, 48, 48/LOCF, 60, 72, 84, 
96, 96/LOCF, 108, 144, 
144/LOCF, 148*, 156, 216, 
216/LOCF, and 220/EOS
Caregiver Impression 
of Change - Xanthoma 
Severity (CIC-Xan)
Score
--
Summary statistics at Week: 
48, 48/LOCF, 60, 72, 84, 96,
96/LOCF, 108, 144, 
144/LOCF, 148* 156, 216, 
216/LOCF, and 220/EOS
Height and Weight 
z-Score
Z-Score
0
2, 4, 8, 12, 16, 24, 36, 48, 
48/LOCF, 60, 72, 84, 96, 
96/LOCF, 108, 120, 132, 
144, 144/LOCF, 148*, 156, 
168, 180, 192, 204, 216^, 
216/LOCF, and 220/EOS
* Applicable to only participants who elect not to participate in the long-term, optional follow-up treatment period-2.
^ Indicates endpoint defined as primary, secondary, or exploratory evaluation.
** The observation obtained at first dose of MRX (either in LUM001-301 or in LUM001-305)


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Table 3: Categorical Analyses of Efficacy Endpoints (including Sensitivity)
Efficacy
Parameter(s)
Scale and Responder Criteria
or Variables
Endpoint
Clinician Scratch Score (CSS)
5-point scale:
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
Change from MRX BL** from 
LUM001-305 at Week:
2, 4, 8, 12, 24, 36, 48, 
48/LOCF, 60, 72, 84, 96, 
96/LOCF, 108, 120, 132, 144, 
144/LOCF, 148*, 156, 168, 
180, 192, 204, 216, 216/LOCF, 
and 220/EOS
Clinician Xanthoma Scale
Improved, Stable, or Worsened
Number and % of subjects at 
Week:
24, 36, 48, 48/LOCF, 60, 72, 
84, 96, 96/LOCF, 108, 120, 
132, 144/LOCF, 148*, 156, 
168, 180, 192, 204, 216, 
216/LOCF, and 220/EOS
* Applicable to only participants who elect not to participate in the long-term, optional follow-up treatment period-2.
^ Indicates endpoint defined as primary, secondary, or exploratory evaluation.
** The observation obtained at first dose of MRX (either in LUM001-301 or in LUM001-305)
2.2.2.5.
Efficacy Parameter Descriptions
Itch Reported Outcome (ItchRO)
The primary assessment of pruritus will be the pruritus severity as assessed using the Itch 
caregiver reported outcome measure (ItchRO[Obs]TM) administered as a twice daily electronic 
diary. 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 


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of their caregiver: ItchRO(Pt). Participants and caregivers will be trained on the use of the 
electronic diary during their participation in LUM001-301 protocol. There is no ItchRO(Pt)
report for participants under the age of 5 years.
Age at screening in the LUM001-301 study will be used as the age for the determination of the 
appropriate ItchRO instrument to be used for the study and this same instrument will be used for 
the duration of the study (regardless of subsequent birthdays after the screening visit).
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. The itch score from the ItchRO(Pt) will not be 
analyzed.
For the ItchRO instrument, the caregiver and/or participant indicate the itch severity (Item 1) in
the morning and in the evening each day during the following periods:
x
Screening through first 12 weeks during the dose escalation and dose optimization 
periods.
x
4 consecutive weeks that follow the Week 24 and Week 44 clinic visits during the 
stable dosing period.
x
2 consecutive weeks that follow the Week 60, Week 72, and Week 84 clinic visits 
during the safety monitoring period.
x
2 consecutive weeks that follow the Week 96, Week 108, Week 120, Week 132 clinic 
visits during the long-term optional follow-up treatment period.
x
2 consecutive weeks that follow each visit in the long-term optional follow-up
treatment period-2; Week 144, Week 156, Week 168, Week 180, Week 192, and 
Week 204.
x
4 consecutive weeks that follow the Week 216 clinic visit.
Completion of the ItchRO instrument occurs as outlined in the Schedule of Procedures in 
Section 3.7. For the ItchRO(Obs) instrument, caregivers also indicate the frequency of itch 
(Item 3).
Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score 
of 4, with 4 representing more severe (Item 1) or more frequent (Item 3) itching. The weekly 
average morning severity score from ItchRO(Obs) is calculated and used in the analysis of 
pruritus.
The weekly average morning severity scores are calculated as the average of the morning scores 
over a defined study week consisting of the 7 days before the scheduled clinic visit (for Baseline 
[Day 0], Weeks 2, 4, 8, and 12) or a 7-day period starting the week after the scheduled clinic 
visit (for Weeks 24, 44, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, and 216).
For the change from baseline calculations in weekly average ItchRO scores, baseline is defined 
in Section 6.1.1. 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.
In deriving weekly average morning severity post-baseline ItchRO score, each visit date will be 


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determined based on the varying eDiary collection periods (as applicable):
A. Weeks 2, 4, 8, and 12:  The scheduled visit date is used.
B. Weeks 26, 46, 62, 74, 86, 98, 110, 122, 134, 146, 158, 170, 182, 194, 206, and 218:
Each scheduled visit date will be determined based on the date of the associated 
scheduled clinic visit (i.e., Weeks 24, 44, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 
180, 192, 204, and 216) 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 
participant 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 Score
The CSS provides an assessment of itch severity. The clinician’s assessment of the participant’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 score uses a 5-point scale, in which 0 designates 
no evidence of scratching, and 4 designates cutaneous mutilation with bleeding, haemorrhage 
and scarring (see Table 3 for complete scale descriptions).
Clinician Xanthoma Scale
The clinician’s assessment of the participant’s xanthomatosis is focused on the number of lesions 
present and the degree to which the participant’s lesions interfere or limit his or her activities.
The clinician xanthoma score uses a 5-point scale, in which 0 represents no evidence of 
xanthomatosis (none), 1 represents fewer than 20 scattered individual lesions (minimal),
2 represents more than 20 lesions that do not interfere with or limit activities (moderate),
3 represents large numbers of lesions that by their large numbers or size cause distortion of the 
face or extremities (disfiguring), and 4 represents xanthomas that interfere with function (such as 
hand use or ability to walk) because of excess size or number (disabling).
Caregiver Impression of Change – Xanthoma Severity (CIC-Xan)
The CIC-Xan is designed to assess the caregiver’s perception of the participant’s xanthoma 
severity after various points of study drug treatment compared to his/her xanthoma severity prior 
to 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.
Pediatric Quality of Life (PedsQL)
The PedsQL13 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 
participants and/or caregivers depending on age using age-appropriate PedsQL modules. The 


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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 in the LUM001-301 study 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) participant 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 participant
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 participant 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.
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.
The scoring algorithms for the PedsQL summary and total scores are presented in Section
.


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2.2.3. Other Endpoints 
Other endpoints of this study include the following:
x
Plasma levels of maralixibat at baseline (pre-dose) and over time.
Pharmacokinetics
Due to poor absorption of maralixibat, very low systemic exposure and plasma drug levels are 
expected. Pharmacokinetic blood samples are collected at baseline and then approximately 4 
hours post-dosing at one additional time point – at Week 2, 8, 12, 24, 36, 48, 96, 144, 148, 216, 
and 220/EOS as selected by the site/investigator.
3.
Overall Study Design and Plan 
3.1.
Overall Design 
This is a multicenter, double-blind study of MRX in children >12 months of age diagnosed with 
ALGS who have completed participation in the LUM001-301 protocol. While all participants
received maralixibat, the investigator, participants and sponsor were blinded to maralixibat dose.  
The study is divided into 6 parts: 
•
Dose Escalation Period (Day 1 – Week 4),
•
Dose Optimization Period (Week 5 – Week 12),
•
Safety Dosing Period (Week 13 – Week 48), 
•
Safety Monitoring Period (Week 49 – Week 96),
•
Long-term Optional Follow-up Treatment Period (Week 97 – Week 144 [148*]),
•
Long-term Optional Follow-up Treatment Period-2 (Week 145 – Week 220).
* Week 148 is only completed for participants who do not wish to enter the long-term optional 
follow-up treatment period-2.
For participants randomized to placebo in the LUM001-301 protocol, or those who complete the 
core study more than 7 days prior to enrollment into this study, the MRX dose during the first 4
weeks of the study will be increased at weekly intervals to 140 μg/kg/day. For participants who 
were randomized to receive active drug in the LUM001-301 protocol, MRX doses will remain 
the same as the dose being taken at Week 13 in the core study. Following the dose escalation 
period, the MRX dose for each participant may be increased or decreased by the investigator. 
Dose optimization will occur in a blinded, titrated manner with four dose levels available as 
treatment options: 35, 70, 140, or 280 μg/kg/day. 
At the end of the optimization period, participants will continue dosing to complete the stable 
dosing and safety monitoring periods at their current dose level. If at any time a participant
experience intolerance due to gastrointestinal (GI) symptoms, the physician investigator may 
lower the dose to a previously tolerated dose.
Following the safety monitoring period, two sequential long-term optional follow-up periods will 
be available to participants willing and eligible to roll over. Participant’s dose of MRX will 


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remain the same as administered at the end of the safety monitoring period. Any participant with
dose interruptions >7 consecutive days due to a protocol amendment will be require dose 
escalation upon resumption of study drug.
Figure 1 depicts an overview of the treatment regimens across the study duration.
Figure 1: Treatment Regimens
* Participants who received MRX in LUM001-301 have their total planned treatment weeks of 
MRX in parenthesis.
3.2.
Sample Size and Power 
Approximately 36 participants meeting the study’s inclusion and exclusion criteria will be 
enrolled in the study. The number of participants enrolled in this study will be determined by the
number of participants who roll-over from the LUM001-301 protocol. Because this is an 
extension study for the LUM001-301 protocol, the sample size is not based on statistical 
considerations.
3.3.
Study Population 
The study population is males and females, between the ages of 12 months and 18 years
(inclusive), diagnosed with ALGS.
3.4.
Treatments Administered 
All participants receive MRX, up to 280 μg/kg/day or a maximum daily dose of 20 mg/day, 
during the initial original protocol planned length of 48 weeks. After completion of 48 weeks of 
treatment participants enter the safety monitoring period for another 48 weeks.
Participants were then given the option to enroll in the optional long-term follow-up period of 48 
additional treatment weeks, if eligible, receiving up to 280 μg/kg/day or a maximum daily dose 
of 20 mg/day of MRX.
A second optional long-term follow-up period was then offered for eligible participants for an 
additional 72 weeks of treatment of MRX receiving up to 280 μg/kg/day or a maximum daily 
dose of 20 mg/day of MRX.
During the study, the study drug may be adjusted if there is a change of ≥10% in body weight 
since the screening visit or if there is a change of ≥10% in weight since the last weight-based 
medication adjustment to maintain the target dose.


Statistical Analysis Plan
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3.4.1. Dose Escalation Period 
Initially, all participants entering the extension study will participate in a 4-week double-blind 
dose escalation period during which:
x
Participants randomized to receive placebo during the LUM001-301 protocol will receive 
weekly dose increases of MRX up to a target dose of 140 μg/kg/day.
x
Participants randomized to active drug during the LUM001-301 protocol will continue to 
receive the dose of MRX that they were taking at Week 13 of the LUM001-301 study. 
The MRX doses for these participants will remain blinded and will not be altered during 
the dose-escalation period.
A minimum period of 7 days must elapse between increases in dose.
3.4.2. Dose Optimization Period 
Following completion of the 4-week dose escalation period, participants will enter an 8 week 
dose-optimization period. During this period, the investigator will have the option to adjust MRX
dosing with the objective of achieving optimal control of pruritus at a dose level that is tolerated 
by the participant and up to a maximum daily dose of 280 μg/kg MRX or 20 mg total dose. 
Study drug dose will be increased or decreased in a double-blind manner. Increases in dose will 
be based on effect on pruritus. Reductions in dose will be based on tolerability. At the 
investigator’s discretion, the doses for participants who were previously reduced may be re 
challenged during the dose optimization period. Each participant will receive one of the 
following dose levels: 
x
MRX 35 μg/kg/day.
x
MRX 70 μg/kg/day.
x
MRX 140 μg/kg/day.
x
MRX 280 μg/kg/day.
A minimum period of 7 days must elapse between increases in dose (see Figure 2).


