Clinical trial NCT02160782
Conditions: Alagille Syndrome
Sponsor: Mirum Pharmaceuticals, Inc.
Start date: 2014-10-28; Completion date: 2020-05-28
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a long-term, open-label study with a double-blind, placebo-controlled, randomized drug withdrawal period in children with Alagille Syndrome (ALGS) designed to evaluate the safety and efficacy of LUM001 (Also known as maralixibat or MRX).

Detailed description:
The study is divided into 6 parts: a 6-week open-label, dose escalation period, a 12-week open-label stable dosing period, a 4-week randomized, double-blind, placebo-controlled drug withdrawal period, a 26-week long-term stable dosing period, and an a 52-week optional follow-up treatment period, and a long-term optional follow-up treatment period for eligible participants who choose to stay on treatment with LUM001.

Arms: arm 1: LUM001, also known as Maralixibat (MRX) will be administered orally once a day (QD) up to 400 microgram per kilogram per day (mcg/kg/day) up to Week 52, followed by an increase in dose orally twice a day (BID) during long-term follow-up based on efficacy (serum bile acid \[sBA\] level and ItchRO\[Obs\] score) and safety assessment.

Note: 400 mcg/kg maralixibat chloride is equivalent to 380 mcg/kg free maralixibat. arm 2: Placebo will be administered orally once a day during randomized withdrawal period (Week 19 to Week 22)
Interventions: intervention 1: LUM001 (Maralixibat) intervention 2: Placebo
Intervention descriptions: intervention 1: LUM001, also known as Maralixibat (MRX) will be administered orally Once Daily (OD). To be administered Twice Daily (BID) for patients who are eligible. intervention 2: Placebo will be administered orally once daily during randomized withdrawal period

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
CLINICAL PROTOCOL 
PROTOCOL NUMBER: LUM001-304 
 
 
 
 
ICONIC STUDY 
 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED DRUG WITHDRAWAL PERIOD OF LUM001, AN APICAL SODIUM-DEPENDENT 
BILE ACID TRANSPORTER INHIBITOR (ASBTi), IN PATIENTS WITH ALAGILLE SYNDROME 
 
 
Protocol Amendment 5.1: 08 February 2019 
Protocol History 
Protocol Amendment 5:  06 Nov 2017 
Protocol Amendment 4:  28 Mar 2017 
Protocol Amendment 3: 
Protocol Amendment 2: 
Protocol Amendment 1: 
13 Nov 2015 
08 May 2015 
06 Mar 2015 
Original Protocol: 20 Mar 2014 
 
 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
United States  
 
 
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. 


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SPONSOR SIGNATURE PAGE 
 
LUM001-304 
 
 
ICONIC STUDY 
 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, PLACEBO-CONTROLLED, 
RANDOMIZED DRUG WITHDRAWAL PERIOD OF LUM001, AN APICAL SODIUM-DEPENDENT 
BILE ACID TRANSPORTER INHIBITOR (ASBTi), IN PATIENTS WITH ALAGILLE SYNDROME 
 
 
 
 
 
Protocol Amendment 5.1: 08 February 2019 
Protocol History 
Protocol Amendment 5: 06 Nov 2017 
Protocol Amendment 4: 28 Mar 2017 
Protocol Amendment 3: 
Protocol Amendment 2: 
Protocol Amendment 1: 
13 Nov 2015 
08 May 2015 
06 Mar 2015 
Original Protocol: 20 Mar 2014 
  
 
 
 
 
 
 
 
Sponsor: 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA  
 
 
 
 
 


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TITLE PAGE 
 
Study Drug: 
LUM001 
 
Protocol Number: 
LUM001-304 
 
Protocol Amendment: 
5.1 
 
Date: 
08 February 2019 
 
EudraCT No: 
2013-005373-43 
 
Study Phase: 
2 
 
Protocol Title: 
Long-Term, Open-Label Study with a Double-Blind, 
Placebo-Controlled, Randomized Drug Withdrawal Period of 
LUM001, an Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi), in Patients 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: medmonitorLUM304@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. 


CONFIDENTIAL 
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Mirum Pharmaceuticals, Inc. 
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PROTOCOL SIGNATURE PAGE 
Sponsor's (Mi·r·· ~7
. p . val 
Signature: 
( 
/, 
,. 
~ 
Thomas Jaecklin, MD 
Date: 
SVP Clinical Development 
I agree to conduct this study in accordance with the requirements of this clinical study protocol 
and also in accordance with the following: 
• 
Declaration of Helsinki (Oct 2008) 
• 
Established principles of Good Clinical Practice (ICH E6; GCP) (Harmonized) 
• 
US Code of Federal Regulations (CFR); Food and Drug Administration (FDA) 
(where applicable) 
• 
European Union (EU) Directives and national laws (where applicable) 
Clinical Study Title: 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, PLACEBO-
CONTROLLED, RANDOMIZED DRUG WITHDRAW AL PERIOD OF LU MOO I, AN 
APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTi), IN 
PATIENTS WITH ALAGILLE SYNDROME 
Protocol Number: 
Protocol: 
Date: 
EudraCT No: 
Sponsor: 
As Agreed: 
LUMOOl-304 
Amendment 5. I 
08 February 2019 
2013-0053 73-43 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
Investigator's Signature 
Investigator's Name (Please print) 
Date 


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EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Premier 
Research Serious Adverse Event Form within 24 hours to the Premier Research 
Pharmacovigilance Department. Applicable fax numbers and e-mail address can be found on the 
form (sent under separate cover) and below. 
Premier Research SAE Reporting: 
US and Canadian sites: fax 215-972-8765, or e-mail GlobalPV-US@premier-research.com 
EU/ROW sites: fax +421 2 6820 3713 or e-mail PVDS-ROW@premier-research.com 
For all urgent protocol- or safety-related issues during and outside of business hours, the 
investigator must contact the Premier Research Medical Monitor: 
Cagil Ozen, MD, Medical Director 
North America (US and Canada) sites: 
Central phone number: +1 512 686 1256 (US) 
European and ROW sites: 
Central phone number: +44 118 936 4096 (United Kingdom) 
For non-emergencies, the Premier Research Medical Monitor may be contacted by e-mail: 
medmonitorLUM304@premier-research.com    
 
 


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


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
TITLE PAGE ...................................................................................................................................3 
PROTOCOL SIGNATURE PAGE .................................................................................................4 
PRODUCT QUALITY COMPLAINTS..........................................................................................6 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................13 
PROTOCOL AMENDMENT 5.1 SUMMARY OF CHANGES ..................................................14 
1 
SYNOPSIS .............................................................................................................................17 
2 
LIST OF ABBREVIATIONS AND TERMS .........................................................................35 
3 
STUDY OBJECTIVES ..........................................................................................................39 
4 
BACKGROUND AND RATIONALE ...................................................................................40 
4.1 
Therapeutic Rationale ..............................................................................................40 
4.2 
Alagille Syndrome ....................................................................................................41 
4.3 
Pruritus .....................................................................................................................41 
4.4 
LUM001 ...................................................................................................................42 
4.4.1 Nonclinical Studies ................................................................................................42 
4.4.1.1 
Pharmacology .........................................................................................42 
4.4.1.2 
Pharmacokinetics ...................................................................................43 
4.4.1.3 
Toxicology .............................................................................................43 
4.4.2 Previous Clinical Experience .................................................................................44 
4.5 
Rationale for Dose and Schedule of Administration ................................................45 
5 
INVESTIGATIONAL PLAN .................................................................................................48 
5.1 
Study Design ............................................................................................................48 
5.2 
Data Monitoring Committee ....................................................................................48 
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 Screening................................................................................................................54 
5.5.2 Treatment ...............................................................................................................54 
5.5.2.1 
Dose Escalation Period ...........................................................................55 
5.5.2.2 
Stable Dosing Treatment Period ............................................................56 
5.5.2.3 
Double-blind Placebo-controlled Study Drug Withdrawal Period.........56 
5.5.2.4 
Long-term Exposure Period ...................................................................56 
5.5.2.5 
52-week Optional Follow-up Treatment Period .....................................56 


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5.5.2.6 
Long-term Optional Follow-up Treatment Period .................................57 
5.5.3 Safety Follow-up Period ........................................................................................58 
5.6 
End of Study .............................................................................................................58 
6 
SUBJECT ENROLLMENT ...................................................................................................60 
6.1 
Screening ..................................................................................................................60 
6.2 
Randomization .........................................................................................................60 
6.3 
Replacement of Subjects ..........................................................................................60 
6.4 
Unblinding of Treatment Assignment ......................................................................61 
7 
SUBJECT ELIGIBILITY .......................................................................................................62 
7.1 
Inclusion Criteria ......................................................................................................62 
7.2 
Exclusion Criteria .....................................................................................................62 
8 
STUDY PROCEDURES ........................................................................................................65 
8.1 
Study Schedule .........................................................................................................65 
8.1.1 Screening Period (Day -28 to Day -1) ...................................................................65 
8.1.2 Dose Escalation Treatment Period (Day 0 to Week 6) ..........................................65 
8.1.3 Stable Dosing Treatment Period (Week 7 to Week 18) .........................................66 
8.1.4 Double-blind, Placebo-controlled Study Withdrawal Period (Week 19 to 
Week 22) ................................................................................................................66 
8.1.5 Long-term Exposure Period (Week 23 to Week 48) .............................................67 
8.1.6 Week 48 .................................................................................................................67 
8.1.7 Early Termination for Subjects without Participation in the 52-week 
Optional Follow-up Treatment Period ...................................................................68 
8.1.8 52-week Optional Follow-up Treatment Period ....................................................68 
8.1.9 Long-term Optional Follow-up Treatment Period .................................................69 
8.1.10 End of Treatment or Early Termination.................................................................73 
8.1.11 Safety Follow-up Period ........................................................................................73 
8.2 
Genetic Testing ........................................................................................................73 
8.3 
Physical Examination, Weight and Height, Vital Signs ...........................................73 
8.4 
Laboratory Assessments ...........................................................................................73 
8.5 
Pruritus and Quality of Life Assessments ................................................................74 
8.5.1 Itch Reported Outcome (ItchRO™) .......................................................................74 
8.5.2 Clinician Scratch Scale ..........................................................................................75 
8.5.3 Clinician Xanthoma Scale ......................................................................................75 
8.5.4 Pediatric Quality of Life Inventory (PedsQL) .......................................................75 
8.5.5 Patient Impression of Change ................................................................................76 
8.5.6 Caregiver Impression of Change ...........................................................................76 
8.5.7 Caregiver Global Therapeutic Benefit ...................................................................76 
8.5.8 Palatability .............................................................................................................76 


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8.6 
Restriction on the Lifestyle of Subjects ...................................................................76 
8.6.1 Contraception Requirements ..................................................................................76 
8.6.2 Fasting Requirements.............................................................................................77 
9 
STUDY DRUG .......................................................................................................................78 
9.1 
Study Drug Description ............................................................................................78 
9.1.1 LUM001 .................................................................................................................78 
9.1.2 Placebo ...................................................................................................................78 
9.2 
Packaging and Labeling ...........................................................................................79 
9.3 
Drug Accountability .................................................................................................79 
10 TREATMENT OF SUBJECTS ..............................................................................................80 
10.1 
Study Drug Administration ......................................................................................80 
10.2 
Treatment Compliance .............................................................................................81 
10.3 
Concomitant Medications ........................................................................................81 
10.4 
Other Protocol-required Drugs .................................................................................81 
10.5 
Safety Monitoring Rules ..........................................................................................81 
10.5.1 General Monitoring Rules......................................................................................81 
10.5.2 Safety Monitoring Rules ........................................................................................82 
10.5.2.1 
Safety Monitoring for Liver Chemistry Tests ........................................83 
10.5.2.2 
Stopping Rules for Liver Chemistry Elevations ....................................84 
10.5.2.3 
Safety Monitoring for Triglycerides ......................................................84 
10.5.2.4 
Safety Monitoring for Fat Soluble Vitamins ..........................................84 
10.5.2.5 
Monitoring/Stopping Rules for Coagulation Panel Results ...................84 
10.6 
Adjustment of Dose ..................................................................................................84 
10.7 
Withdrawal of Subjects from the Study ...................................................................85 
11 SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .................................86 
11.1 
Regulatory Requirements .........................................................................................86 
11.2 
Definitions ................................................................................................................86 
11.2.1 Adverse Event ........................................................................................................86 
11.2.2 Adverse Reaction and Suspected Adverse Reaction .............................................87 
11.2.3 Serious Adverse Event (SAE) ................................................................................87 
11.3 
Monitoring and Recording Adverse Events .............................................................88 
11.3.1 Serious Adverse Events .........................................................................................88 
11.3.2 Non-serious Adverse Events ..................................................................................88 
11.3.3 Evaluation of Adverse Events (Serious and Non-Serious) ....................................89 
11.3.3.1 
Relationship to the Study Drug ..............................................................89 
11.3.3.2 
Severity ...................................................................................................89 
11.3.3.3 
Action Taken with Study Drug ..............................................................90 
11.3.3.4 
Treatment Given for Adverse Event ......................................................90 


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11.3.3.5 
Outcome of the Adverse Event ..............................................................90 
11.4 
Procedures for Handling Special Situations .............................................................90 
11.4.1 Pregnancy Reporting ..............................................................................................91 
11.4.2 Dosing Errors .........................................................................................................91 
11.4.3 Abnormalities of Laboratory Tests ........................................................................91 
12 STATISTICAL CONSIDERATIONS ...................................................................................93 
12.1 
Sample Size Considerations .....................................................................................93 
12.2 
Populations ...............................................................................................................93 
12.2.1 Safety Population ...................................................................................................93 
12.2.2 Efficacy Populations ..............................................................................................93 
12.2.3 Siblings 93 
12.2.4 Demographic and Baseline Characteristics ...........................................................94 
12.2.4.1 
Subject Disposition ................................................................................94 
12.2.4.2 
Baseline Data ..........................................................................................94 
12.2.5 Efficacy Analyses ..................................................................................................94 
12.2.5.1 
Efficacy Variables ..................................................................................94 
12.2.5.2 
Primary Efficacy Analysis .....................................................................96 
12.2.5.3 
Secondary, Exploratory and Other Efficacy Analyses ...........................96 
12.2.6 Safety Analyses ......................................................................................................97 
12.2.6.1 
Safety Assessments ................................................................................97 
12.2.7 Planned Method of Analysis ..................................................................................97 
12.2.8 Safety Analysis ......................................................................................................97 
12.2.8.1 
Adverse Events .......................................................................................97 
12.2.8.2 
Laboratory Tests .....................................................................................98 
12.2.8.3 
Physical Exams, Vital Signs and Weight/Height Measurements ...........98 
12.2.8.4 
Concomitant Medications ......................................................................98 
12.2.8.5 
Study Drug Exposure .............................................................................99 
12.2.8.6 
Serum Alpha-fetoprotein ........................................................................99 
12.2.9 Palatability Analyses ..............................................................................................99 
12.2.10 
Interim Analyses ....................................................................................99 
12.2.11 
Additional Analyses ...............................................................................99 
13 INVESTIGATOR’S REGULATORY OBLIGATIONS .....................................................100 
13.1 
Informed Consent ...................................................................................................100 
13.2 
Study Personnel ......................................................................................................100 
13.3 
Ethical Conduct of the Study .................................................................................101 
13.4 
Independent Ethics Committee/Institutional Review Board ..................................101 
13.5 
Confidentiality ........................................................................................................101 
14 ADMINISTRATIVE AND LEGAL OBLIGATIONS ........................................................103 


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14.1 
Pre-study Documentation Required .......................................................................103 
14.2 
Protocol Amendments ............................................................................................103 
14.3 
Study Termination ..................................................................................................103 
14.4 
Study Documentation and Storage .........................................................................104 
14.5 
Study Monitoring ...................................................................................................104 
14.6 
Language ................................................................................................................105 
14.7 
Compensation for Injury ........................................................................................105 
15 REFERENCES .....................................................................................................................106 
16 APPENDICES ......................................................................................................................107 
16.1 
Schedule of Procedures ..........................................................................................108 
16.1.1 Schedule of Procedures A-D: Study Entry – Week 96 ........................................109 
16.1.2 Schedule of Procedures E-F: Rollover under Protocol Amendment 4 ................118 
16.1.3 Schedule of Procedures G-I: Subject Re-Entry under Protocol Amendment 
4 
123 
16.1.4 Schedule of Procedures J – Study Termination and End of Treatment 
Procedures ............................................................................................................130 
16.2 
List of Laboratory Analytes ...................................................................................132 
16.3 
Alagille Syndrome Diagnostic Criteria ..................................................................133 
16.4 
Itch Reported Outcome Instrument (ItchRO™) .....................................................134 
16.4.1 Patient Itch Reported Outcome Instrument, ItchRO(Pt)™ ..................................135 
16.4.2 Observer Itch Reported Outcome Instrument, ItchRO(Obs)™ ...........................137 
16.5 
Clinician Scratch Scale ...........................................................................................139 
16.6 
Clinician Xanthoma Scale ......................................................................................141 
16.7 
Pediatric Quality of Life Inventory (PedsQL™) ....................................................142 
16.7.1 Parent Report for Infants (1 to 12 months) ..........................................................143 
16.7.2 Parent Report for Infants (13 to 24 months) ........................................................146 
16.7.3 Parent Report for Toddlers (ages 2-4) .................................................................149 
16.7.4 Parent Report for Young Children (ages 5-7) ......................................................151 
16.7.5 Parent Report for Children (ages 8-12) ................................................................153 
16.7.6 Parent Report for Teenagers (ages 13-18) ...........................................................155 
16.7.7 Pediatric Quality of Life Inventory v 4.0 for Young Children (ages 5-7) ...........157 
16.7.8 Pediatric Quality of Life Inventory for Children (ages 8-12) ..............................160 
16.7.9 Pediatric Quality of Life Inventory for Teenagers (ages 13-18) ..........................162 
16.7.10 
Multidimensional Fatigue Scale Parent Report for Toddlers (ages 
2-4) 
164 
16.7.11 
Multidimensional Fatigue Scale Parent Report for Young Children 
(ages 5-7) .............................................................................................................166 


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16.7.12 
Multidimensional Fatigue Scale Parent Report for Children (ages 
8-12) 
168 
16.7.13 
Multidimensional Fatigue Scale Parent Report for Teenagers (ages 
13-18) 
170 
16.7.14 
Multidimensional Fatigue Scale Young Child Report (ages 5-7) ........172 
16.7.15 
Multidimensional Fatigue Scale Child Report (ages 8-12) ..................175 
16.7.16 
Multidimensional Fatigue Scale Teen Report (ages 13-18) .................177 
16.7.17 
Family Impact Module v 2.0 ................................................................179 
16.8 
Patient Impression of Change (PIC) .......................................................................182 
16.9 
Caregiver Impression of Change (CIC) .................................................................183 
16.10 
Caregiver Global Therapeutic Benefit (CGTB) .....................................................185 
16.11 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 ..........186 
16.12 
Palatability Questionnaire ......................................................................................267 
16.13 
Protocol History .....................................................................................................269 
16.13.1 
Protocol Amendment 5 Summary of Changes .....................................269 
16.13.2 
Protocol Amendment 4 Summary of Changes .....................................271 
16.13.3 
Protocol Amendment 3 Summary of Changes .....................................293 
16.13.4 
Protocol Amendment 2 Summary of Changes .....................................306 
16.13.5 
Protocol Amendment 1 Summary of Changes .....................................308 
 
LIST OF TABLES 
Table 1: 
Improvement in Biochemical Markers and Pruritus After Partial 
External Biliary Diversion in PFIC Disease and Alagille Syndrome 
Subjects ..........................................................................................................42 
Table 2: 
Sample Daily Exposure (mg/day) in Pediatric Subjects ................................45 
Table 3: 
GI-associated Adverse Events in Study 003 .................................................46 
Table 4: 
Composition of LUM001 1.0 mL Oral Solution ...........................................78 
Table 5: 
Composition of LUM001 0.5 mL Oral Solution ...........................................78 
Table 6: 
Composition of LUM001 0.25 mL Oral Solution .........................................78 
Table 7: 
Composition of Placebo 1.0 mL Oral Solution .............................................79 
Table 8: 
Composition of Placebo 0.5 mL Oral Solution .............................................79 
Table 9: 
Composition of Placebo 0.25 mL Oral Solution ...........................................79 
 
 
 


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LIST OF FIGURES 
Figure 1: 
Interruption of Enterohepatic Circulation with an ASBT/IBAT 
Inhibitor .........................................................................................................40 
Figure 2: 
Serum Bile Salt Concentration and Degree of Itch .......................................42 
Figure 3: 
Study Design for LUM001-304 (Day 0 – Week 48) .....................................49 
Figure 4: 
52-week Optional Follow-up Treatment Scheme (<7 days from last 
LUM001 dose) ...............................................................................................50 
Figure 5: 
52-week Optional Follow-up Treatment Scheme (≥7 days from last 
LUM001 dose) ...............................................................................................51 
Figure 6: 
Long-term Optional Follow-up Treatment Scheme (≥7 days from Last 
LUM001 Dose between Protocol Amendment 3 and Protocol 
Amendment 4) ...............................................................................................52 
Figure 7: 
Long-term Optional Follow-up Treatment Scheme, without Afternoon 
Dose Escalation (ADE) .................................................................................53 
Figure 8: 
Long-term Optional Follow-up Treatment Scheme under Protocol 
Amendment 4, with Afternoon Dose Escalation (ADE) ...............................54 


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PROTOCOL AMENDMENT 5.1 SUMMARY OF CHANGES 
 
Protocol Number: 
LUM001-304 
 
Protocol Title: 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED DRUG WITHDRAWAL 
PERIOD OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN PATIENTS WITH 
ALAGILLE SYNDROME 
 
Amendment: 
5.1 
 
Date: 
08 February 2019 
 
The LUM001-304 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 5 (06 Nov 2017). Note that 
correction of typographical and grammatical errors are not captured in the below table.  
 


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


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Section 
Description of Change 
Product Quality 
Complaints 
Changed from: 
 
 
Origin 
of 
Product 
Quality 
Complaint 
E-mail Address 
North and South America 
PQC@shire.com 
European Union and Rest of World 
PQCROW@shire.com 
Telephone numbers (provided for reference if needed): 
Shire, Lexington, MA (USA) 
1-800-828-2088 
To:  
Origin 
of 
Product 
Quality 
Complaint 
E-mail Address 
North and South America 
medinfo@mirumpharma.com 
European Union and Rest of 
World 
medinfo@mirumpharma.com 
Telephone numbers (provided for reference if needed): 
Mirum, Menlo Park, CA (USA) 
1-650-667-4085 
 
 


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1 
SYNOPSIS 
Sponsor 
Mirum Pharmaceuticals, Inc. 
Protocol 
Number 
LUM001-304 
Protocol Title 
Long-Term, Open-Label Study with a Double-Blind, Placebo-Controlled, Randomized Drug 
Withdrawal Period of LUM001, an Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi), in Patients with Alagille Syndrome 
Study Phase 
2 
Indication 
Treatment of Patients with Alagille Syndrome (ALGS) 
Objectives 
• To evaluate the long-term safety and tolerability of LUM001 in children with ALGS.  
• To evaluate the effect of LUM001 on serum bile acid levels in children with ALGS.  
• To evaluate the effect of LUM001 on biochemical markers of cholestasis and liver 
disease in children with ALGS. 
• To evaluate the effect of LUM001 on pruritus in children with ALGS. 
• To evaluate the long-term effect of LUM001 in children with ALGS 48 weeks of 
treatment. 
Objectives of Long-term Optional Follow-up Treatment Period (After Week 48): 
• To offer eligible subjects treated in the LUM001-304 study continued study treatment 
after Week 48 until the first of the following occurs: (i) the subjects are eligible to enter 
another LUM001 study, (ii) LUM001 is available commercially, or (iii) the sponsor stops 
the program or development in this indication. 
• To explore twice a day (BID) dosing regimen and higher daily dosing of LUM001. 
• To obtain safety and efficacy data in subjects treated long term on LUM001 including 
genotyping characteristics. 
• To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma. 
• To assess palatability of the LUM001 formulation. 
Study Design 
This is a long-term, open-label study with a double-blind, placebo-controlled, randomized 
drug withdrawal period in children with ALGS designed to evaluate the safety and efficacy 
of LUM001. The study is divided into 6 parts: a 6-week open-label dose escalation period at 
doses up to 400 μg/kg/day, a 12-week open-label stable dosing period, a 4-week randomized, 
double-blind, placebo-controlled drug withdrawal period, a 26-week long-term stable dosing 
period at doses up to 400 μg/kg/day, a 52-week optional follow-up treatment period, and a 
long-term optional follow-up treatment period for eligible subjects who choose to stay on 
treatment with LUM001. During this long-term optional follow-up period, subjects may have 
their dose of LUM001 increased to a maximum of 800 μg/kg/day (400 μg/kg BID), based on 
efficacy (sBA level and ItchRO Observer [Obs] score) and safety assessment. Subjects’ 
participation in the long-term optional follow-up treatment period will continue until the first 
of the following occurs: (i) the subjects are eligible to enter another LUM001 study, (ii) 
LUM001 is available commercially, or (iii) the sponsor stops the program or development in 
this indication. Subjects who do not consent to Protocol Amendment 4 will continue their 
treatment as outlined in Protocol Amendment 3. 
Number of 
Subjects 
Approximately 30 subjects will be enrolled in this study. 
Study 
Population 
Inclusion Criteria 
To participate in this study, subjects must meet all of the following criteria: 


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1. Male or female between the ages of 12 months and 18 years inclusive. 
2. Diagnosis of ALGS based on the diagnostic criteria. 
3. Evidence of cholestasis (one or more of the following): 
a. Total serum bile acid >3x ULN for age. 
b. Conjugated bilirubin >1 mg/dL. 
c. Fat soluble vitamin deficiency otherwise unexplainable. 
d. GGT >3x ULN for age. 
e. Intractable pruritus explainable only by liver disease. 
4. Females of childbearing potential must have a negative serum pregnancy test during 
Screening. 
5. Males and females of child-bearing potential who are sexually active, or are not 
currently sexually active during the study, but become sexually active during the period 
of the study and for 30 days following the last dose of study drug, must agree to use 
acceptable contraception during the trial.  
6. Subject is expected to have a consistent caregiver(s) for the duration of the study. 
7. Informed consent and assent (per IRB/IEC) as appropriate. 
8. Access to phone for scheduled calls from study site. 
9. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary 
device during the study. 
10. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement 
in the eDiary software. 
11. Caregivers (and age appropriate subjects) must complete at least 10 eDiary reports 
(morning or evening) during each of two consecutive weeks of the screening period 
(maximum possible reports = 14 per week). 
12. Average daily score >2 on the Itch Reported Outcome (ItchRO™) questionnaire 
(maximum possible daily score of 4) for two consecutive weeks in the screening period, 
prior to dosing. A daily score is the higher of the scores for the morning and evening 
ItchRO. The average daily score is the sum of all daily scores divided by the number of 
days the ItchRO was completed.  
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Chronic diarrhea requiring ongoing intravenous fluid or nutritional intervention. 
2. Surgical interruption of the enterohepatic circulation. 
3. Previous liver transplant. 
4. Decompensated cirrhosis (ALT >15 x ULN, INR >1.5 [unresponsive to vitamin K 
therapy], albumin <3.0 g/dL, history or presence of clinically significant ascites, variceal 
hemorrhage, and/or encephalopathy). 
5. History or presence of other concomitant liver disease. 
6. History or presence of any other disease or condition known to interfere with the 
absorption, distribution, metabolism or excretion of drugs, including bile salt 
metabolism in the intestine (eg, inflammatory bowel disease). 
7. History or presence of gallstones or kidney stones. 
8. Known diagnosis of human immunodeficiency virus (HIV) infection. 
9. Cancers, except for in situ carcinoma, or cancers treated at least 5 years prior to 
Screening with no evidence of recurrence. 
10. Recent medical history or current status that suggests that the subject may be unable to 


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complete the study. 
11. Any female who is pregnant or lactating or who is planning to become pregnant during 
the study period. 
12. Known history of alcohol or substance abuse. 
13. Administration of bile acid or lipid binding resins within 28 days prior to screening and 
throughout the trial. 
14. Known hypersensitivity to LUM001or any of its components. 
15. Receipt of investigational drug, biologic, or medical device within 28 days prior to 
Screening, or 5 half-lives of the study agent, whichever is longer. 
16. History of non-adherence to medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to non-
adherence with the study protocol based upon investigator judgment. 
17. Any other conditions or abnormalities which, in the opinion of the investigator or 
medical monitor, may compromise the safety of the subject, or interfere with the subject 
participating in or completing the study. 
18. Subjects weighing over 50 kg at screening. 
Protocol Amendment #3: Eligible subjects for the 52-week optional follow-up period: 
Subjects will be considered eligible for the 52-week optional follow-up treatment period if 
they have: 
• 
Completed the protocol through the Week 48 visit with no safety concerns. Subjects 
who were discontinued due to safety reasons can be rechallenged if blood tests are 
back to relatively normal values for this patient population and subject does not 
meet any of the protocol’s stopping rules.  The decision will be made by the 
investigator in consultation with the medical monitor.  
• 
Subjects who have undergone a surgical disruption of the enterohepatic circulation 
will not be eligible to enter into the follow up treatment period.   
• 
Subjects who were discontinued for other reasons will be considered for the 52-
week optional follow-up treatment period on an individual basis. The decision will 
be made by the investigator in consultation with the medical monitor. 
Protocol Amendment 4: Eligible subjects for the long-term optional follow-up period: 
Inclusion Criteria for subjects with LUM001 dosing interruption <7 days, or ≥7 days: 
Subjects will be considered eligible for the long-term optional follow-up treatment period if 
they meet the following criteria: 
1. The subject has either:  
o 
Completed the protocol through the Week 48 visit with no major safety 
concerns 
 
OR 
o 
Discontinued due to safety reasons judged unrelated to the study drug, and 
laboratory results have returned to levels acceptable for this patient 
population or individual and subject does not meet any of the protocol’s 
stopping rules at the time of entry into the follow-up period. The decision 
will be made by the investigator in consultation with the medical monitor. 
[Subjects who were discontinued for other reasons will be considered on 
an individual basis.]  
2. Females of childbearing potential must have a negative urine or serum pregnancy 
test (β-human chorionic gonadotropin [β-hCG]) at the time of entry into the long-
term optional follow-up treatment period. 
3. Males and females of child-bearing potential who are sexually active, or are not 


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currently sexually active during the study, but become sexually active during the 
period of the study and 30 days following the last dose of study drug, must agree 
and use acceptable contraception during the trial. 
4. Informed consent and assent (per IRB/EC) as appropriate. 
5. 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 for Subjects with LUM001 dosing interruption ≥7 days : 
All exclusion criteria mentioned for the core study apply upon entry into the long-term 
optional follow-up period, with the exception of exclusion criterion #18.  
Treatment 
Groups 
All subjects will receive LUM001 up to 400 μg/kg/day or a maximum daily dose of 
20 mg/day. After completion of the 12-week stable dosing period, subjects will be 
randomized 1:1 to either a 4-week double-blind study drug withdrawal period during the 
study or will remain on study drug. Subjects will then enter a 26-week long-term stable 
dosing period and all subjects will receive LUM001 up to 400 μg/kg/day or a maximum 
daily dose of 20 mg/day. Subjects will be considered for a 52-week optional treatment 
period, if eligible, receiving up to 400 μg/kg/day, or the highest tolerated dose below the 400 
μg/kg/day dose. Subjects will then be considered for the long-term optional follow-up 
treatment, if eligible, receiving up to 800 μg/kg/day (given as twice daily doses of 
400 μg/kg), or to a maximum possible daily dose of 50 mg/day. 
Study Drug 
Dosage and 
Administration 
Study Drug Administration 
Subjects will receive a grape-flavored solution containing LUM001, administered orally 
once a day (QD) or twice a day (BID) using the syringe provided. The first dose should be 
taken at least 30 minutes prior to the first meal of the day and the second dose, where 
applicable, should be taken at least 30 minutes prior to dinner (main evening meal). The 
doses will not be administered q12h in order to better cover the luminal bile acid release 
associated with dinner and to minimize the risk of disturbing sleep due to the potential for 
abdominal pain and diarrhea at night. It is recommended that the dose should be taken 
approximately at the same time each day for the duration of the treatment period. 
QD Dosing Regimen 
For QD dosing, the required dose will be delivered in 0.5 mL volume for subjects who weigh 
less than 10 kg and in 1.0 mL for subjects who weigh 10 kg or more. 
BID Dosing Regimen 
For BID dosing, the required dose is delivered in half the dosing volume:  0.25 mL BID for 
subjects who weigh less than 10 kg and 0.50 mL BID for subjects who weigh 10 kg or more. 
For subjects weighing less than 10 kg at study entry, once a weight of 10 kg is reached while 
in the study, the subject will be moved from 0.5 mL maximum daily dosing volume (0.25 
mL BID) to 1.0 mL maximum daily dosing volume ( 0.50 mL BID ). 
Study Drug Dosage 
Initially, the LUM001 dose will be administered as a daily morning dose in either a 1.0 mL 
or 0.5 mL solution. The dose will be increased weekly over a 6-week period up to 
400 μg/kg/day QD or a maximum daily dose of 20 mg/day QD as follows: 
Week 1 Dose: 14 µg/kg/day QD 
Week 2 Dose: 35 µg/kg/day QD 
Week 3 Dose: 70 µg/kg/day QD  
Week 4 Dose: 140 µg/kg/day QD  
Week 5 Dose: 280 µg/kg/day QD 


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Week 6 Dose: 400 µg/kg/day QD (maximum daily dose of 20 mg QD) 
Subjects will continue dosing for another 12 weeks during the stable dosing period 
(to Week 18) using the dose administered at Week 6, which may be 400 µg/kg/day or the 
highest tolerated dose below 400 µg/kg/day. 
At the Week 18 visit, subjects will be randomized 1:1 to continue to receive study drug or a 
corresponding placebo for 4 weeks (1:1 randomized double-blind withdrawal period).  
Following the 4-week study drug randomized withdrawal period, subjects who received 
placebo will receive LUM001 dosed according to a dose escalation schedule that mirrors the 
initial escalation (ie, the LUM001 dose will be increased weekly over a 6-week period to the 
maximum tolerated dose up to 400 μg/kg/day or 20 mg/day or the highest tolerated dose 
below the 400 μg/kg/day dose). Subjects who were randomized to receive LUM001 will 
undergo a simulated dose escalation to maintain the blind in the randomized withdrawal 
period and will continue to receive LUM001 during the long-term exposure period, at the 
same dose administered at Week 22. Dosing with LUM001 will continue in a 26-week long-
term exposure period to complete 48 weeks of study. 
Optional Follow-up Treatment Period 
At Week 48, all subjects will be assessed by the investigator to determine their willingness 
and eligibility to roll-over into the 52-week optional follow-up treatment period. The 3 
following possible scenarios may occur: 
• 
Subjects who are eligible to roll over into the optional follow-up treatment period 
with no LUM001 dosing interruption or an interruption of <7 days will be 
maintained at the same dose level. 
• 
Subjects who are eligible to roll over into the optional follow-up treatment period 
with a LUM001 dosing interruption of ≥7 days will be dose escalated beginning at 
35 μg/kg/day and up to a maximum of 400 μg/kg/day or highest tolerated dose. 
• 
Subjects who do not wish to enter the follow-up treatment period will be contacted 
via telephone by the study site approximately 30 days after the last dose of study 
drug. 
Long-term Optional Follow-up Treatment Period 
Upon completion of the 52-week follow-up treatment period and/or implementation of this 
amendment, whichever occurs first, subjects will be assessed by the investigator to determine 
their willingness and eligibility to roll-over (or enter) into the long-term optional, follow-up 
treatment period. The 3 following possible scenarios may occur: 
Scenario 1: Subjects eligible to roll over into the long-term optional follow-up 
treatment period with no LUM001 dosing interruption or an interruption of <7 days: 
• 
Subjects with normal sBA level AND ItchRO(Obs) score <1.5 will be maintained at 
the same dose level and will continue morning dosing only. 
• 
Subjects with sBA level above normal AND/OR ItchRO(Obs) score ≥1.5 will start 
BID dosing (afternoon dose escalation; ADE) as follows: 
o 
The morning dose will be continued at the same dose level, but the volume 
of the morning dose will be reduced by half at the same time that the 
afternoon dose is initiated. 
o 
The afternoon dose will be initiated at dose level 140 µg/kg and will 
continue at this dose for a period of 4 weeks. If this dose level is tolerated, 
the afternoon dose will then be escalated to 400 µg/kg. 


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Scenario 2: Subjects eligible to roll over into the long-term optional follow-up 
treatment period with a LUM001 interruption of ≥7 days: 
• 
First, the morning dose is escalated up to 400 µg/kg/day or highest tolerated dose 
following a 5-week dose escalation beginning at 35 µg/kg/day. 
• 
Once the morning dose of 400 µg/kg or maximum tolerated dose is achieved, sBA 
and ItchRO(Obs) score will be evaluated. 
o 
Subjects with normal sBA AND ItchRO(Obs) score <1.5 after morning 
dose escalation will be maintained at the same dose level and will continue 
morning dosing only. 
o 
Subjects with sBA above normal AND/OR ItchRO(Obs) score ≥1.5 will 
begin BID dosing (afternoon dose escalation) as follows: 
 
The morning dose will be continued at the same dose level, but 
the volume of the morning dose will be reduced by half at the 
same time that the afternoon dose is initiated. 
 
The afternoon dose will be initiated at dose level 140 µg/kg and 
will continue at this dose for a period of 4 weeks. If this dose 
level is tolerated, the afternoon dose will then be escalated to 400 
µg/kg.  
The following parameters apply to both dosing scenarios outlined above: 
• 
The afternoon dose will only be initiated once the subject has been treated on stable 
morning doses for at least 4 weeks. 
• 
The sBA value used for determination of ADE eligibility will be the most recent 
available value collected within the prior 16 weeks. The ItchRO(Obs) score used 
for ADE eligibility will be derived from the most recent available 7-day interval of 
ItchRO(Obs) collected within the prior 16 weeks.  
• 
The maximum daily dose will be 400 µg/kg BID, ie, 800 µg/kg/day (up to a 
maximum possible daily dose of 50 mg/day). 
Scenario 3:  Subjects who do not consent to Protocol Amendment 4 will continue their 
treatment as outlined in Protocol Amendment 3. 
Rationale for 
Dose and 
Schedule 
Selection  
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. 
If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, 
abdominal pain, cramping) at any time during the study, the physician investigator in 
consultation with the medical monitor may lower the dose to a previously tolerated dose; 
later attempts to escalate the dose are permitted. If the subject is on a BID dosing regimen, 
dose lowering should first be attempted with the afternoon dose. 
The dosage of LUM001 is based upon prior experience with this investigational product in 
healthy volunteers and adult and pediatric subjects with hypercholesterolemia. In these 
subjects, with normal bile flow and without liver disease, an increase in gastrointestinal (GI) 
adverse events (AEs) was observed in those receiving doses above 10 mg per day. These 
signs and symptoms were believed to be caused by increases 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 LUM001 is likely to produce a correspondingly smaller 
increase in free bile acids in the lower colon. There is evidence in subjects with cholestasis to 
suggest that ASBT expression may be upregulated and higher ASBTi concentrations may be 


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required to achieve the desired target inhibition. 
Dosing in pediatric subjects will be based on the subject’s weight. The appropriate dose of 
LUM001 for the lowering of bile acid concentrations and the reduction of pruritus in 
cholestatic populations is not known. Earlier studies in healthy volunteers and 
hypercholesterolemic subjects demonstrated that doses of 10 mg to 30 mg daily (equivalent 
to 140 µg/kg/day to 400 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-associated AEs were generally recorded in the first 
weeks of LUM001 dosing and then at levels 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, diarrhea and abdominal pain or cramps. When the LUM001 
dose was increased after each 7-day dosing period, to a maximum of 5 mg daily, the 
incidence of GI-associated AEs in the LUM001 treatment arm was comparable to the 
reported incidence in the placebo group. 
To reduce the risk of loose stools, diarrhea and abdominal pain or cramps in this study, the 
LUM001 dose will be escalated over the first 6 weeks. Dosing will start at 14 µg/kg/day, and 
will then be increased at 7 day intervals to a maximum dose of 400 µg/kg/day (equivalent to 
approximately 20 mg daily dose in a 50 kg subject).  
For subjects in the long-term optional follow-up treatment period with ≥7 days since the last 
dose of LUM001, dosing will start at 35 µg/kg/day, and will then be increased over the first 
5 weeks up to 400 µg/kg/day or to the maximum tolerated dose. This escalation regimen is 
supported by the safety profile observed in completed and ongoing clinical studies of 
LUM001 and allows for subjects to reach 400 µg/kg/day or a maximum tolerated dose within 
a 5-week period.  
Under Protocol Amendment 4, an afternoon dose is introduced for eligible subjects in the 
long-term optional follow up treatment period. LUM001 doses will be escalated over a 
period of 4-8 weeks up to a maximum dose of 400 µg/kg BID (or maximum tolerated dose). 
The afternoon dose is only initiated and escalated in subjects with elevated sBA and/or 
ItchRO(Obs) ≥1.5 on the maximum (or maximum tolerated) morning dose.  
This escalation regimen is supported by the safety profile observed in completed and 
ongoing clinical studies of LUM001. Twice daily dosing is used in this study based on the 
findings of a healthy volunteers study in adult males (Study SHP625-101), which 
demonstrated that bile acid levels in feces increase with escalating doses and twice-daily 
regimen of LUM001 (up to 100 mg QD and 50 mg BID). In this study, subjects who were 
randomized to LUM001 treatment, received 1 of 4 doses of LUM001 (10, 20, 50, 100 mg) 
during 7 days. No titration was used in this study. There was a dose-dependent increase in 
total fecal BA excretion. In addition, BID dosing (ie, 50 mg BID) led to a further increase in 
fecal BA excretion as compared to QD dosing (ie, 100 mg QD). It is therefore hypothesized 
that twice-daily dosing has the potential to allow for more complete target engagement 
throughout the day at the level of the distal ileum. 
The higher dosing level is also supported by favorable results from a juvenile toxicity study 
conducted in rats administered LUM001 for 43 days (PND21 through PND63). As expected 
for a drug intentionally designed to be minimally absorbed, systemic LUM001 exposure was 
very low and consistent with levels that were previously determined in several oral gavage 
studies in adult rats. No adverse effects were observed on postnatal growth and development 
of offspring at the highest doses tested (200 mg/kg/day in males, 1000 mg/kg/day in 
females). This study was initiated in juvenile animals at PND21, which from a whole animal 
development perspective, is typically representative of a 2-year old child. However, given 
the fact that LUM001 is a minimally absorbed drug, of particular importance is the age at 
which the GI tract is considered functionally mature. In humans this is considered to have 
occurred by 12 months of age; likewise, postnatal maturation of the GI tract in rats occurs 


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during the first 3 weeks of life. Therefore, results from this study can be used to support the 
dosing levels proposed here for children 12 months of age and older. 
Study Visit 
Schedule and 
Procedures 
Study activities will be conducted as described in the Schedule of Procedures.  
The dosage and dosing regimen of concomitant drug therapy other than that specified by the 
protocol should not change during the first 22 weeks of the study, with the exception of 
weight-based study drug adjustments and vitamin supplementation. No new medications 
used to treat pruritus may be added during the first 22 weeks of the study.  
Synopsis Figure 1: Study Design for LUM001-304 (Up to and including Week 48)  
 
Screening Period (Day -28 to Day -1):  After obtaining informed consent (and/or assent 
when appropriate), demographic data (gender, age, and race) will be collected and subjects 
will undergo a medical history and physical examination including body weight, height, and 
vital signs, compilation of concomitant medications, and have blood and urine samples taken 
for clinical laboratory testing. For subjects who do not have documentation of a JAGGED-1 
or NOTCH2 mutation, a blood sample may be obtained for genotyping. The physician will 
provide an assessment of itch severity using the clinician scratch score during Screening. The 
eDiary for assessing pruritus with the Itch Reported Outcome (ItchRO) instrument will be 
dispensed and subjects and caregivers will undergo training during the Screening visit. The 
patient/caregiver ItchROs will be completed twice daily during the Screening period to 
establish eligibility and a baseline score. Subjects 9 years of age and older will continue 
independent twice daily completion of their ItchRO. Subjects 5-8 years of age will continue 
twice daily completion of their ItchRO with the assistance of their caregivers, if needed. 
Caregivers will continue twice daily completion of their ItchRO. Caregivers (and age 
appropriate subjects) must complete at least 10 eDiary reports (morning or evening) during 
each of two consecutive weeks of the screening period, (maximum possible reports = 14 per 
week). Subjects are required to discontinue bile acid resins for at least 28 days prior to 
screening and throughout the study. Females who are of childbearing potential will have a 
serum pregnancy test. Eligibility criteria will be reviewed to confirm a subject’s eligibility 4-
7 days prior to the Baseline Visit. 
Dose Escalation Treatment Period (Day 0 to Week 6):  At the Baseline Visit (Day 0), 
subjects will be assessed to confirm continued study eligibility and undergo a physical 
examination including body weight, height, and vital signs, and have urine and blood 
samples taken for hematology, chemistry, fasting lipid panel, baseline levels of bile acids and 
other cholestasis biochemical markers. Blood will also be collected for determination of 


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baseline fat-soluble vitamins and a plasma LUM001 drug level. Compliance with ItchRO 
will be assessed. The clinician scratch scale, xanthoma scale, and PedsQL questionnaires will 
be completed. Female subjects who are of childbearing potential will have a urine pregnancy 
test prior to dispensing study medication. Study medication for Weeks 1, 2, and 3 will be 
supplied at the Baseline Visit to eligible subjects. Subjects and caregivers will continue twice 
daily completion of their ItchRO throughout the Dose-Escalation Treatment Period. Subjects 
will return to the clinic at Weeks 3 and 6 and follow-up phone calls will be made at Weeks 1, 
2, 4, and 5. On clinic visit days, safety and clinical laboratory evaluations will be performed, 
and a physical exam will be performed (including collection of vital signs, height and weight 
measurements). Clinician scratch scale, adherence to study medication, and ItchRO 
compliance will be assessed. Concomitant medications and any adverse events will be 
recorded. Female subjects who are of childbearing potential will have a urine pregnancy test 
prior to dispensing study medication. Study drug will be supplied at Weeks 3 and 6. 
Stable Dosing Treatment Period (Week 7 to Week 18):  Each subject will continue dosing 
with study drug during a 12-week Stable Dosing Treatment Period using the dose 
administered at Week 6, which may be 400 µg/kg/day or the highest tolerated dose below 
400 µg/kg/day. Subjects 9 years of age and older will continue independent twice daily 
completion of their ItchRO. Subjects 5-8 years of age will continue twice daily completion of 
their ItchRO with the assistance of their caregivers, if needed. Caregivers will continue twice 
daily completion of their ItchRO. Subjects will receive a follow-up phone call at Week 9 and 
return to the clinic at Weeks 12 and 18. At the Week 12 and 18 visits, safety and clinical 
laboratory evaluations will be performed, and a physical exam will be performed (including 
collection of vital signs, height and weight measurements). Blood samples will be taken for 
fasting lipid panel, serum bile acids, fat soluble vitamins, and other cholestasis biochemical 
markers. Blood sampling for study drug determination may also be performed. After the 
baseline pharmacokinetic analysis, blood sampling for an additional pharmacokinetic 
analysis will be done at one additional time point at Week 12, 18, 38, or 48 – to be selected 
by the site/investigator (sample to be taken approximately 4 hours post-dosing). Clinician 
scratch scale, adherence to study medication, ItchRO compliance, and the PedsQL 
questionnaire will be assessed and concomitant medications and any adverse events will be 
recorded. In addition, at the Week 18 visit the Clinician Xanthoma Scale, Patient Impression 
of Change (PIC), Caregiver Impression of Change (CIC), and Caregiver Global Therapeutic 
Benefit (CGTB) assessments will be completed. At the Week 18 visit, subjects will also be 
randomized 1:1 to either continue to receive study drug or a corresponding placebo between 
Week 19 and Week 22. Female subjects who are of childbearing potential will have a urine 
pregnancy test prior to dispensing study medication. Study drug will be supplied at Week 12 
and study drug (or placebo) supplied at Week 18. 
Double-Blind, Placebo-Controlled Study Drug Withdrawal Period (Week 19 to Week 22): 
Age appropriate subjects and caregivers will continue twice daily completion of their 
ItchRO. Subjects will receive a follow-up phone call at Week 20 and return to the clinic at 
Week 22. At the Week 22 visit, safety and clinical laboratory evaluations will be performed, 
and a physical exam will be performed (including collection of vital signs, height and weight 
measurements). Blood samples will be taken for fasting lipid panel, serum bile acids, fat 
soluble vitamins, and other cholestasis biochemical markers. Female subjects who are of 
childbearing potential will have a urine pregnancy test prior to dispensing study medication. 
Study drug will be supplied at Week 22. Clinician scratch scale, adherence to study 
medication, ItchRO compliance, PIC, CIC, CGTB, and the PedsQL questionnaires will be 
assessed and concomitant medications and any adverse events will be recorded.  
Long-Term Exposure Period (Week 23 to Week 48): Following the 4-week double-blind 
study drug withdrawal period, subjects who received placebo will once again receive 
LUM001 according to the schedule where the dose is increased weekly over a 6-week period 
up to 400 μg/kg/day or a maximum daily dose of 20 mg/day. Subjects who were randomized 
to receive LUM001 will undergo a simulated dose escalation to maintain the blind in the 


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randomized withdrawal period and will continue to receive LUM001 during the long-term 
exposure period, at the same dose administered at Week 22. 
Subjects and caregivers will continue twice daily completion of their ItchRO throughout the 
long-term exposure period to the Week 48 clinic visit. Subjects will return to the clinic at 
Weeks 28, 38, and 48. At these visits, safety and clinical laboratory evaluations will be 
performed, and a physical exam will be performed (including collection of vital signs, height 
and weight measurements). Blood samples will be taken for fat soluble vitamins, as well as 
possible pharmacokinetic blood sampling for study drug determination (if not done 
previously at Week 12 or 18). Female subjects who are of childbearing potential will have a 
urine pregnancy test prior to dispensing study medication. Clinician scratch scale, adherence 
to study medication, and ItchRO compliance will be assessed. Subjects/caregivers will 
receive follow-up phone calls at the end of Weeks 23-27, 33, and 43. Concomitant 
medications and adverse events will be recorded at all clinic visits and at scheduled 
telephone contacts.  
At the investigator’s discretion, withdrawal of concomitant medications used for the 
treatment of pruritus may occur during the long-term exposure period. Additional study drug 
will be supplied at each clinic visit during the long-term exposure period. 
Week 48: Subjects will be evaluated by the investigator to determine whether they are 
eligible to roll over into the optional follow-up treatment period. Eligible subjects must have 
documented consents in order to continue in the optional follow-up treatment period. A 
physical exam (including collection of vital signs, height and weight measurements) will be 
performed. Blood and urine samples will be taken for clinical laboratory testing, including a 
fasting lipid panel and determination of fat-soluble vitamins, bile acids, other cholestasis 
biochemical markers, and possibly LUM001 drug level analysis. Female subjects who are of 
childbearing potential will have a urine pregnancy test. The Clinician Scratch Scale, 
Clinician Xanthoma Scale, and PedsQL questionnaires will be completed. The PIC, the CIC, 
and the CGTB assessments will be completed. Concomitant medications and adverse events 
will be recorded. ItchRO and study drug compliance will be assessed and all remaining study 
drug and study supplies will be collected. eDiaries will be returned to the site and Study drug 
will be discontinued at this visit if the subject chooses not to participate in the optional 
follow-up treatment period.  
Subjects who withdraw from the study prior to completion of all treatment period clinic 
visits should undergo the procedures specified for the Week 48/Study Termination visit. 
Follow-up Phone Call: For subjects who do not roll over into the optional follow-up 
treatment period, a safety follow-up phone call will be made 30 days after the last dose of 
study drug. This call will be made for all subjects who complete the study, as well as any 
subject who terminates from the study early. Concomitant medications and adverse events 
noted during this phone call will be recorded.  
Follow-up Treatment Period (post-Week 48):  
Subjects who are eligible to roll over into the follow-up treatment period with no 
LUM001 dosing interruption or an interruption of <7 days will be maintained at the 
same dose level within the 52-week Optional Follow-Up Treatment period. During this 
period, subjects will return to the clinic at Weeks 60, 72, 84, 96, and 100; telephone contacts 
will occur at Weeks 64, 68, 76, 80, 88, and 92. 
 
 
 
 
 


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Synopsis Figure 2: 52-week Optional Follow-up Treatment (<7 days from last 
LUM001 dose) 
 
Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 
400 μg/kg/day or to the highest tolerated dose. The dose escalation (DE) period will proceed 
as follows: 
• 
Week DE-2 Clinic Visit: obtain consent, weight, and draw blood for laboratory 
analyses 
• 
Week DE 0 Clinic Visit: investigator evaluates laboratory results, study drug is 
dispensed, and subject begins at 35 μg/kg/day dose level (if no safety concerns) 
• 
Week DE 49 Telephone Contact: subject escalates to 70 μg/kg/day dose level if 
prior dose level was tolerated 
• 
Week DE 50 Telephone Contact: subject escalates to 140 μg/kg/day dose level if 
prior dose level was tolerated 
• 
Week DE 51 Telephone Contact: subject escalates to 280 μg/kg/day dose level if 
prior dose level was tolerated 
• 
Week DE 52 Clinic Visit: laboratory tests and dose escalates to 400 μg/kg/day dose 
(maximum daily dose of 20 mg), if prior dose level was tolerated 
Synopsis Figure 3: 52-week Optional Follow-up Treatment (≥7 days from last LUM001 
dose)  
 


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If any subject experiences intolerance, the investigator, in consultation with the medical 
monitor, may lower the dose to a previously tolerated dose at any time during the entire 
follow-up treatment period. At the investigator’s discretion and in consultation with the 
medical monitor subjects who were previously down titrated may be rechallenged during the 
follow-up treatment period. 
Long-term Optional Follow-up Treatment Period 
Upon completion of the additional 52-week follow up treatment period and/or 
implementation of this amendment, whichever occurs first, subjects who are eligible to roll 
over onto the long-term optional follow-up treatment period will continue to receive study 
drug until the first of the following occurs:  
i. 
The subjects are eligible to enter another LUM001 study,  
ii. 
LUM001 is commercially available, or  
iii. 
The sponsor stops the program or development of this indication. 
Once Protocol Amendment 4 is implemented at the site, a determination about ADE will be 
made.  
Subjects who are eligible to roll over from the 52-week follow up treatment period into 
the long-term optional follow-up treatment period with no LUM001 dosing 
interruption or an interruption of <7 days prior to implementation of Protocol 
Amendment 4 will be consented and evaluated for eligibility for ADE.  Once a determination 
about ADE has been made, the subject will then either initiate the ADE (Synopsis Figure 6) 
or continue receiving the same dose of LUM001 once a day (Synopsis Figure 5), depending 
on whether they meet criteria for initiating ADE.  
Subjects with ≥7 days since last dose of LUM001 prior to implementation of Protocol 
Amendment 4 who are eligible to enter the long-term optional follow-up treatment period 
will be dose escalated up to 400 µg/kg/day or to the highest tolerated dose beginning with 35 
μg/kg/day, as outlined in Synopsis Figure 4.  
The dose escalation (DE) period will proceed as follows: 
• 
Protocol Amendment 4 DE-2 Clinic Visit: obtain consent, weight, and draw blood 
for laboratory analyses 
• 
Protocol Amendment 4 DE Day 0 Clinic Visit: PI evaluates laboratory results, study 
drug is dispensed, and subject begins at 35 µg/kg/day dose level (if no safety 
concerns) 
• 
Protocol Amendment 4 DE Week 1 Telephone Contact: subject escalates to 
70 µg/kg/day dose level 
• 
Protocol Amendment 4 DE Week 2 Telephone Contact: subject escalates to 
140 µg/kg/day dose level if prior dose level was tolerated 
• 
Protocol Amendment 4 DE Week 3 Telephone Contact: subject escalates to 
280 μg/kg/day dose level if prior dose level was tolerated 
• 
Protocol Amendment 4 DE Week 4 Clinic Visit: laboratory tests and dose escalates 
to 400 µg/kg/day dose (maximum daily dose of 20 mg), if prior dose level was 
tolerated 
• 
Protocol Amendment 4 DE Week 8 Telephone Contact: eligibility for ADE will be 
determined. 
 
 


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Synopsis Figure 4: Long-term Optional Follow-up Treatment (≥7 Days from last 
LUM001 dose between Protocol Amendment 3 and Protocol Amendment 4) 
 
Subjects not eligible for ADE (subjects with normal sBA level AND ItchRO(Obs) score 
<1.5), will be maintained at the same dose level and will continue morning dosing only. 
Subjects will have study activities repeated in repeating 12-week periods as follows, until 
study completion or termination: 
• 
Repeating Period Week 4 (ie, beginning 4 weeks after consent to Protocol 
Amendment 4) Telephone Contact: Collection of concomitant medications and any 
adverse events. 
• 
Repeating Period Week 8 Telephone Contact: Collection of concomitant 
medications and any adverse events.  
• 
Repeating Period Week 12 Clinic Visit: Physical exam, body weight and height, 
vital signs, and blood samples for clinical laboratory testing including fasting lipid 
panel. Blood will also be collected for determination of baseline fat-soluble 
vitamins. Urine samples for clinical laboratory testing will be collected at every 
other visit. ItchRO compliance will be assessed, the electronic diary will be issued, 
the Clinician Scratch Scale and Clinician Xanthoma Scale will be administered, and 
the PedsQL questionnaire will be administered. Additionally, a palatability 
questionnaire will be completed. Female subjects who are of childbearing potential 
will have a urine pregnancy test prior to dispensing study drug. Study drug 
compliance will be assessed and study drug will be dispensed. Concomitant 
medications and adverse events will be collected. 
• 
Subjects who do not qualify for ADE may be assessed at a later time point on a case 
by case basis following discussions between the investigator and medical monitor. 
Such re-evaluations may only occur at the Week 12 visit of any Repeating Period 
beginning with RP2. If in the course of the ADE re-evaluation, a subject is found to 
qualify for ADE, then the subject will move into Schedule F or G, as outlined in 
Section 16.1. During the follow-up treatment period, subjects will return to the 
clinic every 3 months. 
 
 
 


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Synopsis Figure 5:  Long-term Optional Follow-up Treatment without Afternoon Dose 
Escalation (ADE)  
 
If the subject is eligible for ADE, ie, who have sBA level above normal AND/OR 
ItchRO(Obs) score ≥1.5, the subject will begin BID dosing (afternoon dose escalation; 
ADE) as follows: 
• 
On ADE Day 0, morning dosing will continue at 400 µg/kg or the maximum 
tolerated dose. However, the volume of the morning dose will be reduced by half. 
Of note: Morning dosing must have been stable for ≥4 weeks prior to initiation of 
ADE.  
• 
On ADE Day 0, the afternoon dose will be initiated at dose level 140 µg/kg and will 
continue at this dose for a period of 4 weeks. If this dose level is tolerated, the 
afternoon dose will then be escalated to 400 µg/kg. 
The following procedures will occur during the ADE period: 
• 
ADE Day 0 Clinic Visit: Physical exam, body weight and height, vital signs, and 
blood and urine samples for clinical laboratory testing, including fasting lipid panel. 
Blood will also be collected for determination of fat-soluble vitamins. Plasma 
sample will be obtained for LUM001 pharmacokinetics. The Clinician Scratch 
Scale, Clinician Xanthoma Scale, and the PedsQL questionnaire will be 
administered. Female subjects who are of childbearing potential will have a urine 
pregnancy test prior to dispensing study drug. Study drug compliance will be 
assessed and study drug will be dispensed. Concomitant medications and any 
adverse events will be collected. 
• 
ADE Week 1 and Week 2 Telephone Contact: Collection of concomitant 
medications and any adverse events. Subject/caregiver will be reminded of dosing 
instructions. 
• 
ADE Week 4 Clinic Visit:  Physical exam, body weight and height, vital signs, and 
blood and urine samples for clinical laboratory testing, including fasting lipid panel. 
Blood will also be collected for determination of fat-soluble vitamins. Plasma 
sample will be obtained for LUM001 pharmacokinetics. The Clinician Scratch 
Scale, Clinician Xanthoma Scale, and the PedsQL questionnaire will be 


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administered. Female subjects who are of childbearing potential will have a urine 
pregnancy test prior to dispensing study drug. Study drug compliance will be 
assessed and study drug will be dispensed. Concomitant medications and any 
adverse events will be collected. 
• 
ADE Week 5 and Week 6 Telephone Contact: Collection of concomitant 
medications and any adverse events. Subject/caregiver will be reminded of dosing 
instructions. 
• 
ADE Week 8 Clinic Visit: Physical exam, body weight and height, vital signs, and 
blood and urine samples for clinical laboratory testing, including fasting lipid panel. 
Blood will also be collected for determination of fat-soluble vitamins. Plasma 
sample will be obtained for LUM001 pharmacokinetics. The Clinician Scratch 
Scale, Clinician Xanthoma Scale, and the PedsQL questionnaire will be 
administered. Female subjects who are of childbearing potential will have a urine 
pregnancy test prior to dispensing study drug. Study drug compliance will be 
assessed and study drug will be dispensed. Concomitant medications and any 
adverse events will be collected. 
Synopsis Figure 6:  Long-term Optional Follow-up Treatment, with Afternoon Dose 
Escalation (ADE) 
 
If any subject experiences intolerance, the investigator, in consultation with the medical 
monitor, may lower the dose to a previously tolerated dose at any time during the entire 
follow-up treatment period; later attempts to escalate the dose are permitted. At the 
investigator’s discretion, and in consultation with the medical monitor subjects who were 
previously down titrated may be rechallenged during the follow-up treatment period. If the 
subject is on a twice daily dosing regimen, dose lowering should be first attempted with the 
afternoon dose. 
Safety and clinical laboratory evaluations and a physical exam (including collection of vital 
signs, height and weight measurements) will be completed at each clinic visit. In addition, 
the Clinician Scratch Scale, Clinician Xanthoma Scale, and PedsQL will be administered and 
study drug compliance will be assessed (PedsQL will not be performed at certain clinic visits 
– please refer to schedule of procedures). The PIC and CIC and the CGTB assessments will 
be completed at Weeks 84, 96, 100, and the End of Treatment (EOT)/Early Termination (ET) 


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visit. Palatability data will be collected at each clinic visit during the long-term optional 
follow up treatment period (including the EOT/ET visit), with the exception of the PA4 DE, 
and ADE visits.  Plasma samples will be obtained for LUM001 pharmacokinetics at the ADE 
Day 0, ADE Week 4, and ADE Week 8 visits, and at the 3 scheduled clinic visits following 
completion of the ADE period. Subjects/caregivers will receive follow-up phone calls at 
Weeks 64, 68, 76, 80, 88, 92, as well as those outlined within the PA4 DE, ADE, and 
repeating 12-week periods. Concomitant medications and any AEs will be evaluated and 
recorded at all clinic visits and at scheduled telephone contacts. 
Twice daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects during the 2 weeks following the Week 60, 72, 84, 96 clinic visits, at 
PA4 DE Week 4, and every clinic visit within the repeating 12-week periods.  Electronic 
diaries will be provided to subjects and caregivers at these visits and re-training on the use of 
the diary will occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for 
the treatment of pruritus may occur during the long-term exposure period.  
With the exception of the EOT/ET visit, additional study drug will be supplied at each clinic 
visit during the follow-up treatment period. Used and unused study drug will be collected at 
every visit.  
Subjects will be encouraged to complete all study activities and visits. Any subject who 
withdraws from the study prior to completion of all treatment period clinic visits should 
undergo safety and clinical laboratory evaluations, including pharmacokinetic sampling of 
LUM001, determination of serum bile acids, other cholestasis biochemical markers, fat 
soluble vitamins, and AFP. In addition the following assessments should be completed: the 
Clinician Scratch Scale, the Clinician Xanthoma Scale, the PedsQL, the PIC, the CIC, the 
CGTB, and the palatability questionnaire, as defined for ET. For subjects who complete the 
study, an EOT visit will be completed; the assessments performed at this visit will be 
identical to the assessments performed at the ET visit.  
Following completion of the Follow-up Treatment Period or early discontinuation: a safety 
follow-up phone call will be made 30 days after the last dose of study drug. This call will be 
made for all subjects who complete the study, as well as any subject who terminates from the 
study early. Concomitant medications and adverse events noted during this phone call will be 
recorded. 
Safety and 
Tolerability 
Evaluations 
The safety and tolerability of LUM001 will be assessed by determining the incidence, 
relationship to study drug, and severity of treatment-emergent AEs, withdrawals due to AEs, 
and changes in vital signs, laboratory and other safety parameters. Alpha-fetoprotein (AFP), 
a marker of hepatocellular carcinoma, will be measured every 6 months throughout the long-
term optional extension period. 
A Data Monitoring Committee (DMC) will review serious adverse event data, and other key 
subject safety and study data at specified intervals for the duration of the study.  
Safety 
Evaluations 
The following assessments will be used to evaluate safety: 
• 
Adverse events (AEs) and serious adverse events (SAEs). 
• 
Clinical laboratory results, including alpha-fetoprotein (AFP) as a screening for 
hepatocellular carcinoma. 
• 
Vital signs. 
• 
Physical exam findings, including body weight and height. 
• 
Concomitant medication usage. 


