Conditions: Alagille Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
The purpose of this extension study is to determine the long-term safety and tolerability of an investigational treatment (LUM001 also known as Maralixibat) in children with ALGS who have completed participation in a core LUM001 treatment protocol. Efficacy will be assessed by evaluating the effect of LUM001 on pruritus, biochemical markers of pruritus, as well as biochemical markers of cholestasis and liver disease.

Detailed description:

Arms:
arm 1: LUM001 also known as Maralixibat (MRX) administered orally up to twice each day

Interventions: intervention 1: LUM001 (Maralixibat)
Intervention descriptions: intervention 1: Dosing of LUM001 also known as Maralixibat (MRX) with the objective of achieving optimal control of pruritus at a dose level that is tolerated by the participant and up to a maximum daily dose of 560 micrograms per kilogram (mcg/kg).

Protocol document:
Prot_000.pdf: 
 
 
 
 
CLINICAL PROTOCOL 
PROTOCOL NUMBER: LUM001-303 
 
 
 
 
IMAGINE STUDY 
 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE LONG-TERM SAFETY AND 
DURABILITY OF THE THERAPEUTIC EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT 
BILE ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT OF CHOLESTATIC LIVER 
DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
 
 
Protocol Amendment 5.1: 08 February 2019 
Protocol History 
Original Protocol: 13 Sep 2013 
Protocol Amendment 1: 05 Nov 2013 
Protocol Amendment 2: 28 Feb 2014 
Protocol Amendment 3: 17 Sep 2014 
Protocol Amendment 4: 04 Nov 2015 
Protocol Amendment 5:  16 May 2017 
 
EudraCT No: 2013-003832-54 
 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
 
 
CONFIDENTIAL 
This document is a confidential communication of Mirum Pharmaceuticals, Inc.  It is agreed that no 
unpublished information contained herein will be published or disclosed without prior approval from the 
Sponsor.  However, this document can be disclosed to an appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) or authorized representatives of national regulatory 
authorities under the condition that they respect its confidential information. 


Mirum Pharmaceuticals, Inc. 
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08 February 2019 
 
 
SPONSOR SIGNATURE PAGE 
 
LUM001-303 
 
 
 
IMAGINE STUDY 
 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE LONG-TERM SAFETY AND 
DURABILITY OF THE THERAPEUTIC EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT 
BILE ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT OF CHOLESTATIC LIVER 
DISEASE IN PAEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
 
Protocol Amendment 5.1: 08 February 2019 
Protocol History 
Original Protocol: 13 Sep 2013 
Protocol Amendment 1: 05 Nov 2013 
Protocol Amendment 2: 28 Feb 2014 
Protocol Amendment 3: 17 Sep 2014 
Protocol Amendment 4: 04 Nov 2015 
Protocol Amendment 5:  16 May 2017 
 
 
EudraCT No: 2013-003832-54 
 
Developed in Collaboration with ChiLDREN 
 
 
 
Sponsor: 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
 
 
 
 


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08 February 2019 
 
 
TITLE PAGE 
Study Drug: 
LUM001 
 
Protocol Number: 
LUM001-303 
 
Amendment Number: 
5.1  
 
Date: 
08 February 2019 
 
EudraCT No: 
2013-003832-54 
 
Study Phase: 
Phase 2 
 
Protocol Title: 
A Multicentre Extension Study to Evaluate the Long-Term Safety and 
Durability of the Therapeutic Effect of LUM001, an Apical Sodium-
Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment 
of Cholestatic Liver Disease in Pediatric Subjects with Alagille 
Syndrome  
 
Sponsor: 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
 
Medical Monitor: 
Cagil Ozen, MD  
 
Premier Research 
 
Office: +1 215 282 5406 
 
Cell: +1 267 838 2380 
 
Email: medmonitorLUM303@premier-research.com 
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 
 
Compliance Statement: This study will be conducted in accordance with all applicable 
clinical research guidelines including the International Conference on 
Harmonisation (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. 
LUMOOI-303 Protocol Amendment 5.1 
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PROTOCOL SIGNATURE PAGE 
Sponsor's (Mirum) .. ~~~7. 
Signature: 
I 
J 
/ 
r 
. 
~ 
Thomas Jaecklin, MD, MSc 
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: 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE LONG-TERM SAFETY 
AND DURABILITY OF THE THERAPEUTIC EFFECT OF LUMOOI , AN APICAL 
SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR (ASBTI), IN THE 
TREATMENT OF CHOLESTATIC LIVER DISEASE IN PAEDIATRIC SUBJECTS WITH 
ALAGILLE SYNDROME 
Protocol Number: 
Amendment Number: 
Date: 
EudraCT No: 
Sponsor: 
As Agreed: 
Investigator's Signature 
LUMOOl-303 
5.1 
08 February 2019 
2013-003832-54 
Mirum Pharmaceuticals, Inc. 
70 Willow Road, Suite 200 
Menlo Park, California 94025 
USA 
Date 
Investigator's Name (Please print) 


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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: 
medmonitorLUM303@premier-research.com    
 
 


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


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
TITLE PAGE ...................................................................................................................................3 
PROTOCOL SIGNATURE PAGE .................................................................................................4 
EMERGENCY CONTACT INFORMATION ................................................................................5 
PRODUCT QUALITY COMPLAINTS..........................................................................................6 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
PROTOCOL AMENDMENT 5.1 SUMMARY OF CHANGES ..................................................13 
1 
STUDY SYNOPSIS ...............................................................................................................16 
2 
LIST OF ABBREVIATIONS AND TERMS .........................................................................36 
3 
STUDY OBJECTIVES ..........................................................................................................40 
4 
BACKGROUND AND RATIONALE ...................................................................................41 
4.1 
Therapeutic Rationale ..............................................................................................41 
4.2 
Alagille Syndrome ....................................................................................................42 
4.3 
Pruritus .....................................................................................................................43 
4.4 
LUM001 ...................................................................................................................44 
4.4.1 
Nonclinical Studies ...........................................................................................44 
4.4.1.1 
Pharmacology ..............................................................................................44 
4.4.1.2 
Pharmacokinetics ........................................................................................44 
4.4.1.3 
Toxicology ..................................................................................................44 
4.4.2 
Previous Clinical Experience ............................................................................45 
4.5 
Rationale for Dose and Schedule of Administration ................................................46 
5 
INVESTIGATIONAL PLAN .................................................................................................50 
5.1 
Study Design ............................................................................................................50 
5.2 
Data Monitoring Committee ....................................................................................51 
5.3 
Number of Study Centers .........................................................................................52 
5.4 
Number of Subjects ..................................................................................................52 
5.5 
Overall Study Duration and Follow-up ....................................................................52 
5.5.1 
Treatment ..........................................................................................................57 
5.5.1.1 
Dose Escalation Period ...............................................................................58 
5.5.1.2 
Dose Optimization Period ...........................................................................59 
5.5.1.3 
Stable Dosing Period ...................................................................................59 
5.5.1.4 
Optional Follow-up Treatment Period ........................................................59 
5.5.1.5 
Follow-up ....................................................................................................60 
5.5.1.6 
Long-term Optional Follow-up Treatment Period ......................................60 


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5.6 
Study Termination ....................................................................................................61 
6 
SUBJECT ENROLLMENT ...................................................................................................62 
6.1 
Enrollment ................................................................................................................62 
6.2 
Replacement of Subjects ..........................................................................................62 
6.3 
Unblinding of Treatment Assignment ......................................................................62 
7 
SUBJECT ELIGIBILITY .......................................................................................................64 
7.1 
Inclusion Criteria ......................................................................................................64 
7.2 
Exclusion Criteria .....................................................................................................64 
8 
STUDY PROCEDURES ........................................................................................................67 
8.1 
Study Schedule .........................................................................................................67 
8.1.1 
Baseline (Day 0) ................................................................................................67 
8.1.2 
Dose Escalation Treatment Period (Week 0 to Week 4)...................................67 
8.1.3 
Dose Optimization Period (Week 5 to Week 12) ..............................................67 
8.1.4 
Stable Dosing Period (Week 13 to Week 72) ...................................................68 
8.1.5 
Week 72 ............................................................................................................69 
8.1.6 
Early Termination for Subjects without Participation in the 52-week 
Optional Follow-up Treatment Period ..............................................................69 
8.1.7 
Optional Follow-up Treatment Period (post Week 72 to Week 124): ..............69 
8.1.8 
Long-term Optional Follow-up Treatment Period ............................................71 
8.1.9 
End of Treatment or Early Termination ............................................................75 
8.1.10 
Safety Follow-up Period ...................................................................................75 
8.2 
Genetic Testing ........................................................................................................75 
8.3 
Physical Examination, Weight and Height, Vital Signs ...........................................76 
8.4 
Laboratory Assessments ...........................................................................................76 
8.5 
Pruritus and Quality of Life Assessments ................................................................76 
8.5.1 
Itch Reported Outcome (ItchRO™) ..................................................................76 
8.5.2 
Clinician Scratch Scale .....................................................................................77 
8.5.3 
Clinician Xanthoma Scale .................................................................................77 
8.5.4 
Pediatric Quality of Life Inventory (PedsQL) ..................................................78 
8.5.5 
Caregiver Impression of Change .......................................................................78 
8.5.6 
Palatability ........................................................................................................78 
8.6 
Restriction on the Lifestyle of Subjects ...................................................................78 
8.6.1 
Contraception Requirements .............................................................................78 
8.6.2 
Fasting Requirements ........................................................................................79 
9 
STUDY DRUG .......................................................................................................................80 
9.1 
Study Drug Description ............................................................................................80 
9.1.1 
LUM001 ............................................................................................................80 
9.2 
Packaging and Labeling ...........................................................................................80 


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9.3 
Drug Accountability .................................................................................................81 
10 TREATMENT OF SUBJECTS ..............................................................................................82 
10.1 
Study Drug Administration ......................................................................................82 
10.2 
Treatment Compliance .............................................................................................83 
10.3 
Concomitant Medications ........................................................................................83 
10.4 
Other Protocol-required Drugs .................................................................................83 
10.5 
Safety Monitoring Rules ..........................................................................................83 
10.5.1 
General Monitoring Rules .................................................................................83 
10.5.2 
Safety Monitoring Rules ...................................................................................84 
10.5.2.1 Safety Monitoring for Liver Chemistry Tests .............................................84 
10.5.2.2 Stopping Rules for Liver Chemistry Elevations .........................................85 
10.5.2.3 Safety Monitoring for Triglycerides ...........................................................85 
10.5.2.4 Safety Monitoring for Fat Soluble Vitamins ...............................................85 
10.5.2.5 Monitoring/Stopping Rules for Coagulation Panel Results ........................86 
10.6 
Adjustment of Dose ..................................................................................................86 
10.7 
Withdrawal of Subjects from the Study ...................................................................86 
11 SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .................................88 
11.1 
Regulatory Requirements .........................................................................................88 
11.2 
Definitions ................................................................................................................88 
11.2.1 
Adverse Event ...................................................................................................88 
11.2.2 
Adverse Reaction and Suspected Adverse Reaction .........................................89 
11.2.3 
Serious Adverse Event (SAE) ...........................................................................89 
11.3 
Monitoring and Recording Adverse Events .............................................................90 
11.3.1 
Serious Adverse Events.....................................................................................90 
11.3.2 
Non-Serious Adverse Events ............................................................................91 
11.3.3 
Evaluation of Adverse Events (Serious and Non-Serious) ...............................91 
11.3.3.1 Relationship to the Study Drug ...................................................................91 
11.3.3.2 Severity .......................................................................................................91 
11.3.3.3 Action Taken with Study Drug ...................................................................92 
11.3.3.4 Treatment Given for Adverse Event ...........................................................92 
11.3.3.5 Outcome of the Adverse Event ...................................................................92 
11.4 
Procedures for Handling Special Situations .............................................................92 
11.4.1 
Pregnancy Reporting .........................................................................................93 
11.4.2 
Dosing Errors ....................................................................................................93 
11.4.3 
Abnormalities of Laboratory Tests ...................................................................94 
12 STATISTICAL CONSIDERATIONS ...................................................................................95 
12.1 
Sample Size Considerations .....................................................................................95 
12.2 
Population .................................................................................................................96 


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12.2.1 
Safety Population ..............................................................................................96 
12.2.2 
Demographic and Baseline Characteristics .......................................................96 
12.2.2.1 Subject Disposition .....................................................................................96 
12.2.2.2 Baseline Data ..............................................................................................96 
12.2.3 
Efficacy Analyses .............................................................................................97 
12.2.3.1 Efficacy Variables .......................................................................................97 
12.2.3.2 Primary Efficacy Analysis ..........................................................................97 
12.2.3.3 Secondary, Exploratory and Other Efficacy Analyses ................................97 
12.2.4 
Safety Analyses .................................................................................................98 
12.2.4.1 Safety Assessments .....................................................................................98 
12.2.5 
Safety Analysis .................................................................................................98 
12.2.5.1 Adverse Events ...........................................................................................98 
12.2.5.2 Laboratory Tests..........................................................................................99 
12.2.5.3 Physical Exams, Vital Signs and Weight/Height Measurements................99 
12.2.5.4 Concomitant Medications ...........................................................................99 
12.2.5.5 Study Drug Exposure ..................................................................................99 
12.2.5.6 Serum Alpha-fetoprotein ...........................................................................100 
12.2.6 
Palatability Analyses .......................................................................................100 
12.2.7 
Interim Analyses .............................................................................................100 
12.2.8 
Additional Analyses ........................................................................................100 
13 INVESTIGATOR’S REGULATORY OBLIGATIONS .....................................................101 
13.1 
Informed Consent ...................................................................................................101 
13.2 
Study Personnel ......................................................................................................101 
13.3 
Ethical Conduct of the Study .................................................................................101 
13.4 
Independent Ethics Committee/Institutional Review Board ..................................102 
13.5 
Confidentiality ........................................................................................................102 
14 ADMINISTRATIVE AND LEGAL OBLIGATIONS ........................................................104 
14.1 
Pre-study Documentation Required .......................................................................104 
14.2 
Protocol Amendments ............................................................................................104 
14.3 
Study Termination ..................................................................................................104 
14.4 
Study Documentation and Storage .........................................................................105 
14.5 
Study Monitoring ...................................................................................................105 
14.6 
Language ................................................................................................................106 
14.7 
Compensation for Injury ........................................................................................106 
15 REFERENCES .....................................................................................................................107 
16 APPENDICES ......................................................................................................................108 
16.1 
Schedule of Procedures ..........................................................................................109 
16.1.1 
Schedule of Procedures A – (Baseline - Week 12) .........................................110 


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16.1.2 
Schedule of Procedures B - Stable Dosing: Week 16 – Week 72 / Study 
Termination .....................................................................................................112 
16.1.3 
Schedule of Procedures C – 52-Week Optional Follow-Up Treatment 
Period for those subjects < 7 days from last dose of LUM001 (Protocol 
Amendment 4) .................................................................................................114 
16.1.4 
Schedule of Procedure D – 52-Week Optional Follow-up Treatment 
Period: DE-2 –Week 176 for Subjects with ≥7days from last dose of 
LUM001 (Protocol Amendment 4). Includes Evaluation of Eligibility for 
Afternoon Dose Escalation Dosing Regimen .................................................116 
16.1.5 
Schedule of Procedure E – Long-term Optional Follow-up Treatment 
Period: Protocol Amendment 5 Screening (Week -2) and on LUM001. 
Includes Evaluation of Eligibility for Afternoon Dose Escalation Dosing 
Regimen at Protocol Amendment 5, Week 12 ................................................119 
16.1.6 
Schedule of Procedure F-G: Re-entry under Protocol Amendment 5.............122 
16.1.7 
Schedule of Procedures H – Study Termination and End of Treatment 
Procedures .......................................................................................................126 
16.2 
List of Laboratory Analytes ...................................................................................127 
16.3 
Itch Reported Outcome Instrument (ItchRO™) .....................................................128 
16.3.1 
Patient Itch Reported Outcome Instrument, ItchRO(Pt)™ .............................129 
16.3.2 
Observer Itch Reported Outcome Instrument, ItchRO(Obs)™ ......................131 
16.4 
Clinician Scratch Scale ...........................................................................................135 
16.5 
Clinician Xanthoma Scale ......................................................................................136 
16.6 
Pediatric Quality of Life Inventory (PedsQL™) ....................................................137 
16.6.1 
Parent Report for Infants (ages 1-12 months) .................................................138 
16.6.2 
Parent Report for Infants (ages 13-24 months) ...............................................141 
16.6.3 
Parent Report for Toddlers (ages 2-4) .............................................................144 
16.6.4 
Parent Report for Young Children (ages 5-7) .................................................146 
16.6.5 
Parent Report for Children (ages 8-12) ...........................................................148 
16.6.6 
Parent Report for Teenagers (ages 13-18) ......................................................150 
16.6.7 
Pediatric Quality of Life Inventory v 4.0 for Young Children (ages 5-7) ......152 
16.6.8 
Pediatric Quality of Life Inventory for Children (ages 8-12) .........................155 
16.6.9 
Pediatric Quality of Life Inventory for Teenagers (ages 13-18) .....................157 
16.6.10 
Multidimensional Fatigue Scale Parent Report for Toddlers (ages 2-4) .........159 
16.6.11 
Multidimensional Fatigue Scale Parent Report for Young Children (ages 
5-7) ..................................................................................................................161 
16.6.12 
Multidimensional Fatigue Scale Parent Report for Children (ages 8-12) .......163 
16.6.13 
Multidimensional Fatigue Scale Parent Report for Teenagers  (ages 13-
18) ...................................................................................................................165 
16.6.14 
Multidimensional Fatigue Scale Young Child Report (ages 5-7) ...................167 
16.6.15 
Multidimensional Fatigue Scale Child Report (ages 8-12) .............................170 


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16.6.16 
Multidimensional Fatigue Scale Teen Report (ages 13-18) ............................172 
16.6.17 
Family Impact Module v 2.0 ...........................................................................174 
16.7 
Caregiver Impression of Change (CIC) .................................................................177 
16.7.1 
Caregiver Global Therapeutic Benefit (CGTB) ..............................................178 
16.8 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 ..........179 
16.9 
Palatability Questionnaire ......................................................................................180 
16.10 
Protocol History .....................................................................................................183 
16.10.1 
Protocol Amendment 5 Summary of Changes ................................................183 
16.10.2 
Protocol Amendment 4 Summary of Changes ................................................201 
16.10.3 
Protocol Amendment 3 Summary of Changes ................................................209 
16.10.4 
Protocol Amendment 2 Summary of Changes ................................................211 
16.10.5 
Protocol Amendment 1 Summary of Changes ................................................212 
LIST OF TABLES 
Table 1: 
Improvement in Biochemical Markers and Pruritus After Partial External 
Biliary Diversion in PFIC Disease and Alagille Syndrome Subjects ................44 
Table 2: 
Sample Daily Exposure (mg/day) in Pediatric Subjects ....................................47 
Table 3: 
GI-associated Adverse Events in Study 003 ......................................................48 
Table 4: 
Dose Escalation Regimens .................................................................................58 
Table 5: 
Composition of LUM001 1.0 mL Oral Solution ................................................80 
Table 6: 
Composition of LUM001 0.5 mL Oral Solution ................................................80 
Table 7: 
Composition of LUM001 0.25 mL Oral Solution ..............................................80 
 
LIST OF FIGURES 
Figure 1: 
Interruption of Enterohepatic Circulation with an ASBT/IBAT Inhibitor .........42 
Figure 2: 
Serum Bile Salt Concentration and Degree of Itch ............................................43 
Figure 3: 
Study Design for LUM001-303 (Up to and including Week 72) ......................52 
Figure 4: 
Follow-up Treatment Scheme (no interruption in LUM001 dosing or 
interruption <7 days) ..........................................................................................53 
Figure 5: 
Follow-up Treatment Scheme (interruption in LUM001 dosing ≥7 days) ........54 
Figure 6: 
Re-Entry into Long-term Optional Follow-up Treatment under Protocol 
Amendment 5 .....................................................................................................55 
Figure 7: 
Long-term Optional Follow-up Treatment under Protocol Amendment 5, 
without afternoon dose escalation ......................................................................56 
Figure 8: 
Long-term Optional Follow-up Treatment under Protocol Amendment 5, 
with afternoon dose escalation ...........................................................................57 
 


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PROTOCOL AMENDMENT 5.1 SUMMARY OF CHANGES 
 
Protocol Number: 
LUM001-303 
 
Protocol Title: 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
 
Amendment: 
5.1 
 
Date: 
08 February 2019 
 
The LUM001-303 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 (16 May 2017). Note that 
correction of typos and grammatical errors are not captured in the below table.  