Statistical Analysis Plan
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Figure 2:  Study Design for Day 0 – Week 48
3.4.3. Stable Dosing and Safety Monitoring Period 
Following completion of the 8-week dose optimization period, all participants will enter the 
stable dosing period lasting 36 weeks followed by a safety monitoring period lasting up to 48 
weeks. During the stable dosing and safety monitoring periods, participants will be dosed with 
the Week 12 dose, or the highest tolerated dose below the Week 12 dose. However, if a 
participant experiences intolerance due to gastrointestinal symptoms, the investigator, in 
consultation with the ChiLDReN protocol chair and Medical Monitor, may lower the dose to a 
previously tolerated dose for the rest of the study (see Figure 2 and Figure 3).
Participants with dosing interruptions of greater than 7 consecutive days will require re-
integration in the study to ensure that 1) their resumed visit schedule aligns with the protocol, 
and 2) their total MRX exposure during the study does not exceed 216 weeks (see Figure 6).


Statistical Analysis Plan
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Figure 3: Study Design for Week 49 – Week 96
3.4.4. Long-Term Optional Follow-up Treatment Period 
The long-term optional follow-up treatment period is for eligible participants who choose to 
remain on treatment with MRX following the initial 96 weeks of treatment. During this long-
term optional follow-up treatment period, participants with MRX dosing interruptions ≤7 days 
will remain on the same dose they were taking at Week 96. Participants with MRX dosing 
interruptions >7 consecutive days will require dose escalation upon resumption of study drug. 
The dose of MRX will be increased at weekly intervals up to the participant’s previously 
achieved highest tolerated dose. Study drug for each participant will remain blinded and will be 
prepared by the unblinded central pharmacist according to the protocol’s specified dose-
escalation regimen (see Figure 4).


Statistical Analysis Plan
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Figure 4: Study Design for Week 96 – Week 148
3.4.5. Long-Term Optional Follow-up Treatment Period-2 
The long-term optional follow-up treatment period-2 is for eligible participants who choose to 
remain on treatment with MRX for an additional 72 weeks. During this long-term optional 
follow-up treatment period-2, participants will remain on the same dose they were taking at 
Week 144. Study drug for each participant will remain blinded and will be prepared by the 
unblinded central pharmacist according to the protocol’s specified dose-escalation regimen (see
Figure 5).


Statistical Analysis Plan
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Figure 5: Study Design for Week 144 – Week 220
Figure 6:  Study Design for Re-initiation of MRX when Dosing Interruption is Greater 
than 7 Consecutive Days


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3.5.
Method of Assigning Participants to Treatment Groups 
This trial is an open-label extension of LUM001-301, and all participants will receive MRX at 
various dose regimens.
3.6.
Blinding and Unblinding 
Although all participants are treated with MRX, dose optimization will occur in a blinded, 
titrated manner. This regimen will represent a real dose escalation for participants previously 
randomized to placebo and a mock dose escalation for participants previously randomized to 
active study treatment in the LUM001-301 core study.
If in the event of an emergency situation when knowledge of the treatment assignment during the 
double-blind, randomized drug withdrawal period will impact the clinical management of the 
participant, the investigator will have the ability to unblind the treatment assignment for that 
participant. If a participant is unblinded by the investigator, the sponsor must be informed of the 
unblinding within 24 hours. If the blinding is prematurely broken, it is the responsibility of the 
investigator to promptly document and explain any unblinding to the sponsor.
Breaking of the blind should not occur except in the event of a medical emergency where the 
identity of the drug must be known in order to properly treat the participant, or when causality 
must be determined prior to submitting a regulatory safety report for a SAE as defined in the
protocol.
Any unblinding event carried out in connection with submission of a regulatory safety report will 
be conducted by the sponsor as described in the protocol.
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Schedule of Procedures, Section 3.7) before unblinding, as knowledge of the 
treatment arm could influence participant assessment.
An administrative letter (dated 21-Nov-2019) has been accepted by all sites that allows for 
unblinding of subjects’ doses from LUM001-301, as that database has now locked.


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3.7.
Schedule of Procedures 
A detailed schedule of procedures for the study is provided in the below tables. Any references to “Section X.X” in the footnotes in this 
section are referring to the relevant section in the protocol.
3.7.1. Schedule of Procedures A – Baseline – Week 12 
Study Period 
Baseline 
Treatment Period 
Dose Escalationc 
Dose Optimization 
Study Week 
1 
2 
3 
4 
6 
8 
10 
12 
Study Day 
Day 01 
7 
14 
21 
28 
42 
56 
70 
84 
Window (in days) 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
Informed Consent
X
Eligibility Assessment / Medical History
X
Physical Exam
X
Body Weight & Height
X
X
X
X
X
Vital Signs2
X
X
X
X
X
CBC with Differential3
X
X
X
X
X
Coagulation3
X
X
X
X
X
Chemistry Panel3
X
X
X
X
X
Lipid Panel3,4
X
X
X
X
X
Cholestasis Biomarkers3,4
X
X
X
X
X
Fat Soluble Vitamins3,4
X
X
X
Plasma Sample for LUM001d
X
X
X
X
X
Urinalysis3
Xa
Xa
Xa
X
X
Urine Pregnancy Test 5
X
X
X
X
X
Participant eDiary / Caregiver eDiary (ItchRO)
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Xb
Clinician Scratch Scale
X
X
X
X
X
Clinician Xanthoma Scale
X
PedsQL
X
Enrollment
X
Study Drug Supplied
X
X
X
X
X
Assess Study Drug Compliance
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


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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Adverse Events
X
X
X
X
X
X
X
X
X
Phone Contact6
X
X
X
X


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3.7.2. Schedule of Procedures B – Stable Dosing: Week 16 – Week 48 
Study Period
Treatment Period (cont’d)
Stable Dosing
Study Week
166
20
24
28
32
36
40
44
Week 48
Study Day
112
140
168
196
224
252
280
308
336
Window (in days)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
Physical Exam
X6
X
X
X
Body Weight & Height
X6
X
X
X
Vital Signs1
X6
X
X
X
CBC with Differential2
X6
X
X
X
Coagulation2
X6
X
X
X
Chemistry Panel2
X6
X
X
X
Lipid Panel2,3
X6
X
X
X
Cholestasis Biomarkers2,3
X6
X
X
X
Fat Soluble Vitamins2,3
X
X
X
Plasma Sample for LUM001c
X
X
X
Urinalysis2
X6
X
X
Xa
Urine Pregnancy Test 4
X6
X
X
X
Clinician Scratch Scale
X
X
X
Clinician Xanthoma Scale
X
X
X
Subject eDiary/Caregiver eDiary 
(ItchRO)
Xb
Xb
to Week 28
Xb
Xb
to Week 48
PedsQL
X
X
Caregiver Impression of Change 
(CIC)
X
Study Drug Supplied
X
X
X
Assess Study Drug Compliance
X
X
X
X
Review Study Diaries & Assess 
Compliance
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
Phone Contact5
X
X
X
X
X


Statistical Analysis Plan
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Protocol Number LUM001-305
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Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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3.7.3. Schedule of Procedures C – Safety Monitoring Period: Week 52 – Week 96/Early Termination Schedule of Procedures 
Study Period
Treatment Period (cont’d)
Study Termination
Follow-Up
Safety Monitoring Period
Study Week
52
56
60
64
68
72
76
80
84
88
92
Week 96
(or Early Term7)
30 days after 
final dose8
Study Day
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
Window (in days)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±5)
Informed Consent /
Eligibility Assessment 
for PA51
X
Physical Exam
X
X
X
X
Body Weight & Height
X
X
X
X
Vital Signs2
X
X
X
X
CBC with Differential3
X
X
X
X
Coagulation3
X
X
X
X
Chemistry Panel3
X
X
X
X
Lipid Panel3,4
X
X
X
X
Cholestasis 
Biomarkers3,4
X
X
X
X
Fat Soluble Vitamins3,4
X
X
X
X
Plasma Sample for
LUM001
X
Urinalysis3
X
X
X
Xa
Urine Pregnancy Test5
X
X
X
X
Clinician Scratch Scale
X
X
X
X
Clinician Xanthoma 
Scale
X
X
X
X
Subject 
eDiary/Caregiver eDiary 
(ItchRO)
Xb
Xb
to 
Week 
62
Xb
Xb
to 
Week 
74
Xb
Xb
to 
Week 
86
Xb
Xb
to Week 98
PedsQL
X
X
X
X
Caregiver Impression of
Change (CIC)
X
X
X
X
Study Drug Supplied
X
X
X
X
Assess Study Drug 
Compliance
X
X
X
X
Review Study Diaries &
Assess Compliance
Xc
Xc
Xc
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone Contact6
X
X
X
X
X
X
X
X
X


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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3.7.4. Schedule of Procedures D – Long-term Optional Treatment Period: Week 96 – Week 148 
Study Period
Treatment Period (cont’d)
EOT Visit/ET
EOS Visit9
Long-term, Optional Follow-up Treatment Period
Study Week
100
104
108
112
116
120
124
128
132
136
140
Week 1448
Week 148
Study Day
700 
728 
756 
784 
812 
840 
868 
896 
924 
952 
980 
1008 
Window (in days)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±5)
Informed Consent / 
Eligibility Assessment
for PA61,10
X
Physical Exam
X
X
X
X
X
Body Weight2 & Height
X
X
X
X
X
Vital Signs3
X
X
X
X
X
CBC with Differential4
X
X
X
X
X
Coagulation4
X
X
X
X
X
Chemistry Panel4
X
X
X
X
X
Lipid Panel4,5
X
X
X
X
X
Cholestasis 
Biomarkers4,5
X
X
X
X
X
Fat Soluble Vitamins4,5
X
X
X
X
X
Plasma Sample for 
LUM001
X
X
Urinalysis4
X
X
X
Xa
Xa
Urine Pregnancy Test6
X
X
X
X
X
Clinician Scratch Scale
X
X
X
X
X
Clinician Xanthoma 
Scale
X
X
X
X
X
Subject 
eDiary/Caregiver eDiary 
(ItchRO)
Xb
to
Week 
98
Xb
Xb
to
Week 
110
Xb
Xb
to
Week 
122
Xb
Xb
to
Week 
134
Xb
Xb
to Week 148
PedsQL
X
X
X
Caregiver Impression of 
Change (CIC)
X
X
X


Statistical Analysis Plan
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Protocol Number LUM001-305
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Study Period
Treatment Period (cont’d)
EOT Visit/ET
EOS Visit9
Long-term, Optional Follow-up Treatment Period
Study Week
100
104
108
112
116
120
124
128
132
136
140
Week 1448
Week 148
Study Day
700 
728 
756 
784 
812 
840 
868 
896 
924 
952 
980 
1008 
Window (in days)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±5)
Study Drug Supplied
X
X
X
X11
Assess Study Drug
Compliance
X
X
X
X
Review Study Diaries &
Assess Compliance
Xc
Xc
Xc
Xc
Xc
Xc
Concomitant
Medications
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
Phone Contact7
X
X
X
X
X
X
X
X