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Efficacy 
Evaluations 
The primary efficacy endpoints will be the mean change from Week 18 to 22 of fasting 
serum bile acid levels in subjects who previously responded to LUM001 treatment, as 
defined by a reduction in sBA ≥50% from baseline to Week 12 or Week 18. A sensitivity 
analysis will also be conducted using subjects who experienced a reduction from baseline in 
serum bile acids of ≥50% at the Week 48 measurement. 
The secondary efficacy evaluations will include: 
• Change from Week 18 to Week 22 in:  
o Liver enzymes [alanine aminotransferase (ALT), alkaline phosphatase (ALP)] and 
bilirubin (total and direct). 
o Pruritus as measured by ItchRO (Observer ItchRO/patient ItchRO) in subjects who 
previously responded to LUM001 treatment, as defined by a reduction in ItchRO 
scale >1 point from baseline to Week 12 or Week 18. 
• Change from baseline to Week 18 in: 
o Fasting serum bile acid levels. 
o Liver enzymes (ALT, ALP) and bilirubin (total and direct). 
o Pruritus as measured by ItchRO (Observer ItchRO/patient ItchRO).  
The following additional efficacy evaluations will be assessed: 
• Change from baseline to Weeks 18, 22 48, and then every 12 weeks in: 
o Fasting serum bile acid levels. 
o Liver enzymes (ALT, ALP) and bilirubin (total and direct). 
Pruritus as measured by the average daily ItchRO (Observer ItchRO/patient ItchRO). 
o Other biochemical markers of cholestasis [total cholesterol, low-density lipoprotein 
cholesterol (LDL-C)]. 
o Bile acid synthesis [serum 7α-hydroxy-4-cholesten-3-one (7αC4)]. 
• Responder analysis at Weeks 18 and 48 in:  
o Pruritus response rates as measured by ItchRO (Observer ItchRO/patient ItchRO). 
o Clinician scratch score. 
• Change from baseline for PedsQL at Week 18 and Week 48 and change from Week 18 to 
Week 22. 
• PIC at Week 18 and 48 and change from Week 18 to Week 22. 
• CIC at Week 18 and 48 and change from Week 18 to Week 22. 
• CGTB assessment at Weeks 18 and 48 and change from Week 18 to Week 22. 
• Change from Baseline (Day 0) to Week 48 in xanthomas, as measured by Clinician 
Xanthoma Scale. 
 
Additional assessments of efficacy variables will occur during the 52-week and long-term 
optional treatment periods in 12 weekly intervals. Any of the above evaluations may also 
occur at clinic visits during the DE, PA4 DE, and ADE periods. 
Additional exploration of evaluations of safety will be specified in the statistical analysis 
plan. 
Palatability 
Data 
Palatability data will be collected at each clinic visit in the follow up treatment period, with 
the exception of the PA4 DE, and ADE visits. A palatability questionnaire will be completed 
by the subject and/or caregiver (dependent on age). Assessment of change over time will be 
evaluated.  


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Statistical 
Considerations 
Sample Size 
The planned sample size of 30 evaluable subjects was based on practical considerations, 
rather than on statistical considerations and desired power for a pre-specified difference. 
Safety 
All safety analyses will be performed on the Safety Population, defined as all subjects who 
were assigned and received at least one dose of the study drug.  
Safety measures including AEs, clinical laboratory tests, vital signs, physical exams, and 
concomitant medication usage will be summarized descriptively by study period and over the 
entire study duration (Weeks 0-EOT Visit). For quantitative variables, descriptive statistics 
including number of observations, mean, median, standard deviation and range will be given 
for the values themselves as well as for change from baseline at each study visit. Qualitative 
variables will be summarized using counts and percentages at each study visit.  
Drug Level Analysis 
Plasma concentrations of LUM001 will be examined descriptively by visit.  
Efficacy 
The main population for efficacy will be the modified intention-to-treat population (MITT), 
defined as all subjects who were enrolled, received study medication through Week 18, and 
had a reduction from baseline in serum bile acids of ≥50% at the Week 12 or Week 18 
measurement. Subjects will be analyzed by assigned treatment.  
Efficacy endpoints will be displayed by study visit, using summary statistics including the 
number of observations, the mean, median, standard deviation, and range for continuous 
measures and counts and percentages for categorical measures. Actual values as well as 
change from baseline will be presented. The change from baseline will be tested using the 
paired t-test, or comparable nonparametric measures if appropriate.  
Examination of potential treatment effects by dose will be done if the sample sizes in the 
dose groups during the stable dosing phase of the study permit. 
In addition to absolute change from baseline, a responder analysis will also be considered. 
The response definition and its appropriate analysis methodology will be outlined in the 
Statistical Analysis Plan (SAP) for the study.  
Supportive and exploratory efficacy measures will be analyzed similarly as above. Details of 
the analysis methods will be outlined in the SAP.  
Interim Analysis 
There will be an interim analysis (IA) conducted after all subjects complete or discontinue 
the study after Week 48 to guide the future of the program. At the IA the study will be 
unblinded.  
Siblings 
The enrollment of siblings is allowed. During the double-blind, placebo-controlled, 
randomized drug withdrawal period, siblings 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 LUM001-304 study is unblinded. 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 
β-hCG 
beta-sub-unit of human chorionic gonadotropin; pregnancy test 
μg 
microgram 
μM 
micromolar 
7αC4, C4 
7α-hydroxy-4-cholesten-3-one; an indirect method of bile acid 
synthesis 
ac 
before meals 
ADE 
afternoon dose escalation 
ADME 
absorption, distribution, metabolism, excretion 
AE 
adverse event 
AFP 
alpha-feto protein 
ALGS 
Alagille syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANA 
antinuclear antibody 
ANCOVA 
analysis of covariance 
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 
Anatomical Therapeutic Chemical; classification for drugs 
ATX 
autotaxin 
BA 
bile acid 
BID 
twice a day 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CGTB 
Caregiver Global Therapeutic Benefit questionnaire 
cholesterol 7α-hydroxylase 
rate-limiting enzyme in the synthesis of bile acid from cholesterol 
CIC 
Caregiver Impression of Change questionnaire 
CRF 
case report form 


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Abbreviation 
Definition 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae 
DE 
dose escalation 
dL 
deciliter 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EOT 
End of Treatment 
ET 
Early Termination 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor 19; regulates carbohydrate, lipid and bile 
acid metabolism 
FGF-21 
fibroblast growth factor 21; modulates hepatic metabolism 
g 
gram 
GCP 
good clinical practices 
GGT 
gamma-glutamyltransferase 
GGTP (γGTP) 
gamma-glutamyl transpeptidase 
GI 
gastrointestinal 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HMG-CoA reductase 
 
3-hydroxy-3-methyl-glutaryl-CoA reductase; rate-controlling 
enzyme of the pathway that produces cholesterol 
HR 
heart rate 
HRQoL 
health related quality of life 
IAF 
informed assent form 
IB 
investigator’s brochure 
IBAT 
ileal bile acid transporter 


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Abbreviation 
Definition 
IBATi 
ileal bile acid transporter inhibitor 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
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 
ITT 
intention-to-treat 
IU 
international unit(s) 
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 
MITT 
modified intention-to-treat 
mL 
milliliter 
mmol 
millimole 
NBD 
nasal biliary drainage 
NCS 
not clinically significant 
ng 
nanogram 
ObsRO 
observer reported outcome 
PBC 
primary biliary cirrhosis 
PEBD 
partial external biliary diversion 


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Abbreviation 
Definition 
PedsQL 
Pediatric Quality of Life Inventory 
PFIC 
progressive familial intrahepatic cholestasis 
PI 
principal investigator 
PIC 
Patient Impression of Change questionnaire 
PK 
pharmacokinetic 
PSC 
primary sclerosing cholangitis 
PND 
post-natal day 
Pt 
patient 
PT 
prothrombin time 
qAM 
every morning 
QD 
once daily 
q.s. 
quantity sufficient 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acid 
SD-5613 
original designation for LUM001 
sec 
second 
SLC10A2 
solute carrier family 10 member 2; gene that encodes IBAT 
protein 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TG 
triglycerides 
TGR5 
a G protein-coupled receptor for bile acids 
UDCA 
ursodeoxycholic acid, ursodiol 
ULN 
upper limit of normal 
US, USA 
United States of America 
WBC 
white blood cell 
WHO 
World Health Organization 
WMA 
World Medical Association 
yr(s) 
year(s) 


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3 
STUDY OBJECTIVES 
The objectives of this study (up to and including Week 48) are: 
• To evaluate the long-term safety and tolerability of LUM001 in children with ALGS. 
• To evaluate the effect of LUM001 on serum bile acid levels in children with ALGS. 
• To evaluate the effect of LUM001 on biochemical markers of cholestasis and liver disease in 
children with ALGS. 
• To evaluate the effect of LUM001 on pruritus in children with ALGS. 
• To evaluate the long-term effect of LUM001 in children with ALGS during 48 weeks of 
treatment. 
Objectives of Long-term Optional Follow-up Treatment Period (after Week 48): 
• To offer eligible subjects treated in the LUM001-304 study continued study treatment at 
Week 48 until the first of the following occurs: (i) the subjects are eligible to enter another 
LUM001 study (ii) LUM001 is available commercially, or (iii) the sponsor stops the program 
or development in this indication. 
• To explore twice a day (BID) dosing regimen and higher daily dosing of LUM001. 
• To obtain safety and efficacy data in subjects treated long term on LUM001 including 
genotyping characteristics. 
• To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma. 
• To assess palatability of the LUM001 formulation. 


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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). 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 
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. Present in most patients with ALGS, 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 children 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 lumen of 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=apical sodium-dependent bile acid transporter. 
X 
ASBT 
 
Reduction of recycling, 
lowers BA levels in liver, 
preventing liver damage 
X 


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ASBT/IBAT expression is under negative feedback regulation by bile acids; thus in the setting of 
cholestasis, ASBT/IBAT is maladaptively upregulated (Neimark et al., 2004; Hofmann, 2003). 
Therefore, inhibiting the reuptake of bile acids may represent an ideal treatment for cholestatic 
disease. In the current study, ALGS will serve as a model 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 of ileal exclusion 
(Figure 1). 
4.2 
Alagille Syndrome 
Alagille syndrome (ALGS) is an autosomal dominant with variable penetration genetic 
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 the United States is 3 per 100,000. Elevations of serum bilirubin up to 30 
times normal and serum bile salts up to 100 times normal are common. Levels of markers of bile 
duct damage, including gamma-glutamyltransferase (GGTP or GGT) and alkaline phosphatase 
(ALP), usually are significantly elevated. Cholesterol levels may also be elevated. 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, therapies that ameliorate the complications of cholestasis, without a commitment to liver 
transplantation, are highly desirable (Emerick et al., 1999). 
4.3 
Pruritus 
Patients with ALGS and 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. 
Intractable and pharmacologically recalcitrant pruritus is one of the major morbidities afflicting 
children with ALGS. Treatment with anti-pruritics and bile salt resins may provide partial relief 
of itching for children with ALGS, but currently available pharmacologic approaches are of 
limited value. It has been shown that removing bile with surgical procedures such as partial 
external biliary diversion (PEBD) and nasal biliary drainage (NBD) substantially reduces 
pruritus in ALGS (Emerick and Whitington, 2002), progressive familial intrahepatic cholestasis 
(PFIC) and primary biliary cholangitis (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 


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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) 
4.4 
LUM001 
4.4.1 
Nonclinical Studies 
4.4.1.1 
Pharmacology 
LUM001 is a minimally-absorbed, 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 


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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 much higher than those that are pharmacologically active in mice, rats, dogs, 
and monkeys. The most significant effect observed in rodents is a prolongation of coagulation 
time considered secondary to malabsorption of vitamin K, which in turn is related to inhibition of 
bile acid absorption, the pharmacologic effect of LUM001. Reversible prolongation of 
coagulation times was observed primarily in male rats that are especially sensitive to agents that 
alter vitamin K absorption and may not be an appropriate model for predicting vitamin K 
malabsorption in humans. Acute oral doses up to 200 mg/kg LUM001 were well tolerated in 
dogs, with emesis as the primary dose-limiting toxicity. There was no evidence of mutagenic 
activity in vitro and no clastogenic activity in vitro or in vivo. Results from rat and rabbit 
embryo/fetal development studies with doses up to 1000 and 250 mg/kg/day, respectively, 
showed no adverse effects on fetal growth and development.  
To support the use of LUM001 in young children, a toxicity study in juvenile animals was 
completed. As expected for a drug intentionally designed to be minimally absorbed, LUM001 
exposure was very low and consistent with levels that were previously determined in several oral 
gavage studies with adult rats. No adverse effects were observed on postnatal growth and 
development of offspring at a dose of 200 mg/kg/day in males and 1000 mg/kg/day in females, 
the highest doses tested. This study was initiated in juvenile animals at PND21, which from a 
whole animal development perspective is typically representative of a 2 year old child. However 
given the fact that LUM001 is a minimally absorbed drug, as evidenced by this and multiple 
other studies, of particular importance is the age at which the GI tract is considered functionally 
mature. In humans this occurs by 12 months of age; likewise, postnatal maturation of the GI tract 
in rats occurs during the first three weeks of birth. Therefore this study presented evidence to 
support the safety of LUM001 in future clinical trials in children 12 months of age and older. 
These trials have the promise to address a life-threatening clinical need in this patient population. 
Additional toxicology information can be found in the investigator’s brochure. 


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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 
reduction of serum LDL-C in subjects with hypercholesterolemia. The efficacy, 
pharmacokinetics, tolerability, and safety of LUM001 in humans have been evaluated in a total 
of 12 clinical studies, including 2 studies that also tested sustained release formulations. Phase 1 
studies included a single and two multiple dose tolerability studies, an absorption, distribution, 
metabolism, and excretion (ADME) study, a statin co-administration study, a statin interaction 
study, and a food composition study. Phase 2 studies included two dose-ranging studies in adult 
subjects, a tolerability study in adolescents and children, and a multiple dose tolerability and 
efficacy study of three sustained release formulations, compared with the immediate release 
formulation. More than 1,400 human subjects have been exposed to LUM001 (immediate 
release) for up to 10 weeks. 
In previous clinical studies, LUM001 inhibited the postprandial increase in serum total bile acids 
concentrations and increased fecal total bile acids excretion, consistent with the mechanism of 
action of inhibiting ASBT. LUM001 administration resulted in reductions of serum LDL-C in 
healthy volunteers and subjects with elevated cholesterol. These findings confirm that LUM001, 
a minimally absorbed inhibitor of ASBT, is effective in blocking enterohepatic recirculation of 
bile acids with the expected consequences on bile acid and cholesterol metabolism. With 
LUM001 administration, there was also a trend toward increases in high-density lipoprotein 
cholesterol (HDL-C) and total triglycerides relative to placebo.  
Administration of LUM001 at doses up to 100 mg once daily over a four-week period was 
generally safe in healthy volunteers and at 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. These 
GI AEs are also observed in patients who undergo biliary diversion, are believed to be 
mechanism-based, due to elevated bile acid concentrations in the colon. With the exception of a 
single serious adverse event of cholecystitis no other SAEs possibly related or related to 
LUM001 have been reported in the 12 studies conducted to date (over 1,400 subjects exposed). 
The majority of orally administered LUM001 was excreted intact in the feces along with a few 
minor metabolites. LUM001 exposure in adolescents and children (Study 014) was low and 
consistent with a drug that is minimally absorbed. Pharmacokinetic parameters in adolescent and 
children subjects did not significantly differ from those seen in adult subjects.  
No clinically significant laboratory abnormalities were documented in LUM001-treated subjects. 
LUM001 was associated with mild, often transient elevations of serum ALT in a small 
percentage of subjects. Clinically significant reductions of serum fat-soluble vitamin levels were 
not observed with LUM001 treatment in humans; however, levels of the carotenoid β-carotene 
were mildly reduced. No alterations in coagulation parameters were observed, indicating no 


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functional changes in vitamin K status. Fecal fat excretion was not increased compared to 
placebo after four weeks of LUM001 treatment at doses up to 100 mg. 
4.5 
Rationale for Dose and Schedule of Administration 
The dosage of LUM001 chosen for the first studies in cholestatic subjects is based upon prior 
experience with this product in healthy volunteers and subjects with hypercholesterolemia. In 
these subjects, with normal bile flow and without liver disease, tolerability was limited above 
10 mg daily by an increase in GI AEs. These signs and symptoms were believed to be related to 
increased bile acid excretion and an increased concentration of free bile acids in the lower colon. 
In patients with cholestatic liver disease it is likely that bile flow is reduced compared to healthy 
volunteers and hypercholesterolemic patients and LUM001 will produce a correspondingly 
smaller increase in free bile acids in the lower colon, and could potentially lead to the drug being 
better tolerated at the same dose level.  
Ideally, dosing in pediatric subjects should be scaled from that in adults based on intestinal 
length, 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 et al., 1991) 
provided data indicating that the average length of the small intestine increases with age from 
birth through 20 years; this relationship followed a curve that is similar to the height and weight 
growth curves (Weaver et al., 1991). However, a plateau had not been reached at the maximum 
age examined (20 years), precluding predictions of intestinal length for older adults and thus 
scaling to infants and children based on estimated intestinal length. An analysis of intestinal 
length as a function of age, weight, and height in adult cadavers was conducted by Hounnou et al 
(2002). Their analysis demonstrated that age had a negative correlation and body weight a 
positive correlation with intestinal length. Taken as a whole, the existing analyses are 
inconclusive with respect to the dependent variables that predict intestinal length. Consequently, 
the most reasonable approach is to calculate doses in a pediatric subject from those in adults 
based on 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. 
Daily exposure (mg/day) across 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) 
LUM001 
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) 
Dose Level 6 
(560 μg/kg/day) 
10 
0.14 
0.35 
0.70 
1.40 
2.80 
5.60 
15 
0.21 
0.53 
1.05 
2.10 
4.20 
8.40 
20 
0.28 
0.70 
1.40 
2.80 
5.60 
11.20 
25 
0.35 
0.88 
1.75 
3.50 
7.00 
14.00 
30 
0.42 
1.05 
2.10 
4.20 
8.40 
16.80 
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 


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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 between the ages of 12 months and 18 years, inclusive. 
In Study 014 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. A total of 49 of 50 subjects completed 14 days of treatment. Most AEs were assessed 
with a probable or uncertain relationship to study medication and were generally characterized as 
mild or moderate in severity, except for those in six subjects who experienced severe nausea, 
diarrhea, or abdominal pain. These GI events usually resolved during continued treatment. It is 
noteworthy that the AEs were generally recorded in the first seven days of LUM001 dosing, and 
observed at a four-fold lower frequency from Day 8 to 14. This is consistent with the extensive 
adult dosing experience, where GI events were observed at levels similar to those in the placebo 
group after two weeks of continuous dosing.  
To assess the effects of dose titration to mitigate dose-limiting adverse effects, LUM001 was 
evaluated in a 28-day once-daily dosing study in healthy volunteers (Study 003). In one arm, the 
dose was increased after each 7-day dosing period, to a maximum of 5 mg daily (equivalent to a 
dose of 67 µg/kg/day, using the average subject weight). Using this dosing regimen, the 
incidence of GI-associated AEs was lower than those observed in the placebo group (Table 3) 
and in other treatment arms with constant dosing above and below 5 mg daily. 
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% following 2 weeks of treatment. In 


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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.  
The doses explored in the current study (up to 400 µg/kg/day BID) in subjects with ALGS are 
supported by the safety profile observed in completed and ongoing clinical studies of LUM001. 
Twice daily dosing is used in this study based on the findings of a healthy volunteers study in 
adult males (Study SHP625-101), which demonstrated that bile acid levels in feces increase with 
escalating doses and twice-daily regimen of LUM001 (up to 100 mg QD and 50 mg BID, 
respectively). In this study, subjects who were randomized to LUM001 treatment, received 1 of 4 
doses of LUM001 (10, 20, 50, 100 mg) during 7 days. No titration was used in this study. There 
was a dose-dependent increase in total fecal BA excretion. In addition, BID dosing (ie, 50 mg 
BID) led to a further increase in fecal BA excretion as compared to QD dosing (ie, 100 mg QD). 
It is therefore hypothesized that higher doses and twice-daily dosing both have the potential to 
allow for more complete target engagement throughout the day at the level of the distal ileum. 
The higher dosing level is also supported by favorable results from a juvenile toxicity study 
conducted in rats administered LUM001 for 43 days (post-natal day, PND21 through PND63). 
As expected for a drug intentionally designed to be minimally absorbed, systemic LUM001 
exposure was very low and consistent with levels that were previously determined in several oral 
gavage studies in adult rats. No adverse effects were observed on postnatal growth and 
development of offspring at the highest doses tested (200 mg/kg/day in males, 1000 mg/kg/day 
in females). This study was initiated in juvenile animals at PND21, which from a whole animal 
development perspective, is typically representative of a 2-year old child. However, given the 
fact that LUM001 is a minimally absorbed drug, of particular importance is the age at which the 
GI tract is considered functionally mature. In humans this is considered to have occurred by 12 
months of age; likewise, postnatal maturation of the GI tract in rats occurs during the first 3 
weeks of life. Therefore, results from this study can be used to support the dosing levels 
proposed here for children 12 months of age and older. 


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5 
INVESTIGATIONAL PLAN 
5.1 
Study Design 
This is a long-term open-label study with a double-blind, placebo-controlled, randomized drug 
withdrawal period in children with ALGS designed to evaluate the safety and efficacy of 
LUM001. The study is divided into 6 parts: a 6-week open-label, dose escalation period at doses 
up to 400 μg/kg/day, a 12-week open-label stable dosing period, a 4-week randomized, double-
blind, placebo-controlled drug withdrawal period, a 26-week long-term stable dosing period at 
doses up to 400 μg/kg/day, a 52-week optional follow-up treatment period, and a long-term 
optional follow-up treatment period for eligible subjects who choose to stay on treatment with 
LUM001. During this long-term optional follow-up period, subjects may have their dose of 
LUM001 increased to a maximum of 800 μg/kg/day (400 μg/kg BID), based on efficacy (sBA 
level and ItchRO[Obs] score) and safety assessment. Subjects’ participation in the long-term 
optional follow-up treatment period will continue until the first of the following occurs: i) the 
subjects are eligible to enter another LUM001 study, ii) LUM001 is available commercially, or 
(iii) the sponsor stops the program or development in this indication.  
Subjects who do not consent to Protocol Amendment 4 will continue their treatment as outlined 
in Protocol Amendment 3. 
5.2 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will review serious adverse event data, other key subject 
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.   
5.3 
Number of Study Centers 
This will be a multi-center study in approximately 9 clinical sites. 
5.4 
Number of Subjects 
Approximately 30 subjects will be enrolled in this study. 
5.5 
Overall Study Duration and Follow-up 
For an individual subject, the study participation period will consist of a screening period of up 
to 4 weeks, a 48-week treatment period (including a 6-week, open-label dose escalation period, a 
12-week open-label stable dosing period, a 4-week randomized, double-blind, placebo-controlled 
drug withdrawal period, a 26-week long-term stable dosing period) as well as a 52-week optional 
follow-up treatment period, and a long-term optional follow-up treatment period. A safety 
follow-up phone call will be made by the study site 30 days after the last dose of study drug. 


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Following screening, during the 48-week treatment period, subjects who meet all eligibility 
criteria will return to the clinic for 9 visits and will receive 14 telephone contacts from the study 
staff (see Figure 3). Subjects who complete 48 weeks of treatment may be eligible to receive 
further treatment during the 52-week optional follow-up treatment period and the long-term 
optional follow-up treatment period. Subjects’ participation in the long-term optional follow-up 
treatment period will continue until the first of the following occurs: (i) the subjects are eligible 
to enter another LUM001 study, (ii) LUM001 is available commercially, or (iii) the sponsor 
stops the program or development in this indication. 
Study activities will be conducted as described in the Schedule of Procedures (Section 16.1).  
Figure 3: 
Study Design for LUM001-304 (Day 0 – Week 48) 
 
 
 
 
 
 
 
 
 


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Figure 4: 
52-week Optional Follow-up Treatment Scheme (<7 days from last LUM001 
dose) 
Applies to the following subject population: 
• Subjects who experienced no interruption in LUM001 dosing, or interruption <7 days 
between Protocol Amendment 2 and Protocol Amendment 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 5: 
52-week Optional Follow-up Treatment Scheme (≥7 days from last LUM001 
dose) 
Applies to the following subject population: 
• Subjects who experienced an interruption in LUM001 ≥7 days between Protocol 
Amendment 2 and Protocol Amendment 3. 
 
Abbreviations: DE=dose escalation; FTP=follow-up treatment period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 6: 
Long-term Optional Follow-up Treatment Scheme (≥7 days from Last 
LUM001 Dose between Protocol Amendment 3 and Protocol Amendment 4) 
Applies to the following subject population: 
• Subjects who experienced an interruption in LUM001 ≥7 days between Protocol 
Amendment 3 and Protocol Amendment 4. 
 
 
Abbreviations: ADE=afternoon dose escalation; DE=dose escalation; PA=protocol amendment; Wk=week. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 7: 
Long-term Optional Follow-up Treatment Scheme, without Afternoon Dose 
Escalation (ADE) 
Applies to the following subject population: 
• Subjects deemed ineligible for ADE 
 
 
Abbreviations: EOT=end of treatment; ET=early termination; MTD=maximum tolerated dose; Wk=week. 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 8: 
Long-term Optional Follow-up Treatment Scheme under Protocol 
Amendment 4, with Afternoon Dose Escalation (ADE) 
Applies to the following subject population: 
• Subjects whose sBA levels have not normalized and/or whose ItchRO Obs score is ≥1.5 
and therefore qualify for introduction of afternoon dosing. 
 
 
Abbreviations: ADE=afternoon dose escalation; MTD=maximum tolerated dose; Wk=week. 
5.5.1 
Screening 
Each subject who provides informed consent/assent will complete all screening activities in ≤4 
weeks.  
5.5.2 
Treatment 
Study drug will be prepared for each individual subject by a central pharmacy based on the 
subject’s weight at screening. Diluent will be added by the central pharmacy pharmacist prior to 
shipping study drug to the site. Study drug will be dispensed to subjects/caregivers. During the 
course of the study, it may be necessary to instruct the subject/caregiver to return to the site for 
an unscheduled dispensation of study drug. The appropriate amount of study drug will be 
dispensed at the Study Day 0 visit and daily dosing will begin on Study Day 1. 


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Subjects will receive a grape-flavored solution containing LUM001 administered orally once a 
day (QD) or twice a day (BID) using the syringe provided. The first dose should be taken at least 
30 minutes prior to the first meal of the day and the second dose, where applicable, should be 
taken at least 30 minutes prior to dinner (main evening meal). The doses will not be administered 
q12h in order to better cover the luminal bile acid release associated with dinner and to minimize 
the risk of disturbing sleep due to the potential for abdominal pain and diarrhea at night. It is 
recommended that the dose should be taken approximately at the same time each day for the 
duration of the treatment period. 
All subjects will receive LUM001, up to 400 μg/kg/day or a maximum daily dose of 20 mg/day, 
during the initial open-label treatment period of the study. After completion of the 12-week 
stable dosing period, subjects will be randomized 1:1 to either a 4-week double-blind study drug 
withdrawal period during the study or will remain on study drug. Subjects will then enter a 
26-week long-term stable dosing period and all subjects will receive LUM001, up to 400 
μg/kg/day or a maximum daily dose of 20 mg/day during the initial open-label treatment period 
of the study. Subjects will be considered for a 52-week optional treatment period, if eligible, 
receiving up to 400 μg/kg/day, or the highest tolerated dose below the 400 μg/kg/day dose. 
Subjects will then be considered for the long-term optional follow-up treatment, if eligible, 
receiving up to 800 μg/kg/day (given as twice daily doses of 400 μg/kg), or a maximum possible 
daily dose of 50 mg/day. 
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. 
5.5.2.1 
Dose Escalation Period 
Initially, the LUM001 dose will be administered as a daily morning dose in either a 1.0 mL or 
0.5 mL solution. The dose will be increased weekly over a 6-week period up to 400 μg/kg/day 
QD or a maximum daily dose of 20 mg/day QD as follows: 
Week 1 Dose: 14 µg/kg/day QD 
Week 2 Dose: 35 µg/kg/day QD 
Week 3 Dose: 70 µg/kg/day QD 
Week 4 Dose: 140 µg/kg/day QD 
Week 5 Dose: 280 µg/kg/day QD 
Week 6 Dose: 400 µg/kg/day QD (maximum daily dose of 20 mg QD) 
Subjects should be administered study drug daily for at least 7 days at each dose level during the 
dose escalation period. 
If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, abdominal 
pain, cramping) at any time during the study, the physician investigator in consultation with the 
medical monitor may lower the dose to a previously tolerated dose; later attempts to escalate the 
dose are permitted. In these circumstances, an unscheduled visit will occur and the appropriate 


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replacement study medication will be issued to the subject as quickly as possible. If the subject is 
on a BID dosing regimen, dose lowering should first be attempted with the afternoon dose. 
5.5.2.2 
Stable Dosing Treatment Period 
Subjects will continue dosing for another 12 weeks using the dose administered at Week 6, 
which may be 400 µg/kg/day or the highest tolerated dose below 400 µg/kg/day. 
5.5.2.3 
Double-blind Placebo-controlled Study Drug Withdrawal Period 
At the Week 18 visit, eligible subjects will be randomized 1:1 to continue to receive study drug 
or a corresponding placebo for 4 weeks.  
5.5.2.4 
Long-term Exposure Period 
Following the 4-week study drug randomized withdrawal period, subjects who received placebo 
will receive LUM001 dosed according to a dose escalation schedule that mirrors the initial 
escalation (ie, the LUM001 dose will be increased weekly over a 6-week period to the maximum 
tolerated dose up to 400 μg/kg/day or 20 mg/day or the highest tolerated dose below the 
400 μg/kg/day dose). Subjects who were randomized to receive LUM001 during this period will 
continue to receive the same dose of LUM001 and, following Week 22, a simulated dose 
escalation will occur to maintain the blind in the randomized withdrawal period. Dosing with 
LUM001 will continue in a 26-week long-term exposure period to complete 48 weeks of study.  
During the long-term exposure period, the dose may be adjusted to account for a change of 
≥10% in weight since the screening visit (eg the amount of drug dosed may be increased to 
reflect the subject’s weight increase).  
5.5.2.5 
 52-week Optional Follow-up Treatment Period 
At Week 48, all subjects will be assessed by the investigator to determine their willingness and 
eligibility to roll-over into the 52-week optional follow-up treatment period. The 3 following 
possible scenarios may occur: 
• Subjects who are eligible to roll over into the optional follow-up treatment period with no 
LUM001 dosing interruption or an interruption of <7 days will be maintained at the same 
dose level. 
• Subjects who are eligible to roll over into the optional follow-up treatment period with a 
LUM001 dosing interruption of ≥7 days will be dose escalated beginning at 35 μg/kg/day 
and up to a maximum of 400 μg/kg/day or highest tolerated dose (as detailed in Section 
8.1.8. 
• Subjects who do not wish to enter the follow-up treatment period will be contacted via 
telephone by the study site approximately 30 days after the last dose of study drug. 


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5.5.2.6 
 Long-term Optional Follow-up Treatment Period 
Upon completion of the 52-week optional follow-up treatment period, and/or implementation of 
this amendment, whichever occurs first, subjects will be assessed by the investigator to 
determine their willingness and eligibility to roll-over (or enter) the long-term optional treatment 
period. The 3 following possible scenarios may occur: 
Scenario 1: Subjects eligible to roll over into the long-term optional follow-up treatment 
period with no LUM001 dosing interruption or an interruption of <7 continuous days: 
• Subjects with normal sBA level AND ItchRO(Obs) score <1.5 will be maintained at the 
same dose level and will continue morning dosing only. 
• Subjects with sBA level above normal AND/OR ItchRO(Obs) score ≥1.5 will start BID 
dosing (afternoon dose escalation; ADE) as follows: 
o The morning dose will be continued at the same dose level, but the volume of the 
morning dose will be reduced by half at the same time that the afternoon dose is 
initiated. 
o The afternoon dose will be initiated at dose level 140 µg/kg and will continue at 
this dose for a period of 4 weeks. If this dose level is tolerated, the afternoon dose 
will then be escalated to 400 µg/kg. 
Scenario 2: Subjects eligible to roll over into the long-term optional follow-up treatment 
period with a LUM001 interruption of ≥7 days: 
• First, the morning dose is escalated up to 400 µg/kg/day or highest tolerated dose 
following a 5-week dose escalation beginning at 35 µg/kg/day. 
• Once the morning dose of 400 µg/kg or maximum tolerated dose is achieved, sBA and 
ItchRO(Obs) score will be evaluated. 
o Subjects with normal sBA AND ItchRO(Obs) score <1.5 after morning dose 
escalation will be maintained at the same dose level and will continue morning 
dosing only. 
o Subjects with sBA above normal AND/OR ItchRO(Obs) score ≥1.5 will begin 
BID dosing (ADE) as outlined as follows: 
 The morning dose will be continued at the same dose level, but the volume 
of the morning dose will be reduced by half at the same time that the 
afternoon dose is initiated. 
 The afternoon dose will be initiated at dose level 140 µg/kg and will 
continue at this dose for a period of 4 weeks. If this dose level is tolerated, 
the afternoon dose will then be escalated to 400 µg/kg.  


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The following parameters apply to both dosing scenarios outlined above: 
• The afternoon dose will only be initiated once the subject has been treated on stable 
morning doses for at least 4 weeks. 
• The sBA value used for determination of ADE eligibility will be the most recent 
available value collected within the prior 16 weeks. The ItchRO(Obs) score used for 
ADE eligibility will be derived from the most recent available 7-day interval of 
ItchRO(Obs) collected within the prior 16 weeks.  
• The maximum daily dose will be 400 µg/kg BID, ie, 800 µg/kg/day (up to a maximum 
possible daily dose of 50 mg/day). 
Subjects will continue to receive study drug until they are eligible to enter another LUM001 
study, or until LUM001 is available commercially, or until the sponsor stops the program or 
development in this indication, whichever occurs first. 
If a subject experiences intolerance (eg, gastrointestinal symptoms such as diarrhea, abdominal 
pain, cramping) at any time during the study, the physician investigator in consultation with the 
medical monitor may lower the dose for the remainder of the study; later attempts to escalate the 
dose are permitted. If the subject is on a BID dosing regimen, dose lowering should first be 
attempted with the afternoon dose. 
Scenario 3: Subjects who do not consent to Protocol Amendment 4 will continue their 
treatment as outlined in Protocol Amendment 3. 
5.5.3 
Safety Follow-up Period   
A safety follow-up phone call will be made by the study site 30 days after the last dose of study 
drug. This call will be made for all subjects who complete the study, as well as any subject who 
terminates from the study early. Concomitant medications and any AEs noted during this phone 
call will be recorded. Subjects who complete the study or who discontinued early due to reasons 
other than safety may be eligible for participation in the long-term optional follow-up treatment 
period under Protocol Amendment 4.  
Additional study drug will be supplied at each clinic visit during the follow-up treatment period. 
Used study drug will be collected at each clinic visit and dosing compliance will be assessed. 
5.6 
End of Study 
For subjects who do not consent to the long-term optional follow-up treatment period, a subject 
is considered to have completed treatment if treatment was not permanently discontinued prior to 
the Week 48 visit.  A follow-up phone contact is required for all subjects should the final visit 
occur earlier than 30 days from the final dose.  
The subject is considered to have completed treatment and study period for the corresponding 
follow-up treatment period (when consented under Protocol Amendment 3 or Protocol 


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Amendment 4) if study treatment was not discontinued prior to completing Week 96 for Protocol 
Amendment 3 or completing the EOT visit in Schedule J under Protocol Amendment 4. 
Temporary drug interruption is not considered treatment discontinuation. A follow-up contact is 
required for all subjects should the final visit occur earlier than 30 days from the final dose. 
The end of study for the purposes of regulatory reporting is the point at which the last contact 
with the last subject during the protocol-specified scheduled follow-up period is made. 


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6 
SUBJECT ENROLLMENT 
6.1 
Screening 
Before subjects may be screened for eligibility to participate in the study, the sponsor, or 
designee, requires a copy of the appropriate written Independent Ethics Committee (IEC) 
approval of the protocol, informed consent/assent form(s) (ICF), and all other applicable subject 
information and/or recruitment material. 
Following informed consent/assent, the subject will be considered enrolled into the study and 
will be assigned a unique subject identification number before any study procedures, including 
screening procedures, are performed. This number will be used to identify the subject throughout 
the study and must be used on all study documentation related to that subject. The subject 
identification number must remain constant throughout the entire study. In the event the subject 
is re-consented and rescreened, the subject must be given a new subject identification number. 
Subject identification numbers, once assigned, will not be reused. 
Subjects will be enrolled in the 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 the long-term optional follow-up period under Protocol Amendment 4 after the 
subject consents and the investigator has determined the subject meets study entry eligibility 
criteria per Protocol Amendment 4. However, any subject who consents to Protocol Amendment 
4 and does not meet criteria per the investigator is considered a screen failure for the long-term 
optional follow-up period under Protocol Amendment 4. Screen failures are eligible for 
rescreening (Section 8.1.1). 
6.2 
Randomization 
Subjects begin the study at Day 0 and are treated in an open-label fashion from Week 1 to 
Week 18. Subjects will then be randomized 1:1 to continue to receive study drug or a 
corresponding placebo for 4 weeks between Week 19 and Week 22 at the start of the double-
blind, placebo-controlled study drug withdrawal period (Week 19 to Week 22). This 
randomization will be stratified by response criteria where response is defined as a ≥50% 
reduction in serum bile acids between Baseline and Week 12 or Week 18. Serum bile acid results 
will remain blinded after baseline testing. 
During the double-blind, placebo-controlled, randomized drug withdrawal period, siblings will 
be assigned in a blinded manner to the same treatment arm. 
The sponsor (or designee) will prepare the randomization list; the pharmacist at a central 
pharmacy will be unblinded to treatment group. The study staff including the local site 
pharmacist (or qualified delegate) will remain blinded to the assignment. 
6.3 
Replacement of Subjects 
A subject who withdraws from the study prior to completion of the stable dosing treatment 
period (Week 18) may be replaced at the discretion of the sponsor.  


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6.4 
Unblinding of Treatment Assignment 
Although subjects begin the study at Day 0 and are treated in an open-label fashion from Week 1 
to Week 18, subjects will be randomized 1:1 to continue to receive study drug or a corresponding 
placebo for 4 weeks between Week 19 and Week 22 at the start of the double-blind, placebo-
controlled study drug withdrawal period. The sponsor (or designee) will prepare the 
randomization list. All subjects, monitors, and study center personnel related to the study, except 
for the central pharmacist (or qualified designee) who prepares the study drug will be blinded to 
study treatment during the randomized withdrawal period (Weeks 19-22) and the long-term 
exposure period (Weeks 23-48) and to the subject’s study drug withdrawal period treatment 
assignment.  
After Week 48 the study will be unblinded to facilitate preparation of the interim analysis. 
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 
subject, the investigator will have the ability to unblind the treatment assignment for that subject. 
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. 
All subjects will receive LUM001, or LUM001 and placebo during this study. Breaking of the 
blind during the initial 48-week period of the study should not occur before all subjects either 
discontinue or complete Week 48, 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 serious adverse event (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 (ET) 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 assigned to study drug treatment. 
7.1 
Inclusion Criteria 
To participate in this study subjects must meet all of the following criteria: 
1. Male or female between the ages of 12 months and 18 years inclusive. 
2. Diagnosis of ALGS based on the diagnostic criteria outlined in Section 16.3. 
3. Evidence of cholestasis (one or more of the following): 
a. Total serum bile acid > 3x ULN for age. 
b. Conjugated bilirubin > 1 mg/dL. 
c. Fat soluble vitamin deficiency otherwise unexplainable. 
d. GGT > 3x ULN for age. 
e. Intractable pruritus explainable only by liver disease. 
4. Females of childbearing potential must have a negative serum pregnancy test during 
Screening. 
5. Males and females of child-bearing potential who are sexually active, or are not currently 
sexually active during the study, but become sexually active during the period of the study 
and 30 days following the last dose of study drug, must agree and use acceptable 
contraception during the trial, as described in Section 8.6.1. 
6. Subject is expected to have a consistent caregiver(s) for the duration of the study. 
7. Informed consent and assent (per IRB/IEC) as appropriate. 
8. Access to phone for scheduled calls from study site. 
9. Caregivers (and age appropriate subjects) must be willing and able to use an eDiary device 
during the study. 
10. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement in the 
eDiary software. 
11. Caregivers (and age appropriate subjects) must complete at least 10 eDiary reports (morning 
or evening) during each of two consecutive weeks of the screening period (maximum 
possible reports = 14 per week). 
12. Average daily score >2 on the Itch Reported Outcome (ItchRO™) questionnaire (maximum 
possible daily score of 4) for two consecutive weeks in the screening period, prior to dosing. 
A daily score is the higher of the scores for the morning and evening ItchRO. The average 
daily score is the sum of all daily scores divided by the number of days the ItchRO was 
completed.  
7.2 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 


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1. Chronic diarrhea requiring ongoing intravenous fluid or nutritional intervention. 
2. Surgical interruption of the enterohepatic circulation. 
3. Previous liver transplant. 
4. Decompensated cirrhosis (ALT >15 x ULN, INR >1.5 [unresponsive to vitamin K therapy], 
albumin <3.0 g/dL, history or presence of clinically significant ascites, variceal hemorrhage, 
and/or encephalopathy). 
5. History or presence of other concomitant liver disease. 
6. History or presence of any other disease or condition known to interfere with the absorption, 
distribution, metabolism or excretion of drugs, including bile salt metabolism in the intestine 
(eg, inflammatory bowel disease). 
7. History or presence of gallstones or kidney stones. 
8. Known diagnosis of human immunodeficiency virus (HIV) infection. 
9. Cancers, except for in situ carcinoma, or cancers treated at least 5 years prior to Screening 
with no evidence of recurrence. 
10. Recent medical history or current status that suggests that the subject may be unable to 
complete the study. 
11. Any female who is pregnant or lactating or who is planning to become pregnant during the 
study period. 
12. Known history of alcohol or substance abuse. 
13. Administration of bile acid or lipid binding resins within 28 days prior to screening and 
throughout the trial. 
14. Known hypersensitivity to LUM001 or any of its components. 
15. Receipt of investigational drug, biologic, or medical device within 28 days prior to screening, 
or 5 half-lives of the study agent, whichever is longer. 
16. History of non-adherence to medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to non-
adherence with the study protocol based upon investigator judgment. 
17. Any other conditions or abnormalities which, in the opinion of the investigator or medical 
monitor, may compromise the safety of the subject, or interfere with the subject participating 
in or completing the study. 
18. Subjects weighing over 50 kg at screening. 
 
Protocol Amendment 3: Eligible subjects for the 52-week optional follow-up treatment period: 
Subjects will be considered eligible for the 52-week optional follow-up treatment period if they 
have: 
• Completed the protocol through the Week 48 visit with no safety concerns. Subjects who 
were discontinued due to safety reasons can be rechallenged if blood tests are back to 
relatively normal values for this patient population and subject does not meet any of the 


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protocol’s stopping rules.  The decision will be made by the investigator in consultation 
with the medical monitor.  
• Subjects who have undergone a surgical disruption of the enterohepatic circulation will 
not be eligible to enter into the follow up treatment period.   
• Subjects who were discontinued for other reasons will be considered for the 52-week 
optional follow-up treatment period on an individual basis. The decision will be made by 
the investigator in consultation with the medical monitor. 
 
Protocol Amendment 4: Eligible subjects for the long-term optional follow-up treatment period: 
Inclusion Criteria for subjects with LUM001dosing interruption <7 days, or ≥7 days: 
Subjects will be considered eligible for the long-term optional follow-up treatment period if they 
meet the following criteria: 
1. The subject has either:  
o completed the protocol through the Week 48 visit with no major safety concerns 
 
OR 
o discontinued due to safety reasons judged unrelated to the study drug, and 
laboratory results have returned to levels acceptable for this patient population or 
individual and subject does not meet any of the protocol’s stopping rules at the 
time of entry into the follow-up period. The decision will be made by the 
investigator in consultation with the medical monitor. [Subjects who were 
discontinued for other reasons will be considered on an individual basis.]  
2. Females of childbearing potential must have a negative urine or serum pregnancy test (β-
human chorionic gonadotropin [β-hCG]) at the time of entry into the long-term optional 
follow-up treatment period. 
3. Males and females of child-bearing potential who are sexually active, or are not currently 
sexually active during the study, but become sexually active during the period of the 
study and 30 days following the last dose of study drug, must agree and use acceptable 
contraception during the trial, as described in Section 8.6.1. 
4. Informed consent and assent (per IRB/EC) as appropriate. 
5. 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 for Subjects with LUM001 dosing interruption≥7 days: 
All exclusion criteria mentioned in Section 7.2 apply upon entry into the long-term optional 
follow-up period, with the exception of exclusion criterion #18. 


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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 
Screening Period (Day -28 to Day -1) 
Screening evaluations will be performed from Day -28 to Day -1. In the absence of documented 
JAGGED1 or NOTCH2 mutation prior to screening, genetic testing may be performed for 
JAGGED1 and/or NOTCH2 (Spinner et al., 2000). The appropriate genetic counseling will be 
provided to subjects and their legal caregivers at a study visit following the receipt of results of 
genetic testing. Results of genetic screen will not impact continued participation in the study. 
After obtaining informed consent (and/or assent when appropriate), demographic data (gender, 
age, and race) will be collected and subjects will undergo a medical history and physical 
examination including body weight, height, and vital signs, compilation of concomitant 
medications, and have blood and urine samples taken for clinical laboratory testing. For subjects 
who do not have documentation of a JAGGED-1 or NOTCH2 mutation, a blood sample may be 
obtained for genotyping. The physician will provide an assessment of itch severity using the 
clinician scratch score during Screening. The eDiary for assessing pruritus with the Itch Reported 
Outcome (ItchRO) instrument will be dispensed and subjects and caregivers will undergo 
training during the Screening visit. The patient/ caregiver ItchROs (ItchRO [Pt], ItchRO [Obs]) 
will be completed twice daily during the Screening period to establish eligibility and a baseline 
score. Subjects 9 years of age and older will continue independent twice daily completion of 
their ItchRO. Subjects 5-8 years of age will continue twice daily completion of their ItchRO with 
the assistance of their caregivers, if needed. Caregivers will continue twice daily completion of 
their ItchRO. Caregivers (and age appropriate subjects) must complete at least 10 eDiary reports 
(morning or evening) during each of two consecutive weeks of the screening period, (maximum 
possible reports = 14 per week). Subjects are required to discontinue bile acid resins for at least 
28 days prior to screening and throughout the study. Females who are of childbearing potential 
will have a serum pregnancy test. Eligibility criteria will be reviewed to confirm a subject’s 
eligibility 4-7 days prior to the Baseline Visit. 
Rescreening:  If a subject is unable to complete the screening procedures and meet eligibility 
criteria within the 28-day screening period, consideration may be given to rescreening at a later 
date. Screening procedures should be repeated at that time. Subject data pertaining to screening 
will be collected after the subject has been rescreened and determined to meet eligibility.   
8.1.2 
Dose Escalation Treatment Period (Day 0 to Week 6) 
At the Baseline Visit (Day 0), subjects will be assessed to confirm continued study eligibility and 
undergo a physical examination including body weight, height, and vital signs, and have urine 
and blood samples taken for hematology, chemistry, fasting lipid panel, baseline levels of bile 


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acids and other cholestasis biochemical markers. Blood will also be collected for determination 
of baseline fat-soluble vitamins and a plasma LUM001 drug level. Compliance with ItchRO will 
be assessed. The Clinician Scratch Scale, Xanthoma Scale, and PedsQL questionnaires will be 
completed. Female subjects who are of childbearing potential will have a urine pregnancy test 
prior to dispensing study medication. Study medication for Weeks 1, 2, and 3 will be supplied at 
the Baseline Visit to eligible subjects. Subjects and caregivers will continue twice daily 
completion of their ItchRO throughout the Dose-Escalation Treatment Period. Subjects will 
return to the clinic at Weeks 3 and 6 and follow-up phone calls will be made at Weeks 1, 2, 4, 
and 5. On clinic visit days, safety and clinical laboratory evaluations will be performed, and a 
physical exam will be performed (including collection of vital signs, height and weight 
measurements). Clinician scratch scale, adherence to study medication, and ItchRO compliance 
will be assessed. Concomitant medications and any adverse events will be recorded. Female 
subjects who are of childbearing potential will have a urine pregnancy test prior to dispensing 
study medication. Study drug will be supplied at Weeks 3 and 6. 
8.1.3 
Stable Dosing Treatment Period (Week 7 to Week 18) 
Each subject will continue dosing with study drug during a 12-week Stable Dosing Treatment 
Period using the dose administered at Week 6, which may be 400 µg/kg/day or the highest 
tolerated dose below 400 µg/kg/day. Subjects 9 years of age and older will continue independent 
twice daily completion of their ItchRO. Subjects 5-8 years of age will continue twice daily 
completion of their ItchRO with the assistance of their caregivers, if needed. Caregivers will 
continue twice daily completion of their ItchRO. Subjects will receive a follow-up phone call at 
Week 9 and return to the clinic at Weeks 12 and 18. At the Week 12 and 18 visits, safety and 
clinical laboratory evaluations will be performed, and a physical exam will be performed 
(including collection of vital signs, height and weight measurements). Blood samples will be 
taken for fasting lipid panel, serum bile acids, fat soluble vitamins, and other cholestasis 
biochemical markers. Blood sampling for study drug determination may also be performed. After 
the baseline pharmacokinetic analysis, blood sampling for an additional pharmacokinetic 
analysis will be done at one additional time point - at Week 12, 18, 38, or 48 – to be selected by 
the site/investigator (sample to be taken approximately 4 hours post-dosing). Clinician scratch 
scale, adherence to study medication, ItchRO compliance, and the PedsQL questionnaire will be 
assessed and concomitant medications and any adverse events will be recorded. In addition, at 
the Week 18 visit the Clinician Xanthoma Scale, Patient Impression of Change (PIC), Caregiver 
Impression of Change (CIC), and Caregiver Global Therapeutic Benefit (CGTB) assessments 
will be completed. At the Week 18, visit subjects will also be randomized 1:1 to either continue 
to receive study drug or a corresponding placebo between Week 19 and Week 22. Female 
subjects who are of childbearing potential will have a urine pregnancy test prior to dispensing 
study medication. Study drug will be supplied at Week 12 and study drug (or placebo) at 
Week 18.  
8.1.4 
Double-blind, Placebo-controlled Study Withdrawal Period (Week 19 to 
Week 22) 
Age appropriate subjects and caregivers will continue twice daily completion of their ItchRO. 
Subjects will receive a follow-up phone call at Week 20 and return to the clinic at Week 22. At 
the Week 22 visit, safety and clinical laboratory evaluations will be performed, and a physical 


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exam will be performed (including collection of vital signs, height and weight measurements). 
Blood samples will be taken for fasting lipid panel, serum bile acids, fat soluble vitamins, and 
other cholestasis biochemical markers. Female subjects who are of childbearing potential will 
have a urine pregnancy test prior to dispensing study medication. Study drug will be supplied at 
Week 22. Clinician Scratch Scale, adherence to study medication, ItchRO compliance, PIC, CIC, 
CGTB, and the PedsQL questionnaires will be assessed and concomitant medications and any 
adverse events will be recorded. 
8.1.5 
Long-term Exposure Period (Week 23 to Week 48) 
Following the 4-week double-blind, study drug withdrawal period, subjects who received 
placebo will once again receive LUM001 according to the schedule where the dose is increased 
weekly over a 6-week period up to 400 μg/kg/day or a maximum daily dose of 20 mg/day. 
Following the 4-week study drug withdrawal period, subjects who were randomized to receive 
LUM001 will undergo a simulated dose escalation to maintain the blind in the randomized 
withdrawal period and continue to receive LUM001 during the long-term exposure period, at the 
same dose administered at Week 22. 
Subjects and caregivers will continue twice daily completion of their ItchRO throughout the 
long-term exposure period to the Week 48 clinic visit. Subjects will return to the clinic at 
Weeks 28, 38, and 48. At these visits, safety and clinical laboratory evaluations will be 
performed, and a physical exam will be performed (including collection of vital signs, height and 
weight measurements). Blood samples will be taken for fat soluble vitamins, as well as possible 
pharmacokinetic blood sampling for study drug determination (if not done previously at 
Week 12 or 18). Female subjects who are of childbearing potential will have a urine pregnancy 
test prior to dispensing study medication. Clinician scratch scale, adherence to study medication, 
and ItchRO compliance will be assessed. Subjects/caregivers will receive follow-up phone calls 
at the end of Weeks 23-27, 33, and 43. Concomitant medications and adverse events will be 
recorded at all clinic visits and at scheduled telephone contacts.  
At the investigator’s discretion, withdrawal of concomitant medications used for the treatment of 
pruritus may occur during the long-term exposure period. Additional study drug will be supplied 
at each clinic visit during the long-term exposure period. 
8.1.6 
Week 48 
At Week 48, 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, other 
cholestasis biochemical markers, and possibly LUM001 drug level analysis. Females who are of 
childbearing potential will have a urine pregnancy test. The Clinician Scratch Scale, Clinician 
Xanthoma Scale, and PedsQL questionnaire will be completed.  The PIC, the CIC, and the 
CGTB assessments will be completed. Concomitant medications and adverse events will be 
recorded. Study drug compliance will be assessed and all remaining study drug and study 
supplies will be collected. Study drug will be discontinued and eDiaries will be returned to the 
site at this visit.  


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Subjects will then be considered for a 52-week optional follow-up treatment, if eligible, to 
continue on their highest tolerated dose. 
Subjects who withdraw from the study prior to completion of all treatment period clinic visits 
should undergo the procedures specified for the Week 48/Study Termination visit (Schedule of 
Procedures, 16.1). 
8.1.7 
Early Termination for Subjects without Participation in the 52-week 
Optional Follow-up Treatment Period 
Any subject who withdraws from the study prior to completion of all treatment period clinic 
visits should undergo a physical examination, as well as have urine and blood samples taken for 
safety and clinical laboratory evaluations, lipid panel, bile acids, other cholestasis biochemical 
markers, fat soluble vitamins, and drug level. In addition the following assessments should be 
completed: the Clinician Scratch Scale, the Clinician Xanthoma Scale, the PedsQL, the PIC, the 
CIC, and the CGTB assessments, as defined for ET (see Schedule of Procedures, Section 16.1). 
For safety reasons, efforts must be made to follow subjects for at least 30 days following their 
last dose of study drug.  
8.1.8 
52-week Optional Follow-up Treatment Period 
Subjects who are eligible to roll over into the 52-week optional follow-up treatment period 
with no LUM001 dosing interruption or an interruption of <7 days will be maintained at the 
same dose level within the 52-week optional follow-up treatment period (Figure 4). 
During this period, subjects will return to the clinic at Weeks 60, 72, 84, 96, and 100; telephone 
contacts will occur at Weeks 64, 68, 76, 80, 88, and 92.  
Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 400 µg/kg/day or 
to the highest tolerated dose (see Figure 5). The dose escalation (DE) period will proceed as 
follows: 
• Week DE-2 Clinic Visit: obtain consent, weight, and draw blood for laboratory analyses 
• Week DE 0 Clinic Visit: PI evaluates laboratory results, study drug is dispensed, and 
subject begins at 35 µg/kg/day dose level (if no safety concerns) 
• Week DE 49 Telephone Contact: subject escalates to 70 µg/kg/day dose level 
• Week DE 50 Telephone Contact: subject escalates to 140 µg/kg/day dose level if prior 
dose level was tolerated 
• Week DE 51 Telephone Contact: subject escalates to 280 µg/kg/day dose level if prior 
dose level was tolerated 
• Week DE 52 Clinic Visit: laboratory tests and dose escalates to 400 µg/kg/day dose, if 
prior dose level was tolerated 


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If any subject experiences intolerance, the investigator, in consultation with the medical monitor, 
may lower the dose to a previously tolerated dose at any time during the entire follow-up 
treatment period. At the investigator’s discretion, and in consultation with the medical monitor, 
subjects who were previously down-titrated may be rechallenged during the follow-up treatment 
period.  
8.1.9 
Long-term Optional Follow-up Treatment Period  
Upon completion of the additional 52-week optional follow-up treatment period and/or 
implementation of this amendment, whichever occurs first, subjects who are eligible to roll over 
onto the long-term optional follow-up treatment period will continue to receive study drug until 
the first of the following occurs:  
i. 
The subjects are eligible to enter another LUM001 study 
ii. 
LUM001 is available commercially, or 
iii. 
The sponsor stops the program or development in this indication 
Once Protocol Amendment 4 is implemented at the site, a determination about Afternoon Dose 
Escalation (ADE) will be made.  
Refer to Section 5.4 for schematics describing the flow of study visits within this period. 
Subjects who are eligible to roll over from the 52-week optional follow up treatment period 
into the long-term optional follow-up treatment period with no LUM001 dosing 
interruption or an interruption of <7 days prior to implementation of Protocol Amendment 4 
will be consented and evaluated for eligibility for ADE. Once a determination about ADE has 
been made, the subject will then either initiate the ADE (see Figure 8) or continue receiving the 
same dose of LUM001 once a day (Figure 7), depending on whether they meet criteria for 
initiating ADE. 
Screening evaluations for subjects with ≥7 days since last dose of LUM001 prior to 
implementation of Protocol Amendment 4 will be performed from Day -14 to Day -1.  After 
obtaining informed consent (and/or assent when appropriate), subjects will undergo a physical 
examination including body weight, height, and vital signs, and have blood and urine samples 
taken for clinical laboratory testing. Females who are of childbearing potential will have a serum 
pregnancy test. Eligibility criteria will be confirmed prior to the Baseline Visit. The Clinician 
Scratch Scale and Clinician Xanthoma Scale will be completed. Concomitant medications and 
any adverse events will be recorded. 
Rescreening:  If a subject is unable to complete the screening procedures and meet eligibility 
criteria within the 14-day screening period, consideration may be given to rescreening at a later 
date. Screening procedures should be repeated at that time. Subject data pertaining to screening 
will be collected after the subject has been rescreened and determined to meet eligibility. 