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New text indicated in bold; deleted text indicated in strikethrough. 
Section 
Description of Change 
Cover page, 
Sponsor; 
Title Page, Sponsor; 
Sponsor Signature 
Page, Sponsor;  
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 and Premier 
Medical Monitor;  
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 
Schedule E 
Added Drug Compliance at Week 4 
Schedule F 
Added ADE Eligibility Assessment at Week 12 starting at RP2 
Schedule H 
Added Global Therapeutic Questionnaire T EOT/EOS 
Section 16 
Added Caregiver Global Therapeutic Benefit Questionnaire 


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1 
STUDY SYNOPSIS 
Sponsor 
Mirum Pharmaceuticals, Inc. 
Protocol 
Number 
LUM001-303 
Protocol Title 
A Multicentre Extension Study to Evaluate the Long-Term Safety and Durability of the 
Therapeutic Effect of LUM001, an Apical Sodium-Dependent Bile Acid Transporter 
Inhibitor (ASBTi), in the Treatment of Cholestatic Liver Disease in Pediatric Subjects with 
Alagille Syndrome   
Study Phase 
2 
Indication 
Treatment of cholestatic liver disease in Alagille syndrome (ALGS)  
Objectives 
The primary objective of the study (up to and including Week 72) is to:  
• 
Evaluate the long-term safety and tolerability of LUM001 in pediatric subjects with 
ALGS. 
Secondary objectives of the study (up to and including Week 72) are to: 
• 
Evaluate the long-term effect of LUM001 on serum bile acid levels associated with 
ALGS. 
• 
Evaluate the long-term effect of LUM001 on pruritus associated with ALGS. 
• 
Explore the long-term effect of LUM001 on other biochemical markers of 
cholestasis and liver disease. 
• 
Evaluate the long-term effect of LUM001 on xanthomas associated with ALGS. 
• 
Explore an expanded dosing range to identify the doses necessary to achieve the 
optimal benefit-to-risk ratio for this patient population. 
Objectives of the long-term optional follow-up treatment period for subjects who are eligible 
for Protocol Amendment 5: 
• 
To offer eligible subjects in the LUM001-303 study continued study treatment until 
the first of the following occur: (i) the 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.  
• 
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. 
• 
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 multicentre, double-blind study of LUM001 in children ≥12 months of age 
diagnosed with ALGS who have completed participation in the LUM001-302 study. All 
subjects will receive active drug (LUM001) in this study. The study is divided into 5 parts: a 
dose escalation period, a dose optimization period, a stable dosing period, an optional 52-
week follow-up period, and a long-term optional follow-up treatment period for eligible 
subjects who choose to stay on treatment with LUM001.  
Dose Escalation Period 
All subjects entering the extension study will participate in a 4-week double-blind dose 
escalation period during which: 
• Subjects who were randomized to receive placebo during the LUM001-302 study will 
receive weekly dose increases of LUM001 up to a target dose of 140 μg/kg/day. 


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• Subjects who were randomized to receive active drug during the LUM001-302 study will 
continue to receive the dose of LUM001 that they were taking at Week 13 of the 
LUM001-302 study. The LUM001 doses for these subjects will remain blinded and will 
not be altered during the dose-escalation period. 
A minimum period of 7 days must elapse between increases in dose.  
Dose Optimization Period 
Following completion of the 4-week dose escalation period, subjects will enter an 8-week 
dose-optimization period. During this period, the investigator will have the option to adjust 
LUM001 dosing with the objective of achieving optimal control of pruritus at a dose level 
that is tolerated by the subject and up to a maximum daily dose of 280 μg/kg LUM001 or 20 
mg total dose. Study drug dose level will be increased or decreased in a double-blind 
manner. Increases in dose will be based on effect on efficacy (sBA and ItchRO[Obs] score) 
and safety assessments. Reductions in dose will be based on tolerability.  At the 
investigator’s discretion, the doses for subjects who were previously down-titrated may be 
re-challenged during the dose optimization period. Each subject will receive one of the 
following dose levels:  
• LUM001 35 μg/kg/day. 
• LUM001 70 μg/kg/day. 
• LUM001 140 μg/kg/day. 
• LUM001 280 μg/kg/day. 
A minimum period of 7 days must elapse between increases in dose.  
Stable Dosing Period 
Following completion of the 8-week dose optimization period, all subjects will enter the 
stable dosing period lasting 60 weeks.  During the remainder of the study, subjects will be 
dosed with the Week 12 dose, or the highest tolerated dose below the Week 12 dose. 
However, if a subject experiences intolerance due to gastrointestinal symptoms, the 
investigator, in consultation with the medical monitor, may lower the dose to a previously 
tolerated dose. 
Optional Follow-up Treatment Period: 
At Week 72, all subjects will be assessed by the investigator to determine their willingness 
and eligibility to roll-over into the optional 52-week, follow-up treatment period to receive 
study drug at the dose they were receiving at Week 72. 
• 
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 same dose 
level. 
• 
For subjects who are eligible to roll over into the follow-up treatment period having 
≥7 days since the last dose of LUM001, will be dose escalated up to 280 µg/kg/day 
or the highest tolerated dose following a  4 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 30 days after the last dose of study drug. 
Long-term optional Follow Up Treatment Period (Protocol Amendment 5): 
The long-term optional follow up treatment period is 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 560 µg/kg/day (280 
µg/kg BID), based on efficacy (sBA and ItchRO score) and safety assessments. Subjects’ 
participation in the long-term optional follow-up treatment period will continue until the first 


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of the following occur: 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.  
Number of 
Subjects 
Approximately 18 subjects who enrolled in the LUM001-302 study and who meet the 
study’s inclusion and exclusion criteria will be enrolled in the study. 
Study 
Population 
Inclusion Criteria 
To participate in this study, subjects must meet all of the following criteria: 
1. Male or female, 12 months to 18 years of age. 
2. Competent to provide informed consent and assent (per IRB/EC), as appropriate. 
3. Completed participation in study LUM001-302. 
4. Females of childbearing potential must have a negative urine pregnancy test [β human 
chorionic gonadotropin (β-hCG)] at the Baseline Visit. 
5. Males and females of childbearing 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 study.  
6. Subjects are expected to have consistent caregiver(s) for the duration of the study. 
7. Caregivers (and age appropriate subjects) must be able to read and understand English. 
8. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls 
from study site. 
9. Caregivers (and age appropriate subjects) must be willing and able to complete a daily 
electronic diary (ItchRO) during the first consecutive 12 weeks of the study and then for 
4 consecutive weeks following the Week 24 and Week 44 visits. 
10. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement 
in the ItchRO electronic diary software at the outset of the study. 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Experienced an adverse event or serious adverse event (SAE) related to the study drug 
during the LUM001-302 study that led to the discontinuation of the subject from the 
LUM001-302 study. 
2. Any conditions or abnormalities (including laboratory abnormalities) which, in the 
opinion of the investigator or the medical monitor, may compromise the safety of the 
subject, or interfere with the subject participating in or completing the study. 
3. History or presence of gallstones or kidney stones. 
4. History of non-adherence during the subject’s participation in the LUM001-302 study, 
or earlier in the LUM001-303 study. Non-adherence is defined by dosing compliance of 
less than 80% in the LUM001-302 study or earlier in the LUM001-303 study. 
5. Unlikely to comply with the study protocol, or unsuitable for any other reason, as 
judged by the investigator. 
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 72 visit with no safety concerns. 
Subjects who were discontinued due to safety reasons can be re-challenged if blood tests are 


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back to relatively normal values for this patient population and the 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 on an individual basis. 
Inclusion Criteria: 
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: 
a. 
Completed the protocol through either the Week 124 or the ET visit with no 
major safety concerns. 
OR 
b. 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 study. 
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: All exclusion criteria mentioned for the original study LUM001-303 
apply upon re-entry into the long-term optional follow-up treatment period. 
Treatment 
Groups 
Based on tolerability and effect on pruritus each subject will receive one of the following 
dose levels:  
• 
LUM001 35 μg/kg/day 
• 
LUM001 70 μg/kg/day 
• 
LUM001 140 μg/kg/day 
• 
LUM001 280 μg/kg/day 
After Week 124 and/or implementation of this amendment, whichever occurs first, subjects 
will be considered for a long-term optional follow-up treatment period, if eligible, receiving 
up to 560 μg/kg/day (given as twice daily doses of 280 μg/kg), or to a maximum possible 
daily dose of 50 mg/day. 
Study Drug 
Dosage and 
Administration 
Subjects will receive a grape-flavored solution containing LUM001, administered orally 
once a day (QD) or 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 doses should be taken approximately at the 
same time each day for the duration of the treatment period. 


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Study drug will be prepared by a central pharmacy based on the subject’s weight. During the 
study, weight will be monitored at each visit. A change from Baseline in a subject’s weight 
that is ≥10% will require a dose adjustment. Weight-based dose adjustments will be made by 
the central pharmacy at the time of the subject’s next LUM001 preparation.  
Study drug will be dispensed to subjects/caregivers at the study site.  The appropriate 
amount of study drug will be dispensed at the Study Day 0 visit and daily dosing will begin 
on Study Day 1.  
Dose Escalation Period 
For subjects randomized to placebo in the LUM001-302 study, or those who complete the 
LUM001-302 study more than 7 days prior to enrollment into this study, the LUM001 dose 
during the first 4 weeks of the study will be increased at weekly intervals to 140 μg/kg/day, 
or to a maximum tolerated dose below 140 μg/kg/day (10 mg maximum total dose). For 
subjects who were randomized to receive active drug in the LUM001-302 study, LUM001 
doses will remain the same as the dose taken at Week 13. Study treatment for each subject 
will remain blinded and will be prepared by the unblinded central pharmacist according to a 
specified dose-escalation regimen. This regimen will represent a real dose escalation for 
subjects previously randomized to placebo and a mock dose escalation for subjects 
previously randomized to active study treatment.   
The dosing regimen for each treatment group during the dose escalation period is 
summarized in the following table. 
 
 
LUM001-302 
Study 
Extension StudyLUM001-303 
Dose Escalation Period 
Week 13 
(μg/kg/day) 
Week 1 
Days 1 - 7 
(μg/kg/day) 
Week 2 
Days 8 - 14 
(μg/kg/day) 
Week 3 
Days 15 - 21 
(μg/kg/day) 
Week 4 
Days 22 - 28 
(μg/kg/day) 
Placebo1 
14 
35 
70 
140 
352 
35 
35 
35 
35 
703 
70 
70 
70 
70 
1404 
140 
140 
140 
140 
2805 
280 
280 
280 
280 
1. 
For subjects randomized to placebo in the LUM001-302 study, or those who complete the 
LUM001-302 study more than 7 days prior to enrollment into this study, the LUM001 dose 
during the first 4 weeks of the study will be increased at weekly intervals to 140 μg/kg/day, 
or to a maximum tolerated dose below 140 μg/kg/day (10 mg maximum total dose). 
2. 
LUM001 doses for subjects whose stable dose upon completion of LUM001-302 Treatment 
Protocol study was 35 μg/kg/day will remain stable at 35 μg/kg/day, or to a maximum daily 
dose of 2.5 mg/day.  
3. 
LUM001 doses for subjects whose stable dose upon completion of LUM001-302 Treatment 
Protocol was 70 μg/kg/day will remain stable at 70 μg/kg/day, or to a maximum daily dose 
of 5 mg/day.  
4. 
LUM001 doses for subjects whose stable dose upon completion of LUM001-302 Treatment 
Protocol was 140 μg/kg/day will remain stable at 140 μg/kg/day, or to a maximum daily 
dose of 10 mg/day.  
5. 
LUM001 doses for subjects whose stable dose upon completion of LUM001-302 Treatment 
Protocol was 280 μg/kg/day will remain stable at 280 μg/kg/day, or to a maximum daily 
dose of 20 mg/day.  
If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, 
abdominal pain, cramping) at any time during the study, the investigator, in consultation 
with the medical monitor, may lower the dose to a previously tolerated dose. 
Dose Optimization Period  
Following the dose escalation period, the LUM001 dose for each subject may be increased 
and decreased by the investigator as clinically indicated for the control of pruritus at a dose 


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level that is tolerated by the subject. Dose optimization will occur in a blinded, titrated 
manner with four dose levels available as treatment options: 35, 70, 140 or 280 μg/kg/day. 
Adjustments may occur at weekly intervals. Once an optimal LUM001 dose is achieved, the 
dose will be fixed for the duration of the study.   
The maximum daily dose of LUM001 in this study is 280 μg/kg/day, up to a maximum daily 
dose of 20 mg. Blinded investigators may request dose adjustment for any subject based on 
an assessment of tolerability and effect on pruritus. Caregivers and age-appropriate subjects 
will be asked whether they wish to take a higher dose of the study medication to achieve 
greater relief of itching. If so, the dose may be adjusted upward, within the permitted dose 
range. However, the subject, caregiver, physician investigator, or the sponsor medical 
monitor may recommend against further escalation if there are safety or tolerability 
concerns. Doses of LUM001 will not be increased above 280 μg/kg/day or 20 mg per day at 
any time. 
Stable Dosing Period  
At the end of the Dose Optimization Period, subjects will continue dosing to complete 72 
weeks of cumulative LUM001 exposure in this study. 
If, at any time during the study, a subject experiences intolerance due to gastrointestinal 
symptoms, the physician investigator, in consultation with the medical monitor, may lower 
the dose to a previously tolerated dose.  
Optional Follow-up Treatment Period: 
At Week 72, all subjects will be assessed by the investigator to determine their willingness 
and eligibility for entry into the 52-week, follow-up treatment period. The three 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 dose interruption of ≥7 days, will be dose escalated up to 
280 µg/kg/day or a maximum tolerated dose following a 4-week dose escalation 
beginning at 35 µg/kg/day. 
• 
Subjects who do not wish to enter the optional follow-up treatment period, will be 
contacted via telephone by the study site approximately 30 days after the last dose 
of study drug. 
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 for entry into the long-term optional follow-up 
treatment period. All subjects will be re-initiated at the same LUM001 dose they last 
received during LUM001-303. The appropriate amount of study drug will be dispensed at 
the Protocol Amendment 5 Day 0/baseline visit, but daily dosing will not begin until the 
following day, Protocol Amendment 5, Study Day 1. Eligibility assessment for afternoon 
dose escalation will then occur in all subjects based on efficacy (ItchRO[Obs] and sBA) and 
safety assessments following approximately 12 weeks of dose re-initiation as follows: 
• 
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) 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 


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afternoon dose is initiated in order to limit the amount of propylene glycol 
in the diluent administered. 
o 
The afternoon dose will be initiated at half the dose level of the morning 
dose and will continue at this dose for a period of 4 weeks. If this dose level 
is tolerated, the afternoon dose will then be doubled to match the morning 
dose. 
• 
Subjects with abnormal sBA level AND ItchRO(Obs) score ≥1.5 who had normal 
sBA level and ItchRO(Obs) score <1.5 prior to dose interruption will remain on the 
maximum tolerated morning dose (the dose they received last during LUM001-303) 
for an additional 2 weeks until their efficacy and safety assessments are repeated for 
eligibility assessment for afternoon dose escalation. 
• 
The sBA value used for determination of afternoon dose escalation eligibility will be 
the most recent available value collected within the prior 16 weeks. The ItchRO(Obs) 
score used for afternoon dose escalation 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 280 µg/kg BID, ie, 560 µg/kg/day (up to a 
maximum possible daily dose of 50 mg/day). 
• 
Subjects who do not wish to enter the long-term optional follow-up treatment period, 
will be contacted via telephone by the study site approximately 30 days after the last 
dose of study drug. 
Study Drug Administration under Protocol Amendment 5 
 
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 re-entry, once a weight of 10 kg is reached 
while in the study, the subject will be moved from 0.5 mL total daily dosing volume 
(0.25 mL BID) to 1.0 mL total daily dosing volume (0.50 mL BID ). 
Rationale for 
Dose and 
Schedule 
Selection  
The dosage of LUM001 for the first studies in pediatric cholestatic subjects was based upon 
prior experience with this study drug in healthy volunteers and subjects with 
hypercholesterolemia.  In these subjects, with normal bile flow and without liver disease, 
tolerability was limited above 10 mg daily by an increase in gastrointestinal (GI) adverse 
events (AEs).  These signs and symptoms were believed to be related to increased bile acid 
excretion and a concomitant 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 hypercholesterolemic subjects and that LUM001 is likely to produce a 
correspondingly smaller increase in free bile acids in the lower colon.  There is also evidence 
in subjects with cholestasis to suggest that ASBT expression may be upregulated and higher 
LUM001 concentrations may be required to achieve the desired target inhibition of ASBT. 
Dosing in pediatric subjects will be based on subject weight.  Earlier studies in healthy 
volunteers and hypercholesterolemic subjects demonstrated that doses of 10 mg daily, 
equivalent to 140 µg/kg/day for a 70 kg subject, led to a decrease in serum bile acids by 
>50% following 2 weeks of treatment.  
In previous studies with LUM001, GI AEs were generally recorded in the first week of 
LUM001 dosing after 2 to 3 weeks of continuous dosing the observed rates of events was 
similar to those in the placebo group.  In a 4-week dose finding study in healthy volunteers, 
a dose escalation regimen was evaluated to mitigate the risk of loose stools and diarrhea.  
When the LUM001 dose was increased after each 7-day dosing period, to a maximum of 


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5 mg daily, the incidence of GI-associated AEs in the LUM001 treated arm was reduced to 
rates comparable to those reported in the placebo group. 
The starting dose in this clinical study may be as low as 14 µg/kg/day, is equivalent to less 
than the well-tolerated 1 mg dose (~17 µg/kg, 60 kg body weight) used in a previous study 
(Study 014), where LUM001 was tested at doses up to 5 mg/day for 14days in 40 
hyperlipidemic pediatric patients (n=5, children ages 10-11; n=35, adolescents ages 12-17), 
At the 1 mg dose in Study 014, only two out of eight subjects reported moderate or severe 
GI-associated AEs during 14 days. On a weight basis, 23 subjects received a dose ≥14 
µg/kg/day.  The highest starting dose in Study 014 was 168 µg/kg/day.  
To reduce the risk of loose stools and diarrhea in the current study, escalation of LUM001 
doses for LUM001-naïve subjects will occur at 7-day intervals starting at 14 µg/kg/day and 
increasing to 35 µg/kg/day, 70 µg/kg/day, and 140 µg/kg/day.  Thereafter, the dose of 
LUM001 may be adjusted for all study subjects during the dose-optimization period. A 
minimum period of 7-days must elapse between increases in dose. Dose adjustments will be 
made at the investigator’s discretion with the goal of reaching a dose optimized for 
maximum efficacy and tolerability of 35, 70, 140 or 280 μg/kg/day.  The dose may also be 
down-titrated, at the investigator’s discretion and in consultation with the medical monitor, 
for subjects experiencing intolerance to a given dose. During the follow-up treatment period, 
the dose will be escalated for those subjects who had been off treatment for ≥7 days. The 
dose will be escalated over the first 4 weeks up to 280 µg/kg/day or to the maximum 
tolerated dose starting at 35 µg/kg/day. This escalation regimen is supported by the safety 
profile observed in completed and ongoing clinical studies of LUM001 and allows for 
subjects to reach 280 µg/kg/day or a maximum tolerated dose within a 4-week period. 
The 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. 
Under Protocol Amendment 5, 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 280 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.  
If a subject experiences intolerance (such as gastrointestinal symptoms like 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. 
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 [PND] 21 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 


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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. 
Study Visit 
Schedule and 
Procedures 
Study activities will be conducted as described in the Schedule of Procedures.  
Synopsis Figure 1: Study Design for LUM001-303 (Up to and including Week 72):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline (Day 0):  Evaluations and procedures completed for the Week 13 Visit of the 
LUM001-302 study will also serve as the evaluations for the Baseline Visit for the extension 
study. Informed consent (and/or assent when appropriate) for participation in the extension 
study must be obtained for all participating subjects. At the Baseline visit (Week 0), subjects 
will be assessed to confirm continued study eligibility including a review of medical history 
and will undergo a physical examination including body weight, height, and vital signs. 
Blood and urine samples will be taken for clinical laboratory testing, including a fasting lipid 
panel and determination of fat-soluble vitamins, bile acids and other cholestasis biochemical 
markers.  Blood will also be collected for PK analysis.  The clinician scratch scale will be 
administered, as well as the PedsQL. Females who are of childbearing potential will have a 
urine pregnancy test and concomitant medications and any adverse events will be recorded. 
The degree and severity of xanthomatosis will be evaluated for all subjects by the clinician 
xanthoma scale. Study drug for Weeks 1 and 2 will be supplied at the Baseline visit to 
eligible subjects.   
 
Dose Escalation Period (Week 0 to Week 4):  Double-blind dosing in the dose escalation 
period will be initiated on the morning after the Baseline Visit. Caregivers and age 
appropriate subjects will be instructed to complete their ItchRO  
electronic diary twice daily (morning and evening).  Subjects will return to the clinic at 
Weeks 2, and 4, and will receive follow-up phone calls at Weeks 1, and 3.  On clinic visit 
days, safety and clinical laboratory evaluations will be performed.  The clinician scratch 
scale will be administered, adherence to study drug will be assessed and additional dosing 
instructions will be supplied. Study diary compliance will be assessed and concomitant 
medications and any adverse events will be recorded at clinic visits and at scheduled 
telephone contacts. Additional study drug will be supplied at Weeks 2 and 4.   


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Dose Optimization Period (Week 5 to Week 12): During the dose optimization period, the 
dose for each subject may be increased or decreased at the investigator’s discretion in a 
double-blind manner. The purpose of the dose optimization period is to allow the 
investigator to adjust the subject’s LUM001 dose to a level that is both tolerable to the 
subject and maximizes the potential effect of LUM001 on pruritus. Once an optimal dose is 
achieved, the dose will be fixed for the duration of the study.  
 
Electronic diaries will be completed twice daily by age-appropriate subjects and caregivers 
through Week 12 and then collected. Subjects will return to the clinic at Weeks 8 and 12 and 
will receive follow-up telephone calls at Weeks 6 and 10.  At the clinic visits, safety and 
clinical laboratory evaluations will be performed and vital signs, height and weight 
measurements will be collected.  The clinician scratch scale will be administered and a 
review of study diary and medication compliance will be completed. Concomitant 
medications and any adverse events will be assessed and recorded at each visit and at 
scheduled telephone contacts. Additional study drug will be supplied at Weeks 8 and 12.   
 
Stable Dosing Treatment Period (Week 13 to Week 72):  Subjects will continue to receive 
study drug during the stable dosing treatment period according to the dose achieved during 
the dose optimization period. However, if a subject experiences intolerance due to 
gastrointestinal symptoms the investigator, in consultation with the medical monitor, may 
lower the dose to a previously tolerated dose for the remainder of the study.  
 