Statistical Analysis Plan
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Protocol Number LUM001-305
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3.7.5. Schedule of Procedures E – Re-entry into Long-term, Optional Treatment Period/Long-term, Optional Treatment Period-2 
Study Period
Dose Escalation Treatment Period
PA5 DE Study 
Week
PA5 
RI -2h
PA5
RI
Day 0
PA5
RI
Week 1
PA5
RI
Week 2
PA5
RI
Week 3
PA5
RI
Week 4
PA5
Schedule D - Week 
104
Scheduling 
Considerations
0
Window (in 
days)
(±14)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
Informed
Consent/Assent
X
Assess Eligibility
for study re-entry
X
X
Physical Exam
X
X
X
X
Body Weight &
Height
X
X
X
X
Vital Signsa
X
X
X
X
CBC with 
Differentialb
X
X
X
X
Coagulationb
X
X
X
X
Chemistry Panelb
X
X
X
X
Lipid Panelb,c
X
X
X
Cholestasis 
Biomarkersb,c
X
X
X
Fat Soluble 
Vitaminsb,c,d
X
X
X
Urinalysisb
X
X
X
Serum Pregnancy 
Test (if 
indicated)e
X
X
X
X
Clinician Scratch 
Scale
X
X
X
Clinician 
Xanthoma Scale
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
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Study Period
Dose Escalation Treatment Period
PA5 DE Study 
Week
PA5 
RI -2h
PA5
RI
Day 0
PA5
RI
Week 1
PA5
RI
Week 2
PA5
RI
Week 3
PA5
RI
Week 4
PA5
Schedule D - Week 
104
Scheduling
Considerations
0
Window (in 
days)
(±14)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
Caregiver 
ItchRO/ 
Patient ItchRO
X
(collected for 2-week
period following this 
visit)
PedsQL
X
Study Drug 
Suppliedf
X
X
X
Caregiver 
ItchRO/ 
Patient ItchRO
Device Supplied
X
Assess Study 
Drug Compliance
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
Follow-up Phone
Contactg
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
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3.7.6. Schedule of Procedures F – Long-term, Optional Treatment Period-2: Week 144 – Week 220 (Study Completion / 
Termination) 
Study Period
Long-term, Optional Follow-up Treatment Period-2
EOT/ET
Visit
EOS
Visit
Study Week
148
152
156
160
164
168
172
176
180
184
188
192
196
200
204
208
212
Week 
2167
Week 
220
Study Day
Window 
(in days)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±5)
Physical Exam
X
X
X
X
X
X
X
Body Weight1
& Height
X
X
X
X
X
X
X
Vital Signs2
X
X
X
X
X
X
X
CBC with 
Differential3
X
X
X
X
X
X
X
Coagulation3
X
X
X
X
X
X
X
Chemistry
Panel3
X
X
X
X
X
X
X
Lipid Panel3,4
X
X
X
X
X
X
X
Cholestasis
Biomarkers3,4
X
X
X
X
X
X
X
Fat Soluble 
Vitamins3,4
X
X
X
X
X
X
X
Plasma 
Sample for
LUM001
X
X
Urinalysis3
X
X
X
X
X
Xa
Xa
Urine 
Pregnancy 
Test5
X
X
X
X
X
X
X
Clinician
Scratch Scale
X
X
X
X
X
X
X
Clinician 
Xanthoma 
Scale
X
X
X
X
X
X
X


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Study Period
Long-term, Optional Follow-up Treatment Period-2
EOT/ET
Visit
EOS
Visit
Study Week
148
152
156
160
164
168
172
176
180
184
188
192
196
200
204
208
212
Week 
2167
Week 
220
Study Day
Window 
(in days)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±14)
(±5)
Subject 
eDiary/ 
Caregiver 
eDiary 
(ItchRO)
Xb
to
Week 
146
Xb
Xb
to
Week 
158
Xb
Xb
to
Week 
170
Xb
Xb
to
Week 
182
Xb
Xb
to
Week 
194
Xb
Xb
to
Week206
Xb
Xb
to Week 
220
PedsQL
X
X
X
Caregiver 
Impression of
Change (CIC)
X
X
X
Study Drug 
Supplied
X
X
X
X
X
Assess Study 
Drug
Compliance
X
X
X
X
X
X
Review Study 
Diaries & 
Assess
Compliance
Xc
Xc
Xc
Xc
Xc
Xc
ItchRO/Patient 
ItchRO  
Device 
Returned
X
Concomitant 
Medications
X
X
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
X
X
Phone 
Contact6
X
X
X
X
X
X
X
X
X
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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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 primarily using SAS (release 9.4 or higher). 
Continuous (quantitative) variable summaries will include the number of participants (n) with 
non-missing values, mean, standard deviation (SD) and/or standard error (SE) if appropriate,
median, minimum, and maximum.
Categorical (qualitative) variable summaries will include the frequency and percentage of 
participants who are in the particular category. In general, the denominator for the percentage 
calculation will be based upon the total number of participants in the analysis population for the 
treatment group and overall, unless otherwise specified.
For purposes of analysis of disposition of participants, there will be 4 treatment phases in
addition to overall:
•
Original Protocol Phase (Day 1 – Week 48),
•
Protocol Amendment 4 Phase (Week 49 – Week 96)
•
Protocol Amendment 5 Phase (Week 97 – Week 144)
•
Protocol Amendment 6 Phase (Week >144)
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) and measures of spread (standard deviations or errors) will be reported to 1 
degree of precision more than the observed data and measures of spread (SD and/or SE) will be 
reported to 2 degrees of precision more than the observed data.
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, and vitamin A, and pH, will be 
presented to 1 decimal place. Derived values of height, weight and BMI z-scores, and ItchRO 
average values, along with select laboratory values of creatinine, α-tocopherol, retinol binding 
protein (RBP), retinol:RBP molar ratio, and ratio of α-tocopherol to the sum of cholesterol and 
triglycerides will be reported to 2 decimal places. Percentages will be presented to 1 decimal
place, unless otherwise specified. Where the number of participants in a particular category is 0,
a percentage (i.e., 0.0%) will not be displayed.


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All statistical tests will be conducted using 2-tailed tests at the 0.05 significance level. No
inference will be drawn from any p-values presented. Where appropriate, corresponding 95% 
confidence intervals (CIs) will be presented.
4.2.
Interim Analysis 
There is no planned interim analysis (IA) in this study. However, in preparation for briefing 
documents for the End-of-Phase 2 meeting with FDA on 21May2019 and the pre-New Drug 
Application (NDA) meeting with FDA on 19Nov2019, additional interim analyses were 
performed outside of what is noted in the protocol. In preparation for the NDA submission, 
currently planned in Aug2020, the analysis herein described will be performed using an interim 
data cut date of 01Dec2019.
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 and 
the blind is broken. 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
4.3.
Data Monitoring 
A Data Monitoring Committee (DMC) will review serious adverse event (SAE) data and other 
key participant safety and study data at specified intervals for the duration of the study. The 
DMC will be composed of several members who are otherwise independent from the conduct of 
the study: two or more physicians and one 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 stop or modify the study if safety concerns are identified. Further details 
regarding the structure, function and operation of the DMC will be detailed in the DMC charter.
5.
Analysis Populations 
The following analysis population is planned for this study:
x
Safety Population (SAF): The Safety Population is defined as all participants who were 
enrolled and received at least one dose of the study drug. 
The Safety Population will be used for the analyses of all endpoints. Safety analyses will be 
conducted according to the treatment received and be displayed by treatment sequence from the 
core study in LUM001-301 (i.e., PBO-MRX, or MRX-MRX), as appropriate.
As of the 01Dec2019 datacut, a total of 34 patients were enrolled in this study from the 
LUM001-301 core study. Of those, 28 completed, 6 discontinued (1 re-entered after Week 96) 
by Week 48. At Week 96, 25 patients had completed, 1 had discontinued, and 2 did not consent 
to the amendment. At Week 144 there were 21 completers, and 4 discontinuations. The 
remaining 21 patients are still ongoing in the study. Visit-based safety data collected after the 


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drug interruption, at the point of study drug re-initiation, will be analyzed separately as a 
sensitivity analysis.
6.
General Issues for Statistical Analysis 
6.1.
Statistical Definitions and Algorithms 
6.1.1. Baseline 
All Efficacy Assessments and Safety Assessments Before Drug Interruption
For all visit-based efficacy analyses, and for visit-based safety data that is collected/assessed 
before an extended (>28-day) drug interruption period (between protocol amendments), the
following baseline will be used for change from baseline values:
•
MRX Baseline: The observation obtained at first dose of MRX (either in LUM001-301 or 
in LUM001-305) will be used as the MRX baseline observation for all calculations of 
change from MRX baseline. This baseline is applicable only to visit-based analyses.
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 in the respective study.
Safety Assessments After Drug Interruption
For visit-based analyses on safety data collected/assessed after an extended drug interruption 
period > 28 days (between protocol amendments), as described in Section 5, the following 
baseline definitions will be used for change from baseline values. 
•
MRX Baseline: Same definition as above.
•
Baseline (PA Day 0): The last observation obtained before the first re-initiation dose after 
the drug interruption will be used as the baseline (PA Day 0) observation for all 
calculations of change from baseline (PA Day 0). For participants with a drug 
interruption between protocol amendments 2 and 3, the PA Day 0 visit is described as 
“Dose Escalation Day 0” in the database. For participants with a drug interruption 
between protocol amendments 3 and 4, the PA Day 0 visit is described as “PA4 Dose 
Escalation Day 0”. For participants with a drug interruption between protocol 
amendments 4 and 5, the PA Day 0 visit is described as “PA5 Dose Escalation Day 0”.
6.1.2. Study Day 
Study Day 1 is defined as the date of first study drug administration in this study (LUM001-305).
Study day is calculated relative to the date of Study Day 1.
MRX Day 1 is defined as the date of first MRX administration in either this study (LUM001-
305) or the lead-in study (LUM001-301). MRX study day is calculated relative to the date of 
MRX Day 1. This study day definition will only be used for future ad hoc analyses, if needed, 


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and will not be used in any of the analyses outlined in this SAP.
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 
6.1.5.1.
General
While all possible efforts will be made to ensure that participants stay in the study and all data is 
collected as scheduled, the occurrence of missing data cannot be completely eliminated.
Any participant who withdraws from the study are scheduled to undergo all procedures specified 
for the EOT/ET visit. Per the protocol, the ET visits should be scheduled within 7 days of the last 
dose of study drug. However, in the event an ET visit occurs more than 7 days after the date of 
last dose, prior to the respective ET visit (i.e., Week 48/ET, 96/ET, 144/ET, EOT/ET), visit-
based assessments performed during that visit will not be used in analysis summaries.
For a participant who prematurely discontinues the study, their ET visit data will be assigned to a 
protocol-specified visit window as described in Section 6.1.7.
The procedures for handling dropouts or missing data, including the handling of missing 
individual daily ItchRO scores, PedsQL scale score items, and adverse event severity and 
relationship to study drug are described in the below subsections.
Rules for handling missing or partial AE or birth dates are described in Section 6.1.10.
6.1.5.2.
LOCF Imputation
In addition to the time points specified in the protocol, safety and efficacy variables analyzed by 
time point will also be analyzed (as a sensitivity analysis) at the following LOCF time points: 
Week 48/LOCF, Week 96/LOCF, Week 144/LOCF, and Week 216/LOCF time points, where 
appropriate (i.e., if a participant entered a respective period; for example, if a participant did not 
enter the safety monitoring period, that participant would not have Week 96/LOCF, Week 
144/LOCF, or Week 216/LOCF time points). Week 46/LOCF, Week 98/LOCF, Week 
146/LOCF, and Week 218/LOCF imputed time points are only applicable for ItchRO(Obs) 
weekly morning average scores.
For participants that discontinue early, these time points are defined as the last post-baseline 
value obtained on or before the date of last dose plus 7 days (prior to the ET visit date). ItchRO 
assessments that occur more than 7 days after the date of last dose (prior to the ET visit date) will 


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not be used to derive LOCF average scores. In this event, the LOCF average score will include 
assessments made up to the last 7 days immediately following the date of last dose (see Section 
6.1.7).
6.1.5.3.
Missing ItchRO Scores
In deriving the ItchRO weekly average morning score, each scheduled visit date will be 
determined from 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 participant 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.
In the event that a participant/caregiver failed to complete the morning/evening report, the 
morning/evening score for that day will be treated as missing data.
On-study compliance for post-baseline ItchRO is defined as having at least 4 of the 7 daily
scores for a 7-day period. Compliance restrictions are not set for baseline ItchRO average scores.
If a participant/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. Additionally, the same ItchRO assessment day 
(morning/evening daily score) will not be used across different weekly time periods (i.e. no 
overlap).
6.1.5.4.
Missing PedsQL Scores
For PedsQL scale scores, if more than 50% of the items in the scale are missing, the scale score 
is not computed (see Section
).
6.1.5.5.
Missing Last Dose
For participants who are missing the date of last dose of study drug, the last known contact date 
will be used in the calculation of treatment duration and study drug exposure.
6.1.5.6.
Missing Adverse Event Severity/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 recorded 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 reported for analysis purposes as “Severity Not Recorded”.