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Subjects with ≥7 days since last dose of LUM001 prior to implementation of Protocol 
Amendment 4 will be dose escalated up to 400 µg/kg/day or to the highest tolerated dose 
beginning at Dose Level 2 (35 μg/kg/day), as outlined in Figure 6.  
The dose escalation (DE) period will proceed as follows: 
• Protocol Amendment 4 DE Week -2 Clinic Visit: obtain consent, weight, and draw blood for 
laboratory analyses 
• Protocol Amendment 4 DE Day 0 Clinic Visit: investigator evaluates laboratory results, 
study drug is dispensed, and subject begins at 35 μg/kg/day dose level (if no safety concerns) 
• Protocol Amendment 4 DE Week 1 Telephone Contact: subject escalates to 70μg/kg/day 
dose level if prior dose level was tolerated 
• Protocol Amendment 4 DE Week 2 Telephone Contact: subject escalates to 140 μg/kg/day 
dose level if prior dose level was tolerated 
• Protocol Amendment 4 DE Week 3 Telephone Contact: subject escalates to 280 μg/kg/day 
dose, if prior dose level was tolerated 
• Protocol Amendment 4 DE Week 4 Clinic Visit: laboratory tests and dose escalates to 
400 µg/kg/day dose (maximum daily dose of 20 mg), if prior dose level was tolerated 
• Protocol Amendment 4 DE Week 8 Telephone Contact: eligibility for ADE will be 
determined 
Subjects not eligible for the ADE (subjects with normal sBA level AND ItchRO[Obs] score 
<1.5) will be maintained at the same dose level and will continue morning dosing only. Subjects 
will have study activities then repeated in repeating 12-week periods as follows, until study 
completion or termination (see Figure 7). 
• Repeating Period Week 4 Telephone Contact (ie, beginning 4 weeks after consent to Protocol 
Amendment 4): Collection of concomitant medications and any adverse events. 
• Repeating Period Week 8 Telephone Contact: Collection of concomitant medications and 
any adverse events.  
• Repeating Period Week 12 Clinic Visit: Physical exam, body weight and height, vital signs, 
and blood samples for clinical laboratory testing including fasting lipid panel. Blood will also 
be collected for determination of baseline fat-soluble vitamins. Urine samples for clinical 
laboratory testing will be collected at every other visit. ItchRO compliance will be assessed, 
the electronic diary will be issued, the Clinician Scratch Scale and Clinician Xanthoma Scale 
will be administered, and the PedsQL questionnaire will be administered. Additionally, a 
palatability questionnaire will be completed. Female subjects who are of childbearing 
potential will have a urine pregnancy test prior to dispensing study drug. Study drug 
compliance will be assessed and study drug will be dispensed. Concomitant medications and 
adverse events will be collected. 
• Subjects who do not qualify for ADE may be assessed at a later time point on a case by case 
basis following discussions between the investigator and medical monitor. Such re-


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evaluations may only occur at the Week 12 visit of any Repeating Period beginning with 
RP2. If in the course of the ADE re-evaluation, a subject is found to qualify for ADE, then 
the subject will move into Schedule F or G, as outlined in Section 16.1. During the follow-up 
treatment period, subjects will return to the clinic every 3 months. 
Subjects eligible for ADE, (ie, who have sBA level above normal AND/OR ItchRO [Obs] 
score ≥1.5), will begin BID dosing (ADE) as follows (see Figure 8): 
• On ADE Day 0, morning dosing will continue at 400 µg/kg or the maximum tolerated 
dose. However, the volume of the morning dose will be reduced by half. Of note: 
Morning dosing must have been stable for ≥4 weeks prior to initiation of ADE.  
• On ADE Day 0, the afternoon dose will be initiated at 140 µg/kg/day and will continue at 
this dose for a period of 4 weeks. If this dose level is tolerated, the afternoon dose then 
will be escalated up to 400 µg/kg (ie, up to a maximum 800 µg/kg/day or maximum 
tolerated dose). 
The following procedures will occur during the ADE period: 
• ADE Day 0 Clinic Visit:  Physical exam, body weight and height, vital signs, and blood 
and urine samples for clinical laboratory testing, including fasting lipid panel. Blood will 
also be collected for determination of fat-soluble vitamins. Plasma sample will be 
obtained for LUM001 pharmacokinetics. The Clinician Scratch Scale, Clinician 
Xanthoma Scale, and the PedsQL questionnaire will be administered. Female subjects 
who are of childbearing potential will have a urine pregnancy test prior to dispensing 
study drug.  Study drug compliance will be assessed and study drug will be dispensed 
upon completion of other study procedures. Concomitant medications and any adverse 
events will be collected. 
• ADE Week 1 and Week 2 Telephone Contact:  Collection of concomitant medications 
and any adverse events. Subject/caregiver will be reminded of dosing instructions. 
• ADE Week 4 Clinic Visit:  Physical exam, body weight and height, vital signs, and blood 
and urine samples for clinical laboratory testing, including fasting lipid panel.  Blood will 
also be collected for determination of fat-soluble vitamins. Plasma sample will be 
obtained for LUM001 pharmacokinetics. The Clinician Scratch Scale, Clinician 
Xanthoma Scale, and the PedsQL questionnaire will be administered. Female subjects 
who are of childbearing potential will have a urine pregnancy test prior to dispensing 
study drug. Study drug compliance will be assessed and study drug will be dispensed 
upon completion of other study procedures. Concomitant medications and any adverse 
events will be collected. 
• ADE Week 5 and Week 6 Telephone Contact:  Collection of concomitant medications 
and any adverse events.  Subject/caregiver will be reminded of dosing instructions. 
• ADE Week 8 Clinic Visit:  Physical exam, body weight and height, vital signs, and blood 
and urine samples for clinical laboratory testing, including fasting lipid panel.  Blood will 
also be collected for determination of fat-soluble vitamins. Plasma sample will be 
obtained for LUM001 pharmacokinetics. The Clinician Scratch Scale, Clinician 


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Xanthoma Scale, and the PedsQL questionnaire will be administered. Female subjects 
who are of childbearing potential will have a urine pregnancy test prior to dispensing 
study drug. Study drug compliance will be assessed and study drug will be dispensed 
upon completion of other study procedures. Concomitant medications and any adverse 
events will be collected. 
Thereafter, subjects will have study activities repeated in repeating 12-week periods as described 
above, until study completion or termination (see Figure 8) 
If any subject experiences intolerance, the investigator, in consultation with the medical monitor, 
may lower the dose to a previously tolerated dose at any time during the entire follow-up 
treatment period; later attempts to escalate the dose are permitted. At the investigator’s discretion 
and in consultation with the medical monitor, subjects who were previously down-titrated may 
be rechallenged during the follow-up treatment period. If the subject is on a twice daily dosing 
regimen, dose lowering should first be attempted with the afternoon dose. 
Safety and clinical laboratory evaluations and a physical exam (including collection of vital 
signs, height and weight measurements) will be completed at each clinic visit. In addition, the 
Clinician Scratch Scale, Clinician Xanthoma Scale, and PedsQL will be administered and study 
drug compliance will be assessed (PedsQL will not be performed at certain clinic visits - please 
refer to schedule of procedures). The PIC, CIC, and CGTB assessments will be completed at 
Weeks 84, 96, 100, and the End of Treatment (EOT) / ET visit. Palatability data will be collected 
at each clinic visit during the long-term optional follow up treatment period (including the 
EOT/ET visit), with the exception of the PA4 DE, and ADE visits. Plasma samples will be 
obtained for LUM001 pharmacokinetics at the ADE Day 0, ADE Week 4, and ADE Week 8 
visits, and at the 3 scheduled clinic visits following completion of the ADE period. 
Subjects/caregivers will receive follow-up phone calls at Weeks 64, 68, 76, 80, 88, 92, as well as 
those outlined within the DE, PA4 DE, and repeating 12-week periods. Concomitant medications 
and any AEs will be evaluated and recorded at all clinic visits and at scheduled telephone 
contacts. 
Twice daily completion of the electronic diary will be required by caregivers and age appropriate 
subjects during the 2 weeks following the Week 60, 72, 84, and 96 clinic visits, at PA4 DE 
Week 4, and at every clinic visit within the repeating 12-week periods. Electronic diaries will be 
provided to subjects and caregivers at these visits and re-training on the use of the diary will 
occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for the 
treatment of pruritus may occur during the long-term exposure period.  
With the exception of the EOT/ET visit, additional study drug will be supplied at each clinic visit 
during the follow-up treatment period. Unused study drug will be collected at every visit.  
Subjects will be encouraged to complete all study activities and visits. Any subject who 
withdraws from the study prior to completion of all treatment period clinic visits should undergo 
safety and clinical laboratory evaluations, including pharmacokinetic sampling of LUM001, 
determination of serum bile acids, other cholestasis biochemical markers, fat soluble vitamins, 


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and AFP. In addition the following assessments should be completed: the Clinician Scratch 
Scale, Clinician Xanthoma Scale, the PedsQL, the PIC, the CIC, the CGTB, and the palatability 
questionnaire, as defined for ET (see Schedule of Procedures, Section 16.1). For subjects who 
complete the study, the assessments performed at the EOT visit will be identical to the 
assessments performed at the ET visit. 
8.1.10 
End of Treatment or Early Termination 
Any subject who completes or withdraws from the study should undergo all procedures specified 
for the EOT/ET visit (see Schedule J). The following assessments are to be completed at the 
EOT/ET visit: safety and clinical laboratory evaluations, including determination of serum bile 
acids, lipid panel, other cholestasis biochemical markers, fat soluble vitamins and AFP. Female 
subjects who are of childbearing potential will have a urine pregnancy test. Study drug 
compliance will be assessed. Concomitant medications and adverse events will be collected. In 
addition, the following assessments should be completed: the Clinician Scratch Scale, Clinician 
Xanthoma Scale, the PedsQL, the PIC, the CIC, and the CGTB assessments, as defined for the 
ET visit (see Schedule of Procedures, Section 16.1).  
8.1.11 
Safety Follow-up 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 adverse events noted during this phone call will be 
recorded.  
8.2 
Genetic Testing 
JAGGED1 and NOTCH2 mutations can be predictive of ALGS. For ALGS subjects who meet 
clinical diagnostic criteria for ALGS (see Section 16.3) but do not have documentation of a 
JAGGED1 or NOTCH2 mutation, the clinical diagnosis of ALGS may be confirmed by 
genotyping. Genetic counseling, as appropriate, will be provided to subjects and their legal 
caregivers. Subjects for whom prior genotyping was performed may need to have an optional 
repeat analysis performed if the original information collected at screening was insufficient for 
complete documentation of the diagnosis of ALGS including the type of mutation recorded. For 
those participants for which the type of the mutation cannot be documented, genetic testing may 
be conducted and the results recorded. 
8.3 
Physical Examination, Weight and Height, Vital Signs 
A physician investigator will conduct a physical examination on each subject at screening and at 
every study clinic visit. In addition, body weight, height, and vital signs, including body 
temperature, blood pressure, respiration and pulse, will be determined at every study clinic visit. 
8.4 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study. A list of planned tests is 
compiled in Section 16.2. 


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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 11.4.3 regarding 
laboratory abnormalities. 
8.5 
Pruritus and Quality of Life Assessments 
8.5.1 
Itch Reported Outcome (ItchRO™) 
Pruritus will be assessed using the Itch caregiver and patient reported outcome measures 
(ItchRO) administered as a twice daily electronic diary. Caregivers for all subjects will complete 
the Observer instrument: ItchRO(Obs)™. Children ≥9 years of age will independently complete 
the patient instrument: ItchRO(Pt)™. Children between the ages of 5 and 8 years will complete 
the patient instrument with the assistance of their caregiver: ItchRO(Pt), if needed. Age at 
screening 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). The primary measure of pruritus 
will be made using the ItchRO(Obs). 
Subjects and caregivers will be trained in the use of the electronic diary during the screening 
visit. Beginning with the screening period, pruritus will be assessed and recorded twice daily by 
caregivers and subjects (ItchRO), as described in Section 16.4.  
To be eligible for study entry, caregivers must complete at least 10 eDiary reports (morning 
and/or evening) during each of two consecutive weeks of the screening period and have an 
average daily score of >2 for 2 consecutive weeks prior to study start. In addition, 
subjects ≥9 years of age must complete at least 10 eDiary reports (morning and/or evening) 
during each of two consecutive weeks of the screening period. Subjects are required to 
discontinue bile acid resins for at least 28 days prior to screening and throughout the study.  
ALGS subjects/caregivers will be required to submit twice daily assessments using the electronic 
diary for the duration of the study. Electronic diaries will be returned to the study site at the 
Week 48 clinic visit (or sooner if the subject has withdrawn from the study before the Week 48 
visit). For subjects who enter the 52-week and long-term optional follow-up treatment periods, 
completion of the diary will occur as outlined in the Schedule of Procedures in Section 16.1.  
Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score 
of 4, with 4 representing more severe itching. The highest score between the morning and 
evening reports will represent the daily score: a measure of the worst itching over the previous 
24-hour period. In the event that either the morning or evening report is not completed within the 
allowed reporting window, whichever report has been completed will represent the daily score. 
In the event that a subject/caregiver failed to complete both the morning and evening reports, the 
daily score for that day will be treated as missing data. The handling of missing data on the daily 
ItchRO score will be outlined in the SAP for the study.  


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8.5.2 
Clinician Scratch Scale 
A clinician’s assessment of pruritus made by the principal investigator or appropriate designee 
using the clinician scratch scale (Section 16.5) will be recorded at screening, Day 0 (baseline), 
Weeks 3, 6, 12, 18, 22, 28, 38, and 48. For subjects who enter the 52-week and long-term 
optional follow-up treatment periods, the clinician scratch scale will also be administered at 
clinic visits as outlined in the Schedule of Procedures in Section 16.1.  
The clinician’s assessment of the subject’s pruritus is focused on scratching and visible damage 
to the skin as a result of scratching as observed by the physician. The clinician scratch scale uses 
a 5-point scale, in which 0 designates no evidence of scratching and 4 designates cutaneous 
mutilation with bleeding, hemorrhage and scarring. Whenever possible, the same individual 
should make the assessments for a subject’s visits. 
8.5.3 
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 16.6). This assessment will be 
completed at Baseline (Day 0) and at Weeks 18, and 48. For subjects who enter the 52-week and 
long-term optional follow-up treatment periods, the Clinician Xanthoma Scale will be recorded 
as outlined in the Schedule of Procedures in Section 16.1. 
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).  
8.5.4 
Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL™ is a questionnaire that will be administered to subjects and/or caregivers at the 
Week 0 (baseline), 18, 22, and 48. For subjects who enter the 52-week and long-term optional 
follow-up treatment periods, the PedsQL will be administered as outlined in the Schedule of 
Procedures in Section 16.1. For subjects with interruptions in LUM001 dosing of ≥7 days, the 
PedsQL will also be administered at DE Day 0. The PedsQL is a validated, modular instrument 
designed to measure health-related quality of life (HRQoL) in children and adolescents (Varni et 
al., 2001). In addition to the core generic PedsQL module, the multidimensional fatigue and 
family impact questionnaire will also be administered at the Week 0 (baseline), 18, 22, and Week 
48 using the age-appropriate module (see Section 16.7). Age at baseline will be used as the age 
for the determination of the appropriate module to be used for the study and this same module 
will be used for the duration of the study (regardless of subsequent birthdays after the baseline 
visit). For subjects who enter the 52-week and long-term optional follow-up treatment periods, 
the multidimensional fatigue and family impact questionnaire will be administered as outlined in 
the Schedule of Procedures in Section 16.1. 


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8.5.5 
Patient Impression of Change 
The PIC is designed to assess the subject’s perception of his/her itching after various points of 
study drug treatment compared to his/her itching prior to the start of treatment with study drug. 
The PIC will be completed, by subjects who were 9 years of age or older at the Week 18, 22, and 
48 visits. For subjects who enter the 52-week and long-term optional follow-up treatment 
periods, the PIC will be completed by subjects who were 9 years of age or older at clinic visits as 
outlined in the Schedule of Procedures in Section 16.1.  
8.5.6 
Caregiver Impression of Change 
The CIC is designed to assess the caregiver’s perception of the subject’s itch related symptoms 
and xanthoma severity after various points of study drug treatment compared to his/her itch 
related symptoms and xanthoma severity prior to the start of treatment with study drug. The CIC 
will be completed by all caregivers at the Week 18, 22, and 48 visits. For subjects who enter the 
52-week and long-term optional follow-up treatment periods, the CIC will be completed as 
outlined in the Schedule of Procedures in Section 16.1.  
8.5.7 
Caregiver Global Therapeutic Benefit 
The CGTB questionnaire is designed to assess the caregiver’s perception of the treatment 
benefits on the subject’s itching compared to the side effects experienced with study drug. The 
CGTB will be completed by all caregivers at the Week 18, 22, and 48 visits. For subjects who 
enter the 52-week and long-term optional follow-up treatment periods, the CGTB will be 
completed as outlined in the Schedule of Procedures in Section 16.1.  
8.5.8 
Palatability 
A palatability questionnaire (see Section 16.12) will be completed by the subject and/or 
caregiver (dependent on age) at clinic visits at time points as outlined in the Schedule of 
Procedures in Section 16.1. 
8.6 
Restriction on the Lifestyle of Subjects 
8.6.1 
Contraception Requirements 
Sexually active female subjects of childbearing potential must continue to use acceptable 
contraception with their partners, or refrain from sexual activity, from the time of screening, 
throughout the study period and for 30 days following the last dose of study drug.  
If hormonal contraceptives are used they should be administered according to the package insert. 
Females of child-bearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days following the last dose of the IP. 
Acceptable methods of contraception are: 


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a. Hormonal contraceptives (eg, oral contraceptive pill, depot, patch, intramuscular implant 
or injection, or vaginal ring), stabilized for at least 30 days if first use, plus condoms; 
and/or 
b. Barrier method, eg, (i) condom (male or female) or (ii) diaphragm, with spermicide; or 
c. Intrauterine device (IUD). 
d. or a sexual partner who is surgically sterilized.  
Male Contraception: 
Contraception is required for all sexually-active male subjects and their partners. All male 
subjects agree not to donate sperm, and to use 1 of the following approved methods of 
contraception until 30 days following study discharge: 
a. Male condom with spermicide 
b. Intrauterine device with spermicide (use by female sexual partner) 
c. Female condom with spermicide (use by female sexual partner) 
d. Contraceptive sponge with spermicide (use by female sexual partner) 
e. Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with spermicide, or a 
cervical cap with spermicide) (use by female sexual partner) 
f. Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female 
sexual partner). 
8.6.2 
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, 5 mL, or 0.25 qAM, ac), in the morning 30 minutes before breakfast. After breakfast only 
water should be consumed until the scheduled clinic visit.  


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9 
STUDY DRUG 
9.1 
Study Drug Description 
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 compositions of LUM001 study drug 1.0 mL, 0.5 mL, and 
0.25 mL oral solutions are described, respectively, in Table 4, Table 5, and Table 6. 
Table 4: 
Composition of LUM001 1.0 mL Oral Solution  
Component 
Function 
Quantity per 1.0 mL 
LUM001 
Active Ingredient 
up to 50.0 mg 
Propylene Glycol 
Co-solvent 
250.0 mg 
Sucralose 
Sweetener 
7.5 mg 
Grape Flavoring Agent 
Taste Masking Agent 
5.0 mg 
Water 
Vehicle 
q.s. to 1.0 mL 
q.s = quantity sufficient 
Table 5: 
Composition of LUM001 0.5 mL Oral Solution 
Component 
Function 
Quantity per 0.5 mL 
LUM001 
Active Ingredient 
up to 25.0 mg 
Propylene Glycol 
Co-solvent 
125.0 mg 
Sucralose 
Sweetener 
3.75 mg 
Grape Flavoring Agent 
Taste Masking Agent 
2.5 mg 
Water 
Vehicle 
q.s. to 0.5 mL 
q.s = quantity sufficient 
Table 6: 
Composition of LUM001 0.25 mL Oral Solution 
Component 
Function 
Quantity per 0.25 mL 
LUM001 
Active Ingredient 
up to 12.5 mg 
Propylene Glycol 
Co-solvent 
62.5 mg 
Sucralose 
Sweetener 
1.875 mg 
Grape Flavoring Agent 
Taste Masking Agent 
1.25 mg 
Water 
Vehicle 
q.s. to 0.25 mL 
q.s = quantity sufficient 
9.1.2 
Placebo 
The matching placebo contains the diluent with no active ingredient. The compositions of 
placebo 1.0 mL, 0.5 mL, and 0.25 mL study drug oral solutions are described, respectively, in 
Table 7, Table 8, and Table 9.  


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Table 7: 
Composition of Placebo 1.0 mL Oral Solution 
Component 
Function 
Quantity per 1.0 mL 
Propylene Glycol 
Co-solvent 
250 mg 
Sucralose 
Sweetener 
7.5 mg 
Grape Flavoring Agent 
Taste Masking Agent 
5 mg 
Water 
Vehicle 
q.s. to 1.0 mL 
q.s = quantity sufficient 
Table 8: 
Composition of Placebo 0.5 mL Oral Solution 
Component 
Function 
Quantity per 0.5 mL 
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 
q.s = quantity sufficient 
Table 9: 
Composition of Placebo 0.25 mL Oral Solution 
Component 
Function 
Quantity per 0.5 mL 
Propylene Glycol 
Co-solvent 
62.5 mg 
Sucralose 
Sweetener 
1.875 mg 
Grape Flavoring Agent 
Taste Masking Agent 
1.25 mg 
Water 
Vehicle 
q.s. to 0.25 mL 
q.s = quantity sufficient 
9.2 
Packaging and Labeling 
The sponsor will provide the investigator with packaged study drug labeled in accordance with 
specific country regulatory requirements. Standard syringes will be provided for oral 
administration of study drug. 
9.3 
Drug Accountability 
Study staff is 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 (including placebo), as well as original 
containers (even if empty), will be returned to the sponsor or handled according to written 
instructions from the sponsor, following approval by the sponsor.  


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10 
TREATMENT OF SUBJECTS 
10.1 
Study Drug Administration 
The dose of study drug (LUM001 or placebo) in this study is based on weight. The subject’s 
weight determined at the screening visit will be used to calculate the administered dose of study 
drug for the first 22 weeks of the study. During the study, the study drug may be adjusted if there 
is a change of ≥10% in 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 (μg/kg/day). The 
dose may also be down-titrated, at the investigator’s discretion and in consultation with the 
medical monitor, for subjects experiencing intolerance (eg, gastrointestinal symptoms such as 
diarrhea, abdominal pain, cramping) to a given dose. If the subject is on twice daily dosing 
regimen, dose reduction should first be attempted with the afternoon dose. Subjects who were 
previously down-titrated may be rechallenged during the long-term exposure period. 
Study drug will be prepared for each subject by a central pharmacy based on the subject’s weight 
at screening. Grape flavored diluent will be added by the central pharmacy pharmacist prior to 
shipping study drug to the site. Once study drug has been added to the diluent the resulting 
solution is stable at temperatures ranging from 4-8oC to room temperature for at least 12 months. 
Subjects will receive a grape-flavored solution containing LUM001. Each subject dose will be 
administered orally once a day (QD) or twice a day (BID) using the syringe provided. The first 
dose should be taken at least 30 minutes prior to the first meal of the day and the second dose, 
where applicable, should be taken at least 30 minutes prior to dinner (evening meal). The doses 
will not be administered q12h in order to better cover the luminal bile acid release associated 
with dinner and to minimize the risk of disturbing sleep due to the potential for abdominal pain 
and diarrhea at night. It is recommended that the doses should be taken approximately at the 
same time each day for the duration of the treatment period. See Section 5.5.2 for information 
regarding dosing during the treatment periods, respectively. 
QD Dosing Regimen 
For QD dosing, the required dose will be delivered in 0.5 mL volume for subjects who weigh 
less than 10 kg and in 1.0 mL for subjects who weigh 10 kg or more. 
BID Dosing Regimen 
For BID dosing, the required dose is delivered in half the dosing volume: 0.25 mL BID for 
subjects who weigh less than 10 kg and 0.50 mL BID for subjects who weigh 10 kg or more. 
For subjects weighing less than 10 kg at study entry, once a weight of 10 kg is reached while in 
the study, the subject will be moved from 0.5 mL maximum daily dosing volume (0.25 mL BID) 
to 1.0 mL maximum daily dosing volume (0.50 mL BID). 
Please refer to the Study Drug Manual provided by the sponsor for more detailed instructions for 
study drug preparation, administration and storage.  


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10.2 
Treatment Compliance 
Compliance with treatment dosing will be monitored and recorded by the study center staff. 
Subjects and/or caregivers will be asked to complete a paper drug dosing diary indicating when 
they took their study medication and when they ate breakfast and, for subjects who receive a BID 
regimen, when they ate dinner (evening meal). 
10.3 
Concomitant Medications 
A concomitant medication is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered during 
participation in the study (the period from the first day of screening through the last contact.  
All subjects will have fat soluble vitamin levels monitored; blood samples for fat soluble 
vitamins should be obtained before the daily dose of vitamins is administered, and approximately 
4 hours after any food or formula. 
All medications (other than study drug) taken by subjects during the course of the study will be 
recorded and reviewed by the principal investigator (PI)/investigator’s designee. Concomitant 
medication will be coded using the World Health Organization (WHO) Drug Dictionary (release 
date 01 Sep 2008, or more recent version if available). AEs related to administration of these 
medications must also be documented. 
Subjects are required to discontinue bile acid resins for at least 28 days prior to screening and for 
duration of the study. The dosage and dosing regimen of concomitant drug therapy other than 
that specified by the protocol should not change during the first 22 weeks of study, with the 
exception of weight-based dose adjustments and vitamin supplementation. No new medications 
used to treat pruritus may be added during the first 22 weeks of the study. All modifications to a 
subject’s concomitant drug therapy, including weight-based dose adjustments and vitamin 
supplementation regimen must be carefully documented in the relevant case report forms. If drug 
therapy other than that specified by the protocol is taken, a joint decision will be made by the 
investigator or investigator’s designee and sponsor to continue or discontinue the subject.  
10.4 
Other Protocol-required Drugs 
There are no other protocol required drugs. Subjects are expected to maintain a stable dose and 
administration schedule for all permitted concomitant medications throughout the course of the 
study. 
10.5 
Safety Monitoring Rules 
10.5.1 
General Monitoring Rules 
In the evaluation of adverse events and the potential relationship to study drug it is important to 
note that due to their liver disease many patients with ALGS have abnormal liver enzyme levels 
(eg ALT, ALP) and total bilirubin at baseline. If an individual subject exhibits a CTCAE Grade 3 
treatment emergent laboratory abnormality, with the exception of the specific rules outlined 


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below (Sections 10.5.2), dosing can be suspended or continued as per the investigator’s judgment 
and following discussion with the medical monitor. If suspended the investigator and medical 
monitor will evaluate the subject’s safety data and make a decision to either restart dosing at the 
same level, restart dosing at a lower dose level, or discontinue dosing.  
To ensure subject safety, if 6 or more subjects at a dose level lower, suspend or stop study 
medication or exhibit treatment emergent toxicity of CTCAE Grade 3 or greater in the same 
system organ class (SOC), with the exception of the specific rules outlined below, further dosing 
of subjects at that dose level and any higher dose levels will be halted until a safety assessment is 
completed. Study visits and completion of the ItchRO diaries, for all randomized subjects, will 
continue during the assessment period. After review a decision will be made whether to restart 
dosing at the same dose level, restart dosing at a lower dose level, or discontinue the subjects 
from the study. The Data Monitoring Committee (DMC) will be notified of any SAE as specified 
in the DMC charter.  
10.5.2 
Safety Monitoring Rules 
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 on new specimens. Of note: the INR re-test should be conducted by the central 
laboratory, but may also be conducted at a local laboratory on an as needed basis. All new 
specimen collections should take place as soon as possible, ideally within 48 to 72 hours of the 
notification of the laboratory result. It may be difficult for some subjects who live far from the 
study site to return to the study site promptly. In this case, the subjects should be retested locally, 
but normal laboratory ranges should be recorded, results should be made available to study 
investigators and medical monitors immediately, and the data should be included in the case 
reports. 
Stopping Rule Guidance:  Subject dosing must be suspended until the retest results are available. 
If any of the stopping criteria described below (see Section 10.5.2.2 and Section 10.5.2.5) is 
confirmed, the physician investigator (PI) in consultation with the medical monitor (or 
appropriately qualified designee) will permanently discontinue the subject from further treatment 
with study drug (LUM001 or placebo). The subject will be evaluated as outlined below and will 
be encouraged to complete the ET study procedures (Week 48 visit). Subjects who do not meet 
the stopping rules based on retest may continue dosing and the investigator and the medical 
monitor (or 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), in particular whether the event should be considered as an important medical event, ie, 
an event that would have met one of the other seriousness criteria in the absence of appropriate 
medical interventions.  


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10.5.2.1 
Safety Monitoring for Liver Chemistry Tests 
Safety monitoring criteria take into consideration the subject’s baseline ALT and total bilirubin 
levels. The baseline will be defined as the last evaluation before dosing with study drug (Day 0).  
If at any time in the study an ALT or total bilirubin result meets the criteria shown in the table 
below, in relation to the subject’s baseline level, the initial measurement(s) should be confirmed 
within 48 to 72 hours of notification of the laboratory result.  
Baseline ALT 
ALT 
< ULN 
> 5 x ULN 
> ULN 
> 3 x baseline and > 5 x ULN 
 
Baseline Total Bilirubin 
Total Bilirubin 
Total Bilirubin 1-10 mg/dL 
3 mg increase 
Total Bilirubin >10 mg/dL 
5 mg increase  
 
Frequency of Repeat Measurements: Subjects with a confirmed ALT or total bilirubin level that 
is continuing to rise should have their liver chemistry tests (ALT, ALP, INR and total bilirubin) 
retested as clinically indicated, until levels stabilize or begin to recover. 
Further Investigation into Liver Chemistry Elevations: Based on the inclusion criteria for this 
study the population to be enrolled will have pre-existing baseline liver disease and will be 
closely monitored by the investigators with experience in the management of pediatric hepatic 
diseases. For subjects with a confirmed elevation in ALT or total bilirubin level as described 
above, the following evaluations should be performed as clinically indicated: 
• Close and frequent monitoring of liver enzyme and serum bilirubin tests as clinically 
indicated. Frequency of retesting can decrease if abnormalities stabilize or the study 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)]. 
 


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Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the investigator, in consultation with the 
medical monitor.  
10.5.2.2 
Stopping Rules for Liver Chemistry Elevations 
In the event of confirmed laboratory results exceeding the following criteria, and the event is 
without an alternative explanation as discussed with the medical monitor, discontinuation of 
dosing of a subject with study drug (LUM001 or placebo) will be considered if: 
Baseline Tests 
Change Observed 
ALT (any level) 
ALT ≥ 20 x ULN 
Total Bilirubin 1-10 mg/dL 
5 mg increase and a 2 x increase over baseline level 
Total Bilirubin >10 mg/dL 
2 x increase over baseline level 
 
10.5.2.3 
Safety Monitoring for Triglycerides 
In the event of a confirmed laboratory result for fasting total triglyceride >500 mg/dL, the 
investigator and the medical monitor may consider a temporary interruption of study drug. 
Dosing may resume when the triglyceride level returns to <300 mg/dL or to the subject’s 
baseline level. 
10.5.2.4 
Safety Monitoring for Fat Soluble Vitamins 
Vitamin status will be assessed per the schedule of procedures (see Section 16.1), and 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]), or for an 
elevated INR (as a proxy for vitamin K status), the investigator should make the appropriate 
modification to the subject’s vitamin supplementation regimen.  
The response to the change in regimen will be assessed by relevant follow up blood work one 
month later. Changes will continue to be made until the levels are in the desired range. 
Adjustments may be discontinued outside of the desired range if there is agreement between the 
investigator and medical monitor that vitamin sufficiency cannot be reasonably expected. 
10.5.2.5 
Monitoring/Stopping Rules for Coagulation Panel Results 
In the event of a confirmed laboratory result for INR >1.5 that is unresponsive to vitamin K 
therapy, the investigator 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 


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toxicity, study drug dose may be lowered to a previously well tolerated dose; later attempts to 
escalate the dose are permitted. If the subject is on a twice daily dosing regimen, dose lowering 
should first be attempted with the afternoon dose. This decision should be made in consultation 
with the medical monitor. A requirement for intravenous fluids as treatment for diarrhea will 
lead to discontinuation of study drug.  
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 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.  
Any investigator decision to withdraw a subject from the study must first be discussed with the 
medical monitor prior to withdrawal. The investigator will provide the reason for withdrawal on 
the appropriate eCRF.  
For any subject who requests to stop study treatment or has withdrawn from study treatment at 
the request of the legal caregiver, investigator or sponsor before completion of the protocol-
specified treatment period, and has received >1 dose of study drug, every effort should be made 
to complete the assessments scheduled for the ET visit (see Section 16.1), provided the subject 
has not withdrawn full consent. The ET visit should be scheduled within 7 days of the last study 
drug dose. The eDiary must also be retrieved. 
For safety reasons, efforts must be made to follow subjects for at least 28 days following their 
last dose of study drug. If a subject withdraws due to an AE, the investigator should arrange for 
the subject to have follow-up visit(s) until the AE has resolved or stabilized.  
Subjects must be withdrawn from the study for any of the following reasons: 
• Withdrawal of consent/assent by the subject or legal caregiver. 
• Pregnancy. 
• An AE (including disease progression) that leads the investigator to decide that the subject 
should be withdrawn. If a subject suffers an AE that, in the judgment of the investigator or 
the sponsor, presents an unacceptable consequence or risk to the subject, the subject must be 
discontinued from the study. 
• Significant protocol deviation (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 or 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 serious adverse events (SAEs) including suspected unexpected serious adverse 
reactions (SUSARs) per the International Conference on Harmonisation (ICH) guidelines E2A 
and ICH E6. Country-specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines. 
The investigator should immediately report all SAEs to the sponsor or designee. It is essential to 
report SAEs in a timely manner to the sponsor, or designee, along with completed documentation 
of adverse events to allow the sponsor, or designee, to identify potential study-related, study 
drug- or dose-related adverse events.  
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 Committee 
(DMC) will be notified of any SAE as specified in the DMC 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 adverse event (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 adverse event does not include the following: 
• Continuous persistent disease/symptom present before the start of study drug, which does not 
unexpectedly progress, or change in severity following drug administration. 


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• Disease being studied and/or signs and symptoms associated with the disease, such as 
jaundice or itching, or abnormalities in liver enzymes already present during the screening 
period or at the baseline visit. 
• Treatment failure or lack of efficacy. 
11.2.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any adverse event caused by the study drug. 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than an adverse reaction. 
11.2.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event 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).  
• 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 


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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 will be collected as medical history unless the AE 
started within 30 days of last dose. Symptoms of the disease under study should not be classed as 
AEs as long as they are within the normal day-to-day fluctuation or expected progression of the 
disease and are part of the efficacy data to be collected in the study; however, significant 
worsening of the symptoms should be recorded as an AE. The investigator should always group 
signs and symptoms into a single term that constitutes a single unifying diagnosis if possible. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom. Following questioning and evaluation, all AEs, whether believed by the 
investigator to be related or unrelated to the study drug, must be documented in the subject’s 
medical records, in accordance with the investigator’s normal clinical practice, and on the AE 
eCRF. Each AE is to be evaluated for seriousness, causal relationship to the study drug, 
intensity, action taken, any treatment given, outcome, and duration. It should be noted that the 
term “severe” used to grade intensity is not synonymous with the term “serious.” 
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/assent form and stop 30 days after the last dose 
of study drug.  
When the investigator is reporting by telephone, it is important to speak to someone in person 
versus leaving a message. An initial report of the SAE should be completed and a copy should be 
transmitted to the sponsor or designee.  
Detailed information should be actively sought and provided to the sponsor or designee as soon 
as additional information becomes available. All SAEs will be followed until resolution. SAEs 
that remain ongoing past the subject’s last protocol-specified follow-up visit will be evaluated by 
the investigator and sponsor. If the investigator and sponsor agree the subject’s condition is 
unlikely to resolve, the investigator and sponsor will determine the follow-up requirement.  
11.3.2 
Non-serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed consent/assent 
form and will stop 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.  


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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 rechallenge 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 Common Terminology Criteria for Adverse Events (CTCAE) grade of the event should be 
reported according to CTCAE Version 4.0 (Section 16.11). If the CTCAE does not have a 
grading for a particular adverse event, 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. 
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).  


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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 study 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 an SAE then the event’s outcome is characterized by one of the following: 
• Ongoing:  SAE continuing. 
• Persists (as non-serious AE):  Subject has not fully recovered but the event no longer meets 
serious criteria and should be captured as an AE on the non-serious AE eCRF (the SAE 
resolution date should be entered as the date of onset of that AE). 
• Recovered:  Subject recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date). 
• Fatal:  Subject died (the date of death should be entered as the SAE resolution date). 
11.4 
Procedures for Handling Special Situations 
The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours. 
• Serious adverse event (SAE; see Section 11.3.1) 


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• Pregnancy 
• Dosing errors 
• Treatment unblinding for any reason (see Section 6.4) 
11.4.1 
Pregnancy Reporting 
If a subject becomes pregnant or a pregnancy is suspected during the study, the study center staff 
must be informed immediately. The sponsor or designee should be notified within 24 hours of 
first learning of the occurrence of pregnancy. Follow-up information including delivery or 
termination should be reported within 24 hours. 
If pregnancy is suspected during the study (including follow-up), a pregnancy test will be 
performed. A subject with a confirmed pregnancy will be immediately withdrawn from treatment 
with study drug. However, the subject will be encouraged to complete the ET 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 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 if the event was accidental or intentional.  
Dosing details should be captured on the appropriate eCRF. If the subject takes a dose of study 
drug that exceeds protocol specifications and the subject is symptomatic, then the symptom(s) 
should be documented as an AE and be reported per Section 11.3. 
Should an overdose occur, the investigator or designee should refer to the Guidance to 
investigator’s section of the investigator’s brochure and contact the sponsor or designee within 
24 hours.  
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 and medical 


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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 finalized prior to unblinding of the data. 
Continuous variables will be summarized using descriptive statistics including n, mean, median, 
standard deviation, range (eg, minimum and maximum). Qualitative variables will be 
summarized using counts and percentages. Summaries will be provided overall, as well as by 
phase, dose level, and treatment group as appropriate. Unless otherwise specified, statistical 
analyses will be performed using SAS Version 9 or higher. Where appropriate, statistical tests 
will be conducted at the 0.05 significance level using two-tailed tests and p-values will be 
reported if applicable. Given the rare nature of ALGS, the statistical power of any comparisons is 
limited. As such the analysis will be largely descriptive in nature. 
12.1 
Sample Size Considerations 
Alagille syndrome is a rare disease. The planned sample size of 30 evaluable ALGS subjects is 
based on practical considerations, rather than a desired power for a pre-specified difference.  
12.2 
Populations 
12.2.1 
Safety Population 
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 the treatment they received.  
12.2.2 
Efficacy Populations 
The main population for efficacy will be the modified intention-to-treat population (MITT), 
defined as all subjects who were enrolled, received study medication through Week 18, and had 
a reduction from baseline in serum bile acids of ≥50% at the Week 12 or Week 18 measurement. 
Subjects will be analyzed by assigned treatment. 
The intention-to-treat (ITT) Population includes all subjects who were enrolled and received at 
least one dose of the study medication. Subjects will be analyzed by assigned treatment. 
Membership in the analysis populations will be determined before study unblinding. 
12.2.3 
Siblings 
The enrollment of siblings is allowed. During the double-blind, placebo-controlled, randomized 
drug withdrawal period, siblings 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 
LUM001-304 study is unblinded. Details of the analysis methods will be outlined in the SAP. 


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12.2.4 
Demographic and Baseline Characteristics 
12.2.4.1 
Subject Disposition 
Subject disposition will be summarized descriptively. The number and percentage of subjects 
enrolled, completed, and withdrawing, along with reasons for withdrawal, will be tabulated 
overall, and by study phase and treatment group. For purposes of analysis, there will be 3 study 
phases: Dose escalation/stable dose (Weeks 0-18), Randomized Withdrawal (Weeks 19-22) and 
Long-Term Exposure (Weeks 23-48 and 23-100).  
The number of subjects in each analysis population will be reported. Line listings will be 
prepared for all subjects not following the planned dosing schedule, showing all doses and dose 
changes occurring.  
Other disposition and study conduct information, including major protocol violations will be 
listed. Duration of the follow-up period will be summarized. 
12.2.4.2 
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, genotyping results, pruritus scores, liver biochemistries). 
• Prior medications of interest (eg, ursodiol [UDCA], rifampicin) and concomitant 
medications. 
Demographic and baseline characteristics will be summarized descriptively overall, by dose 
group (as appropriate), responder group and treatment group. 
Treatment group comparisons will be made using analysis of variance for continuous measures 
and the chi-square test for categorical measures. Adjustment for responder stratification will be 
made as appropriate. These analyses will be conducted on the Safety Population. 
Medical history information will be presented in listings. 
12.2.5 
Efficacy Analyses 
The primary analysis population for the efficacy analysis will be the MITT population defined in 
Section 12.2.2. Analyses for the primary and secondary efficacy outcome variables will also be 
done on the ITT population. No adjustment for multiplicity will be made. All data will be 
included in data listings. 
12.2.5.1 
Efficacy Variables 
The primary efficacy endpoint will be the mean change from Week 18 to 22 of fasting serum bile 
acid levels in subjects who previously responded to LUM001 treatment, as defined by a 
reduction in sBA ≥50% from baseline to Week 12 or Week 18. A sensitivity analysis will also be 


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conducted using subjects who experienced a reduction from baseline in serum bile acids of ≥50% 
at the Week 48 measurement.  
Secondary efficacy endpoints include mean change from Week 18 to Week 22 in liver enzymes 
(ALP, ALT, and bilirubin [total and direct]) and pruritus as measured by ItchRO (Observer 
ItchRO/patient ItchRO), in subjects who previously responded to LUM001 treatment, as defined 
by a reduction in ItchRO scale >1 point from baseline to Week 12 or Week 18. Secondary 
efficacy endpoints also include mean change from baseline to Week 18 in fasting serum bile acid 
levels, liver enzymes (ALP, ALT, and bilirubin [total and direct]) and pruritus as measured by 
ItchRO (Observer ItchRO/Patient ItchRO).  
The assessment of pruritus in this study will be the ItchRO assessment from the eDiary. Given 
the age range of this population and the small sample size, the ItchRO score will be derived from 
the ItchRO(Obs) instrument. The itch score from the ItchRO(Pt) will be analyzed separately. 
Subjects 9 years of age or older will complete the ItchRO(Pt) independently. Subjects between 
the ages of 5 and 8 years of age or where the investigator has expressed concern about the 
subject’s ability to reliably complete the data (eg, due to developmental delay) will complete the 
ItchRO(Pt) with the help of the caregiver. There will be no ItchRO(Pt) report for subjects under 
the age of 5.  
For this instrument the caregiver and/or subject will indicate the itch severity in the morning and 
in the evening each day for the duration of the study (baseline to Week 48). The daily score will 
be assessed as outlined in Section 16.4 and will have a range from 0-4, with the higher score 
indicating increasing itch severity. A daily score is defined as the higher of the scores from the 
morning and evening ItchRO, representing the most severe itch over the 24 hour period. For the 
change from baseline calculation in average daily ItchRO score, baseline is defined as the 
average daily ItchRO score in the week consisting of the 7 days immediately prior to Day 0. The 
average daily score will be the average of the daily scores over a defined study week consisting 
of the 7 days prior to the visit. 
In addition, an analysis for a daily score defined as an average of morning and evening scores 
will be conducted. 
If a caregiver is not compliant with the ItchRO(Obs) during the week prior to a study visit, the 
average daily score from the most recent, previous compliant week will be used in a Last 
Observation Carried Forward format. On study compliance for the ItchRO(Obs) will be defined 
as having at least 4 of the 7 daily ItchRO(Obs) scores for a 7-day period. Similar methods will be 
used for the ItchRO(Pt). Missing data imputation will not be done for other efficacy endpoints. 
The additional questions included in the ItchRO(Obs/Pt) that are not scored, will be tabulated 
overall and by treatment group. 
The following additional efficacy evaluations will be assessed: 
• Change from baseline to Weeks 18, 22, 48 and then every 12 weeks in: 
o Fasting serum bile acid levels 


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o Liver enzymes (ALT, ALP) and bilirubin (total and direct) 
o Pruritus as measured by the average daily ItchRO (Observer ItchRO/patient ItchRO) 
o Other biochemical markers of cholestasis [total cholesterol, low-density lipoprotein 
cholesterol (LDL-C)] 
o Bile acid synthesis [serum 7α-hydroxy-4-cholesten-3-one (7αC4)] 
• Responder analysis at Weeks 18, 48, 60, 72, 84, 96, and 100 in:  
o Pruritus response rates as measured by ItchRO (Observer ItchRO/patient ItchRO) 
o Clinician scratch scale 
• Change from baseline for PedsQL at Week 18, 22, 48, 60, 72, 84, 96, and 100 and change 
from Week 18 to Week 22 
• PIC at Week 18, 22, 48, 84, 96, and 100 and change from Week 18 to Week 22 
• CIC at Week 18, 22, 48, 84, 96, and 100 and change from Week 18 to Week 22 
• CGTB assessment at Weeks 18, 22, 48, 84, 96, and 100 and change from Week 18 to 
Week 22 
• Change from Baseline (Day 0) to Week 48 in xanthomas, as measured by Clinician 
Xanthoma Scale 
Additional assessments of efficacy variables will occur during the 52-week and long-term 
optional treatment periods in 12-week intervals. Any of the above evaluations may also occur at 
clinic visits during the DE, PA4 DE, and ADE periods. Additional exploration of evaluations 
will be specified in the statistical analysis plan. 
A number of sensitivity analyses will be performed to assess the robustness of the results as well 
as consider the time course of the efficacy assessments. Details of these analyses will be outlined 
in the SAP for the study. 
12.2.5.2 
Primary Efficacy Analysis 
The change from baseline in serum bile acid will be displayed for each treatment group during 
the randomized withdrawal phase 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. 
The difference between treatment groups in change from Week 18 to Week 22 in serum bile acid 
will be evaluated using an ANCOVA model with treatment group as a factor, and Week 18 
serum bile acid as a covariate. Treatment group differences within responder groups as well as 
the potential interaction between responder group and treatment group will also be examined 
where possible. 
12.2.5.3 
Secondary, Exploratory and Other Efficacy Analyses 
Secondary and exploratory efficacy variables that are continuous measures will be analyzed 
similarly to the primary efficacy analyses. Where sample size allows, treatment effects over time 
will be examined using methods appropriate for repeated observations.  


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Exploratory efficacy measures that are categorical will be analyzed using the chi-square test or 
Fisher’s Exact test as appropriate based on sample sizes. Additionally, the Cochran-Mantel-
Haenszel test will be used to adjust for response group. Exploratory efficacy measures will be 
summarized by frequencies and percents, overall, and by phase and treatment group. This 
includes the responder definition for pruritus, which will be outlined in the SAP. P-values from 
the secondary and exploratory efficacy analyses will be considered nominal. 
The sensitivity of the results for pruritus to missing data assumptions will be explored as outlined 
in the SAP for the study. The sensitivity analyses may include analyses using observed cases as 
well as various assumptions for missing data from subjects who terminate from the study early. 
Additional exploratory analyses may be performed and will be defined and outlined in the SAP 
for the study. 
12.2.6 
Safety Analyses 
Safety analyses will be performed on the Safety Population.  
12.2.6.1 
Safety Assessments 
The following assessments will be used to monitor safety: 
• Adverse events (AEs) and SAEs 
• Clinical laboratory results 
• Vital signs 
• Physical exam findings, including body weight and height 
• Concomitant medication usage 
• Serum alpha-fetoprotein (AFP) 
12.2.7 
Planned Method of Analysis 
Safety data, including AEs, clinical laboratory tests, vital signs, physical examinations, and 
concomitant medication usage will be summarized descriptively overall, by phase 
(Section 12.2.4.1) and by treatment group for the Safety Population. Summaries may also be 
provided by dose group if appropriate. Individual subject listings will be prepared for all safety 
data. 
12.2.8 
Safety Analysis 
Safety data, including AEs, clinical laboratory tests, vital signs, physical examinations, and 
concomitant medication usage will be summarized descriptively for the Safety population. 
Individual subject listings will be prepared for all safety data. 
12.2.8.1 
Adverse Events 
Frequencies (number and percentage) of subjects with one or more treatment emergent AEs will 
be summarized by dose group and/or treatment group, by system organ class and preferred term 


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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 over the entire study and then separately for 
the dose escalation/stable dose periods (weeks 0-18), randomized withdrawal, and long-term 
exposure 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.  
12.2.8.2 
Laboratory Tests 
Clinical laboratory (chemistry panel, complete blood count (CBC) with differential, coagulation, 
lipid panel, cholestasis biomarkers, fat soluble vitamins, and urinalysis parameters) test 
parameters will be listed for individual subjects and summarized using descriptive statistics by 
study visit and treatment group. Change from baseline for the safety variables will also be 
presented over time after study drug administration, as appropriate. Percent change from baseline 
will be added for laboratory values as outlined in the SAP. Baseline for clinical laboratory 
parameters will be defined as the last evaluation before dosing with study drug (Day 0).  
A separate listing will present laboratory values of all subjects who change from normal to 
abnormal or from abnormal to normal during the course of the study, where normal ranges for 
this population are outlined in the SAP. Changes within a treatment group for selected safety 
measures will be assessed at Weeks 3, 6, 12, 18, 22, 28, 38, 48, 60, 72, 84, 96 and at additional 
time points during the 52-week and long-term optional treatment periods and final study 
evaluation visit using methods to be specified in the SAP prior to unblinding the data. 
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 presenting 
laboratory values of all subjects who change from sufficient to insufficient or from insufficient to 
sufficient during the course of the study will be created.  
12.2.8.3 
Physical Exams, Vital Signs and Weight/Height Measurements 
Changes in physical exam findings after baseline will be listed for individual subjects. 
Vital signs, weight and height (both weight and height are to be measured as an absolute number 
and as a z-score for age and gender) will be listed for individual subjects and summarized using 
descriptive statistics by study visit and treatment group. Changes from baseline for all visits after 
the baseline visit will be included in the summary table. Baseline for vital signs will be defined 
as the last evaluation before dosing with study drug. In general this will be the Day 0 visit.  
12.2.8.4 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary and summarized descriptively by Anatomical Therapeutic Chemical (ATC) class, 


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using counts and percentages. Medications started prior to the first dose of study medication will 
be indicated in the data listing. A separate listing for medications taken for pruritus will be given 
that clearly indicates the phase of the study. 
12.2.8.5 
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 approximately 4 hours post dose at baseline 
and one other visit during the study as determined by the investigator. Data will be summarized 
and listed across the treatment period. Average daily dose, total drug exposure, and total subject 
days of exposure to study medication will be summarized descriptively overall and by phase and 
treatment group. 
12.2.8.6 
Serum Alpha-fetoprotein 
Assessments of serum AFP will be listed for individual subjects and summarized using 
descriptive statistics by study visit.  
12.2.9 
Palatability Analyses 
Palatability data will be collected at each clinic visit in the follow up treatment period, with the 
exception of the DE, PA4 DE, and ADE visits. A palatability questionnaire will be completed by 
the subject and/or caregiver (dependent on age). Data will be listed for individual subjects and 
summarized using descriptive statistics by study visit. Assessment of change over time will be 
evaluated. Baseline will be defined as the first recorded evaluation. 
12.2.10 Interim Analyses  
There will be an interim analysis (IA) conducted after all subjects complete or discontinue the 
study after Week 48 to guide the future of the program. At the IA the study will be unblinded.   
12.2.11 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 documents should be prepared in the languages of the 
potential patient population, based on an English template version provided by the sponsor or 
designee. 
The investigator is responsible for obtaining written informed consent/assent from the subject 
and/or their legally acceptable representative(s). Before any screening tests or assessments are 
performed, an adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study will be provided to the subject and/or legally acceptable representative. The 
subject and/or legally acceptable representative must be given sufficient time to consider whether 
to participate in the study and be assured that withdrawal from the study may be requested at any 
time without jeopardizing medical care related to or required as a result of study participation.  
Subjects and/or their legally acceptable representative(s) will be required to read, sign, and date 
an IEC approved informed consent/assent form (ICF/IAF) summarizing the discussion at 
screening. Since this is a pediatric study, in addition to the written informed consent, the assent 
of the child must also be obtained. The person who conducted the informed consent discussion 
(not necessarily an investigator) should also sign and date the ICF/IAF. The original signed 
ICF/IAF should be retained in accordance with institutional policy. Subjects and/or their legally 
acceptable representative(s) will be given a copy of their ICF/ 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/IAF will be kept in the investigator’s central study file. Regulatory 
authorities may check the existence of the signed ICF/IAF in this central study folder if not 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 a 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 study.  
13.2 
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 site’s 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 study duties are recorded on a sponsor-approved Delegation of Site Responsibilities 
Form. 


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13.3 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated October 
2008, the applicable regulations and guidelines of current Good Clinical Practice (GCP) as well 
as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed.  
13.4 
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/assent forms 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 adverse events 
occurring at the study center and other adverse event 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. 
13.5 
Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained. On the case report 
forms or other documents submitted to the sponsor or designee, subjects should be identified by 
unique initials and a subject study number only. Documents that are not for submission to the 
sponsor or designee (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 sponsor, regulatory 
agency(ies), and the IEC/IRB direct access to review subjects’ 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 and/or their 
legally acceptable representative to permit named representatives to have access to his/her study-
related records without violating the confidentiality of the subject. 


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All information concerning this study and which was not previously published is considered 
confidential information. This confidential information shall remain the sole property of Mirum 
Pharmaceuticals, Inc.; it shall not be disclosed to others without written consent of Mirum 
Pharmaceuticals, Inc.; and shall not be used except in the performance of this study. 
The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only by Mirum Pharmaceuticals, Inc., as they 
deem necessary. To allow the use of the information derived from this clinical study and to 
ensure compliance to current federal regulations, the investigator is obliged to furnish Mirum 
Pharmaceuticals, Inc., with the complete test results and all data compiled in this study. 


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14 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
14.1 
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 site’s regulatory document binder): 
• Signed and dated Protocol Signature Page.  
• Completed and signed statement of investigator (Form FDA 1572/financial disclosure form) 
(where applicable).  
• Curriculum vitae (CV) of the investigator and sub-investigators (where applicable, all 
persons listed on Form FDA 1572). 
• Letter of approval from the IEC/IRB for both protocol and consent/assent forms. 
• Copy of the IEC/IRB-approved written informed consent/assent forms, and any other written 
information and/or advertisement to be used. 
• IEC/IRB membership list or compliance certification letter. 
• Name and location of the laboratory utilized for laboratory assays, and other facilities 
conducting tests, including a copy of the laboratory certificate (where applicable).  
• In case a laboratory certification is not available, a written statement as to how the laboratory 
complies with quality assurance should be provided. The sponsor's monitor must be notified 
if the laboratory is changed. 
• List of normal laboratory values (where applicable).  
In addition, in advance of enrollment of subjects, study staff are required to complete all required 
training. 
14.2 
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 study. The investigator must send a copy of the approval letter 
from the IEC/IRB to the sponsor or designee. Amendments to the protocol will not be 
implemented until written IEC/IRB approval has been received. 
14.3 
Study Termination 
Both the sponsor or designee and the investigator reserve the right to terminate the study at 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 study’s completion or ET and send a copy 
of the notification to the sponsor or designee. 


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The sponsor or designee reserves the right to terminate the study overall. 
14.4 
Study Documentation and Storage 
Source documents are original documents, data, and records from which the subject’s case report 
form data are obtained. These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, imaging, and correspondence. All original 
source documents supporting entries in the case report forms must be maintained and be readily 
available. 
The investigator and the study center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the sponsor or designee and/or applicable regulatory authorities. The clinical site’s regulatory 
document binder essential elements should include: 
• Subject files containing completed case report forms (eCRFs), informed consents/assents, 
and supporting copies of source documentation. 
• Study files containing the protocol with all amendments, investigator’s brochure, copies of 
pre-study documentation and all correspondence to and from the IEC/IRB and the sponsor or 
designee. 
• If drug supplies are maintained at the study center, documentation for proof of receipt, study 
drug accountability records, return of study drug for destruction, final study drug product 
reconciliation statement, and all drug-related correspondence. 
No study document should be destroyed without prior written agreement between the sponsor or 
designee and the investigator. Should the investigator wish to assign the study records to another 
party or move them to another location, he/she must notify the sponsor or designee. 
14.5 
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 study (eg, case report forms and other pertinent data) provided that 
subject confidentiality is respected. Quality control audits may be performed at the sponsor’s 
discretion. 
Throughout the course of the study, a study monitor will make frequent contacts with the 
investigator and/or study staff. This will include telephone calls and on-site visits. During the 
on-site visits, the CRFs will be reviewed for completeness and adherence to the protocol, 
accuracy, consistency of the data, and adherence to local regulations on the conduct of clinical 
research. The monitor will need access to subject medical records and other study-related records 
needed to verify the entries on the case report forms. The study monitor will also perform drug 
accountability checks and review the clinical site’s regulatory document binder to assure 
completeness of documentation in all respects of clinical study conduct. On completion of the 


Mirum Pharmaceuticals, Inc. 
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SHP625 
 
08 February 2019 
 
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. 
14.6 
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. 
14.7 
Compensation for Injury 
The sponsor maintains appropriate insurance coverage for clinical studies 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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SHP625 
 
08 February 2019 
 
15 
REFERENCES 
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. 
Spinner, N., Hutchinson, A., Krantz, I. & Kamath, B. 2000. Alagille Syndrome [Online]. Seattle, 
WA. Available: http://www.ncbi.nlm.nih.gov/pubmed/20301450 2000]. 
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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SHP625 
08 February 2019 
 
 
16.1 
Schedule of Procedures 
Overall Scheme and Corresponding Schedule of Procedures 
The following schematic shows the study flow and corresponding Schedule of Procedures (A – I).   
Study Termination and End of Treatment Procedures are outlined in Schedule J. 
 
 
 


Mirum Pharmaceuticals, Inc.  
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LUM001-304 Protocol Amendment 5.1 
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16.1.1 
Schedule of Procedures A-D: Study Entry – Week 96 
Schedule of Procedures A – Screening – Week 22 
Study Period 
Screening 
Baseline 
Treatment Period 
Dose Escalationi 
Stable Dose 
Randomized 
Withdrawal 
Study Week 
 
 
1 
2 
3 
4 
5 
6 
9 
12 
18 
20 
22 
Study Day 
Day -28 to -1 
Day 0 
7 
14 
21 
28 
35 
42 
63 
84 
126 
140 
154 
Window (in days) 
 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment/ 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Body Weight & Height 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Randomization to Placebo vs. 
LUM001 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital Signsa 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
CBC with Differentialb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Coagulationb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Chemistry Panelb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Lipid Panelb,c 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Cholestasis Biomarkersb,c 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Total Serum bile acidsc 
Xk 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Fat Soluble Vitaminsb,c 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
JAGGED1/NOTCH2 Genotypingd (if 
needed)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Sample for LUM001 
 
Xj 
 
 
 
 
 
 
 
Xj 
Xj 
 
 
Urinalysisb 
X 
Xg 
 
 
Xg 
 
 
Xg 
 
X 
X 
 
X 
Serum or Urine Pregnancy Test 
(if indicated)e 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Subject eDiary/Caregiver eDiary 
(ItchRO) 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Clinician Scratch Scale 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Clinician Xanthoma Scale 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
PedsQL 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Patient/Caregiver Impression of 
Change 
 
 
 
 
 
 
 
 
 
 
X 
 
X 


Mirum Pharmaceuticals, Inc.  
CONFIDENTIAL  
Page 110 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures A – Screening – Week 22 
Study Period 
Screening 
Baseline 
Treatment Period 
Dose Escalationi 
Stable Dose 
Randomized 
Withdrawal 
Study Week 
 
 
1 
2 
3 
4 
5 
6 
9 
12 
18 
20 
22 
Study Day 
Day -28 to -1 
Day 0 
7 
14 
21 
28 
35 
42 
63 
84 
126 
140 
154 
Window (in days) 
 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
(±5) 
Caregiver Global Therapeutic Benefit 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Supplied 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
Review Study Diaries & Assess 
Compliance 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X 
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 Contactf 
 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
a 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
b 
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. 
c 
Subjects are required to fast at least 4 hrs (only water permitted prior to collection). 
d 
Optional genotype sample will be performed to provide a full characterization and the associated documentation of the mutation in support of the diagnosis of 
ALGS. 
e 
For females of childbearing potential, result must be reviewed prior to dispensing study drug. 
f 
Subjects must be available to receive a phone call from study staff. 
g 
At the indicated visits during the treatment period, oxalate will be part of the urinalysis. 
h 
During screening and throughout the study, the eDiary (ItchRO) will be completed twice daily (AM & PM). Compliance will be assessed at each visit/phone contact. 
i 
Subjects should be dosed for at least 7 days at each dose level. 
j 
Pharmacokinetic analysis will be done at Baseline, and then approximately 4 hours post-dosing at one additional time point – at Week 12, 18, 38, or 48 (to be 
selected by site/investigator). 
k 
Subjects are NOT required to fast prior to sample collection at the screening visit. 
 