During the stable dosing period, subjects will return to the clinic at Weeks 24, 36, 44, 48, 60 
and 72. Subjects who undergo a dose change at the Week 12 visit will also return to the 
clinic at Week 16 (see below). With the exception of Week 44, safety and clinical laboratory 
evaluations, blood sampling for study drug determination, and a physical exam (including 
collection of vital signs, height and weight measurements) will be completed at each clinic 
visit. In addition, the clinician scratch scale will be administered and study drug compliance 
will be assessed. The PedsQL will be completed at Weeks 24, 48 and 72 the Caregiver 
Impression of Change (CIC) will be completed at Weeks 48 and 72. Subjects/caregivers will 
receive follow-up phone calls at Weeks 16, 20, 28, 32 and 40. Concomitant medications and 
any adverse events will be evaluated and recorded at all clinic visits and at scheduled 
telephone contacts.  
Subjects who undergo a dose change at the Week 12 visit will complete an on-site clinic 
visit at Week 16. Subjects who do not undergo a dose change at Week 12 will receive a 
follow-up phone call at Week 16. The study activities that will be conducted at the Week 16 
clinic visit are described in the Schedule of Procedures. 
Electronic diaries will be completed by age-appropriate subjects and caregivers following 
the Week 24 and Week 44 visits. The diaries will be redistributed at Week 24 and completed 
twice daily for 4 weeks before being collected at Week 28. The diaries will then be 
redistributed at Week 44 and completed twice daily until Week 48. Re-training on the use of 
the diary will occur as appropriate at the Week 24 and Week 44 visits. 
At the physician investigator’s discretion, tapering or withdrawal of concomitant 
medications used for the treatment of pruritus may occur during the stable dosing period.  
 
Additional study drug will be supplied at each clinic visit during the stable dosing period.   
 
Week 72: Subjects will be evaluated by the investigator to determine whether they are 
eligible to roll over into the optional 52-week treatment period. Eligible subjects must have 
documented consent 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 


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performed. Blood and urine samples will be taken for clinical laboratory testing, including a 
fasting lipid panel and determination of fat-soluble vitamins, bile acids and other cholestasis 
biochemical markers.  Blood will also be collected for PK analysis.  The clinician scratch 
scale and PedsQL will be administered and the degree and severity of xanthomatosis will be 
evaluated for all subjects using the clinician xanthoma scale.  Females who are of 
childbearing potential will have a urine pregnancy test and concomitant medications and any 
adverse events will be recorded. Study drug compliance will also be assessed and all used 
and unused study drug and study supplies will be collected. Study drug will be discontinued 
at this visit if the subject chooses not to participate in the optional follow-up treatment 
period.   
 
Subjects will be encouraged to complete all study activities and visits. Any subject who 
withdraws from the study prior to completion of all treatment period clinic visits should 
undergo the procedures specified for the Week 72 visit. For safety reasons, efforts must be 
made to follow subjects for at least 30 days following their last dose of study drug.   
 
Follow-up Period (post-Week 72): For subjects who do not roll over into the 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. This call will be made for all subjects who 
complete the study, as well as any subject who terminates from the study early.  
Concomitant medications and any adverse events noted during this phone call will be 
recorded. 
 
Optional Follow-up Treatment Period (post Week 72 to Week 124):  
Subjects who are eligible to roll over into the follow-up treatment period will continue to 
receive study drug at the dose they were receiving at Week 72 for up to 52 weeks or until a 
new study opens to enrollment, whichever occurs first (Synopsis Figure 2).  During the 
follow-up treatment period, subjects will return to the clinic every 12 weeks, at Weeks 84, 
96, 108, 120, and 124.  
 
Synopsis Figure 2: Follow-up Treatment Scheme  
(no interruption in LUM001 dosing, or interruption <7 days)  
 
 
Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 280 µg/kg/day 
or to the highest tolerated dose starting at 35 µg/kg/day (Synopsis Figure 3). This escalation 
regimen is supported by the safety profile observed in completed and ongoing clinical 
Core 303 
LUM001 
Treatment Study
= Clinic Visit
= Phone Contact
LUM001 70 µg/kg/day
LUM001 140 µg/kg/day
LUM001 280 µg/kg/day
LUM001 35 µg/kg/day
52-Week Optional Follow-Up Treatment Period
Study
Week
84
96
108
120
124
72
76
80
Obtain 303 Extension Consent 
(if not already), 
& Laboratory Tests
=
Follow
-up
88
92
100
116
112
104
LUM001 280 µg/kg/day
= eDiary completion for 2 weeks 
following the specified clinic visit
**In consultation with Medical Monitor, the dose may be lowered to a previously well-tolerated dose to address tolerability issues at any time during the study**
**At the Investigator’s discretion, subjects who were previously down-titrated may be re-challenged during the follow-up period**
128


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studies of LUM001 and allows for subjects to reach 280 µg/kg/day or a highest tolerated 
dose within a 4-week period. The dose escalation (DE) period will proceed as follows: 
• 
DE Week -2 Clinic Visit: obtain consent, obtain weight, and draw labs.   
• 
DE Day 0 Clinic Visit: investigator evaluates laboratory results, study drug is 
dispensed and subject begins at 35 µg/kg/day dose level. 
• 
DE Week 73 Telephone Contact: subject escalates to 70 µg/kg/day dose level if 
prior dose level was tolerated.  
• 
DE Week 74 Clinic Visit: subject escalates to 140 µg/kg/day dose level if prior 
dose level was tolerated. 
• 
DE Week 75 Telephone Contact: subject escalates to 280 µg/kg/day dose, if prior 
dose level was tolerated. 
• 
DE Week 76 Clinic Visit: subject continues in Follow-up Treatment Period at 280 
µg/kg/day, or highest tolerated dose 
Synopsis Figure 3:  Follow-up Treatment Scheme  
(interruption in LUM001 dosing ≥7 days): 
 
Safety and clinical laboratory evaluations and a physical exam (including collection of vital 
signs, height and weight measurements) will be completed at each clinic visit. In addition, 
the clinician scratch scale will be administered and study drug compliance will be assessed. 
The PedsQL will be administered at DE Day 0 (for subjects requiring dose escalation) and at 
Weeks 84, 96, 108, 120, and 124 or ET visit. The Caregiver Impression of Change (CIC) 
assessment will be completed at Weeks 108, 120, and 124 or ET visit. Subjects/caregivers 
will receive follow-up phone calls at Weeks 76, 80, 88, 92, 100, 104, 112, 116, and at 30 
days following the last dose of study drug. Concomitant medications and any AEs will be 
evaluated and recorded at all clinic visits and at scheduled telephone contacts.  
Twice daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects during the 2 weeks following the Week 84, 96, 108, and 120. Electronic 
diaries will be provided to subjects and caregivers at these visits and re-training on the use of 
the diary will occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for 
the treatment of pruritus may occur during the long-term exposure period.  
With the exception of the Week 120 and Week 124 visit, 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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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 re-challenged during 
the follow-up treatment period. 
Long-term Optional Follow-up Treatment Period 
Subjects who either complete 124 weeks of treatment and/or are considered eligible for 
Protocol Amendment 5 may be eligible to receive further treatment under Protocol 
Amendment 5. Subjects who are eligible for re-entry into the long-term optional follow-up 
treatment period will continue to receive study drug until the first of the following occurs:  
i. 
The subjects 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 5 is implemented at the site and the subject consents to enter the 
long-term optional follow-up period, and the subject consents to enter the long-term optional 
follow-up period, the subject will be re-initiated at the same LUM001 dose they last received 
during LUM001-303 for approximately 12 weeks. The appropriate amount of study drug 
will be dispensed at the Protocol Amendment 5 Day 0/baseline visit, but daily dosing will 
not begin until the following day, Protocol Amendment 5, Study Day 1. At the Week 12 
visit, a determination about afternoon dose escalation will be made based on efficacy 
(ItchRO[Obs] and sBA) and safety assessments. Study activities will proceed as follows: 
• 
Protocol Amendment 5 Screening: Screening evaluations 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 urine pregnancy test. 
The electronic diary will be issued and caregivers and age-appropriate subjects will 
be asked to complete the diary twice daily during the 2 weeks following the screening 
visit. Eligibility criteria will be confirmed prior to the Baseline Visit. Concomitant 
medications and any adverse events will be recorded. 
• 
Protocol Amendment 5 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. Screen failures are eligible 
for rescreening on a case by case basis following discussions between the investigator 
and the medical monitor. 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. 
• 
Protocol Amendment 5 Day 0/Baseline Clinic Visit: Physical exam, body weight and 
height, vital signs, and blood and urine samples for clinical laboratory testing, 
including fasting lipid panel and cholestasis biomarkers. Blood will also be collected 
for determination of baseline fat-soluble vitamins. The clinician scratch scale, 
clinician xanthoma scale, and PedsQL questionnaire will be administered. ItchRO 
compliance will be assessed. Female subjects who are of childbearing potential will 
have a urine pregnancy test prior to dispensing study drug. Study drug will be 
dispensed and concomitant medications and adverse events will be collected.  
• 
Protocol Amendment 5 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 and cholestasis biomarkers. Blood will also be collected for 
determination of baseline fat-soluble vitamins. Caregivers and age-appropriate 
subjects will be asked to complete the diary twice daily during the 2 weeks following 
the Week 4 visit. The clinician scratch scale and the clinician xanthoma scale will be 


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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. The electronic diary will be issued and caregivers and age-
appropriate subjects will be asked to complete the diary twice daily during the 2 
weeks following the Week 4 visit. Study drug compliance will be assessed and study 
drug will be dispensed. Concomitant medications and adverse events will be 
collected.  
• 
Protocol Amendment 5 Week 8 Telephone Contact: Collection of concomitant 
medications and any adverse events. 
• 
Protocol Amendment 5 Week 12: Physical exam, body weight and height, vital signs, 
and blood and urine samples for clinical laboratory testing, including fasting lipid 
panel and cholestasis biomarkers. Blood will also be collected for determination of 
baseline fat-soluble vitamins. ItchRO compliance will be assessed, and the clinician 
scratch scale and clinician xanthoma scale 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 will be assessed for 
afternoon dose escalation eligibility. The sBA value used for determination of 
afternoon dose escalation eligibility will be the most recent available value collected 
within the prior 12 weeks. The ItchRO(Obs) score used for afternoon dose escalation 
eligibility will be derived from the most recent available 7-day interval of 
ItchRO(Obs) collected within the prior 8 weeks. 
Subjects who are eligible for re-entry into the long-term optional follow-up treatment 
period will be consented and initiate treatment at the same dose level they last received 
during LUM001-303 (Synopsis Figure 4). After approximately 12 weeks of treatment, 
subjects will be evaluated for eligibility for afternoon dose escalation at Week 12. Once a 
decision about afternoon dose escalation has been made, the subject will then either: 
- 
continue receiving the same dose of LUM001 QD (Synopsis Figure 5) if they do 
not meet the criteria for afternoon dose escalation OR 
- 
initiate the afternoon dose escalation (Synopsis Figure 6).   
 
Synopsis Figure 4: Re-entry into Long-term Optional Follow-up Treatment under 
Protocol Amendment 5 
 
 
Subjects not eligible for afternoon dose escalation (subjects with normal sBA level AND 
ItchRO(Obs) score <1.5; Synopsis Figure 5), will be maintained at the same dose level 


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and will continue morning dosing only. Subjects will have study activities repeated in 
recurring 12-week periods as follows, until study completion or termination: 
• 
Repeating Period Week 1 (not pictured in Synopsis Figure 5): subject deemed 
ineligible for afternoon dose escalation and continues QD dosing. 
• 
Repeating Period Week 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. ItchRO compliance will be assessed, the electronic diary will be issued, 
the clinician scratch scale, clinician xanthoma scale, 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. Urine samples for clinical laboratory testing will be collected at every 
other visit. 
• 
Subjects who do not qualify for afternoon dose escalation 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 (RP) beginning with RP2 within Schedule F. If, in the course 
of the afternoon dose escalation re-evaluation, a subject is found to qualify for 
afternoon dose escalation, then the subject will move into Schedule G. During the 
follow-up treatment period, subjects will return to the clinic every 12 weeks. 
Synopsis Figure 5: Long-term Optional Follow-up Treatment under Protocol 
Amendment 5, without afternoon dose escalation 
 
If the subject is eligible for afternoon dose escalation, ie, who has sBA level above 
normal AND/OR ItchRO(Obs) score ≥1.5, the subject will begin BID dosing (afternoon 
dose escalation) as follows: 


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• 
On afternoon dose escalation Day 0, morning dosing will continue at 280 µg/kg or 
the maximum tolerated dose. However, the volume of the morning dose will be 
reduced by half. Of note: morning dosing must have been stable for ≥4 weeks prior 
to initiation of afternoon dose escalation.  
• 
On afternoon dose escalation Day 0, the afternoon dose will be initiated at half the 
maximum tolerated morning dose and will continue at this dose level for a period of 
4 weeks.  If this dose level is tolerated, the afternoon dose then will be doubled (ie, 
at afternoon dose escalation Week 4) to a maximum of 280 µg/kg/day (ie, up to a 
maximum 560 µg/kg/day or maximum tolerated dose).   
The following procedures will occur during the afternoon dose escalation period: 
• 
Afternoon dose escalation 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. 
• 
Afternoon dose escalation Week 1 and Week 2 Telephone Contact: Collection of 
concomitant medications and any adverse events. Subject/caregiver will be 
reminded of dosing instructions. 
• 
Afternoon dose escalation 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. 
• 
Afternoon dose escalation Week 5 and Week 6 Telephone Contact: Collection of 
concomitant medications and any adverse events. Subject/caregiver will be 
reminded of dosing instructions. 
• 
Afternoon dose escalation 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 upon completion of other study 
procedures. Concomitant medications and any adverse events will be collected. 


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Synopsis Figure 6: Long-term Optional Follow-up Treatment under Protocol 
Amendment 5, with afternoon dose escalation 
 
Thereafter, subjects will have study activities repeated in recurring 12-week periods as 
described within Synopsis Figure 6, until study completion or termination. 
If any subject experiences intolerance, the investigator, in consultation with the medical 
monitor, may lower the dose at any time during the entire follow-up treatment period.  If the 
subject is on a twice daily dosing regimen, dose lowering should first be attempted with the 
afternoon dose.  At the investigator’s discretion, and in consultation with the medical 
monitor, subjects who were previously down titrated may be re-challenged during the 
follow-up treatment period. During the long-term optional follow-Up treatment period, 
subjects will return to the clinic every 12 weeks. 
Safety and clinical laboratory evaluations and a physical exam (including collection of vital 
signs, height and weight measurements) will be completed at each clinic visit. In addition, 
the clinician scratch scale will be administered and study drug compliance will be assessed. 


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The PedsQL will be administered at Protocol Amendment 5 Day 0/Baseline visit and every 
24 weeks thereafter. Subjects/caregivers will receive follow-up phone calls as outlined in the 
repeating 12 week periods. Concomitant medications and any AEs will be evaluated and 
recorded at all clinic visits and at scheduled telephone contacts. 
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 afternoon dose 
escalation visits.   
Twice-daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects during the 2 consecutive weeks following the Protocol Amendment 5 
Week 4 visit 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 follow-up 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 the following assessments as outlined for the EOT/ET visit: physical exam, body 
weight and height, vital signs, and blood and urine samples for clinical laboratory samples, 
including fasting lipid panel and pharmacokinetic sampling of LUM001. Blood will also be 
collected for determination of fat-soluble vitamins and AFP.  Female subjects who are of 
child-bearing potential will have a urine pregnancy test.  Study drug compliance will be 
assessed. Concomitant medications and adverse events will be collected. The clinician-
administered pruritus scale, the PedsQL, the Patient Impression of Change, the Caregiver 
Impression of Change, clinician xanthoma scale, and palatability questionnaire will also be 
completed.  
At completion of the long-term optional 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 terminated 
early. Concomitant medications and adverse events noted during this phone call will be 
recorded. 
Drug Level 
Evaluations 
Plasma levels of LUM001 will be evaluated at Baseline and Weeks 12, 24, 36, and 48 and 
72. Blood will be drawn approximately 4 hours post-dosing for drug level analysis. 
Additionally, for subjects in which afternoon dose escalation is initiated, samples will also 
be drawn at 4 hours following the morning dose on afternoon dose escalation Day 0, 
afternoon dose escalation Week 4, afternoon dose escalation Week 8, and at the 3 scheduled 
clinic visits following completion of the afternoon dose escalation treatment period. 
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. Α-fetoprotein (AFP), a 
marker of hepatocellular carcinoma will be measured every 6 months throughout the 
remainder of the study.  
Alterations in liver parameters assessed for the purposes of safety monitoring will be relative 
to the baseline (Day 0) of the LUM001-302 study in which the subject was enrolled.  
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.   


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Efficacy 
Evaluations 
The primary evaluation will be the mean change from Baseline (Day 0) to Week 48 in: 
• 
Fasting serum bile acid level. 
Secondary evaluations will be the mean change from Baseline (Day 0) to Week 48 and the 
change from Week 12 to Week 48 in: 
• 
Biochemical markers of cholestasis and liver disease [alanine aminotransferase (ALT), 
gamma-glutamyltransferase (GGT) and total bilirubin]. 
• 
Pruritus as measured by the electronic diary ItchRO instruments (ItchRO(Obs)TM, 
caregiver instrument/ItchRO(Pt) TM patient instrument). 
• 
During the first 12 weeks of the study, the electronic diary (ItchRO) will be completed 
twice daily (AM & PM). During the stable dosing period (Weeks 13-48), twice daily 
completion of the electronic diary (ItchRO) for 4 consecutive weeks will be required 
following the Week 24 and Week 44 clinic visits.   
• 
Xanthomas as measured by clinician xanthoma scale. 
Additional exploration, including behavior during the dose escalation and optimization 
phases will be specified in the statistical analysis plan.  
Palatability Data 
Palatability data will be collected at each clinic visit in the long-term optional follow up 
treatment period, with the exception of the afternoon dose escalation visits. A palatability 
questionnaire will be completed by the subject and/or caregiver (dependent on age). 
Assessments over time will be evaluated. 
Statistical 
Considerations 
Sample Size 
Approximately 18 subjects meeting the study’s inclusion and exclusion criteria will be 
enrolled in the study.  The number of subjects enrolled in this study will be determined by 
the number of subjects who roll-over from the LUM001-302 study. Because this is an 
extension study for the LUM001-302 study, the sample size is not based on statistical 
considerations.  
 
Safety 
All safety analyses will be performed on the Safety Population, defined as all subjects who 
received at least one dose of the study drug during the extension study.   
 
Adverse Events will be examined over the entire treatment period, and for the dose 
escalation and optimization periods. Adverse events for each study period will be 
summarized overall by treatment group based on the treatment group at enrollment in the 
extension study (baseline). Adverse events for the stable dosing period will also be 
summarized overall and by treatment group based on the stable dosing group. 
 
Other safety measures including clinical laboratory tests, vital signs, physical exams, and 
concomitant medication usage will be summarized descriptively.  For quantitative variables, 
descriptive statistics including number of observations, mean, median, standard deviation 
and range will be given for the values themselves and by their mean changes from pre-
defined reference points (see below) at each visit. Qualitative variables will be summarized 
using counts and percentages by baseline treatment group at each study visit.   
 
Drug Level Analysis 
Descriptive statistics analysis of LUM001 concentrations will be carried out on the plasma 
concentration data. 
 
Interim Analysis 
There may be one or more interim analysis (IA) conducted during the conduct of the study in 
order to guide the future of the development program. The IA may result in an interim report 
or publication. 


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Efficacy 
All efficacy analyses will also be performed on the Safety Population, defined as all subjects 
who received at least one dose of the study drug during the extension study. 
 
Special attention will be paid to change from baseline for those on placebo at baseline and 
during the first 12 weeks for those on active study drug at baseline and during the stable 
dosing period for all subjects at all dose levels. 
 
Secondary efficacy measures will be analyzed similarly as above.  Details of the analysis 
methods will be outlined in the SAP.  
 
All data will be included in data listings. 
 


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2 
LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
7αC4, C4 
7α-hydroxy-4-cholesten-3-one; an indirect method of bile acid 
synthesis 
Ac 
before meals 
AE 
adverse event 
ALGS 
Alagille syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
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 
Anatomic Therapeutic Chemical; classification for drugs 
ATX 
autotaxin 
BA 
bile acid 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cholesterol 7α-
hydroxylase 
rate-limiting enzyme in the synthesis of bile acid from 
cholesterol 
CIC 
Caregiver Impression of Change 
CMV IgM 
cytomegalovirus IgM antibody 
CRF 
case report form 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events  
CV 
curriculum vitae 
dL 
decilitre 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
electronic case report form 


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Abbreviation 
Definition 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor 19; regulates carbohydrate, lipid and 
bile acid metabolism 
FGF-21 
fibroblast growth factor 21; modulates hepatic metabolism 
FIC1 
familial intrahepatic cholestasis 1 
G 
gram 
GCP 
good clinical practices 
GGT  
gamma-glutamyltransferase 
GGTP (γGTP) 
gamma-glutamyl transpeptidase 
GI 
gastrointestinal 
HAV IgM 
Hepatitis A virus IgM antibody 
HbsAg 
surface antigen of the hepatitis B virus 
HCV 
Hepatitis C virus 
HDL 
high-density lipoprotein 
HDL-C 
high-density lipoprotein cholesterol 
HIV 
human immunodeficiency virus 
HMG-CoA reductase 
 
3-hydroxy-3-methyl-glutaryl-CoA reductase; rate-controlling 
enzyme of the pathway that produces cholesterol 
HR 
heart rate 
HRQoL 
health related quality of life 
IAF 
informed assent form 
IB 
investigator’s Brochure 
IBAT 
ileal bile acid transporter 
IBATi 
ileal bile acid transporter inhibitor 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethic committee 
INR 
international normalized ratio 
IRB 
institutional review board 


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Abbreviation 
Definition 
ItchRO™ 
Itch Reported Outcome 
ItchRO(Obs)™ 
Itch Reported Outcome observer instrument 
ItchRO(Pt)™ 
Itch Reported Outcome patient instrument 
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 
mL 
milliliter 
mmol 
millimole 
MRI 
magnetic resonance imaging 
NBD 
nasal biliary drainage 
NCS 
not clinically significant 
ObsRO 
observer reported outcome 
PBC 
primary biliary cirrhosis 
PEBD 
partial external biliary diversion 
PedsQL 
Pediatric Quality of Life Inventory 
PFIC 
progressive familial intrahepatic cholestasis 
PI 
principal investigator 
PK 
pharmacokinetic 
PROM 
patient reported outcome measure 
PSC 
primary sclerosing cholangitis 
Pt 
patient 
PT 
prothrombin time 


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Abbreviation 
Definition 
q.s. 
quantity sufficient 
qAM 
every morning 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD-5613 
original designation for LUM001 
Sec 
second 
SLC10A2 
solute carrier family 10 member 2; gene that encodes IBAT 
protein  
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) 
β-hCG 
beta-subunit of human chorionic gonadotropin; pregnancy test 
Μg 
microgram 
μM 
micromolar 


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3 
STUDY OBJECTIVES 
The primary objective of the study (up to and including Week 72) is to:  
• Evaluate the long-term safety and tolerability of LUM001 in pediatric subjects with 
ALGS. 
Secondary objectives of the study (up to and including Week 72) are to: 
• Evaluate the long-term effect of LUM001 on serum bile acid levels associated with 
ALGS. 
• Evaluate the long-term effect of LUM001 on pruritus associated with ALGS.  
• Explore the long-term effect of LUM001 on other biochemical markers of cholestasis and 
liver disease.  
• Evaluate the long-term effect of LUM001 on xanthomas associated with ALGS. 
• Explore an expanded dosing range to identify the doses necessary to achieve the optimal 
benefit-to-risk ratio for this patient population. 
 