Statistical Analysis Plan
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6.1.5.7.
Missing 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. Investigative Sites 
An investigative site is defined as a single principal investigator (including sub-investigators) 
who enrols participants 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 participant could be transferred to a principal investigator that did not 
enrol the participant. Unless otherwise specified, the investigative site of the enrolling 
investigator will be used for the unique participant identification (ID).
6.1.7. 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. The below tables address scheduled post-baseline 
assessments; baseline assessments are described in Section 6.1.1. Scheduled visits will be 
selected over unscheduled visits.
For those participants who discontinue early from the study, the below tables (as appropriate) 
will also be used to assign the appropriate analysis visit to the ET visit. For participants that were 
dose-escalated after an extended 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 
PA3, PA4, and PA5) will not be assigned to a post-dose analysis visit. Only the DE Day 0 values 
will be used as baseline values as described in Section Error! Reference source not found..
The study day will be calculated for each scheduled or ET post-baseline visit (and/or 
assessment), as described below, and compared to the assessment window presented in Table 4
or Table 5, 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 15 but a specific assessment 
(e.g., sBA sample or Clinician Xanthoma Scale score) was not scheduled at that visit (see
Section 3.7, 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 4. For analysis visits past 
Week 48, ItchRO average weekly scores are based on the 2-week period following the scheduled 
in-clinic visit. Thus, the “Analysis Visit” and “Analysis Visit Name” will be adjusted 
accordingly (e.g., “Week 62” rather than “Week 60”). 


Statistical Analysis Plan
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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.
Efficacy and Visit-Based Safety Assessments Before Drug Interruption
Analyses of all efficacy variables, regardless of drug interruptions, will be performed using the 
analysis visit windows defined by study day relative to the first dose of study drug as outlined 
below in Table 4. For participants with an extended drug interruption, efficacy assessments after 
the interruption are essentially treated as if the participant was on study drug during the period of 
time that the participant was off study drug.
The analysis visit windows in Table 4 will also be used for all visit-based safety assessments that 
occurred before a drug interruption (due to a protocol amendment), including those participants
without such a drug interruption.


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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Table 4: Analysis Visit Windows – Primary Analysis
Analysis 
Visit
Analysis Visit 
Name
Target Day of 
Planned Visit
Assessment Window
(Study Days1)
2
Week 2
14
Post-dose – 21
4
Week 4
28
22 – 36
8
Week 8
56
37 – 70
12
Week 12
84
71 – 98
16
Week 16
112
99 – 133
24
Week 24
154
134 – 203
36
Week 36
252
204 – 301
48
Week 48
336
302 – 378
60
Week 60
420
379 – 462
72
Week 72
504
463 – 546
84
Week 84
588
547 – 630
96
Week 96
672
631 – 714
108
Week 108
756
715 – 798
120
Week 120
840
799 – 882
132
Week 132
924
883 – 966
144
Week 144
1008
967 – 1050
156
Week 156
1092
1051 – 1134
168
Week 168
1176
1135 – 1218
180
Week 180
1260
1219 – 1302
192
Week 192
1344
1303 – 1386
204
Week 204
1428
1387 – 1470
216
Week 216
1512
1471 – 1554
1 Study day relative to the date of first dose of study medication on LUM001-305, unless 
otherwise specified.


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Visit-Based Safety Assessments After Drug Interruption
For visit-based safety data, the primary analysis will exclude any safety data collected or 
assessed after a drug interruption > 28 days due to a participant being off study (between 
protocol amendments). Safety chemistry data for laboratory samples collected after the drug 
interruption, at the point of study drug re-initiation, will be analyzed separately as a sensitivity 
analysis. FSV level abnormalities (e.g., sufficient, insufficient, excess) will also be analyzed 
separately as a sensitivity analysis using laboratory samples collected after the drug interruption. 
All visit-based safety data collected or assessed after the drug interruption period will be 
provided separately in participant listings.
For visit-based analyses (and listings) on safety data collected or assessed after an extended drug 
interruption period > 28 days between protocol amendments, as described in Section 5, the 
analysis visit windows defined in Table 5 will be used. The analysis visit windows below are 
defined by study day relative to the date of first re-initiation of study drug after the drug 
interruption (i.e., PA Day 0; see Section 6.1.1).
Table 5: Analysis Visit Windows – Supporting Subgroup Analysis 
(Data Assessed after an Extended Drug Interruption)
Analysis 
Visit
Analysis Visit 
Name
Target Day of 
Planned Visit
Assessment Window
(Study Days1)
4
Week 4
28
Post-dose – 56
12
Week 12
84
57 – 112
20
Week 20
140
113 – 168
28
Week 28
196
169 – 224
36
Week 36
252
225 – 280
44
Week 44
308
281 – 336
52
Week 52
364
337 – 392
60
Week 60
420
393 – 448
68
Week 68
476
449 – 504
76
Week 76
532
505 – 560
84
Week 84
588
561 – 616
92
Week 92
644
617 – 672
100
Week 100
700
673 – 728
108
Week 108
756
729 – 784
116
Week 116
812
785 – 840
124
Week 124
868
841 – 896
132
Week 140
924
953 – 1008
140
Week 148
980
1009 – 1064
148
Week 156
1036
1065 – 1120
1 Study day relative to the date of first re-initiation of study drug after the drug interruption
(i.e., PA Day 0).


Statistical Analysis Plan
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6.1.8. Variable Definitions
x
“Week 46/LOCF” / “Week 48/LOCF” (see Section 6.1.5.2)
x
“Week 96/LOCF” / “Week 98/LOCF” (see Section 6.1.5.2)
x
“Week 144/LOCF” / “Week 146/LOCF” (see Section 6.1.5.2)
x
“Week 216/LOCF” / “Week 218/LOCF” (see Section 6.1.5.2)
x
Treatment-emergent adverse events (TEAEs) are defined in Section Error! 
Reference source not found..
x
Concomitant medications are defined in Section Error! Reference source not 
found..
6.1.9. Derived Variables 
x
Age (months) at Baseline:
For participants under 2 years of age, the 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) / 30.44
Partial birth dates are imputed for analysis purposes as described in 
Section 6.1.10.
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) =
௪௘௜௚௛௧ ௜௡ ௞௜௟௢௚௥௔௠௦
(௛௘௜௚௛௧ ௜௡ ௠௘௧௘௥௦)మ
x
Treatment Duration (days) = LASTDAY – FIRSTDAY + 1 day - GAP 


Statistical Analysis Plan
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LASTDAY = date of the EOT visit OR the date of last dose for participants that 
withdrew from the study, FIRSTDAY = date of first dose, and GAP = total # of 
days participant was off study between protocol amendments.  
For ET participants, the date of last dose is considered. For participants who are missing 
the date of last dose of study drug, the last known contact date will be used in the 
calculation of treatment duration and study drug exposure.
x
% Compliance = 100 x Number of days at least 1 dose is taken / QD Treatment Duration 
(days)
where, 
Number of days at least 1 dose is taken = Treatment Duration (days) – Number of 
days a dose was missed [during the specified time period, not including dosing gaps 
due to the participant being off study between protocol amendments]
Compliance is derived overall (Week 0-EOT) and for the following treatment 
phases: Week 0-48, Week >48-96, Week >96-144, and Week >144. Study drug 
compliance will not be calculated for those participants whose date of last dose is 
unknown.
x
Total Dose Received (μg/kg) = Dose (μg/kg/day) x Treatment Duration (days), for a 
given dose level 
x
Total Drug Exposure (μg/kg) = ∑ [Treatment duration (days)i x Total dose received 
(μg/kg)i )]
where, 
i = 1 to k, (k = number of days participant is receiving a constant dose)
Total drug exposure is derived overall (Week 0-EOT) and for each treatment 
phase: Week 0-48, Week >48-96, Week >96-144, and Week >144. The time 
periods for which no study drug was administered due to dosing gaps while a 
participant is off study (between protocol amendments) are not included. For 
participants who are missing the date of last dose of study drug, the last 
known contact date will be used in the calculation of treatment duration and 
study drug exposure.  
x
Average Daily Dose (μg/kg/day) =  Total Drug Exposure (μg/kg) / Treatment Duration 
(days)
Average daily dose is derived overall (Week 0-EOT) and for each treatment 
phase: Week 0-48, Week >48-96, Week >96-144, and Week >144. The time 


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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periods for which no study drug was administered due to dosing gaps while a 
participant is off study (between protocol amendments) are not included. 
x
ItchRO Weekly Average Morning Severity Score = Sum of ItchRO daily morning 
scores (over a 7-day period) divided by the number of days ItchRO completed
The above definition applies to both severity (Item 1) and frequency (Item 3,
Observer only) weekly average score. The baseline weekly morning average score 
is derived using the 7 days immediately before the baseline visit date, according 
to the baseline definitions described in Section 6.1.1.
x
Estimated Total Lipids, mg/dL = cholesterol (mg/dL) + triglycerides (mg/dL)
x
Ratio of Alpha Tocopherol to Estimated Total Lipids (the sum of Cholesterol + 
Triglycerides), mg/g = 1000 x alpha tocopherol (mg/dL) / Estimated 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.
x
Corrected Sodium, mmol/L = sodium (mmol/L) + [ 0.00216 x Estimated Total Lipids 
(the sum of cholesterol + triglycerides) (mg/dL) ]
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:
Sufficient if level ≥20 to 96 ng/mL
Insufficient if level <20 ng/mL
Excess if level >96 ng/mL
Lipid Ratio of Alpha Tocopherol to Estimated Total Lipids: Sufficient if ratio >0.8 to <3.5 mg/g
Insufficient if ratio ≤0.8 mg/g
Excess if ratio ≥3.5 mg/g
Corrected Sodium:
Normal if level ≥135 to 148 mmol/L
Low if level <135 mmol/L
High if level >148 mmol/L
Prothrombin Intl. Normalized Ratio:
Sufficient if ratio <1.2
Indeterminate if ratio ≥1.2 to 1.5
Possibly Insufficient if ratio >1.5