 
 
Clinic Visit 
 
Phone Contact 
 


Mirum Pharmaceuticals, Inc.   
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LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures B – Long-term Exposure: Week 23–Week 48 
Study Period 
Treatment Period (cont’d) 
 
 
Long-Term Exposure 
 
Follow Up 
Study Week 
23 
24 
25 
26 
27 
28 
33 
38 
43 
Week 48 
(or Early 
Terminationf) 
 
Study Day 
161 
168 
175 
182 
189 
196 
231 
266 
301 
336 
30 days after 
final dose 
Window (in days) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
(±14) 
(±5) 
Physical Exam 
 
 
 
 
 
X 
 
X 
 
X 
 
Body Weight & Height 
 
 
 
 
 
X 
 
X 
 
X 
 
Vital Signsa 
 
 
 
 
 
X 
 
X 
 
X 
 
CBC with Differentialb 
 
 
 
 
 
X 
 
X 
 
X 
 
Coagulationb 
 
 
 
 
 
X 
 
X 
 
X 
 
Chemistry Panelb 
 
 
 
 
 
X 
 
X 
 
X 
 
Lipid Panelb,c 
 
 
 
 
 
 
 
 
 
X 
 
Total Serum bile acidsc 
 
 
 
 
 
 
 
 
 
X 
 
Cholestasis Biomarkersb,c 
 
 
 
 
 
 
 
 
 
X 
 
Fat Soluble Vitaminsb,c  
 
 
 
 
 
X 
 
X 
 
X 
 
Plasma Sample for LUM001 
 
 
 
 
 
 
 
Xi 
 
Xi 
 
Urinalysisb 
 
 
 
 
 
X 
 
X 
 
Xg 
 
Urine Pregnancy Test (if indicated)d 
 
 
 
 
 
X 
 
X 
 
X 
 
Clinician Scratch Scale 
 
 
 
 
 
X 
 
X 
 
X 
 
Clinician Xanthoma Scale 
 
 
 
 
 
 
 
 
 
X 
 
Subject eDiary/Caregiver eDiary (ItchRO) 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
 
PedsQL 
 
 
 
 
 
 
 
 
 
X 
 
Patient & Caregiver Impression of Change  
 
 
 
 
 
 
 
 
 
X 
 
Caregiver Global Therapeutic Benefit 
 
 
 
 
 
 
 
 
 
X 
 
Study Drug Supplied 
 
 
 
 
 
X 
 
X 
 
Xj 
 
Review Study Diaries & Assess Compliance 
 
 
 
 
 
X 
 
X 
 
X 
 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contacte 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 112 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures B – Long-term Exposure: Week 23–Week 48 
Study Period 
Treatment Period (cont’d) 
 
 
Long-Term Exposure 
 
Follow Up 
Study Week 
23 
24 
25 
26 
27 
28 
33 
38 
43 
Week 48 
(or Early 
Terminationf) 
 
Study Day 
161 
168 
175 
182 
189 
196 
231 
266 
301 
336 
30 days after 
final dose 
Window (in days) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
(±14) 
(±5) 
a 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
b 
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. 
c 
Subjects are required to fast at least 4 hrs (only water permitted prior to collection). 
d 
For females of childbearing potential, result must be reviewed prior to dispensing study drug. 
e 
Subjects must be available to receive a phone call from study staff. 
f 
Subjects who withdraw early should complete all evaluations at this visit. 
g 
At the indicated visits during the treatment period, oxalate will be part of the urinalysis. 
h 
During screening and throughout the study, the eDiary (ItchRO) will be completed twice daily (AM and PM). Compliance will be assessed at each visit/phone 
contact. 
i 
Pharmacokinetic analysis will be done at Baseline, and then approximately 4 hours post-dosing at one additional time point – at Week 12, 18, 38, or 48 (to be 
selected by site/investigator). 
j 
For subjects entering optional Follow-up Treatment Period, once corresponding consent is signed. 
 
 
 
Clinic Visit 
 
Phone Contact 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 113 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures C – 52-week Optional Follow-up Treatment Period (FTP): Week 48-96 for Those Subjects <7 Days 
from the Last Dose of LUM001.  Includes evaluation of eligibility for BID dosing regimen. 
Study Period 
52-week FTP  
 
Study Week 
52 
56 
60 
64 
68 
72 
76 
80 
84 
 
 
88 
 
 
92 
 
 
96 
Study Day 
364 
392 
420 
448 
476 
504 
532 
560 
588 
 
 
616 
 
 
644 
 
 
672 
Window (in days) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Informed Consent/Assent for PA4g 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Afternoon Dose Escalation (ADE) 
eligibility assessment followed by shift 
in visit scheduleh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
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 
 
 
X 
Cholestasis Biomarkersb,c 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Fat Soluble Vitaminsb,c  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Optional Genotypingd 
 
 
X 
 
 
 
 
 
 
 
 
 
Urinalysisb 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urine Pregnancy Test (if indicated)e 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician Scratch Scale 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician Xanthoma Scale 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Subject eDiary/Caregiver eDiary 
(ItchRO) 
 
 
Xi 
Xi to 
Week 
62 
 
Xi 
Xi to 
Week 
74 
 
Xi 
Xi to 
Week 
86 
 
Xi 
PedsQL 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Patient & Caregiver Impression of 
Change  
 
 
 
 
 
 
 
 
X 
 
 
X 
Caregiver Global Therapeutic Benefit 
 
 
 
 
 
 
 
 
X 
 
 
X 
Study Drug Supplied 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Review Study Diaries & Assess 
Compliance 
 
 
X 
 
 
X 
 
 
X 
 
 
X 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 114 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures C – 52-week Optional Follow-up Treatment Period (FTP): Week 48-96 for Those Subjects <7 Days 
from the Last Dose of LUM001.  Includes evaluation of eligibility for BID dosing regimen. 
Study Period 
52-week FTP  
 
Study Week 
52 
56 
60 
64 
68 
72 
76 
80 
84 
 
 
88 
 
 
92 
 
 
96 
Study Day 
364 
392 
420 
448 
476 
504 
532 
560 
588 
 
 
616 
 
 
644 
 
 
672 
Window (in days) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone contactf 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
a 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
b 
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. 
c 
Subjects are required to fast at least 4 hrs (only water permitted prior to collection). 
d 
Genotyping sample will be drawn at Week 60 or at the time of re-consent for the optional follow-up treatment period; sample will be used to provide a full 
characterization and documentation of the mutation type in support of the diagnosis of ALGS. 
e 
For females of childbearing potential, result must be reviewed prior to dispensing study drug. 
f 
Subjects must be available to receive a phone call from study staff. 
g 
Once necessary approvals are received for Protocol Amendment 4 and associated consent/assent documents are available, site will consent/assent patient for 
Protocol Amendment 4 at the next clinic visit. 
h 
Once the Protocol Amendment 4 consent/assent has been signed, site will assess subject eligibility for Protocol Amendment 4 and ADE. Depending on the outcome 
of ADE eligibility assessment, subject will move into either Schedule of Procedures E or F. Of note: It is possible that subject will not necessarily complete up 
through Week 96 before they move to Schedule of Procedures E or F. ADE eligibility assessments may occur any time between Week 52 and Week 100.  
i 
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 60, Week 72, and Week 84 visits. 
 
 
 
Clinic Visit 
 
Phone Contact 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 115 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures D – 52-week Optional Follow-up Treatment Period: DE -2 – Week 96 for Those Subjects ≥7 Days 
from the Last Dose of LUM001.  Includes evaluation of eligibility for BID dosing regimen. 
Study Period 
Treatment Period (cont’d) 
FTP 
Dose Escalation (DE)  
FTP 
FTP Study Week 
DE -
2 
DE 0 
DE 
49 
 
DE 
50 
DE 
51 
DE 
52 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
DE Study Day 
-14 
0 
343 a 
350 a 
357 a 
364 a 
420 a 
448a 
476 a 
504 a 
532 a 
560 a 
588 a 
616 a 
644 a 
672 a 
Window  
(in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Informed 
Consent/Assent for 
study re-entry under 
PA3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Assessment for 
study re-entry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent/Assent for 
PA4h 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Afternoon Dose 
Escalation (ADE) 
eligibility 
assessment followed 
by shift in visit 
schedulei 
 
 
 
 
 
 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Xi 
Physical Exam 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & 
Height 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Vital Signsb 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
CBC with 
Differentialc 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Coagulationc 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Chemistry Panelc 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Lipid Panelc,d 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Cholestasis 
Biomarkersc,d 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Fat Soluble 
Vitaminsc,d  
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Optional 
Genotypinge 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisc 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Urine Pregnancy 
Testf 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 116 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures D – 52-week Optional Follow-up Treatment Period: DE -2 – Week 96 for Those Subjects ≥7 Days 
from the Last Dose of LUM001.  Includes evaluation of eligibility for BID dosing regimen. 
Study Period 
Treatment Period (cont’d) 
FTP 
Dose Escalation (DE)  
FTP 
FTP Study Week 
DE -
2 
DE 0 
DE 
49 
 
DE 
50 
DE 
51 
DE 
52 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
DE Study Day 
-14 
0 
343 a 
350 a 
357 a 
364 a 
420 a 
448a 
476 a 
504 a 
532 a 
560 a 
588 a 
616 a 
644 a 
672 a 
Window  
(in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
Clinician Scratch 
Scale 
X 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician Xanthoma 
Scale 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Subject 
eDiary/Caregiver 
eDiary 
 
 
 
 
 
 
Xj 
Xj 
to Week 
62 
 
Xj 
Xj 
to Week 
74 
 
Xa 
Xj 
to 
Week 
86 
 
Xa 
PedsQL 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Patient & Caregiver 
Impression of 
Change  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Caregiver Global 
Therapeutic Benefit 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Study Drug 
Supplied 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
Review Study 
Diaries & Assess 
Compliance 
 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications  
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 
Phone Contactg 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
a 
Calculation of Study Day includes subject’s participation through the first 48 weeks. 
b 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
c 
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 d 
supplementation. 
d 
Subjects are required to fast at least 4 hrs (only water permitted prior to collection). 
e 
Optional genotype sample will be performed to provide a full characterization and the associated documentation of the mutation type in support of the diagnosis of 
ALGS. Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
f 
For females of childbearing potential, result must be reviewed prior to dispensing study drug. 
g 
Subjects must be available to receive a phone call from study staff. 
h 
 Once necessary approvals are received for Protocol Amendment 4 and associated consent/assent documents are available, site will consent/assent subject for 
Protocol Amendment 4 at the next clinic visit. 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 117 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures D – 52-week Optional Follow-up Treatment Period: DE -2 – Week 96 for Those Subjects ≥7 Days 
from the Last Dose of LUM001.  Includes evaluation of eligibility for BID dosing regimen. 
Study Period 
Treatment Period (cont’d) 
FTP 
Dose Escalation (DE)  
FTP 
FTP Study Week 
DE -
2 
DE 0 
DE 
49 
 
DE 
50 
DE 
51 
DE 
52 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
DE Study Day 
-14 
0 
343 a 
350 a 
357 a 
364 a 
420 a 
448a 
476 a 
504 a 
532 a 
560 a 
588 a 
616 a 
644 a 
672 a 
Window  
(in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
i 
Once the Protocol Amendment 4 consent/assent has been signed, site will assess subject eligibility for Protocol Amendment 4 and ADE. Depending on the outcome 
of ADE eligibility assessment, subject will move into either Schedule of Procedures E or F.  Of note: It is possible that subject will not necessarily complete up 
through Week 96 before they move to Schedule of Procedures E or F. ADE eligibility assessments may occur any time between Week 60 and Week 100.  
j 
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 68, Week 96, and Week 120 visits. 
 
 
 
 
Clinic Visit 
 
Phone Contact 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 118 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
16.1.2 
Schedule of Procedures E-F: Rollover under Protocol Amendment 4 
Schedule of Procedures E – Extension of Long-term Optional Follow-up Treatment Period, for subjects ineligible for ADE, 
applicable as follows:  
• Subject did not yet complete the long-term optional follow up treatment period as outlined under Protocol Amendment 
3 and is able to consent to Protocol Amendment 4 activities without an interruption in  LUM001 dosing, OR 
• 
Subject completed long-term optional follow up treatment period as outlined under PA3 and dosing interruption was 
<7 days. 
• 
Subject deemed ineligible for ADE. 
 
 
Below study activities repeat in repeating 12-week periodsh 
Repeating Period Week (RPx) 
RPx Week 4 
RPx Week 8 
RPx Week 12 
Scheduling Considerations 
4 weeks after consent 
under PA4 
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Physical Exam 
 
 
X 
Body Weight & Height 
 
 
X 
Vital Signsa 
 
 
X 
CBC with Differentialb 
 
 
X 
Coagulationb 
 
 
X 
Chemistry Panelb 
 
 
X 
Lipid Panelb,c 
 
 
X 
Cholestasis Biomarkersb,c 
 
 
X 
Fat Soluble Vitaminsb,c,d 
 
 
X 
Urinalysisb 
 
 
Xj 
AFP Sample 
 
 
Xi 
Serum or Urine Pregnancy Test 
(if indicated)e 
 
 
X 
Clinician Scratch Scale 
 
 
X 
Clinician Xanthoma Scale 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
X  
(collected for 2 
week period 
following this 
visit) 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 119 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
 
Below study activities repeat in repeating 12-week periodsh 
Repeating Period Week (RPx) 
RPx Week 4 
RPx Week 8 
RPx Week 12 
Scheduling Considerations 
4 weeks after consent 
under PA4 
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
PedsQL 
 
 
X 
Palatability Questionnaire 
 
 
X 
Study Drug Suppliedf 
 
 
X 
Assess Compliance 
 
 
X 
Concomitant Medications  
X 
X 
X 
Adverse Events 
X 
X 
X 
Follow-up Phone Contactg 
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 
Study visits will continue in the same pattern until the first of the following occur: (i) 
subjects are eligible to enter another LUM001 study, (ii) LUM001 is available 
commercially, or (iii) the sponsor stops the program or development in this indication. 
i 
Sample will be drawn at every other clinic visit starting with RP1 Week 12.   
j 
At indicated visits during treatment period, oxalate will be part of the urinalysis. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 
 
 
 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 120 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures F – Extension of Long-term Optional Follow-up Treatment Period, for subjects eligible for ADE, 
applicable as follows:  
• Subject did not yet complete the long-term optional follow up treatment period as outlined under Protocol Amendment 
3 (PA3) and is able to consent to Protocol Amendment 4 activities without an interruption in  LUM001 dosing OR 
• Subject completed the long-term optional follow up treatment period as outlined under PA3 and dosing interruption 
was <7 days. 
• Subject deemed eligible for ADE. 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in repeating 12-week periods 
after completion of the ADE periodh 
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Physical Exam 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & 
Height 
X 
 
 
X 
 
 
X 
 
 
X 
Vital 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 
 
 
X 
Cholestasis 
Biomarkersb,c 
X 
 
 
X 
 
 
X 
 
 
X 
Fat Soluble 
Vitaminsb,c,d 
X 
 
 
X 
 
 
X 
 
 
X 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 121 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in repeating 12-week periods 
after completion of the ADE periodh 
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Urinalysisb 
X 
 
 
X 
 
 
X 
 
 
Xk 
AFP Sample 
 
 
 
 
 
 
 
 
 
Xi 
Plasma Sample 
for LUM001j 
X 
 
 
X 
 
 
X 
 
 
Xj 
Serum or Urine 
Pregnancy Test 
(if indicated)e 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician Scratch 
Scale 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician 
Xanthoma Scale 
X 
 
 
X 
 
 
X 
 
 
X 
Caregiver 
ItchRO/ 
Patient ItchRO 
 
 
 
 
 
 
 
 
 
X 
(collected for 2 
week period 
following this 
visit) 
PedsQL 
X 
 
 
X 
 
 
X 
 
 
X 
Palatability 
Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Suppliedf 
X 
 
 
X 
 
 
X 
 
 
X 
Assess 
Compliance 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 122 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in repeating 12-week periods 
after completion of the ADE periodh 
Study Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone 
Contactg 
 
X 
X 
 
X 
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 
Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another LUM001 study, (ii) LUM001 is available 
commercially, or (iii) the sponsor stops the program or development in this indication. 
i 
Sample will be drawn at every other clinic visit starting with RP1 Week 12. 
j 
Pharmacokinetic sample will additionally be collected at the three scheduled clinic visits following completion of the afternoon dose escalation period.   
k 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 123 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
16.1.3 
Schedule of Procedures G-I: Subject Re-Entry under Protocol Amendment 4 
Schedule of Procedures G – Long-term Optional Follow-up Treatment Period: Re-entry under Protocol Amendment 4, 
applicable as follows:  
• Subject previously completed (or early terminated from) the long-term optional follow up treatment period as defined 
under Protocol Amendment 3 and has subsequently experienced an interruption in LUM001 dosing ≥7days. 
• Subject is considered eligible for study re-entry under Protocol Amendment 4. 
• Subject eligibility will be assessed for afternoon dose escalation at Protocol Amendment 4 DE Week 8 shown in the 
table below.   
o If subject is found to be ineligible for ADE, subject will move from Schedule G to Schedule H. 
o If subject is found to be eligible for ADE, subject will move from Schedule G to Schedule I. 
 
Study Period 
Protocol Amendment 4 Follow-up Treatment Period  
Dose Escalation (DE) 
PA4 DE Study 
Week 
PA4 
DE -2 
PA4 
DE 
Day 0 
PA4 
DE  
Week 1 
PA4 
DE 
Week 2 
PA4 
DE  
Week 3 
PA4 
DE  
Week 4 
PA4  
DE  
Week 8 
Scheduling 
Considerations 
-14 
0 
 
 
 
 
 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
Assess Eligibility for 
study re-entry 
X 
X 
 
 
 
 
 
Assess Eligibility for 
ADE 
 
 
 
 
 
 
X 
Physical Exam 
X 
X 
 
 
 
X 
 
Body Weight & 
Height 
X 
X 
 
 
 
X 
 
Vital Signsa 
X 
X 
 
 
 
X 
 
CBC with 
Differentialb 
X 
X 
 
 
 
X 
 
Coagulationb 
X 
X 
 
 
 
X 
 
Chemistry Panelb 
X 
X 
 
 
 
X 
 
Lipid Panelb,c 
X 
X 
 
 
 
X 
 
Cholestasis 
Biomarkersb,c 
X 
X 
 
 
 
X 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 124 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Study Period 
Protocol Amendment 4 Follow-up Treatment Period  
Dose Escalation (DE) 
PA4 DE Study 
Week 
PA4 
DE -2 
PA4 
DE 
Day 0 
PA4 
DE  
Week 1 
PA4 
DE 
Week 2 
PA4 
DE  
Week 3 
PA4 
DE  
Week 4 
PA4  
DE  
Week 8 
Scheduling 
Considerations 
-14 
0 
 
 
 
 
 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
(±14) 
Fat Soluble 
Vitaminsb,c,d 
X 
X 
 
 
 
X 
 
Urinalysisb 
X 
X 
 
 
 
X 
 
Serum or Urine 
Pregnancy Test (if 
indicated)e 
X 
X 
 
 
 
X 
 
Clinician Scratch 
Scale 
X 
X 
 
 
 
X 
 
Clinician Xanthoma 
Scale 
X 
X 
 
 
 
X 
 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
 
 
 
X  
(collected for 2 
week period 
following this visit) 
 
PedsQL 
 
X 
 
 
 
 
 
Study Drug Suppliedf 
 
X 
 
 
 
X 
 
Assess Compliance 
 
 
 
 
 
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 
 
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. 
 
 
 
 
Clinic Visit 
 
Phone Contact 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 125 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures H – Long-term Optional Follow-up Treatment Period: Re-entry under Protocol Amendment 4, subject 
ineligible for ADE 
 
Below study activities repeat in repeating 12-week periodsh 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
The Week 4 visit of 
the first repeating 
period will take place 
4 weeks after PA4 DE 
Week 8  
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Physical Exam 
 
 
X 
Body Weight & Height 
 
 
X 
Vital Signsa 
 
 
X 
CBC with Differentialb 
 
 
X 
Coagulationb 
 
 
X 
Chemistry Panelb 
 
 
X 
Lipid Panelb,c 
 
 
X 
Cholestasis Biomarkersb,c 
 
 
X 
Fat Soluble Vitaminsb,c,d 
 
 
X 
Urinalysisb 
 
 
Xj 
AFP Sample 
 
 
Xi 
Serum or Urine Pregnancy Test 
(if indicated)e 
 
 
X 
Clinician Scratch Scale 
 
 
X 
Clinician Xanthoma Scale 
 
 
X 
Caregiver ItchRO/ 
Patient ItchRO 
 
 
X  
(collected for 2 week period 
following this visit) 
PedsQL 
 
 
X 
Palatability Questionnaire 
 
 
X 
Study Drug Suppliedf 
 
 
X 
Assess Compliance 
 
 
X 
Concomitant Medications  
X 
X 
X 
Adverse Events 
X 
X 
X 
Follow-up Phone Contactg 
X 
X 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 126 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
 
Below study activities repeat in repeating 12-week periodsh 
Repeating Period Week 
Week 4 
Week 8 
Week 12 
Scheduling Considerations 
The Week 4 visit of 
the first repeating 
period will take place 
4 weeks after PA4 DE 
Week 8  
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
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 
Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to 
enter another LUM001 study, (ii) LUM001 is available commercially, or (iii) the sponsor stops the program 
or development in this indication. 
i 
Sample will be drawn at every other clinic visit starting with RP1 Week 12  
j 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 127 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures I – Long-term Optional Follow-up Treatment Period: Re-entry under Protocol Amendment 4, subject 
eligible for ADE 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeating in repeating 12-week periods 
after completion of the ADE periodh 
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility 
is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Physical Exam 
X 
 
 
X 
 
 
X 
 
 
X 
Body Weight & 
Height 
X 
 
 
X 
 
 
X 
 
 
X 
Vital 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 
 
 
X 
Cholestasis 
Biomarkersb,c 
X 
 
 
X 
 
 
X 
 
 
X 
Fat Soluble 
Vitaminsb,c,d 
X 
 
 
X 
 
 
X 
 
 
X 
Urinalysisb 
X 
 
 
X 
 
 
X 
 
 
Xk 
AFP Sample 
 
 
 
 
 
 
 
 
 
Xi 
Plasma Sample 
for LUM001j 
X 
 
 
X 
 
 
X 
 
 
Xj 
Serum or Urine 
Pregnancy Test 
(if indicated)e 
X 
 
 
X 
 
 
X 
 
 
X 
Clinician Scratch 
Scale 
X 
 
 
X 
 
 
X 
 
 
X 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 128 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeating in repeating 12-week periods 
after completion of the ADE periodh 
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility 
is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
Clinician 
Xanthoma Scale 
X 
 
 
X 
 
 
X 
 
 
X 
Caregiver 
ItchRO/ 
Patient ItchRO 
 
 
 
 
 
 
 
 
 
X 
(collected for 2 
week period 
following this 
visit) 
PedsQL 
X 
 
 
X 
 
 
X 
 
 
X 
Palatability 
Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Suppliedf 
X 
 
 
X 
 
 
X 
 
 
X 
Assess 
Compliance 
X 
 
 
X 
 
 
X 
 
 
X 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone 
Contactg 
 
X 
X 
 
X 
X 
 
X 
X 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 129 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Study Period 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeating in repeating 12-week periods 
after completion of the ADE periodh 
FTP Study 
Week 
ADE 
Day 0 
ADE 
Week 1 
ADE 
Week 2 
ADE  
Week 4 
ADE  
Week 5 
ADE  
Week 6 
ADE  
Week 8 
Week 4 
Week 8 
Week 12 
Scheduling 
Considerations 
To be 
scheduled 
as soon as 
ADE 
eligibility 
is 
confirmed 
and 
materials 
are on-site 
 
 
 
 
 
 
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE 
Week 8.   
 
 
Window (in 
days) 
N/A – see 
above 
(±2) 
(±2) 
(±2) 
 
(±2) 
(±2) 
(±7) 
(±7) 
(±14) 
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 
Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another LUM001 study, or (ii) LUM001 is 
available commercially, or (iii) the sponsor stops the program or development in this indication. 
i 
Sample will be drawn at every other clinic visit starting with RP1 Week 129.  
j 
Pharmacokinetic sample will additionally be collected at the three scheduled clinic visits following completion of the afternoon dose escalation period. 
k 
At indicated visits during treatment period, oxalate will be part of the UA. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 
 
 
 
 
 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 130 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
16.1.4 
Schedule of Procedures J – Study Termination and End of Treatment Procedures 
 
Schedule of Procedures J – End of Treatment (EOT) / Early 
Termination (ET) Visit and Post-Treatment Safety Follow Up 
 
EOT  / ET 
Safety Follow Up 
Scheduling Considerations 
To take place upon 
completion of studyg or at 
the time of early 
withdrawal 
Minimum of 30 days after final 
dose 
Physical Exam 
X 
 
Body Weight & Height 
X 
 
Vital Signsa 
X 
 
CBC with Differentialb 
X 
 
Coagulationb 
X 
 
Chemistry Panelb 
X 
 
Lipid Panelb,c 
X 
 
Cholestasis Biomarkersb,c 
X 
 
Fat Soluble Vitaminsb,c,d 
X 
 
Urinalysisb 
Xh 
 
AFP Sample 
X 
 
Serum or Urine Pregnancy 
Test (if indicated)e 
X 
 
Clinician Scratch Scale 
X 
 
Clinician Xanthoma Scale 
X 
 
PedsQL 
X 
 
Patient/Caregiver 
Impression of Change 
X 
 
Caregiver Global 
Therapeutic Benefit 
X 
 
Palatability Questionnaire 
X 
 
Assess Compliance 
X 
 
Concomitant Medications  
X 
X 
Adverse Events 
X 
X 
Follow-up Phone Contactf 
 
X 


Mirum Pharmaceuticals, Inc.   
CONFIDENTIAL  
Page 131 
LUM001-304 Protocol Amendment 5.1 
SHP625 
08 February 2019 
 
 
Schedule of Procedures J – End of Treatment (EOT) / Early 
Termination (ET) Visit and Post-Treatment Safety Follow Up 
 
EOT  / ET 
Safety Follow Up 
Scheduling Considerations 
To take place upon 
completion of studyg or at 
the time of early 
withdrawal 
Minimum of 30 days after final 
dose 
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. 
f 
Subjects must be available to receive a phone call from study staff. 
g 
Will take place when the first of the following occur: (i) subjects are eligible to enter another LUM001 
study, (ii) LUM001 is available commercially, or (iii) or the sponsor stops the program or development in 
this indication.   
h 
At indicated visits during treatment period, oxalate will be part of the urinalysis. 
 
 
 
Clinic Visit 
 
Phone Contact 
 
 


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16.2 
List of Laboratory Analytes 
Screening Tests 
JAGGED1/NOTCH2 
Genotyping  
(if indicated) 
Serum βhCG  
(if indicated) 
CBC with Differential 
Red blood cells 
Hemoglobin 
Hematocrit 
MCV, MCH, MCHC 
Platelets 
White blood cells 
WBC Differential 
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Coagulation 
aPTT (sec) 
PT (sec) 
INR 
Clinical Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Phosphorus 
Glucose 
BUN 
Creatinine 
Uric Acid 
Total bilirubin 
Direct bilirubin  
Alkaline phosphatase 
(ALP) 
AST (SGOT) 
ALT (SGPT) 
GGT 
 
Lipid Panela 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Triglycerides (TG) 
Cholestasis Biomarkers1 
Serum bile acids 
7α hydroxy-4-cholesten-3-
one (C4) 
Fat Soluble Vitaminsb 
25-hydroxy vitamin D 
Retinol 
Retinol binding protein 
Tocopherol (α) 
 
Marker of hepatocellular 
carcinoma 
alpha-fetoprotein (AFP) 
Urinalysis 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Occult blood and cells 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic examinationc 
Oxalated 
LUM001 Drug Levels 
LUM001 in plasma 
 
 
a 
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. 
b 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. 
c 
Will be performed on abnormal findings unless otherwise specified. 
d 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 
Alagille Syndrome Diagnostic Criteria 
Major clinical criteria/features for ALGS include:  cholestasis, consistent cardiac, renal, vascular, 
ocular, skeletal involvement, or characteristic “Alagille” facies. 
ALGS Family Historya 
Paucity 
JAGGED1 or 
NOTCH2 Mutation 
# Major Clinical 
Criteria Needed for Diagnosis 
Present or Absent 
Present 
Identifiedb 
Any or no features 
None (proband) 
Absent or unknown 
Identified 
1 or more features 
None (proband) 
Present 
Not identifiedc 
3 or more features 
None (proband) 
Absent or unknown 
Not identified 
4 or more features 
Present 
Absent or unknown 
Identified 
Any or no features 
Present 
Present 
Not identified 
1 or more features 
Present 
Absent or unknown 
Not identified 
2 or more features 
a 
Family history = ALGS present in a first degree relative. 
b 
Identified = JAGGED1 or NOTCH2 mutation identified in clinical laboratory. 
c 
Not identified = Not identified on screening, or not screened for. 
 


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16.4 
Itch Reported Outcome Instrument (ItchRO™) 
Many of the ALGS subjects in this study are expected to be between the ages of 2 and 10, 
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 (PRO) instrument 
for pediatric subjects (9 years of age and older) and an ObsRO for caregivers/parents. The 
ItchRO will be completed using an electronic diary (eDiary) twice daily (morning and evening) 
for both the PRO and ObsRO.  


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16.4.1 
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. 
 
 
If the patient selects “I didn’t feel itchy at all” the diary is complete, if not the following screens 
will be shown on the eDiary: 
 
0 
1 
2 
3 
4 


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


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16.4.2 
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 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 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: 
 
 
16.5 
Clinician Scratch Scale  
This scoring scale was originally developed to assess pruritus before and after surgical 
intervention in children with ALGS and PFIC (Whitington and Whitington, 1988).  


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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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16.6 
Clinician Xanthoma Scale  
This 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 (Emerick and Whitington, 2002), “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 of ability to 
walk) because of excess size or number.  


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16.7 
Pediatric Quality of Life Inventory (PedsQL™) 
The PedsQL Generic Cores Scale is composed of 23 items to assess pediatric HRQoL 
measurements across 4 domains:  Physical Functioning (8 items), Emotional Functioning 
(5 items), Social Functioning (5 items), and School Functioning (5 items). Each item consists of 
a 5-level Likert item survey (0-4). Each PedsQL™ age-appropriate form should take less than 
four minutes to complete.  
Pediatric HRQoL measurement instruments must be sensitive to cognitive development and must 
include both child self-report and parent proxy-report. Accordingly, the PedsQL consists of 
developmentally appropriate forms for children ages 1-12 months and 13-24 months, and 2-4, 5-
7, 8-12, and 13-18 years. Pediatric self-report is measured in children and adolescents ages 5-18 
years, and parent proxy-report of child HRQOL is measured for children and adolescents ages 2-
18 years. Subjects will continue to fill out the same questionnaire used at baseline for continuity 
of data collection, regardless of subsequent birthdays after the baseline visit. 
Quality of life will be assessed using the appropriate PedsQLTM module(s) provided below. 
 


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16.7.1 
Parent Report for Infants (1 to 12 months) 
 


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16.7.2 
Parent Report for Infants (13 to 24 months) 
 


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16.7.3 
Parent Report for Toddlers (ages 2-4) 
 


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16.7.4 
Parent Report for Young Children (ages 5-7) 
 
 


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16.7.5 
Parent Report for Children (ages 8-12) 
 


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16.7.6 
Parent Report for Teenagers (ages 13-18) 
 


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16.7.7 
Pediatric Quality of Life Inventory v 4.0 for Young Children (ages 5-7) 
 


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16.7.8 
Pediatric Quality of Life Inventory for Children (ages 8-12) 
 


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16.7.9 
Pediatric Quality of Life Inventory for Teenagers (ages 13-18) 
 


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


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


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


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


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


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


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


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16.7.17 Family Impact Module v 2.0 
 


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16.8 
Patient Impression of Change (PIC) 
 
The Patient Impression of Change (PIC) is designed to assess the subject’s perception of his/her 
itching at the end of study drug treatment compared to his/her itching prior to the start of 
treatment with study drug. The PIC will be completed by subjects who were 9 years of age or 
older at the Week 18, 22 and 48 visits. For subjects who enter the 52-week and long-term 
optional follow-up treatment periods, the CIC will be completed as outlined in the Schedule of 
Procedures in Section 16.1. 
The questionnaire is designed for self-administration and uses a 7-point scale in which 1 
designates the best outcome and 7 designate the worst outcome.  
PIC 
 
How much has your itching changed, if at all, since you started this study?  
 
 
Much better (1) 
Better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Worse (6) 
Much worse (7) 
 


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16.9 
Caregiver Impression of Change (CIC) 
 
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s perception of 
the subject’s itch related symptoms and xanthoma severity at the end of study drug treatment 
compared to his/her itch related symptoms and xanthoma severity prior to the start of treatment 
with study drug. The CIC will be completed by all caregivers at the Week 18, 22 and 48 visits. 
For subjects who enter the 52-week and long-term optional follow-up treatment periods, the CIC 
will be completed as outlined in the Schedule of Procedures in Section 16.1. 
The questionnaire is designed for self-administration and uses a 7-point scale in which 
1 designates the best outcome and 7 designates the worst outcome.  
CIC 
 
How would you rate the change in your child’s itch related symptoms since the start of the 
study? 
 
 
Much better (1) 
Better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Worse (6) 
Much worse (7) 
 
 
 


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


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16.10 Caregiver Global Therapeutic Benefit (CGTB)  
 
The Caregiver Global Therapeutic Benefit (CGTB) questionnaire is designed to assess the 
caregiver’s perception of the treatment benefits on the subject’s itching compared to the side 
effects experienced with study drug. The CGTB will be completed by all caregivers at the 
Week 18, 22 and 48 visits. For subjects who enter the 52-week and long-term optional follow-up 
treatment periods, the CIC will be completed as outlined in the Schedule of Procedures in 
Section 16.1. 
The questionnaire is designed for self-administration and uses a 5-point scale in which 
1 designates the best outcome and 5 designates the worst outcome.  
CGTB 
 
Considering all aspects of your child’s treatment, do you feel that the benefits of this treatment 
outweigh the side-effects? 
 
 
Definitely (1) 
Somewhat (2) 
About the same (3) 
Maybe not (4) 
Definitely not (5) 


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16.11 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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16.12 Palatability Questionnaire 
 


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16.13 Protocol History 
Document 
Date 
Global/Country/Site Specific 
Original Protocol 
20 Mar 2014 
 
Amendment 1 
06 Mar 2015 
Global 
Amendment 2 
08 May 2015 
Global 
Amendment 3 
13 Nov 2015 
Global 
Amendment 4 
28 Mar 2017 
Global 
Amendment 5 
06 Nov 2017 
Global 
 
16.13.1 Protocol Amendment 5 Summary of Changes 
 
Protocol Number: 
LUM001-304 
 
Protocol Title: 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED DRUG WITHDRAWAL 
PERIOD OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN PATIENTS WITH 
ALAGILLE SYNDROME 
 
Amendment: 
5 
 
Date: 
06 Nov 2017 
 
 
The LUM001-304 protocol is being amended to change the study design going forward to an 
open label study, beyond what was previously described in Protocol Amendment 4. As all 
subjects have now either reached Week 48 or discontinued prior to Week 48, the interim analysis 
will be performed and the study will be unblinded.  
In addition, in the Appendices, Study Schedule I and J have been updated to include clinician 
xanthoma scale. 
The following changes have been made to the Protocol Amendment 4 (28 March 2017). Note 
that correction of typographical and grammatical errors are not captured in the below table.  
New text indicated in bold; deleted text indicated in strikethrough. 


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Description of Change 
Synopsis, Statistical 
considerations 
Interim Analysis  
Interim Analysis 
There will be an interim analysis (IA) conducted after all subjects complete or discontinue 
the study after Week 48 to guide the future of the program. At the IA the study will be 
unblinded. The IA may result in an interim report or publications. The IA will be 
conducted internally by an unblinded sponsor team as outlined in the unblinded study plan 
charter. The unblinded sponsor team will not be involved in the day to day clinical study 
activities..   
 
Subject Enrollment 
6.4 Unblinding of 
Treatment 
Assignment 
After Week 48 the study will be unblinded to facilitate preparation of the interim 
analysis. A designated statistician will securely maintain an unblinded randomization 
schema.   
All subjects will receive LUM001, or LUM001 and placebo during this study. Breaking of 
the blind during the initial 48-week period of the study should not occur before all 
subjects either discontinue or complete Week 48, 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 serious adverse event (SAE) (as defined in Section 11.2.3). 
Statistical 
Considerations 
Section 12.2.10 
Interim Analyses 
 
There will be an interim analysis (IA) conducted after all subjects complete or discontinue 
the study after Week 48 to guide the future of the program. At the IA the study will be 
unblinded. The IA may result in an interim report or publications. The IA will be 
conducted internally by an unblinded sponsor team as outlined in the unblinded study plan 
charter. The unblinded sponsor team will not be involved in the day to day clinical study 
activities..   
 
16 Appendices 
16.1.3 Schedule of 
Procedures I – 
Long-Term 
Optional Follow-up 
Treatment Period: 
Re-entry under 
Protocol 
Amendment 4, 
subject eligible for 
ADE  
Insertion of clinician xanthoma scale  
 
16 Appendices 
16.1.4 Schedule of 
Procedures J – 
Study Termination 
and End of 
Treatment 
Insertion of clinician xanthoma scale  
 


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Procedures  
 
 
16.13.2 Protocol Amendment 4 Summary of Changes 
 
Protocol Number: 
LUM001-304 
 
Protocol Title: 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED DRUG WITHDRAWAL 
PERIOD OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN PATIENTS WITH 
ALAGILLE SYNDROME 
 
Amendment: 
4 
 
Date: 
28 Mar 2017 
 
The changes below were made to Protocol Amendment 3. 
The following table provides a summary list of changes that were included in Protocol 
Amendment 3 (new text indicated in bold; deleted text indicated in strikethrough): 


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Cover page, Sponsor; 
Title Page, Sponsor; Sponsor 
Signature Page  
 Sponsor 
Protocol Signature page, Sponsor 
Changed from: 
 
Lumena Pharmaceuticals, Inc. 
 
12531 High Bluff Drive, Suite 110 
San Diego, CA 92130 
USA 
 
To:  
Lumena Pharmaceuticals LLC* 
300 Shire Way 
Lexington, MA 02421 
USA 
 
 
*Lumena Pharmaceuticals LLC is an 
indirect wholly-owned subsidiary of 
Shire North American Group, Inc 
Title Page , Medical Lead;  
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: 
Thomas Jaecklin, MD 
 
Shire 
 
Zahlerweg 10 
6300 Zug 
Switzerland 
Phone:  +41(0) 79 850 77 18   
Email:  thomas.jaecklin@shire.com 
Emergency Contact Information 
Inserted new page containing emergency contact information for 
reporting of serious adverse events (SAEs) to be aligned with Shire 
protocol template. 
Product Quality Complaints 
Inserted new page containing product quality complaint information for 
reporting of investigational product quality complaints to be aligned 
with Shire protocol template. 
Synopsis, Objectives; 
Section 3, Study Objectives 
Objectives of Long-term Optional Follow-up Treatment  Period (After 
Week 48): 
• 
To offer eligible subjects in the LUM001-304 study continued 
study treatment after Week 48 until the first of the following 
occurs: (i) up to 52 weeks of additional treatment (Week 100) 
or (ii) in the event that a new study opens to enrollment (i) the 
subjects are eligible to enter another LUM001 study, (ii) 
LUM001 is available commercially, or (iii) the sponsor 
stops the program or development in this indication. 
• 
To explore twice a day (BID) dosing regimen and higher 
daily dosing of LUM001. 


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• 
To assess the level of alpha-fetoprotein (AFP), a marker of 
hepatocellular carcinoma. 
• 
To assess palatability of the LUM001 formulation. 
Synopsis, Study Design; 
Section 5.1, Study Design 
The study is divided into 56 parts: ….a 12-week open-label stable 
dosing period, a 4-week randomized, double-blind, placebo-controlled 
drug withdrawal period, a 26-week long-term stable dosing period at 
doses up to 400 μg/kg/day, and an a 52-week optional follow-up 
treatment period, and a long-term optional follow-up treatment 
period for eligible subjects who choose to stay on treatment with 
LUM001.   
 
During this long-term optional follow-up treatment period, subjects 
may have their dose of LUM001 increased to a maximum of 
800 μg/kg/day (400 μg/kg BID), based on efficacy (sBA level and 
ItchRO [Obs] score) and safety assessment.  
 
Subjects’ participation in the long-term optional follow-up treatment 
period will continue until the first of the following occur: (i) up to 52 
weeks of additional treatment (Week 100) or (ii) in the event that a new 
study opens to enrollment (i) the subjects are eligible to enter another 
LUM001 study, (ii) LUM001 is available commercially, or (iii) the 
sponsor stops the program or development in this indication. 
Subjects who do not consent to Protocol Amendment 4 will continue 
their treatment as outlined in Protocol Amendment 3. 
Synopsis, Inclusion Criteria; 
Section 7.1, Inclusion Criteria 
5. 
Males and females of child-bearing potential who are 
sexually active females, or are not currently sexually active during 
the study, but become sexually active during the period of the study 
and 30 days following the last dose of study drug, must be prepared 
to agree and use an effective method (≤ 1% failure rate) of acceptable 
contraception during the trial. Effective methods of contraception are 
considered to be described in Section 8.6.1. 
a. 
Hormonal (e.g., contraceptive pill, patch, intramuscular 
implant or injection); or 
b. 
Barrier method, e.g., (a) condom (male or female) or (b) 
diaphragm, with spermicide; or 
c. 
Intrauterine device (IUD). 
Synopsis, Inclusion Criteria; 
Section 7.2, Exclusion Criteria 
Protocol Amendment 4: Eligible Subjects for the long-term optional 
follow-up treatment period: 
 
Inclusion Criteria for subjects with LUM001 dosing interruption <7 
days, or ≥7 days: 
Subjects will be considered eligible for the long-term optional 
follow-up treatment period if they meet the following criteria: 
1. The subject has either:  
o 
completed the protocol through the Week 48 visit 
with no major safety concerns.  
OR 
o 
discontinued due to safety reasons judged 
unrelated to the study drug, and laboratory results 
have returned to levels acceptable for this patient 
population or individual and subject does not meet 
any of the protocol's stopping rules at the time of 


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entry into the follow-up period. The decision will 
be made by the investigator in consultation with 
the sponsor medical monitor. [Subjects who were 
discontinued for other reasons will be considered 
on an individual basis.]  
2. Females of childbearing potential must have a negative 
urine or serum pregnancy test (β-hCG) at the time of entry 
into the long-term optional follow-up treatment period. 
3. Males and females of child-bearing potential who are 
sexually active, or are not currently sexually active during 
the study, but become sexually active during the period of 
the study and 30 days following the last dose of study drug, 
must agree and use acceptable contraception during the 
trial. 
4. Informed consent and assent (per IRB/EC) as appropriate. 
5. 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 for Subjects with LUM001 dosing 
interruption≥7 days : 
All exclusion criteria mentioned for the core study apply upon 
entry into the long-term optional follow-up period, with the 
exception of exclusion criterion #18. 
Synopsis, Treatment Groups; 
Section 5.5.2, Treatment; 
 
Subjects will be considered for a 52-week optional treatment period, 
if eligible, receiving up to 400 μg/kg/day, or the highest tolerated 
dose below the 400 μg/kg/day dose. Subjects will then be considered 
for the long-term optional 52-week follow-up treatment, if eligible, to 
continue on their highest tolerated dose receiving up to 800 μg/kg/day 
(given as twice daily doses of 400 μg/kg), or to a maximum possible 
daily dose of 50 mg/day. 
Synopsis, Study Drug Dosage and 
Administration; Section 10.1, Study 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
Subjects who weigh 10 kg or more at screening will receive 1.0 mL a 
grape-flavored solution containing LUM001 or placebo. Subjects who 
weigh less than 10 kg at screening will receive 0.5 mL grape flavored 
solution containing LUM001. The volume administered, either 1.0 mL 
or 0.5 mL will not change during orally once a day (QD) or twice a 
day (BID) using the the course of the study. Each daily  syringe 
provided. The first dose will should be administered in the morning 
taken at least 30 minutes prior to dinner (main evening meal).  The 
doses will not be administered q12h in order to better cover the 
luminal bile acid release associated with dinner and to minimize the 
risk of disturbing sleep due to the potential for abdominal pain and 
diarrhea at night.  It is recommended that the dose should be taken 
approximately at the same time every day each day for the duration of 
the treatment period. 
 
QD Dosing Regimen 
For QD dosing, the required dose will be delivered in 0.5 mL 
volume for subjects who weigh less than 10 kg and in 1.0 mL for 
subjects who weigh 10 kg or more. 


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Section 5.5.2.1, Dose Escalation 
Period 
 
 
Section 5.5.2.4, Long-term Exposure 
Period 
 
 
 
 
 
 
 
 
Section 5.5.2.5, 52-week Optional 
Follow-up Treatment Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.5.2.6, Long-term Optional 
Follow-up Treatment Period 
 
 
BID Dosing Regimen 
For BID dosing, the required dose is delivered in half the dosing 
volume:  0.25 mL BID for subjects who weigh less than 10 kg and 
0.50 mL BID for subjects who weigh 10 kg or more. 
For subjects weighing less than 10 kg at study entry, once a weight 
of 10 kg is reached while in the study, the subject will be moved 
from 0.5 mL maximum daily dosing volume (0.25 mL BID) to 1.0 
mL maximum daily dosing volume (0.50 mL BID). 
 
Study Drug Dosage 
Initially, the LUM0001 dose will be administered as a daily morning 
dose in either a 1.0 mL or 0.5 mL solution. The dose will be 
increased weekly over a 6-week period up to 400 µg/kg/day QD or a 
maximum daily dose of 20 mg/day QD as follows… 
 
Following the 4-week study drug randomized withdrawal period, 
subjects who received placebo will receive LUM001 dosed according to 
a dose escalation schedule that mirrors the initial escalation (ie the 
LUM001 dose will be increased weekly over a 6-week period to the 
maximum tolerated dose up to 400 μg/kg/day or a maximum daily 
dose of 20 mg/day or the highest tolerated dose below the 400 
μg/kg/day dose). 
 
Optional Follow-up Treatment Period 
At Week 48, all subjects will be assessed by the investigator to 
determine their willingness and eligibility to roll-over into the 52 week, 
optional follow-up treatment period. The 3 following possible scenarios 
may occur: 
… 
• 
Subjects who are eligible to roll over into the optional follow-
up treatment period with a LUM001 dosing interruption of ≥7 
days will be dose escalated beginning at 35 µg/kg/day and up 
to a maximum of 400 µg/kg/day or highest tolerated dose 
following a 5-week dose escalation beginning at 35 µg/kg/day. 
• 
Subjects who do not wish to enter the follow-up treatment 
period will be contacted via telephone by the study site 
approximately 2830 days after the last dose of study drug. 
 
During the study, the study drug may be adjusted if there is a change of 
≥10% in 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 (μg/kg/day). 
 
 
Long-term Optional Follow-up Treatment Period 
Upon completion of the 52-week follow-up treatment period and/or 
implementation of this amendment, whichever occurs first, subjects 
will be assessed by the investigator to determine their willingness 
and eligibility to roll-over (or enter) into the long-term optional, 


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follow-up treatment period. The 3 following possible scenarios may 
occur: 
 
Scenario 1: Subjects eligible to roll over into the long-term optional 
follow-up treatment period with no LUM001 dosing interruption or 
an interruption of <7 days: 
• 
Subjects with normal sBA level AND ItchRO(Obs) score 
<1.5 will be maintained at the same dose level and will 
continue morning dosing only. 
• 
Subjects with sBA level above normal AND/OR 
ItchRO(Obs) score ≥1.5 will start BID dosing (afternoon 
dose escalation; ADE) as follows: 
o 
The morning dose will be continued at the same 
dose level, but the volume of the morning dose will 
be reduced by half at the same time that the 
afternoon dose is initiated. 
o 
The afternoon dose will be initiated at dose level 
140 µg/kg and will continue at this dose for a 
period of 4 weeks. If this dose level is tolerated, the 
afternoon dose will then be escalated to 400 µg/kg. 
Scenario 2: Subjects eligible to roll over into the long-term optional 
follow-up treatment period with a LUM001 interruption of ≥7 days: 
• 
First, the morning dose is escalated up to 400 µg/kg/day or 
highest tolerated dose following a 5-week dose escalation 
beginning at 35 µg/kg/day. 
• 
Once the morning dose of 400 µg/kg or maximum tolerated 
dose is achieved, sBA and ItchRO(Obs) score will be 
evaluated. 
o 
Subjects with normal sBA AND ItchRO(Obs) 
score <1.5 after morning dose escalation will be 
maintained at the same dose level and will continue 
morning dosing only. 
o 
Subjects with sBA above normal AND/OR 
ItchRO(Obs) score ≥1.5 will begin BID dosing 
(ADE) as follows: 
 
The morning dose will be continued at the 
same dose level, but the volume of the 
morning dose will be reduced by half at 
the same time that the afternoon dose is 
initiated. 
 
The afternoon dose will be initiated at 
dose level 140 µg/kg and will continue at 
this dose for a period of 4 weeks. If this 
dose level is tolerated, the afternoon dose 
will then be escalated to 400 µg/kg.  
The following parameters apply to both dosing scenarios outlined 
above: 
• 
The afternoon dose will only be initiated once the subject 
has been treated on stable morning doses for at least 4 
weeks. 
• 
The sBA value used for determination of ADE eligibility 
will be the most recent available value collected within the 


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prior 16 weeks. The ItchRO(Obs) score used for ADE 
eligibility will be derived from the most recent available 7-
day interval of ItchRO(Obs) collected within the prior 16 
weeks.  
• 
The maximum daily dose will be 400 µg/kg BID, ie, 
800 µg/kg/day (up to a maximum possible daily dose of 
50 mg/day). 
 
Scenario 3:  Subjects who do not consent to Protocol Amendment 4 
will continue their treatment as outlined in Protocol Amendment 3. 
Synopsis, Rationale for Dose and 
Schedule Selection 
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. 
If a subject experiences intolerance due to gastrointestinal 
symptoms (eg, diarrhea, abdominal pain, cramping) at any time 
during the study, the physician investigator in consultation with the 
sponsor medical monitor may lower the dose to a previously 
tolerated dose; later attempts to escalate the dose are permitted. If 
the subject is on a BID dosing regimen, dose lowering should first 
be attempted with the afternoon dose 
… 
The dose may be down-titrated, at the investigator’s discretion and in 
consultation with the Sponsor Medical Monitor, for subjects 
experiencing intolerance to a given dose. 
 
Under Protocol Amendment 4, an afternoon dose is introduced for 
eligible subjects in the long-term optional follow up treatment 
period. LUM001 doses will be escalated over a period of 4-8 weeks 
up to a maximum dose of 400 µg/kg BID (or maximum tolerated 
dose). The afternoon dose is only initiated and escalated in subjects 
with elevated sBA and/or ItchRO(Obs) ≥1.5 on the maximum (or 
maximum tolerated) morning dose.  
This escalation regimen is supported by the safety profile observed 
in completed and ongoing clinical studies of LUM001. Twice daily 
dosing is used in this study based on the findings of a healthy 
volunteers study in adult males (Study SHP625-101), which 
demonstrated that bile acid levels in feces increase with escalating 
doses and twice-daily regimen of LUM001 (up to 100 mg QD and 50 
mg BID). In this study, subjects who were randomized to LUM001 
treatment, received 1 of 4 doses of LUM001 (10, 20, 50, 100 mg) 
during 7 days. No titration was used in this study. There was a dose-
dependent increase in total fecal BA excretion. In addition, BID 
dosing (ie, 50 mg BID) led to a further increase in fecal BA 
excretion as compared to QD dosing (ie, 100 mg QD). It is therefore 
hypothesized that twice-daily dosing has the potential to allow for 
more complete target engagement throughout the day at the level of 
the distal ileum. 
The higher dosing level is also supported by favorable results from 
a juvenile toxicity study conducted in rats administered LUM001 
for 43 days (post-natal day, PND21 through PND63). As expected 


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for a drug intentionally designed to be minimally absorbed, 
systemic LUM001 exposure was very low and consistent with levels 
that were previously determined in several oral gavage studies in 
adult rats. No adverse effects were observed on postnatal growth 
and development of offspring at the highest doses tested (200 
mg/kg/day in males, 1000 mg/kg/day in females). This study was 
initiated in juvenile animals at PND21, which from a whole animal 
development perspective, is typically representative of a 2-year old 
child. However, given the fact that LUM001 is a minimally 
absorbed drug, of particular importance is the age at which the GI 
tract is considered functionally mature. In humans this is 
considered to have occurred by 12 months of age; likewise, 
postnatal maturation of the GI tract in rats occurs during the first 3 
weeks of life. Therefore, results from this study can be used to 
support the dosing levels proposed here for children 12 months of 
age and older. 
Synopsis, Study Visit Schedule and 
Procedures; Section 5.5 
 
 
Synopsis only 
 
 
 
 
 
 
 
 
Synopsis, Study Visit Schedule and 
Procedures; 
Section 8.1.1, Screening Period (Day -
28 to -1) 
 
Synopsis, Study Visit Schedule and 
Procedures; 
Section 8.1.9, Long-term Optional 
Follow-up Treatment Period 
 
 
 
 
 
 
 
Section 8.1.8 (only, not synopsis), 52-
week Optional Follow-up Treatment 
Period 
 
 
 
Clarified titles of study design schemes and updated figures to reflect 
the addition of the extended follow-up treatment period beyond what 
was previously described in Protocol Amendment 3. 
 
For an individual subject, the study participation period will consist of a 
screening period of up to 4 weeks, a 48-week treatment period (a 6-
week open-label, dose escalation period, a 12-week open-label stable 
dosing period, a 4-week randomized, double-blind, placebo-controlled 
drug withdrawal period, and a 26-week long-term exposure period), and 
a follow-up period of up to 4 weeks.  Subjects who complete 48 weeks 
of treatment and those subjects who were previously treated with 
LUM001 may be eligible to receive treatment for up to 52 weeks during 
the optional follow-up treatment period. 
 
Screening Period (Day -28 to Day -1):  …. For subjects who do not 
have documentation of a JAGGED-1 or NOTCH2 mutation, a blood 
sample will may be obtained for genotyping. 
 
 
In addition the following assessments should be completed: the ItchRO 
(Pt and Obs), the clinician scratch scale, the clinician xanthoma scale, 
the PedsQL, the Patient Impression of Change (PIC), the CIC, the 
Caregiver Impression of Change, the CGTB, Caregiver Global 
Therapeutic Benefit assessments, and the palatability questionnaire, as 
defined for ET Early Termination. Efforts must be made to follow.  For 
subjects for at least 4 weeks following their last dose of who complete 
the study drug, an EOT visit will be completed; the assessments 
performed at this visit will be identical to the assessments 
performed at the ET visit. 
 
52-week Optional Follow-up Treatment Period post-Week 48 to Week 
100): 
Subjects who are eligible to roll over onto into the 52-week optional 
follow-up treatment period with no LUM001 dosing interruption or 
an interruption of <7days will be maintained at the same dose level 
within the 52-week optional follow-up treatment period (Figure 4). 


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Synopsis, Study Visit Schedule and 
Procedures;  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.9 (only, not synopsis), 
Long-term Optional Follow-up 
Treatment Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
will continue to receive study drug at the dose they were receiving at 
Week 48 for up to  52 weeks of additional treatment  or in the event that 
a new study opens to enrollment, whatever occurs first. 
Subjects who are eligible to roll over into the follow-up treatment 
period with no LUM001 dosing interruption or an interruption of <7 
days will be maintained at the same dose level.  During the this  follow-
up treatment period, subjects will return to the clinic at Weeks 60, 72, 
84, 96, and 100; and telephone contacts to will occur at Weeks 52, 56, 
64, 68, 76, 80, 88, and 92. 
 
Long-term Optional Follow-up Treatment Period 
Upon completion of the additional 52-week follow up treatment 
period and/or implementation of this amendment, whichever occurs 
first, subjects who are eligible to roll over onto the long-term 
optional follow-up treatment period will continue to receive study 
drug until the first of the following occurs:  
i. 
The subjects are eligible to enter another LUM001 study,  
ii. 
LUM001 is commercially available, or  
iii. 
The sponsor stops the program or development of this 
indication. 
 
Once Protocol Amendment 4 is implemented at the site, a 
determination about ADE will be made.  
 
Subjects who are eligible to roll over from the 52-week follow-up 
treatment period into the long-term optional follow-up treatment 
period with no LUM001 dosing interruption or an interruption of 
<7 days prior to implementation of Protocol Amendment 4 will be 
consented and evaluated for eligibility for ADE.  Once a 
determination about ADE has been made, the subject will then 
either initiate the ADE (Synopsis Figure 6) or continue receiving the 
same dose of LUM001 once a day (Synopsis Figure 5), depending on 
whether they meet criteria for initiating ADE.  
 
Screening evaluations for subjects with ≥7 days since last dose of 
LUM001 prior to implementation of Protocol Amendment 4 will be 
performed from Day -14 to Day -1.  After obtaining informed 
consent (and/or assent when appropriate), subjects will undergo a 
physical examination including body weight, height, and vital signs, 
and have blood and urine samples taken for clinical laboratory 
testing. Females who are of childbearing potential will have a serum 
pregnancy test. Eligibility criteria will be confirmed prior to the 
Baseline Visit. The clinician scratch scale and clinician xanthoma 
scale will be completed. Concomitant medications and any adverse 
events will be recorded. 
Rescreening:  If a subject is unable to complete the screening 
procedures and meet eligibility criteria within the 14-day screening 
period, consideration may be given to rescreening at a later date. 
Screening procedures should be repeated at that time. Subject data 
pertaining to screening will be collected after the subject has been 
rescreened and determined to meet eligibility. 
 


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Synopsis, Study Visit Schedule and 
Procedures; Section 8.1.9, Long-term 
Optional Follow-up Treatment Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with ≥7 days since last dose of LUM001 prior to 
implementation of Protocol Amendment 4 will be dose escalated up 
to 400 µg/kg/day or to the highest tolerated dose beginning at Dose 
Level 2 (35 µg/kg/day), as outlined in Synopsis Figure 4 (or Figure 6 
for body of protocol).  
The dose escalation (DE) period will proceed as follows: 
• 
Protocol Amendment 4 DE-2 Clinic Visit: obtain consent, 
weight, and draw blood for laboratory analyses 
• 
Protocol Amendment 4 DE Day 0 Clinic Visit: investigator 
evaluates laboratory results, study drug is dispensed, and 
subject begins at 35 µg/kg/day dose level (if no safety 
concerns) 
• 
Protocol Amendment 4 DE Week 1 Telephone Contact: 
subject escalates to 70 µg/kg/day dose level 
• 
Protocol Amendment 4 DE Week 2 Telephone Contact: 
subject escalates to 140 µg/kg/day dose level if prior dose 
level was tolerated 
• 
Protocol Amendment 4 DE Week 3 Telephone Contact: 
subject escalates to 280 µg/kg/day dose level if prior dose 
level was tolerated 
• 
Protocol Amendment 4 DE Week 4 Clinic Visit: laboratory 
tests and dose escalates to 400 µg/kg/day dose (maximum 
daily dose of 20 mg), if prior dose level was tolerated 
• 
Protocol Amendment 4 DE Week 8 Telephone Contact: 
eligibility for ADE will be determined. 
 
Subjects not eligible for ADE (subjects with normal sBA level AND 
ItchRO(Obs) score <1.5), will be maintained at the same dose level 
and will continue morning dosing only. Subjects will have study 
activities repeated in repeating 12-week periods as follows, until 
study completion or termination: 
• 
Repeating Period Week 4 Telephone Contact (ie, beginning 
4 weeks after consent to Protocol Amendment 4): 
Collection of concomitant medications and any adverse 
events. 
• 
Repeating Period Week 8 Telephone Contact: Collection of 
concomitant medications and any adverse events.  
• 
Repeating Period Week 12 Clinic Visit: Physical exam, 
body weight and height, vital signs, and blood samples for 
clinical laboratory testing including fasting lipid panel. 
Blood will also be collected for determination of baseline 
fat-soluble vitamins. Urine samples for clinical laboratory 
testing will be collected at every other visit. ItchRO 
compliance will be assessed, the electronic diary will be 
issued, the clinician scratch scale and clinician xanthoma 
scale will be administered, and the PedsQL questionnaire 
will be administered. Additionally, a palatability 
questionnaire will be completed. Female subjects who are 
of childbearing potential will have a urine pregnancy test 
prior to dispensing study drug. Study drug compliance will 


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be assessed and study drug will be dispensed. Concomitant 
medications and adverse events will be collected. 
• 
Subjects who do not qualify for ADE may be assessed at a 
later time point on a case by case basis following 
discussions between the investigator and medical monitor. 
Such re-evaluations may only occur at the Week 12 visit of 
any Repeating Period beginning with RP2. If in the course 
of the ADE re-evaluation, a subject is found to qualify for 
ADE, then the subject will move into Schedule F or G, as 
outlined in Section 16.1. During the follow-up treatment 
period, subjects will return to the clinic every 3 months. 
 
Subjects eligible for ADE,( ie, who have sBA level above normal 
AND/OR ItchRO(Obs) score ≥1.5), will begin BID dosing 
(afternoon dose escalation; ADE) as follows (see Figure 8): 
• 
On ADE Day 0, morning dosing will continue at 400 µg/kg 
or the maximum tolerated dose. However, the volume of 
the morning dose will be reduced by half. Of note: Morning 
dosing must have been stable for ≥4 weeks prior to 
initiation of ADE.  
• 
On ADE Day 0, the afternoon dose will be initiated at dose 
level 140 µg/kg and will continue at this dose for a period of 
4 weeks. If this dose level is tolerated, the afternoon dose 
will then be escalated to 400 µg/kg. 
The following procedures will occur during the ADE period: 
• 
ADE Day 0 Clinic Visit: Physical exam, body weight and 
height, vital signs, and blood and urine samples for clinical 
laboratory testing, including fasting lipid panel. Blood will 
also be collected for determination of fat-soluble vitamins. 
Plasma sample will be obtained for LUM001 
pharmacokinetics. The clinician scratch scale, clinician 
xanthoma scale, and the PedsQL questionnaire will be 
administered. Female subjects who are of childbearing 
potential will have a urine pregnancy test prior to 
dispensing study drug. Study drug compliance will be 
assessed and study drug will be dispensed. Concomitant 
medications and any adverse events will be collected. 
• 
ADE Week 1 and Week 2 Telephone Contact: Collection of 
concomitant medications and any adverse events. 
Subject/caregiver will be reminded of dosing instructions. 
• 
ADE Week 4 Clinic Visit:  Physical exam, body weight and 
height, vital signs, and blood and urine samples for clinical 
laboratory testing, including fasting lipid panel. Blood will 
also be collected for determination of fat-soluble vitamins. 
Plasma sample will be obtained for LUM001 
pharmacokinetics. The clinician scratch scale, clinician 
xanthoma scale, and the PedsQL questionnaire will be 
administered. Female subjects who are of childbearing 
potential will have a urine pregnancy test prior to 
dispensing study drug. Study drug compliance will be 


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assessed and study drug will be dispensed. Concomitant 
medications and any adverse events will be collected. 
• 
ADE Week 5 and Week 6 Telephone Contact: Collection of 
concomitant medications and any adverse events. 
Subject/caregiver will be reminded of dosing instructions. 
• 
ADE Week 8 Clinic Visit: Physical exam, body weight and 
height, vital signs, and blood and urine samples for clinical 
laboratory testing, including fasting lipid panel. Blood will 
also be collected for determination of fat-soluble vitamins. 
Plasma sample will be obtained for LUM001 
pharmacokinetics. The clinician scratch scale, clinician 
xanthoma scale, and the PedsQL questionnaire will be 
administered. Female subjects who are of childbearing 
potential will have a urine pregnancy test prior to 
dispensing study drug. Study drug compliance will be 
assessed and study drug will be dispensed. Concomitant 
medications and any adverse events will be collected. 
 