Objectives of the long-term optional follow-up treatment period for subjects who are eligible for 
Protocol Amendment 5: 
• To offer eligible subjects in the LUM001-303 study continued study treatment until the 
first of the following occur: (i) the 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. 
• 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. 
• 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).  At this time, further development for this indication is not 
planned.  By virtue of its ability to inhibit bile acid absorption, LUM001 is being developed as a 
therapeutic agent for signs and symptoms of cholestatic liver disease.  
4.1 
Therapeutic Rationale 
Alagille syndrome (ALGS) is an example of cholestatic liver disease in children. In patients with 
ALGS, impairment of the egress of bile acids from the liver leads to cholestasis, hepatocellular 
injury and damage, and progressive liver disease that may ultimately lead to the need for liver 
transplantation.   Itch is the archetypal symptom of cholestasis, occurring at all stages of 
cholestatic liver disease, with or without jaundice.  
Surgical interruption of the enterohepatic circulation in patients with cholestatic liver disease has 
been shown to be beneficial. However, complications do occur and many patients and their 
families are reluctant to accept a permanent external ostomy in spite of the expected benefits.  
Pharmacological diversion of bile acids to the distal gut with an ASBTi/IBATi could be an 
attractive alternative to surgical intervention in ALGS.   
LUM001 is a potent inhibitor of ASBT/IBAT.  The ASBT/IBAT is present in the terminal 25% 
of the small intestine.  This transporter mediates the uptake of conjugated bile acids across the 
brush border membrane of the enterocyte.  Additional proteins and transporters carry bile acids 
from the enterocyte through the intestinal wall into the blood stream, where they are circulated to 
the liver via the portal vein and then re-secreted into the intestine in a system known as the 
enterohepatic circulation.  Ninety-five percent of bile acids that enter the gut lumen are recycled 
to the gallbladder where they are stored for future release to the duodenum.  


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Figure 1: 
Interruption of Enterohepatic Circulation with an ASBT/IBAT Inhibitor 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASBT/IBAT expression is under negative feedback regulation by bile acids; thus in the setting of 
cholestasis, ASBT/IBAT is maladaptively upregulated (Neimark, Chen, Li, & Shneider, 2004)  
(Hofmann, 2003). Therefore, inhibiting the reuptake of bile acids may represent an ideal 
treatment for cholestatic disease.  In the current study, ALGS will serve as models for 
generalized cholestasis.  By inhibiting the intestinal reabsorption of bile acids, LUM001 could 
interrupt the enterohepatic circulation and mimic the effects of partial external biliary diversion 
or ileal exclusion.  The current extension study will test this hypothesis.   
4.2 
Alagille Syndrome 
Alagille syndrome (ALGS) is an autosomal dominant with variable penetration multisystem 
disorder.  The clinical diagnosis is based on the presence of intrahepatic bile duct paucity on 
liver biopsy in association with at least three of the major clinical features: chronic cholestasis, 
cardiac disease, skeletal abnormalities, ocular abnormalities and characteristic facial features.  
Fewer than 200 patients with ALGS are born each year in the United States.  The estimated 
prevalence in Europe is 1.4/100,000 (Orphanet: The portal for rare diseases and orphan drugs).  
Elevations of serum bilirubin up to 30 times normal and serum bile salts up to 100 times normal 
are not uncommon.  Levels of markers of bile duct damage, including gamma-
glutamyltransferase (GGTP or GGT) and alkaline phosphatase (ALP), usually are significantly 
elevated.  Cholesterol levels may exceed 25.9–51.7 mmol/L.  Multiple xanthomas are common 
sequelae of severe cholestasis.  The pruritus seen in patients with this condition is among the 
most severe of any chronic liver disease and it is present in most children by the third year of 
life.  Although surgical interruption of the enterohepatic circulation has been successfully 
employed in the treatment of cholestasis and hypercholesterolemia in ALGS (Emerick & 
Whitington, 2002) (Modi, Suh, Jonas, Lillehei, & Kim, 2007), the management of cholestasis in 
ALGS remains largely supportive at this time.  As cholestasis tends to improve over the first 5 to 
10 years of life, therapies that ameliorate the complications of cholestasis, without a commitment 
to liver transplantation, are particularly attractive (Emerick, et al., 1999). 
 
ASBT 
 
Preventing recycling, 
lowers bile acid (BA) 
levels in liver, preventing 
liver damage 
X 


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4.3 
Pruritus 
Patients with cholestatic liver disease frequently present with pruritus, which can be severe, even 
in the absence of jaundice.  Elevation of serum bile acids is frequently accompanied by pruritus, 
and a causal association between pruritus and bile acids is suggested by the following:  (1) 
pruritus can been induced in volunteers by applying topical unconjugated bile acids, 
deoxycholate and chenodeoxycholate to the skin; and (2) pruritus can be relieved by surgical 
interruption of the enterohepatic circulation, which dramatically lowers serum bile acids.  
Nevertheless, the correlation between the levels of serum and skin bile acids and the degree of 
pruritus is poor.    
Intractable and pharmacologically recalcitrant pruritus is one of the major morbidities afflicting 
children with ALGS or progressive familial intrahepatic cholestasis (PFIC).  Treatment with 
antipruritics and bile salt resins may provide partial relief of itching for children with ALGS, but 
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 & Whitington, 
2002), PFIC, and PBC.  Almost complete resolution of pruritus has been observed in children 
with PFIC disease in a period of as little as two to four weeks following the procedure.  The 
rapid resolution of itch in response to therapy can be seen in Figure 2 extracted from the original 
description of this procedure by Whitington and Whitington  (Whitington & 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 & Whitington, 1988) 
 


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Table 1: 
Improvement in Biochemical Markers and Pruritus After Partial External 
Biliary Diversion in PFIC Disease and Alagille Syndrome Subjects 
4.4 
LUM001 
4.4.1 Nonclinical Studies 
4.4.1.1 
Pharmacology 
LUM001 is a potent selective inhibitor of the ileal apical sodium-dependent bile transporter, a 
transmembrane protein localized on the luminal surface of ileal enterocytes, commonly referred 
to as ASBT/IBAT.  The drug is a competitive inhibitor for bile acid substrate with a high affinity 
for the transporter.  Nonclinical studies indicate that selective inhibition of ASBT by LUM001 
results in increased fecal bile acid excretion, inhibition of the postprandial rise in serum bile 
acids, and decrease in serum total cholesterol.  It also increases the activity of hepatic cholesterol 
7α-hydroxylase and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, consistent with 
inhibition of bile acid reabsorption as the mechanism of action. 
4.4.1.2 
Pharmacokinetics 
Because of its large molecular weight and the presence of a quaternary nitrogen atom, LUM001 
is poorly absorbed from the gut.  In rats and dogs, oral bioavailability was < 0.4% at all doses 
tested.  LUM001 is metabolically stable after oral administration. After intravenous 
administration, the majority of drug is excreted in the feces, with approximately 5% excretion in 
the urine. 
4.4.1.3 
Toxicology 
A comprehensive assessment of LUM001 has been conducted in vitro and in animals.  LUM001 
is not toxic at doses far higher than those that are pharmacologically active in mice, rats, dogs, 
and monkeys.  The most significant effect observed in rodents is a prolongation of coagulation 
time considered secondary to malabsorption of vitamin K, which in turn is related to inhibition of 
bile acid absorption, the pharmacologic effect of LUM001.  Reversible prolongation of 
coagulation times was observed primarily in male rats that are especially sensitive to agents that 
alter vitamin K absorption and may not be an appropriate model for predicting vitamin K 
malabsorption in humans.  Acute oral doses up to 200 mg/kg LUM001 were well tolerated in 
dogs, with emesis as the primary dose-limiting toxicity.  There was no evidence of mutagenic 
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 & Whitington, 1988). 


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activity in vitro and no clastogenic activity in vitro or in vivo.  Results from rat and rabbit 
embryo/fetal development studies with doses up to 1000 and 250 mg/kg/day, respectively, 
showed no adverse effects on fetal growth and development.  Additional toxicology information 
can be found in the investigator’s brochure. 
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 adsorption, distribution, 
metabolism, and excretion (ADME) study, a statin co-administration study, a statin interaction 
study, and a food composition study.  Phase 2 studies included two dose-ranging studies in adult 
subjects, a tolerability study in adolescents and children, and a multiple dose tolerability and 
efficacy study of three sustained release formulations, compared with the immediate release 
formulation.  More than 1,400 human subjects have been exposed to LUM001 (immediate 
release) for up to 10 weeks. 
In previous clinical studies, LUM001 inhibited the postprandial increase in serum total bile acids 
concentrations and increased fecal total bile acids excretion, consistent with the mechanism of 
action of inhibiting ASBT.  LUM001 administration resulted in reductions of serum LDL-C in 
healthy volunteers and patients with elevated cholesterol.  These findings confirm that LUM001, 
a minimally absorbed inhibitor of ASBT, is effective in blocking enterohepatic recirculation of 
bile acids with the expected consequences on bile acid and cholesterol metabolism.  With 
LUM001 administration, there was also a trend toward increases in high-density lipoprotein 
cholesterol (HDL-C) and total triglycerides relative to placebo.   
Administration of LUM001 at doses up to 100 mg once daily over a four-week period was 
generally safe in healthy volunteers and at doses up to 40 mg once daily for up to 10 weeks in 
subjects with hypercholesterolemia.  The most commonly reported adverse drug reactions in 
LUM001-treated subjects were abdominal cramping (pain) and diarrhea and loose stools. With 
the exception of a single serious adverse event of cholecystitis no other SAEs possibly related or 
related to LUM001 have been reported, (over 1,400 subjects exposed). 
The majority of orally administered LUM001 was excreted intact in the feces along with a few 
minor metabolites.  LUM001 exposure in adolescents and children (Study 014) was low and 
consistent with a drug that is minimally absorbed.  Pharmacokinetic parameters in adolescent and 
children subjects did not significantly differ from those seen in adult subjects.   
No clinically significant laboratory abnormalities were documented in LUM001-treated subjects.  
LUM001 was associated with mild, often transient elevations of serum ALT in a small 
percentage of subjects.  Clinically significant reductions of serum fat-soluble vitamin levels were 


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not observed with LUM001 treatment in humans; however, levels of the carotenoid β-carotene 
were mildly reduced.  No alterations in coagulation parameters were observed, indicating no 
functional changes in vitamin K status.  Fecal fat excretion was not increased compared to 
placebo after four weeks of LUM001 treatment at doses up to 100 mg. 
4.5 
Rationale for Dose and Schedule of Administration 
The dosage of LUM001 chosen for the first studies in pediatric cholestatic subjects was 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, Austin, & Cole, 
1991) provided data indicating that the average length of the small intestine increases with age 
from birth through 20 years; this relationship followed a curve that is similar to the height and 
weight growth curves.  However, a plateau had not been reached at the maximum age examined 
(20 years), precluding predictions of intestinal length for older adults and thus scaling to infants 
and children based on estimated intestinal length.  An analysis of intestinal length as a function 
of age, weight, and height in adult cadavers was conducted by (Hounnou, Destrieux, Desme, 
Bertrand, & Velut, 2001).  Their analysis demonstrated that age had a negative and body weight 
a positive correlation with intestinal length.  Taken as a whole, the existing analyses are 
inconclusive with respect to the dependent variables that predict intestinal length.  Consequently, 
the most reasonable approach is to calculate doses in a pediatric subject from those in adults 
based using a direct mg/kg scaling.  For reference in an average adult subject, weighing 70 kg, a 
10 mg daily dose is equivalent to 140 µg/kg/day. 
Sample daily exposure (mg/day) across proposed dose levels for subjects ranging in weight from 
10-30 kg is depicted in Table 2. 


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Table 2: 
Sample Daily Exposure (mg/day) in Pediatric Subjects 
Weight 
(kg) 
Daily Exposure of LUM001 (mg) 
Dose Level 1 
(35 μg/kg/day) 
Dose Level 2 
(70 μg/kg/day) 
Dose Level 3 
(140 μg/kg/day) 
Dose Level 4 
(280 μg/kg/day) 
Dose Level 5 
(560 μg/kg/day) 
10 
0.35 
0.70 
1.40 
2.80 
5.60 
15 
0.53 
1.05 
2.10 
4.20 
8.40 
20 
0.70 
1.40 
2.80 
5.60 
11.20 
25 
0.88 
1.75 
3.50 
7.00 
14.00 
30 
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 
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, Cappon, Hurtt, & Zoetis, 2005) (van den Anker, Schwab, & 
Kearns, 2011). This study will enroll children ages 12 months to 18 years. 
In Study 014, as with all other studies of LUM001, no drug related serious AEs were observed.  
The most frequently reported AEs in all treatment groups (LUM001 and placebo) were diarrhea, 
abdominal pain, loose stools and nausea.  Most AEs were assessed with a probable or uncertain 
relationship to study medication and were generally characterized as mild or moderate in 
severity, except for those in six subjects who experienced severe nausea, diarrhea or abdominal 
pain.  These GI events usually resolved during continued treatment. Thirty-nine (39) out of 40 
subjects randomized to receive LUM001 completed the 14-day treatment period. One subject in 
the 0.3 mg group experienced severe diarrhea and abdominal pain that resulted in withdrawal 
from the study after 4 days of treatment. It is noteworthy that the AEs in Study 014 were 
generally recorded in the first seven days of LUM001 dosing, and observed at a four-fold lower 
frequency from 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. 


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Table 3: 
GI-associated Adverse Events in Study 003 
 GI Adverse Events 
Placebo 
(n=20) 
1 mg qAM 
(n=8) 
2.5 mg 
qAM 
(n=25) 
5 mg qAM 
(n=26) 
0.5-5 mg qAM* 
(n=16) 
Abdominal pain 
2 (10%) 
3 (37%) 
4 (16%) 
5 (17%) 
1 (6.3%) 
Constipation 
2 (10%) 
0 
3 (12%) 
0 
0 
Diarrhea  
1 (5%) 
1 (12%) 
5 (20%) 
2 (7%) 
0 
Nausea 
0 
0 
1 (4%) 
1 (4%) 
0 
Pruritus Ani 
0 
0 
6 (24%) 
4 (15%) 
0 
*Escalation regimen: 0.5 mg qAM (7 µg/kg/day) on Days 1-7, 1 mg qAM (13 µg/kg/day) on Days 8-14, 2.5 mg 
qAM (33 µg/kg/day) on Days 15-21, 5 mg qAM (67 µg/kg/day) on Days 22-28.  Average body weight 75 kg. 
The appropriate efficacious dose of LUM001 for the lowering of bile acid concentrations and the 
reduction of pruritus in cholestatic populations is not known.  However, earlier studies 
demonstrated that doses of 10 mg daily (equivalent to 140 µg/kg/day for a 70 kg subject) led to a 
decrease in serum bile acids in healthy volunteers by >50%.  In the PFIC population, there is 
some evidence that ASBT is upregulated, suggesting that higher doses may be required to 
saturate transporters and reach the desired effect in PFIC disease.  
To reduce the risk of loose stools and diarrhea in the current study, escalation of LUM001 doses 
for LUM001-naïve subjects will occur at 7-day intervals starting at 14 µg/kg/day and increasing 
to 35 µg/kg/day, 70 µg/kg/day, and 140 µg/kg/day.  Thereafter, the dose of LUM001 may be 
adjusted for all study subjects during the dose-optimization period. A minimum period of 7-days 
must elapse between increases in dose. Dose adjustments will be made at the investigator’s 
discretion with the goal of reaching a dose optimized for maximum efficacy and tolerability of 
either 35, 70, 140 or 280 μg/kg/day. 
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. 
Under Protocol Amendment 5, 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 280 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.  
If a subject experiences intolerance (such as gastrointestinal symptoms like 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. 
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 


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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 [PND] 21 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 multicentre, double-blind study of LUM001 in children ≥12 months of age diagnosed 
with ALGS who have completed participation in the LUM001-302 study. All subjects will 
receive active drug LUM001 in this study. The study is divided into 5 parts: a dose escalation 
period, a dose optimization period, a stable dosing period, an optional 52-week follow-up 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 560 ug/kg/day (280 ug/kg BID), 
based on efficacy (sBA level and ItchRO Observer (Obs) score) and safety assessments. 
Subjects’ participation in the long-term optional follow-up treatment period will continue 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.  Subjects who do not consent and/or are not eligible for Protocol Amendment 5 will 
continue their study participation in Protocol Amendment 4. 
Dose Escalation Period 
All subjects entering the extension study will participate in a 4-week double-blind dose 
escalation period during which: 
• Subjects who were randomized to receive placebo during the LUM001-302 study will 
receive weekly dose increases of LUM001 up to a target dose of 140 μg/kg/day. 
• Subjects who were randomized to receive active drug during the LUM001-302 study will 
continue to receive the dose of LUM001 that they were taking at Week 13 of the 
LUM001-302 study. The LUM001 doses for these subjects will remain blinded and will 
not be altered during the dose-escalation period.  
A minimum period of 7 days must elapse between increases in dose. 
Dose Optimization Period 
Following completion of the 4-week dose escalation period, subjects will enter an 8-week dose-
optimization period. During this period, the investigator will have the option to adjust LUM001 
dosing with the objective of achieving optimal control of pruritus at a dose level that is tolerated 
by the subject and up to a maximum daily dose of 280 μg/kg LUM001 or 20 mg total dose. 
Study drug dose level will be increased or decreased in a double-blind manner. Increases in dose 
will be based on effect on efficacy (sBA and ItchRO[Obs] score) and safety assessments. 
Reductions in dose will be based on tolerability.  At the investigator’s discretion, the doses for 
subjects who were previously down-titrated may be re-challenged during the dose optimization 
period. Each subject will receive one of the following dose levels:  
• LUM001 35 μg/kg/day 
• LUM001 70 μg/kg/day 


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• LUM001 140 μg/kg/day 
• LUM001 280 μg/kg/day 
A minimum period of 7 days must elapse between increases in dose.  
Stable Dosing Period 
Following completion of the 8-week dose optimization period, all subjects will enter the stable 
dosing period lasting 60 weeks.  During the remainder of the study subjects will be dosed with 
the Week 12 dose, or the highest tolerated dose below the Week 12 dose. However, if a subject 
experiences intolerance due to gastrointestinal symptoms, the investigator, in consultation with 
the medical monitor, may lower the dose to a previously tolerated dose. 
Optional Follow-up Treatment Period: 
At Week 72, 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: 
• 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 same dose level. 
• For subjects who are eligible to roll over into the follow-up treatment period having ≥7 
days since the last dose of LUM001, will be dose escalated up to 280 µg/kg/day or the 
highest tolerated dose following a  4 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 30 days after the last dose of study drug. 
Long-term optional Follow-up Treatment Period (Protocol Amendment 5): 
The long-term optional follow up treatment period is 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 560 µg/kg/day (280 µg/kg BID), 
based on efficacy (sBA and ItchRO score) and safety assessments. Subjects’ participation in the 
long-term optional follow-up treatment period will continue until the first of the following occur: 
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. 
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 at least 2 members who are otherwise independent from the conduct of the study: 
one or more physicians and at least 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 sponsor to stop or modify the study if safety concerns are identified. Further 


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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 multicentre study in the 3 clinical centers that participated in Study LUM001-302. 
5.4 
Number of Subjects 
Approximately 18 subjects meeting the study’s inclusion and exclusion criteria may be enrolled 
in the study.  
5.5 
Overall Study Duration and Follow-up 
For an individual subject, the study participation period will consist of a 4-week dose escalation 
period, an 8-week dose optimization period, a 60-week stable dosing period, an optional 52-week 
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. 
Study activities will be conducted as described in the Schedule of Procedures (Section 16.1).  
Figure 3: 
Study Design for LUM001-303 (Up to and including Week 72) 
 
 
 
 


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


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Figure 5: 
Follow-up Treatment Scheme (interruption in LUM001 dosing ≥7 days) 
Applies to the following population: 
• Subjects who experienced an interruption in LUM001 dosing ≥7 days between Protocol 
Amendment 3 and Protocol Amendment 4. 
 