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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Retinol:RBP Molar Ratio: Sufficient if ratio ≥0.8 mol/mol
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 
For missing FSV values, a category of “Missing” is used.
x
Baseline Value = Value obtained at baseline visit
Change from Baseline = Value at current time point – Value at baseline
% Change from Baseline = 100 x Change from Baseline / Value at baseline
Refer to Section 6.1.1 for various baseline definitions.
For ItchRO average scores, “Value” is the average score over the specified time
period, as defined above. If Change from Baseline = 0 and Baseline Value = 0, 
then set % Change from Baseline to 0.
x
Body Weight, Height, and BMI z-Scores:
Height, weight, and BMI z-scores are based on a participant’s gender and age at each 
scheduled visit. For participants less than 24 months of age, the World Health Organization 
(WHO) growth charts11 are recommended by the Centers for Disease Control (CDC) and 
will be used to derive z-scores. For participants at least 24 months of age, the CDC growth 
charts12 will be used to derive z-scores. 
x
PedsQL Scoring Algorithm
For each item of the PedsQL instrument (parent and participant), a 5-point response scale 
is used (0 = never, 1 = almost never, 2 = sometimes, 3 = often, 4 = almost always). Items 
are reverse-scored and linearly transformed to a 0-100 scale (0 → 100, 1 → 75, 2 → 50, 
3 → 25, 4 → 0), so that higher scores indicate better HRQoL (less negative impact). 
Scale scores are computed as the sum of the items divided by the number of items 
answered (this accounts for missing data). If more than 50% of the items in the scale are 
missing, the scale score is not computed. See Reference 13 in Section 12 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)
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 


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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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 
participant reports.
6.1.10. Data Adjustments/Handling/Conventions 
Data not subject to analysis according to this plan will not appear in any tables, listings, or 
graphs.
Participant Age
Age at screening from the LUM001-301 study will be used as the age for the determination of 
the appropriate ItchRO instrument and the appropriate PedsQL module to be used for the study. 
The same age-appropriate instrument will be used for the duration of the study (regardless of 
subsequent birthdays after the baseline visit).
Adverse Event and Concomitant Medication Coding
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1. Prior and concomitant medications will be coded using WHO-Drug Dictionary 
(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


Statistical Analysis Plan
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A concomitant medication is any non-protocol specified drug or substance administered during 
participation in the study. In general, this period of participation is from the first day of screening 
through the date of last contact. 
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 participants 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.
Medications that treat pruritus include ATC preferred terms of rifampicin, phenobarbital, 
alimemazine, brompheniramine maleate, cetirizine hydrochloride, desloratadine, 
dexchlorpheniramine maleate, dimetindene maleate, ketotifen fumarate, levocetirizine 
dihydrochloride, loratadine, mequitazine, promethazine, promethazine hydrochloride, ornithine 
aspartate, ursodeoxycholic acid, colestyramine, naltrexone, naltrexone hydrochloride, and 
sertraline.
Treatment-Emergent Adverse Event Definition and Handling of Data
In general, TEAEs are defined as AEs with a start date on or after the first dose date of study 
drug and started before the last dose of study drug plus 14 days. For participants with >14 days 
of study drug interruption/withdrawal, the definition of a TEAE will consider both the date of the 
last dose before study drug interruption and the actual last dose. For these participants, 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 event which started before the first dose and worsens in severity or changes from non-
serious to serious on or after the first dose date will also be designated as a treatment-emergent 
event. If an event worsens in severity during the study, the lower grade event is marked as “Not 
recovered/not resolved” on the AE case report form (CRF) and an end date entered. A new event 
is recorded on the AE CRF with a start date that matches the end date, and the term recorded 
includes “Worsened” (e.g., “Worsened Headaches”). If an event becomes serious, the date that 
the event became serious is recorded on the AE CRF as the End Date of that AE and the Start
Date of the corresponding SAE.
Adverse event severity grades are reported according to the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. 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 
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)”.


Statistical Analysis Plan
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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 recorded relationship to study drug will be considered as “Possibly
Related” to study drug. If severity of an AE is missing, severity of the event will be reported for 
analysis purposes as “Severity Not Recorded”.
Adverse Events of Special Interest
The following events have been defined as AEs of special interest (AESI) due to the nature of 
ALGS as well as of MRX:
x
Diarrhoea events
x
FSV deficiency events
x
Elevated transaminases events
x
Elevated bilirubin events
ALGS is associated with FSV deficiency and fluctuating transaminase and bilirubin elevations. 
MRX is associated with gastrointestinal disturbances such as diarrhea.
The list of PTs used to identify FSV deficiency events are provided in Appendix 3. Diarrhoea 
events include PTs of ‘Diarrhoea’ and ‘Gastroenteritis’. Elevated transaminases events include 
PTs of ‘Alanine aminotransferase increased’ and ‘Aspartate aminotransferase increased’. 
Elevated bilirubin events include the PT of ‘Blood bilirubin increased’.
Partial Date Imputation
If partial dates occur, the convention for replacing missing dates for the purpose of calculating 
derived variables is as follows:
Partial ALGS Diagnosis Dates
For partial original ALGS 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 Dates of Birth
Several of the investigative sites are located in countries that do not permit the reporting of 
complete dates of birth. These sites only report the month and year of date of birth. Complete 
date of birth is required, however, to derive a participant’s weight and height z-scores at each 
scheduled study visit. For partial birth dates, the convention for replacing missing dates for 
the purpose of statistical analysis is as follows: the day is assigned the 15th day of the month 
(15). 


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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Partial AE or Medication Dates
Adverse events or medications with entirely missing start dates will be classified as 
treatment-emergent or concomitant, as appropriate. For the below, first dose date is with 
respect to the first dose in LUM001-305.
For partial AE or prior/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
(or the AE is ongoing), 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) 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 or the AE is 
ongoing, 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).
Lower and Upper Limit of Quantitation
In general, for quantitative laboratory values reported as “<” or “≤” the lower limit of 
quantitation (LLOQ), one-half of the reported value (i.e., LLOQ/2) will be used for analysis. The 
exception to this data treatment is for plasma MRX concentrations that are reported as <LLOQ, 
where a value of zero will be used in calculating summary statistics.
For quantitative laboratory values reported as “>” or “≥” the upper limit of quantitation (ULOQ), 
the reported value (i.e., ULOQ) will be used for analysis.
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.
Dose Used in Safety Analysis
For all safety and tolerability analyses, participants will be analyzed by the treatment received. 
For AE summaries, MRX treatment groups are based on the dose received at the onset of the 
event.
Treatment Duration and Exposure
For participants who are missing the date of last study drug, for any reason, the last known 
contact date will be used in the calculation of treatment duration and study drug exposure. Study 
drug compliance will not be calculated for those participants whose date of last study drug 
application is unknown.


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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7.
Study Participants and Demographics 
7.1.
Disposition of Participants and Withdrawals 
Participant disposition will be presented overall and by treatment phase and treatment group.
Participant disposition will include tabulations of the number and percentage of participants in 
each of the analysis populations, dose reduced during the study, completed treatment, and 
discontinued treatment early (along with reasons for withdrawal). For the overall summary and 
the Week >48 treatment period, participants that did not consent to the optional long-term 
treatment extensions (PA4, PA5, or PA6) are not considered to have completed treatment. 
Reasons for withdrawal will include those collected on the CRF, along with not consenting to 
PA4, PA5, or PA6 (separately). 
For the by study phase and treatment group summaries, the number and percentage of 
participants presented will be based on the number of participants in each treatment period.
The participant disposition tabulation will also include the number of participants screened for 
eligibility (under the original protocol), the number of screen failures (under the original 
protocol), enrolled/randomized/continued, as appropriate for each treatment phase.
Study drug accountability and compliance listings will be prepared for all participants, showing 
when the planned dosing schedule was not followed, along with the date and type of dosing 
deviation. Other disposition and study conduct information, including major protocol deviations 
will be listed. Additionally, a listing will be provided that identifies if a subject enters each 
phase, as discussed in Section 4.1.
7.2.
Protocol Violations and Deviations 
Protocol deviations will be tracked, recorded, and reviewed prior to database lock, following the 
Protocol Deviation Guidance Plan for the Maralixibat program, including: 
• ICF process or signature/version issue
• Violation of inclusion/exclusion criteria
• Deviation from study protocol procedures
• Dosing error
• 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 significant 
safety issue or significant impact on the statistical analysis of the clinical data. 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 classification,
however all deviation will be reviewed with the study team at regular intervals.


Statistical Analysis Plan
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Major protocol deviations may include:
• Significant and/or persistent dosing error
• Participant did not meet criteria for assignment and does not have a waiver or 
dispensation by medical monitor
• Error in randomization (i.e., received wrong drug)
• Use of prohibited concomitant treatment during participation in the trial
Major protocol violations/deviations will be presented in a participant listing. Additionally, 
inclusion and exclusion criteria not met and reasons for screen failures will be listed.
7.3.
Demographics and Other Baseline Characteristics 
Participant demographics and other baseline characteristics will be presented by treatment group 
and overall.
Summary statistics for age (at baseline), age group, gender, country, weight z-score, height 
z-score, and BMI z-score will be presented. Age group categories are defined as <2, 2-4, 5-8, 9-
12, and 13-18 years of age at baseline.
These analyses will be conducted for the Safety Population.
7.4.
Prior Medications 
Prior medications will be summarized descriptively by treatment group and overall, using the 
number and percent of participants by ATC class and preferred term. Summaries will be 
presented separately for: (1) prior anti-pruritus medications, (2) prior medications (excluding 
anti-pruritus medications), and (3) therapies to treat pruritus in the past, as collected specifically 
on the Disease History CRF under categories of topical, oral, and other therapies. Each summary 
will also include tabulations for the following categories: no medication, 1 medication, 2 
medications, and at least 3 medications.
Prior medications will be presented separately from concomitant medications.
Prior and concomitant medications will also be presented separately in participant listings. A 
separate listing of prior medications that treat pruritus will also be presented.
7.5.
Treatment Compliance 
Treatment compliance will be calculated for each participant and summarized descriptively. This 
analysis will be completed using the Safety Population for each of the following study phases:  
Weeks 0-48, Weeks >48-96, Weeks >96-144, Weeks >144, and overall (Weeks 0-EOT). 
Participants that withdraw early before any given study phase are not included in the analysis of 
that study phase.


Statistical Analysis Plan
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Protocol Number LUM001-305
PCN Number LUME3562 
 
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A participant is considered compliant with treatment (for a given day) if any amount of study 
drug was administered. 
Study drug accountability will be presented in a participant listing.
8.
Efficacy Analysis 
The primary analysis population for efficacy analysis will be the Safety Population. Analyses for 
the primary and secondary efficacy outcome variables will also be done on the Safety
Population. All sensitivity analysis will be done on the Safety Population. Efficacy data 
summaries will be provided by treatment group and overall, unless otherwise specified.
All efficacy data will be presented in participant listings
8.1.
Primary Efficacy Analysis 
The change from baseline in serum bile acid will be displayed for each treatment group and 
overall using summary statistics including a 95% confidence interval on the mean change. For 
each post-baseline analysis visit, the null hypothesis that the mean change is equal to zero will be 
tested using the Student’s t-test to determine if the mean change is statistically significant.
8.2.
Secondary, Exploratory and Other Efficacy Analyses 
Secondary, exploratory, and other efficacy variables that are continuous measures will be 
analyzed similarly to the primary efficacy analyses, using summary statistics and Student’s t-test
to determine if the mean change is statistically significant, where applicable. Categorical 
measures will be presented by level of response with frequencies and percentages.
Change from baseline in ItchRO(Obs) weekly average morning severity score, sBA, C4, 
bilirubin (total and direct), ALT, ALP, GGT, AST, total cholesterol, LDL-C, height and weight 
z-scores, and PedsQL total scale and multidimensional fatigue scale scores (parent) will be 
displayed graphically over the treatment period.
Planned efficacy figures are described in Section Error! Reference source not found..
Additional figures may be added post-hoc to further examine study data.
9.
Safety and Tolerability Analysis 
All safety analyses will be performed on the Safety Population.
Safety measures including treatment exposure, AEs, clinical laboratory values, physical 
examination findings (including BMI), vital signs, and concomitant treatment usage will be 
summarized descriptively. No inferential statistical tests will be performed, unless otherwise 
specified.