If any subject experiences intolerance, the investigator, in 
consultation with the sponsor medical monitor, may lower the dose 
to a previously tolerated dose at any time during the entire follow-
up treatment period; later attempts to escalate the dose are 
permitted. At the investigator’s discretion, and in consultation with 
the sponsor medical monitor subjects who were previously down 
titrated may be rechallenged during the follow-up treatment period. 
If the subject is on a twice daily dosing regimen, dose lowering 
should be first attempted with the afternoon dose. 
Safety and clinical laboratory evaluations…, and PedsQL will be 
administered and study drug compliance will be assessed (PedsQL will 
not be performed at DE-2 or DE52).certain clinic visits – please refer 
to schedule of procedures). The Patient and Caregiver Impression of 
Change (PIC & CIC), and the Caregiver Global Therapeutic Benefit 
assessments will be completed at Weeks 84, 96, and 100. 
Subjects/caregivers will receive follow-up phone calls at Weeks 64, 68, 
76, 80, 88, and 92.100, and the End of Treatment (EOT)/Early 
Termination (ET) visit. Palatability data will be collected at each 
clinic visit during the long-term optional follow up treatment period 
(including the EOT/ET visit), with the exception of the PA4 DE, and 
ADE visits.  Plasma samples will be obtained for LUM001 
pharmacokinetics at the ADE Day 0, ADE Week 4, and ADE Week 
8 visits, and at the 3 scheduled clinic visits following completion of 
the ADE period. Subjects/caregivers will receive follow-up phone calls 
at Weeks 64, 68, 76, 80, 88, 92, as well as those outlined within the 
PA4 DE, ADE, and repeating 12-week periods. 
 
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, 84, and 96 clinic visits, at PA4 DE Week 4, and 
every clinic visit within the repeating 12-week periods.   
 
With the exception of the Week 96 and Week 100 EOT/ET visit (Study 


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Termination),… 
 
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 safety and clinical 
laboratory evaluations, including pharmacokinetic sampling of 
LUM001, determination of serum bile acids, other cholestasis 
biochemical markers, fat soluble vitamins, and plasma drug level.AFP. 
In addition the following assessments should be completed: the ItchRO 
(Pt and Obs), the clinician scratch scale, clinician xanthoma scale, the 
PedsQL, the Patient Impression of ChangePIC, the CIC, the Caregiver 
Impression of Change CGTB, and the Caregiver Global Therapeutic 
Benefit palatability questionnaire, as defined for Early Termination. 
Efforts must be made to follow (ET). For subjects for at least 4 weeks 
following their last dose of who complete the study drug. , an EOT 
visit will be completed; the assessments performed at this visit will 
be identical to the assessments performed at the ET visit. 
 
At Following completion of the Follow-up Treatment Period or early 
discontinuation: a safety follow-up phone call will be made 4 weeks30 
days after the last dose of study drug (Week 100). 
Synopsis, Safety and Tolerability; 
Alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma, 
will be measured every 6 months throughout the optional extension 
period. 
Synopsis, Study Visit Schedule and 
Procedures; 
 Section 8.1.9, Long-term Optional 
Follow-up Treatment Period 
Plasma samples will be obtained for LUM001 pharmacokinetics at 
the ADE Day 0, ADE Week 4, and ADE Week 8 visits, and at the 3 
scheduled clinic visits following completion of the ADE period. 
Synopsis, Safety Evaluations 
The following assessments will be used to evaluate safety: 
• 
Adverse events (AEs) and serious adverse events (SAEs). 
• 
Clinical laboratory results, including alpha-fetoprotein (AFP) 
as a screening for hepatocellular carcinoma. 
• 
Vital signs. 
• 
Physical exam findings, including body weight and height. 
• 
Concomitant medication usage. 
Synopsis, Efficacy Evaluations; 
Section 12.2.5.1, Efficacy Variables 
The primary efficacy evaluation endpoint will be the mean change in 
from Week 18 to 22 of fasting serum bile acid levels from Week 18 to 
Week 22 for those who in subjects who previously responded to 
LUM001 treatment, which is as defined as subjects who had by a >50% 
reduction serum bile acid levels sBA>70% from baseline to Week 12 
or Week 18. A sensitivity analysis will also be conducted using 
subjects who experienced a reduction from baseline in serum bile 
acids of ≥50% at the Week 48 measurement. 
… 
o 
Pruritus as measured by ItchRO (Observer ItchRO/patient 
ItchRO).) in subjects who previously responded to LUM001 
treatment, as defined by a reduction in ItchRO scale >1 
point from baseline to Week 12 or Week 18. 
… 
o 
Change from baseline to Weeks 18, 22 48, and 48 then every 


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12 weeks in: 
Evaluations will be the mean Change from Baseline (Day 0) to Week 
18, prior to randomization, and  the change from Week 18 to Week 48 
and Week 18 to Week 100 in: 
• 
Biochemical markers of cholestasis and liver disease [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), caregiver instrument/ItchRO(Pt) 
patient instrument). 
• 
The change from Baseline (Day 0) to Week 48 in xanthomas, 
as measured by clinician xanthoma scale will also be 
evaluated. 
Additional assessments of efficacy variables will occur during the 52-
week optional treatment period. For subjects entering the 52-week 
optional treatment period with ≥7 days since last dose of LUM001, in 
12 weekly intervals. Any of the above evaluations may also occur at 
clinic visits during the DE period, PA4 DE, and ADE periods. 
Synopsis, Palatability Data; 
 
Section 12.2.9, Palatability Analyses 
 
Section 16.12, Palatability 
Questionnaire 
Palatability data will be collected at each clinic visit in the follow up 
treatment period, with the exception of the DE, PA4 DE, and ADE 
visits.  A palatability questionnaire will be completed by the subject 
and/or caregiver (dependent on age). Assessment of change over 
time will be evaluated. Baseline will be defined as the first recorded 
evaluation. 
 
Added palatability questionnaire 
Section 8.5.8, Palatability 
A palatability questionnaire (see Section 16.12) will be completed by 
the subject and/or caregiver (dependent on age) at clinic visits at 
time points as outlines in the Schedule of Procedure in Section 16.1 
Synopsis, Statistical Considerations 
 
 
 
 
Section 12.2.10, Statistical 
Considerations 
Safety measures including AEs, clinical laboratory tests, vital signs, 
physical exams, and concomitant medication usage will be summarized 
descriptively by study period and over the entire study duration (Weeks 
0-48). EOT Visit). 
 
Interim Analysis 
There will be an interim analysis (IA) conducted after all subjects 
complete or discontinue the study after Week 48 to guide the future 
of the program. The IA may result in an interim report or 
publication. The IA will be conducted internally by an unblinded 
sponsor team as outlined in the unblinded study plan charter. The 
unblinded sponsor team will not be involved in the day-to-day 
clinical study activities. 
Section 4.4.1.3, Toxicology 
The results from this study were very favorable. As expected for a drug 
intentionally designed to work in the intestinal lumen and to be 
minimally absorbed, LUM001 exposure was very low and consistent 
with levels that were previously determined in several oral gavage 
studies with adult rats. 
Section 4.5, Rationale for Dose and 
Updated Sample Daily Exposure (mg/day) in Pediatric Subjects table. 


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Schedule of Administration 
 
In the current study, safety and efficacy of LUM001 will be assessed in 
children with ALGS and cholestatic liver disease, 12 months of age and 
older.  The highest dose is equivalent to less than the well tolerated 1 
mg dose used in Study 014 (~17 µg/kg, 60 kg body weight), where only 
two subjects reported moderate or severe GI-associated AEs during 14 
days.  On a weight basis, 23 subjects received a dose approximately ≥14 
µg/kg/day.  The highest starting dose in Study 014 was 168 µg/kg/day.  
To reduce the risk of loose stools and diarrhea in subjects in study 
LUM001-304, the LUM001 dose will be escalated over an up to 6-week 
period; dosing will start at 14 µg/kg/day, and will then be increased at 7-
day intervals to 35 µg/kg/day, 70 µg/kg/day, 140 µg/kg/day, 280 
µg/kg/day, and 400 µg/kg/day (equivalent to 20 mg daily dose in a 50 
kg subject). 
 
The doses explored in the current study (up to 400 µg/kg/day BID) 
in subjects with ALGS are supported by the safety profile observed 
in completed and ongoing clinical studies of LUM001. Twice daily 
dosing is used in this study based on the findings of a healthy 
volunteers study in adult males (Study SHP625-101), which 
demonstrated that bile acid levels in feces increase with escalating 
doses and twice-daily regimen of LUM001 (up to 100 mg QD and 50 
mg BID, respectively). In this study, subjects who were randomized 
to LUM001 treatment, received 1 of 4 doses of LUM001 (10, 20, 50, 
100 mg) during 7 days. No titration was used in this study. There 
was a dose-dependent increase in total fecal BA excretion. In 
addition, BID dosing (i.e. 50 mg BID) led to a further increase in 
fecal BA excretion as compared to QD dosing (i.e. 100 mg QD). It is 
therefore hypothesized that higher doses and twice-daily dosing 
both have the potential to allow for more complete target 
engagement throughout the day at the level of the distal ileum. 
The higher dosing level is also supported by favourable results from 
a juvenile toxicity study conducted in rats administered LUM001 
for 43 days (PND21 through PND63). As expected for a drug 
intentionally designed to be minimally absorbed, systemic LUM001 
exposure was very low and consistent with levels that were 
previously determined in several oral gavage studies in adult rats. 
No adverse effects were observed on postnatal growth and 
development of offspring at the highest doses tested (200 mg/kg/day 
in males, 1000 mg/kg/day in females). This study was initiated in 
juvenile animals at PND21, which from a whole animal 
development perspective, is typically representative of a 2-year old 
child. However, given the fact that LUM001 is a minimally 
absorbed drug, of particular importance is the age at which the GI 
tract is considered functionally mature. In humans this is 
considered to have occurred by 12 months of age; likewise, 
postnatal maturation of the GI tract in rats occurs during the first 3 
weeks of life. Therefore, results from this study can be used to 
support the dosing levels proposed here for children 12 months of 
age and older. 
Section 5.1, Study Design 
At Week 48, all subjects will be assessed by the investigator to 
determine their willingness and eligibility to roll-over into the 52-week, 
optional follow-up treatment period. The 3 following possible scenarios 


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may occur: 
• 
For subjects who are eligible to roll over into the follow-up 
treatment period, those with <7 days since the last dose of 
LUM001 will be maintained at the highest tolerated dose at 
Week 48. 
• 
For subjects who are eligible to roll over into the follow-up 
treatment period, those with ≥7 days since the last dose of 
LUM001 will be dose escalated up to 400 µg/kg/day or highest 
tolerated dose following a  5-week dose escalation beginning at 
35 µg/kg/day. 
• 
For subjects who do not wish to enter the follow-up treatment 
period, or are not eligible to enter the follow-up treatment 
period, a safety follow-up phone call will be made by the study 
site 28 days after the last dose of study drug 
Section 5.5, Overall Study Duration 
and Follow-up 
For an individual subject, the duration of the study, including subject 
participation period will consist of a screening, period of up to 4 
weeks, a 48-week treatment period (including a 6-week, open-label, 
dose escalation period, a 12-week open-label stable dosing period, a 
4-week randomized, double-blind, placebo-controlled drug 
withdrawal period, safety a 26-week long-term exposure period) as 
well as a 52-week optional follow-up treatment period, and a long-
term optional treatment period. A safety follow-up is expected to 
phone call will be approximately 56 weeks. made by the study site 
30 days after the last dose of study drug. 
Section 5.5.2, Treatment 
Study drug will be dispensed to subjects/caregivers at the study. During 
the course of the study, it may be necessary to instruct the 
subject/caregiver to return to the site.  for an unscheduled 
dispensation of study drug. 
 
Subjects who weigh 10 kg or more at screening will receive a 1.0 mL 
grape-flavored solution per day containing LUM001 Subjects who 
weigh less than 10 kg at screening will receive a 0.5 mL grape-flavored 
solution per day containing LUM001. The daily volume administered 
will not change during the course of the study. Dosing will occur over a 
48-week treatment period. Each daily dose will be administered in the 
morning at least 30 minutes before breakfast (qAM, ac).  Study drug 
should be administered approximately at the same time every day. 
 
Subjects will receive a grape-flavored solution containing LUM001 
administered orally once a day (QD) or twice a day (BID) using the 
syringe provided. The first dose should be taken at least 30 minutes 
prior to the first meal of the day and the second dose, where 
applicable, should be taken at least 30 minutes prior to dinner 
(main evening meal). The doses will not be administered q12h in 
order to better cover the luminal bile acid release associated with 
dinner and to minimize the risk of disturbing sleep due to the 
potential for abdominal pain and diarrhea at night. It is 
recommended that the dose should be taken approximately at the 
same time each day for the duration of the treatment period. 
 
All subjects will receive LUM001, up to 400 μg/kg/day or a 
maximum daily dose of 20 mg/day during the initial open-label 


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treatment period of the study. After completion of the 12-week 
stable dosing period, subjects will be randomized 1:1 to either a 4-
week double-blind study drug withdrawal period during the study 
or will remain on study drug. Subjects will then enter a 26-week 
long-term stable dosing period and all subjects will receive 
LUM001, up to 400 μg/kg/day or a maximum daily dose of 20 
mg/day during the initial open-label treatment period of the study. 
Subjects will then be considered for an optional follow-up 
treatment, if eligible, to continue on their highest tolerated dose 
receiving up to 800 μg/kg/day (given as twice daily doses of 
400 μg/kg), or a maximum possible daily dose of 50 mg/day. 
Section 5.5.2.1, Dose Escalation 
Period 
 
Initially, the LUM001 dose will be administered as a daily morning 
dose in either a 1.0 mL or 0.5 mL solution. The dose will be 
increased weekly over a 6-week period up to 400 g/kg/day QD or a 
maximum daily dose of 20 mg/day QD as follows 
Section 5.5.2.4, Long-term Exposure 
Period 
During the long-term exposure period, the dose may be adjusted to 
account for a change of ≥10% in weight since the screening visit 
(e.g. the amount of drug dosed may be increased to reflect the 
subject’s weight increase). 
Section 5.5.2.6, Long-term Optional 
Follow-up Treatment Period 
Subjects who are eligible to roll over into the optional follow-up 
treatment period, those with <7 days since the last dose of  will 
continue treatment under dosing scenarios based on whether their 
LUM001 will be maintained at the highest tolerated dose at Week 48 
dosing will continue 1) without interruption/interruption of <7 
continuous days, or 2) with interruption ≥7 days. Eligibility for BID 
dosing will be determined based on efficacy as measured by sBA 
level and ItchRO score. The 2 following dosing scenarios may occur. 
Section 5.5.3, Safety Follow-up 
Period 
A safety follow-up phone call will be made by the study site 2830 days 
after the last dose of study drug. This call will be made for all subjects 
who complete the study, as well as any subject who terminates from the 
study early. Concomitant medications and any AEs noted during 
this phone call will be recorded. Subjects who complete the study or 
who discontinued early due to reasons other than safety may be 
eligible for participation in the optional follow-up treatment period 
under Protocol Amendment 4.  
If any subject experiences intolerance, the investigator, in consultation 
with the Sponsor Medical Monitor, may lower the dose to a previously 
tolerated dose at any time during the entire follow-up treatment period. 
At the investigator’s discretion, and in consultation with the Sponsor 
Medical Monitor, subjects who were previously down titrated may be 
re-challenged during the follow-up treatment period. During the follow-
up treatment period, subjects will return to the clinic at Weeks 60, 72, 
84, 96, and 100.  
Safety and clinical laboratory evaluations and a physical exam 
(including collection of vital signs, height and weight measurements) 
will be completed at each clinic visit. In addition, the clinician scratch 
scale, clinician xanthoma scale, and PedsQL (clinician xanthoma scale 
and Peds QL will not be evaluated at DE -2 and DE 52) will be 
administered and study drug compliance will be assessed. The Patient 
and Caregiver Impression of Change (PIC & CIC), and the Caregiver 
Global Therapeutic Benefit assessments will be completed at Weeks 84, 
96, and 100. Subjects/caregivers will receive follow-up phone calls at 
Weeks 64, 68, 76, 80, 88, and 92. Concomitant medications and any 


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AEs will be evaluated and recorded at all clinic visits and at scheduled 
telephone contacts.  
Twice daily completion of the electronic diary will be required by 
caregivers and age appropriate subjects during the 2 weeks following 
the Week 60, 72, 84, and 96 clinic visits. Electronic diaries will be 
provided to subjects and caregivers at these visits and re-training on the 
use of the diary will occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant 
medications used for the treatment of pruritus may occur during the 
long-term exposure period.  
With the exception of the Week 96 and Week 100 visit (Study 
Termination), Additional study drug will be supplied at each clinic visit 
during the follow-up treatment period. Used and unused study drug will 
be collected at every each clinic visit and dosing compliance will be 
assessed. 
Section 5.6, End of Study 
For subjects who do not consent to the long-term optional follow-up 
treatment period, a subject is considered to have completed 
treatment if treatment was not permanently discontinued prior to 
the Week 48 visit.  A follow-up phone contact is required for all 
subjects should the final visit occur earlier than 30 days from the 
final dose.  
The subject is considered to have completed treatment and study 
period for the corresponding follow-up treatment period (when 
consented under Protocol Amendment 3 or Protocol Amendment 4) 
if study treatment was not discontinued prior to completing Week 
96 for Protocol Amendment 3 or completing the EOT visit in 
Schedule J under Protocol Amendment 4. Temporary drug 
interruption is not considered treatment discontinuation. A follow-
up contact is required for all subjects should the final visit occur 
earlier than 30 days from the final dose. 
The end of study for the purposes of regulatory reporting is the point at 
which the last contact with the last subject during the protocol-specified 
scheduled follow-up period is made. 
Section 6.1, Screening 
Subjects will be enrolled in the 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 the long-term optional follow-up period under Protocol 
Amendment 4 after the subject consents and the investigator has 
determined the subject meets study entry eligibility criteria per 
Protocol Amendment 4. However, any subject who consents to 
Protocol Amendment 4 and does not meet criteria per the 
investigator is considered a screen failure for the long-term optional 
follow-up period under Protocol Amendment 4. Screen failures are 
eligible for rescreening (Section 8.1.1). 
Section 8.1.1, Screening Period (Day -
28 to Day -1) 
In the absence of documented JAGGED1 or NOTCH2 mutation prior to 
screening, genetic testing may be performed for JAGGED1 and/or 
NOTCH2 (Spinner et al., 2000). 
… 
For subjects who do not have documentation of a JAGGED-1 or 
NOTCH2 mutation, a blood sample may be obtained for genotyping. 
… 
Rescreening: … Subject data pertaining to screening will be 
collected after the subject has been rescreened and determined to 


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meet eligibility.   
Section 8.1.10, End of Treatment of 
Early Termination  
Any subject subject who completes or withdraws from the study prior 
to completion of all treatment period clinic visits should undergo all 
procedures specified for the EOT/ET visit (see Schedule J). The 
following assessments are to be completed at the EOT/ET visit: 
safety and clinical laboratory evaluations, including determination of 
serum bile acids, lipid panel, other cholestasis biochemical markers, fat 
soluble vitamins, and plasma drug level. In addition and AFP. Female 
subjects who are of childbearing potential will have a urine 
pregnancy test. Study drug compliance will be assessed. 
Concomitant medications and adverse events will be collected. In 
addition, the following assessments … Efforts must be made to follow 
subjects for at least 4 weeks following their last dose of study drug. 
Section 8.1.11, Safety Follow-up 
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 adverse events noted 
during this phone call will be recorded. 
Section 8.5.1, Itch Reported Outcome 
(ItchRO™); Section 8.5.2, Clinician 
Scratch Scale; Section 8.5.3, Clinician 
Xanthoma Scale; Section 8.5.4, 
Pediatric Quality of Life Inventory 
(PedsQL); Section 8.5.5, Patient 
Impression of Change; Section 8.5.6, 
Caregiver Impression of Change; 
Section 8.5.7, Caregiver Global 
Therapeutic Benefit 
Edited text to indicate all assessments will be performed as outlined in 
the Schedule of Procedures in Section 16.1. 
Section 8.6.1, Contraception 
Requirements 
Sexually active female subjects of childbearing potential must continue 
to use acceptable contraception with their partners, or refrain from 
sexual activity, from the time of screening until the end of the study, 
throughout the study period and for 30 days following the last dose 
of the study drug.  
If hormonal contraceptives are used they should be administered 
according to the package insert. 
Females of child-bearing potential who are not currently sexually 
active must agree to use acceptable contraception, as defined below, 
if they become sexually active during the period of the study and 30 
days following the last dose of the IP. 
Acceptable methods of contraception are: 
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. 
a. 
Hormonal contraceptives (eg, oral contraceptive pill, depot, 
patch, intramuscular implant or injection, or vaginal ring), 
stabilized for at least 30 days if first use, plus condoms; and/or 
b. 
Barrier method, eg, (i) condom (male or female) or (ii) 
diaphragm, with spermicide; or 
c. 
Intrauterine device (IUD). 
d. 
or a sexual partner who is surgically sterilized. 
 


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Male Contraception: 
Contraception is required for all sexually-active male subjects and 
their partners. All male subjects agree not to donate sperm, and to 
use 1 of the following approved methods of contraception until 30 
days following study discharge: 
 
a. 
Male condom with spermicide 
b. 
Intrauterine device with spermicide (use by female sexual 
partner) 
c. 
Female condom with spermicide (use by female sexual 
partner) 
d. 
Contraceptive sponge with spermicide (use by female 
sexual partner) 
e. 
Intravaginal system (eg, vaginal ring with spermicide, a 
diaphragm with spermicide, or a cervical cap with spermicide) (use 
by female sexual partner) 
f. 
Oral, implantable, transdermal, or injectable hormonal 
contraceptive (use by female sexual partner). 
Section 8.6.2, Fasting Requirements 
On these visit days study drug should be administered as usual (1 mL, 5 
mL, or 0.5 mL 25 qAM, ac), in the morning 30 minutes before 
breakfast. 
Section 9.1.1, LUM001 
 
Added new composition of LUM001 1.0 mL, 0.5 mL, and 0.25 mL Oral 
Solution tables. 
Section 9.1.2, Placebo 
 
Added new composition of placebo 1.0 mL, 0.5 mL, and 0.25 mL Oral 
Solution tables. 
Section 10.1, Study Drug 
Administration 
The dose may also be down-titrated, at the investigator’s discretion 
and in consultation with the sponsor medical monitor, for subjects 
experiencing intolerance (eg, gastrointestinal symptoms such as 
diarrhea, abdominal pain, cramping) to a given dose.  If the subject 
is on twice daily dosing regimen, dose reduction should first be 
attempted with the afternoon dose.  Subjects who were previously 
down-titrated may be rechallenged during the long-term exposure 
period. 
… 
Study drug will be dispensed to subjects/caregivers at the study site. 
… 
Each subject dose for subjects who weigh 10 kg or more Subjects will 
be administered orally as a receive a grape-flavored solution 
containing study drug (LUM001 or placebo) using the syringes 
provided. . Each subject dose for subjects who weigh less than 10 kg 
will be administered orally as once a 0.5 mL solution containing study 
drug (LUM001day (QD) or placebo twice a day (BID) using the 
syringes syringe provided. The daily volume administered will not 
change during the course of the study. Study drug first dose should be 
taken at least 30 minutes prior to the first meal of the day (qAM, ac) and 
should and the second dose, where applicable, should be taken at 
least 30 minutes prior to dinner (evening meal). The doses will not 
be administered q12h in order to better cover the luminal bile acid 
release associated with dinner and to minimize the risk of 
disturbing sleep due to the potential for abdominal pain and 
diarrhea at night. It is recommended that the doses should be taken 
approximately at the same time each day for the duration of the 


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treatment period. 
Section 10.2, Treatment Compliance 
Subjects and/or caregivers will be asked to complete a paper diary 
indicating when they took their study medication and when they ate 
breakfast and, for subjects who receive a BID regimen, when they 
ate dinner (evening meal). 
Section 10.5.1, 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 (Sections 10.5.2), dosing will can be suspended. 
Continued dosing with study drug may be considered or continued as 
per the investigator’s judgement and following discussion with the 
sponsor medical monitor. If suspended the… 
 
The Data Monitoring Committee (DMC) will be notified of any SAE 
as specified in the DMC charter. 
Section 10.5.2, Safety Monitoring 
Rules 
Of note: the INR re-test should be conducted by the central 
laboratory, but may also be conducted at a local laboratory on an as 
needed basis…. In this case, the subjects should be retested locally, but 
normal laboratory ranges should be recorded, results should be made 
available to study investigators and medical monitors immediately… 
 
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), in particular 
whether the event should be considered as an important medical 
event, ie. an event that would have met one of the other seriousness 
criteria in the absence of appropriate medical interventions. 
Section 10.6, Adjustment of Dose 
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; later attempts to escalate the dose are 
permitted. If the subject is on twice daily dosing regimen, dose 
lowering should first be attempted with the afternoon dose.   
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 will be collected as medical history unless 
the AE started within 30 days of last dose. 
Section 11.3.1, Serious Adverse 
Events 
The collection of SAEs will begin after the subject signs the informed 
consent/assent form and stop at the end of the subject’s follow-up 
period which is defined as Week 52 for subjects who do not roll over 
into the optional treatment follow-up period, Week 100 for subjects who 
do roll over into the optional treatment follow-up period, or 28 days 
after the last dose of study drug for those subjects that terminate prior to 
the Week 96 visit 30 days after the last dose of study drug. 
Section 11.3.2, Non-serious Adverse 
Events 
The recording of non-serious AEs will begin after the subject signs the 
informed consent/assent form and will stop at the end of the subject’s 
follow-up period, which is defined as Week 52 for subjects who do not 
roll over into the optional treatment follow-up period, Week 100 for 
subjects who do roll over into the optional treatment follow-up period, 
or 30 days after the last dose of study drug for those subjects that 
terminate prior to the Week 96 visit 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 


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monitoring for liver chemistry tests given that subjects with ALGS 
may have abnormal liver enzyme levels at baseline. 
Section 12.2.2, Efficacy Populations 
The main population for efficacy will be the modified intention-to-treat 
population (MITT), defined as all subjects who were enrolled, received 
study medication through Week 18, had a reduction from baseline in 
serum bile acids of ≥50% at the Week 12 or Week 18 measurement. 
Section 12.2.5.1, Efficacy Variables 
A sensitivity analysis will also be conducted using subjects who 
experienced a reduction from baseline in serum bile acids of ≥50% 
at the Week 48 measurement. 
… in subjects who previously responded to LUM001 treatment, as 
defined by a reduction in ItchRO scale >1 point from baseline to 
Week 12 or Week 18. 
In addition, an analysis for a daily score defined as an average of 
morning and evening scores will be conducted. 
Section 12.2.6.1, Safety Assessments 
• 
Serum alpha-fetoprotein (AFP) 
Section 12.2.8.2, Laboratory Tests 
Changes within a treatment group for selected safety measures will be 
assessed at Weeks 3, 6, 12, 18, 22, 28, 38, 48, 60, 72, 84, 96, and at 
additional time points during the 52-week and long-term optional 
treatment periods… 
Section 12.2.8.6, Serum Alpha-
fetoprotein 
(new section) 
Assessments of serum AFP will be listed for individual subjects and 
summarized using descriptive statistics by study visit. 
Section 16.1.2, Schedule of 
Procedures E-F 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 16.1.3, Schedule of 
Procedures G-I 
Added Overall Scheme and Corresponding Schedule of Procedures 
Added Schedule of Procedures E-F: Rollover under Protocol 
Amendment 4: 
Schedule of Procedures E – Extension of Long-term Optional Follow-
up Treatment Period, for subjects ineligible for ADE, applicable as 
follows: 
• 
Subject did not yet complete the optional follow up treatment 
period as outlined under Protocol Amendment 3 and is able to 
consent to Protocol Amendment 4 activities without an 
interruption in LUM001 dosing, OR 
• 
Subject completed long-term optional follow up treatment 
period as outlined under PA3 and dosing interruption was <7 
days. 
• 
Subject deemed ineligible for ADE. 
Schedule of Procedures F – Extension of Long-term Optional Follow-up 
Treatment Period, for subjects eligible for ADE, applicable as follows: 
 
• 
Subject did not yet complete the long-term optional follow up 
treatment period as outlined under Protocol Amendment 3. and 
is able to consent to Protocol Amendment 4 activities without 
an interruption in LUM001 dosing, OR 
• 
Subject completed the optional follow up treatment period as 
outlined under PA3 and dosing interruption was <7 days. 
• 
Subject deemed eligible for ADE. 
 
Added Schedule of Procedures G-I: Rollover under Protocol 
Amendment 4: 
 


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Schedule of Procedures G – Long-term Optional Follow-up Treatment 
Period: Re-entry under Protocol Amendment 4, applicable as follows: 
• 
Subject previously completed (or early terminated from) the 
optional follow up treatment period as defined under Protocol 
Amendment 3 and has subsequently experienced an 
interruption in LUM001 dosing ≥7days 
• 
Subject is considered eligible for study re-entry under Protocol 
Amendment 4 
• 
Subject eligibility will be assessed for afternoon dose 
escalation at Protocol Amendment 4 DE Week 8 shown in the 
table below. 
o 
If subject is found to be ineligible for ADE, subject 
will move from Schedule G to Schedule H. 
o 
If subject is found to be eligible for ADE, subject will 
move from Schedule G to Schedule I. 
Schedule of Procedures H – Long-term Optional Follow-up Treatment 
Period: Re-entry under Protocol Amendment 4, subject ineligible for 
ADE 
 
Schedule of Procedures I – Long-term Optional Follow-up Treatment 
Period: Re-entry under Protocol Amendment 4, subject eligible for ADE 
 
Added Schedule of Procedures J - Study Termination and End of 
Treatment Procedures 
Section 16.2, List of Laboratory 
Analytes 
Added alpha-fetoprotein (AFP) under Marker of hepatocellular 
carcinoma 
Section 16.7, Pediatric Quality of Life 
Inventory (PedsQL™) 
Subjects will continue to fill out the same questionnaire used at 
baseline for continuity of data collection, regardless of subsequent 
birthdays after the baseline visit. 
 
16.13.3 Protocol Amendment 3 Summary of Changes 
 
Protocol Number: 
LUM001-304 
 
Protocol Title: 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED DRUG WITHDRAWAL 
PERIOD OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN PATIENTS WITH 
ALAGILLE SYNDROME 
 
Amendment: 
3 
 
Date: 
13 Nov 2015 
 
The changes below were made to Protocol Amendment 2. 
The following table provides a summary list of changes that were included in Protocol 
Amendment 3 (new text indicated in bold; deleted text indicated in strikethrough): 


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Title Page, 
Sponsor 
Medical 
Monitor 
Added: 
Sponsor Medical Monitor: 
Susanne Schmidt, MD, PhD 
 
Premier Research 
 
Office: +1 215 282 5406 
 
Cell: +1 267 838 2380 
 
 Email: medmonitorLUM304@premier-research.com 
Title Page, 
Medical Lead 
Changed from: 
Ciara Kennedy, PhD 
Lumena Pharmaceuticals, Inc. 
Phone:  00-1-858-337-7922 
Email: cikennedy@shire.com 
To: 
Beatriz Caballero, MD 
Shire, Inc. 
Zahlerweg 10 
6300 Zug 
Switzerland 
Phone:  +41(0) 41 288 42 30 
Email: bcaballero@shire.com 
Study 
Synopsis, 
Objectives; 
Section 3, 
Study 
Objectives  
• To evaluate the effect of LUM001 on serum bile acid levels in children with ALGS.  
• To evaluate the effect of LUM001 on biochemical markers of cholestasis and liver disease 
in children with ALGS. 
• To evaluate the effect of LUM001 on pruritus in children with ALGS. 
• To evaluate the long-term durability of effect of LUM001 in children with ALGS 48-weeks 
of treatment. 
• To evaluate the long-term safety and tolerability of LUM001 in children with ALGS.  
 
Objectives of Optional Follow-up Treatment Period (After Week 48): 
• To offer eligible subjects treated in the LUM001-304 study continued study treatment 
after Week 48 until the first of the following occur: (i) up to 52 weeks of additional 
treatment (Week 100), or (ii) in the event that a new study opens to enrollment. 
• To obtain safety and efficacy data in patients treated long term on LUM001 including 
genotyping characteristics. 
Synopsis 
(Section 1), 
Study Design 
and Overall 
Study Duration 
and Follow-up 
(Sections 5.1 
and 5.4), 
Schedule of 
Procedures 
(Appendix 
16.1) 
This is a long-term, open-label study with a double-blind, placebo-controlled, 
randomized drug withdrawal period in children with ALGS designed to evaluate the 
safety and efficacy of LUM001. The study is divided into 5 parts: a 6-week open-label, 
dose escalation period at doses up to 400 μg/kg/day, a 12-week stable dosing period, a 
4-week randomized, double-blind, placebo-controlled drug withdrawal period, a 26-
week long-term stable dosing period at doses up to 400 μg/kg/day, and an optional 
52-week follow-up treatment period for eligible subjects who choose to stay on 
treatment with LUM001. Subjects’ participation in the optional follow-up treatment 
period will continue until the first of the following occur: (i) completion of 52 weeks of 
additional treatment (Week 100), or (ii) in the event that a new study of LUM001 
opens to enrollment. 
 
This is a long-term, open-label study with a double-blind, placebo-controlled, randomized 
drug withdrawal period in children with ALGS designed to evaluate the safety and efficacy 


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of LUM001. The study is divided into 4 parts: a 6-week open-label, dose escalation period 
at doses up to 400 μg/kg/day, a 12-week stable dosing period, a 4-week randomized, 
double-blind, placebo-controlled drug withdrawal period, and a 26-week long-term stable 
dosing period at doses up to 400 μg/kg/day. 
Synopsis 
(Section 1), 
Study 
population 
(Section 7) 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Chronic diarrhea requiring ongoing intravenous fluid or nutritional intervention. 
2. Surgical interruption of the enterohepatic circulation. 
3. Previous liver transplant. 
4. Decompensated cirrhosis [ALT >15 x ULN, INR >1.5 (unresponsive to vitamin K 
therapy), albumin <3.0 g/dL, history or presence of clinically significant ascites, variceal 
hemorrhage, and/or encephalopathy]. 
5. History or presence of other concomitant liver disease. 
6. History or presence of any other disease or condition known to interfere with the 
absorption, distribution, metabolism or excretion of drugs, including bile salt metabolism 
in the intestine (eg, inflammatory bowel disease). 
7. History or presence of gallstones or kidney stones. 
8. Known diagnosis of human immunodeficiency virus (HIV) infection. 
9. Cancers, except for in situ carcinoma, or cancers treated at least 5 years prior to Screening 
with no evidence of recurrence. 
10. Recent medical history or current status that suggests that the subject may be unable to 
complete the study. 
11. Any female who is pregnant or lactating or who is planning to become pregnant during the 
study period. 
12. Known history of alcohol or substance abuse. 
13. Administration of bile acid or lipid binding resins within 28 days prior to screening and 
throughout the trial. 
14. Known hypersensitivity to LUM001or any of its components. 
15. Receipt of investigational drug, biologic, or medical device within 28 days prior to 
Screening, or 5 half-lives of the study agent, whichever is longer. 
16. History of non-adherence to medical regimens, unreliability, mental instability or 
incompetence that could compromise the validity of informed consent or lead to non-
adherence with the study protocol based upon investigator judgment. 
17. Any other conditions or abnormalities which, in the opinion of the investigator or sponsor 
medical monitor, may compromise the safety of the subject, or interfere with the subject 
participating in or completing the study. 
18. Subjects weighing over 50 kg at screening. 
 
Eligible subjects for the 52-week follow-up period: 
Subjects will be considered eligible for the optional 52-week follow-up treatment period if 
they have: 
• Completed the protocol through the Week 48 visit with no safety concerns. Subjects 
who were discontinued due to safety reasons can be rechallenged if blood tests are 
back to relatively normal values for this patient population and subject does not meet 
any of the protocol’s stopping rules.  The decision will be made by the investigator in 


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consultation with the sponsor medical monitor.  
• Subjects who have undergone a surgical disruption of the enterohepatic circulation 
will not be eligible to enter into the follow up treatment period.   
• Subjects who were discontinued for other reasons will be considered for the optional 
52-week follow-up treatment period on an individual basis. The decision will be made 
by the investigator in consultation with the sponsor medical monitor. 
Synopsis 
(Section 1) 
All subjects will receive LUM001, up to 400 μg/kg/day or a maximum daily dose of 
20 mg/day. After completion of the 12-week stable dosing period, subjects will be randomized 
1:1 to either a 4-week study drug withdrawal period during the study or will remain on study 
drug. Subjects will then enter a 26-week long-term stable dosing period and all subjects will 
receive LUM001, up to 400 μg/kg/day or a maximum daily dose of 20 mg/day. Subjects will 
then be considered for an optional 52-week follow-up treatment, if eligible, to continue on 
their highest tolerated dose. 
Synopsis 
(Section 1), 
Study Design 
(Section 5.1) 
Optional Follow-up Treatment Period 
At Week 48, all subjects will be assessed by the investigator to determine their willingness 
and eligibility to roll-over into the 52-week, follow-up treatment period. The 3 following 
possible scenarios may occur: 
• Subjects who are eligible to roll over into the optional follow-up treatment period with 
no LUM001 dosing interruption or an interruption of <7 days will be maintained at 
the same dose level. 
• Subjects who are eligible to roll over into the optional follow-up treatment period with 
a LUM001 dosing interruption of ≥7 days,  will be dose escalated up to 400 µg/kg/day 
or highest tolerated dose following a 5-week dose escalation beginning at 35 µg/kg/day. 
• Subjects who do not wish to enter the follow-up treatment period will be contacted via 
telephone by the study site approximately 28 days after the last dose of study drug. 
During the study, the study drug may be adjusted if there is a change of ≥10% in 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 (μg/kg/day). 
The anticipated adverse reaction or intolerance is gastrointestinal in nature (e.g., diarrhea, 
abdominal pain, cramping, etc.). During the respective escalation periods, in the absence of 
intolerance, escalation to the next dose level for an individual subject will occur following a 
scheduled phone call or visit (see Schedule of Procedures, Section 16.1). 
If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, 
abdominal pain, cramping) at any time during the study, the physician investigator in 
consultation with the sponsor medical monitor may lower the dose to a previously tolerated 
dose. At the investigator’s discretion, subjects who had their dose reduced due to intolerability 
may have a one-time dose re-challenge during the long-term exposure period with a higher 
dose. 
Synopsis 
(Section 1), 
Overall Study 
Duration and 
Follow-up 
(Section 5.4) 
Added to synopsis: 
For subjects in the 52-week optional follow-up treatment period with ≥7 days since the 
last dose of LUM001, dosing will start at 35 µg/kg/day, and will then be increased over the 
first 5 weeks up to 400 µg/kg/day or to the maximum tolerated dose. This escalation 
regimen is supported by the safety profile observed in completed and ongoing clinical 
studies of LUM001 and allows for subjects to reach 400 µg/kg/day or a maximum 
tolerated dose within a 5-week period. The dose may be down-titrated, at the 
investigator’s discretion and in consultation with the sponsor medical monitor, for 


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subjects experiencing intolerance to a given dose. 
Change in Section 5.5: 
Subjects who complete 48 weeks of treatment may be eligible to receive treatment for up 
to 52 weeks during the optional follow-up treatment period (see Figure 3 and Figure 4). 
Study activities will be conducted as described in the Schedule of Procedures 
(Section 16.1).  
Figure 1: 
Study Design for LUM001-304 (Up to and Including Week 
52) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2:  
Follow-up Treatment Scheme (No Interruption in LUM001 
Dosing or Interruption <7 days) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 3: 
Follow-up Treatment Scheme (Interruption in LUM001 
Dosing ≥7 Days) 
 
Synopsis 
(Section 1), 
Study Schedule 
(Section 8.1) 
Week 48/Study Termination: Subjects will be evaluated by the investigator to determine 
whether they are eligible to roll over into the optional 52-week follow-up treatment 
period. Eligible subjects must have documented consents in order to continue in the 
optional follow-up treatment period. 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, other cholestasis biochemical markers, and possibly LUM001 drug level 
analysis. Female subjects who are of childbearing potential will have a urine pregnancy test. 
The clinician scratch scale, xanthoma scale, and PedsQL questionnaires will be completed. The 
Patient Impression of Change, the Caregiver Impression of Change, and the Caregiver Global 
Therapeutic Benefit assessments will be completed. Concomitant medications and adverse 
events will be recorded. ItchRO and study drug compliance will be assessed and all remaining 
study drug and study supplies will be collected. eDiaries will be returned to the site and 
study drug will be discontinued at this visit and eDiaries will be returned to the site if the 
subject chooses not to participate in the optional follow-up treatment period.  
Subjects who withdraw from the study prior to completion of all treatment period clinic visits 
should undergo the procedures specified for the Week 48/Study Termination visit 
(Section 16.1). 
Follow-up Phone Call Period: For subjects who do not roll over into the optional follow-up 
treatment period, a safety follow-up phone call will be made 4 weeks after the last dose of 
study drug. This call will be made for all subjects who complete the study, as well as any 
subject who terminates from the study early. Concomitant medications and adverse events 
noted during this phone call will be recorded.  
Follow-up Treatment Period (post-Week 48 to Week 100): Subjects who are eligible to 
roll over onto the follow-up treatment period will continue to receive study drug at the 
dose they were receiving at Week 48 for up to 52 weeks of additional treatment  or in the 


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Description of Change 
event that a new study opens to enrollment, whatever occurs first. 
 
Subjects who are eligible to roll over into the follow-up treatment period with no LUM001 
dosing interruption or an interruption of <7 days will be maintained at the same dose 
level. Telephone contacts to occur at Week 52 and Week 56. During the follow-up treatment 
period, subjects will return to the clinic at Weeks 60, 72, 84, 96, and 100; and telephone 
contacts to occur at Weeks 64, 68, 76, 80, 88, and 92. 
Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 
400 µg/kg/day or to the highest tolerated dose with 35 µg/kg/day. This escalation regimen 
is supported by the safety profile observed in completed and ongoing clinical trials of 
LUM001 and allows for subjects to reach 400 µg/kg/day or highest tolerated dose within a 
5-week period. The dose escalation (DE) period will proceed as follows: 
• Week DE-2 Clinic Visit: obtain consent, weight, and draw blood for laboratory 
analyses.  
• Week DE 0 Clinic Visit: PI evaluates laboratory results, study drug is dispensed, and 
subject begins at 35 µg/kg/day dose level (if no safety concerns). 
• Week DE 49 Telephone Contact: subject escalates to 70 µg/kg/day dose level.  
• Week DE 50 Telephone Contact: subject escalates to 140 µg/kg/day dose level if prior 
dose level was tolerated. 
• Week DE 51 Telephone Contact: subject escalates to 280 µg/kg/day dose level if prior 
dose level was tolerated. 
• Week DE 52 Clinic Visit: laboratory tests and dose escalates to 400 µg/kg/day dose 
(maximum daily dose of 20 mg), if prior dose level was tolerated. 
If any subject experiences intolerance , the investigator, in consultation with the sponsor 
medical monitor, may lower the dose to a previously tolerated dose at any time during the 
entire follow-up treatment period. At the investigator’s discretion, and in consultation 
with the sponsor medical monitor subjects who were previously down titrated may be 
rechallenged during the follow-up treatment period. 
Safety and clinical laboratory evaluations and a physical exam (including collection of 
vital signs, height and weight measurements) will be completed at each clinic visit. In 
addition, the clinician scratch scale, clinician xanthoma scale, and PedsQL will be 
administered and study drug compliance will be assessed (PedsQL will not be performed 
at DE-2 or DE52). The Patient and Caregiver Impression of Change (PIC & CIC), and 
the Caregiver Global Therapeutic Benefit assessments will be completed at Weeks 84, 96, 
and 100. Subjects/caregivers will receive follow-up phone calls at Weeks 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 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. 
Electronic diaries will be provided to subjects and caregivers at these visits and 
re-training on the use of the diary will occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications used 
for the treatment of pruritus may occur during the long-term exposure period.  
With the exception of the Week 96 and Week 100 visit (Study Termination), additional 
study drug will be supplied at each clinic visit during the follow-up treatment period. 
Used and unused study drug will be collected at every visit.  


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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 safety and clinical laboratory evaluations, including determination of serum bile acids, 
other cholestasis biochemical markers, fat soluble vitamins, and plasma drug level. In addition 
the following assessments should be completed: the ItchRO (Pt and Obs), the clinician scratch 
scale, clinician xanthoma scale, the PedsQL, the Patient Impression of Change, the Caregiver 
Impression of Change, and the Caregiver Global Therapeutic Benefit assessments, as defined 
for ET (see Schedule of Procedures, Section 16.1) Efforts must be made to follow subjects for 
at least 4 weeks following their last dose of study drug.  
At completion of the Follow-up Treatment Period: a safety follow-up phone call will be 
made 4 weeks after the last dose of study drug (Week 100). This call will be made for all 
subjects who complete the study, as well as any subject who terminates from the study 
early. Concomitant medications and adverse events noted during this phone call will be 
recorded. 
Synopsis 
(Section 1), 
Pruritus and 
Quality of Life 
Assessments 
(Section 8.5), 
Efficacy 
Variables 
(Section 
12.2.5.1) 
From the synopsis: 
Evaluations for the durability of the therapeutic effect will be the mean change from Baseline 
(Day 0) to Week 18, prior to randomization, and  the change from Week 18 to Week 48 in: 
• Biochemical markers of cholestasis and liver disease [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), caregiver 
instrument/ItchRO(Pt) patient instrument). 
 
The change from Baseline (Day 0) to Week 48 in xanthomas, as measured by clinician 
xanthoma scale will also be evaluated. 
Additional assessments of efficacy variables will occur during the 52-week optional 
treatment period. For subjects entering the 52-week optional treatment period with ≥7 
days since last dose of LUM001, any of the above evaluations may also occur at clinic 
visits during the DE period. 
Additional exploration of evaluations of safety and the durability of the therapeutic effect will 
be specified in the statistical analysis plan. 
Section 8.5: 
8.5 
Pruritus and Quality of Life Assessments 
8.5.1 
Itch Reported Outcome (ItchRO™) 
ALGS subjects/caregivers will be required to submit twice daily assessments using the 
electronic diary for the duration of the study. Electronic diaries will be returned to the study site 
at the Week 48 clinic visit (or sooner if the subject has withdrawn from the study before the 
Week 48 visit). For subjects who enter the optional follow-up treatment period, daily 
completion of the diary will also occur during the 2 weeks following the Week 60, 72, 84, 
and 96 clinic visits. 
8.5.2 
Clinician Scratch Scale 
A clinician’s assessment of pruritus made by the principal investigator or appropriate designee 
using the clinician scratch scale (Section 16.5) will be recorded at screening, Day 0 (baseline), 
Weeks 3, 6, 12, 18, 22, 28, 38, and 48. For subjects who enter the optional follow-up 
treatment period the clinician scratch scale will be recorded at Weeks 60, 72, 84, 96, and 
100. For subjects with interruptions in LUM001 dosing of ≥7 days, assessments will also 


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be conducted during the DE period at DE -2, DE Day 0, and DE 52.  
8.5.3 
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 16.6). This assessment will be 
completed at Baseline (Day 0) and at Weeks 18, and 48. For subjects who enter the optional 
follow-up treatment period the clinician xanthoma scale will be recorded at 60, 72, 84, 96, 
and 100. For subjects with interruptions in LUM001 dosing of ≥7 days, assessments will 
also be conducted during the DE period at DE Day 0, and DE 52.  
8.5.4 
Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL™ is a questionnaire that will be administered to subjects and/or caregivers at the 
Week 0 (baseline), 18, 22, and 48. For subjects who enter the optional follow-up treatment 
period, the PedsQL will be administered at Weeks 60, 72, 84, 96, and 100 using the age-
appropriate PedsQL module (see Section 16.7). For subjects with interruptions in LUM001 
dosing of ≥7 days, the PedsQL will also be administered at DE Day 0. The PedsQL is a 
validated, modular instrument designed to measure health-related quality of life (HRQoL) in 
children and adolescents (Varni, Seid, & Kurtin, 2001). In addition to the core generic 
PedsQL module, the multidimensional fatigue and family impact questionnaire will also 
be administered at the Week 0 (baseline), 18, 22, and Week 48 using the age-appropriate 
module (see Section 16.7). Age at baseline will be used as the age for the determination of 
the appropriate module to be used for the study and this same module will be used for the 
duration of the study (regardless of subsequent birthdays after the baseline visit). 
8.5.5 
Patient Impression of Change 
The Patient Impression of Change (PIC) is designed to assess the subject’s perception of his/her 
itching after various points of study drug treatment compared to his/her itching prior to the start 
of treatment with study drug. The PIC will be completed, by subjects who were 9 years of age 
or older at the Week 18, 22, and 48 visits. For subjects who enter the optional follow-up 
treatment period, the PIC will be completed by subjects who were 9 years of age or older 
at the Week 60, 72, 84, 96, and 100 visits (see Section 16.8).  
8.5.6 
Caregiver Impression of Change 
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s perception of 
the subject’s itch related symptoms and xanthoma severity after various points of study drug 
treatment compared to his/her itch related symptoms and xanthoma severity prior to the start of 
treatment with study drug. The CIC will be completed by all caregivers at the Week 18, 22, and 
48 visits. For subjects who enter the optional follow-up treatment period the CIC will be 
completed at Week 84, 96, and 100 visits (see Section 16.9).  
8.5.7 
Caregiver Global Therapeutic Benefit 
The Caregiver Global Therapeutic Benefit (CGTB) questionnaire is designed to assess the 
caregiver’s perception of the treatment benefits on the subject’s itching compared to the side 
effects experienced with study drug. The CGTB will be completed by all caregivers at the 
Week 18, 22, and 48 visits. For subjects who enter the optional follow-up treatment period 
the CGTB will be completed at Week 84, 96, and 100 visits (see Section 16.10). 
Section 12.2.5.1: 
The following additional efficacy evaluations will be assessed: 
Change from baseline to Weeks 18, 22, 48, 60, 72, 84, 96, and 100 in: 
o 
Fasting serum bile acid levels. 


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o 
Liver enzymes (ALT, ALP) and bilirubin (total and direct). 
o 
Pruritus as measured by the average daily ItchRO (Observer ItchRO/patient ItchRO). 
o 
Other biochemical markers of cholestasis [total cholesterol, low-density lipoprotein 
cholesterol (LDL-C)]. 
o 
Bile acid synthesis [serum 7α-hydroxy-4-cholesten-3-one (7αC4)]. 
Responder analysis at Weeks 18, 48, 60, 72, 84, 96, and 100 in:  
o 
Pruritus response rates as measured by ItchRO (Observer ItchRO/patient ItchRO) 
o 
Clinician scratch scale 
Change from baseline for PedsQL at Week 18, 22, 48, 60, 72, 84, 96, and 100 and change from 
Week 18 to Week 22. 
o 
Patient Impression of Change (PIC) at Week 18, 22, 48, 84, 96, and 100 and change 
from Week 18 to Week 22. 
o 
Caregiver Impression of Change (CIC) at Week 18, 22, 48, 84, 96, and 100 and 
change from Week 18 to Week 22. 
o 
Caregiver Global Therapeutic Benefit (CGTB) assessment at Weeks 18, 22, 48, 84, 
96, and 100 and change from Week 18 to Week 22. 
Evaluations for the durability of the therapeutic effect will be the mean change from Baseline 
(Day 0) to Week 18, prior to randomization, and the change from Week 18 to Week 48 and 
Week 18 to Week 100 in: 
• 
Biochemical markers of cholestasis and liver disease [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), 
caregiver instrument/ItchRO(Pt) patient instrument). 
 
The change from Baseline (Day 0) to Week 48 and to Week 100 in xanthomas, as measured by 
clinician xanthoma scale will also be evaluated. 
For subjects entering the 52-week optional treatment period with ≥7 days since last dose 
of LUM001, any of the above evaluations may also occur at clinic visits during the DE 
period. Additional exploration of evaluations of durability of therapeutic effect will be 
specified in the statistical analysis plan. 
Dose 
Escalation 
Period 
(Section 5.5.2.1
) 
The anticipated adverse reaction or intolerance is gastrointestinal in nature (e.g., diarrhea, 
abdominal pain, cramping, etc.). In the absence of intolerance as determined by the physician 
investigator, escalation to the next dose level for an individual subject will occur following a 
scheduled phone call or visit (see Schedule of Procedures, Section 16.1). 
If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, abdominal 
pain, cramping) at any time during the study, the physician investigator in consultation with 
the sponsor medical monitor may lower the dose to a previously tolerated dose. In these 
circumstances an unscheduled visit will occur and the appropriate replacement study 
medication will be issued to the subject as quickly as possible. 
Genetic 
Testing 
(Section 8.2)  
and List of 
Laboratory 
Analytes 
JAGGED1 and NOTCH2 mutations can be predictive of ALGS. For ALGS subjects who meet 
clinical diagnostic criteria for ALGS (see Section 16.3) but do not have documentation of a 
JAGGED1 or NOTCH2 mutation, the clinical diagnosis of ALGS may be confirmed by 
genotyping. Genetic counseling, as appropriate, will be provided to subjects and their legal 
caregivers. Subjects for whom prior genotyping was performed may need to have an 
optional repeat analysis performed if the original information collected at screening was 


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(Appendix 
16.2) 
insufficient for complete documentation of the diagnosis of ALGS including the type of 
mutation recorded. For those participants for which the type of the mutation cannot be 
documented, genetic testing may be conducted and the results recorded. 
Study Drug 
Description 
(Section 9.1) 
Table 1: 
Composition of LUM001 1.0 mL Oral Solution  
Component 
Quantity per 1.0 mL 
LUM001 
0.02 0.05 to 20 mg 
Propylene Glycol 
250 mg 
Sucralose 
7.5 mg 
Grape Flavoring Agent 
5 mg 
Water 
q.s. to 1.0 mL 
 
Table 2: 
Composition of LUM001 0.5 mL Oral Solution 
Component 
Quantity per 0.5 mL 
LUM001 
0.02 0.05 to 20 mg 
Propylene Glycol 
125 mg 
Sucralose 
3.75 mg 
Grape Flavoring Agent 
2.5 mg 
Water 
q.s. to 0.5 mL 
Monitoring and 
Recording 
Adverse Events 
(Section 11.3) 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of 
the study (i.e., before informed consent) should be recorded as Medical History and not 
recorded as AEs unless the pre-existing condition worsened. Symptoms of the disease under 
study should not be classed as AEs as long as they are within the normal day-to-day 
fluctuation or expected progression of the disease and are part of the efficacy data to be 
collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. The investigator should always group signs and symptoms into a single 
term that constitutes a single unifying diagnosis if possible. 
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/assent form and stop at the end of the 
subject’s follow-up period which is defined as Week 52 for subject who do not roll over into 
the optional treatment follow-up period, Week 52 100 for subjects who do roll over into 
the optional treatment follow-up period, or 28 days after the last dose of study drug for those 
subjects that terminate the prior to the Week 48 100 visit.  
11.3.2 Non-serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed consent/assent 
form and will stop at the end of the subject’s follow-up period, which is defined as Week 52 
for subjects who do not roll over into the optional treatment follow-up period, Week 100 
for subjects who do roll over into the optional treatment follow-up period, or 30 days 
after the last dose of study drug for those subjects that terminate prior to the Week 100 
visit. The investigator will monitor each subject closely and record all observed or volunteered 


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AEs on the Adverse Event Case Report Form.  
Subject 
Disposition 
(Section 
12.2.4.1) 
Subject disposition will be summarized descriptively. The number and percentage of subjects 
enrolled, completed, and withdrawing, along with reasons for withdrawal, will be tabulated 
overall, and by study phase and treatment group. For purposes of analysis there will be 3 study 
phases: Dose escalation/stable dose (Weeks 0-18), Randomized Withdrawal (Weeks 19-22) and 
Long-Term Exposure (Weeks 23-48 and 23-100).  
Laboratory 
Tests (Section 
12.2.8.2) 
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, where normal ranges for 
this population are outlined in the SAP. Changes within a treatment group for selected safety 
measures will be assessed at Weeks 3, 6, 12, 18, 22, 28, 38, 48, 60, 72, 84, 96, and final study 
evaluation visit using methods to be specified in the SAP prior to unblinding the data. 
Schedule of 
Procedures 
(Section 16.1) 
Added to Screening – Week 22 (footnote): 
Optional genotype sample will be performed to provide a full characterization and the 
associated documentation of the mutation in support of the diagnosis of ALGS. 
Schedule of Procedures (cont’d) – Long-term Exposure: Week 23–Week 48: “Study 
Termination” removed. 
Schedule of Procedures – Follow-up Treatment Period (FTP) for Those Subjects <7 Days from 
the Last Dose of LUM001 and Schedule of Procedures – Follow-up Treatment Period for 
Those Subjects ≥ 7 Days from the Last Dose of LUM001added. 
List of 
Laboratory 
Analytes 
(Section 16.2) 
NOTCH2 added. 
Overall change 
Throughout the protocol, reference evaluating durability of effect of LUM001 was removed. 
Durability of effect may not be assessed in this study, as a treatment effect has not yet been 
established, and the randomized withdrawal design is not statistically powered. 
 


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16.13.4 Protocol Amendment 2 Summary of Changes 
 
Protocol Number: 
LUM001-304 
 
Protocol Title: 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED DRUG WITHDRAWAL 
PERIOD OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN PATIENTS WITH 
ALAGILLE SYNDROME 
 
Amendment: 
2 
 
Date: 
08 May 2015 
 
The changes below have been made to Protocol Amendment 1. 
The following table provides a summary list of changes to Protocol Amendment 2: 
Section 
Description of Change 
Study Synopsis and Section 7 
Exclusion criteria added: 
18. Subjects weighing over 50 kg at screening. 
Study Synopsis 
“…26-week open label period…” changed to “…enter a 
26-week long-term stable dosing period…” 
Study Synopsis, Section 4.5 
“equivalent to approximately 30 mg daily dose in a 70 kg 
adult” changed to “equivalent to approximately 20 mg 
daily dose in a 50 kg subject” 
Study Synopsis; Sections 5.5.2.1, 5.5.2.4, and 8.1.5 
Maximum daily dose changed from 30 mg/day to 
20 mg/day. 
Study Synopsis, Section 8.1.3, Table 6 and Table 7 
Time of usage of placebo corrected to the following: 
“Study drug (or placebo) will be supplied at Weeks 12 and 
study drug (or placebo) supplied at Week 18.” 
changed to: 
“Study drug will be supplied at Week 12 and study drug 
(or placebo) supplied at Week 18.” 
Study Synopsis and Sections 6.2, 12.2.2, and 
12.2.5.1  
Responder definition corrected from Week 18 to Week 12: 
…serum bile acid levels from baseline to Week 12 
… serum bile acids ≥50% at the Week 12 measurement 
Study Synopsis; Section 8.1.3; Section 16.1: 
Schedule of Procedures – Screening – Week 22, 
Footnote d;  
Section 16.1: Schedule of Procedures – Long-Term 
Exposure: Week 23 – Week 48 / Study Termination, 
Footnote c 
“2 to 4 hours post-dosing” changed to “approximately 
4 hours post-dosing” 
Study Synopsis, Section 12.2.3 
Language added to address the randomization and 
statistical management of data generated from siblings 


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enrolled in the study: 
 
Siblings 
The enrollment of siblings is allowed. During the placebo-
controlled, randomized drug withdrawal period, siblings 
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 LUM001-304 study is unblinded. Details of the 
analysis methods will be outlined in the SAP. 
Section 5.5.3, Section 8.1.8 
Language added to describe a planned extension study: 
Subjects who complete the study may be eligible for 
participation in an extension study of LUM001. 
Section 6.2 
Language added to address the randomization of siblings 
enrolled in the study: 
During the placebo-controlled, randomized drug 
withdrawal period, siblings will be assigned in a blinded 
manner to the same treatment arm. 
Section 6.4, Section 12.2.4.1 
Randomized withdrawal period corrected from “Weeks 18-
22” to “Weeks 19-22” 
Section 8.5.4 
“Age at screening…” changed to “Age at baseline…” 
“…birthdays after the screening visit” changed to 
“…birthdays after the baseline visit” 
Section 10.1 
“…at least 8 weeks” changed to”…at least 12 months” 
Sections 10.5.2.4, Section 16.2 
“tocopherol [(α)], total lipids” changed to “tocopherol [α]” 
Total lipids removed from 16.2 table. 
Section 16.1, Schedule of Procedures – Long-Term 
Exposure: Week 25 – Week 48 / Study Termination 
Header changed to: 
… Long-Term Exposure: Week 23 – Week 48 
Section 16.1, Schedule of Procedures – Long-Term  
Exposure: Week 23 – Week 48 / Study Termination 
Study days corrected to: 
161, 168, 175, 182, 189, 196, 231, 266, 301 
 


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16.13.5 Protocol Amendment 1 Summary of Changes 
 
Protocol Number: 
LUM001-304 
 
Protocol Title: 
LONG-TERM, OPEN-LABEL STUDY WITH A DOUBLE-BLIND, 
PLACEBO-CONTROLLED, RANDOMIZED DRUG WITHDRAWAL 
PERIOD OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTi), IN PATIENTS WITH 
ALAGILLE SYNDROME 
 
Amendment: 
1 
 
Date: 
06 Mar 2015 
 
The changes below were made to the original protocol. 
The following table provides a summary list of changes that were included in Protocol 
Amendment 1: 
Section 
Description of Change 
Exclusion Criteria (Section 1, Synopsis and Section 
7, Subject Eligibility) 
 
 
Additional exclusion criteria were added: 
• 
History or presence of gallstones or kidney stones. 
• 
Known hypersensitivity to LUM001 or any of its 
components. 
 