 
Abbreviations: DE=dose escalation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 6: 
Re-Entry into Long-term Optional Follow-up Treatment under Protocol 
Amendment 5 
Applies to the following population: 
• 
Subjects who either complete 124 weeks of treatment and/or are considered eligible for 
Protocol Amendment 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 7: 
Long-term Optional Follow-up Treatment under Protocol Amendment 5, 
without afternoon dose escalation 
Applies to the following population: 
• Subjects deemed ineligible for afternoon dose escalation. 
 
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 under Protocol Amendment 5, 
with afternoon dose escalation 
Applies to the following 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 Treatment 
The Week 13 visit from the LUM001-302 study will also serve as the Baseline Visit for the 
LUM001-303 extension protocol. Eligible subjects will be enrolled in the extension study at the 
Baseline Visit (Day 0).  Dosing with study drug will begin on Day 1, following the Baseline 
Visit on (Day 0). 
Study drug will be prepared by a central pharmacy based on the subject’s weight. During the 
study, weight will be monitored at each visit. A change from Baseline in a subject’s weight that 
≥10% will require a dose adjustment. The central pharmacy will make weight-based dose 
adjustments at the time of the subject’s next LUM001 preparation.  
Diluent will be added by the central pharmacy pharmacist prior to shipping study drug to the site.  
Study drug will be dispensed to subjects/caregivers.  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 


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daily dosing will begin on Study Day 1. Subjects will receive a grape-flavored solution 
containing LUM001 administered orally once a day (QD) or 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.  
5.5.1.1 
Dose Escalation Period 
For subjects randomized to placebo in the LUM001-302 study, or those who complete the 
LUM001-302 more than 7 days prior to enrollment into this study, the LUM001 dose during the 
first 4 weeks of the study will be increased at weekly intervals to 140 μg/kg/day, or to a 
maximum tolerated dose below 140 μg/kg/day (10 mg maximum total dose). For subjects who 
were randomized to receive active drug in the LUM001-302 study LUM001 doses will remain 
the same as the dose taken at Week 13 of the LUM001-302 study. Study treatment for each 
subject will remain blinded and will be prepared by the unblinded central pharmacist according 
to a specified dose-escalation regimen. This regimen will represent a real dose escalation for 
subjects previously randomized to placebo and a mock dose escalation for subjects previously 
randomized to active study treatment.  The dosing regimen for each treatment group during the 
dose escalation period is summarized in Table 4.  
Table 4: 
Dose Escalation Regimens 
LUM001-302 
Study 
Extension Study LUM001-303 
Dose Escalation Period 
Week 13 
(μg/kg/day) 
Week 1 
Days 1 - 7 
(μg/kg/day) 
Week 2 
Days 8 - 14 
(μg/kg/day) 
Week 3 
Days 15 - 21 
(μg/kg/day) 
Week 4 
Days 22 - 28 
(μg/kg/day) 
Placebo 1 
14 
35 
70 
140 
35 2 
35 
35 
35 
35 
70 3 
70 
70 
70 
70 
140 4 
140 
140 
140 
140 
280 5 
280 
280 
280 
280 
1 
For subjects randomized to placebo in theLUM001-302 study, or those who complete the core study more than 7 
days prior to enrollment into this study, the LUM001 dose during the first 4 weeks of the study will be increased 
at weekly intervals to 140 μg/kg/day, or to a maximum tolerated dose below 140 μg/kg/day (10 mg maximum 
total dose). 
2 
LUM001 doses for subjects whose stable dose upon completion of LUM001-302 study was 35 μg/kg/day will 
remain stable at 35 μg/kg/day, or to a maximum daily dose of 2.5 mg/day.  
3 
LUM001 doses for subjects whose stable dose upon completion of LUM001-302 study was 70 μg/kg/day will 
remain stable at 70 μg/kg/day, or to a maximum daily dose of 5 mg/day.  
4 
LUM001 doses for subjects whose stable dose upon completion of LUM001-302 study was 140 μg/kg/day will 
remain stable at 140 μg/kg/day, or to a maximum daily dose of 10 mg/day.  
5 
LUM001 doses for subjects whose stable dose upon completion of LUM001-302 study was 280 μg/kg/day will 
remain stable at 280 μg/kg/day, or to a maximum daily dose of 20 mg/day.  
 


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If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, abdominal 
pain, cramping) at any time during the study, the 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 
replacement study medication will be provided to the subject/caregiver. 
5.5.1.2 
Dose Optimization Period 
Following the dose escalation period, the LUM001 dose for each subject may be increased or 
decreased by the investigator as clinically indicated with the objective of achieving control of 
pruritus at a dose level that is tolerated by the subject. Dose optimization will occur in a blinded, 
titrated manner with four dose levels available as treatment options: 35, 70, 140 or 280 
μg/kg/day.  Adjustments may occur at weekly intervals. Once an optimal LUM001 dose is 
achieved, the dose will be fixed for the duration of the period.  However, if at any time during 
the study, a subject experiences intolerance due to gastrointestinal symptoms, the physician 
investigator, in consultation with the medical monitor, may lower the dose to a previously 
tolerated dose.  
The maximum daily dose of LUM001 in this period is 280 μg/kg/day, up to a maximum daily 
dose of 20 mg. Blinded investigators may request dose adjustment for any subject based on an 
assessment of tolerability and effect on pruritus. Caregivers and age-appropriate subjects will be 
asked whether they wish to take a higher dose of the study medication to achieve greater relief of 
itching. If so, the dose may be adjusted upward, within the permitted dose range. However, the 
subject, caregiver, physician investigator, or the medical monitor may recommend against further 
escalation if there are safety or tolerability concerns. Doses of LUM001 will not be increased 
above 280 μg/kg/day or 20 mg per day during this period. 
5.5.1.3 
Stable Dosing Period 
At the end of the Dose Optimization Period, subjects will continue dosing to complete 72 weeks 
of cumulative LUM001 exposure in this study.   
If, at any time during the study, a subject experiences intolerance due to gastrointestinal 
symptoms, the physician investigator, in consultation with the medical monitor, may lower the 
dose to a previously tolerated dose. 
To ensure the safety of subjects participating in this study, a DMC will review serious adverse 
event data, other key subject safety and study data at specified intervals for the duration of the 
study. 
5.5.1.4 
Optional Follow-up Treatment Period 
Subjects who are eligible to roll over on to the optional follow-up treatment period with no 
LUM001 dosing interruption or an interruption of <7 days will continue to receive study drug at 
the dose they were receiving at Week 72 for up to 52 weeks of additional treatment or in the 
event that a new study opens to enrollment, whichever occurs first.  


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Subjects who are eligible to roll over into the follow-up treatment period with no LUM001 
dosing interruption or an interruption of <7 days will be maintained at the same dose level.  
Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 280 µg/kg/day or 
to the highest tolerated dose starting at 35 µg/kg/day. This escalation regimen is supported by the 
safety profile observed in completed and ongoing clinical studies of LUM001 and allows for 
subjects to reach 280 µg/kg/day or a highest tolerated dose within a 4-week period. The dose 
escalation (DE) period will proceed as follows: 
5.5.1.5 
Follow-up  
Study drug will be discontinued at Week 72 if the subject chooses not to participate in the 
optional follow-up treatment period. A safety follow-up phone call will be made by the study site 
at 30 days after the last dose of study drug. Follow-up phone calls will be made for all subjects 
who complete the study, as well as any subject who terminates from the study early.  
Concomitant medications and any adverse events noted during this phone call will be recorded.   
5.5.1.6 
Long-term Optional Follow-up Treatment Period 
Upon completion (or early termination) of the 52-week optional follow-up treatment period 
and/or implementation of this amendment, subjects will be assessed by the investigator to 
determine their willingness and eligibility for entry into the long-term optional follow-up 
treatment period. All subjects will be re-initiated at the same LUM001 dose they last received 
during LUM001-303. Eligibility assessment for afternoon dose escalation will then occur in all 
subjects based on efficacy (ItchRO[Obs] and sBA) and safety assessments following 
approximately 12 weeks of dose re-initiation as follows:  
• 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) 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 in order to limit the amount of propylene glycol in the diluent 
administered. 
o The afternoon dose will be initiated at half the dose level of the morning dose and 
will continue at this dose for a period of 4 weeks. If this dose level is tolerated, the 
afternoon dose will then be doubled to match the morning dose. 
• Subjects with abnormal sBA level AND ItchRO(Obs) score ≥1.5 who had normal sBA 
level and ItchRO(Obs) score <1.5 prior to dose interruption will remain on the maximum 
tolerated morning dose (the dose they received last during LUM001-303) for an additional 
2 weeks until their efficacy and safety assessments are repeated for eligibility assessment 
for afternoon dose escalation. 
• The sBA value used for determination of afternoon dose escalation eligibility will be the 
most recent available value collected within the prior 16 weeks. The ItchRO(Obs) score 


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used for afternoon dose escalation 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 280 µg/kg BID, ie, 560 µg/kg/day (up to a maximum 
possible daily dose of 50 mg/day). 
• Subjects who do not wish to enter the long-term optional follow-up treatment period, will 
be contacted via telephone by the study site approximately 30 days after the last dose of 
study drug. 
5.6 
Study Termination 
A subject is considered to have completed the study period(s) based on the version of the 
protocol they participated under. For subjects who consent to the long-term optional follow-up 
treatment period, the subject is considered to have completed the study if they participated in the 
EOT visit per Scheduled H. 
The end of study for the purposes of regulatory reporting is the point at which the last contact 
with the last subject during the protocol-specified scheduled follow-up treatment period is made. 


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6 
SUBJECT ENROLLMENT 
6.1 
Enrollment 
Before subjects may be enrolled to participate in the study, the sponsor, or designee, requires a 
copy of the appropriate written Independent Ethic Committee (IEC) or Institutional Review 
Board (IRB) approval of the protocol, informed consent/assent form(s) (ICF), and all other 
applicable subject information. 
Following informed consent/assent, the subject will be considered enrolled into the study.  The 
unique 6-digit subject identification number assigned to the subject upon screening in the 
LUM001-302 study will be used to identify the subject in the LUM001-303 extension study. 
This number will be used to identify the subject throughout the study. The subject’s 
identification number must remain constant and must be used on all study documentation related 
to that subject.   
Subjects will be enrolled in the 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 5 after the 
subject consents and the investigator has determined the subject meets study entry eligibility 
criteria per Protocol Amendment 5. However, any subject who consents to Protocol Amendment 
5 and does not meet criteria per the investigator is considered a screen failure for the long-term 
optional follow-up period under Protocol Amendment 5. Screen failures are eligible for 
rescreening on a case by case basis following discussions between the investigator and the 
medical monitor. Final consent and eligibility determined for subjects rescreened will be 
collected in the case report form. 
6.2 
Replacement of Subjects 
There will be no replacement of subjects who withdraw from the study. 
6.3 
Unblinding of Treatment Assignment 
All subjects, investigators, and study center personnel, except for the central pharmacist who 
prepares the study drug and the pharmacy monitor who monitors the pharmacy records and 
procedures, will remain blinded to all subjects’ treatment assignments until after the study 
database for the LUM001-303 protocol has been locked. Sponsor personnel and CRO personnel 
will remain blinded to all subjects’ dose levels until after the study database for the LUM001-
302 study has been locked. Once the treatment assignments for these core studies have been 
unblinded, access to the unblinded treatment assignments for subjects participating in 
LUM001-303 will be provided to sponsor and CRO personnel on a need-to-know basis only, 
with such access being restricted to the maximum extent feasible, consistent with their 
performing a comprehensive and timely analysis of the data from the LUM001-302 treatment 
study. 
If in the event of an emergency situation when knowledge of the treatment assignment will 
impact the clinical management of the subject, the investigator will have the ability to unblind 


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the treatment assignment for that subject at any time by contacting the study’s central 
pharmacy.  If a subject is unblinded by the investigator, the sponsor must be informed of the 
unblinding within 24 hrs.  If the blinding is prematurely broken, it is the responsibility of the 
investigator to promptly document and explain any unblinding to the sponsor. 
Breaking of the blind should not occur except in the event of a medical emergency where the 
identity of the drug must be known in order to properly treat the subject, or when causality must 
be determined prior to submitting a regulatory safety report for a 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 study procedures and 
observations (see Schedule of Procedures, Section 16.1) prior to unblinding, as knowledge of the 
treatment arm could influence subject assessment. 


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7 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
before being dispensed study drug treatment. 
7.1 
Inclusion Criteria 
To participate in this study, subjects must meet all of the following criteria: 
1. Male or female, 12 months to 18 years of age. 
2. Competent to provide informed consent and assent (per IRB/EC), as appropriate. 
3. Completed participation in study LUM001-302. 
4. Females of childbearing potential must have a negative urine pregnancy test [β human 
chorionic gonadotropin (β-hCG)] at the Baseline Visit. 
5. Males and females of child-bearing potential who are sexually active, or are not currently 
sexually active during the study, but become sexually active during the period of the study 
and for 30 days following the last dose of study drug, must agree to use acceptable 
contraception during the study. Effective methods of contraception are described in 
Section 8.6.1.  
6. Subjects are expected to have consistent caregiver(s) for the duration of the study. 
7. Caregiver (and age appropriate subjects) must be able to read and understand English. 
8. Caregivers (and age appropriate subjects) must have access to phone for scheduled calls from 
study site. 
9. Caregivers (and age appropriate subjects) must be willing and able to complete a daily 
electronic diary (ItchRO) during the first consecutive 12 weeks of the study and then for 4 
consecutive weeks following the Week 24 and Week 44 visits. 
10. Caregivers (and age appropriate subjects) must digitally accept the licensing agreement in the 
ItchRO electronic diary software at the outset of the study. 
7.2 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 


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1. Experienced an adverse event or serious adverse event (SAE) related to the study drug during 
the LUM001-302 study that led to the discontinuation of the subject from the LUM001-302 
study. 
2. Any conditions or abnormalities (including laboratory abnormalities) which, in the opinion of 
the investigator or the medical monitor, may compromise the safety of the subject, or 
interfere with the subject participating in or completing the study. 
3. History or presence of gallstones or kidney stones. 
4. History of non-adherence during the subject’s participation in the LUM001-302 study, or 
earlier in the LUM001-303 study. Non-adherence is defined by dosing compliance1 of less 
than 80% in the LUM001-302 study, or earlier in the LUM001-303 study.  
5. Unlikely to comply with the study protocol, or unsuitable for any other reason, as judged by 
the investigator. 
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 72 visit with no safety concerns. 
Subjects who were discontinued due to safety reasons can be re-challenged if blood tests are 
back to relatively normal values for this patient population and subject does not meet any of 
the protocol’s stopping rules; the decision will be made by the investigator in consultation 
with the medical monitor. Subjects who have undergone a surgical disruption of the 
enterohepatic circulation will not be eligible to enter into the follow-up treatment period. 
Subjects who were discontinued for other reasons will be considered on an individual basis. 
Protocol Amendment 5: Eligible subjects for the long-term optional follow-up treatment 
period 
Inclusion Criteria: 
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: 
a. Completed the protocol through either the Week 124 or the ET visit with no major 
safety concerns. 
OR 
b. 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. 
                                                        
1. 
Dosing compliance is calculated by [the total number of doses that were actually taken by the subject] divided by [the 
total number of doses that should have been taken by the subject] multiplied by 100.  


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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 study. 
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:   
All exclusion criteria mentioned for the original study LUM001-303 apply upon re-entry into the 
long-term optional follow-up treatment period. 


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8 
STUDY PROCEDURES 
8.1 
Study Schedule 
The schedule of assessments for this study is provided in the Schedule of Procedures, Section 
16.1. Subject-related events and activities including specific instructions, procedures, 
concomitant medications, dispensing of study drug, and descriptions of AEs should be recorded 
in the appropriate source documents and CRFs. 
8.1.1 Baseline (Day 0) 
Evaluations and procedures completed for the Week 13 Visit of the LUM001-302 study will also 
serve as the evaluations for the Baseline Visit for the LUM001-303 extension study. Informed 
consent (and/or assent when appropriate) for participation in the extension study must be 
obtained for all participating subjects. At the Baseline visit (Week 0), subjects will be assessed to 
confirm continued study eligibility including a review of medical history and will undergo a 
physical examination including body weight, height, and vital signs. Blood and urine samples 
will be taken for clinical laboratory testing, including a fasting lipid panel and determination of 
fat-soluble vitamins, bile acids and other cholestasis biochemical markers.  Blood will also be 
collected for PK analysis.  The clinician scratch scale will be administered, as will the PedsQL. 
Females who are of childbearing potential will have a urine pregnancy test and concomitant 
medications and any adverse events will be recorded. The degree and severity of xanthomatosis 
will be evaluated for all subjects by the clinician xanthoma scale. Study drug for Weeks 1, and 2 
will be supplied at the Baseline visit to eligible subjects.  
8.1.2 Dose Escalation Treatment Period (Week 0 to Week 4) 
Double-blind dosing in the dose escalation period will be initiated on the morning after the 
Baseline Visit. Caregivers and age appropriate subjects will be instructed to complete their 
ItchRO electronic diary (eDiary) twice daily (morning and evening).  Subjects will return to the 
clinic at Weeks 2, and 4, and will receive follow-up phone calls at Weeks 1 and 3.  On clinic 
visit days, vital signs (including height and weight measurements) will be collected and blood 
and urine samples will be taken for clinical laboratory testing, including a fasting lipid panel and 
determination of fat-soluble vitamins, bile acids and other cholestasis biochemical markers. The 
clinician scratch scale will be administered, adherence to study drug will be assessed and 
additional dosing instructions will be supplied. Study diary compliance will be assessed and 
concomitant medications and any adverse events will be recorded at clinic visits and at scheduled 
telephone contacts. Additional study drug will be supplied at Week 2 and Week 4. 
Clinic visits and follow-up phone calls during the dose escalation period are allowed a ±2 day 
scheduling window. 
8.1.3 Dose Optimization Period (Week 5 to Week 12) 
During the dose optimization period, the dose for each subject may be increased or decreased at 
the investigator’s discretion in a double-blind manner. The purpose of the dose optimization 
period is to allow the investigator to adjust the subject’s LUM001 dose to a level that is both 


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tolerable to the subject and maximizes the potential effect of LUM001 on pruritus. Once an 
optimal dose is achieved, the dose will be fixed for the duration of the study.  
Electronic diaries will be completed twice daily by age-appropriate subjects and caregivers 
through Week 12 and then collected. Subjects will return to the clinic at Weeks 8 and 12 and will 
receive follow-up telephone calls at Weeks 6 and 10.  At the clinic visits, vital signs (including 
height and weight measurements) will be collected and blood and urine samples will be taken for 
clinical laboratory testing, including a fasting lipid panel and determination of fat-soluble 
vitamins, bile acids and other cholestasis biochemical markers.  The clinician scratch scale will 
be administered and a review of study diary and medication compliance will be completed. 
Concomitant medications and any adverse events will be assessed and recorded at each visit and 
at scheduled telephone contacts. Additional study drug will be supplied at Weeks 8 and 12.  
Clinic visits and follow-up phone calls during the dose optimization period are allowed a ±5 day 
scheduling window. 
8.1.4 Stable Dosing Period (Week 13 to Week 72) 
Subjects will continue to receive study drug during the stable dosing treatment period according 
to the dose achieved during the dose optimization period. However, if a subject experiences 
intolerance due to gastrointestinal symptoms the investigator, in consultation with the medical 
monitor, may lower the dose to a previously tolerated dose; later attempts to escalate the dose are 
permitted.  
During the stable dosing period, subjects will return to the clinic at Weeks 24, 36, 44, 48, 60 and 
72. Subjects who undergo a dose change at the Week 12 visit will also return to the clinic at 
Week 16 (see below). With the exception of Week 44, safety and clinical laboratory evaluations, 
blood sampling for study drug determination, and a physical exam (including collection of vital 
signs, height and weight measurements) will be completed at each clinic visit. In addition, the 
clinician scratch scale will be administered and study drug compliance will be assessed. The 
PedsQL will be completed at Weeks 24, 48 and 72 and the Caregiver Impression of Change 
(CIC) will be completed at Weeks 48 and 72. Subjects/caregivers will receive follow-up phone 
calls at Weeks 16, 20, 28, 32 and 40. Concomitant medications and any adverse events will be 
evaluated and recorded at all clinic visits and at scheduled telephone contacts.  
Subjects who undergo a dose change at the Week 12 visit will complete an on-site clinic visit at 
Week 16. Subjects who do not undergo a dose change at Week 12 will receive a follow-up phone 
call at Week 16. The study activities that will be conducted at the Week 16 clinic visit are 
described in the Schedule of Procedures (Section 16.1). 
Electronic diaries will be completed by age-appropriate subjects and caregivers following the 
Week 24 and Week 44 visits. The diaries will be redistributed at Week 24 and completed twice 
daily for 4 weeks before being collected at Week 28. The diaries will then be redistributed at 
Week 44 and completed twice daily until the end of the study (Week 48). Re-training on the use 
of the diary will occur as appropriate at the Week 24 and Week 44 visits. 