Statistical Analysis Plan
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For visit-based safety data (i.e., vital signs, BMI, and safety labs), the primary analysis will 
exclude any data collected or assessed after an extended drug interruption > 28 days due to a 
participant being off study between protocol amendments. Visit-based data collected after the
drug interruption, at the point of study drug re-initiation, will be analyzed separately as a 
sensitivity analysis.
For all safety analyses, participants will be analyzed by the treatment received. In general, safety 
data summaries will be provided by treatment phase and treatment group. For AE summaries,
MRX treatment groups are based on the dose received at the onset of the event.
All safety and tolerability data will be presented by treatment sequence in participant listings. All
visit-based safety data collected or assessed after the drug interruption period (between protocol 
amendments) will be presented in separate participant listings. 
9.1.
Treatment Exposure 
Treatment exposure will be summarized descriptively overall and by each of the following 
treatment phases: Weeks 0-48, Weeks >48-96, Weeks >96-144, Weeks >144, and overall 
(Weeks 0-EOT). These summaries will include: average daily dose (μg/kg/day), total drug 
exposure (μg/kg), and treatment duration (days). Reference Section Error! Reference source 
not found. for the derivation of these variables.
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 – interval of drug interruption off study) will also be 
summarized categorically using the following mutually exclusive time intervals:
x
≤ 13 Weeks
x
> 13 to 23 Weeks
x
> 23 to 78 Weeks (0.5-1.5 yrs)
x
> 78 to 104 Weeks (1.5-2 yrs)
x
> 104 to 156 Weeks (2-3 yrs)
x
> 156 to 208 Weeks (3-4 yrs)
x
> 208 Weeks (>4 years)
9.2.
Adverse Events 
In general, TEAEs are AEs with a start date on or after the first dose date of study drug (in
LUM001-305) and a start date before the last dose of study drug plus 14 days. For participants
with >14 days of study drug interruption/withdrawal, the definition of a TEAE considers both the 
date of the last dose prior to drug interruption and the actual last dose (see Section Error! 
Reference source not found.).


Statistical Analysis Plan
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Analysis of TEAEs will be performed by treatment group and overall. TEAEs will be 
summarized overall and by MRX dose at the onset of the event.
A summary of TEAEs will be presented by treatment group and overall (including MRX overall 
and dose at onset). The summary will include the total number and percent of participants
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
The number and percent of participants reporting TEAEs, grouped by MedDRA system organ 
class (SOC) and preferred term (PT), will be tabulated overall and by maximum severity. These 
adverse event summaries will be repeated for treatment-related AEs. In the case of multiple 
occurrences of the same TEAE within the same participant, each participant will only be counted 
once for each preferred term.
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 
(overall participants) 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 Error! Reference source 
not found..
In the AE data listings, events that are treatment-emergent will be flagged. AEs will be presented 
in by-participant listings, detailing the treatment phase, treatment received at the start of the 
event including dose for active study drug, SOC, PT, verbatim term given by the investigator,
onset date and study day, end date and study day, event duration, severity, relationship to study 
drug, outcome, action taken with study drug, seriousness, and treatment required. 
9.2.1. Adverse Events Leading to Withdrawal 
AEs that lead to permanent discontinuation of study drug will be tabulated by SOC and PT 
overall by dose at onset of the event. Participant listings of AEs that lead to permanent 
discontinuation of study drug will also be presented.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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9.2.2. Deaths and Serious Adverse Events 
Treatment-emergent SAEs, and SAEs potentially related to study drug will be summarized in the 
same manner as AEs that lead to permanent discontinuation of study drug. Participant listings of 
all SAEs will also be presented.
Any deaths that occur during the study, including post-treatment follow-up periods, will be 
presented in a participant listing. The listing will include participant ID, treatment period, study 
drug and dose received at the time of death (or the last study drug/dose received prior to death), 
date of death, number of days from the 1st and last dose, MedDRA PT, and relationship to study 
drug.
9.2.3. Adverse Events of Special Interest 
Due to the nature of Alagille disease, as well as MRX, the following events have been defined as 
AESIs: diarrhea events, FSV deficiency events, elevated transaminases, and elevated bilirubin. 
The list of PTs used to identify FSV deficiency events are provided in Appendix 3.
The incidence of TEAEs of special interest will be summarized in the same manner as AEs that 
lead to permanent discontinuation of study drug.
9.3.
Clinical Laboratory Evaluations 
The primary analysis of safety laboratory data will exclude any laboratory samples that were
collected from a participant after a drug interruption due to the participant being off study 
(between protocol amendments).
Safety laboratory test results will be summarized using descriptive statistics by laboratory test
panel (i.e., chemistry, hematology, FSVs, and lipids), treatment group and analysis visit as 
observed and change from baseline values.
Specific laboratory tests, and associated units of measure, that will be used for safety reporting 
are listed in Appendix 2. As noted, summary statistics will not be presented for urinalysis results, 
but rather included in participant listings. Bilirubin (total and direct), ALP, and ALT are 
considered as both safety and efficacy laboratory tests, and will only be summarized as efficacy 
variables. All safety laboratory test parameters will be presented (by panel) in participant
listings.
For select FSVs, including 25-hydroxyvitamin D, lipid ratio of alpha tocopherol to estimated 
total lipids, corrected sodium, INR, retinol:RBP molar ratio, and vitamin A, a summary of 
abnormalities will be presented. The number and percent of participants within each test level 
category will be presented. For these fat soluble vitamins, categories may include normal, 
sufficient, insufficient, possibly insufficient, indeterminate, and excess (see Section Error! 
Reference source not found. for specific definitions). Missing lab values will be reported in a 
“Missing” category.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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In addition to participant listings for each laboratory test, a listing that includes the timing of 
sample collection, date and time of last dose and last meal before sample collection.  Pregnancy 
test results, for both serum and urine, along with screening-specific laboratory results will also be 
presented in participant listings.
Sensitivity Analyses on Laboratory Data Collected After Drug Interruption
A separate sensitivity analysis will be performed on chemistry panel test data from samples that 
are collected after an extended drug interruption due to a participant being off study between 
protocol amendments. Chemistry test results will be summarized using descriptive statistics by 
analysis visit as observed, change from baseline (Day 0), and change from baseline (PA Day 0) 
values. Baseline definitions for this analysis are described in Section Error! Reference source 
not found.. The analysis visit windows to be used (see Table 5) are defined by study day relative 
to the date of first re-initiation of study drug after the drug interruption (i.e., PA Day 0).
FSV level abnormalities (e.g., sufficient, insufficient, excess) will also be analyzed separately as 
a sensitivity analysis using laboratory samples collected after a drug interruption. The number 
and percent of participants within each test level category (see Section Error! Reference source 
not found. for category definitions) will be presented.
9.4.
Physical Examination 
BMI z-scores will be summarized using descriptive statistics by analysis visit as observed and 
change from baseline values as described above for safety laboratory evaluations.
Physical examination findings, including body height, body weight, and BMI (and their 
corresponding z-scores), will be included in participant listings.
9.5.
Vital Signs 
Vital signs (blood pressure, heart rate, body temperature, and respiration rate) will be 
summarized using descriptive statistics by scheduled study visit as both observed values and 
change from baseline values.
9.6.
Concomitant Medication 
A concomitant medication is any non-protocol specified drug or substance administered after the 
first dose of study drug. For participants 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 by treatment group and overall,
using the number and percent of participants by ATC class and preferred term. Pruritus 
medications that treat pruritus are listed in Section Error! Reference source not found..