 
 

SAP_001.pdf: 
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|    AD-PR-109.01 Effective date: 26 Jun 2017
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   Statistical Analysis Plan 
Sponsor
Mirum Pharmaceuticals, Inc.
Protocol Title:
Long-Term, Open-Label Study with a Double-Blind, Placebo-
Controlled, Randomized Drug Withdrawal Period of LUM001, an 
Apical Sodium-Dependent Bile Acid Transporter Inhibitor 
(ASBTi), in Patients with Alagille Syndrome
Protocol Number:
LUM001-304
Premier Research PCN:
LUME3296
Document Version:
FINAL Version 1.0
Document Date: 
17 Mar 2020
Approvals
Role
Signatures
Date
Biostatistician
Print Name: Jana Steinmetz
Sign Name:
Mirum
Pharmaceuticals, 
Inc. Representative
Print Name: Thomas Jaecklin, MD
Sign Name:
	

	


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 2 of 128
Table of Contents
Approvals........................................................................................................................................ 1 
Table of Contents............................................................................................................................ 2 
List of Tables .................................................................................................................................. 5 
1. 
OVERVIEW ....................................................................................................................... 6 
2. 
STUDY OBJECTIVES AND ENDPOINTS...................................................................... 7 
2.1. 
Study Objectives ........................................................................................................... 7 
2.2. 
Study Endpoints............................................................................................................ 8 
2.2.1. Safety Endpoints........................................................................................................... 8 
2.2.2. Efficacy Endpoints........................................................................................................ 9 
2.2.3. Other Endpoints .......................................................................................................... 19 
3. 
OVERALL STUDY DESIGN AND PLAN..................................................................... 20 
3.1. 
Overall Design ............................................................................................................ 20 
3.2. 
Sample Size and Power............................................................................................... 21 
3.3. 
Study Population......................................................................................................... 21 
3.4. 
Treatments Administered............................................................................................ 21 
3.4.1. Dose Escalation Period ............................................................................................... 21 
3.4.2. Stable Dosing Period................................................................................................... 22 
3.4.3. Double-Blind Placebo-Controlled Study Drug Withdrawal Period............................ 22 
3.4.4. Long-Term Exposure Period....................................................................................... 22 
3.4.5. 52-Week Optional Follow-up Treatment Period ........................................................ 23 
3.4.6. Long-Term Optional Follow-up Treatment Period..................................................... 24 
3.5. 
Method of Assigning Subjects to Treatment Groups.................................................. 26 
3.6. 
Blinding and Unblinding............................................................................................. 26 
3.7. 
Schedule of Procedures............................................................................................... 28 
3.7.1. Schedule of Procedures A-D: Study Entry – Week 96............................................... 29 
3.7.2. Schedule of Procedures E-F: Rollover under Protocol Amendment 4 ....................... 37 
3.7.3. Schedule of Procedures G-I: Subject Re-Entry under Protocol Amendment 4.......... 42 
3.7.4. Schedule of Procedures J: Study Termination and End of Treatment Procedures ..... 49 
4. 
STATISTICAL ANALYSIS AND REPORTING ........................................................... 51 
4.1. 
Introduction................................................................................................................. 51 
4.2. 
Interim Analysis.......................................................................................................... 52 
4.3. 
Data Monitoring.......................................................................................................... 52 
5. 
ANALYSIS POPULATIONS .......................................................................................... 53 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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6. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS.................................................. 54 
6.1. 
Statistical Definitions and Algorithms........................................................................ 54 
6.1.1. Baseline....................................................................................................................... 54 
6.1.2. Study Day.................................................................................................................... 55 
6.1.3. Adjustments for Covariates......................................................................................... 55 
6.1.4. Multiple Comparisons................................................................................................. 55 
6.1.5. Handling of Dropouts or Missing Data....................................................................... 56 
6.1.6. Investigative Sites....................................................................................................... 59 
6.1.7. Analysis Visit Windows ............................................................................................. 59 
6.1.8. Variable Definitions.................................................................................................... 63 
6.1.9. Derived Variables ....................................................................................................... 63 
6.1.10. Data Adjustments/Handling/Conventions .................................................................. 70 
7. 
STUDY SUBJECTS AND DEMOGRAPHICS............................................................... 74 
7.1. 
Disposition of Subjects and Withdrawals................................................................... 74 
7.2. 
Protocol Violations and Deviations ............................................................................ 75 
7.3. 
Demographics and Other Baseline Characteristics..................................................... 75 
7.4. 
Disease History and Baseline Disease Characteristics ............................................... 76 
7.5. 
Prior Medications........................................................................................................ 77 
7.6. 
Treatment Compliance................................................................................................ 77 
8. 
EFFICACY ANALYSIS .................................................................................................. 77 
8.1. 
Primary Efficacy Analysis.......................................................................................... 78 
8.2. 
Secondary, Exploratory and Other Efficacy Analyses ............................................... 78 
8.2.1. Continuous Measures.................................................................................................. 79 
8.2.2. Categorical Measures.................................................................................................. 84 
9. 
SAFETY AND TOLERABILITY ANALYSIS ............................................................... 85 
9.1. 
Treatment Exposure.................................................................................................... 86 
9.2. 
Adverse Events ........................................................................................................... 86 
9.2.1. Adverse Events Leading to Withdrawal ..................................................................... 88 
9.2.2. Deaths and Serious Adverse Events ........................................................................... 88 
9.2.3. Adverse Events of Special Interest ............................................................................. 88 
9.3. 
Safety Laboratory Evaluations.................................................................................... 88 
9.4. 
Physical Examination.................................................................................................. 90 
9.5. 
Vital Signs................................................................................................................... 90 
9.6. 
Concomitant Medication............................................................................................. 90 


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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9.7. 
Safety Data Graphical Presentations........................................................................... 90 
10. 
OTHER ANALYSES ....................................................................................................... 91 
10.1. Palatability Analysis ................................................................................................... 91 
10.2. Pharmacokinetic Analysis........................................................................................... 91 
10.3. Genotyping Characteristics......................................................................................... 91 
11. 
CHANGES FROM PLANNED ANALYSIS................................................................... 91 
12. 
REFERENCES ................................................................................................................. 93 
13. 
TABLES, LISTINGS, AND FIGURES ........................................................................... 94 
13.1. Planned Table Descriptions ........................................................................................ 94 
13.1.1. Disposition, Demographic, Disease History, Prior Medications, and Study Drug 
Compliance Summary Tables..................................................................................... 94 
13.1.2. Efficacy Data Summary Tables .................................................................................. 95 
13.1.3. Safety Data Tables .................................................................................................... 107 
13.1.4. Other Data Summary Tables..................................................................................... 112 
13.2. Planned Listing Descriptions.................................................................................... 113 
13.3. Planned Figure Descriptions..................................................................................... 117 
13.3.1. Efficacy Figures........................................................................................................ 117 
13.3.2. Study Drug Exposure Figure .................................................................................... 118 
13.3.3. Adverse Event Figures.............................................................................................. 118 
14. 
TABLES, LISTINGS, AND LISTING SHELLS........................................................... 120 
14.1. Standard Layout for all Tables, Listings, and Figures.............................................. 120 
Appendix 1 
Premier Research Library of Abbreviations ....................................................... 121 
Appendix 2 
Listing of Safety and Efficacy Laboratory Analytes .......................................... 125 
Appendix 3 
Listing Fat Soluble Vitamin Deficiency Events ................................................. 126 


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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List of Tables
Table 1 
Secondary Efficacy Endpoints.................................................................................... 10 
Table 2 
Analysis of Continuous Efficacy Endpoints (including Sensitivity) .......................... 11 
Table 3 
Categorical Analyses of Efficacy Endpoints (including Sensitivity) ......................... 14 
Table 4 
Analysis Visit Windows – Efficacy and Primary Safety Analysis............................. 61 
Table 5 
Analysis Visit Windows – Supporting Safety Subgroup Analysis (Data Assessed after 
an Extended Drug Interruption)............................................................................................ 62 
Table 6 
Disposition, Demographic, Disease History, Prior Medications, and Study Drug 
Compliance Summary Tables............................................................................................... 94 
Table 7 
Efficacy Data Summary Tables .................................................................................. 95 
Table 8 
Safety Data Summary Tables.................................................................................... 107 
Table 9 
Other Data Summary Tables..................................................................................... 112 
Table 10 Planned Subject Listings........................................................................................... 113 
Table 11 Planned Figures......................................................................................................... 119 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
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1.
OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Mirum
Pharmaceuticals Inc. (Mirum) protocol LUM001-304, Long-Term, Open-Label Study with a 
Double-Blind, Placebo-Controlled, Randomized Drug Withdrawal Period of LUM001, an Apical 
Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in Patients with Alagille 
Syndrome, dated 08 Feb2019 (Amendment 5.1).
The original LUM001-304 protocol, dated 20 Mar 2014, planned for a 48-week treatment period. 
This treatment period included 4 parts: a 6-week open-label (OL) dose escalation period at doses 
up to 400 μg/kg/day; a 12 week OL stable dosing period; a 4-week randomized, double-blind, 
placebo-controlled drug withdrawal period; and a 26-week long-term stable dosing period at 
doses up to 400 μg/kg/day.
There have been 6 protocol amendments to date. The summary list of changes to each of the 
protocol amendments are described in the final amendment, Protocol Amendment 5.1. Several of 
the protocol amendments included optional long-term treatment extensions and one of the later 
amendments added a twice-a-day (BID) dosing regimen. 
Protocol Amendment 3, dated 13 Nov 2015, provided for an optional 52-week treatment period. 
At Week 48, all subjects were to be assessed by the investigator to determine the subject’s 
willingness and eligibility to roll over into the 52-week, follow-up treatment period. 
Protocol Amendment 4, dated 28 Mar 2017, allowed continued participation in the long-term 
optional follow-up treatment period, beyond what was previously described in Protocol 
Amendment 3. During this long-term optional follow-up treatment period, subjects may have 
their dose of LUM001 increased to a maximum of 800 μg/kg/day (400 μg/kg BID) based on 
efficacy and safety assessments. Study treatment in the long-term optional follow-up treatment 
period was to continue until the first of the following occurred: (i) the subjects are eligible to 
enter another LUM001 study, (ii) LUM001 is available commercially, or (iii) Mirum
Pharmaceuticals stops the program or development in the indication of Alagille syndrome
(ALGS).
Protocol Amendment 5, dated 06 Nov 2017, primarily changed the study design going forward to 
an open-label study. 
The final protocol amendment, Amendment 5.1, amended Protocol Amendment 5 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 enrollment of siblings was allowed, however, no siblings enrolled in the study. Thus, the
analysis plan does not address the handling of siblings.
A subject may have been off study drug for an extended period of time during the course of their 
study treatment. The reasons for being off study drug include drug interruption (e.g., as directed 
by an investigator due to an AE), study drug compliance issues (e.g., missed consecutive doses), 
and dosing gaps due to being off study between protocol amendments. For example, a subject


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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could complete study drug treatment through Week 48 under the original protocol before
implementation of Protocol Amendment 3 that extended treatment through Week 100. The 
subject could subsequently provide informed consent under the amendment and be re-initiated on 
study drug.
Subjects with a drug interruption of at least 7 days had their study drug dose re-escalated
beginning at 35 μg/kg/day. Subjects were escalated up to a maximum of 400 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.
2.
STUDY OBJECTIVES AND ENDPOINTS 
2.1.
Study Objectives 
The objectives of this study (up to and including Week 48) are:
x
To evaluate the long-term safety and tolerability of MRX in children with ALGS.
x
To evaluate the effect of MRX on serum bile acid levels in children with ALGS.
x
To evaluate the effect of MRX on biochemical markers of cholestasis and liver disease 
in children with ALGS.
x
To evaluate the effect of MRX on pruritus in children with ALGS.
x
To evaluate the long-term effect of MRX in children with ALGS during 48 weeks 
of treatment.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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The objectives of the long-term optional follow-up treatment period (after Week 48) are:
x
To offer eligible subjects treated in the LUM001-304 study continued study treatment at 
Week 48 until the first of the following occurs: (i) the subjects are eligible to enter 
another MRX study (ii) MRX is available commercially, or (iii) Mirum Pharmaceuticals
stops the program or development in this indication.
x
To explore twice a day (BID) dosing regimen and higher daily dosing of MRX.
x
To obtain safety and efficacy data in subjects treated long term on MRX
including genotyping characteristics.
x
To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma.
x
To assess palatability of the MRX formulation.
2.2.
Study Endpoints 
Safety and efficacy endpoints are examined for each of the 3 treatment phases:
x
Open-label (OL) Phase (Day 1 – Week 18), 
x
Randomized Withdrawal (RW) Phase (Weeks 19 - 22), and 
x
After Randomized Withdrawal (ARW) Phase (Week > 22).
Subjects who withdrew early during the OL Phase will not be included in the RW or ARW 
analyses. Similarly, subjects terminated during the OL or RW phases will not be included in the
ARW analyses.
For select analyses, the 3rd treatment phase will be presented as 2 separate treatment phases:
ARW (Week > 22 – Week 48) and ARW (Week > 48). Unless otherwise specified, summaries 
will be provided by treatment phase and treatment group/sequence.
2.2.1. Safety Endpoints 
The safety and tolerability endpoints for this study include the following:
x
Incidence of adverse events (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 baseline (Day 0) in clinical safety laboratory values at each clinic visit (if 
applicable).
x
Change from Week 18 in clinical safety laboratory values at Week 22 (if applicable).
x
Observed AFP values over time.
x
Change from baseline (Day 0) in physical examination findings and vital signs at each 
clinic visit.
x
Change from Week 18 in physical examination findings and vital signs at Week 22.
x
Concomitant medication usage.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Physical examination findings include body mass index (BMI). Vital signs include heart rate, 
respiratory rate, body temperature, and blood pressure.
Safety laboratory tests, and associated units of measure, that will be used for reporting are listed 
in Appendix 2. Note that bilirubin (total and direct), alanine phosphatase (ALP), and alanine 
aminotransferase (ALT) are considered as both safety and efficacy laboratory tests. For select fat 
soluble vitamins (FSVs), including 25-hydroxyvitamin D, 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 at baseline, Week 18, Week 22 (by treatment group), and Week 
48. For these FSVs, categories may include normal, sufficient, insufficient, possibly insufficient, 
indeterminate, and excess (see Section 6.1.9 for specific definitions).
Serum samples for AFP, a marker of hepatocellular carcinoma, are only drawn during the 
optional follow-up treatment period at every other 12-week repeating period clinic visit (i.e., 
every 6 months) and at the end-of-treatment (EOT)/early termination (ET) visit.
2.2.2. Efficacy Endpoints 
2.2.2.1.
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is the mean change from Week 18 to Week 22 of
fasting serum bile acid (sBA) levels in subjects who previously responded to MRX treatment, as 
defined by a reduction in sBA ≥50% from baseline to Week 12 or Week 18 (i.e., Modified 
Intent-to-Treat [MITT] Population).
2.2.2.2.
Secondary Endpoints
Secondary efficacy endpoints include mean change from Week 18 to Week 22 in liver enzymes 
(ALP, ALT, and bilirubin [total and direct]) and pruritus as measured by ItchRO Observer 
(ItchRO[Obs]) and ItchRO Patient (ItchRO[Pt]), in subjects who previously responded to MRX
treatment, as defined by a reduction in ItchRO scale ≥1 point from baseline to Week 12 or 
Week 18. The ItchRO(Obs) weekly average morning score is used in defining an ItchRO 
responder.
Secondary efficacy endpoints also include mean change from baseline to Week 18 in fasting 
serum bile acid levels, liver enzymes (ALP, ALT, and bilirubin [total and direct]) and pruritus as 
measured by ItchRO (Observer ItchRO/Patient ItchRO).
For secondary ItchRO variables, the weekly average severity score is used, where the daily score 
is defined as the higher of the scores from the morning and evening ItchRO score.
The secondary efficacy endpoints for this study are summarized in Table 1.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
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Table 1
Secondary Efficacy Endpoints
Efficacy
Parameter(s)
Variable(s)
Mean Change
From Week
To Week
ItchRO(Obs),
ItchRO(Pt)
Weekly average severity score (based on daily 
maximum of morning and evening scores) [1]
0
18
18
22
sBA
Laboratory test level
0
18
Liver enzymes
(ALP, ALT, total 
bilirubin, direct bilirubin)
Laboratory test level
0
18
18
22
[1] For change from Week 18 to Week 22, analysis is performed in subjects who previously responded to MRX treatment, as 
defined by a reduction in ItchRO(Obs) weekly average morning score ≥1 point from baseline to Week 12 or Week 18.
2.2.2.3.
Additional Efficacy Endpoints
The following additional efficacy evaluations will be assessed:
x
Change from baseline to Weeks 18, 22, 48 and then every 12 weeks in:
o
Fasting serum bile acid levels
o
Liver enzymes (ALT, ALP) and bilirubin (total and direct)
o
Pruritus as measured by the average daily ItchRO (ItchRO[Obs]/ItchRO[Pt])
o
Other biochemical markers of cholestasis (total cholesterol, low-density lipoprotein 
cholesterol [LDL-C])
o
Bile acid synthesis (serum 7α-hydroxy-4-cholesten-3-one [C4])
x
Responder analysis at Weeks 18, 48, 60, 72, 84, 96, and 100 in:
o
Pruritus response rates as measured by ItchRO (ItchRO[Obs]/ItchRO[Pt])
o
Clinician scratch scale
x
Change from baseline for PedsQL at Week 18, 22, 48, 60, 72, 84, 96, and 100 and change 
from Week 18 to Week 22
x
PIC at Week 18, 22, 48, 84, 96, and 100 and change from Week 18 to Week 22
x
CIC at Week 18, 22, 48, 84, 96, and 100 and change from Week 18 to Week 22
x
CGTB assessment at Weeks 18, 22, 48, 84, 96, and 100 and change from Week 18 to 
Week 22
x
Change from Baseline (Day 0) to Week 48 in xanthomas, as measured by Clinician 
Xanthoma Scale score


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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2.2.2.4.
Sensitivity Endpoints
The definition of the pruritus endpoint used to assess efficacy was not pre-specified in the 
LUM001-304 study protocol or the Week 48 Statistical Interim Analysis Plan (SIAP). Because 
there is no single primary pruritus endpoint or statistical analysis approach pre-specified for this 
study, the pruritus data should be robust to various endpoint definitions and analysis methods 
that are considered reasonable a priori. 
All efficacy endpoints for this study, including non-protocol defined pruritus endpoints based on 
ItchRO scores and other sensitivity endpoints (e.g., body height and weight z-scores), are
described in Table 2 and Table 3, for continuous and categorical endpoints, respectively. Note 
that data for subjects who early terminated from the study prior to Week 100 or are otherwise 
missing Week 18, Week 22, Week 48, and/or Week 100 data will be imputed in a 
last-observation-carried-forward (LOCF) sensitivity analysis approach (see Section 6.1.5.3).
Table 2
Analysis of Continuous Efficacy Endpoints (including Sensitivity)
Efficacy
Parameter(s)
Variable(s)
Mean Change
From
Week
To Week
ItchRO(Obs)
Weekly average morning severity 
score [1];
Weekly average evening severity 
score [1];
Weekly average morning
frequency score [1];
Weekly average evening
frequency score [1];
Weekly average severity score 
(based on daily maximum of 
morning and evening scores);
Weekly average severity score 
(based on daily average of 
morning and evening scores)
0
3, 6, 12, 18*, 18/LOCF, 19, 20, 21, 22, 
22/LOCF, 28, 38, 48, 48/LOCF, 62, 74, 86, 98, 
and 100/LOCF, and each 12-week repeating 
period (i.e., Week 120, 132, 144, 156, etc.)
18
19, 20, 21, 22*, 22/LOCF
4-Week average morning severity 
score [1];
4-Week average evening severity 
score [1];
4-Week average morning
frequency score [1];
4-Week average evening
frequency score [1]
0
6, 12, 18*, 18/LOCF, 22, 28, 38, 48, 48/LOCF
18
22*


Statistical Analysis Plan
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Protocol Number LUM001-304
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Efficacy
Parameter(s)
Variable(s)
Mean Change
From
Week
To Week
ItchRO(Pt)
Weekly average morning severity 
score [1];
Weekly average evening severity 
score [1];
Weekly average severity score 
(based on daily maximum of 
morning and evening scores)
Weekly average severity score 
(based on daily average of 
morning and evening scores)
0
3, 6, 12, 18*, 18/LOCF, 19, 20, 21, 22, 28, 38, 
48, 48/LOCF, 62, 74, 86, 98, 100/LOCF, and 
each 12-week repeating period
18
19, 20, 21, 22*
4-Week average morning severity 
score [1];
4-Week average evening severity 
score [1]
0
6, 12, 18*, 18/LOCF, 22, 28, 38, 48, 48/LOCF
18
22*
sBA
Laboratory test level
0
12, 18*, 18/LOCF, 22, 48, 48/LOCF, 60, 72, 
84, 96, 100/LOCF, BID Day 0, BID Week 4, 
BID Week 8, and each 12-week repeating 
period
18
22*
Liver enzymes
(ALP, ALT, total 
bilirubin, direct 
bilirubin)
Laboratory test level
0
3, 6, 12, 18*, 18/LOCF, 22, 28, 38, 48, 
48/LOCF, 60, 72, 84, 96, 100/LOCF, 
BID Day 0, BID Week 4, BID Week 8, and 
each 12-week repeating period
18
22*
Lipid panel and 
cholestasis biomarkers
(cholesterol, LDL-C, 
C4)
Laboratory test level
0
12, 18, 18/LOCF, 22, 48, 48/LOCF, 60, 72, 84, 
96, 100/LOCF, BID Day 0, BID Week 4, BID 
Week 8, and each 12-week repeating period
18
22
Clinician Scratch 
Score (CSS)
Score for CSS
0
3, 6, 12, 18, 18/LOCF, 22, 28, 38, 48, 
48/LOCF, 60, 72, 84, 96, 100/LOCF, BID Day 
0, BID Week 4, BID Week 8, and each 
12-week repeating period
18
22


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Version 1.0    |
Date: 17 Mar 2020
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Efficacy
Parameter(s)
Variable(s)
Mean Change
From
Week
To Week
Body Height
Body Weight
z-score
0
3, 6, 12, 18, 18/LOCF, 22, 28, 38, 48, 
48/LOCF, 60, 72, 84, 96, 100/LOCF, BID Day 
0, BID Week 4, BID Week 8, and each 
12-week repeating period
Clinician Xanthoma 
Scale
Score
0
18, 18/LOCF, 48, 48/LOCF, 60, 72, 84, 96, 
100/LOCF, BID Day 0, BID Week 4, 
BID Week 8, and each 12-week repeating 
period
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
18, 18/LOCF, 22, 48, 48/LOCF, 60, 72, 84, 96, 
100/LOCF, BID Day 0, BID Week 4, BID 
Week 8, and each 12-week repeating period
18
22
Caregiver Impression 
of Change – Itch 
Related Symptoms 
(CIC-Itch),
Caregiver Impression 
of Change –
Xanthoma Severity 
(CIC-Xan), 
Patient Impression of 
Change (PIC)
Caregiver Global 
Therapeutic Benefit 
(CGTB)
Score
--
Summary statistics at Week:
18, 18/LOCF, 22, 48, 48/LOCF, 84, 96, 
100/LOCF
18
22
* Indicates endpoint defined as primary, secondary, or exploratory; BID = twice-a-day dosing regimen
[1] Sensitivity pruritus endpoint not pre-defined in the study protocol. See Sections 2.2.2.5 and 6.1.9.


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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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
Responder Definitions:
Decrease from baseline score ≥ 1
Decrease from baseline score ≥ 2
Change from baseline (Day 0) at 
Week:
3, 6, 12, 18, 18/LOCF, 22, 28, 
38, 48, 48/LOCF, 60, 72, 84, 96,
100/LOCF, 156 (3 years), and 
204 (4 years)
Caregiver Impression of Change –
Itch Related Symptoms (CIC-Itch),
Caregiver Impression of Change –
Xanthoma Severity (CIC-Xan), 
Patient Impression of Change (PIC)
7-point scale:
1 = much better
2 = better
3 = a little better
4 = no change
5 = a little worse
6 = worse
7 = much worse
Responder: ≤ 3 score 
Number and % of Subjects at Week:
18, 18/LOCF, 22, 48, 48/LOCF, 84, 
96, 100/LOCF
Caregiver Global Therapeutic 
Benefit (CGTB)
5-point scale:
1 = definitely
2 = somewhat
3 = about the same
4 = maybe not
5 = definitely not
Responder: ≤ 2 score
Number and % of Subjects at Week:
18, 18/LOCF, 22, 48, 48/LOCF, 84, 
96, 100/LOCF


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Efficacy
Parameter(s)
Scale and Responder Criteria
or Variables
Endpoint
ItchRO(Obs),
ItchRO(Pt)
ItchRO(Obs) morning severity score
[1];
ItchRO(Pt) morning severity score
[1]
Number and % of Days Scores are 
≤1 Point During each of the 
following Time Periods:
Day 1 – Week 6,
Weeks > 6 - 12,
Weeks > 12 - 18,
Weeks > 18 - 22,
Weeks > 22 - 48,
Weeks > 48 - 108,
Weeks > 108 - 156 (> 2 - 3 years),
Weeks > 156 - 204 (> 3 - 4 years),
Weeks > 204 (> 4 years)
[1] Sensitivity pruritus endpoint not pre-defined in the study protocol. See Sections 2.2.2.5 and 6.1.9.for endpoint descriptions 
and derivations, respectively.
2.2.2.5.
Efficacy Parameter Descriptions
Itch Reported Outcome (ItchRO)
The primary efficacy assessment in this study is pruritus severity as measured by the itch
reported outcome measures (ItchRO) administered as a twice daily electronic diary (eDiary)
completed by caregivers (ItchRO[Obs]). Subjects 9 years of age or older independently complete 
the patient instrument: ItchRO(Pt). Subjects between 5 and 8 years of age, or where the 
investigator has expressed concern about the subject’s ability to reliably complete the data (e.g.,
due to developmental delay) complete the patient instrument with the assistance of their 
caregiver, if needed. There is no ItchRO(Pt) report for subjects under the age of 5 years.
Age at screening 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 be 
analyzed separately.
For the ItchRO instrument, the caregiver and/or subject indicate the itch severity (Item 1) in the 
morning and in the evening each day during the following periods:
x
Screening through first 48 weeks of the treatment period
x
2 consecutive weeks that follow the Week 60, Week 72, Week 84, and Week 96 
clinic visits
x
2 consecutive weeks that follow each recurring 12-week clinic visit during the
optional extension follow-up treatment period.


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
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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 following
10 ItchRO summary scores are calculated and used in the analysis of pruritus:
x
Weekly average morning severity score
x
Weekly average evening severity score
x
4-Week average morning severity score
x
4-Week average evening severity score
x
Weekly average morning frequency score (ItchRO[Obs] only)
x
Weekly average evening frequency score (ItchRO[Obs] only)
x
4-week average morning frequency score (ItchRO[Obs] only)
x
4-week average evening frequency score (ItchRO[Obs] only)
x
Weekly average severity score (based on daily average of morning and evening scores) 
(ItchRO[Obs] only)
x
Weekly average severity score (based on daily maximum of morning and evening scores) 
(ItchRO[Obs] only)
Weekly average scores for Baseline (Day 0) and Weeks 3, 6, 12, 18, 22, 28, 38, and 48 are 
calculated as the average of the daily scores over a defined study week consisting of the 7 days 
before the scheduled visit. Starting with Week 62 (i.e., Weeks 62, 74, 86, 98, and every three 
months thereafter), the previous study visit date plus 2 weeks is used as the anchor (e.g., the date 
for Week 62 is based on the Week 60 study visit date plus 2 weeks) in deriving weekly average 
scores. During the randomized withdrawal period, weekly average scores are also calculated at 
Weeks 19, 20, and 21, using the Week 22 scheduled visit date as the anchor. 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.
4-week average scores are calculated as the average of the evening/morning scores over a 
defined period consisting of the 28 days before the scheduled visit (i.e., Baseline [Day 0], Weeks 
6, 12, 18, 22, 28, 38, 48, 22, 28, 38, and 48). For the change from baseline calculation in 4-week 
average ItchRO scores, baseline is defined in Section 6.1.1. Post-baseline 4-week average 
ItchRO scores are only computed if at least 20 of the 28 daily ItchRO scores for the 28-day 
period are available.
In deriving weekly or 4-week (where applicable) average post-baseline ItchRO scores, each visit 
date will be determined based on the varying eDiary collection periods (as applicable): (A) Week 


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3, 6, 12, 18, 22, 28, 38, and 48, (B) Week 19, 20, and 21, (C) Week 62, 74, 86, 98, and, recurring 
12-week periods during the optional extension follow-up treatment period.
A. Week 3, 6, 12, 18, 22, 28, 38, and 48: The scheduled visit date is used.
B. Week 19, 20, and 21: The Week 22 scheduled visit date will be used as the anchor 
point, where: the Week 21 average score will be based on the 7-day period 
immediately before the Week 22 date; and the Week 19 and Week 20 average scores 
will be based on the 7-day periods immediately before the 7-day period used in
determining the previous week’s average score.
C. Week 62, 74, 86, 98, and recurring 12-week periods: Each scheduled visit date will be 
determined based on the date of the associated scheduled clinic visit (i.e., Week 60,
72, 84, and 96) plus 14 days.
In general, scheduled visit dates will be determined based on the date of the vital signs 
assessment. If the date of vital signs is missing, then the date of the physical examination will be 
used. If both of these dates are missing for a specific scheduled visit then the start date from the 
subject visits derived dataset will be used. Further, for missing but expected dates (where ItchRO 
data exists), the last visit past the missing date is used and the appropriate amount of days is 
subtracted.
Clinician Scratch Score
The CSS provides an assessment of itch severity. The clinician’s assessment of the subject’s 
pruritus is focused on scratching and visible damage to the skin as a result of scratching as 
observed by the physician. The clinician scratch 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 Score
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 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 – Itch Related Symptoms (CIC-Itch)
The CIC-Itch is designed to assess the caregiver’s perception of the subject’s itch-related 
symptoms after various points of study drug treatment compared to his/her itch-related 
symptoms 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 (see Table 3 for complete scale descriptions).


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Caregiver Impression of Change – Xanthoma Severity (CIC-Xan)
The CIC-Xan is designed to assess the caregiver’s perception of the subject’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 (see 
Table 3 for complete scale descriptions).
Patient Impression of Change (PIC)
The PIC is designed to assess the subject’s perception of his/her itching after various points of 
study drug treatment compared to his/her itching prior to the start of treatment with study drug. 
The PIC is completed by subjects who were 9 years of age or older at clinic visits as outlined in 
the Schedule of Procedures in Section 3.7. 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 (see Table 3 for complete scale descriptions).
Caregiver Global Therapeutic Benefit (CGTB)
The CGTB questionnaire is designed to assess the caregiver’s perception of the treatment 
benefits on the subject’s itching compared to the side effects experienced with study drug. The 
questionnaire is designed for self-administration and uses a 5-point scale in which 1 designates 
the best outcome and 5 designates the worst outcome (see Table 3 for complete scale 
descriptions).
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 
subjects and/or caregivers depending on age using age-appropriate PedsQL modules. The 
PedsQL consists of developmentally appropriate forms for infants/children ages 1 - 12 months, 
13 - 24 months, 2 - 4, 5 - 7, 8 - 12, and 13 - 18 years.
Pediatric self-report is measured in children and adolescents ages 5 - 18 years, and parent proxy-
report of child HRQoL is measured for children and adolescents ages 12 months to 18 years. 
In addition to the core generic PedsQL module, the multidimensional fatigue and family impact 
questionnaires are also administered using the age-appropriate module.
Age at baseline will be used as the age for the determination of the appropriate module to be 
used for the study, and this same module will be used for the duration of the study (regardless of 
subsequent birthdays after the baseline visit). 
With the exception of the 5 - 7 year age group (Young Child) subject report, each item of the 
PedsQL consists of a 5-level Likert-type item survey (0 - 4), where 0 = Never, 1 = Almost never, 
2 = Sometimes, 3 = Often, and 4 = Almost always. Items of the PedsQL Young Child subject 
report are scored on a 3-point scale, where 0 = Not at all, 2 = Sometimes, and 4 = A lot. 


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The PedsQL Generic Core Scale is composed of items to assess pediatric HRQoL measurements 
across 6 subscales: Physical Functioning, Physical Symptoms (only applicable for infants, 1 - 24
months), Emotional Functioning, Social Functioning, Cognitive Functioning [only applicable for 
infants, 1 - 24 months], and School Functioning (only applicable for children, 2 - 18 years). 
The Total Scale Score, Physical Health Summary Score and Psychosocial Health Summary 
Score are computed individually for both the parent and subject reports of the PedsQL Generic
Core Scale. The Total Scale Score is computed from all items. The Physical Health Summary 
Score is computed from the items of the Physical Functioning domain, and the Physical 
Symptoms domain (infants only). The Psychosocial Health Summary Score is computed from 
items of the Emotional, Social, and School Functioning domains, and the Cognitive Functioning 
domain (infants only).
The PedsQL Multidimensional Fatigue Scale is composed of items across 3 subscales: General 
Fatigue, Sleep/Rest Fatigue, and Mental Fatigue. Respondents use the scale to indicate how 
frequently certain fatigue-related symptoms and complaints trouble them. The Multidimensional 
Fatigue Scale Score is computed from all items of the PedsQL Multidimensional Fatigue Scale.
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 6.1.9.
2.2.3. Other Endpoints 
Other endpoints of this study include the following:
x
Palatability of the MRX formulation over time.
x
Plasma levels of MRX at baseline (pre-dose) and over time.
2.2.3.1.
Palatability
Palatability of the MRX formulation is assessed in all subjects, by caregiver-proxy in non-
collaborating subjects (generally subjects < 4 years of age) and by subject questionnaire in 
subjects > 8 years of age or caregiver and collaborating child if 4 to 8 years of age. Palatability 
assessments are obtained at each clinic visit in the optional follow-up treatment period, with the 
exception of the DE, PA4 DE, and ADE visits.


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2.2.3.2.
Pharmacokinetics
Due to poor absorption of MRX, 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 12, 18, 38, or 48, as selected by the 
site/investigator. Plasma samples will additionally be collected at the ADE-Day 0, ADE-Week 4,
and ADE-Week 8, and at the 3 scheduled clinic visits following completion of the ADE period.
2.2.3.3.
Genotyping Characteristics
All subjects enrolled to the LUM001-304 study have documented JAGGED-1 mutation.
3.
OVERALL STUDY DESIGN AND PLAN 
3.1.
Overall Design 
This is a long-term open-label study with a 4-week double-blind, placebo-controlled, randomized 
drug withdrawal period in children with ALGS designed to evaluate the safety and efficacy of 
MRX. The study is divided into 6 parts: 
•
6-week open-label, dose escalation period at doses up to 400 μg/kg/day
•
12-week open-label stable dosing period
•
4-week randomized, double-blind, placebo-controlled drug withdrawal period
•
26-week long-term stable dosing period at doses up to 400 μg/kg/day
•
52-week optional follow-up treatment period (protocol amendment 3)
•
Long-term optional follow-up treatment period for eligible subjects who choose to stay 
on treatment with MRX (protocol amendment 4)
During the long-term optional follow-up period, subjects may have their dose of MRX increased 
to a maximum of 800 μg/kg/day (400 μg/kg BID), based on efficacy (sBA level and ItchRO
[Obs] score) and safety assessment. Subjects’ participation in the long-term optional follow-up
treatment period will continue until the first of the following occurs: i) the subjects are eligible to 
enter another MRX study, ii) MRX is available commercially, or (iii) Mirum Pharmaceuticals
stops the program or development in this indication.
Figure 1 depicts an overview of the treatment regimens across the study duration.
Figure 1
Treatment Regimens
Protocol Version
Treatment Week
0
18
22
48
100
12-WK Repeating Periods 
Treatment 
Regimen
MRX up to 400 μg/kg/day
MRX up to 400 μg/kg BID
Amendment 4
Original
Amendment 3
MRX up to 400 
μg/kg/day
MRX
(400 μg/kg/day)
Placebo


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3.2.
Sample Size and Power 
ALGS is a rare disease. The planned sample size of 30 evaluable ALGS subjects is based on 
practical considerations, rather than a desired power for a pre-specified difference.
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 subjects receive MRX, up to 400 μg/kg/day or a maximum daily dose of 20 mg/day, during 
the initial open-label treatment period of the study. After completion of the 12-week stable 
dosing period, subjects were randomized 1:1 to either continue receiving MRX or a 
corresponding placebo (PBO) for a 4-week double-blind study drug withdrawal period. The
randomization was stratified by response criteria where response was defined as a ≥50% 
reduction in serum bile acids between Baseline and Week 12. Subjects then entered a 26-week 
long-term stable dosing period, and all subjects received MRX, up to 400 μg/kg/day or a 
maximum daily dose of 20 mg/day. 
Subjects were considered for a 52-week optional treatment period, if eligible, receiving up to 400 
μg/kg/day, or the highest tolerated dose below the 400 μg/kg/day dose. Subjects were then
considered for the long-term optional follow-up treatment, if eligible, receiving up to 800
μg/kg/day (given as twice daily doses of 400 μg/kg), or a maximum possible daily dose of 50 
mg/day.
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.
3.4.1. Dose Escalation Period 
Initially, the MRX dose was administered as a daily morning dose in either a 1.0 mL or 0.5 mL 
solution. The dose was increased weekly over a 6-week period up to 400 μg/kg/day QD or a 
maximum daily dose of 20 mg/day QD as follows:
Week 1 Dose: 14 μg/kg/day QD
Week 2 Dose: 35 μg/kg/day QD
Week 3 Dose: 70 μg/kg/day QD
Week 4 Dose: 140 μg/kg/day QD
Week 5 Dose: 280 μg/kg/day QD
Week 6 Dose: 400 μg/kg/day QD (maximum daily dose of 20 mg QD)
If a subject experiences intolerance due to gastrointestinal symptoms (e.g., diarrhoea, abdominal 
pain, cramping) at any time during the study, the physician investigator in consultation with the 


Statistical Analysis Plan
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medical monitor may lower the dose to a previously tolerated dose; later attempts to escalate the 
dose are permitted. If the subject is on a BID dosing regimen, dose lowering should first be 
attempted with the afternoon dose.
3.4.2. Stable Dosing Period 
Subjects continued dosing for another 12 weeks using the dose administered at Week 6, which 
may be 400 μg/kg/day or the highest tolerated dose below 400 μg/kg/day.
3.4.3. Double-Blind Placebo-Controlled Study Drug Withdrawal Period 
At the Week 18 visit, eligible subjects were randomized to continue to receive study drug or a 
corresponding placebo for 4 weeks.
3.4.4. Long-Term Exposure Period 
Following the 4-week study drug randomized withdrawal period, subjects who received placebo 
receive MRX dosed according to a dose escalation schedule that mirrors the initial escalation.
Subjects who were randomized to receive MRX during this period will continue to receive the 
same dose of MRX and, following Week 22, a simulated dose escalation will occur to maintain 
the blind in the randomized withdrawal period. Dosing with MRX will continue in a 26-week 
long-term exposure period to complete 48 weeks of treatment (see Figure 2).
During the long-term exposure period, the dose may be adjusted to account for a change of
≥10% in weight since the screening visit (e.g., the amount of drug dosed may be increased to
reflect the subject’s weight increase).
Figure 2
Study Design for Original Protocol (Day 0 – Week 48)


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3.4.5. 52-Week Optional Follow-up Treatment Period 
At Week 48, all subjects were assessed by the investigator to determine their willingness and 
eligibility to roll-over into the 52-week optional follow-up treatment period. The 3 following 
possible scenarios may have occurred:
•
Subjects who were eligible to roll over into the optional follow-up treatment 
period with no MRX dosing interruption or an interruption of < 7 days were
maintained at the same dose level (see Figure 3).
•
Subjects who were eligible to roll over into the optional follow-up treatment 
period with a MRX dosing interruption of ≥7 days were dose escalated 
beginning at 35 μg/kg/day and up to a maximum of 400 μg/kg/day or highest 
tolerated dose (see Figure 4, where DE=dose escalation, FTP=follow-up
treatment period).
•
Subjects who did not wish to enter the follow-up treatment period were contacted 
via telephone by the study site approximately 30 days after the last dose of study 
drug.
Figure 3
Study Design for 52-Week Optional Follow-up Treatment Scheme for 
Subjects Who Experienced No Interruption in MRX or Interruption
< 7 Days Between Protocol Amendment 2 and Protocol Amendment 3


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Figure 4
Study Design for 52-Week Optional Follow-up Treatment Scheme for 
Subjects Who Experienced an Interruption in MRX ≥7 Days Between 
Protocol Amendment 2 and Protocol Amendment 3
3.4.6. Long-Term Optional Follow-up Treatment Period 
Upon completion of the 52-week optional follow-up treatment period, and/or implementation of 
protocol amendment 4, whichever occurred first, subjects were assessed by the investigator to 
determine their willingness and eligibility to roll-over (or enter) the long-term optional treatment 
period. 
x
Subjects who are eligible to roll over from the 52-week follow up treatment period into 
the long-term optional follow-up treatment period with no MRX dosing interruption or an 
interruption of < 7 days prior to implementation of PA 4 will be evaluated and either 
initiate the ADE (Figure 7) or continue receiving the same dose of MRX once a day 
(Figure 6).
x
Subjects with ≥7 days since last dose of MRX prior to implementation of PA 4 who are 
eligible to enter the long-term optional follow-up treatment period will be dose escalated up 
to 400 μg/kg/day or to the highest tolerated dose beginning with 35 μg/kg/day (Figure 5)
prior to being assessed for ADE eligibility and either initiating the ADE (Figure 7) or 
continue receiving the same dose of MRX once a day (Figure 6).
Note: ADE=afternoon dose escalation, DE=dose escalation, PA=protocol amendment, EOT=end 
of treatment, ET=early termination, MTD=maximum tolerated dose.


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Figure 5
Study Design for Long-Term Optional Follow-up Treatment Scheme for Subjects 
Who Experienced an Interruption in MRX ≥7 Days Between PA 3 and PA 4
Figure 6
Study Design for Long-Term Optional Follow-up Treatment Scheme, Without 
Afternoon Dose Escalation (ADE)


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Figure 7
Study Design for Long-Term Optional Follow-up Treatment Scheme, With 
Afternoon Dose Escalation
3.5.
Method of Assigning Subjects to Treatment Groups 
At the end of the 12-week stable dosing period, subjects are randomized to treatment using the 
Interactive Response Technology (IRT) System. The randomization schedule was generated by 
an independent biostatistician using a permuted block algorithm that was stratified by response 
criteria where response was defined as a ≥50% reduction in serum bile acids between Baseline 
and Week 12. The method by which the randomization schedule was administered used a central 
by block randomization process (within IRT), with entire blocks assigned by study site.
Study drug is prepared by a central pharmacy based on the subject’s weight at screening. Diluent 
is added by the central pharmacy pharmacist before shipping study drug to the site. The 
pharmacist at the central pharmacy is unblinded to treatment group. The study staff including the 
local site pharmacist (or qualified delegate) will remain blinded to the treatment assignment.
3.6.
Blinding and Unblinding 
Although subjects are treated in an open-label fashion from Week 1 to Week 18, subjects are
randomized 1:1 to continue to receive study drug or a corresponding placebo for 4 weeks 
between the start of Week 19 and the end of Week 22 (i.e., the double-blind, placebo-controlled 
study drug withdrawal period). All subjects, monitors, and study center personnel related to the 


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study, except for the central pharmacist (or qualified designee) who prepares the study drug, will 
be blinded to study treatment during the randomized withdrawal period (Weeks 19 - 22) and the 
long-term exposure period (Weeks 23 - 48), and to the subject’s study drug withdrawal period 
treatment assignment. A designated statistician will securely maintain an unblinded 
randomization schema.
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 
subject, the investigator will have the ability to unblind the treatment assignment for that subject. 
If a subject is unblinded by the investigator, Mirum Pharmaceuticals 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 Mirum Pharmaceuticals.
Breaking of the blind during the initial 48-week period of the study should not occur before all 
subjects either discontinue or complete Week 48, 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 before submitting a regulatory safety report for a serious adverse 
event (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 subject assessment.
The study protocol was amended on 06 Nov 2017 (Protocol Amendment 5) to change the study 
design going forward to an open label study. At that time all subjects had either completed 
Week 48 or discontinued prior to Week 48. The study was unblinded on 10 Jan 2018 for the 
interim analysis, as planned in the protocol.


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3.7.
Schedule of Procedures 
A detailed schedule of procedures for the study is provided in the below tables. The following schematic shows the study flow and 
corresponding Schedule of Procedures (A-I).
Study Termination and End of Treatment Procedures are outlined in Schedule J.


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3.7.1. Schedule of Procedures A-D: Study Entry – Week 96  
Schedule of Procedures A: Screening – Week 22
Study Period
Screening
Baseline
Treatment Period
Dose Escalationi
Stable Dose
Randomized 
Withdrawal
Study Week
1
2
3
4
5
6
9
12
18
20
22
Study Day
Day -28 to -1
Day 0
7
14
21
28
35
42
63
84
126
140
154
Window (in days)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±5)
(±5)
(±5)
(±5)
(±5)
Informed Consent
X
Eligibility Assessment/ Medical History
X
X
Demographics
X
Physical Exam
X
X
X
X
X
X
X
Body Weight & Height
X
X
X
X
X
X
X
Randomization to Placebo vs. 
LUM001
X
Vital Signsa
X
X
X
X
X
X
X
CBC with Differentialb
X
X
X
X
X
X
X
Coagulationb
X
X
X
X
X
X
X
Chemistry Panelb
X
X
X
X
X
X
X
Lipid Panelb,c
X
X
X
X
Cholestasis Biomarkersb,c
X
X
X
X
Total Serum bile acidsc
Xk
X
X
X
X
Fat Soluble Vitaminsb,c
X
X
X
X
JAGGED1/NOTCH2 Genotypingd (if 
needed)
X
Plasma Sample for LUM001
Xj
Xj
Xj
Urinalysisb
X
Xg
Xg
Xg
X
X
X
Serum or Urine Pregnancy Test (if 
indicated)e
X
X
X
X
X
X
X
Subject eDiary/Caregiver eDiary 
(ItchRO)
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Clinician Scratch Scale
X
X
X
X
X
X
X
Clinician Xanthoma Scale
X
X
PedsQL
X
X
X
Patient/Caregiver Impression of Change
X
X


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 30 of 128
Schedule of Procedures A: Screening – Week 22 (cont’d)
Study Period
Screening
Baseline
Treatment Period
Dose Escalationi
Stable Dose
Randomized 
Withdrawal
Study Week
1
2
3
4
5
6
9
12
18
20
22
Study Day
Day -28 to -1
Day 0
7
14
21
28
35
42
63
84
126
140
154
Window (in days)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±5)
(±5)
(±5)
(±5)
(±5)
Caregiver Global Therapeutic Benefit
X
X
Enrollment
X
Study Drug Supplied
X
X
X
X
X
X
Review Study Diaries & Assess 
Compliance
X
X
X
X
X
X
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 Contactf
X
X
X
X
X
X
a
Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b
See Appendix 2 for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins should be drawn prior to administration of vitamin 
supplementation.
c
Subjects are required to fast at least 4 hrs (only water permitted prior to collection).
d
Optional genotype sample will be performed to provide a full characterization and the associated documentation of the mutation in support of the diagnosis of ALGS.
e
For females of childbearing potential, result must be reviewed prior to dispensing study drug.
f
Subjects must be available to receive a phone call from study staff.
g
At the indicated visits during the treatment period, oxalate will be part of the urinalysis.
h
During screening and throughout the study, the eDiary (ItchRO) will be completed twice daily (AM & PM). Compliance will be assessed at each visit/phone contact.
i
Subjects should be dosed for at least 7 days at each dose level.
j
Pharmacokinetic analysis will be done at Baseline, and then approximately 4 hours post-dosing at one additional time point – at Week 12, 18, 38, or 48 (to be selected 
by site/investigator).
k
Subjects are NOT required to fast prior to sample collection at the screening visit.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 31 of 128
Schedule of Procedures B: Long-term Exposure: Week 23–Week 48
Study Period
Treatment Period (cont’d)
Follow Up
Long-Term Exposure
Study Week
23
24
25
26
27
28
33
38
43
Week 48 (or 
Early
Terminationf)
Study Day
161
168
175
182
189
196
231
266
301
336
30 days after 
final dose
Window (in days)
(±2)
(±2)
(±2)
(±2)
(±2)
(±5)
(±5)
(±5)
(±5)
(±14)
(±5)
Physical Exam
X
X
X
Body Weight & Height
X
X
X
Vital Signsa
X
X
X
CBC with Differentialb
X
X
X
Coagulationb
X
X
X
Chemistry Panelb
X
X
X
Lipid Panelb,c
X
Total Serum bile acidsc
X
Cholestasis Biomarkersb,c
X
Fat Soluble Vitaminsb,c
X
X
X
Plasma sample for MRX
Xi
Xi
Urinalysisb
X
X
Xg
Urine Pregnancy Test (if indicated)d
X
X
X
Clinician Scratch Scale
X
X
X
Clinician Xanthoma Scale
X
Subject eDiary/Caregiver eDiary (ItchRO)
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
PedsQL
X
Patient & Caregiver Impression of Change
X
Caregiver Global Therapeutic Benefit
X
Study Drug Supplied
X
X
Xj
Review Study Diaries & Assess Compliance
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Phone Contacte
X
X
X
X
X
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 32 of 128
Schedule of Procedures B – Long-term Exposure: Week 23–Week 48 (cont’d)
Study Period
Treatment Period (cont’d)
Follow Up
Long-Term Exposure
Study Week
23
24
25
26
27
28
33
38
43
Week 48 (or 
Early
Terminationf)
Study Day
161
168
175
182
189
196
231
266
301
336
30 days after 
final dose
Window (in days)
(±2)
(±2)
(±2)
(±2)
(±2)
(±5)
(±5)
(±5)
(±5)
(±14)
(±5)
a
Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b
See Appendix 2 for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins should be drawn prior to administration of vitamin 
supplementation.
c
Subjects are required to fast at least 4 hrs (only water permitted prior to collection).
d
For females of childbearing potential, result must be reviewed prior to dispensing study drug.
e
Subjects must be available to receive a phone call from study staff.
f
Subjects who withdraw early should complete all evaluations at this visit.
g
At the indicated visits during the treatment period, oxalate will be part of the urinalysis.
h
During screening and throughout the study, the eDiary (ItchRO) will be completed twice daily (AM and PM). Compliance will be assessed at each visit/phone contact.
i
Pharmacokinetic analysis will be done at Baseline, and then approximately 4 hours post-dosing at one additional time point – at Week 12, 18, 38, or 48 (to be selected 
by site/investigator).
j
For subjects entering optional Follow-up Treatment Period, once corresponding consent is signed.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 33 of 128
Schedule of Procedures C: 52-Week Optional Follow-up Treatment Period (FTP) – Week 48-96 for Those Subjects < 7 Days 
from the Last Dose of MRX (Includes evaluation of eligibility for BID dosing regimen)
Study Period
52-week FTP
Study Week
52
56
60
64
68
72
76
80
84
88
92
96
Study Day
364
392
420
448
476
504
532
560
588
616
644
672
Window (in days)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
Informed Consent/Assent for PA4g
X
X
X
X
Afternoon Dose Escalation (ADE) eligibility 
assessment followed by shift in visit scheduleh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
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
X
Cholestasis Biomarkersb,c
X
X
X
X
Fat Soluble Vitaminsb,c
X
X
X
X
Optional Genotypingd
X
Urinalysisb
X
X
X
X
Urine Pregnancy Test (if indicated)e
X
X
X
X
Clinician Scratch Scale
X
X
X
X
Clinician Xanthoma Scale
X
X
X
X
Subject eDiary/Caregiver eDiary (ItchRO)
Xi
Xi to
Week 62
Xi
Xi to
Week 74
Xi
Xi to
Week 86
Xi
PedsQL
X
X
X
X
Patient & Caregiver Impression of Change
X
X
Caregiver Global Therapeutic Benefit
X
X
Study Drug Supplied
X
X
X
X
Review Study Diaries & Assess Compliance
X
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 34 of 128
Schedule of Procedures C: 52-Week Optional Follow-up Treatment Period (FTP) – Week 48-96 for Those Subjects < 7 Days
from the Last Dose of MRX (cont’d)
Study Period
52-week FTP
Study Week
52
56
60
64
68
72
76
80
84
88
92
96
Study Day
364
392
420
448
476
504
532
560
588
616
644
672
Window (in days)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
Phone contactf
X
X
X
X
X
X
X
X
a
Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b
See Appendix 2 for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins should be drawn prior to administration of vitamin 
supplementation.
c
Subjects are required to fast at least 4 hrs (only water permitted prior to collection).
d
Genotyping sample will be drawn at Week 60 or at the time of re-consent for the optional follow-up treatment period; sample will be used to provide a full 
characterization and documentation of the mutation type in support of the diagnosis of ALGS.
e
For females of childbearing potential, result must be reviewed prior to dispensing study drug.
f
Subjects must be available to receive a phone call from study staff.
g
Once necessary approvals are received for Protocol Amendment 4 and associated consent/assent documents are available, site will consent/assent patient for Protocol 
Amendment 4 at the next clinic visit.
h
Once the Protocol Amendment 4 consent/assent has been signed, site will assess subject eligibility for Protocol Amendment 4 and ADE. Depending on the outcome of 
ADE eligibility assessment, subject will move into either Schedule of Procedures E or F. Of note: It is possible that subject will not necessarily complete up through 
Week 96 before they move to Schedule of Procedures E or F. ADE eligibility assessments may occur any time between Week 52 and Week 100.
i
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 60, Week 72, and Week 84visits.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 35 of 128
Schedule of Procedures D: 52-Week Optional Follow-up Treatment Period – DE -2 – Week 96 for Those Subjects ≥7 Days 
from the Last Dose of MRX (Includes evaluation of eligibility for BID dosing regimen)
       Study Period
Treatment Period (cont’d)
FTP Dose Escalation (DE)
FTP
FTP Study Week
DE - 2
DE 0
DE 49
DE 50
DE 51
DE 52
60
64
68
72
76
80
84
88
92
96
DE Study Day
-14
0
343 a
350 a
357 a
364 a
420 a
448a
476 a
504 a
532 a
560 a
588 a
616 a
644 a
672 a
Window (in days)
(±14)
(±2)
(±2)
(±2)
(±2)
(±2)
(±14)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
Informed Consent/Assent for 
study re-entry under PA3
X
Eligibility Assessment for study 
re-entry
X
Informed Consent/Assent for 
PA4h
X
X
X
X
Afternoon Dose Escalation 
(ADE) eligibility assessment 
followed by shift in visit
schedulei
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Physical Exam
X
X
X
X
X
X
X
Body Weight & Height
X
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
CBC with Differentialc
X
X
X
X
X
X
X
Coagulationc
X
X
X
X
X
X
X
Chemistry Panelc
X
X
X
X
X
X
X
Lipid Panelc,d
X
X
X
X
X
X
X
Cholestasis Biomarkersc,d
X
X
X
X
X
X
X
Fat Soluble Vitaminsc,d
X
X
X
X
X
X
X
Optional Genotypinge
X
Urinalysisc
X
X
X
X
X
X
X
Urine Pregnancy Testf
X
X
X
X
X
X
X
Clinician Scratch Scale
X
X
X
X
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 36 of 128
Schedule of Procedures D: 52-Week Optional Follow-up Treatment Period – DE -2 – Week 96 for Those Subjects ≥7 Days 
from the Last Dose of MRX (cont’d)
Study Period
Treatment Period (cont’d)
FTP Dose Escalation (DE)
FTP
FTP Study Week
DE - 2
DE 0
DE 49
DE 50
DE 51
DE 52
60
64
68
72
76
80
84
88
92
96
DE Study Day
-14
0
343 a
350 a
357 a
364 a
420 a
448a
476 a
504 a
532 a
560 a
588 a
616 a
644 a
672 a
Window (in days)
(±14)
(±2)
(±2)
(±2)
(±2)
(±2)
(±14)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
(±7)
(±7)
(±14)
Clinician Xanthoma Scale
X
X
X
X
X
X
Subject eDiary/Caregiver eDiary
Xj
Xj
to Week 62
Xj
Xj
to Week 74
Xa
Xj
to Week 86
Xa
PedsQL
X
X
X
X
X
Patient & Caregiver Impression of Change
X
X
Caregiver Global Therapeutic Benefit
X
X
Study Drug Supplied
X
X
X
X
X
Review Study Diaries & Assess
Compliance
X
X
X
X
X
Concomitant Medications
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
Phone Contactg
X
X
X
X
X
X
X
X
X
a Calculation of Study Day includes subject’s participation through the first 48 weeks.
b Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
c See Appendix 2 for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins should be drawn prior to administration of vitamin D supplementation.
d Subjects are required to fast at least 4 hrs (only water permitted prior to collection).
e Optional genotype sample will be performed to provide a full characterization and the associated documentation of the mutation type in support of the diagnosis of ALGS. 
Females of childbearing potential, result must be reviewed prior to dispensing study drug.
f For females of childbearing potential, result must be reviewed prior to dispensing study drug.
g Subjects must be available to receive a phone call from study staff.
h Once necessary approvals are received for Protocol Amendment 4 and associated consent/assent documents are available, site will consent/assent subject for Protocol 
Amendment 4 at the next clinic visit.
i
Once the Protocol Amendment 4 consent/assent has been signed, site will assess subject eligibility for Protocol Amendment 4 and ADE. Depending on the outcome of ADE 
eligibility assessment, subject will move into either Schedule of Procedures E or F. Of note: It is possible that subject will not necessarily complete up through Week 96 
before they move to Schedule of Procedures E or F. ADE eligibility assessments may occur any time between Week 60 and Week 100.
j
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 68, Week 96, and Week 120 visits.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 37 of 128
3.7.2. Schedule of Procedures E-F: Rollover under Protocol Amendment 4 
Schedule of Procedures E – Extension of Long-term Optional Follow-up Treatment Period, for subjects ineligible for ADE, 
applicable as follows:
x
Subject did not yet complete the long-term optional follow up treatment period as outlined under ProtocolAmendment 3
and is able to consent to Protocol Amendment 4 activities without an interruption in MRX dosing, OR
x
Subject completed long-term optional followup treatment period as outlined under PA3 and dosing interruption was
< 7 days.
x
Subject deemed ineligible for ADE.
Below study activities repeat in repeating 12-week periodsh
Repeating Period Week (RPx)
RPx Week 4
RPx Week 8
RPx Week 12
Scheduling Considerations
4 weeks after consent 
under PA4
Window (in days)
(±7)
(±7)
(±14)
Physical Exam
X
Body Weight & Height
X
Vital Signsa
X
CBC with Differentialb
X
Coagulationb
X
Chemistry Panelb
X
Lipid Panelb,c
X
Cholestasis Biomarkersb,c
X
Fat Soluble Vitaminsb,c,d
X
Urinalysisb
Xj
AFP Sample
Xi
Serum or Urine Pregnancy Test (if indicated)e
X
Clinician Scratch Scale
X
Clinician Xanthoma Scale
X
Caregiver ItchRO/ Patient ItchRO
X
(collected for 2 week period
following this visit)