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At the physician investigator’s discretion, tapering or withdrawal of concomitant medications 
used for the treatment of pruritus may occur during the stable dosing period.  
Additional study drug will be supplied at each clinic visit. 
Clinic visits and follow-up phone calls during the stable dosing period are allowed a ±14 day 
scheduling window. 
8.1.5 Week 72  
At the Week 72 visit, a physical exam (including collection of vital signs, height and weight 
measurements) will be performed. Blood and urine samples will be taken for clinical laboratory 
testing, including a fasting lipid panel and determination of fat-soluble vitamins, bile acids and 
other cholestasis biochemical markers.  Blood will also be collected for PK analysis.  The 
clinician scratch scale, PedsQL and CIC will be administered and the degree and severity of 
xanthomatosis will be evaluated using the clinician xanthoma scale.  Females who are of 
childbearing potential will have a urine pregnancy test and concomitant medications and any 
adverse events will be recorded. Study drug compliance will also be assessed and all used and 
unused study drug and study supplies will be collected.  
8.1.6 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 up to Week 72 or who is not eligible or willing to roll into the 52-week optional treatment 
period, should undergo the procedures specified for the Week 72 Visit. These procedures include 
a physical exam (including collection of vital signs, height and weight measurements), blood and 
urine sampling for safety and clinical laboratory evaluations (including bile acids, other 
cholestasis biochemical markers, fat soluble vitamins) and blood collection for PK analysis. In 
addition, the following assessments should be completed: the clinician scratch scale, the PedsQL, 
CIC and the clinician xanthoma scale.  Females who are of childbearing potential will have a 
urine pregnancy test and concomitant medications and any adverse events will be recorded. 
Study drug compliance will also be assessed and all used and unused study drug and study 
supplies will be collected. Study drug will be discontinued at this visit.  For safety reasons, 
efforts must be made to follow subjects for at least 30 days following their last dose of study 
drug.   
8.1.7 Optional Follow-up Treatment Period (post Week 72 to Week 124): 
Subjects who are eligible to roll over into the follow-up treatment period will continue to receive 
study drug at the dose they were receiving at Week 72 for up to 52 weeks or until a new study 
opens to enrollment, whichever occurs first. 
Subjects who are eligible to roll over into the follow-up treatment period with no LUM001 
dosing interruption or an interruption of <7 days will be maintained at the same dose level.  


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Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 280 µg/kg/day or 
to the maximum tolerated dose starting at 35 µg/kg/day. This escalation regimen is supported by 
the safety profile observed in completed and ongoing clinical studies of LUM001 and allows for 
subjects to reach 280 µg/kg/day or a maximum tolerated dose within a 4-week period. The dose 
escalation (DE) period will proceed as follows: 
• DE Week -2 Clinic Visit: obtain consent, obtain weight, and draw labs.   
• DE Day 0 Clinic Visit: investigator evaluates laboratory results, study drug is dispensed 
and subject begins at 35 µg/kg/day dose level. 
• DE Week 73 Telephone Contact: subject escalates to 70 µg/kg/day dose level if prior 
dose level was tolerated.  
• DE Week 74 Clinic Visit: subject escalates to 140 µg/kg/day dose level if prior dose level 
was tolerated. 
• DE Week 75 Telephone Contact: subject escalates to 280 µg/kg/day dose, if prior dose 
level was tolerated. 
• DE Week 76 Clinic Visit: subject continues in Follow-up Treatment Period at 
280 µg/kg/day, or highest tolerated 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 will be administered and study drug compliance will be assessed. The 
PedsQL will be administered at DE Day 0 (for subjects requiring dose escalation) and at Weeks 
84, 96, 108, 120, and 124 or ET visit. The Caregiver Impression of Change (CIC) assessment 
will be completed at Weeks 108, 120, and 124 or ET visit. Subjects/caregivers will receive 
follow-up phone calls at Weeks 76, 80, 88, 92, 100, 104, 112, 116, and at 30 days following the 
last dose of study drug. Concomitant medications and any AEs will be evaluated and recorded at 
all clinic visits and at scheduled telephone contacts.  
Twice daily completion of the electronic diary will be required by caregivers and age appropriate 
subjects during the 2 weeks following the Week 84, 96, 108, and 120. Electronic diaries will be 
provided to subjects and caregivers at these visits and re-training on the use of the diary will 
occur, as appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications used for the 
treatment of pruritus may occur during the long-term exposure period.  
With the exception of the Week 120 and Week 124 visit, 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. 
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 re-challenged during the follow-up treatment 
period. 


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8.1.8 Long-term Optional Follow-up Treatment Period 
Subjects who either complete 124 weeks of treatment and/or are considered eligible for re-entry 
into Protocol Amendment 5 may be eligible to receive further treatment under Protocol 
Amendment 5. Subjects who are eligible for re-entry into the long-term optional follow-up 
treatment period will continue to receive study drug until the first of the following occurs:  
i. 
The subjects are eligible to enter another LUM001 study,  
ii. 
LUM001 is commercially available, or  
iii. 
The sponsor stops the program or development of this indication. 
Refer to Section 5.5 for schematics describing the flow of study visits within this period. 
Once Protocol Amendment 5 is implemented at the site, and the subject consents to enter the 
long-term optional follow-up period, the subject will be re-initiated at the same LUM001 dose 
they last received during LUM001-303 for approximately 12 weeks. The appropriate amount of 
study drug will be dispensed at the Protocol Amendment 5 Day 0/baseline visit, but daily dosing 
will not begin until the following day. Protocol Amendment 5, Study Day 1. At the Week 12 
visit, a determination about afternoon dose escalation will be made based on efficacy 
(ItchRO[Obs] and sBA) and safety assessments.  Study activities will proceed as follows:   
• Protocol Amendment 5 Screening: Screening evaluations 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 urine pregnancy test. The electronic diary will be issued 
and caregivers and age-appropriate subjects will be asked to complete the diary twice daily 
during the 2 weeks following the screening visit. Eligibility criteria will be confirmed prior 
to the Baseline Visit. Concomitant medications and any adverse events will be recorded. 
• Protocol Amendment 5 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. Screen failures are eligible for rescreening on 
a case by case basis following discussions between the investigator and the medical 
monitor. 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. 
• Protocol Amendment 5 Day 0/Baseline Clinic Visit: Physical exam, body weight and 
height, vital signs, and blood and urine samples for clinical laboratory testing, including 
fasting lipid panel and cholestasis biomarkers. Blood will also be collected for 
determination of baseline fat-soluble vitamins. The clinician scratch scale, clinician 
xanthoma scale, and PedsQL questionnaire will be administered. ItchRO compliance will 
be assessed. Female subjects who are of childbearing potential will have a urine pregnancy 
test prior to dispensing study drug. Study drug will be dispensed and concomitant 
medications and adverse events will be collected.  
• Protocol Amendment 5 Week 4 Clinic Visit: Physical exam, body weight and height, vital 
signs, and blood and urine samples for clinical laboratory testing, including fasting lipid 


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panel and cholestasis biomarkers. Blood will also be collected for determination of baseline 
fat-soluble vitamins. Caregivers and age-appropriate subjects will be asked to complete the 
diary twice daily during the 2 weeks following the Week 4 visit. The clinician scratch scale 
and the clinician xanthoma scale 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. The electronic diary will be 
issued and caregivers and age-appropriate subjects will be asked to complete the diary 
twice daily during the 2 weeks following the Week 4 visit. Study drug compliance will be 
assessed and study drug will be dispensed. Concomitant medications and adverse events 
will be collected.  
• Protocol Amendment 5 Week 8 Telephone Contact: Collection of concomitant medications 
and any adverse events. 
• Protocol Amendment 5 Week 12: Physical exam, body weight and height, vital signs, and 
blood and urine samples for clinical laboratory testing, including fasting lipid panel and 
cholestasis biomarkers. Blood will also be collected for determination of baseline fat-
soluble vitamins. ItchRO compliance will be assessed, and the clinician scratch scale and 
clinician xanthoma scale 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 will be assessed for afternoon dose escalation eligibility. The sBA value 
used for determination of afternoon dose escalation eligibility will be the most recent 
available value collected within the prior 12 weeks. The ItchRO(Obs) score used for 
afternoon dose escalation eligibility will be derived from the most recent available 7-day 
interval of ItchRO(Obs) collected within the prior 8 weeks. 
Subjects who are eligible for re-entry into the long-term optional follow-up treatment 
period will be consented and initiate treatment at the same dose level they last received during 
LUM001-303 (Figure 6). After approximately 12 weeks of treatment, subjects will be evaluated 
for eligibility for afternoon dose escalation at Week 12. Once a decision about afternoon dose 
escalation has been made, the subject will then either continue receiving the same dose of 
LUM001 QD (Figure 7) if they do not meet the criteria for afternoon dose escalation, or initiate 
the afternoon dose escalation (Figure 8).   
Subjects not eligible for afternoon dose escalation (subjects with normal sBA level AND 
ItchRO(Obs) score <1.5; (Figure 7), will be maintained at the same dose level and will 
continue morning dosing only. Subjects will have study activities repeated in recurring 12-week 
periods as follows, until study completion or termination: 
• Repeating Period Week 1 (not pictured in Figure 7): subject deemed ineligible for 
afternoon dose escalation and continues QD dosing. 
• Repeating Period Week 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 


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also be collected for determination of baseline fat-soluble vitamins. ItchRO compliance 
will be assessed, the electronic diary will be issued, the clinician scratch scale, clinician 
xanthoma scale, 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. Urine samples for clinical laboratory testing will be 
collected at every other visit. 
• Subjects who do not qualify for afternoon dose escalation 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 within Schedule F. If, in the course of the afternoon dose escalation 
re-evaluation, a subject is found to qualify for afternoon dose escalation, then the subject 
will move into Schedule G as outlined in Section 16.1. During the follow-up treatment 
period, subjects will return to the clinic every 12 weeks. 
Subjects eligible for afternoon dose escalation (ie, who have sBA level above normal 
AND/OR ItchRO(Obs) score ≥1.5) will begin BID dosing (afternoon dose escalation) as 
follows: 
• On afternoon dose escalation Day 0, morning dosing will continue at 280 µg/kg or the 
maximum tolerated dose. However, the volume of the morning dose will be reduced by 
half. Of note: morning dosing must have been stable for ≥4 weeks prior to initiation of 
afternoon dose escalation.  
• On afternoon dose escalation Day 0, the afternoon dose will be initiated at half the 
maximum tolerated morning dose and will continue at this dose level for a period of 4 
weeks.  If this dose level is tolerated, the afternoon dose then will be doubled (ie, at 
afternoon dose escalation Week 4) to a maximum of 280 µg/kg/day (ie, up to a maximum 
560 µg/kg/day or maximum tolerated dose).   
The following procedures will occur during the afternoon dose escalation period: 
• Afternoon dose escalation 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. 
• Afternoon dose escalation Week 1 and Week 2 Telephone Contact: Collection of 
concomitant medications and any adverse events. Subject/caregiver will be reminded of 
dosing instructions. 
• Afternoon dose escalation 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 


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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. 
• Afternoon dose escalation Week 5 and Week 6 Telephone Contact: Collection of 
concomitant medications and any adverse events. Subject/caregiver will be reminded of 
dosing instructions. 
• Afternoon dose escalation 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 upon completion of other study procedures. Concomitant medications and any 
adverse events will be collected. 
Thereafter, subjects will have study activities repeated in recurring 12-week periods as described 
within Figure 8, until study completion or termination. 
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 re-challenged during the follow-up treatment 
period. During the long-term optional follow-up treatment period, subjects will return to the 
clinic every 12 weeks. 
Safety and clinical laboratory evaluations and a physical exam (including collection of vital 
signs, height and weight measurements) will be completed at each clinic visit. In addition, the 
clinician scratch scale will be administered and study drug compliance will be assessed. The 
PedsQL will be administered at Protocol Amendment 5 Day 0/Baseline visit and every 24 weeks 
thereafter. Subjects/caregivers will receive follow-up phone calls as outlined in the repeating 
12-week periods. Concomitant medications and any AEs will be evaluated and recorded at all 
clinic visits and at scheduled telephone contacts. 
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 afternoon dose 
escalation visits.  Plasma samples will be obtained for LUM001 pharmacokinetics at the 
afternoon dose escalation Day 0, afternoon dose escalation Week 4, afternoon dose escalation 
Week 8 visits, and at the 3 scheduled clinic visits following completion of the afternoon dose 
escalation period. 
Twice-daily completion of the electronic diary will be required by caregivers and age appropriate 
subjects during the 2 consecutive weeks following the Protocol Amendment 5 Week 4 visit and 
at every clinic visit within the repeating 12-week periods. Electronic diaries will be provided to 


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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 follow-up 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 
the following assessments as outlined for the EOT/ET visit: physical exam, body weight and 
height, vital signs, and blood and urine samples for clinical laboratory samples, including fasting 
lipid panel and pharmacokinetic sampling of LUM001. Blood will also be collected for 
determination of fat-soluble vitamins and AFP.  Female subjects who are of child-bearing 
potential will have a urine pregnancy test.  Study drug compliance will be assessed. Concomitant 
medications and adverse events will be collected. The clinician-administered pruritus scale, the 
PedsQL, the Patient Impression of Change, the Caregiver Impression of Change, clinician 
xanthoma scale, and palatability questionnaire will also be completed. 
8.1.9 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 H). 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 Patient Impression of Change, the Caregiver Impression of 
Change, and the Caregiver Global Therapeutic Benefit assessments, as defined for Early 
Termination (see Schedule of Procedures, Section 16.1). 
8.1.10 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 are predictive of ALGS. For subjects who do not have 
complete documentation of a JAGGED1 or NOTCH2 mutation, blood samples for genotyping 
will be collected at the screening visit. The appropriate genetic counseling in accordance with 
local laws will be provided to any subject and their legal caregivers at a study visit following the 


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receipt of results of genetic testing, at no cost to the subject. Subjects for whom prior genotyping 
was performed may need to have an optional repeat analysis performed if the original 
information collected at screening was insufficient for complete documentation of the diagnosis 
of ALGS including the type of mutation recorded. For those participants for which the type of 
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 Baseline, at 
Weeks 24, 36, 48, 60 and 72 and at Week 16 on subjects who undergo a change in dose at their 
Week 12 visit. A physical examination will also be conducted for any subject who terminates 
from the study early at the Early Termination Visit. For subjects who enter into the 52-week 
optional and long-term optional follow-up treatment periods, physical examinations will be 
conducted as outlined in the Schedule of Procedures in Section 16.1. 
Body weight, height, and vital signs, including body temperature, blood pressure, respiration and 
pulse, will be determined at every study clinic visit. A change in weight that is ≥10% of the 
weight used to calculate the subject’s current LUM001 dose will result in a dose adjustment. 
This dose adjustment will be made by the central pharmacy when they make the subject’s next 
LUM001 preparation. 
8.4 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of planned tests is 
compiled in Section 16.2. 
The investigator is responsible for reviewing and signing all laboratory reports.  The clinical 
significance of each value outside of the reference range will be assessed and documented as 
either not clinically significant (NCS) or clinically significant (CS).  See Section 11.4.3 
regarding laboratory abnormalities. 
8.5 
Pruritus and Quality of Life Assessments 
8.5.1 Itch Reported Outcome (ItchRO™) 
Pruritus will be assessed using a newly developed Itch caregiver/patient reported outcome 
measure (ItchROTM) administered as a twice daily electronic diary as described in Section 16.3.  
Caregivers for all subjects will complete the Observer instrument: ItchRO(Obs)™. Children ≥9 
years of age will complete the patient instrument: ItchRO(Pt)™. Children between the ages of 5 
and 8 years of age will complete the patient instrument with the assistance of their caregiver: 
ItchRO (Pt) Subjects and caregivers will be trained on the use of the electronic diary during their 
participation in a core LUM001 treatment protocol.   
During the dose escalation and dose optimization periods (Week 0 - Week 12), 
subjects/caregivers will be required to submit twice daily assessments using the electronic diary. 
The electronic diary will be returned to the study centre during the Week 12 visit. 


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During the stable dosing period, daily completion of the diary will be required by subjects and 
caregivers only during the 4 consecutive weeks that follow the Week 24 and Week 44 clinic 
visits.  At Week 24 and Week 44, subjects/caregivers will be provided with the electronic diary 
and re-trained on its use, as needed. At the Week 24 visit, subjects/caregivers will also be 
provided with prepaid/pre-labeled mailing supplies that should be used to return the electronic 
diary to the study centre immediately after they have completed the 4 weeks of diary entries. At 
the Week 44 visit, subjects/caregivers will be instructed to bring their electronic diary with them 
when they return for the Week 48 clinic visit. For subjects who enter into the 52-week optional 
and long-term optional follow-up treatment periods, daily completion of the diary will occur as 
outlined in the Schedule of Procedures in Section 16.1.  
8.5.2 Clinician Scratch Scale 
A clinician’s assessment of pruritus will be made by the principle investigator or sub-investigator 
using the clinician scratch scale (Section 16.4). This assessment will be completed at Baseline 
(Day 0) and at all clinic visits thereafter (Weeks 2, 4, 8, 12, 24, 36, 48, 60 and 72). For subjects 
who enter into the 52-week optional and long-term optional follow-up treatment periods, the 
clinician scratch scale will be administered 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 visits. 
8.5.3 Clinician Xanthoma Scale 
A clinician’s assessment of xanthomatosis will be made by the principle investigator or 
appropriate designee using the clinician xanthoma scale (Section 16.5). This assessment will be 
completed at Baseline (Day 0) and at Weeks 24, 36, 48, 60 and 72.  
For subjects who enter into the 52-week optional and long-term optional follow-up treatment 
periods, the clinician’s assessment of xanthomatosis will be administered 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 & Whitington, 2002). 


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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 
Baseline (Day 0) and Weeks 24, 48 and 72 clinical visits using the age-appropriate PedsQL 
module (Section 16.6). For subjects who enter the 52-week optional follow-up treatment period, 
the PedsQL will also be administered at Weeks 84, 96, 108, 120, and 124. For subjects with 
interruptions in LUM001 dosing of ≥7 days, the PedsQL will also be administered at DE Day 0. 
The PedsQL is a validated, modular instrument designed to measure health-related quality of life 
(HRQoL) in children and adolescent  (Varni, Seid, & Kurtin, 2001).  In addition to the core 
generic PedsQL module, the multidimensional fatigue and family impact questionnaires will also 
be administered at the Baseline (Day 0) and Weeks 24, 48 and 72 clinical visits using the age-
appropriate module, see Section 16.6. For subjects who enter into the 52 week optional and long-
term optional follow-up treatment periods, the multidimensional fatigue and family impact 
questionnaires will be administered as outlined in the Schedule of Procedures in Section 16.1. 
Age at the LUM001-302 baseline visit will be used as the age for the determination of the 
appropriate questionnaire to be used for the study.  This same module will be used for the 
duration of the study regardless of subsequent birthdays throughout the study. 
8.5.5 Caregiver Impression of Change 
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s perception of 
the subject’s xanthoma severity at the end of study drug treatment compared to his/her xanthoma 
severity prior to the start of treatment with study drug.  The CIC will be completed by all 
caregivers at the Week 48 and Week 72 visit, see Section 16.1. For subjects who enter into the 
52 week optional follow-up treatment periods, the CIC will be administered as outlined in the 
Schedule of Procedures in Section 16.1. 
8.5.6 Palatability 
A palatability questionnaire (see Section 16.9) 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 enrollment 
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.  


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Acceptable methods of contraception are: 
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); or 
d. 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 or 5 mL, or 0.25 mL qAM, ac), in the morning 30 minutes before breakfast. After breakfast 
only water should be consumed until the scheduled clinic visit.  
All subjects will have fat soluble vitamin levels monitored; blood samples for the analysis of fat 
soluble vitamins should be obtained before the daily dose of vitamins is administered, and 
approximately 4 hours after any food or formula. 


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9 
STUDY DRUG 
9.1 
Study Drug Description 
9.1.1 LUM001 
LUM001 is a powder that is to be dissolved with an appropriate diluent in order to administer the 
study drug as an oral solution.  The compositions of LUM001 study drug 1.0 mL, 0.5 mL, and 
0.25 mL oral solutions are described, respectively, in Table 5, Table 6, and Table 7. 
Table 5: 
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 6: 
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 7: 
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 
9.2 
Packaging and Labeling 
The sponsor will provide the central pharmacy with packaged study drug labeled in accordance 
with specific country regulatory requirements. Standard syringes will be provided by the sponsor 
for administration of study drug. 


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9.3 
Drug Accountability 
The central pharmacy and all study staff are required to document the receipt, dispensing and 
return/destruction of study drug supplies provided by the sponsor.   
At the conclusion of the study, any unused drugs, as well as original containers (even if empty), 
will be returned to the sponsor or handled according to written instructions from the sponsor, 
following approval by the sponsor.   


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10 
TREATMENT OF SUBJECTS 
10.1 Study Drug Administration 
The dose of study drug in this study is based on weight.  During the study, the subject’s weight 
will be monitored at each visit. A change in weight that is ≥10% of the weight used to calculate 
the subject’s current LUM001 dose will result in a dose adjustment. This dose adjustment will be 
made by the central pharmacy when they make the subject’s next LUM001 preparation. The 
dose may also be down-titrated, at the investigator’s discretion and in consultation with the 
medical monitor, for subjects experiencing intolerance (eg, gastrointestinal symptoms such as 
diarrhea, abdominal pain, cramping) to a given dose. If the subject is on twice daily dosing 
regimen, dose reduction should first be attempted with the afternoon dose. Subjects who were 
previously down-titrated may be re-challenged during the long-term exposure period. 
Study drug (LUM001 with diluent) will be prepared by a central pharmacy based on the 
subject’s last recorded weight from the LUM001-302 study. Diluent will be added by the central 
pharmacy pharmacist prior to shipping study drug to the site.  Study drug will be dispensed to 
subjects/caregivers at the study site.   
Subjects will receive a grape-flavored solution containing LUM001, administered orally QD or 
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 
doses should be taken approximately at the same time each day for the duration of the treatment 
period. See Section 5.5.1 for information regarding dosing during the treatment periods, 
respectively. 
Study Drug Administration under Protocol Amendment 5: 
 
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 re-entry, once a weight of 10 kg is reached while 
in the study, the subject will be moved from 0.5 mL total daily dosing volume (0.25 mL BID) to 
1.0 mL total daily dosing volume (0.50 mL BID). 
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 site staff.  
Subjects and/or guardians will be asked to complete a paper diary indicating when they took 
their study medication and when they ate breakfast 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 (from baseline/Day 0 of LUM001-303 entry until completing the final 
required assessment while enrolled in LUM001-303).   
All medications (other than study drug) taken by subjects during the course of the study will be 
recorded and reviewed by the Principal investigator (PI)/investigator’s designee.  Concomitant 
medication will be coded using the World Health Organization (WHO) Drug Dictionary (release 
date 01 September 2008, or more recent version if available).  AEs related to administration of 
these medications must also be documented. 
At the physician investigator’s discretion, tapering or withdrawal of concomitant medications 
used for the treatment of pruritus may occur during stable dosing period. With the exception of 
vitamin supplementation and anti-pruritic medications, the dosage and dosing regimen of other 
concomitant medications should not change during the course of the study. All modifications to 
concomitant medications must be carefully documented in the relevant case report forms 
Concomitant use of bile acid or lipid binding resins or any investigational drug product other 
than LUM001 is not allowed during the study.   
10.4 Other Protocol-required Drugs 
There are no other protocol required drugs. Subjects are expected to maintain a stable dose and 
administration schedule for all permitted concomitant medications throughout the course of the 
study. 
10.5 Safety Monitoring Rules 
10.5.1 General Monitoring Rules 
In the evaluation of adverse events and the potential relationship to study drug it is important to 
note that due to their liver disease many patients with Alagille syndrome will have abnormal 
liver enzyme levels (eg, ALT, ALP) total bilirubin, cholesterol and serum bile acids prior to their 
exposure to study drug in the lead-in study. If an individual subject exhibits a CTCAE Grade 3 
treatment emergent laboratory abnormality, with the exception of the specific rules outlined 
below (Section 10.5) 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.   