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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Concomitant medications will also be presented in participant listings. Medications that were 
started before the first dose of study drug in LUM001-305 and are ongoing at the time of first 
dose will be flagged.
9.7.
Safety Data Graphical Presentations 
Study drug exposure and TEAEs of special interest will be displayed graphically over time, as 
described in Section Error! Reference source not found.. Additional figures may be added post-
hoc to further examine study data.
10.
Other Analysis 
10.1.
Pharmacokinetic Analysis 
MRX plasma concentrations will be summarized using descriptive statistics by study visit and 
the last dose of MRX received prior to the blood sample collection. 
11.
Changes from Planned Analysis 
The protocol states all analyses will be descriptive in nature, however primary and secondary 
continuous measures include 95% CIs and a Student’s t-test of mean change for consistency with 
other open-label trials.
The protocol defines Baseline (Day 0) and Baseline from LUM001-301, however in 
LUM001-305 at the sponsor’s request, the first dose of MRX (either in LUM001-301 or 
LUM001-305) will be used as the baseline visit. As a result of this request, all endpoints have the 
terminology “change from MRX baseline” which is different from the nomenclature in the 
protocol.
In order to maintain consistency across other protocols in this program, efficacy analyses for 
AST and GGT were added.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
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Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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12.
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. http://www.amstat.org/about/ethicalguidelines.cfm
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014.
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf.
4. Molenberghs G., Kenward M. G. 2007. Missing Data in Clinical Studies. New York: Wiley.
5. Molenberghs G., Thijs H., Jansen I., et al. 2004. Analyzing incomplete longitudinal clinical 
trial data. Biostatistics, 5, 445-464.
6. Mallinckrodt C. H., Clark W. S., David S. R. 2001. Accounting for dropout bias using 
mixed-effects models. Journal of Biopharmaceuticals Statistics, 11, 9-21.
7. European Medicines Agency. 2010. Guideline on Missing Data in Confirmatory Clinical 
Trials.
8. Siddiqui O., Hung H. M., O'Neill R. 2009. MMRM vs. LOCF: a comprehensive comparison 
based on simulation study and 25 NDA datasets. Journal of Biopharmaceuticals Statistics,
19(2), 227-246.
9. Mallinckrodt C. H., Roger J., Chuang-Stein C., Molenberghs G., O'Kelly M., Ratitch B.,
Janssens M., Bunouf P. 2013. Recent Developments in the Prevention and Treatment of 
Missing Data. Drug Information Journal, 48, 68-80.
10. Little R., Rubin D. 1987. Statistical Analysis with Missing Data. New York: John Wiley.
11. 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).
12. 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).
13. The PedsQL Measurement Model for the Pediatric Quality of Life Inventory – Scoring 
Instructions (www.pedsql.org).
 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
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Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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13.
Tables, Listings, and Figures 
All listings, tables, and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (listing number, where applicable).
13.1.
Planned Table Descriptions 
The following are planned summary tables for protocol number LUM001-305. The table
numbers are place holders only and will be determined when the tables are produced.
Table Number
Table Title
14.1  Disposition, Demographic, Disease History, Prior Medications, and Study Drug Compliance
14.1.1.1
Participant Disposition: Overall – All Participants
14.1.1.2
Participant Disposition by Study Phase – Enrolled Participants
14.1.2
Demographics and Baseline Characteristics – Safety Population
14.1.3
Disease History and Baseline Disease Characteristics – Safety Population
14.1.5.1
Summary of Prior Anti-Pruritus Medications – Safety Population
14.1.5.2
Summary of Prior Medications (Excluding Anti-Pruritus Medications) – Safety Population
14.1.5.3
Summary of Therapies to Treat Pruritus in the Past – Safety Population
14.1.6
Study Drug Compliance – Safety Population
14.2  Efficacy Data
14.2.1
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Safety Population
14.2.2
Summary of sBA (umol/L) and Change from Baseline by Analysis Visit – Safety Population
14.2.3
Summary of ALP (U/L) and Change from Baseline by Analysis Visit – Safety Population
14.2.4
Summary of ALT (U/L) and Change from Baseline by Analysis Visit – Safety Population
14.2.5
Summary of AST (U/L) and Change from Baseline by Analysis Visit – Safety Population
14.2.6
Summary of GGT (U/L) and Change from Baseline by Analysis Visit – Safety Population
14.2.7
Summary of Total Bilirubin (mg/dL) and Change from Baseline by Analysis Visit – Safety 
Population
14.2.8
Summary of Direct Bilirubin (mg/dL) and Change from Baseline by Analysis Visit – Safety 
Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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14.2.9
Summary of C4 (ng/mL) and Change from Baseline by Analysis Visit – Safety Population
14.2.10
Summary of Total Cholesterol (mg/dL) and Change from Baseline by Analysis Visit –
Safety Population
14.2.11
Summary of LDL-C (mg/dL) and Change from Baseline by Analysis Visit – Safety 
Population
14.2.12.1
Summary of Clinician Scratch Score (CSS) and Change from Baseline by Analysis Visit –
Safety Population
14.2.12.2
Summary of Clinician Scratch Score (CSS) Change from Baseline by Analysis Visit –
Categorical Data Analysis – Safety Population
14.2.13.1
Summary of Clinician Xanthoma Severity Score and Change from Baseline by Analysis 
Visit – Safety Population
14.2.13.2
Summary of Clinician Xanthoma Severity Score and Change from Baseline by Analysis 
Visit – Categorical Data Analysis – Safety Population
14.2.14
Summary of Height Z-Score and Change from Baseline by Analysis Visit – Safety 
Population
14.2.15
Summary of Weight Z-Score and Change from Baseline by Analysis Visit – Safety 
Population
14.2.16
Summary of CIC (Itch-Related Symptoms) and Change from Baseline by Analysis Visit –
Safety Population
14.2.17
Summary of CIC  (Xanthoma Severity) and Change from Baseline by Analysis Visit –
Safety Population
14.2.18
Summary of PedsQL Total Scale Score (Parent) and Change from Baseline by Analysis 
Visit – Safety Population
14.2.19
Summary of PedsQL Multidimensional Fatigue Scale Score (Parent) and Change from 
Baseline by Analysis Visit – Safety Population
14.2.20
Summary of PedsQL Family Impact Total Scale Score and Change from Baseline by 
Analysis Visit – Safety Population
14.2.21
Summary of PedsQL Psychosocial Health Summary Score (Parent) and Change from 
Baseline by Analysis Visit – Safety Population
14.2.22
Summary of PedsQL Total Scale Score (Child) and Change from Baseline by Analysis Visit 
– Safety Population
14.2.23
Summary of PedsQL Multidimensional Fatigue Scale Score (Child) and Change from 
Baseline by Analysis Visit – Safety Population
14.3  Safety Data
14.3.1  Study Drug Exposure
14.3.1
Study Drug Exposure by Treatment Phase – Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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14.3.2  Displays of Adverse Events
14.3.2.1
Summary of Treatment-Emergent Adverse Events by Dose at Onset of TEAE – Safety 
Population
14.3.2.2
Incidence of Treatment-Emergent Adverse Events by Dose at Onset of TEAE – Safety 
Population
14.3.2.3
Incidence of Treatment-Emergent Adverse Events by Maximum Severity and Dose at Onset of 
TEAE – Safety Population
14.3.2.4
Incidence of Treatment Related Adverse Events by Dose at Onset of TEAE – Safety 
Population
14.3.2.5
Incidence of Treatment Related Adverse Events by Maximum Severity and Dose at Onset of 
TEAE – Safety Population
14.3.3  Summary of Deaths, Other Serious and Significant Adverse Events
14.3.3.1
Incidence of Treatment-Emergent SAEs by Dose at Onset of TEAE – Safety Population
14.3.3.2
Incidence of Treatment Related SAEs by Dose at Onset of TEAE – Safety Population
14.3.3.3
Incidence of Adverse Events Leading to Permanent Treatment Discontinuation by Dose at 
Onset of TEAE – Safety Population
14.3.3.4
Incidence of Treatment-Emergent Adverse Events of Special Interest – Diarrhoea Events by 
Dose at Onset of TEAE – Safety Population
14.3.3.5
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated 
Transaminases Events by Dose at Onset of TEAE – Safety Population
14.3.3.6
Incidence of Treatment-Emergent Adverse Events of Special Interest – Fat Soluble Vitamin 
Deficiency Events by Dose at Onset of TEAE – Safety Population
14.3.3.7
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated Bilirubin 
Events by Dose at Onset of TEAE – Safety Population
14.3.4  Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events
14.3.4.1
Listing of Serious Adverse Events – Safety Population
14.3.4.2
Listing of Adverse Events Leading to Permanent Treatment Discontinuation – Safety Population
14.3.4.3
Listing of Deaths
14.3.5  Laboratory Data Summary Tables
14.3.5.1.1
Summary of Safety Laboratory Data by Analysis Visit: Chemistry – Safety Population
14.3.5.1.2
Summary of Safety Chemistry Data by Analysis Visit – on Laboratory Samples Collected After 
Extended Drug Interruption – Safety Population
14.3.5.2
Summary of Safety Laboratory Data by Analysis Visit: Hematology – Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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14.3.5.3.1
Summary of Safety Laboratory Data by Analysis Visit: Fat Soluble Vitamins – Safety 
Population
14.3.5.3.2
Summary of Fat Soluble Vitamin Level Abnormalities – Safety Population
14.3.5.3.3
Summary of Fat Soluble Vitamin Level Abnormalities – on Laboratory Samples Collected After 
Extended Drug Interruption – Safety Population
14.3.5.4
Summary of Safety Laboratory Data by Analysis Visit: Lipid Panel – Safety Population
14.3.5.5
Summary of Safety Laboratory Data  by Analysis Visit: Alpha-Fetoprotein (AFP) – Safety 
Population
14.3.6  Other Safety Data Summary Tables
14.3.6.1
Summary of BMI Z-Score by Analysis Visit – Safety Population
14.3.6.2
Summary of Vital Signs by Analysis Visit: Systolic Blood Pressure (mmHg) – Safety 
Population
14.3.6.3
Summary of Vital Signs by Analysis Visit: Diastolic Blood Pressure (mmHg) – Safety 
Population
14.3.6.4
Summary of Vital Signs by Analysis Visit: Heart Rate (bpm) – Safety Population
14.3.6.5
Summary of Vital Signs by Analysis Visit: Body Temperature (oC) – Safety Population
14.3.6.6
Summary of Vital Signs by Analysis Visit: Respiratory Rate (rpm) – Safety Population
14.3.7
Concomitant Medications
14.3.7.1
Summary of Concomitant Medications – Safety Population
14.3.7.2
Summary of Concomitant Medications that Treat Pruritus – Safety Population
14.4 Other Data Summaries
14.4.1
Pharmacokinetic Data
14.4.1
Summary of Plasma Sample Maralixibat Concentrations (ng/mL) by Analysis Visit – Safety 
Population
 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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13.2.
Planned Listing Descriptions 
For the planned interim analysis for protocol number LUM001-305, 3 participant data listings 
will be produced: SAEs, TEAEs leading to permanent treatment discontinuation, and deaths.
These listings are imbedded within the safety tables and are included in Section 13.1.
All listings will be sorted by treatment phase, treatment received, site, and participant number.
All calculated variables (e.g., study day, TEAE flag) will be included in the listings.
In all listings, a blank line will be placed between each participant. Within a data listing, if an 
item appears line after line (e.g., repetition of participant number), then only the first occurrence 
will be displayed.
In data listings, the information for one participant will be kept on one page if at all possible, 
rather than splitting a participant’s information across pages.
Listing Number
Participant Listing Title
16.2
Participant Disposition
16.2.1
Analysis Populations and Treatment Assignments – Enrolled Participants
16.2.2
Participant Disposition – Enrolled Participants
16.2.3
Participant Disposition – Screen Failure
16.2.4
Participant Disposition – Entrance into Study Phases
16.3
Protocol Deviations/Participants Excluded from Efficacy Analyses
16.3.1
Inclusion and Exclusion Criteria – Enrolled Participants
16.3.2
Participant Excluded from Efficacy Analyses – Enrolled Participants
16.3.3
Major Protocol Deviations – Safety Population
16.4
Demographic Data and Other Baseline Characteristics
16.4.1
Demographics and Informed Consent – Safety Population
16.4.2
Medical History – Safety Population
16.4.3
Prior Medications – Safety Population
16.5
Study Drug Exposure, Compliance and Changes to MRX Dose
16.5.1
Study Drug Exposure – Safety Population
16.5.2
Study Drug Accountability and Compliance – Safety Population
16.5.3
Maralixibat Chloride Dose Changes – Safety Population
16.6
Individual Efficacy Response Data


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
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Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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Listing Number
Participant Listing Title
16.6.1
ItchRO (Obs) Weekly Average Morning Severity Score and sBA Results – Safety 
Population
16.6.2
Clinician Scratch and Xanthoma Scores – Safety Population
16.6.3
Liver Biochemical Enzymes – Safety Population
16.6.5
ItchRO Reported Outcomes (Caregiver) Daily Morning Scores – Safety Population
16.6.6
CIC, and CIC-Xan – Safety Population
16.6.7
Efficacy Laboratory Tests – Safety Population
16.6.8
Total sBA – Safety Population
16.6.9
Height and Weight Z-Scores – Safety Population
16.2.10.1.1.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Physical Functioning –
Safety Population
16.6.10.1.1.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Physical 
Functioning – Safety Population
16.6.10.1.2
Pediatric Quality of Life Inventory (Parent Report for Infants) - Physical Symptoms –
Safety Population
16.6.10.1.3.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Emotional Functioning –
Safety Population
16.6.10.1.3.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Emotional 
Functioning – Safety Population
16.6.10.1.4.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Social Functioning –
Safety Population
16.6.10.1.4.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Social 
Functioning – Safety Population
16.6.10.1.5
Pediatric Quality of Life Inventory (Parent Report for Infants) - Cognitive Functioning –
Safety Population
16.6.10.1.6
Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) -
Nursery/Day Care/School Functioning – Safety Population
16.6.10.2.1
Pediatric Quality of Life Inventory (Participant Report) - Physical Functioning – Safety 
Population
16.6.10.2.2
Pediatric Quality of Life Inventory (Participant Report) - Emotional Functioning – Safety 
Population
16.6.10.2.3
Pediatric Quality of Life Inventory (Participant Report) - Social Functioning – Safety 
Population
16.6.10.2.4
Pediatric Quality of Life Inventory (Participant Report) - School Functioning – Safety 
Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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Listing Number
Participant Listing Title
16.6.10.3.1
Multidimensional Fatigue Scale (Parent Report) - General Fatigue – Safety Population
16.6.10.3.2
Multidimensional Fatigue Scale (Parent Report) - Sleep/Rest Fatigue – Safety Population
16.6.10.3.3
Multidimensional Fatigue Scale (Parent Report) - Mental Fatigue – Safety Population
16.6.10.4.1
Multidimensional Fatigue Scale (Participant Report) - General Fatigue – Safety Population
16.6.10.4.2
Multidimensional Fatigue Scale (Participant Report) - Sleep/Rest Fatigue – Safety 
Population
16.6.10.4.3
Multidimensional Fatigue Scale (Participant Report) - Cognitive Fatigue – Safety 
Population
16.6.10.5.1
Family Impact Module (Parent Report) - Physical Functioning – Safety Population
16.6.10.5.2
Family Impact Module (Parent Report) - Emotional Functioning – Safety Population
16.6.10.5.3
Family Impact Module (Parent Report) - Social Functioning – Safety Population
16.6.10.5.4
Family Impact Module (Parent Report) - Cognitive Functioning – Safety Population
16.6.10.5.5
Family Impact Module (Parent Report) – Communication – Safety Population
16.6.10.5.6
Family Impact Module (Parent Report) – Worry – Safety Population
16.6.10.5.7
Family Impact Module (Parent Report) - Daily Activities – Safety Population
16.6.10.5.8
Family Impact Module (Parent Report) - Family Relationships – Safety Population
16.6.10.6.1
Pediatric Quality of Life Inventory (Parent Report) - Total Scale and Summary Scores –
Safety Population
16.6.10.6.2
Pediatric Quality of Life Inventory (Participant Report) - Total Scale and Summary Scores
– Safety Population
16.7
Adverse Events
16.7.1
Adverse Events – Safety Population
16.7.2.1
Adverse Events of Special Interest: Diarrhoea Events – Safety Population
16.7.2.2
Adverse Events of Special Interest: Fat Soluble Vitamin Deficiency Events – Safety 
Population
16.7.2.3
Adverse Events of Special Interest: Elevated Transaminases Events – Safety Population
16.7.2.4
Adverse Events of Special Interest: Elevated Bilirubin Events – Safety Population
16.7.3.1
Serious Adverse Events – Safety Population
16.7.3.2
Serious Related Adverse Events – Safety Population
16.7.4.1
Adverse Events Leading to Study Drug Discontinuation – Safety Population
16.7.4.2
Adverse Events Leading to Dose Reduction – Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
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Listing Number
Participant Listing Title
16.7.5.1
Severe or Life Threatening Adverse Events – Safety Population
16.7.5.2
Life Threatening Adverse Events – Safety Population
16.7.6
Adverse Events Causing Death – Safety Population
16.8
Laboratory Values
16.8.1.1
Safety Laboratory Tests: Chemistry – Safety Population
16.8.1.2
Safety Laboratory Tests: Chemistry – on Samples Collected After Extended Drug 
Interruption – Safety Population
16.8.2.1
Safety Laboratory Tests: Hematology – Safety Population
16.8.2.2
Safety Laboratory Tests: Hematology – on Samples Collected After Extended Drug 
Interruption – Safety Population
16.8.3.1
Safety Laboratory Tests: Urinalysis – Safety Population
16.8.3.2
Safety Laboratory Tests: Urinalysis – on Samples Collected After Extended Drug 
Interruption - Safety Population
16.8.4.1
Safety Laboratory Tests: Fat Soluble Vitamins – Safety Population
16.8.4.2
Safety Laboratory Tests: Fat Soluble Vitamins – on Samples Collected After Extended Drug 
Interruption - Safety Population
16.8.5.1
Safety Laboratory Tests: Lipid Panel – Safety Population
16.8.5.2
Safety Laboratory Tests: Lipid Panel – on Samples Collected After Extended Drug 
Interruption - Safety Population
16.8.6
Safety Laboratory Tests: Hepatocellular Carcinoma Marker – Alpha-Fetoprotein (AFP) –
Safety Population
16.8.7
Clinical Laboratory Tests : Timing of Sample Collection, Last Dose and Last Meal – Safety 
Population
16.8.8
Pregnancy Test Results – Safety Population
16.9
Vital Signs/Physical Examination/Telephone Contact Log
16.9.1.1
Vital Signs – Safety Population
16.9.1.2
Vital Signs – on Measures After Extended Drug Interruption - Safety Population
16.9.2
Physical Examination – Safety Population
16.9.3
Telephone Contact Log – Enrolled Participants
16.10
Concomitant Medications
16.10.1
Concomitant Medications – Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 74 of 83
Listing Number
Participant Listing Title
16.10.2
Concomitant Medications that Treat Pruritus – Safety Population
16.11
Drug Concentration Data
16.11
Plasma Sample Maralixibat Concentrations