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 38 of 128
Schedule of Procedures E: Extension of Long-term Optional Follow-up Treatment Period, for subjects ineligible for ADE
(cont’d)
Below study activities repeat in repeating 12-week periodsh
Repeating Period Week (RPx)
RPx Week 4
RPx Week 8
RPx Week 12
Scheduling Considerations
4 weeks after consent under PA4
Window (in days)
(±7)
(±7)
(±14)
PedsQL
X
Palatability Questionnaire
X
Study Drug Suppliedf
X
Assess Compliance
X
Concomitant Medications
X
X
X
Adverse Events
X
X
X
Follow-up Phone Contactg
X
X
a
Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b
See Appendix 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
Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to 
enter another MRX study, (ii) MRX is available commercially, or (iii) the sponsor stops the program or 
development in thisindication.
i
Sample will be drawn at every other clinic visit starting with RP1 Week 12.
j
At indicated visits during treatment period, oxalate will be part of the urinalysis.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 39 of 128
Schedule of Procedures F: Extension of Long-term Optional Follow-up Treatment Period, for subjects eligible for ADE, 
applicable as follows:
x
Subject did not yet complete the long-term optional follow up treatment period as outlined under ProtocolAmendment 
3 (PA3) and is able to consent to Protocol Amendment 4 activities without an interruption in MRX dosingOR
x
Subject completed the long-term optional follow up treatment period as outlined under PA3 and dosing interruption 
was < 7 days.
x
Subject deemed eligible for ADE.
Study Period
Follow-up Treatment Period Afternoon Dose Escalation (ADE)
Study activities repeat in repeating 12-
week periods after completion of the 
ADE periodh
Study Week
ADE
Day 0
ADE
Week 1
ADE
Week 2
ADE
Week 4
ADE
Week 5
ADE
Week 6
ADE
Week 8
Week 4
Week 8
Week 12
Scheduling 
Considerations
To be scheduled
as soon as ADE
eligibility is 
confirmed and 
materials
are on-site
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE
Week 8.
Window (in days)
N/A – see above
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±7)
(±7)
(±14)
Physical Exam
X
X
X
X
Body Weight & 
Height
X
X
X
X
Vital 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
X
Cholestasis 
Biomarkersb,c
X
X
X
X
Fat Soluble 
Vitaminsb,c,d
X
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 40 of 128
Schedule of Procedures F: Extension of Long-term Optional Follow-up Treatment Period, for subjects eligible for ADE (cont’d)
Study Period
Follow-up Treatment Period Afternoon Dose Escalation (ADE)
Study activities repeat in repeating 12-
week periods after completion of the ADE 
periodh
Study Week
ADE
Day 0
ADE
Week 1
ADE
Week 2
ADE
Week 4
ADE
Week 5
ADE
Week 6
ADE
Week 8
Week 4
Week 8
Week 12
Scheduling Considerations
To be scheduled as 
soon as ADE
eligibility is 
confirmed and 
materials
are on-site
The initial 
Week 4 contact 
will be 
scheduled 4 
weeks following 
ADE
Week 8.
Window (in days)
N/A – see above
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±7)
(±7)
(±14)
Urinalysisb
X
X
X
Xk
AFP Sample
Xi
Plasma sample for MRXj
X
X
X
Xj
Serum or Urine
Pregnancy Test (if indicated)e
X
X
X
X
Clinician Scratch Scale
X
X
X
X
Clinician Xanthoma Scale
X
X
X
X
Caregiver ItchRO/ Patient 
ItchRO
X
(collected for 2 
week period 
following this visit)
PedsQL
X
X
X
X
Palatability Questionnaire
X
Study Drug Suppliedf
X
X
X
X
Assess Compliance
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 41 of 128
Schedule of Procedures F: Extension of Long-term Optional Follow-up Treatment Period, for subjects eligible for ADE (cont’d)
Study Period
Follow-up Treatment Period Afternoon Dose Escalation (ADE)
Study activities repeat in repeating 12-week 
periods after completion of the ADE periodh
Study Week
ADE
Day 0
ADE
Week 1
ADE
Week 2
ADE
Week 4
ADE
Week 5
ADE
Week 6
ADE
Week 8
Week 4
Week 8
Week 12
Scheduling 
Considerations
To be scheduled as 
soon as ADE
eligibility is 
confirmed and 
materials
are on-site
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE
Week 8.
Window (in days)
N/A – see above
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±7)
(±7)
(±14)
Adverse Events
X
X
X
X
X
X
X
X
X
X
Follow-up Phone Contactg
X
X
X
X
X
X
a
Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b
See Appendix 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
Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another MRX study, (ii) MRX is available 
commercially, or (iii) the sponsor stops the program or development in this indication.
i
Sample will be drawn at every other clinic visit starting with RP1 Week 12.
j
Pharmacokinetic sample will additionally be collected at the three scheduled clinic visits following completion of the afternoon dose escalation period.
k
At indicated visits during treatment period, oxalate will be part of the UA.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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3.7.3. Schedule of Procedures G-I: Subject Re-Entry under Protocol Amendment 4 
Schedule of Procedures G: Long-term Optional Follow-up Treatment Period - Re-entry under Protocol Amendment 4, 
applicable as follows:
x
Subject previously completed (or early terminated from) the long-term optional follow up treatment period as defined 
under Protocol Amendment 3 and has subsequently experienced an interruption in MRX dosing ≥7days.
x
Subject is considered eligible for study re-entry under Protocol Amendment 4.
x
Subject eligibility will be assessed for afternoon dose escalation at Protocol Amendment 4 DE Week 8 shown inthe 
table below.
o
If subject is found to be ineligible for ADE, subject will move from Schedule G to Schedule H.
o
If subject is found to be eligible for ADE, subject will move from Schedule G to Schedule I.
Study Period
Protocol Amendment 4 Follow-up Treatment Period Dose Escalation (DE)
PA4 DE Study Week
PA4 DE -2
PA4 DE
Day 0
PA4 DE
Week 1
PA4 DE
Week 2
PA4 DE
Week 3
PA4 DE
Week 4
PA4 DE
Week 8
Scheduling Considerations
-14
0
Window (in days)
(±14)
(±2)
(±2)
(±2)
(±2)
(±2)
(±14)
Informed Consent/Assent
X
Assess Eligibility for study re-entry
X
X
Assess Eligibility for ADE
X
Physical Exam
X
X
X
Body Weight & Height
X
X
X
Vital Signsa
X
X
X
CBC with Differentialb
X
X
X
Coagulationb
X
X
X
Chemistry Panelb
X
X
X
Lipid Panelb,c
X
X
X
Cholestasis Biomarkersb,c
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 43 of 128
Schedule of Procedures G: Long-term Optional Follow-up Treatment Period - Re-entry under Protocol Amendment 4 (cont’d)
Study Period
Protocol Amendment 4 Follow-up Treatment Period Dose Escalation (DE)
PA4 DE Study Week
PA4 DE -2
PA4 DE
Day 0
PA4 DE
Week 1
PA4 DE
Week 2
PA4 DE
Week 3
PA4 DE
Week 4
PA4 DE
Week 8
Scheduling Considerations
-14
0
Window (in days)
(±14)
(±2)
(±2)
(±2)
(±2)
(±2)
(±14)
Fat Soluble Vitaminsb,c,d
X
X
X
Urinalysisb
X
X
X
Serum or Urine Pregnancy Test (if indicated)e
X
X
X
Clinician Scratch Scale
X
X
X
Clinician Xanthoma Scale
X
X
X
Caregiver ItchRO/ Patient ItchRO
X
(collected for 2 
week period 
following this visit)
PedsQL
X
Study Drug Suppliedf
X
X
Assess Compliance
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
X
a
Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b
See Appendix 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.
Clinic Visit
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 44 of 128
Schedule of Procedures H: Long-term Optional Follow-up Treatment Period: Re-entry under Protocol Amendment 4, 
subject ineligible for ADE
Below study activities repeat in repeating 12-week periodsh
Repeating Period Week
Week 4
Week 8
Week 12
Scheduling Considerations
The Week 4 visit of the 
first repeating period 
will take place 4 weeks 
after PA4 DE
Week 8
Window (in days)
(±7)
(±7)
(±14)
Physical Exam
X
Body Weight & Height
X
Vital Signsa
X
CBC with Differentialb
X
Coagulationb
X
Chemistry Panelb
X
Lipid Panelb,c
X
Cholestasis Biomarkersb,c
X
Fat Soluble Vitaminsb,c,d
X
Urinalysisb
Xj
AFP Sample
Xi
Serum or Urine Pregnancy Test (if indicated)e
X
Clinician Scratch Scale
X
Clinician Xanthoma Scale
X
Caregiver ItchRO/ Patient ItchRO
X
(collected for 2 week period 
following this visit)
PedsQL
X
Palatability Questionnaire
X
Study Drug Suppliedf
X
Assess Compliance
X
Concomitant Medications
X
X
X
Adverse Events
X
X
X
Follow-up Phone Contactg
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 45 of 128
Schedule of Procedures H – Long-term Optional Follow-up Treatment Period: Re-entry under Protocol Amendment 4, 
subject ineligible for ADE (cont’d)
Below study activities repeat in repeating 12-week periodsh
Repeating Period Week
Week 4
Week 8
Week 12
Scheduling Considerations
The Week 4 visit of the first 
repeating period will take 
place 4 weeks after PA4 DE
Week 8
Window (in days)
(±7)
(±7)
(±14)
a
Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b
See Appendix 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.
hStudy visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another MRX study, 
(ii) MRX is available commercially, or (iii) the sponsor stops the program or development in this indication.
i
Sample will be drawn at every other clinic visit starting with RP1 Week 12
j
At indicated visits during treatment period, oxalate will be part of the UA.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 46 of 128
Schedule of Procedures I: Long-term Optional Follow-up Treatment Period - Re-entry under Protocol Amendment 4, 
subject eligible for ADE
Study Period
Follow-up Treatment Period Afternoon Dose Escalation (ADE)
Study activities repeating in repeating 
12-week periods after completion of the 
ADE periodh
FTP Study Week
ADE
Day 0
ADE
Week 1
ADE
Week 2
ADE
Week 4
ADE
Week 5
ADE
Week 6
ADE
Week 8
Week 4
Week 8
Week 12
Scheduling 
Considerations
To be scheduled as 
soon as ADE
eligibility is     
confirmed and 
materials
are on-site
The initial 
Week 4 contact 
will be 
scheduled 4 
weeks following 
ADE Week 8.
Window (in days)
N/A – see above
(±2)
(±2)
(±2)
(±2)
(±2)
(±7)
(±7)
(±14)
Physical Exam
X
X
X
X
Body Weight & Height
X
X
X
X
Vital 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
X
Cholestasis Biomarkersb,c
X
X
X
X
Fat Soluble Vitaminsb,c,d
X
X
X
X
Urinalysisb
X
X
X
Xk
AFP Sample
Xi
Plasma sample for MRXj
X
X
X
Xj
Serum or Urine Pregnancy 
Test (if indicated)e
X
X
X
X
Clinician Scratch Scale
X
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 47 of 128
Schedule of Procedures I: Long-term Optional Follow-up Treatment Period - Re-entry under Protocol Amendment 4, subject 
eligible for ADE (cont’d)
Study Period
Follow-up Treatment Period Afternoon Dose Escalation (ADE)
Study activities repeating in repeating 12-
week periods after completion of the ADE 
periodh
FTP Study Week
ADE
Day 0
ADE
Week 1
ADE
Week 2
ADE
Week 4
ADE
Week 5
ADE
Week 6
ADE
Week 8
Week 4
Week 8
Week 12
Scheduling 
Considerations
To be scheduled 
as soon as ADE
eligibility is     
confirmed and 
materials
are on-site
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE
Week 8.
Window (in days)
N/A – see above
(±2)
(±2)
(±2)
(±2)
(±2)
(±7)
(±7)
(±14)
Clinician Xanthoma Scale
X
X
X
X
Caregiver ItchRO/ Patient 
ItchRO
X
(collected for 2 
week period
following this 
visit)
PedsQL
X
X
X
X
Palatability Questionnaire
X
Study Drug Suppliedf
X
X
X
X
Assess Compliance
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Follow-up Phone Contactg
X
X
X
X
X
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 48 of 128
Schedule of Procedures I: Long-term Optional Follow-up Treatment Period - Re-entry under Protocol Amendment 4, 
subject eligible for ADE (cont’d)
Study Period
Follow-up Treatment Period Afternoon Dose Escalation (ADE)
Study activities repeating in repeating 12-
week periods after completion of the ADE 
periodh
FTP Study Week
ADE
Day 0
ADE
Week 1
ADE
Week 2
ADE
Week 4
ADE
Week 5
ADE
Week 6
ADE
Week 8
Week 4
Week 8
Week 12
Scheduling 
Considerations
To be scheduled 
as soon as ADE
eligibility is 
confirmed and 
materials are on-
site
The initial Week 4 
contact will be 
scheduled 4 weeks 
following ADE
Week 8.
Window (in days)
N/A – see above
(±2)
(±2)
(±2)
(±2)
(±2)
(±7)
(±7)
(±14)
a
Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b
See Appendix 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
Study visits will continue in the same pattern until the first of the following occur: (i) subjects are eligible to enter another MRX study, or (ii) MRX is 
available commercially, or (iii) the sponsor stops the program or development in this indication.
i
Sample will be drawn at every other clinic visit starting with RP1 Week 129.
j
Pharmacokinetic sample will additionally be collected at the three scheduled clinic visits following completion of the afternoon dose escalation period.
k
At indicated visits during treatment period, oxalate will be part of the UA.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 49 of 128
3.7.4. Schedule of Procedures J: Study Termination and End of Treatment Procedures 
Schedule of Procedures J: End of Treatment (EOT) / Early Termination (ET) Visit and 
Post-Treatment Safety Follow Up
EOT / ET
Safety Follow Up
Scheduling Considerations
To take place upon completion of studyg or 
at the time of early withdrawal
Minimum of 30 days after final dose
Physical Exam
X
Body Weight & Height
X
Vital Signsa
X
CBC with Differentialb
X
Coagulationb
X
Chemistry Panelb
X
Lipid Panelb,c
X
Cholestasis Biomarkersb,c
X
Fat Soluble Vitaminsb,c,d
X
Urinalysisb
Xh
AFP Sample
X
Serum or Urine Pregnancy Test (if indicated)e
X
Clinician Scratch Scale
X
Clinician Xanthoma Scale
X
PedsQL
X
Patient/Caregiver Impression of Change
X
Caregiver Global Therapeutic Benefit
X
Palatability Questionnaire
X
Assess Compliance
X
Concomitant Medications
X
X
Adverse Events
X
X
Follow-up Phone Contactf
X


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 50 of 128
Schedule of Procedures J: End of Treatment (EOT) / Early Termination (ET) Visit and 
Post-Treatment Safety Follow Up
EOT / ET
Safety Follow Up
Scheduling Considerations
To take place upon completion of studyg or at
the time of early withdrawal
Minimum of 30 days after final dose
a Blood pressure (BP), heart rate (HR), temperature, respiratory rate.
b See Appendix 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.
f
Subjects must be available to receive a phone call from study staff.
g Will take place when the first of the following occur: (i) subjects are eligible to enter another MRX study, (ii) MRX is
available commercially, or (iii) or the sponsor stops the program or development in this indication.
h At indicated visits during treatment period, oxalate will be part of the urinalysis.
Clinic Visit 
Phone Contact


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 51 of 128
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 subjects (n) with 
non-missing values, mean, 2-sided 95% CI for the mean, standard deviation (SD) and/or standard 
error (SE) if appropriate, median, minimum, and maximum.
Categorical (qualitative) variable summaries will include the number and percentage of subjects 
who are in the particular category. In general, the denominator for the percentage calculation will 
be based upon the total number of subjects in the analysis population for the treatment phase 
and/or treatment group/sequence, unless otherwise specified.
For purposes of analysis, there will be 3 treatment phases:
•
Open-Label Phase (Day 1 – Week 18),
•
Randomized Withdrawal Phase (Weeks 19 - 22), and
•
After Randomized Withdrawal Phase (Week > 22)
For select analysis, the 3rd treatment phase will be presented as 2 separate treatment phases:
ARW (Week > 22 – Week 48) and ARW (Week > 48). Unless otherwise specified, summaries 
will be provided by treatment phase and treatment group/sequence.
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) will be reported to 
2 degrees of precision more than the observed data. Confidence intervals (CIs) for the mean are 
reported to the same degree of precision as the mean.
The minimum and maximum values for derived and select observed values will be reported as 
follows, with measures of location and spread following the above rules. Derived values for 
corrected sodium, along with select laboratory values of autotaxin, FGF-19, and FGF-21, will be 
presented as integers. Derived values for BMI, PedsQL summary and total scale scores, along 
with select laboratory values of sBA, 25-hydroxyvitamin D, and vitamin A, and pH, will be 
presented to 1 decimal place. Derived values of height and weight 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.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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Percentages will be presented to 1 decimal place, unless otherwise specified. Where the number 
of subjects in a particular category is 0, a percentage (i.e., 0.0%) will not be displayed.
Statistical tests will be conducted using 2-tailed tests at the 0.05 significance level. P-values will 
be reported for all statistical tests and will be interpreted as nominal p-values in establishing 
statistical significance. Where appropriate, corresponding 95% CIs will be presented.
A p-value of d 0.10 but > 0.05 will be considered evidence of a trend.
4.2.
Interim Analysis 
A planned unblinded interim analysis (IA) was conducted after all subjects completed the study 
through Week 48 or discontinued the study before the Week 48 clinic visit. A SIAP, dated 
04 Feb 2018, describes the analysis performed on assessments through the Week 48 visit (per 
Protocol Amendment 4). The final interim analysis for the 48-week treatment period was
performed on unblinded (actual) treatment codes. The purpose of this 1st interim analysis was to 
guide the future of the program. 
Since the efficacy analysis comparing treatment arms (MRX versus PBO) will be performed 
only once on the final efficacy data (i.e., during the randomized placebo-controlled withdrawal 
period), there will be no statistical penalty.
In preparation for briefing documents for the End-of-Phase 2 meeting with FDA on 21May2019 
and the pre-NDA meeting with FDA on 19 Nov 2019, additional interim analyses were 
performed. In preparation for the NDA submission, currently planned in August 2020, the 
analysis herein described will be performed using an interim data cut date of 01 Dec 2019.
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 SAE data and other key subject safety and 
study data at specified intervals for the duration of the study. The DMC will be composed of 
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.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 53 of 128
5.
ANALYSIS POPULATIONS 
The following analysis populations are planned for this study:
x
Safety Population (SAF): The Safety Population is defined as all subjects who were 
enrolled and received at least one dose of the study drug. 
x
Intent-To-Treat Population (ITT): The ITT Population includes all subjects who were 
enrolled and received at least one dose of the study drug. 
x
Modified Intent-To-Treat Population (MITT): The MITT Population includes all 
subjects who were enrolled, received study drug through Week 18, and had a reduction 
from baseline in sBA of ≥50% at the Week 12 or Week 18 measurement (sBA responder).
For each treatment phase, the following subjects will be included in each respective analysis 
population:
OL Phase: Subjects dosed during the OL phase.
RW Phase: Subjects randomized and dosed during the RW phase.
ARW Phase: Subjects dosed after the RW phase.
The Safety Population will be used for the analyses of safety endpoints. Safety analyses will be 
conducted according to the treatment received.
The ITT and MITT populations will be used for analyses of efficacy endpoints, as described in
Section 8. Efficacy analyses will be conducted according to the assigned treatment (i.e., MRX or 
PBO) or treatment sequence (i.e., MRX-MRX-MRX or MRX-PBO-MRX), as appropriate.
There are 13 subjects that were off study drug for an extended period of time (i.e., at least 7 
weeks) due to the subject being off study between protocol amendments. Of the 13 subjects that 
were off study (between protocol amendments), 5 had interruptions that occurred between 
protocol amendments 2 and 3 (after the Week 48 visit), while 8 others had interruptions that 
occurred between amendments 3 and 4 (after the Week 100 visit). No subject was off study 
between protocol amendments more than once. For select visit-based safety data, the primary 
analysis will exclude any safety data collected or assessed after a drug interruption of > 28 days
due to a subject being off study. Visit-based data collected after the drug interruption, at the point 
of study drug re-initiation, will be analyzed separately as a sensitivity analysis.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 54 of 128
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), there 
are two baselines that will be used for change from baseline values, defined as follows:
•
Baseline (Day 0): The observation obtained at Study Day 0 (before first dose of study 
drug) will be used as the baseline (Day 0) observation for all calculations of change from 
baseline (Day 0). If Study Day 0 is not available/missing, the last value obtained during 
the screening period is used as the baseline (Day 0) observation. This baseline is 
applicable for each of the 3 treatment phases (OL, RW, and ARW).
•
Baseline (Week 18): The observation obtained at Week 18 (before the Randomized 
Withdrawal Phase) will be used as the baseline (Week 18) observation for all calculations 
of change from baseline (Week 18). If Week 18 is not available/missing, the last value 
obtained prior to the Randomized Withdrawal Phase will be used as the baseline (Week 
18) observation. This baseline is only applicable for the RW treatment phase.
For ItchRO weekly average scores, each of the 2 baselines are defined as the average of daily 
scores in the week consisting of the 7 days immediately before the associated baseline visit. For 
ItchRO 4-week average scores, each of the baselines are defined as the average of daily scores in 
the 4-week period consisting of the 28 days immediately before the associated baseline visit.
Safety Assessments After Drug Interruption
For visit-based analyses on safety data collected/assessed after an extended drug interruption
period (between protocol amendments), as described in Section 5, the following baseline 
definitions will be used for change from baseline values. 
•
Baseline (Day 0): 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 subjects 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 subjects with a drug interruption between 
protocol amendments 3 and 4, the PA Day 0 visit is described as “PA4 Dose Escalation 
Day 0”.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
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Because drug interruptions of > 28 days (between protocol amendments) occurred after the 
randomized withdrawal period, the above baselines are only applicable for the ARW treatment 
phase.
6.1.2. Study Day 
Day 1 is defined as the date of first study drug administration. Study day is calculated relative to 
the date of Day 1.
6.1.3. Adjustments for Covariates 
Analysis of covariance (ANCOVA) on the primary and secondary endpoints, with change from 
baseline as the dependent variable, will include the stratification variable sBA responder 
indicator as a covariate. These models will also include an interaction term for the covariate by 
treatment sequence (i.e., MRX-PBO-MRX or MRX-MRX-MRX).
If there appears to be a relative significant difference among treatment sequences with respect to 
baseline characteristics, that baseline variable may be added to the statistical model as a blocking 
factor or covariate to determine the effect on treatment. For this analysis, an interaction term for 
the covariate by treatment sequence will not be included.
ANCOVA models which only include the baseline value (of the variable of interest) as a single 
covariate will also be included.
ItchRO weekly morning severity scores, which are assessed over time during the 4-week 
Randomized Withdrawal phase, will also be analyzed using a mixed-effects model for repeated 
measures (MMRM). The MMRM model with change from baseline (Week 18) as the dependent 
variable, will include fixed, categorical effects of treatment group, visit (time point), and 
treatment group-by-visit interaction as well as the continuous, fixed covariates of baseline
ItchRO score and baseline-by-visit interaction.
6.1.4. Multiple Comparisons 
No adjustments will be made for multiple comparisons.
Because the definition of the pruritus endpoint used to assess efficacy was not pre-specified in 
the protocol (or SIAP) and the Type I error was not specifically controlled for, p-values for the 
analyses will be treated as nominal. The focus of the efficacy results will be on consistency and 
robustness of effect across multiple pruritus endpoints and methods of analysis.


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6.1.5. Handling of Dropouts or Missing Data 
6.1.5.1.
General
While all possible efforts will be made to ensure that subjects stay in the study and all data is 
collected as scheduled, the occurrence of missing data cannot be completely eliminated.
Any subject who withdraws from the study is 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, 100/ET, and EOT/ET), visit-based 
assessments performed during that visit will not be used in analysis summaries. 
For a subject who prematurely discontinues the study, their ET visit data will be assigned to a 
protocol-specified visit window (for analysis purposes) 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 (AE) 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.
MMRM Analysis Method
ItchRO weekly average morning severity scores derived for each week over the 4-week RW
treatment phase (i.e., Weeks 19, 20, 21, and 22) will be analyzed using a restricted maximum 
likelihood (REML)-based repeated-measures approach, as the principal sensitivity analysis 
method. Details on the MMRM model to be used are described in Section 8.
The MMRM method has been demonstrated extensively as an appropriate choice for the primary 
analysis in confirmatory clinical trials with continuous endpoints. This analysis method, which is 
from a broader class of direct-likelihood analyses methods, makes use of fully and partially 
observed data sequences from individual subjects by estimating the covariance between data 
from different time points (Molenberghs and Kenward, 20074). Further, it is often useful to 
implement MMRM using an unstructured approach to modeling both the treatment-by-time 
means and the variances and covariances, leading to what is essentially a multivariate normal 
model wherein treatment group means at the primary time point (Week 22 in this case) are 
adjusted to reflect both the actual observed data and the projected outcomes from the subjects 
with missing data (Molenberghs et al., 20045, Molenberghs and Kenward, 20074).
As a direct likelihood method, the MMRM method is a preferred approach for handling missing 
data in such designs. MMRM is a full multivariate model in nature, which avoids potential bias 
as a predetermined model and operates in a more general missing at random (MAR) framework
(Mallinckrodt et al., 20016). Data are considered MAR if, conditional upon the independent 
variables in the analytic model, the missingness depends on the observed outcomes of the 
variable being analyzed but does not depend on the unobserved outcomes of the variable being 


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analyzed. This assumption implies that the behavior of the post dropout observations can be 
predicted from the observed variables, and therefore that treatment effect can be estimated 
without bias using the observed data (European Medicines Agency, 20107). For studies of 
missing data in a controlled clinical trial setting, MAR is usually considered as a plausible 
underlying missing mechanism (Molenberghs and Kenward, 20074; Siddiqui et al., 20098,
Mallinckrodt et al., 20139). The assumption of MAR is often reasonable because the observed 
data and the models used to analyze them can explain much of the missingness (Little and Rubin, 
198710).
6.1.5.3.
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 18/LOCF, Week 22/LOCF, Week 48/LOCF, and Week 100/LOCF time points, where 
appropriate. Week 22/LOCF imputed time points are only applicable for ItchRO(Obs) weekly 
average score variables during the RW phase; there are no missing Week 22 assessments for 
ItchRO(Pt). 
For subjects who early terminated from the study prior to Week 100 or are otherwise missing 
Week 18, Week 22, Week 48, and/or Week 100 data will be imputed in a LOCF approach as 
follows:
x
OL Phase: last observation on or before Week 18 imputed as Week 18/LOCF;
x
RW Phase: last observation between Week 18 and end of Week 22 imputed as 
Week 22/LOCF (only applicable for ItchRO[Obs] weekly average score variables);
x
ARW Phase: last observation between Week 22 and end of Week 48 imputed as 
Week 48/LOCF and last observation after Week 22 and end of Week 100 imputed as 
Week 100/LOCF
For subjects 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 
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).
6.1.5.4.
Missing ItchRO Scores
In deriving ItchRO weekly and 4-week average scores, 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 subject visits derived dataset will be used. Further, for 
missing but expected dates (where ItchRO data exists), the last visit past the missing date is used 
and the appropriate amount of days is subtracted.


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In the event that a subject/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 and at least 20 of the 28 daily scores for a 28-day period. Compliance 
restrictions are not set for baseline ItchRO average scores.
If a subject/caregiver is not compliant with reporting ItchRO assessments during the 7-day 
period before a study visit, the weekly average score from the most recent, previous compliant 
7-day period will be used in a LOCF format. For non-compliant 4-week ItchRO assessments, the 
most recent compliant 28-day period will be used, where the 28 days minus the 7 days 
immediately prior to the study visit will be used. This process will be repeated as necessary. For 
example, if the 28-day period before the Week 6 visit (e.g., Study Days 15-42) is non-compliant, 
then Study Days 8-35 would be used. If that 4-week period is non-compliant then Study Days 
1-28 would be used. If that 4-week period is non-compliant then the 4-week ItchRO score would 
be missing. Additionally, the same ItchRO assessment day (morning/evening daily score) will 
not be used across different weekly/4-week time periods (i.e., no overlap).
6.1.5.5.
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 6.1.9).
6.1.5.6.
Responder Definitions
If a subject has a missing sBA, ItchRO, or CSS value at a week required in determining 
responder status, then the missing change from baseline value will be considered as not meeting 
the criteria for a responder.
6.1.5.7.
Missing Last Dose
For subjects 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.
6.1.5.8.
Missing Adverse Event Severity/Relationship
For analysis purposes, only the following rules will be applied for missing AE severity or 
relationship to study drug. For an AE that does not have a recorded relationship to study drug,
the event will be conservatively considered as “Possibly Related” to study drug. If the severity of 
an AE is missing, the severity will be reported as “Severity Not Recorded”.
6.1.5.9.
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.


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6.1.6. Investigative Sites 
An investigative site is defined as a single principal investigator (including sub-investigators) 
who enrols subjects for the study. If an investigator has multiple practice locations, these 
locations are considered a single investigative site.
Analyses will be based on data pooled across investigative sites. 
There is the potential that a subject could be transferred to a principal investigator that did not 
enrol the subject. Unless otherwise specified, the investigative site of the enrolling investigator 
will be used for the unique subject ID.
6.1.7. 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 subjects 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 subjects that were dose-
escalated after a drug interruption of > 28 days (between protocol amendments), the data 
collected/assessed during the dose-escalation period (i.e., DE Week -2 and DE Day 0 for both 
PA3 and PA4) will not be assigned to a post-dose analysis visit. Only the DE Day 0 values will 
be used as baseline values as described in Section 6.1.1.
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 3 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”).
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.


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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 subjects with an extended drug interruption, efficacy assessments after the 
interruption are essentially treated as if the subject was on study drug during the period of time 
that the subject was off study drug.
The analysis visit windows in Table 4 will also be used for all visit-based safety assessments that 
occurred before a drug interruption (due to a protocol amendment), including those subjects 
without such a drug interruption.


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Table 4
Analysis Visit Windows – Efficacy and Primary Safety Analysis
Analysis 
Visit
Analysis Visit 
Name
Target Day of 
Planned Visit
Assessment Window
(Study Days1)
3
Week 3
21
Post-dose ─ 31
6
Week 6
42
32 ─ 62
12
Week 12
84
63 ─ 105
18
Week 18
126
106 – Week 18 Visit Day2
22
Week 22
154
n/a3
28
Week 28
196
Week 22 Visit Day2 (plus 1 day) – 232
38
Week 38
266
233 – 301
48
Week 48
336
302 – 378
60
Week 60
420
379 – 476
72
Week 72
504
477 – 546
84
Week 84
588
547 – 630
96
Week 96
672
631 – 714
108
Week 108
756
715 – 812
120
Week 120
840
813 – 882
132
Week 132
924
883 – 966
144
Week 144
1008
967 – 1054
156
Week 156
1092
1055 – 1148
168
Week 168
1176
1149 – 1218
180
Week 180
1260
1219 – 1302
192
Week 192
1344
1303 – 1385
204
Week 204
1428
1386 – 1470
216
Week 216
1512
1471 – 1554
228
Week 228
1596
1555 – 1638
240
Week 240
1680
1639 – 1722
252
Week 252
1764
1723 – 1806
264
Week 264
1848
1807 – 1890
276
Week 276
1932
1891 – 1974
288
Week 288
2016
1975 – 2058
300
Week 300
2100
2059 – 2142
1 Study day relative to the date of first dose of study medication, unless otherwise specified.
2 All 29 subjects in the RW phase completed their Week 18 and Week 22 clinic visits.
3 For Week 22, the nominal visit or time point as collected in the CRF and/or database.


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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 subject 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 
subject listings.
For visit-based analyses (and listings) on safety data collected or assessed after a 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 Safety 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 ─ 98
16
Week 16
112
99 – 129
24
Week 24
168
130 - 196
36
Week 36
252
197 - 283
48
Week 48
336
284 – 367
60
Week 60
420
368 – 451
72
Week 72
504
452 – 535
84
Week 84
588
536 – 619
96
Week 96
672
620 – 703
108
Week 108
756
704 – 787
120
Week 120
840
788 – 871
132
Week 132
924
872 – 955
144
Week 144
1008
956 – 1039
156
Week 156
1092
1040 – 1123
168
Week 168
1176
1124 – 1207
180
Week 180
1260
1208 – 1291
192
Week 192
1344
1292 – 1375
204
Week 204
1428
1376 – 1459
1 Study day relative to the date of first re-initiation of study drug after the drug interruption.


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Because drug interruptions between protocol amendments occurred after the RW phase, all 
subjects were administered MRX at all post-interruption time points.
6.1.8. Variable Definitions 
x
“Open-Label Phase” is defined for analysis purposes as the period of time between 
the first dose of study drug and the end of study Week 18 (i.e., through the Week 18
visit date). 
x
“Randomized Withdrawal Phase” is defined for analysis purposes as the period of 
time between the beginning of Week 19 (i.e., Week 18 visit date plus 1 day) and the 
Week 22 visit (inclusive).
x
“After Randomized Withdrawal Phase” is defined for analysis purposes as the period 
of time between the beginning of Week 23 (i.e., Week 22 visit date plus 1 day) and 
the EOT visit (inclusive).
x
“Week 18/LOCF” (see Section 6.1.5.3)
x
“Week 22/LOCF” (see Section 6.1.5.3)
x
“Week 48/LOCF” (see Section 6.1.5.3)
x
“Week 100/LOCF” (see Section 6.1.5.3)
x
“sBA Responder” is defined as a subject with a reduction in sBA ≥50% from baseline 
(Day 0) to clinic visit Week 12 or Week 18. See Section 6.1.5.6.
x
“ItchRO Responder” is defined as a subject with a reduction in ItchRO(Obs) weekly 
average morning severity score ≥1.0 point from baseline (Day 0) to clinic visit Week 
12 or Week 18. See Section 6.1.5.6.
If a subject has a missing sBA or ItchRO value at a clinic visit required in 
determining responder status, then the missing change from baseline value would be 
considered as not meeting the criteria for a responder (non-responder).
x
Treatment-emergent adverse events (TEAEs) are defined in Section 6.1.10.
x
Concomitant medications are defined in Section 6.1.10.
6.1.9. Derived Variables 
x
Age (months) at Baseline:
For subjects 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


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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 - 4 years
3 if age (full years) at baseline is 5 - 8 years
4 if age (full years) at baseline is 9 - 12 years
5 if age (full years) at baseline is 13 - 18 years
x
Body Mass Index (kg/m2) =
௪௘௜௚௛௧ ௜௡ ௞௜௟௢௚௥௔௠௦
(௛௘௜௚௛௧ ௜௡ ௠௘௧௘௥௦)మ
x
Treatment Duration (days) = LASTDAY – FIRSTDAY + 1 day – GAP
Treatment duration is derived overall and for each treatment phase (see below). For the 
OL and ARW (Week > 22 - 48) treatment phases, treatment duration is derived for the 
MRX QD dosing regimen. For the RW phase, treatment duration is derived separately for 
the MRX and PBO (QD) treatment groups. For the ARW (Week > 48) phase, treatment 
duration is derived separately for the MRX QD and MRX BID dosing regimens. For the 
overall study, treatment duration is derived for the MRX treatment group, where both QD 
and BID dosing regimens are considered.
For the OL Phase (Week 0 - 18): LASTDAY = date of the Week 18 visit OR the 
date of last dose for subjects that ET before their Week 18 visit,
FIRSTDAY = date of first dose, and GAP = 0; 
For the RW Phase (Week > 18 - 22): LASTDAY = date of the Week 22 visit OR 
the date of last dose for subjects that ET before their Week 22 visit,
FIRSTDAY = date of the Week 18 visit plus 1 day, and GAP = 0;
For the ARW Phase (Week > 22 - 48): LASTDAY = date of the Week 48 visit OR 
the date of last dose for subjects that ET before their Week 48 visit,
FIRSTDAY = date of the Week 22 visit plus 1 day, and GAP = 0;
For the ARW Phase (Week > 48):
During the Week > 48 treatment phase, subjects may only receive MRX QD 
dosing or both QD and BID dosing, and potentially switch between QD to BID 
to QD dosing (depending upon their safety profile). Thus, treatment duration 
will be derived separately for MRX QD and MRX BID dosing. 


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MRX QD Treatment Duration is derived as the sum over the days on which 
a subject is on a QD dosing regimen minus GAP, where GAP = # days 
subject was off study between protocol amendments (i.e., PA2 and PA3 or 
PA3 and PA4).
MRX BID Treatment Duration is derived as the sum over the days on which 
a subject is on a BID dosing regimen (GAP = 0).
The date of the Week 48 visit plus 1 day would be the earliest date on 
which treatment duration would be derived during the Week > 48 phase.
For the Overall Study Phase (Week 0 – EOT): LASTDAY = date of the EOT visit
OR the date of last dose for subjects that withdrew from the study, FIRSTDAY = 
date of first dose, and GAP = total # of days subject was off study between 
protocol amendments.
For ET subjects, the date of last dose is considered, rather than the last visit date during 
the study phase in which the subject early terminated. For subjects 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 During QD Dosing = 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 subject being off study between protocol amendments]
Compliance is derived overall (Week 0-EOT) and for the following treatment 
phases: Week 0 - 18, Week > 18 - 22, Week > 22 - 48, and Week > 48. Study 
drug compliance will not be calculated for those subjects whose date of last dose 
is unknown.
x
% Compliance During BID Dosing = 100 x Number of days both morning and evening 
dose is taken / BID Treatment Duration (days)
where, 
Number of days both morning and evening dose is taken = BID Treatment Duration 
(days) – Number of days the morning and/or evening dose was missed during the 
BID treatment period [not including dosing gaps due to the subject being off study 
between protocol amendments]


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BID dosing compliance is determined for the Week > 48 study phase, while 
subjects are on the BID dosing regimen. Only subjects that initiated ADE are 
included.
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 subject is receiving a constant dose)
Total drug exposure is derived overall (Week 0-EOT) and for each treatment 
phase: Week 0 - 18, Week > 18 - 22, Week > 22 - 48, and Week > 48. The time 
periods for which no study drug was administered due to dosing gaps while a 
subject is off study (between protocol amendments) are not included. For
subjects 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.
For the ARW (Week > 48) phase, total drug exposure is derived separately for 
the MRX QD and MRX BID dosing regimens. For the overall study, total drug 
exposure is derived for the MRX treatment group, where both QD and BID 
dosing regimens are considered. 
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 - 18, Week > 18 - 22, Week > 22 - 48, and Week > 48. The time 
periods for which no study drug was administered due to dosing gaps while a 
subject is off study (between protocol amendments) are not included.
For the ARW (Week > 48) phase, average daily dose is derived separately for 
the MRX QD and MRX BID dosing regimens. For the overall study, average 
daily dose is derived for the MRX treatment group, where both QD and BID 
dosing regimens are considered.
x
ItchRO Weekly Average Morning Score = Sum of ItchRO daily morning scores (over 
a 7-day period) divided by the number of days ItchRO completed
ItchRO Weekly Average Evening Score = Sum of ItchRO daily evening scores (over a 
7-day period) divided by the number of days ItchRO completed 


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PCN Number LUME3296 
 
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The above definitions apply to both severity (Item 1) and frequency (Item 3,
Observer only) weekly average scores. The baseline weekly morning/average 
evening score is derived using the 7 days immediately before the baseline visit 
date, according to the baseline definitions described in Section 6.1.1. The 
derivation for post-baseline weekly morning/average evening scores are
described in Section 2.2.2.5.
x
ItchRO 4-Week Average Morning Score = Sum of ItchRO daily morning scores (over 
a 28-day period) divided by the number of days ItchRO completed
ItchRO 4-Week Average Evening Score = Sum of ItchRO daily evening scores (over a 
28-day period) divided by the number of days ItchRO completed 
The above definitions apply to both severity (Item 1) and frequency (Item 3, 
Observer only) 4-week average scores. The baseline 4-week morning/average 
evening score is derived using the 28 days immediately before the baseline visit 
date, according to the baseline definitions described in Section 6.1.1. The 
derivation for post-baseline 4-week morning/average evening scores are 
described in Section 2.2.2.5.
x
ItchRO(Obs) Weekly Average Severity Score (based on the daily average of 
morning and evening scores) = Sum of ItchRO(Obs) daily average of morning and 
evening scores (over a 7-day period) divided by the number of days ItchRO completed
ItchRO(Obs) Weekly Average Severity Score (based on the daily maximum of 
morning and evening scores) = Sum of ItchRO(Obs) daily maximum of morning and 
evening scores (over a 7-day period) divided by the number of days ItchRO completed 
The baseline weekly average severity scores are derived using the 7 days 
immediately before the baseline visit date, according to the baseline definitions
described in Section 6.1.1. The derivation for post-baseline weekly average 
severity scores are described in Section 2.2.2.5.
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.


Statistical Analysis Plan
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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
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
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.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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x
PedsQL Scoring Algorithm:
For each item of the PedsQL instrument (parent and subject), a 5-point response scale is 
used (0 = never, 1 = almost never, 2 = sometimes, 3 = often, 4 = almost always). Items 
are reverse-scored and linearly transformed to a 0-100 scale (0 → 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:
¾
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)
¾
Physical Health Summary Score – computed as the sum of the items over the 
number of items answered in the Physical Functioning Scale (and Physical 
Symptoms Scale for infants) from the PedsQL Generic Core Scales (up to 19 
items)
¾
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)
¾
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)
¾
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)
¾
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)
¾
Family Impact Summary Score – computed as the sum of the items over the 
number of items answered in the Daily Activities and Family Relationships 
Scales from the PedsQL Family Impact module (8 items)
Total scale, physical health summary, psychosocial health summary, and 
multidimensional fatigue scale scores are computed individually for the parent and 
subject reports. Family impact and parent functioning total scale and summary scores are 
based on parent-reported items. 


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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|    AD-PR-109.01 Effective date: 26 Jun 2017
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x
Body Weight and Height z-Scores:
Height and weight z-scores are based on a subject’s gender and age at each scheduled visit. 
For subjects less than 24 months of age, the World Health Organization (WHO) growth 
charts11 are recommended by the Centers for Disease Control (CDC) and will be used to 
derive z-scores. For subjects at least 24 months of age, the CDC growth charts12 will be 
used to derive z-scores. 
x
Responder Definitions:
sBA Responder is defined as a subject with a reduction in sBA ≥50% from baseline 
(Day 0) to clinic visit Week 12 or Week 18.
sBA Responder at Week 48 is defined as a subject with a reduction in sBA ≥50% 
from baseline (Day 0) to clinic visit Week 48.
ItchRO Responder is defined as a subject with a reduction in ItchRO(Obs) weekly 
average morning severity score ≥1.0 point from baseline (Day 0) to clinic visit
Week 12 or Week 18.
CSS Responder – A responder is defined (separately at each analysis visit) as a:
o
Decrease from baseline ≥1
o
Decrease from baseline ≥ 2
CIC-Itch, CIC-Xan, and PIC, Responders - A responder is defined (separately at 
each analysis visit) as a score ≤ 3 (i.e., a little better, better, or much better).
CGTB Responder - A responder is defined (separately at each analysis visit) as a 
score ≤ 2 (i.e., somewhat, or definitely).
If a subject has a missing value at a clinic visit required in determining responder status, 
then the missing observed or decrease from baseline value would be considered as not 
meeting the criteria for a responder (non-responder).
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.
Subject Age
Age at screening will be used as the age for the determination of the appropriate ItchRO 
instrument to be used for the study. The age of a subject at Study Day 0 (baseline) will be used 
as the age for the determination of the appropriate PedsQL module to be used for the study. The 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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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 thesaurus. Prior and concomitant medications will be coded using WHO-DD
(Enhanced version Sept 2019), Anatomical Therapeutic Chemical (ATC) level 2 for ATC class
and Clinical Substance for preferred term.
Prior and Concomitant Medication Definition and Handling of Data
A concomitant medication is any non-protocol specified drug or substance administered during 
participation in the study. 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 subjects with study drug interruptions (for any reason), any concomitant medication that 
starts > 14 days after the last dose before the drug interruption and ended before the study drug 
was re-initiated will not be considered (for analysis purposes) as a concomitant medication.
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 subjects 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 subjects, AEs that start 
> 14 days after the last dose (before study drug interruption) and ended before the drug is re-
initiated will not be considered as treatment-emergent.
Any 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 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” 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
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(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 4.0. If the CTCAE does not have a grading for a particular 
AE, the severity of the event is reported by the investigator as mild, moderate, or severe. If 
CTCAE is not used and the event is reported as life-threatening then the severity of the event is 
considered as “Life-Threatening (CTCAE Grade 4)” for analysis purposes. Similarly, if CTCAE 
is not used and the event results in death then, for analysis purposes, the severity of the event is 
considered as “Fatal (CTCAE Grade 5)”.
A treatment-related AE is any AE with a relationship to the study drug of related or possibly 
related.
An AE that does not have a 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 
Alagille disease 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 elevations. MRX is 
associated with gastrointestinal disturbances such as diarrhoea.
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 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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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 subject’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). 
Partial AE or Medication Dates
Adverse events or medications with entirely missing start dates will be classified as 
treatment-emergent or concomitant, as appropriate.
For partial AE or 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, 
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, 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 Quantification
In general, for quantitative laboratory values reported as “<” or “≤” the lower limit of 
quantification (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 quantification 
(ULOQ), the reported value (i.e., ULOQ) will be used for analysis.
Repeat Laboratory Test Results
For analysis purposes, repeat laboratory test results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non-missing repeat 
laboratory value will be used for data analysis.


Statistical Analysis Plan
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Dose Used in Safety Analysis
For all safety and tolerability analyses, subjects 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. 
For all other safety summaries, treatment groups will be presented as either MRX (or PBO,
where applicable).
Treatment Duration and Exposure
For subjects 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 subjects whose date of last study drug application is 
unknown.
7.
STUDY SUBJECTS AND DEMOGRAPHICS 
7.1.
Disposition of Subjects and Withdrawals 
Subject disposition will be presented overall and by treatment period and assigned treatment 
group.
Subject disposition will include tabulations of the number and percentage of subjects 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, subjects that did not consent to the optional long-term treatment extensions 
(PA3 or PA4) are not considered to have completed treatment. Reasons for withdrawal will 
include those collected on the CRF, along with not consenting to PA3 or PA4 (separately). 
For the by study phase and treatment group summaries, the number and percentage of subjects
presented will be based on the number of subjects in each treatment period (OL, RW, ARW 
Week 23 - 48, and ARW Week > 48) and treatment group (i.e., MRX and PBO for the RW phase 
only).
The subject disposition tabulation will also include the number of subjects screened for 
eligibility (under the original protocol), the number of screen failures (under the original 
protocol), and enrolled/randomized/continued, as appropriate for each treatment phase.
For the overall summary, the number and percentage of subjects that were initiated on the BID 
dosing regimen, and discontinued early during BID dosing regimen (along with reasons for 
withdrawal) will also be summarized. Percentages will be based on the number of subjects in the 
Safety Population.
Study drug accountability and compliance listings will be prepared for all subjects, showing 
when the planned dosing schedule was not followed, along with the date and type of dosing 
deviation. Other disposition and study conduct information, including major protocol deviations 
will be listed.


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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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 a 
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 Mirum Pharmaceuticals and Premier to 
determine the final classification, however all deviations will be reviewed with the study team at 
regular intervals.
Major protocol deviations may include:
• Significant and/or persistent dosing error
• Subject 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 subject listing. Additionally, inclusion 
and exclusion criteria not met and reasons for screen failures will be listed.
7.3.
Demographics and Other Baseline Characteristics 
Subject demographics and other baseline characteristics will be presented (1) by treatment period 
and assigned treatment group, (2) by sBA responder/non-responder and assigned treatment group 
(overall and during the RW phase), and (3) by ItchRO responder/non-responder and assigned 
treatment group (overall and during the RW phase).
Summary statistics for age (at baseline), age group, gender, country, mutation type, weight 
z-score, height z-score, and BMI 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.


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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7.4.
Disease History and Baseline Disease Characteristics 
Disease history and baseline disease characteristics will be presented (1) by treatment period and 
assigned treatment group, (2) by sBA responder/non-responder and assigned treatment group 
(overall and during the RW phase), and (3) by ItchRO responder/non-responder and assigned 
treatment group (overall and during the RW phase).
Summary statistics will be presented for the following baseline variables:
• time since original diagnosis of ALGS
• family history of ALGS (yes/no)
• presence of paucity (yes/no/unknown)
• mutation present (JAGGED1/NOTCH2)
• additional clinical criteria/features of ALGS (chronic cholestasis, cardiac disease, renal 
abnormalities, vascular abnormalities, skeletal abnormalities, ocular abnormalities, and 
characteristic facial features)
• used anything to treat itch in the past (yes/no)
• type of therapy used to treat itch in the past (topical/oral/other)
• specific therapy used to treat itch in the past (reference list on Disease History CRF)
• baseline pruritus assessments:
– CSS (continuous and categorical [0,1,2,3,4])
– ItchRO(Obs) weekly average morning severity score
– ItchRO(Obs) weekly average morning frequency score
– Clinician Xanthoma Scale score (continuous and categorical [0,1,2,3,4])
• baseline levels of select efficacy laboratory tests:
– serum bile acids (sBA)
– ALP
– ALT
– bilirubin (total and direct)
– cholesterol
– LDL-C
– C4
The analyses of disease history and baseline disease characteristics will be conducted on the
Safety Population.
A summary of demographic and baseline disease characteristics for all enrolled subjects will also 
be provided.


Statistical Analysis Plan
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Subject demographics and baseline characteristics, and medical and surgical history information
will be presented in subject listings.
7.5.
Prior Medications 
Prior medications will be summarized descriptively by treatment phase (OL, RW, and ARW), 
and treatment group for the RW treatment phase, using the number and percent of subjects by 
ATC class and preferred term (i.e., chemical substance). 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/therapy,
1 medication/therapy, 2 medications/therapies, and at least 3 medications/therapies. For (1) and 
(2), medications that treat pruritus are listed in Section 6.1.10.
Prior medications will be presented separately from concomitant medications.
Prior and concomitant medications will also be presented separately in subject listings. A
separate listing of prior medications that treat pruritus will also be presented.
7.6.
Treatment Compliance 
Treatment compliance will be calculated for each subject and summarized descriptively. This 
analysis will be completed using the Safety Population for each of the following study phases:
Weeks 0 - 18, Weeks > 18 - 22, Weeks > 22 - 48, Weeks > 48, and overall (Weeks 0 - EOT). 
Subjects that withdraw early before any given study phase are not included in the analysis of that 
study phase.
For the RW treatment phase, treatment compliance will be summarized for both treatment groups 
(MRX and PBO).
For the ARW Week > 48 treatment period, treatment compliance will be summarized separately 
for the MRX QD and BID dosing regimens.
During the QD dosing regimen, a subject is considered compliant with treatment (for a given 
day) if any amount of study drug was administered. During the BID dosing regimen, a subject is 
considered compliant with treatment (for a given day) if both the morning and evening doses of 
study drug were administered.
Study drug accountability will be presented in a subject listing.
8.
EFFICACY ANALYSIS 
The primary analysis population for efficacy analysis will be the MITT Population defined in 
Section 5. Analyses for the primary and secondary efficacy outcome variables will also be 


Statistical Analysis Plan
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performed on the ITT Population. All sensitivity analysis will be performed on the ITT 
Population, unless otherwise specified.
Subjects will be analyzed by assigned treatment group (MRX or PBO during the RW phase) 
and/or by assigned treatment sequence (e.g., MRX-PBO-MRX, MRX-MRX-MRX). Efficacy 
data summaries will be provided by treatment phase and treatment group/sequence, unless 
otherwise specified.
All efficacy data will be presented in subject listings.
8.1.
Primary Efficacy Analysis 
The change from baseline in serum bile acid will be displayed for each treatment group during 
the randomized withdrawal phase using summary statistics including a 95% CI 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.
The difference between treatment groups in change from Week 18 to Week 22 in serum bile acid 
will be evaluated using an ANCOVA model with treatment group as a factor, and Week 18 
serum bile acid as a covariate. An ANCOVA model that includes the stratification variable sBA 
responder indicator as an additional covariate will also be performed on the ITT Population. This 
model will also include the sBA responder covariate by treatment sequence interaction term. The 
LS mean difference between treatment groups (MRX minus PBO) with standard error, 95% CI 
for the LS mean difference, and p-value for testing if the treatment group LS means are equal 
will be calculated to determine if the change in sBA levels between the treatment groups are 
statistically significant.
The primary analysis population will be the MITT Population. Analysis on the ITT Population
will also be performed.
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, with the 
exception of PIC, CIC, and CGTB, by ANCOVA. For the ItchRO weekly average morning
severity scores during the RW treatment phase, treatment effects over the 4-week time period
will also be analyzed using a REML-based repeated-measures approach.
Correlation analysis on change from baseline to Week 18, change from baseline to Week 48, and 
change from Week 18 to Week 22 values will also be performed on ItchRO weekly average 
scores and CSS scores.
Efficacy measures that are categorical binary responder outcomes will be analyzed using the chi-
square or Fisher’s Exact test, as appropriate based on sample sizes. Fisher’s Exact test will be 
chosen over the chi-square test if any of the cell counts are less than 5. For ordinal non-binary 


Statistical Analysis Plan
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outcomes, the Cochran-Mantel-Haenszel (CMH) test will be used to take the ordinal nature of 
the variable into account.
Analyses specific to each efficacy variable are described below.
8.2.1. Continuous Measures 
Efficacy variables that will be analyzed as continuous measures (i.e., ItchRO scores, efficacy lab 
levels, CSS, Clinician Xanthoma Scale score, CIC, PIC, CGTB, height and weight z-scores, and 
select PedsQL total/summary scale scores) will be examined by analysis visit for each of the
following 3 treatment phases:
OL Phase (Day 1 – Week 18): Observed and change from baseline (Day 0) values.
RW Phase (Weeks 19 - 22): Observed, change from baseline (Day 0), and change from 
Week 18 values, where applicable (e.g., not applicable for Clinician Xanthoma Scale score 
or height and weight z-scores).
ARW Phase (Weeks > 22): Observed and change from baseline (Day 0) values.
Efficacy laboratory tests that will be statistically summarized include sBA, ALP, ALT, bilirubin 
(total and direct), C4, cholesterol, and LDL-C. A complete list of efficacy laboratory tests, and 
associated units of measure to be used for reporting, are listed in Appendix 2, noting that several 
efficacy laboratory results will not be statistically summarized, but rather included in subject 
listings. Bilirubin (total and direct), ALP, and ALT are considered as both safety and efficacy 
laboratory tests, and will be analyzed as efficacy variables. CSS, CIC-Itch, CIC-Xan, PIC, and 
CGTB will be examined as continuous and categorical measures.
A complete list of continuous efficacy variables and endpoint definitions (including sensitivity) 
are provided in Table 2.
Summary statistics, ANCOVA, MMRM, and correlation analyses will be performed as described 
below.
8.2.1.1.
Summary Statistics by Analysis Visit
Summary statistics for all continuous efficacy measures will be presented by analysis visit on the 
ITT Population as observed and change from baseline values. For the OL and ARW treatment 
phases, summary statistics will be presented overall and for each treatment group during the RW 
phase. For the RW phase, summary statistics will be presented by the randomized treatment 
group. 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.
For ItchRO(Obs) weekly average morning severity scores and sBA levels, summary statistics by 
analysis visit will also be presented for the following subgroups:


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•
Age group (up to 24 months, 2 - 12 years, > 12 years)
•
Baseline sBA (< 275 μmol/L, ≥275 μmol/L)
•
Baseline total bilirubin (< 3.8 mg/dL, ≥3.8 mg/dL)
•
Baseline ALT (< 90 U/L, ≥90 U/L)
•
Baseline ItchRO(Obs) weekly average morning severity score (< 3 pts, ≥3 pts)
For the subgroup analyses, observed and change from baseline (Day 0) values will be presented 
for the OL and ARW phases. For the RW phase, observed and change from Week 18 values will 
be presented for the MRX and PBO treatment groups.
Summary statistics will be presented in the ITT Population.
8.2.1.2.
ANCOVA by Analysis Visit
For all continuous efficacy variables that are assessed at the baseline visit, an ANCOVA will be 
performed for each post-baseline analysis visit. The ANCOVA model will include change from 
baseline as the dependent variable, treatment sequence (MRX-MRX-MRX or MRX-PBO-MRX)
as a fixed effect, and baseline value as a covariate. The ANCOVA will use a REML estimation 
method for the covariance parameter. 
For each analysis visit, least squares (LS) means with SE, 95% CI for the LS means, and p-value 
for testing if the LS mean is zero will be calculated for each treatment sequence on observed and 
change from baseline values. For each analysis visit, the LS mean difference between treatment 
sequences (MRX-MRX-MRX minus MRX-PBO-MRX) with standard error, 95% CI for the LS 
mean difference, and p-value for testing if the treatment sequence LS means are equal will be 
presented.
The ANCOVA will be repeated in the following subgroups and/or data treatments as sensitivity 
analyses:
x
Subjects considered to be an ItchRO Responder (see Section 6.1.9). This analysis 
will be performed on change from baseline in the following variables: ItchRO(Obs) 
weekly average morning severity score, ItchRO(Obs) and ItchRO(Pt) weekly 
average severity scores based on the daily maximum of morning and evening scores, 
ItchRO(Obs) and ItchRO(Pt) weekly average severity scores based on the daily 
average of morning and evening scores, and each efficacy laboratory test level.
x
Subjects considered to be a sBA Responder at Week 48 (see Section 6.1.9). This 
analysis will be performed on change from baseline in ItchRO(Obs) weekly average 
morning severity score, and sBA level.
x
As a sensitivity analysis, ItchRO(Obs) weekly average morning severity scores are 
alternatively derived using a minimum of 3 (rather than 4) daily morning scores to 
determine a “compliant” weekly average score. This analysis will be performed on


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change from baseline in ItchRO(Obs) weekly average morning severity score using the 
alternate definition of a compliant week. Based on the alternate definition, there are no 
missing weekly average morning scores for each week of the RW treatment phase.
x
For subject 050007, the 4-week time period immediately after the Week 18 visit date 
will be used to derive ItchRO weekly scores for Weeks 19, 20, 21, and 22. This
sensitivity analysis will be performed on change from baseline in ItchRO(Obs)
weekly average morning severity score, and sBA level, for analysis visits during the 
RW and ARW phases. An sBA sample was not collected in the 4-week time period 
following the Week 18 visit date for this subject, thus the sensitivity analysis on sBA 
levels will not include a “true” Week 22 sBA result. 
Subject 050007 was hospitalized during the RW phase for a SAE of 
polytraumatism/splenic rupture which made it impossible for the subject to comply 
with in-clinic visits and study drug treatment. It was decided by the Medical 
Monitors that this subject should discontinue study medication until the SAE 
resolved and the subject was able to comply with study requirements. The subject 
was on placebo for the first 5 weeks of the RW phase and then discontinued study
drug for 13 weeks before their “Week 22” clinic visit. The primary analysis uses the
"Week 22" sBA sample and the clinic visit date as the anchor in deriving Week 22 
ItchRO weekly average scores, rather than (i) excluding this subject’s sBA data 
during the RW phase, or (ii) using ItchRO data from the 4 weeks immediately 
following this subject's Week 18 clinic visit.
x
If there appears to be a relative significant difference among treatment sequences
with respect to baseline characteristics, that baseline variable may be added to 
individual ANCOVA models as a blocking factor or covariate to determine the effect 
on treatment. For this analysis, an interaction term for the covariate by treatment 
sequence will not be included. These analyses will be performed on change from 
baseline ItchRO(Obs) weekly average morning severity score.
The following baseline covariates are currently considered as a covariate for this 
analysis: presence of paucity, CSS, sBA, total bilirubin, C4, age in months, BMI, 
ALT, family history of ALGS, cholesterol, GGT, and Clinician Xanthoma Scale 
score.
An ANCOVA that also includes the stratification variable, sBA responder group, as an
additional covariate and the sBA responder group by treatment sequence interaction term in the 
model will also be performed. This analysis will be performed in change from baseline on the 
following efficacy variables: ItchRO(Obs) and ItchRO(Pt) weekly average morning severity 
scores, laboratory test levels, CSS, height and weight z-scores, and the select PedsQL total scale 
and summary scores.
ANCOVA described above will be performed on the ITT Population.


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For the MITT Population (i.e., sBA Responders), the ANCOVA model that includes change 
from baseline as the dependent variable, treatment sequence as a fixed effect, and baseline value 
as a covariate will also be used for the following efficacy variables: ItchRO(Obs) weekly average 
morning severity score, ItchRO(Obs) and ItchRO(Pt) weekly average severity scores based on 
the daily maximum of morning and evening scores, ItchRO(Obs) and ItchRO(Pt) weekly average 
severity scores based on the daily average of morning and evening scores, and each efficacy 
laboratory test level.
8.2.1.3.
MMRM Analyses
ItchRO(Obs) and ItchRO(Pt) weekly average morning severity scores derived for each week 
over the 4-week RW treatment phase (i.e., Weeks 19, 20, 21, and 22) will be analyzed using a 
REML-based repeated-measures approach, as the principal sensitivity analysis method. The 
MMRM analysis model, with change from baseline (Week 18) as the dependent variable, will 
include the fixed, categorical effects of treatment group, visit (time point), and treatment group-
by-visit interaction as well as the continuous covariates of baseline and baseline-by-visit 
interaction.
An unstructured variance/covariance matrix, shared across treatment groups, will be used to 
model the variances and covariances for the 4 time points included in the model. The 
unstructured variance/covariance does not impose any restrictions on the pattern of the matrix 
elements. Every attempt (e.g., relaxing the convergence criteria, increasing the iteration limit, 
choosing reasonable starting values for the estimates) will be made to ensure convergence using 
the unstructured modeling of within-subject correlations. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom and adjust standard errors.
The p-value for testing the statistical significance of each effect in the MMRM model will be 
presented. For each time point, LS means with SE, 95% CI for the LS means, and p-value for 
testing if the LS mean is zero will be present for each treatment group on change from baseline 
(Week 18). For each time point, the LS mean difference between treatment groups (MRX minus 
PBO) with standard error, 95% CI for the LS mean difference, and p-value for testing if the 
treatment group LS means are equal will be presented.
The primary comparison will be the contrast (difference in least-squares mean) between 
treatments at the last visit during the RW phase (Week 22). The overall p-value for the model 
will also be presented to test the null hypothesis that there is no change at any time point. 
For ItchRO(Obs) weekly average morning severity scores, MMRM analyses will be repeated as 
sensitivity analyses using the below data treatments or added covariates:
x
A minimum of 3 (rather than 4) daily morning scores will be used to determine a 
“compliant” weekly average score. Based on this alternate definition, there are no 
missing weekly average morning scores at any of the 4 time points during the RW 
treatment phase.


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x
For subject 050007, the 4-week time period immediately after the Week 18 visit date 
will be used to derive ItchRO weekly scores for Weeks 19, 20, 21, and 22. See above 
for further information regarding this subject.
x
Include the stratification variable, sBA responder group, as an additional covariate in
the model.
x
Include baseline BMI as an additional covariate in the model.
x
Includes gender, age (in months), and baseline BMI as additional covariates in the model.
The MMRM analyses described above will be performed on the ITT Population.
8.2.1.4.
Correlation Analyses
Pairwise correlation analysis on change from baseline to Week 18, change from baseline to 
Week 48, and change from Week 18 to Week 22 values will also be performed on the following 
efficacy variables:
•
ItchRO(Obs) weekly average morning severity score
•
ItchRO(Obs) weekly average evening severity score
•
ItchRO(Pt) weekly average morning severity score
•
ItchRO(Pt) weekly average evening severity score
•
CSS score
For each pairwise correlation, the number of non-missing pairs, the Pearson correlation 
coefficient, and associated 95% confidence limits and p-value will be presented. The confidence 
limits on the correlation coefficients will be based on Fisher’s z transformation (without bias 
adjustment). 
Correlation coefficient estimates for change from Week 18 to Week 22 will be presented by 
treatment sequence.
Correlation analyses will be performed on the ITT Population.
8.2.1.5.
Efficacy Graphical Presentations
Change from baseline in ItchRO(Obs) and ItchRO(Pt) weekly average morning scores, sBA, C4, 
bilirubin (total and direct), ALT, ALP, 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.
Change from Week 18 to Week 22 LS means and associated 95% CIs in sBA based on the 
ANCOVA will also be displayed using the MITT Population.
Planned efficacy figures are described in Section 13.3. Additional figures may be added post-hoc 
to further examine study data.