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10.5.2 Safety Monitoring Rules 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations.   
Confirmation Guidance:  At any time during the study, the initial clinical laboratory results 
exceeding the safety monitoring criteria presented below must be confirmed by performing 
measurements (in the central laboratory that performed the initial measurement) on new 
specimens.  Of note: the INR 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 3 days of the initial collection).  The results from 
the retest must be available prior to the next scheduled clinic visit or phone follow-up.   
Stopping Rule Guidance: Subject dosing must be suspended until the retest results are available.  
If any of the stopping criteria described below (refer to Section 10.5.2.2 and Section 10.5.2.5) are 
confirmed, the investigator in consultation with the medical monitor or appropriately qualified 
designee, will permanently discontinue the subject from further treatment with study drug. The 
subject will be evaluated as outlined below and will be encouraged to complete the early 
termination study procedures.  Subjects who do not meet the stopping rules based on retest may 
continue dosing and the investigator 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. 
10.5.2.1 
Safety Monitoring for Liver Chemistry Tests 
Safety monitoring criteria take into consideration the subject’s historical baseline ALT and total 
bilirubin levels.   Historical baseline levels will be defined as the values reported for each subject 
at their baseline visit for the LUM001-302 study.  
If at any time in the study an ALT or total bilirubin result exceeds the criteria shown in the table 
below, in relation to the subject’s historical baseline level, the initial measurement(s) should be 
confirmed ideally within 14 days of the initial collection.   


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Historical Baseline1 ALT 
ALT 
< ULN 
> 5 x ULN  
> ULN 
> 3 x historical baseline and > 5 x ULN 
 
Historical Baseline1 Total Bilirubin 
Total Bilirubin 
Total Bilirubin 1-10 mg/dL  
(17.10 – 171.04 μmol/L) 
3 mg increase over historical baseline level 
Total Bilirubin >10 mg/dL  
(>171.04 μmol/L) 
3 mg increase over historical baseline level 
1 Historical baseline values are those reported at baseline of the LUM001-302 study. 
 
Frequency of Repeat Measurements: Subjects with confirmed a ALT or total bilirubin level that 
is continuing to rise should have their liver chemistry tests (ALT, ALP, INR and total bilirubin) 
retested as clinically indicated, until levels stabilize or begin to recover. 
Further Investigation into Liver Chemistry Elevations:  Based on the inclusion/exclusion criteria 
for this study, the population to be enrolled, will have pre-existing baseline liver disease and will 
be closely monitored by the investigators with experience in the management of pediatric hepatic 
diseases. For subjects with a confirmed ALT or total bilirubin level, as described above, 
appropriate additional diagnostic investigations should be considered by 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 meeting 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 will be considered if: 
Historical Baseline Tests 
Change Observed 
ALT (any level) 
ALT ≥ 20 x ULN 
Total Bilirubin 1-10 mg/dL  
(17.10 – 171.04 μmol/L) 
5 mg increased and a 2 x increase over historical 
baseline level 
Total Bilirubin >10 mg/dL 
(>171.04 μmol/L) 
2 x increase over historical baseline level 
1 Historical Baseline values are those reported at baseline of the LUM001 -302 study.  
10.5.2.3 
Safety Monitoring for Triglycerides 
In the event of a confirmed laboratory result for fasting total triglyceride >500 mg/dL (>5.65 
mmol/L), the investigator and the medical monitor may consider a temporary interruption of 
study drug.  Dosing may resume when the triglyceride level returns to <300 mg/dL (3.39 
mmol/L) or to the subject’s baseline level. 
10.5.2.4 
Safety Monitoring for Fat Soluble Vitamins 
Vitamin status will be assessed per the schedule of procedures (see Section 16.1), blood samples 
will be obtained at the study visits before the daily dose of vitamins is administered. In the event 
of a confirmed laboratory result that falls either below or above the normal range for a vitamin 


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(25-hydroxy vitamin D, retinol, retinol binding protein, tocopherol (α), total lipids), or for an 
elevated INR (as a proxy for vitamin K status), the investigator should make the appropriate 
modification to the subject’s vitamin supplementation regimen.  
The response to the change in regimen will be assessed by relevant follow-up blood work one 
month later.  Changes will continue to be made until the levels are in the desired range.  
Adjustments may be discontinued outside of the desired range if there is agreement between the 
investigator and medical monitor that vitamin sufficiency cannot be reasonably expected. 
10.5.2.5 
Monitoring/Stopping Rules for Coagulation Panel Results 
In the event of a confirmed laboratory result for INR >1.5 (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 
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 (without 
an alternative explanation) will lead to discontinuation of study drug.  
 
If a subject experiences an acute illness requiring temporary discontinuation of study drug, they 
may continue their participation in the study and resume study treatment as long as the period of 
discontinuation does not exceed 7 days.  
10.7 Withdrawal of Subjects from the Study 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution.  Any subject who 
withdraws consent to participate in the study will be removed from further treatment and/or 
study observation immediately upon the date of the request.   
Any investigator decision to withdraw a subject from the study must first be discussed with the 
medical monitor prior to withdrawal. The investigator will provide the reason for withdrawal on 
the appropriate eCRF.  
For any subject who requests to stop study treatment or has withdrawn from study treatment at 
the request of the legal guardian, investigator or sponsor before completion of the protocol-
specified treatment period, and has received >1 dose of study drug, every effort should be made 
to complete the assessments scheduled for the Early Termination visit (see Schedule of 
Procedures, Section 16.1), provided the subject has not withdrawn full consent.  The Early 


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Termination visit should be scheduled within 7 days of the last study drug dose.  The electronic 
diary must also be retrieved. 
For safety reasons, efforts must be made to follow subjects for at least 30 days following their 
last dose of study drug.  If a subject withdraws due to an AE, the investigator should arrange for 
the subject to have follow-up visit(s) until the AE has resolved or stabilized.   
Subjects must be withdrawn from the study for any of the following reasons: 
• Withdrawal of consent/assent by the subject or legal guardian. 
• Pregnancy. 
• An AE (including disease progression) that leads the investigator to decide that the 
subject should be withdrawn.  If a subject suffers an AE that, in the judgment of the 
investigator or the sponsor, presents an unacceptable consequence or risk to the subject, 
the subject must be discontinued from the study. 
• Significant protocol deviation (eg, medication or treatment that is prohibited by the 
protocol). 
• At the discretion of the investigator if deemed not medically acceptable to continue study 
treatment. 
• Noncompliance, including failure to adhere to the study requirements as stated in the 
study protocol. 
• Administrative decision by the investigator or sponsor. 


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11 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
All AEs, whether observed by the investigator, reported by the subject, the subject’s caregiver, 
from laboratory findings, or other means, will be recorded on the AE eCRF and medical record. 
Safety information will be collected, reviewed, and evaluated by the sponsor or designee 
throughout the conduct of the study. 
11.1 Regulatory Requirements 
The sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of 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 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. 
 


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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. 
• Disease being studied and/or signs and symptoms associated with the disease, such as 
jaundice or itching, or abnormalities in liver enzymes already present at the baseline visit. 
• Treatment failure or lack of efficacy. 
11.2.2 Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any 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). 


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• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
11.3 Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the 
study (ie, before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  In addition, AEs that occur while the subject is 
not enrolled in the study during a gap period 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 centre’s first knowledge of the event.  The collection of SAEs will 
begin after the subject signs the informed consent form and stop 30 days after the last dose of 
study drug.  
When the investigator is reporting by telephone, it is important to speak to someone in person 
versus leaving a message.  An initial report of the SAE should be completed and a copy should 
be transmitted to the sponsor or designee.   
Detailed information should be actively sought and provided to the sponsor or designee as soon 
as additional information becomes available.  All SAEs will be followed until resolution.  SAEs 
that remain ongoing past the subject’s last protocol-specified follow-up visit will be evaluated by 
the investigator and sponsor.  If the investigator and sponsor agree the subject’s condition is 
unlikely to resolve, the investigator and sponsor will determine the follow-up requirement.  


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11.3.2 Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed consent 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.  
11.3.3 Evaluation of Adverse Events (Serious and Non-Serious) 
The following should be documented on the Adverse Event Case Report Form. 
11.3.3.1 
Relationship to the Study Drug 
The investigator will document his/her opinion of the relationship of the AE to treatment with 
study drug using the following criteria:  
• Related:  There is clear evidence that the event is related to the use of study drug (eg, 
confirmation by positive re-challenge test). 
• Possible:  The event cannot be explained by the subject’s medical condition, concomitant 
therapy, or other causes, and there is a plausible temporal relationship between the event 
and study drug administration. 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (eg, 
concomitant medications or ongoing medical conditions) or the temporal relationship to 
study drug administration and/or exposure suggests that a causal relationship is unlikely 
(For reporting purposes, Unlikely/Remote will be grouped together with Not Related). 
• Not Related:  The event can be readily explained by the subject’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the investigator believes 
no relationship exists between the event and study drug. 
11.3.3.2 
Severity 
The Common Terminology Criteria for Adverse Events (CTCAE) grade of the event should be 
reported according to CTCAE Version 4.0 (Section 16.8).  If the CTCAE does not have a 
grading for a particular 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. 


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Please also refer to Section 10.5.2 regarding specific safety monitoring for liver chemistry tests 
given that subjects with ALGS may have abnormal liver enzymes at baseline. 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 11.2.3).  
11.3.3.3 
Action Taken with Study Drug 
Action taken with study drug due to the event is characterized by one of the following; 
• None: No changes were made to study drug administration and dose. 
• Permanently Discontinued:  Study drug was discontinued and not restarted. 
• Temporarily Interrupted, restarted – same dose:  Dosing was temporarily interrupted or 
delayed due to the AE and restarted at the same dose. 
• Reduced dose:  Dosing was reduced, temporarily interrupted or delayed due to the AE 
and restarted at the next lower dose. 
11.3.3.4 
Treatment Given for Adverse Event 
Any treatment (eg, medications or procedures) given for the AE should be recorded on the AE 
eCRF (treatment should also be recorded on the concomitant treatment or ancillary procedures 
CRF as appropriate). 
11.3.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE then the event’s outcome is characterized by one of the 
following: 
• AE Persists:  Subject terminates from the 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 a SAE then the event’s outcome is characterized by one of the following: 
• Ongoing:  SAE continuing. 
• Recovered:  Subject recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date). 
• Fatal:  Subject died (the date of death should be entered as the SAE resolution date). 
11.4 Procedures for Handling Special Situations 


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The following categories of medical events that could occur during participation in a clinical 
study must be reported within 24 hours. 
• Serious adverse event (SAE, see Section 11.3.1). 
• Pregnancy. 
• Dosing errors. 
• Treatment unblinding for any reason (see Section 6.3). 
11.4.1 Pregnancy Reporting 
If a subject becomes pregnant or a pregnancy is suspected in either a subject or in the partner of a 
male study participant during the study, the study center staff must be informed immediately.  
The sponsor or designee should be notified within 24 hours of first learning of the occurrence of 
pregnancy.  Follow-up information including delivery or termination should be reported within 
24 hours. 
If pregnancy is suspected during the study (including follow-up), a pregnancy test will be 
performed.  The subject with a confirmed pregnancy will be immediately withdrawn from 
treatment with study drug.  However, the subject will be encouraged to complete the Early 
Termination procedures to the extent that study procedures do not interfere with the pregnancy.  
Regardless of continued study participation, the study physician will assist the subject in getting 
obstetrical care and the progress of the pregnancy will be followed until the outcome of the 
pregnancy is known (ie, delivery, elective termination, or spontaneous abortion).  If the 
pregnancy results in the birth of a child, the study center and sponsor may require access to the 
mother and infant’s medical records for an additional follow-up after birth. 
Payment for all aspects of obstetrical care, child or related care will be the subject’s 
responsibility.   
11.4.2 Dosing Errors 
Study drug dosing errors should be documented as protocol deviations.  A brief description 
should be provided in the deviation, including whether the subject was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional.   
Dosing details should be captured on the appropriate eCRF and paper subject diaries.  If the 
subject takes a dose of study drug that exceeds protocol specifications and the subject is 
symptomatic, then the symptom(s) should be documented as an AE and be reported per Section 
11.3. 
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.    


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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 
monitor.  Laboratory abnormalities deemed not clinically significant (NCS) by the investigator 
should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs by the 
investigator should not be deemed NCS on the laboratory sheet. 
The investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents. 


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12 
STATISTICAL CONSIDERATIONS 
This section presents a summary of the planned statistical analyses.  A statistical analysis plan 
(SAP) will be written for the study that contains detailed descriptions of the analyses to be 
performed.  The SAP will be written prior database lock. 
Approximately 18 subjects meeting the study’s inclusion and exclusion criteria will be enrolled 
in the study.  The number of subjects enrolled in this study will be determined by the number of 
subjects who roll-over from the preceding LUM001-302 study. Because this is an extension 
study for LUM001-302, the sample size is not based on statistical considerations.  
Safety 
All safety analyses will be performed on the Safety Population, defined as all subjects who 
received at least one dose of the study drug during the extension study.   
Adverse Events will be examined over the entire treatment period, and for the dose escalation 
and optimization periods. Adverse events for each study period will be summarized overall by 
treatment group based on the treatment group at enrollment in the extension study at baseline 
(Study Day 0). Adverse events for the stable dosing period will also be summarized overall and 
by treatment group based on the stable dosing group. 
Other safety measures including clinical laboratory tests, vital signs, physical exams, and 
concomitant medication usage will be summarized descriptively.  For quantitative variables, 
descriptive statistics including number of observations, mean, median, standard deviation and 
range will be given for the values themselves and by their mean changes from pre-defined 
reference points (see below) at each visit. Qualitative variables will be summarized using counts 
and percentages by baseline treatment group at each study visit.   
Drug Level Analysis 
Descriptive statistics analysis of LUM001 concentrations will be carried out on the plasma 
concentration data. 
Efficacy  
All efficacy analyses will also be performed on the Safety Population, defined as all subjects 
who received at least one dose of the study drug during the extension study. 
Special attention will be paid to change from baseline for those on placebo at baseline and during 
the first 12 weeks for those on active study drug at baseline and during the stable dosing period 
for all subjects at all dose levels. 
Secondary efficacy measures will be analyzed similarly as above.  Details of the analysis 
methods will be outlined in the SAP.  
12.1 Sample Size Considerations 


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Approximately 18 subjects meeting the study’s inclusion and exclusion criteria may be enrolled 
in the study.  Because this is an extension study for subjects who participated in the LUM001-
302 study, the sample size is not based on statistical considerations. 
12.2 Population 
12.2.1 Safety Population 
Because of the design of the study, there will be only one analysis population for the study. The 
Safety Population is defined as all subjects who were enrolled and received at least one dose of 
the study drug.  The Safety Population will be used for all safety analyses.  Subjects will be 
analyzed by treatment received.   
12.2.2 Demographic and Baseline Characteristics 
12.2.2.1 
Subject Disposition 
Subject disposition will be summarized descriptively.  The number and percentage of subjects 
enrolled, completed, and withdrawn, along with reasons for withdrawal, will be tabulated 
overall, and by treatment group when entering the study as well as after the dose optimization 
period.   
The number and percentage of subjects receiving study drug following the protocol specified 
dose escalation procedure and stable dosing regimen will be tabulated by treatment group.  Line 
listings will be prepared for all subjects not following the planned dosing schedule, showing all 
doses and dose changes occurring.  
Other disposition and study conduct information, including major protocol violations will be 
listed.  Duration of the follow-up period will be tabulated. 
12.2.2.2 
Baseline Data 
The following baseline data will be used to describe the study population: 
• Demographic variables, including age, gender and race/ethnicity. 
• Medical history. 
• Baseline disease characteristics (eg, pruritus scores, liver biochemistries). 
• Prior medications of interest [eg, ursodiol (UDCA), rifampicin] and concomitant 
medications. 
Demographic and baseline characteristics will be summarized descriptively for each treatment 
group and overall.   
Baseline for this study will be considered Day 0. 
Medical history information will be presented in listings. 


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12.2.3 Efficacy Analyses 
12.2.3.1 
Efficacy Variables 
The primary evaluation will be the mean change from Baseline (Day 0) to Week 48 in:  
• Fasting serum bile acid level. 
Secondary evaluations will be the mean change from Baseline (Day 0) to Week 48 and the 
change from Week 12 to Week 48 in: 
• Biochemical markers of cholestasis and liver disease [ALT, GGT and total bilirubin]. 
• Pruritus as measured by the ItchRO instruments (ItchRO(Obs)TM, caregiver 
instrument/ItchRO(Pt) TM patient instrument). 
• During the first 12 weeks of the study, the electronic diary (ItchRO) will be 
completed twice daily (AM & PM). During the stable dosing period (Weeks 13-
48), twice daily completion of the electronic diary (ItchRO) for 4 consecutive 
weeks will be required following the Week 24 and Week 44 clinic visits.  For 
subjects who continue in the follow-up treatment period, twice daily completion 
of the electronic diary (ItchRO) for 2 consecutive weeks will be required 
following the Week 84, 96, 108, and 120 clinic visits. 
• Xanthomas as measured by clinician xanthoma scale. 
Change from Week 12 to Week 48 in fasting serum bile acid will also be examined.  
Efficacy variables will be presented for each time point at which they are measured (see Section 
16.1). Additional exploration, including behavior during the dose escalation and optimization 
phases, will be specified in the SAP.  
12.2.3.2 
Primary Efficacy Analysis 
The change from baseline to Week 48 in the serum bile acid will be displayed for each treatment 
group by study visit, 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 baseline to Week 48 in the serum bile 
acids will be evaluated using an ANCOVA model with treatment and baseline serum bile acid as 
a covariate.  
12.2.3.3 
Secondary, Exploratory and Other Efficacy Analyses 
Secondary efficacy variables that are continuous measures will be analyzed similarly to the 
primary efficacy analyses.  
Change from baseline in Xanthoma scale will be categorized as improved, stable or worsened 
and will be compared between treatment groups using the chi-square test. 


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P-values from the secondary and exploratory efficacy analyses will be considered nominal. 
Additional exploratory analyses may be performed and will be defined and outlined in the SAP 
for the study.  
12.2.4 Safety Analyses 
Safety analyses will be performed on the Safety Population.   
12.2.4.1 
Safety Assessments 
The following assessments will be used to monitor safety: 
• Adverse events (AEs) and serious adverse events (SAEs). 
• Clinical laboratory results. 
• Vital signs. 
• Physical exam findings, including body weight and height. 
• Concomitant medication usage. 
• Serum alpha-fetoprotein (AFP). 
Safety variables will be presented for each time point at which they are measured (see Section 
16.1). 
12.2.5 Safety Analysis 
Safety analyses will be performed on the Safety Population.   
Safety data, including AEs, clinical laboratory tests, vital signs, physical examinations, and 
concomitant medication usage will be summarized descriptively overall and by treatment group 
for the safety population.  Individual subject listings will be prepared for all safety data. 
12.2.5.1 
Adverse Events 
Frequencies (number and percentage) of subjects with one or more treatment emergent AEs will 
be summarized by treatment group, by system organ class and preferred term according to the 
Medical Dictionary for Regulatory Activities (MedDRA™) terminology.  All treatment 
emergent AEs, all treatment emergent AEs potentially related to study drug, all treatment 
emergent SAEs and all treatment emergent SAEs potentially related to study drug will be 
summarized.  Specific AEs of special interest, particularly GI related AEs, will be outlined in the 
SAP and summarized.  AEs will be summarized overall and then separately for the dose 
escalation/optimization and stable dose periods of the study. 
 