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 75 of 83
13.3.
Planned Figure Descriptions 
The following are planned summary figures for protocol number LUM001-305. The figure 
numbers and page numbers are place holders only and will be determined when the figures are 
produced.
Mean (± SE) change from baseline for select efficacy variables will be displayed graphically by 
study week over time. For these line plots over time, study week will be based on the analysis 
visit mapping described in Table 4. Separate methods of displaying this data will be used as 
described below.
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 participant 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. Treatment sequence will be identified for 
each participant.
Figure Number
Figure Title
14.2  Efficacy Data
14.2.1
Plot of Mean (± SE) Change from Baseline in ItchRO (Obs) Weekly Average Morning Severity Score 
by Treatment Group Over Time - Safety Population
14.2.2
Plot of Mean (± SE) Change from Baseline in sBA (umol/L) by Treatment Group Over Time - Safety 
Population
14.2.3
Plot of Mean (± SE) Change from Baseline in ALP (U/L) by Treatment Group Over Time - Safety 
Population
14.2.4
Plot of Mean (± SE) Change from Baseline in ALT (U/L) by Treatment Group Over Time - Safety 
Population
14.2.5
Plot of Mean (± SE) Change from Baseline in ALT (U/L) by Treatment Group Over Time - Safety 
Population
14.2.6
Plot of Mean (± SE) Change from Baseline in GGT (U/L) by Treatment Group Over Time - Safety 
Population
14.2.7
Plot of Mean (± SE) Change from Baseline in Total Bilirubin (mg/dL) by Treatment Group Over Time -
Safety Population
14.2.8
Plot of Mean (± SE) Change from Baseline in Direct Bilirubin (mg/dL) by Treatment Group Over Time 
- Safety Population
14.2.9
Plot of Mean (± SE) Change from Baseline in C4 (ng/mL) by Treatment Group Over Time - Safety 
Population
14.2.10
Plot of Mean (± SE) Change from Baseline in Total Cholesterol (mg/dL) by Treatment Group Over 
Time - Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 76 of 83
14.2.11
Plot of Mean (± SE) Change from Baseline in LDL-C (mg/dL) by Treatment Group Over Time - Safety 
Population
14.2.12
Plot of Mean (± SE) Change from Baseline in Height Z-Score by Treatment Group Over Time - Safety 
Population
14.2.13
Plot of Mean (± SE) Change from Baseline in Weight Z-Score by Treatment Group Over Time - Safety 
Population
14.2.14
Plot of Mean (± SE) Change from Baseline in PedsQL Total Score (Parent) by Treatment Group Over 
Time - Safety Population
14.2.15
Plot of Mean (± SE) Change from Baseline in PedsQL Multidimensional Fatigue Scale Score (Parent) 
by Treatment Group Over Time - Safety Population
14.3.1  Display of Study Drug Exposure
14.3.1
Study Drug Exposure Over Time by Participant – Safety Population
14.3.2  Displays of Adverse Events
14.3.2
Plot of Treatment-Emergent Adverse Events of Special Interest Over Time by Preferred Term and 
Individual Participant – Safety Population
14.
Tables, Listings, and Listing Shells 
14.1.
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 LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 77 of 83
Appendix 1:  Premier Research Library of Abbreviations 
Abbreviation
Definition
AE
adverse event
AESI
adverse events of special interest
ALGS
alagille syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASBTi
apical sodium dependent bile acid transporter inhibitor
ATC
anatomical therapeutic chemical
AST
aspartate aminotransferase
BMI
body mass index
C4
7-alpha-hydroxy-4-cholesten-3-one
CDC
Centers for Disease control
ChiLDReN
Childhood Liver Disease Research Network
CI
confidence interval
CIC
caregiver impression of change
CRF
case report form
CSR
clinical study report


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 78 of 83
Abbreviation
Definition
CSS
clinician scratch score
CTCAE
common terminology criteria for adverse events
DMC
data monitoring committee
DSMB
data safety monitoring board
eDiary
electronic diary
EMA
European Medicines Agency
EOS
end of study
EOT
end of treatment
ET
early termination
FDA
food and drug administration
FGF-19
fibroblast growth factor 19
FGF-21
fibroblast growth factor 21
FSV
fat soluble vitamin
GI
gastrointestinal
IA
interim analysis
ICH
International Council for Harmonisation 
ID
identification
ItchRO
itch reported outcome
LLOQ
lower limit of quantitation


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 79 of 83
Abbreviation
Definition
LOCF
last-observation-carried-forward
MedDRA
medical dictionary for regulatory activities
MRX
maralixibat
NDA
new drug application
PA
protocol amendment
PBO
placebo
PedsQL
pediatric quality of life
PT
preferred term
RBP
retinol binding protein
SAE
serious adverse event
SAP
statistical analysis plan
sBA
serum bile acid
SD
standard deviation
SE
standard error
SOC
system organ class
TEAE
treatment-emergent adverse event
ULOQ
upper limit of quantification
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 80 of 83
Appendix 2: Listing of Safety and Efficacy Laboratory Analytes 
SAFETY LABS
CBC with Differential
Erythrocytes (RBC), 
106/μL
Hemoglobin, g/dL
Hematocrit, %
MCV, fL
MCH, pg
MCHC, g/dL
Platelets, 103/μL
Leukocytes (WBC), 
103/μL
Differential
(% and 103/μL)
x Neutrophils
x Eosinophils
x Basophils
x Lymphocytes
x Monocytes
Clinical Chemistry
Sodium, mEq/L
Potassium, mEq/L
Chloride, mEq/L
Bicarbonate, mEq/L
Total Protein, g/dL
Albumin, g/dL
Calcium, mg/dL
Phosphate, mg/dL
Glucose, mg/dL
BUN, mg/dL
Creatinine, mg/dL
Urate, mg/dL
Corrected Sodium, 
mmol/L
AST (SGOT), U/L
GGT, U/L
Coagulation
aPTT (sec)
PT (sec)
Lipid Panel
Triglycerides, mg/dL
Fat Soluble Vitamins
25-Hydroxy Vitamin D, ng/mL
Vitamin A (retinol), μg/dL
Retinol Binding Protein, mg/dL
Alpha Tocopherol, mg/dL
INR (surrogate marker for Vitamin 
K deficiency)
Retinol:RBP Molar Ratio, mol/mol
Lipid Ratio of Alpha Tocopherol to 
the sum of Cholesterol and 
Triglycerides, mg/g
Marker of hepatocellular carcinoma
Alpha Fetoprotein (AFP), ng/mL
Urinalysis [1]
pH
Specific Gravity
Oxalate, μmol/L
Epithelial Cells, HPF
Granular Casts, LPF
Hyaline Casts, LPF
RBC Casts, LPF
Urine Erythrocytes, HPF
Urine Leukocytes, HPF
WBC Casts, LPF
Waxy Casts, LPF
Urine Protein *
Urine Glucose * 
Ketones *
Urine Bilirubin *
Nitrite *
Urobilinogen *
Leukocyte Esterase *
Crystals *
Mucous Threads *
Urine Bacteria *
Urine Hemoglobin *
Yeast Cells *
EFFICACY LABS
Clinical Chemistry [2]
Total Bilirubin, mg/dL
Direct Bilirubin, 
mg/dL
Alkaline Phosphatase 
(ALP), U/L
ALT (SGPT), U/L
Lipid Panel
Cholesterol, mg/dL
LDL-C, mg/dL
HDL-C, mg/dL [1]
Cholestasis Biomarkers
Serum Bile Acids, μmol/L
7 alpha hydroxy-4-cholesten-3-one (C4), ng/mL
Autotaxin, ng/mL [1]
FGF-19, pg/mL [1]
FGF-21, pg/mL [1]
Bile Acid Subspecies, μmol/L
(15 subspecies) [1]
% Unconjugated Bile Acids, % [1]
Total Conjugated Bile Acids, μmol/L [1]
Total Unconjugated Bile Acids, μmol/L [1]
[1] Listing only; [2] Safety and efficacy laboratory tests; * Qualitative urinalysis
 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 81 of 83
Appendix 3: Listing 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


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 82 of 83
-
palpitation
-
hyperhidrosis
-
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


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-305
PCN Number LUME3562 
 
AD-ST-33.04 Effective date: 30-Jun-2017
Version 1.0    |
Date: 09-Apr-2020      |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 83 of 83
-
international normalised ratio increased
-
international normalised ratio abnormal
-
haemorrhage
-
melaena                       
-
epistaxis
-
haematochezia
-
haemoptysis