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8.2.1.6.
Efficacy Subject Listings
All efficacy data will be presented in subject listings, including the following efficacy variables 
that were not included in tabular summaries: 
x
ItchRO(Obs) and ItchRO(Pt) morning and evening daily scores, along with responses to 
all other questions on the ItchRO questionnaire.
x
PedsQL total scale and summary scores, along with all individual responses to questions 
in the core generic PedsQL module, and the multidimensional fatigue and family impact 
questionnaires.
x
Cholestasis biomarkers including autotaxin, FGF-19, FGF-21, % unconjugated bile acids, 
total conjugated bile acids, total unconjugated bile acids, and the 15 bile acid subspecies
(i.e., chenodeoxycholic acid, cholic acid, deoxycholic acid, glycochenodeoxycholic acid, 
glycocholic acid, glycodeoxycholic acid, glycolithocholic acid, glycoursodeoxycholic 
acid, lithocholic acid, taurochenodeoxycholic acid, taurocholic acid, taurodeoxycholic 
acid, taurolithocholic acid, tauroursodeoxycholic acid, and ursodeoxycholic acid).
8.2.2. Categorical Measures 
CSS, PIC, CIC-Itch, CIC-Xan, and CGTB will be analyzed as both ordinal and binary 
(responder/non-responder) measures using CMH and chi-square (or Fisher’s Exact) tests, 
respectively. These variables will be examined by analysis visit for each of the 3 treatment 
phases (i.e., OL, RW, and ARW).
ItchRO(Obs) and ItchRO(Pt) morning severity scores will be summarized by time period, overall 
and by treatment group, as the number and percent of days the daily morning score is ≤1 point. 
Time periods include Day 1 - Week 6, Weeks 7 - 12, Weeks 13 - 18, Weeks 19 - 22,
Weeks 23 - 48, Weeks 49 - 98, and Week > 98. No inferential statistical tests will be performed.
Contingency cross-classification tables of ItchRO(Obs) and ItchRO(Pt) daily severity scores at 
Week 18 and Week 22 (i.e., for all 7 days in the week) will be presented individually for 
morning and evening scores. No inferential statistical tests will be performed.
For ALT and total bilirubin, the number and percent of subjects at varying threshold levels will 
be presented by analysis visit, overall and by treatment sequence. ALT thresholds include > 3 x 
upper limit normal (ULN), > 5 x ULN, > 10 x ULN, and > 20 x ULN, noting that these 
categories are not mutually exclusive. The threshold for total bilirubin is > 2.5 mg/dL. No 
inferential statistical tests will be performed.
Categorical analyses will be performed on the ITT Population.
8.2.2.1.
CMH Analyses
For ordinal measures, the CMH test will be applied to test for no association between treatment 
group and the variable of interest. For the OL and ARW treatment phases, the number and 


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percentage of subjects at each level of the 7- or 5-point scale, for PIC/CIC or CGTB respectively, 
will be presented overall and for each treatment group during the RW phase. For the RW phase, 
the number and percentage of subjects at each level will be presented by the randomized 
treatment group. Similar analysis will be performed on change from baseline in CSS scores by 
analysis visit.
8.2.2.2.
Chi-Square or Fisher’s Exact Tests
For binary measures, the chi-square or Fisher’s Exact test will be used to test for no association 
between treatment group and response (responder/non-responder). For the OL and ARW 
treatment phases, the number and percentage of subjects categorized as a responder and non-
responder will be presented overall and for each treatment group during the RW phase. For the 
RW phase, the number and percentage of subjects categorized as a responder and non-responder 
will be presented by the randomized treatment group. For PIC and CIC, a responder is defined as 
an impression of change score of ≤3 (i.e., a little better, better, or much better). For CGTB, a 
responder is defined as a score of ≤2 (i.e., somewhat, or definitely). For CSS, 2 responder 
definitions are analyzed separately. CSS responder criteria include (a) a decrease from baseline 
score of at least 1, and (b) a decrease from baseline score of at least 2.
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.
For visit-based safety data (i.e., vital signs, BMI, and safety labs), the primary analysis will 
exclude any data collected or assessed after a drug interruption > 28 days due to a subject being 
off study (between protocol amendments). Visit-based data collected after the drug interruption, 
at the point of study drug re-initiation, will be analyzed separately as a sensitivity analysis.
For all safety analyses, subjects 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. For all other 
safety summaries, treatment groups will be presented as either MRX (or PBO, where applicable).


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All safety and tolerability data will be presented by treatment sequence in subject listings. All
visit-based safety data collected or assessed after the drug interruption period (between protocol 
amendments) will be presented in separate subject listings.
9.1.
Treatment Exposure 
Treatment exposure will be summarized descriptively overall and by each of the following 
treatment periods: OL, RW, ARW Week > 22 - 48, and ARW Week > 48. These summaries will 
include: average daily dose (μg/kg/day), total drug exposure (μg/kg), and treatment duration 
(days). Reference Section 6.1.9 for the derivation of these variables.
For the RW treatment phase, treatment duration will be summarized for both treatment groups 
(MRX and PBO).
For the ARW Week > 48 treatment period, average daily dose, total drug exposure, and 
treatment duration will be summarized separately for the MRX QD and BID dosing regimens.
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:
•
≤ 13 Weeks
•
> 13 to 23 Weeks
•
> 23 to 78 Weeks (0.5 - 1.5 yrs)
•
> 78 to 104 Weeks (1.5 - 2 yrs)
•
> 104 to 156 Weeks (2 - 3 yrs)
•
> 156 to 208 Weeks (3 - 4 yrs)
•
> 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 and a 
start date before the last dose of study drug plus 14 days. For subjects with > 14 days of study 
drug interruption/withdrawal, the definition of a TEAE considers both the date of the last dose 
prior to drug interruption and the actual last dose (see Section 6.1.10).
Analysis of TEAEs will be performed overall and separately for each of the following treatment 
periods: OL, RW, ARW Week > 22 - 48, and ARW Week > 48. For the overall summary and the
OL and ARW periods, TEAEs will be summarized overall and by MRX dose at the onset of the 
event. For the RW period, TEAEs will be summarized by treatment group, noting that during the 
RW period all subjects on MRX were dosed at a 400 μg/kg QD dosing regimen.
Subjects that withdrew early during the OL phase will not be included in the RW or ARW
analyses. Similarly, subjects that withdrew early during the OL or RW phases will not be 


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included in the ARW analyses. In summarizing AEs for the 4 treatment periods, events will only 
be counted in the period in which the event started. For example, if an event starts during 
Week 16 and continues into Week 19, the event will only be counted in the OL phase.
A summary of TEAEs will be presented overall and by treatment period, and treatment group
(including MRX overall and dose at onset). The summary will include the total number and 
percent of subjects reporting:
x
Any TEAEs
x
Any treatment-related TEAE
x
Any serious TEAE
x
Any serious treatment-related TEAE
x
Any TEAE leading to study discontinuation
x
TEAEs resulting in death
Similar TEAE summaries will also be presented by age group (< 2, 2 - 12, and > 12 years at 
baseline) and by MRX dose group (< 400, 400, and > 400 μg/kg/day). These summaries will not
be presented by treatment period.
The number and percent of subjects reporting TEAEs, grouped by MedDRA system organ class 
(SOC) and preferred term (PT), will be tabulated overall and by maximum severity. These AE
summaries will be repeated for treatment-related AEs. In the case of multiple occurrences of the 
same TEAE within the same subject (and the same treatment period), each subject will only be 
counted once for each preferred term.
In presenting TEAEs for the individual treatment periods, events will only be counted in the 
treatment period in which the event started. TEAEs that started on or after the date of the first 
dose and on or before the subject’s Week 18 visit date are assigned to the OL period. TEAEs that 
started the day after the subject’s Week 18 visit date and on or before the subject’s Week 22 visit 
date are assigned to the RW period. TEAEs that started the day after the subject’s Week 22 visit 
date and on or before the subject’s Week 48 visit date are assigned to the ARW Week > 22 - 48
period. TEAEs that started the day after the subject’s Week 48 visit date up to and including 14
days after the EOT visit date are assigned to the ARW Week > 48 period. TEAEs are assigned to 
the treatment and dose that the subject was receiving at the date of the start of the event.
All AEs will be coded using MedDRA version 22.1 thesaurus. All TEAEs summarized by SOC 
and PT will be sorted in alphabetical order of the SOC and by descending frequency order of the 
PT within each SOC.
Missing and partially missing AE start and/or stop dates will be imputed, for the purpose of 
statistical analysis, according to the specifications described in Section 6.1.10.
In the AE data listings, events that are treatment-emergent will be flagged. AEs will be presented 
in by-subject listings, detailing the treatment phase, treatment received at the start of the event
including dose for active study drug, SOC, PT, verbatim term given by the investigator, onset 


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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 and separately for each of the 4 treatment periods by dose at onset of the event. Subject 
listings of AEs that lead to permanent discontinuation of study drug will also be presented.
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. Subject 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 subject listing. The listing will include subject 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: diarrhoea events, FSV deficiency events, elevated transaminases, and elevated bilirubin. 
For each of the AESI events, the PTs are described in Section 6.1.10.
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.
Safety Laboratory Evaluations 
The primary analysis of safety laboratory data will exclude any laboratory samples that were 
collected from a subject after a drug interruption > 28 days due to the subject 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 phase, and analysis visit as 
observed and change from baseline values. Summary statistics will be presented for each of the 
following 3 treatment phases:


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OL Phase (Day 1 – Week 18): Observed and change from baseline (Day 0) values. 
RW Phase (Weeks 19 - 22): Observed, change from baseline (Day 0), and change from 
Week 18 values.
ARW Phase (Weeks > 22): Observed and change from baseline (Day 0) values.
For the OL and ARW treatment phases, summary statistics will be presented for the MRX 
treatment group. For the RW phase, summary statistics will be presented by the randomized 
treatment group (MRX or PBO). 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.
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 subject 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 subject listings.
For select FSVs, including 25-hydroxyvitamin D, 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 subjects within each test level 
category will be presented for each of the following analysis visits: Baseline, Week 18, Week 22 
(by treatment group), and Week 48. For these fat soluble vitamins, categories may include 
normal, sufficient, insufficient, possibly insufficient, indeterminate, and excess (see Section 6.1.9
for specific definitions). Missing lab values will be reported in a “Missing” category.
Observed values of AFP will also be summarized descriptively by time point, noting that AFP 
samples are only drawn during the optional follow-up treatment period at every other 12-week 
repeating period clinic visit and at the EOT/ET visit.
In addition to subject 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 subject 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 a drug interruption > 28 days due to a subject 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 6.1.1. 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).


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
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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 subjects within each test level category (see Section 6.1.9 for category definitions)
will be presented for each of the following analysis visits: Baseline (Day 0), Baseline 
(PA Day 0), Week 4, Week 12, Week 24, Week 36, and Week 48.
Because drug interruptions between protocol amendments occurred after the RW phase, all 
subjects were administered MRX following drug interruptions (between protocol amendments).
9.4.
Physical Examination 
BMI will be summarized using descriptive statistics by treatment phase and analysis visit as 
observed and change from baseline values as described above for safety laboratory evaluations.
Physical examination findings, body height, and body weight will be included in subject listings.
9.5.
Vital Signs 
Vital signs (body temperature, blood pressure, heart rate, and respiratory rate) will be 
summarized using descriptive statistics by analysis visit as observed 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 subjects with study drug interruptions (for any reason), any 
concomitant medication that starts > 14 days after the last dose before the drug interruption and 
ended before the study drug was re-initiated will not be considered (for analysis purposes) as a 
concomitant medication.
Concomitant medications will be summarized descriptively by treatment phase (OL, RW, and 
ARW), and treatment group for the RW treatment phase, using the number and percent of 
subjects by ATC class and preferred term. A separate summary of concomitant medications that 
treat pruritus will also be presented. Pruritus medications that treat pruritus are listed in
Section 6.1.10.
Concomitant medications will also be presented in subject listings. Medications that were started 
before the first dose of study drug and are ongoing at the time of first dose will be flagged. A
separate listing of concomitant medications that treat pruritus will also be presented.
9.7.
Safety Data Graphical Presentations 
Study drug exposure and TEAEs of special interest will be displayed graphically over the 
treatment period, as described in Section 13.3. Additional figures may be added post-hoc to 
further examine study data.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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10.
OTHER ANALYSES 
10.1.
Palatability Analysis 
Palatability data, which is collected at each clinic visit in the follow-up treatment period, will be 
listed for individual subjects and summarized by analysis visit. For each palatability question, the 
number and percent of subjects will be presented for each answer given. 
10.2.
Pharmacokinetic Analysis 
MRX plasma concentrations will be summarized using descriptive statistics by analysis visit,
overall and by the last dose of MRX received prior to the blood sample collection. 
10.3.
Genotyping Characteristics 
Genotyping characteristics will be limited to the presentation of mutation type in a listing.
11.
CHANGES FROM PLANNED ANALYSIS 
The protocol states that the randomization will be conducted using a permuted block algorithm 
that is stratified by response criteria where response was defined as a ≥50% reduction in serum 
bile acids between Baseline and Week 12 or Week 18. The active protocol during randomization 
was Protocol Amendment 3 (dated 15Nov2015) which specified randomization based on sBA 
response at Week 12. Protocol Amendment 4 (dated 28Mar2017) was implemented after all 
eligible subjects were randomized. The description of the randomization criteria was changed in 
Protocol Amendment 4, despite randomization already being complete. Subjects were, in fact, 
randomized based on their sBA response at Week 12. Further, the method by which the 
randomization schedule was administered used a central by block randomization process (within 
IRT), with entire blocks assigned by study site. This randomization allocation method resulted in 
more subjects in the placebo group from those subjects with a ≥50% reduction in sBA at Week 
12.
The protocol specifies that secondary efficacy evaluations of change from Week 18 to Week 22 
will be performed in subjects who previously responded to MRX treatment, as defined by a 
reduction in ItchRO score > 1 point from baseline to Week 12 or Week 18. Validation of the 
ItchRO instrument, however, has indicated that a reduction of ≥1 point is considered clinically 
meaningful. Thus, the SAP defines an ItchRO responder as a subject with a reduction in ItchRO 
of ≥1 point from baseline to Week 12 or Week 18. The ItchRO(Obs) weekly average morning
score is used in defining an ItchRO responder because it is considered as the primary pruritus 
endpoint, and the various ItchRO variables are consistent relative to determining a clinically 
meaningful response.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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The protocol specifies that treatment group comparisons will be made using inferential statistics 
for demographic and baseline disease characteristics. In following Mirum Pharmaceutical’s 
standards, only descriptive statistics will be presented for these baseline variables.
The protocol specifies that race and ethnicity will be summarized descriptively, however, these 
demographic variables are not collected in the countries where subjects are enrolled.
The protocol states that the subject disposition summary will include a tabulation of the duration 
of the follow-up period. This tabulation will not be included.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 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 LUM001-304
PCN Number LUME3296 
 
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Version 1.0    |
Date: 17 Mar 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 that includes the Mirum Pharmaceuticals,
Protocol LUM001-304, and the output version. The footer will include the file name and path,
the date and time of program execution, and the data extraction date. Immediately below table-
and figure-specific footnotes, the source of the data will be provided, where applicable (i.e., 
listing number(s) for tables, and table number(s) for figures).
13.1.
Planned Table Descriptions 
Table 6, Table 7, Table 8, and Table 9 list the planned summary tables for protocol number 
LUM001-304. The table numbers are place holders only and will be determined when the tables
are produced.
13.1.1. Disposition, Demographic, Disease History, Prior Medications, and Study Drug 
Compliance Summary Tables 
Table 6
Disposition, Demographic, Disease History, Prior Medications, and Study Drug 
Compliance Summary Tables
Table Number
Table Title
14.1 Disposition, Demographic, Disease History, Prior Medications, and Study Drug Compliance
14.1.1.1
Subject Disposition: Overall – All Subjects
14.1.1.2
Subject Disposition by Study Phase – Enrolled Subjects
14.1.2.1
Demographics and Baseline Characteristics – Safety Population
14.1.2.2
Demographics and Baseline Characteristics - (by sBA and ItchRO Responder/Non-Responder 
Groups) – Safety Population
14.1.3.1
Disease History and Baseline Disease Characteristics – Safety Population
14.1.3.2
Disease History and Baseline Disease Characteristics - (by sBA and ItchRO 
Responder/Non-Responder Groups) – Safety Population
14.1.4
Demographic and Baseline Disease Characteristics by Subject – 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


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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13.1.2. Efficacy Data Summary Tables 
Table 7
Efficacy Data Summary Tables
Table Number
Table Title
14.2 Efficacy Data
14.2.1.1
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.1.2
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.1.3
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA
Controlling for sBA Responder Group - ITT Population
14.2.1.4
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
MITT Population
14.2.1.5
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population in ItchRO Responders
14.2.1.6
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population in sBA Responders at Week 48
14.2.1.7
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit: Adjusting Subject 050007 Analysis Visits during Randomized 
Withdrawal Phase – Tabulation of Fitted Summary Statistics from ANCOVA - ITT 
Population
14.2.1.8
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Age Group – ITT Population
14.2.1.9
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Baseline sBA Group – ITT Population
14.2.1.10
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Baseline Total Bilirubin Group – ITT Population
14.2.1.11
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Baseline ALT Group – ITT Population
14.2.1.12
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Baseline ItchRO (Obs) Weekly Average Morning Severity Score Group – ITT
Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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Table Number
Table Title
14.2.1.13
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit: Using Minimum of 3 (rather than 4) Daily Scores to 
Determine a Compliant Weekly Average Score – Tabulation of Fitted Summary Statistics 
from ANCOVA - ITT Population
14.2.1.14
Percent of Days ItchRO (Obs) Morning Severity Score is ≤1 Point by Time Period – ITT 
Population
14.2.1.15
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline Presence of Paucity - ITT Population
14.2.1.16
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline Clinician Scratch Scale Score - ITT Population
14.2.1.17
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline sBA Level - ITT Population
14.2.1.18
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline Total Bilirubin Level - ITT Population
14.2.1.19
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline C4 Level - ITT Population
14.2.1.20
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Age (months) at Baseline - ITT Population
14.2.1.21
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for BMI at Baseline - ITT Population
14.2.1.22
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline ALT Level - ITT Population
14.2.1.23
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Family History of ALGS - ITT Population
14.2.1.24
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline Cholesterol Level - ITT Population
14.2.1.25
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline GGT Level - ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 97 of 128
Table Number
Table Title
14.2.1.26
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for Baseline Clinician Xanthoma Severity Score - ITT Population
14.2.1.27.1
Repeated Measures ANCOVA of Change from Baseline in ItchRO (Obs) Weekly Average 
Morning Severity Score - Over the Randomized Withdrawal Period – ITT Population
14.2.1.27.2
Change from Baseline in ItchRO (Obs) Weekly Average Morning Severity Score Over the 
Randomized Withdrawal Period – Tabulation of Fitted Summary Statistics from Repeated 
Measures ANCOVA – ITT Population
14.2.1.28.1
Repeated Measures ANCOVA of Change from Baseline in ItchRO (Obs) Weekly Average 
Morning Severity Score - Over the Randomized Withdrawal Period (Controlling for sBA 
Responder Group) – ITT Population
14.2.1.28.2
Change from Baseline in ItchRO (Obs) Weekly Average Morning Severity Score Over the 
Randomized Withdrawal Period – Tabulation of Fitted Summary Statistics from Repeated 
Measures ANCOVA Controlling for sBA Responder Group – ITT Population
14.2.1.29.1
Repeated Measures ANCOVA of Change from Baseline in ItchRO (Obs) Weekly Average 
Morning Severity Score: Adjusting Subject 050007 Analysis Visits - Over the 
Randomized Withdrawal Period – ITT Population
14.2.1.29.2
Change from Baseline in ItchRO (Obs) Weekly Average Morning Severity Score Over the 
Randomized Withdrawal Period – Tabulation of Fitted Summary Statistics from Repeated 
Measures ANCOVA (Adjusting Subject 050007 Analysis Visits) – ITT Population
14.2.1.30.1
Repeated Measures ANCOVA of Change from Baseline in ItchRO (Obs) Weekly Average 
Morning Severity Score: - Using Minimum of 3 (rather than 4) Daily Scores to Determine 
a Compliant Weekly Average Score - Over the Randomized Withdrawal Period – ITT 
Population
14.2.1.30.2
Change from Baseline in ItchRO (Obs) Weekly Average Morning Severity Score Over the 
Randomized Withdrawal Period – Using Minimum of 3 (rather than 4) Daily Scores to 
Determine a Compliant Weekly Average Score - Tabulation of Fitted Summary Statistics 
from Repeated Measures ANCOVA – ITT Population
14.2.1.31.1
Repeated Measures ANCOVA of Change from Baseline in ItchRO (Obs) Weekly Average 
Morning Severity Score - Over the Randomized Withdrawal Period (Controlling for BMI 
at Baseline) – ITT Population
14.2.1.31.2
Change from Baseline in ItchRO (Obs) Weekly Average Morning Severity Score Over the 
Randomized Withdrawal Period – Tabulation of Fitted Summary Statistics from Repeated 
Measures ANCOVA Controlling for BMI at Baseline – ITT Population
14.2.1.32.1
Repeated Measures ANCOVA of Change from Baseline in ItchRO (Obs) Weekly Average 
Morning Severity Score - Over the Randomized Withdrawal Period (Controlling for Sex, 
and Age (months) and BMI at Baseline) – ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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Table Number
Table Title
14.2.1.32.2
Change from Baseline in ItchRO (Obs) Weekly Average Morning Severity Score Over the 
Randomized Withdrawal Period – Tabulation of Fitted Summary Statistics from Repeated 
Measures ANCOVA Controlling for Sex, and Age (months) and BMI at Baseline – ITT 
Population
14.2.2.1
Summary of ItchRO (Obs) Weekly Average Evening Severity Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.2.2
Summary of ItchRO (Obs) Weekly Average Evening Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.3.1
Summary of ItchRO (Obs) 4-Week Average Morning Severity Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.3.2
Summary of ItchRO (Obs) 4-Week Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.4.1
Summary of ItchRO (Obs) 4-Week Average Evening Severity Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.4.2
Summary of ItchRO (Obs) 4-Week Average Evening Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.5.1
Summary of ItchRO (Obs) Weekly Average Morning Frequency Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.5.2
Summary of ItchRO (Obs) Weekly Average Morning Frequency Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.6.1
Summary of ItchRO (Obs) Weekly Average Evening Frequency Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.6.2
Summary of ItchRO (Obs) Weekly Average Evening Frequency Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.7.1
Summary of ItchRO (Obs) 4-Week Average Morning Frequency Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.7.2
Summary of ItchRO (Obs) 4-Week Average Morning Frequency Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 99 of 128
Table Number
Table Title
14.2.8.1
Summary of ItchRO (Obs) 4-Week Average Evening Frequency Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.8.2
Summary of ItchRO (Obs) 4-Week Average Evening Frequency Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.9.1
Summary of ItchRO (Obs) Weekly Average Severity Score (Based on Daily Average of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit - ITT 
Population
14.2.9.2
Summary of ItchRO (Obs) Weekly Average Severity Score (Based on Daily Average of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit – Tabulation 
of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.9.3
Summary of ItchRO (Obs) Weekly Average Morning Severity Score (Based on Daily 
Average of Morning and Evening Scores) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - MITT Population
14.2.9.4
Summary of ItchRO (Obs) Weekly Average Morning Severity Score (Based on Daily 
Average of Morning and Evening Scores) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO 
Responders
14.2.10.1
Summary of ItchRO (Obs) Weekly Average Severity Score (Based on Daily Maximum of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit - ITT 
Population
14.2.10.2
Summary of ItchRO (Obs) Weekly Average Severity Score (Based on Daily Maximum of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit – Tabulation 
of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.10.3
Summary of ItchRO (Obs) Weekly Average Severity Score (Based on Daily Maximum of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit – Tabulation 
of Fitted Summary Statistics from ANCOVA - MITT Population
14.2.10.4
Summary of ItchRO (Obs) Weekly Average Severity Score (Based on Daily Maximum of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit – Tabulation 
of Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO Responders
14.2.11.1
Summary of ItchRO (Pt) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.11.2
Summary of ItchRO (Pt) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.11.3
Summary of ItchRO (Pt) Weekly Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for sBA Responder Group - ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 100 of 128
Table Number
Table Title
14.2.11.4.1
Repeated Measures ANCOVA of Change from Baseline in ItchRO (Pt) Weekly Average 
Morning Severity Score - Over the Randomized Withdrawal Period – ITT Population
14.2.11.4.2
Change from Baseline in ItchRO (Pt) Weekly Average Morning Severity Score Over the 
Randomized Withdrawal Period – Tabulation of Fitted Summary Statistics from Repeated 
Measures ANCOVA – ITT Population
14.2.11.5
Percent of Days ItchRO (Pt) Morning Severity Score is ≤1 Point by Time Period – ITT 
Population
14.2.12.1
Summary of ItchRO (Pt) Weekly Average Evening Severity Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.12.2
Summary of ItchRO (Pt) Weekly Average Evening Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.13.1
Summary of ItchRO (Pt) 4-Week Average Morning Severity Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.13.2
Summary of ItchRO (Pt) 4-Week Average Morning Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.14.1
Summary of ItchRO (Pt) 4-Week Average Evening Severity Score and Change from 
Baseline by Analysis Visit - ITT Population
14.2.14.2
Summary of ItchRO (Pt) 4-Week Average Evening Severity Score and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.15.1
Summary of ItchRO (Pt) Weekly Average Severity Score (Based on Daily Average of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit - ITT 
Population
14.2.15.2
Summary of ItchRO (Pt) Weekly Average Severity Score (Based on Daily Average of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit – Tabulation 
of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.15.3
Summary of ItchRO (Pt) Weekly Average Morning Severity Score (Based on Daily 
Average of Morning and Evening Scores) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - MITT Population
14.2.15.4
Summary of ItchRO (Pt) Weekly Average Morning Severity Score (Based on Daily 
Average of Morning and Evening Scores) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO 
Responders


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 101 of 128
Table Number
Table Title
14.2.16.1
Summary of ItchRO (Pt) Weekly Average Severity Score (Based on Daily Maximum of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit - ITT 
Population
14.2.16.2
Summary of ItchRO (Pt) Weekly Average Severity Score (Based on Daily Maximum of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit – Tabulation 
of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.16.3
Summary of ItchRO (Pt) Weekly Average Severity Score (Based on Daily Maximum of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit – Tabulation 
of Fitted Summary Statistics from ANCOVA - MITT Population
14.2.16.4
Summary of ItchRO (Pt) Weekly Average Severity Score (Based on Daily Maximum of 
Morning and Evening Scores) and Change from Baseline by Analysis Visit – Tabulation 
of Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO Responders
14.2.17.1
Summary of sBA (umol/L) and Change from Baseline by Analysis Visit - ITT Population
14.2.17.2
Summary of sBA (umol/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population
14.2.17.3
Summary of sBA (umol/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA Controlling for sBA Responder Group - ITT 
Population
14.2.17.4
Summary of sBA (umol/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - MITT Population
14.2.17.5
Summary of sBA (umol/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO Responders
14.2.17.6
Summary of sBA (umol/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population in sBA Responders at 
Week 48
14.2.17.7
Summary of sBA (umol/L) and Change from Baseline by Analysis Visit: Adjusting Subject 
050007 Analysis Visits during Randomized Withdrawal Phase – Tabulation of Fitted 
Summary Statistics from ANCOVA - ITT Population
14.2.17.8
Summary of sBA (umol/L) and Change from Baseline by Age Group - ITT Population
14.2.17.9
Summary of sBA (umol/L) and Change from Baseline by Baseline sBA Group - ITT 
Population
14.2.17.10
Summary of sBA (umol/L) and Change from Baseline by Baseline Total Bilirubin Group -
ITT Population
14.2.17.11
Summary of sBA (umol/L) and Change from Baseline by Baseline ALT Group - ITT 
Population
14.2.17.12
Summary of sBA (umol/L) and Change from Baseline by Baseline ItchRO (Obs) Weekly 
Average Morning Severity Score Group - ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 102 of 128
Table Number
Table Title
14.2.18.1
Summary of ALP (U/L) and Change from Baseline by Analysis Visit - ITT Population
14.2.18.2
Summary of ALP (U/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population
14.2.18.3
Summary of ALP (U/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA Controlling for sBA Responder Group - ITT 
Population
14.2.18.4
Summary of ALP (U/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - MITT Population
14.2.18.5
Summary of ALP (U/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO Responders
14.2.19.1
Summary of ALT (U/L) and Change from Baseline by Analysis Visit - ITT Population
14.2.19.2
Summary of ALT (U/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population
14.2.19.3
Summary of ALT (U/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA Controlling for sBA Responder Group - ITT 
Population
14.2.19.4
Summary of ALT (U/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - MITT Population
14.2.19.5
Summary of ALT (U/L) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO Responders
14.2.19.6
ALT Threshold Summary by Analysis Visit – ITT Population
14.2.20.1
Summary of Total Bilirubin (mg/dL) and Change from Baseline by Analysis Visit - ITT 
Population
14.2.20.2
Summary of Total Bilirubin (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.20.3
Summary of Total Bilirubin (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA Controlling for sBA Responder 
Group - ITT Population
14.2.20.4
Summary of Total Bilirubin (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - MITT Population
14.2.20.5
Summary of Total Bilirubin (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO 
Responders
14.2.20.6
Total Bilirubin Threshold Summary by Analysis Visit – ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 103 of 128
Table Number
Table Title
14.2.21.1
Summary of Direct Bilirubin (mg/dL) and Change from Baseline by Analysis Visit - ITT 
Population
14.2.21.2
Summary of Direct Bilirubin (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.21.3
Summary of Direct Bilirubin (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA Controlling for sBA Responder 
Group - ITT Population
14.2.21.4
Summary of Direct Bilirubin (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - MITT Population
14.2.21.5
Summary of Direct Bilirubin (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population in ItchRO 
Responders
14.2.22.1
Summary of C4 (ng/mL) and Change from Baseline by Analysis Visit - ITT Population
14.2.22.2
Summary of C4 (ng/mL) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population
14.2.22.3
Summary of C4 (ng/mL) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA Controlling for sBA Responder Group - ITT 
Population
14.2.23.1
Summary of Total Cholesterol (mg/dL) and Change from Baseline by Analysis Visit - ITT 
Population
14.2.23.2
Summary of Total Cholesterol (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.23.3
Summary of Total Cholesterol (mg/dL) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA Controlling for sBA Responder 
Group - ITT Population
14.2.24.1
Summary of LDL-C (mg/dL) and Change from Baseline by Analysis Visit - ITT 
Population
14.2.24.2
Summary of LDL-C (mg/dL) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population
14.2.24.3
Summary of LDL-C (mg/dL) and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA Controlling for sBA Responder Group - ITT 
Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 104 of 128
Table Number
Table Title
14.2.25.1
Summary of Clinician Scratch Score (CSS) and Change from Baseline by Analysis Visit -
ITT Population
14.2.25.2
Summary of Clinician Scratch Score (CSS) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.25.3
Summary of Clinician Scratch Score (CSS) and Change from Baseline by Analysis Visit –
Tabulation of Fitted Summary Statistics from ANCOVA Controlling for sBA Responder 
Group - ITT Population
14.2.25.4
Summary of Clinician Scratch Score (CSS) Change from Baseline by Analysis Visit –
Categorical Data Analysis – ITT Population
14.2.26.1
Summary of Clinician Xanthoma Severity Score and Change from Baseline by Analysis 
Visit - ITT Population
14.2.26.2
Summary of Clinician Xanthoma Severity Score and Change from Baseline by Analysis 
Visit – Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.27.1
Summary of Height Z-Score and Change from Baseline by Analysis Visit - ITT 
Population
14.2.27.2
Summary of Height Z-Score and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population
14.2.27.3
Summary of Height Z-Score and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA Controlling for sBA Responder Group - ITT 
Population
14.2.28.1
Summary of Weight Z-Score and Change from Baseline by Analysis Visit - ITT 
Population
14.2.28.2
Summary of Weight Z-Score and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA - ITT Population
14.2.28.3
Summary of Weight Z-Score and Change from Baseline by Analysis Visit – Tabulation of 
Fitted Summary Statistics from ANCOVA Controlling for sBA Responder Group - ITT 
Population
14.2.29.1
Summary of PedsQL Total Scale Score (Parent) and Change from Baseline by Analysis 
Visit - ITT Population
14.2.29.2
Summary of PedsQL Total Scale Score (Parent) and Change from Baseline by Analysis 
Visit – Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.29.3
Summary of PedsQL Total Scale Score (Parent) and Change from Baseline by Analysis 
Visit – Tabulation of Fitted Summary Statistics from ANCOVA Controlling for sBA 
Responder Group - ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 105 of 128
Table Number
Table Title
14.2.30.1
Summary of PedsQL Multidimensional Fatigue Scale Score (Parent) and Change from 
Baseline by Analysis Visit - ITT Population
14.2.30.2
Summary of PedsQL Multidimensional Fatigue Scale Score (Parent) and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.30.3
Summary of PedsQL Multidimensional Fatigue Scale Score (Parent) and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for sBA Responder Group - ITT Population
14.2.31.1
Summary of PedsQL Family Impact Total Scale Score and Change from Baseline by 
Analysis Visit - ITT Population
14.2.31.2
Summary of PedsQL Family Impact Total Scale Score and Change from Baseline by 
Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.31.3
Summary of PedsQL Family Impact Total Scale Score and Change from Baseline by 
Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA Controlling for 
sBA Responder Group - ITT Population
14.2.32.1
Summary of PedsQL Psychosocial Health Summary Score (Parent) and Change from 
Baseline by Analysis Visit - ITT Population
14.2.32.2
Summary of PedsQL Psychosocial Health Summary Score (Parent) and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.32.3
Summary of PedsQL Psychosocial Health Summary Score (Parent) and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for sBA Responder Group - ITT Population
14.2.33.1
Summary of PedsQL Total Scale Score (Child) and Change from Baseline by Analysis 
Visit - ITT Population
14.2.33.2
Summary of PedsQL Total Scale Score (Child) and Change from Baseline by Analysis 
Visit – Tabulation of Fitted Summary Statistics from ANCOVA - ITT Population
14.2.33.3
Summary of PedsQL Total Scale Score (Child) and Change from Baseline by Analysis 
Visit – Tabulation of Fitted Summary Statistics from ANCOVA Controlling for sBA 
Responder Group - ITT Population
14.2.34.1
Summary of PedsQL Multidimensional Fatigue Scale Score (Child) and Change from 
Baseline by Analysis Visit - ITT Population
14.2.34.2
Summary of PedsQL Multidimensional Fatigue Scale Score (Child) and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA -
ITT Population
14.2.34.3
Summary of PedsQL Multidimensional Fatigue Scale Score (Child) and Change from 
Baseline by Analysis Visit – Tabulation of Fitted Summary Statistics from ANCOVA 
Controlling for sBA Responder Group - ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 106 of 128
Table Number
Table Title
14.2.35.1
Summary of PIC by Analysis Visit and Change from Week 18 to Week 22 - ITT 
Population
14.2.35.2
Summary of PIC by Analysis Visit – Categorical Data Analysis – ITT Population
14.2.36.1
Summary of CIC (Itch-Related Symptoms) by Analysis Visit and Change from Week 18 
to Week 22 - ITT Population
14.2.36.2
Summary of CIC (Itch-Related Symptoms) by Analysis Visit – Categorical Data Analysis 
– ITT Population
14.2.37.1
Summary of CIC (Xanthoma Severity) by Analysis Visit and Change from Week 18 to 
Week 22 - ITT Population
14.2.37.2
Summary of CIC (Xanthoma Severity) by Analysis Visit – Categorical Data Analysis –
ITT Population
14.2.38.1
Summary of CGTB by Analysis Visit and Change from Week 18 to Week 22 - ITT 
Population
14.2.38.2
Summary of CGTB by Analysis Visit – Categorical Data Analysis – ITT Population
14.2.39.1
Contingency Table of ItchRO (Pt) and ItchRO (Obs) Morning Scores – for the Weekly 
Average Morning Score at Week 18 - ITT Population
14.2.39.2
Contingency Table of ItchRO (Pt) and ItchRO (Obs) Evening Scores – for the Weekly 
Average Evening Score at Week 18 - ITT Population
14.2.39.3
Contingency Table of ItchRO (Pt) and ItchRO (Obs) Morning Scores – for the Weekly 
Average Morning Score at Week 22 - ITT Population
14.2.39.4
Contingency Table of ItchRO (Pt) and ItchRO (Obs) Evening Scores – for the Weekly
Average Evening Score at Week 22 - ITT Population
14.2.40.1
Pairwise Correlation Estimates for Change from Baseline to Week 18 and Week 48 in 
ItchRO and CSS Variables – ITT Population
14.2.40.2
Pairwise Correlation Estimates for Change from Week 18 to Week 22 in ItchRO and CSS 
Variables – ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
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13.1.3. Safety Data Tables 
Table 8
Safety Data Summary Tables
Table Number
Table Title
14.3.1 Study Drug Exposure
14.3.1
Study Drug Exposure by Treatment Phase – Safety Population
14.3.2 Displays of Adverse Events
14.3.2.1.1
Summary of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: Overall MRX 
– Safety Population
14.3.2.1.2
Summary of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: Open-Label 
Phase (Day 1 – Week 18) – Safety Population
14.3.2.1.3
Summary of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: Randomized 
Withdrawal Phase – Safety Population
14.3.2.1.4
Summary of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: After 
Randomized Withdrawal Phase (Week > 22 - 48) – Safety Population
14.3.2.1.5
Summary of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: After 
Randomized Withdrawal Phase (Week > 48) – Safety Population
14.3.2.1.6
Summary of Treatment-Emergent Adverse Events by Age Group at Baseline – Safety 
Population – Subjects on Maralixibat Chloride
14.3.2.1.7
Summary of Treatment-Emergent Adverse Events by Maralixibat Chloride Dose Group
(at Onset of TEAE) – Safety Population
14.3.2.2.1
Incidence of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: Overall MRX 
– Safety Population
14.3.2.2.2
Incidence of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: Open-Label 
Phase (Day 1 – Week 18) – Safety Population
14.3.2.2.3
Incidence of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: Randomized 
Withdrawal Phase – Safety Population
14.3.2.2.4
Incidence of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: After 
Randomized Withdrawal Phase (Week > 22 - 48) – Safety Population
14.3.2.2.5
Incidence of Treatment-Emergent Adverse Events by Dose at Onset of TEAE: After 
Randomized Withdrawal Phase (Week > 48) – Safety Population
14.3.2.3.1
Incidence of Treatment-Emergent Adverse Events by Maximum Severity and Dose at Onset 
of TEAE: Overall MRX – Safety Population
14.3.2.3.2
Incidence of Treatment-Emergent Adverse Events by Maximum Severity and Dose at Onset 
of TEAE: Open-Label Phase (Day 1 – Week 18) – Safety Population
14.3.2.3.3
Incidence of Treatment-Emergent Adverse Events by Maximum Severity and Dose at Onset 
of TEAE: Randomized Withdrawal Phase – Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 108 of 128
Table Number
Table Title
14.3.2.3.4
Incidence of Treatment-Emergent Adverse Events by Maximum Severity and Dose at Onset 
of TEAE: After Randomized Withdrawal Phase (Week > 22 - 48) – Safety Population
14.3.2.3.5
Incidence of Treatment-Emergent Adverse Events by Maximum Severity and Dose at 
Onset of TEAE: After Randomized Withdrawal Phase (Week > 48) – Safety Population
14.3.2.4.1
Incidence of Treatment Related Adverse Events by Dose at Onset of TEAE: Overall MRX –
Safety Population
14.3.2.4.2
Incidence of Treatment Related Adverse Events by Dose at Onset of TEAE: Open-Label 
Phase (Day 1 – Week 18) – Safety Population
14.3.2.4.3
Incidence of Treatment Related Adverse Events by Dose at Onset of TEAE: Randomized 
Withdrawal Phase – Safety Population
14.3.2.4.4
Incidence of Treatment Related Adverse Events by Dose at Onset of TEAE: After 
Randomized Withdrawal Phase (Week > 22 - 48) – Safety Population
14.3.2.4.5
Incidence of Treatment Related Adverse Events by Dose at Onset of TEAE: After 
Randomized Withdrawal Phase (Week > 48) – Safety Population
14.3.2.5.1
Incidence of Treatment Related Adverse Events by Maximum Severity and Dose at Onset of 
TEAE: Overall MRX – Safety Population
14.3.2.5.2
Incidence of Treatment Related Adverse Events by Maximum Severity and Dose at Onset of 
TEAE: Open-Label Phase (Day 1 – Week 18) – Safety Population
14.3.2.5.3
Incidence of Treatment Related Adverse Events by Maximum Severity and Dose at Onset of 
TEAE: Randomized Withdrawal Phase – Safety Population
14.3.2.5.4
Incidence of Treatment Related Adverse Events by Maximum Severity and Dose at Onset of 
TEAE: After Randomized Withdrawal Phase (Week > 22 - 48) – Safety Population
14.3.2.5.5
Incidence of Treatment Related Adverse Events by Maximum Severity and Dose at Onset of 
TEAE: After Randomized Withdrawal Phase (Week > 48) – Safety Population
14.3.3 Summary of Deaths, Other Serious and Significant Adverse Events
14.3.3.1.1
Incidence of Treatment-Emergent SAEs by Dose at Onset of TEAE: Overall MRX – Safety 
Population
14.3.3.1.2
Incidence of Treatment-Emergent SAEs by Dose at Onset of TEAE: Open-Label Phase 
(Day 1 – Week 18) – Safety Population
14.3.3.1.3
Incidence of Treatment-Emergent SAEs by Dose at Onset of TEAE: Randomized Withdrawal 
Phase – Safety Population
14.3.3.1.4
Incidence of Treatment-Emergent SAEs by Dose at Onset of TEAE: After Randomized 
Withdrawal Phase (Week > 22 - 48) – Safety Population
14.3.3.1.5
Incidence of Treatment-Emergent SAEs by Dose at Onset of TEAE: After Randomized 
Withdrawal Phase (Week > 48) – Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 109 of 128
Table Number
Table Title
14.3.3.2.1
Incidence of Treatment Related SAEs by Dose at Onset of TEAE: Overall MRX – Safety 
Population
14.3.3.2.2
Incidence of Treatment Related SAEs by Dose at Onset of TEAE: Open-Label Phase 
(Day 1 - Week 18) – Safety Population
14.3.3.2.3
Incidence of Treatment Related SAEs by Dose at Onset of TEAE: Randomized Withdrawal 
Phase – Safety Population
14.3.3.2.4
Incidence of Treatment Related SAEs by Dose at Onset of TEAE: After Randomized 
Withdrawal Phase (Week > 22 - 48) – Safety Population
14.3.3.2.5
Incidence of Treatment Related SAEs by Dose at Onset of TEAE: After Randomized 
Withdrawal Phase (Week > 48) – Safety Population
14.3.3.3.1
Incidence of Adverse Events Leading to Permanent Treatment Discontinuation by Dose at 
Onset of TEAE: Overall MRX – Safety Population
14.3.3.3.2
Incidence of Adverse Events Leading to Permanent Treatment Discontinuation by Dose at 
Onset of TEAE: Open-Label Phase (Day 1 – Week 18) – Safety Population
14.3.3.3.3
Incidence of Adverse Events Leading to Permanent Treatment Discontinuation by Dose at 
Onset of TEAE: Randomized Withdrawal Phase – Safety Population
14.3.3.3.4
Incidence of Adverse Events Leading to Permanent Treatment Discontinuation by Dose at 
Onset of TEAE: After Randomized Withdrawal Phase (Week > 22 - 48) – Safety Population
14.3.3.3.5
Incidence of Adverse Events Leading to Permanent Treatment Discontinuation by Dose at 
Onset of TEAE: After Randomized Withdrawal Phase (Week > 48) – Safety Population
14.3.3.4.1
Incidence of Treatment-Emergent Adverse Events of Special Interest – Diarrhoea Events by 
Dose at Onset of TEAE: Overall MRX – Safety Population
14.3.3.4.2
Incidence of Treatment-Emergent Adverse Events of Special Interest – Diarrhoea Events by 
Dose at Onset of TEAE: Open-Label Phase (Day 1 - Week 18) – Safety Population
14.3.3.4.3
Incidence of Treatment-Emergent Adverse Events of Special Interest – Diarrhoea Events by 
Dose at Onset of TEAE: Randomized Withdrawal Phase – Safety Population
14.3.3.4.4
Incidence of Treatment-Emergent Adverse Events of Special Interest – Diarrhoea Events by 
Dose at Onset of TEAE: After Randomized Withdrawal Phase (Week > 22 - 48) – Safety 
Population
14.3.3.4.5
Incidence of Treatment-Emergent Adverse Events of Special Interest – Diarrhoea Events 
by Dose at Onset of TEAE: After Randomized Withdrawal Phase (Week > 48) – Safety 
Population
14.3.3.5.1
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated 
Transaminases Events by Dose at Onset of TEAE: Overall MRX – Safety Population
14.3.3.5.2
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated 
Transaminases Events by Dose at Onset of TEAE: Open-Label Phase (Day 1 - Week 18) –
Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 110 of 128
Table Number
Table Title
14.3.3.5.3
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated 
Transaminases Events by Dose at Onset of TEAE: Randomized Withdrawal Phase – Safety 
Population
14.3.3.5.4
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated 
Transaminases Events by Dose at Onset of TEAE: After Randomized Withdrawal Phase 
(Week > 22 - 48) – Safety Population
14.3.3.5.5
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated 
Transaminases Events by Dose at Onset of TEAE: After Randomized Withdrawal Phase 
(Week > 48) – Safety Population
14.3.3.6.1
Incidence of Treatment-Emergent Adverse Events of Special Interest – Fat Soluble Vitamin 
Deficiency Events by Dose at Onset of TEAE: Overall MRX – Safety Population
14.3.3.6.2
Incidence of Treatment-Emergent Adverse Events of Special Interest – Fat Soluble Vitamin 
Deficiency Events by Dose at Onset of TEAE: Open-Label Phase (Day 1 - Week 18) – Safety 
Population
14.3.3.6.3
Incidence of Treatment-Emergent Adverse Events of Special Interest – Fat Soluble Vitamin 
Deficiency Events by Dose at Onset of TEAE: Randomized Withdrawal Phase – Safety 
Population
14.3.3.6.4
Incidence of Treatment-Emergent Adverse Events of Special Interest – Fat Soluble Vitamin 
Deficiency Events by Dose at Onset of TEAE: After Randomized Withdrawal Phase 
(Week > 22 - 48) – Safety Population
14.3.3.6.5
Incidence of Treatment-Emergent Adverse Events of Special Interest – Fat Soluble 
Vitamin Deficiency Events by Dose at Onset of TEAE: After Randomized Withdrawal 
Phase (Week > 48) – Safety Population
14.3.3.7.1
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated Bilirubin 
Events by Dose at Onset of TEAE: Overall MRX – Safety Population
14.3.3.7.2
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated Bilirubin 
Events by Dose at Onset of TEAE: Open-Label Phase (Day 1 - Week 18) – Safety Population
14.3.3.7.3
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated Bilirubin 
Events by Dose at Onset of TEAE: Randomized Withdrawal Phase – Safety Population
14.3.3.7.4
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated Bilirubin 
Events by Dose at Onset of TEAE: After Randomized Withdrawal Phase (Week > 22 - 48) –
Safety Population
14.3.3.7.5
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated Bilirubin 
Events by Dose at Onset of TEAE: After Randomized Withdrawal Phase (Week > 48) –
Safety Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 111 of 128
Table Number
Table Title
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
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 (kg/m2) 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


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Table Number
Table Title
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
13.1.4. Other Data Summary Tables 
Table 9
Other Data Summary Tables
Table Number
Table Title
14.4 Other Data Summaries
14.4.1
Palatability Data
14.4.1
Summary of Palatability Data by Analysis Visit – Safety Population
14.4.2
Pharmacokinetic Data
14.4.2
Summary of Plasma Sample Maralixibat Concentrations (ng/mL) by Analysis Visit – Safety 
Population


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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13.2.
Planned Listing Descriptions 
Table 10 provides the planned listings for protocol number LUM001-304. The listing numbers 
are place holders only and will be determined when the listings are produced. Three subject data 
listings will be imbedded within the safety tables: SAEs, AEs leading to permanent treatment 
discontinuation, and deaths (see Table 8).
Subject listings will be presented by treatment sequence, and sorted by site, subject ID, and
assessment date (where applicable). All pertinent calculated variables (e.g., study day, TEAE 
flag) will be included in the listings, along with the treatment received (MRX dose or Placebo) 
on the date of assessment/sample collection.
In all listings, a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (e.g., repetition of subject number), then only the first occurrence will be 
displayed. The information for one subject will be kept on one page if at all possible, rather than 
splitting a subject’s information across pages.
Table 10
Planned Subject Listings
Listing Number
Subject Listing Title
16.1
Subject Profile Listings
16.1.1
Subject Profile: Select Efficacy Labs and Pruritus Scores – ITT Population
16.1.2
Subject Profile: PedsQL Total Scale and Summary Scores – ITT Population
16.1.3
Subject Profile: Serum Bile Acid, Lipids, and Fat Soluble Vitamins – ITT Population
16.2
Subject Disposition
16.2.1
Analysis Populations and Treatment Assignments – Enrolled Subjects
16.2.2
Subject Disposition – Enrolled Subjects
16.2.3
Subject Disposition – Screen Failure
16.3
Protocol Deviations/Subjects Excluded from Efficacy Analyses
16.3.1
Inclusion and Exclusion Criteria – Enrolled Subjects
16.3.2
Subject Excluded from Efficacy Analyses – Enrolled Subjects
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
ALGS Disease History – Safety Population
16.4.4
Prior Medications – Safety Population


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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Listing Number
Subject Listing Title
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
16.5.3
Maralixibat Chloride Dose Changes – Safety Population
16.6
Individual Efficacy Response Data
16.6.1
ItchRO (Obs) Weekly Average Morning Score and sBA Results – (Baseline, Week 48, 
and Change from Baseline to Week 48) – ITT Population
16.6.2
Clinician Scratch and Xanthoma Scores – ITT Population
16.6.3
Liver Biochemical Enzymes – (Baseline and Change from Baseline to Week 48 – ITT 
Population
16.6.4
ItchRO Reported Outcomes (Subject and Caregiver) Weekly Morning and Average 
Evening Scores – ITT Population
16.6.5
ItchRO Reported Outcomes (Subject and Caregiver) Daily Morning and Evening Scores –
ITT Population
16.6.6
PIC, CIC, and CGTB – ITT Population
16.6.7
Efficacy Laboratory Tests – ITT Population
16.6.8
Total sBA – ITT Population
16.6.9
Height and Weight Z-Scores – ITT Population
16.2.10.1.1.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Physical Functioning -
ITT Population
16.6.10.1.1.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Physical 
Functioning - ITT Population
16.6.10.1.2
Pediatric Quality of Life Inventory (Parent Report for Infants) - Physical Symptoms - ITT 
Population
16.6.10.1.3.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Emotional Functioning -
ITT Population
16.6.10.1.3.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Emotional 
Functioning - ITT Population
16.6.10.1.4.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Social Functioning - ITT 
Population
16.6.10.1.4.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Social 
Functioning - ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Listing Number
Subject Listing Title
16.6.10.1.5
Pediatric Quality of Life Inventory (Parent Report for Infants) - Cognitive Functioning -
ITT Population
16.6.10.1.6
Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) -
Nursery/Day Care/School Functioning - ITT Population
16.6.10.2.1
Pediatric Quality of Life Inventory (Subject Report) - Physical Functioning - ITT
Population
16.6.10.2.2
Pediatric Quality of Life Inventory (Subject Report) - Emotional Functioning - ITT
Population
16.6.10.2.3
Pediatric Quality of Life Inventory (Subject Report) - Social Functioning - ITT Population
16.6.10.2.4
Pediatric Quality of Life Inventory (Subject Report) - School Functioning - ITT Population
16.6.10.3.1
Multidimensional Fatigue Scale (Parent Report) - General Fatigue - ITT Population
16.6.10.3.2
Multidimensional Fatigue Scale (Parent Report) - Sleep/Rest Fatigue - ITT Population
16.6.10.3.3
Multidimensional Fatigue Scale (Parent Report) - Mental Fatigue - ITT Population
16.6.10.4.1
Multidimensional Fatigue Scale (Subject Report) - General Fatigue - ITT Population
16.6.10.4.2
Multidimensional Fatigue Scale (Subject Report) - Sleep/Rest Fatigue - ITT Population
16.6.10.4.3
Multidimensional Fatigue Scale (Subject Report) - Cognitive Fatigue - ITT Population
16.6.10.5.1
Family Impact Module (Parent Report) - Physical Functioning - ITT Population
16.6.10.5.2
Family Impact Module (Parent Report) - Emotional Functioning - ITT Population
16.6.10.5.3
Family Impact Module (Parent Report) - Social Functioning - ITT Population
16.6.10.5.4
Family Impact Module (Parent Report) - Cognitive Functioning - ITT Population
16.6.10.5.5
Family Impact Module (Parent Report) – Communication - ITT Population
16.6.10.5.6
Family Impact Module (Parent Report) – Worry - ITT Population
16.6.10.5.7
Family Impact Module (Parent Report) - Daily Activities - ITT Population
16.6.10.5.8
Family Impact Module (Parent Report) - Family Relationships - ITT Population
16.6.10.6.1
Pediatric Quality of Life Inventory (Parent Report) - Total Scale and Summary Scores -
ITT Population
16.6.10.6.2
Pediatric Quality of Life Inventory (Subject Report) - Total Scale and Summary Scores -
ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Listing Number
Subject Listing Title
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
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


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Date: 17 Mar 2020
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Listing Number
Subject Listing Title
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 Subjects
16.10
Concomitant Medications
16.10.1
Concomitant Medications – Safety Population
16.10.2
Concomitant Medications that Treat Pruritus – Safety Population
16.11
Palatability Data
16.11
Palatability Questionnaire – Safety Population
16.12
Drug Concentration Data
16.12
Plasma Sample Maralixibat Concentrations
13.3.
Planned Figure Descriptions 
Table 11 provides the planned figures for protocol number LUM001-304. The figure numbers 
are place holders only and will be determined when the figures are produced. Additional figures 
may be added post-hoc to further examine study data.
13.3.1. Efficacy Figures 
ANCOVA LS means and associated 95% CIs will be graphically displayed for sBA change from 
Week 18 to Week 22 in the MITT Population. This plot will display the LS means and CIs for 
each treatment group and the difference (MRX minus Placebo), along with the associated 
p-value for testing statistically significance between treatment groups.  Each of the LS means 
will be displayed side-by-side, with vertical lines emanating from each mean to represent the
95% CI for the mean.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Mean (± SE) change from baseline (Day 0) for select efficacy variables will be displayed 
graphically by study week over the treatment period. For these line plots over time, study week 
will be based on the analysis visit mapping described in Table 4. Separate methods of displaying 
this data will be used as described below.
For ItchRO(Obs) and ItchRO(Pt) weekly average morning scores and sBA, 2 figures will be 
presented. One plot will display the data by treatment sequence up through Week 48, with 
vertical references lines included at the Week 18 and Week 22 time points to represent the RW 
phase. The other plot will present consolidated data (i.e., treatment sequences combined) through 
the entire treatment period, with the exclusion of the Week 22 time point.
For ALP, ALT, bilirubin (total and direct), C4, total cholesterol, and LDL-C, the first 48 weeks 
of data will be broken out by treatment sequence, with a consolidated single line (labeled as 
“MRX Extension”) for post-Week 48 data. Vertical reference lines will be displayed at the Week 
18 and Week 22 time points to represent the RW phase.
For height and weight z-scores, and PedsQL total scale and multidimensional fatigue scale scores 
(parent), data will be presented as a single line graph through the entire treatment period. 
Vertical reference lines will be displayed at the Week 18 and Week 22 time points to represent 
the RW phase.
13.3.2. Study Drug Exposure Figure 
Study drug exposure will be displayed as a swimmer plot that includes a horizontal bar showing 
treatment duration for each subject in the study. Each bar will be color coded in a manner that 
displays the time periods in which each subject was on the varying daily doses (i.e., 
14 μg/kg/day, 35 μg/kg/day, 70 μg/kg/day, 140 μg/kg/day, 280 μg/kg/day, 400 μg/kg/day, 
540 μg/kg/day, 800 μg/kg/day, and placebo). Gaps in line segments will indicate a drug 
interruption or missed dose for any reason.
13.3.3. Adverse Event Figures 
TEAEs of special interest will be displayed in swimmer-type plots. A plot will be displayed for 
each individual AESI (as the preferred term) and present the start and stop study day of each 
event over time. The vertical axis will represent each unique subject that reported the respective 
AESI. The horizontal axis will represent time, as study day. The severity of each event will be 
depicted as color-coded lines and symbols. Treatment sequence will be identified for each 
subject.


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Table 11 Planned Figures
Figure Number
Figure Title
14.2 Efficacy Data
14.2.1.1.1
Plot of Mean (± SE) Change from Baseline in ItchRO (Obs) Weekly Average Morning Score by 
Randomized Treatment Group Over Time (through Week 48) - ITT Population
14.2.1.1.2
Plot of Mean (± SE) Change from Baseline in ItchRO (Obs) Weekly Average Morning Score by 
Randomized Treatment Group Over Time (through Treatment Duration) - ITT Population
14.2.1.11.1 Plot of Mean (± SE) Change from Baseline in ItchRO (Pt) Weekly Average Morning Score by 
Randomized Treatment Group Over Time (through Week 48) - ITT Population
14.2.1.11.2 Plot of Mean (± SE) Change from Baseline in ItchRO (Pt) Weekly Average Morning Score by 
Randomized Treatment Group Over Time (through Treatment Duration) - ITT Population
14.2.17.1.1 Plot of Mean (± SE) Change from Baseline in sBA (umol/L) by Randomized Treatment Group Over 
Time (through Week 48) - ITT Population
14.2.17.1.2 Plot of Mean (± SE) Change from Baseline in sBA (umol/L) by Randomized Treatment Group Over 
Time (through Treatment Duration) - ITT Population
14.2.17.4
Plot of sBA (umol/L) Change from Week 18 to Week 22 LS Means and 95% Confidence Intervals from
ANCOVA – MITT Population
14.2.18.1
Plot of Mean (± SE) Change from Baseline in ALP (U/L) by Randomized Treatment Group Over Time 
- ITT Population
14.2.19.1
Plot of Mean (± SE) Change from Baseline in ALT (U/L) by Randomized Treatment Group Over Time 
- ITT Population
14.2.20.1
Plot of Mean (± SE) Change from Baseline in Total Bilirubin (mg/dL) by Randomized Treatment Group 
Over Time - ITT Population
14.2.21.1
Plot of Mean (± SE) Change from Baseline in Direct Bilirubin (mg/dL) by Randomized Treatment 
Group Over Time - ITT Population
14.2.22.1
Plot of Mean (± SE) Change from Baseline in C4 (ng/mL) by Randomized Treatment Group Over Time 
- ITT Population
14.2.23.1
Plot of Mean (± SE) Change from Baseline in Total Cholesterol (mg/dL) by Randomized Treatment 
Group Over Time - ITT Population
14.2.24.1
Plot of Mean (± SE) Change from Baseline in LDL-C (mg/dL) by Randomized Treatment Group Over 
Time - ITT Population
14.2.27.1
Plot of Mean (± SE) Change from Baseline in Height Z-Score Over Time - ITT Population
14.2.28.1
Plot of Mean (± SE) Change from Baseline in Weight Z-Score Over Time - ITT Population
14.2.29.1
Plot of Mean (SE) Change from Baseline in PedsQL Total Score (Parent) Over Time - ITT Population


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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14.2.30.1
Plot of Mean (± SE) Change from Baseline in PedsQL Multidimensional Fatigue Scale Score (Parent)
Over Time - ITT Population
14.3.1  Display of Study Drug Exposure
14.3.1
Study Drug Exposure Over Time by Subject – Safety Population
14.3.2 Displays of Adverse Events
14.3.3
Plot of Treatment-Emergent Adverse Events of Special Interest Over Time by Preferred Term and 
Individual Subject – 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 LUM001-304
PCN Number LUME3296 
 
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Appendix 1 
Premier Research Library of Abbreviations 
Abbreviation
Definition
AE
adverse event
AESI
adverse events of special interest
AFP
alpha-fetoprotein
ALGS
Alagille syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ARW
after randomized withdrawal
ASA
American statistical association
ASBTi
apical sodium dependent bile acid transporter inhibitor
AST
aspartate aminotransferase
BID
twice-a-day dosing regimen
BP
blood pressure
C4
7-alpha-hydroxy-4-cholesten-3-one
CDC
centers for disease control
CGTB
caregiver global therapeutic benefit
CI
confidence interval
CIC-Itch
caregiver impression of change (itch-related symptoms)


Statistical Analysis Plan
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Protocol Number LUM001-304
PCN Number LUME3296 
 
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Abbreviation
Definition
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CSS
clinician scratch score
CTCAE
common terminology criteria for adverse events
DMC
data monitoring committee
eDiary
electronic diary
EMA
European medicines agency
ET
early termination
FDA
food and drug administration
FGF-19
fibroblast growth factor 19
FGF-21
fibroblast growth factor 21
FSV
fat soluble vitamin
GGT
gamma glutamyl transferase
GI
gastrointestinal
HR
heart rate
HRQoL
health-related quality of life
IA
interim analysis
ICH
international council for harmonization 
IRT
interactive response technology


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Abbreviation
Definition
ItchRO
itch reported outcome
ITT
intent-to-treat
LLOQ
lower limit of quantification
LOCF
last-observation-carried-forward
LS
least squares
MedDRA
medical dictionary for regulatory activities
MMRM
mixed-effects model for repeated measurements
MRX
MRX
OL
open-label
PBO
placebo
PedsQL
pediatric quality of life
PIC
patient impression of change
PT
preferred term
RBP
retinol binding protein
REML
restricted maximum likelihood
RSS
royal statistical society
RW
randomized withdrawal
SAE
serious adverse event
SAS®
a software system used for data analysis


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Version 1.0    |
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Abbreviation
Definition
sBA
serum bile acid
SD
standard deviation
SE
standard error
SIAP
statistical interim analysis plan
SOC
system organ class
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
ULN
upper limit normal
ULOQ
upper limit of quantification
WHO
world health organization
 


Statistical Analysis Plan
Sponsor Mirum Pharmaceuticals, Inc.
Protocol Number LUM001-304
PCN Number LUME3296 
 
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Version 1.0    |
Date: 17 Mar 2020
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Appendix 2 
Listing of Safety and Efficacy Laboratory Analytes 
SAFETY LABS
Hematology
Erythrocytes (RBC), 
106/μL
Hemoglobin, g/dL
Hematocrit, %
MCV, fL
MCH, pg
MCHC, g/dL
Platelets, 103/μL
Leukocytes (WBC), 
103/μL
Differential
(% and 103/μL)
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
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
Ratio of Alpha Tocopherol to the 
sum of Cholesterol and 
Triglycerides, mg/g
aPTT, sec (surrogate for FSV)
PT, sec (surrogate for FSV)
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
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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 LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 127 of 128
-
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 LUM001-304
PCN Number LUME3296 
 
AD-ST-33.04 Effective date: 30 Jun 2017
Version 1.0    |
Date: 17 Mar 2020
|    AD-PR-109.01 Effective date: 26 Jun 2017
Page 128 of 128
-
international normalised ratio increased
-
international normalised ratio abnormal
-
haemorrhage
-
melaena                       
-
epistaxis
-
haematochezia
-
haemoptysis