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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.  
12.2.5.2 
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 baseline will also be presented over time, as 
appropriate.  Percent change from baseline will be added for laboratory values as outlined in the 
SAP.   
A separate listing will present laboratory values of all subjects who change from normal to 
abnormal or from abnormal to normal during the course of the study.  Changes within a 
treatment group for selected safety measures will be assessed at Weeks 8, 12, 24, 36, 48, 60, 72, 
and at additional time points during the 52-week optional follow-up treatment and long-term 
optional treatment periods using methods to be specified in the SAP.  
The effect of LUM001 on fat soluble vitamin levels will be assessed.  These laboratory values 
will be summarized as above and listed for individual subjects.  A separate listing will present 
laboratory values of all subjects who change from sufficient to insufficient or from insufficient to 
sufficient during the course of the study.   
12.2.5.3 
Physical Exams, Vital Signs and Weight/Height Measurements 
Changes in physical exam findings after baseline will be listed for individual subjects. 
Vital signs, weight and height (both weight and height are to be measured as an absolute number 
and as a z-score for age and gender) will be listed for individual subjects and summarized using 
descriptive statistics by clinical visit 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.   
12.2.5.4 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary and summarized descriptively by Anatomic Therapeutic Chemical (ATC) class, using 
counts and percentages.   
12.2.5.5 
Study Drug Exposure 
Due to poor absorption of LUM001, very low systemic exposure and plasma drug levels are 
expected.  The key measurement will be the pharmacodynamic effect on serum bile acid levels. 
However, exposure to study drug will be measured at specified study visits approximately 4 
hours post dose and data will be summarized and listed across the treatment period by treatment 


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group.  Average daily dose, total drug exposure, and total subject days of exposure to study 
medication will be summarized descriptively by treatment group. 
12.2.5.6 
Serum Alpha-fetoprotein 
Assessments of serum AFP will be listed for individual subjects and summarized using 
descriptive statistics by study visit. 
12.2.6 Palatability Analyses 
Palatability data will be collected at each clinic visit in the long-term optional follow up 
treatment period, with the exception of the afternoon dose escalation visits. A palatability 
questionnaire will be completed by the subject and/or caregiver (dependent on age). Assessments 
over time will be evaluated. 
12.2.7 Interim Analyses 
There may be one or more interim analysis (IA) conducted during the conduct of the study in 
order to guide the future of the development program. The IA may result in an interim report or 
publication. 
12.2.8 Additional Analyses 
Additional analyses may be performed to explore both safety and efficacy measures collected in 
this study.  The precise methods and analyses will be determined after the database is locked and 
the blind is broken.  Thus all such analyses will be interpreted cautiously and not used for formal 
inference, although inferential statistics may be used as part of the data summary.   


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13 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
13.1 Informed Consent 
The written informed consent/assent document(s) should be prepared in the language(s) of the 
potential patient population, on an English version provided by the sponsor or designee. 
 
The investigator is responsible for obtaining written informed consent/assent from the subject 
and/or their legally acceptable representative(s).  Before any tests or assessments are performed, 
an adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study will be provided to the subject and/or legally acceptable representative.  The subject and/or 
legally acceptable representative must be given sufficient time to consider whether to participate 
in the study and be assured that withdrawal from the study may be requested at any time without 
jeopardizing medical care related to or required as a result of study participation.   
Subjects and/or their legally acceptable representative(s) will be required to read, sign, and date 
an IEC approved informed consent/ascent form (ICF/IAF) summarizing the discussion prior to 
enrollment.  Since this is a pediatric study, in addition to the written informed consent, the assent 
of the child must also be obtained.  The person who conducted the informed consent discussion 
(not necessarily an investigator) should also sign and date the ICF/IAF.  The original signed 
ICF/IAF should be retained in accordance with institutional policy.  Subjects and/or their legally 
acceptable representative(s) will be given a copy of their ICF, and IAF.   
The subject’s and/or legal representative’s agreement and the acquisition of informed consent 
should be documented in the subject’s medical record.  When the study is completed and the 
CRF has been monitored, the ICF will be kept in the investigator’s central study file.  Regulatory 
authorities may check the existence of the signed ICF in this central study folder if not having 
done so during the performance of the study. 
Over the course of the study, the ICF/IAF may be modified, as appropriate (eg, due to protocol 
amendment or significant new safety information).  The resulting IEC-approved ICF/IAF will be 
used for all subjects subsequently entering the study or those already enrolled and still actively 
participating in the 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, and 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. 
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 


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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/assents form(s) 
must be received by the sponsor or designee before recruitment of subjects into the study and 
shipment of study drug.  A copy of the written approval of any other items/materials that must be 
approved by the study centre 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 centre 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 company, regulatory 
agency(ies), and the IEC/IRB direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The investigator is obligated to inform and obtain the consent of the subject to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the subject. 
All information concerning this study and which was not previously published is considered 
confidential information.  This confidential information shall remain the sole property of Mirum 
Pharmaceuticals, Inc.; it shall not be disclosed to others without written consent of Mirum 
Pharmaceuticals, Inc.; and shall not be used except in the performance of this study. 


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The information compiled during the conduct of this clinical study is also considered 
confidential and may be disclosed and/or used only Mirum Pharmaceuticals, Inc., as they deem 
necessary.  To allow the use of the information derived from this clinical study and to ensure 
compliance to current federal regulations, the investigator is obliged to furnish Mirum 
Pharmaceuticals, Inc., with the complete test results and all data compiled in this study. 


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


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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 centre 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 centre, 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 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. 


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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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15 
REFERENCES 
Emerick, K., & Whitington, P. (2002). Partial external biliary diversion for intractable pruritus and 
xanthomas in Alagille syndrome. Hepatology, 35, 1501–6. 
Emerick, K., Rand, E., Goldmuntz, E., Krantz, I., Spinner, N., & Piccoli, D. (1999). Features of 
Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology, 29, 
822–9. 
Hofmann, A. (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. (2001). Anatomical study of the 
length of the human intestine. Surg. Radiol. Anat., 24, 290-4. 
Modi, B., Suh, M., Jonas, M., Lillehei, C., & Kim, H. (2007). Ileal exclusion for refractory 
symptomatic cholestasis in Alagille syndrome. J Pediatr Surg, 42, 800-5. 
Neimark, E., Chen, F., Li, X., & Shneider, B. (2004). Bile acid-induced negative feedback 
regulation of the human ileal bile acid transporter. Hepatology, 40, 149-156. 
Orphanet: The portal for rare diseases and orphan drugs. (n.d.). Retrieved from 
http://www.orphanet.net 
van den Anker, J., Schwab, M., & Kearns, G. (2011). Developmental Pharmacokinetics. In H. 
Seyberth, A. Rane, & M. Schwab (Eds.), Pediatric Clinical Pharmacology (pp. 51-75). 
Varni, J., Seid, M., & Kurtin, P. (2001). PedsQL (TM) 4.0: Reliability and validity of the pediatric 
quality of life inventory (TM) version 4.0 generic core scales in healthy and patient 
populations. Medical Care, 39, 800-12. 
Walthall, K., Cappon, G., Hurtt, M., & Zoetis, T. (2005). Postnatal Development of the 
Gastrointestinal System: A Species Comparison. Birth Defects Res, 74, 132-56. 
Weaver, L., Austin, S., & Cole, T. (1991). Small intestinal length: a factor essential for gut 
adaptation. Gut, 32, 1321-3. 
Whitington, P., & Whitington, G. (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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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 – 
G).   
Study Termination and End of Treatment Procedures are outlined in Schedule H. 


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16.1.1 Schedule of Procedures A – (Baseline - Week 12) 
Study Period 
Baseline 
Treatment Period 
Dose Escalationi 
Dose Optimization 
Study Week 
 
1 
2 
3 
4 
6 
8 
10 
12 
Study Day 
Day 0a 
7 
14 
21 
28 
42 
56 
70 
84 
Window (in days) 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Assessment / Medical History 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
Body Weight & Height 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signsb 
X 
 
X 
 
X 
 
X 
 
X 
CBC with Differentialc 
X 
 
X 
 
X 
 
X 
 
X 
Coagulationc 
X 
 
X 
 
X 
 
X 
 
X 
Chemistry Panelc 
X 
 
X 
 
X 
 
X 
 
X 
Lipid Panelc,d 
X 
 
X 
 
X 
 
X 
 
X 
Cholestasis Biomarkersc,d 
X 
 
X 
 
X 
 
X 
 
X 
Fat Soluble Vitaminsc,d 
X 
 
 
 
 
 
X 
 
X 
Plasma Sample for LUM001 
X 
 
 
 
 
 
 
 
X 
Urinalysisc 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
Urine Pregnancy Teste 
X 
 
X 
 
X 
 
X 
 
X 
Subject eDiary / Caregiver eDiary (ItchRO) 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Clinician Scratch Scale 
X 
 
X 
 
X 
 
X 
 
X 
Clinician Xanthoma Scale 
X 
 
 
 
 
 
 
 
 
PedsQL 
X 
 
 
 
 
 
 
 
 
Enrolment 
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 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contactf 
 
X 
 
X 
 
X 
 
X 
 
a 
Evaluations and procedures completed for the Week 13 Visit of LUM001-302 study will also serve as the evaluations for the Baseline Visit for this extension study.  
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 supplementation. 
d 
Subjects are required to fast at least 4 hr (only water permitted prior to collection). 
e 
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 the first 12 weeks of the study, the eDiary (ItchRO) will be completed twice daily (AM & PM). Compliance will be assessed at each visit/phone contact. 


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Study Period 
Baseline 
Treatment Period 
Dose Escalationi 
Dose Optimization 
Study Week 
 
1 
2 
3 
4 
6 
8 
10 
12 
Study Day 
Day 0a 
7 
14 
21 
28 
42 
56 
70 
84 
Window (in days) 
 
(±2) 
(±2) 
(±2) 
(±2) 
(±5) 
(±5) 
(±5) 
(±5) 
i 
Subjects should be dosed for at least 7 days at each dose level. 
 
 
 
 
Clinic Visit 
 
Phone Contact 


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16.1.2 Schedule of Procedures B - Stable Dosing: Week 16 – Week 72 / Study Termination 
Study Period 
Treatment Period (continued) 
Study 
Terminationh 
Follow-Upi 
Stable Dosing 
Study Week 
16f 
20 
24 
28 
32 
36 
40 
44 
48 
60 
Week 72 
(or Early Termg) 
30 days 
after final 
doseh 
Study Day 
112 
140 
168 
196 
224 
252 
280 
308 
336 
420 
504 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
Physical Exam 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Body Weight & Height 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Vital Signsa 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
CBC with Differentialb 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Coagulationc 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Chemistry Panelc 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Lipid Panelc,d 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Cholestasis Biomarkersc,d 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Fat Soluble Vitaminsc,d 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Plasma Sample for LUM001 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Urinalysisb 
Xf,j 
 
Xj 
 
 
Xj 
 
 
Xj 
Xj 
Xj 
 
Urine Pregnancy Teste 
Xf 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Clinician Scratch Scale 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Clinician Xanthoma Scale 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Subject eDiary/Caregiver eDiary 
 
 
Xk 
Xk 
to 
Week 
28 
 
 
 
Xk 
Xk to 
Week 
48 
 
 
PedsQL 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Caregiver Impression of Change  
 
 
 
 
 
 
 
 
X 
 
X 
 
Study Drug Supplied 
 
 
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 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contactf 
X 
X 
 
X 
X 
 
X 
 
 
 
 
X 


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LUM001-303 Protocol Amendment 5.1 
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08 February 2019 
 
 
Study Period 
Treatment Period (continued) 
Study 
Terminationh 
Follow-Upi 
Stable Dosing 
Study Week 
16f 
20 
24 
28 
32 
36 
40 
44 
48 
60 
Week 72 
(or Early Termg) 
30 days 
after final 
doseh 
Study Day 
112 
140 
168 
196 
224 
252 
280 
308 
336 
420 
504 
Window (in days) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±14) 
(±5) 
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 hr (only water permitted prior to collection). 
d 
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 
A Week 16 Clinic Visit will be completed for all subjects who undergo a change in dose at Week 12; Subjects who do not undergo a dose change at Week 12 will be contacted by phone at 
Week 16. 
g 
Subjects who withdraw early should complete all evaluations at this visit. 
h 
Subjects who roll directly into the Week 76 visit will not have a follow-up visit until after Week 124. 
i 
Follow-up visit is only for subjects who exit the study at the Study Termination Visit.  
j 
At the indicated visits during the treatment period, oxalate will be part of the urinalysis  
k 
During the stable dosing period, twice daily completion of the eDiary (ItchRO) for 4 consecutive weeks will be required following the Week 24 and Week 44 clinic visits. 
 
 
 
Clinic Visit 
 
Phone Contact 


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16.1.3 Schedule of Procedures C – 52-Week Optional Follow-Up Treatment Period for those subjects < 7 days from 
last dose of LUM001 (Protocol Amendment 4) 
Study Period 
 
52-week FU Treatment Period 
Study 
Terminationj 
Follow- 
Upk 
Study Week 
76 
80 
84 
88 
92 
96 
 
 
100 
104 
108 
112 
 
 
116 
120 
124i 
30 days 
after 
final 
dose 
Study Day 
553 
560 
588 
616 
644 
672 
 
700 
728 
756 
 
336 
 
812 
 
840 
868 
Window (in days) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±14) 
(±5) 
Informed Consent/Assent for 
Protocol Amendment 5a 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Afternoon dose escalation 
eligibility assessment followed 
by shift in visit scheduleb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Physical Exam 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Body Weight & Height 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital Signsc 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
CBC with Differentiald 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Coagulationd 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Chemistry Paneld 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Lipid Paneld,e 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Cholestasis Biomarkersd,e 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Fat Soluble Vitaminsd,e 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Optional Genotypingf 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisd 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Xl 
 
Urine Pregnancy Testg 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Clinician Scratch Scale 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Clinician Xanthoma Scale 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Subject eDiary/Caregiver eDiary 
 
 
Xm 
Xm 
to 
Week 
86 
 
Xb 
Xm 
to 
Week 
98 
 
Xb 
Xm 
to 
Week 
110 
 
Xm 
Xm 
to 
Week 122 
 
PedsQL 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Caregiver Impression of Change  
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Study Drug Supplied 
 
 
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 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Contacth 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 


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16.1.3 Schedule of Procedures C – 52-Week Optional Follow-Up Treatment Period for those subjects < 7 days from 
last dose of LUM001 (Protocol Amendment 4) 
Study Period 
 
52-week FU Treatment Period 
Study 
Terminationj 
Follow- 
Upk 
Study Week 
76 
80 
84 
88 
92 
96 
 
 
100 
104 
108 
112 
 
 
116 
120 
124i 
30 days 
after 
final 
dose 
Study Day 
553 
560 
588 
616 
644 
672 
 
700 
728 
756 
 
336 
 
812 
 
840 
868 
Window (in days) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±14) 
(±5) 
a 
Once necessary approvals are received for Protocol Amendment 5 and associated consent/assent documents are available, site will consent/assent subject for Protocol Amendment 5 at the 
next clinic visit. 
b 
Once necessary approvals are received for Protocol Amendment 5 and associated consent/assent has been signed, site will assess subject eligibility for Protocol Amendment 5. Depending on 
the outcome of afternoon dose escalation eligibility assessment, the subject will move into either Schedule of Procedures F or G. Note: It is possible that subject will not necessarily complete 
up through Week 124 before they move to Schedule of Procedures F or G. 
c 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
d 
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. 
e 
Subjects are required to fast at least 4 hr (only water permitted prior to collection). 
f 
Genotyping sample will be drawn at Week 84 or at the time of re-consent for the optional follow-up treatment period; sample will be used to provide a full characterization and 
documentation of the mutation type in support of the diagnosis of ALGS. 
g 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
h 
Subjects must be available to receive a phone call from study staff. 
i 
Subjects who withdraw early should complete all evaluations at this visit. 
j 
Study termination only for subjects who discontinue early and/or decide not to continue into optional follow-up period(s). Subjects who choose to stay in the study go straight from this visit 
to the Optional Follow-up Treatment Period (Weeks 72-124). 
k 
Follow-up visit is only for subjects who exit the study at the Study Termination Visit. 
l 
At the indicated visits during the treatment period, oxalate will be part of the urinalysis. 
m 
During the stable dosing period, twice daily completion of the eDiary (ItchRO) for 2 consecutive weeks will be required following the Weeks 84, 96, 108, 120 clinic visits. 
 
  
 
Clinic Visit 
 
Phone Contact 


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16.1.4 Schedule of Procedure D – 52-Week Optional Follow-up Treatment Period: DE-2 –Week 176 for Subjects with 
≥7days from last dose of LUM001 (Protocol Amendment 4). Includes Evaluation of Eligibility for Afternoon 
Dose Escalation Dosing Regimen 
Study Period 
Treatment Period (continued) 
Study 
Terminationk 
Follow- 
Upl 
Follow-up Treatment Period  
Dose Escalation (DE) 
Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 
DE 
73 
DE 
74 
DE 
75 
DE 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Week 124 
(or ETk) 
30 days 
after 
final 
dose 
Study Day 
-14 
0 
511a 518a 525a 532a 560a 
588a 
616a 
644a 
672a 
700a 
728a 
756a 
784a 
812a 
840a 
868a 
 
Window (in days) 
(±14) 
(±2) 
(±2) (±2) (±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±14) 
(±5) 
Informed 
Consent/Assent for 
Protocol 
Amendment 5b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess eligibility 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Afternoon Dose 
Escalation (ADE) 
eligibility 
assessment followed 
by shift in visit 
schedulec 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Physical Exam 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Body Weight & 
Height 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital Signsd 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
CBC with 
Differentiale 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Coagulatione 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Chemistry Panele 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Lipid Panele,f 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Cholestasis 
Biomarkerse,f 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Fat Soluble 
Vitaminse,f, g 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Optional 
Genotypingh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysise 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Xm 
 


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CONFIDENTIAL 
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16.1.4 Schedule of Procedure D – 52-Week Optional Follow-up Treatment Period: DE-2 –Week 176 for Subjects with 
≥7days from last dose of LUM001 (Protocol Amendment 4). Includes Evaluation of Eligibility for Afternoon 
Dose Escalation Dosing Regimen 
Study Period 
Treatment Period (continued) 
Study 
Terminationk 
Follow- 
Upl 
Follow-up Treatment Period  
Dose Escalation (DE) 
Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 
DE 
73 
DE 
74 
DE 
75 
DE 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Week 124 
(or ETk) 
30 days 
after 
final 
dose 
Study Day 
-14 
0 
511a 518a 525a 532a 560a 
588a 
616a 
644a 
672a 
700a 
728a 
756a 
784a 
812a 
840a 
868a 
 
Window (in days) 
(±14) 
(±2) 
(±2) (±2) (±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±14) 
(±5) 
Urine Pregnancy 
Test (if indicated)i 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Clinician Scratch 
Scale 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Clinician Xanthoma 
Scale 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Subject 
eDiary/Caregiver 
eDiary 
 
 
 
 
 
 
 
Xn 
Xn 
to 
Week 
86 
 
Xn 
Xn 
to 
Week 
98 
 
Xn 
Xn 
to 
Week 
110 
 
Xn 
Xn 
to Week 
122 
 
PedsQL 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Caregiver 
Impression of 
Change  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Study Drug 
Supplied 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Review Study 
Diaries and Assess 
Compliance 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Phone 
Contactj 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 


Mirum Pharmaceuticals, Inc. 
CONFIDENTIAL 
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LUM001-303 Protocol Amendment 5.1 
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08 February 2019 
 
 
16.1.4 Schedule of Procedure D – 52-Week Optional Follow-up Treatment Period: DE-2 –Week 176 for Subjects with 
≥7days from last dose of LUM001 (Protocol Amendment 4). Includes Evaluation of Eligibility for Afternoon 
Dose Escalation Dosing Regimen 
Study Period 
Treatment Period (continued) 
Study 
Terminationk 
Follow- 
Upl 
Follow-up Treatment Period  
Dose Escalation (DE) 
Follow-up Treatment 
 
FTP Study Week 
DE -2 
DE 
Day 0 
DE 
73 
DE 
74 
DE 
75 
DE 
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
Week 124 
(or ETk) 
30 days 
after 
final 
dose 
Study Day 
-14 
0 
511a 518a 525a 532a 560a 
588a 
616a 
644a 
672a 
700a 
728a 
756a 
784a 
812a 
840a 
868a 
 
Window (in days) 
(±14) 
(±2) 
(±2) (±2) (±2) 
(±2) (±14) (±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±7) 
(±7) 
(±14) 
(±14) 
(±5) 
a 
Calculation of Study Day includes subject’s participation through the first 72 weeks. 
b 
Once necessary approvals are received for Protocol Amendment 5 and associated consent/assent are available, site will consent/assent subject for Protocol Amendment 5 at the next clinic visit.  
c 
Depending on the outcome of afternoon dose escalation eligibility assessment, the subject will move into either Schedule of Procedures For G. Note: It is possible that subject will not 
necessarily complete up through Week 124 before they move to Schedule of Procedures F or G. 
d 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
e 
See Section 16.2 for detailed list of laboratory analytes. 
f 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
g 
Blood samples must be drawn before administration of vitamin supplementation. 
h 
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. 
i 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
j 
Subjects must be available to receive a phone call from study staff. 
k 
Subjects who withdraw early should complete all evaluations at this visit. 
l 
Follow-up visit is only for subjects who exit the study at the Study Termination Visit. 
m 
At indicated visits during treatment period, oxalate will be part of the UA. 
n 
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 74, Week 84, Week 96, Week 108,  and Week 120 visits . 
 
 
 
Clinic Visit 
 
Phone Contact 
 


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16.1.5 Schedule of Procedure E – Long-term Optional Follow-up Treatment Period: Protocol Amendment 5 Screening 
(Week -2) and on LUM001. Includes Evaluation of Eligibility for Afternoon Dose Escalation Dosing Regimen at 
Protocol Amendment 5, Week 12 
• Any subject who re-enters the study under Protocol Amendment 5. The subject returns to their last previously 
administered dose for 12 weeks and then moves to either Schedule F or G, depending on afternoon dose eligibility.  
• 
Proceed to Schedule H for Early Termination or End of Treatment Procedures. 
 
Study Period 
Treatment Period (continued) 
Long-Term Optional Follow-up Treatment Period 
FTP Study Week 
Screening  PA5 
(Week -2) 
PA 5 Day 0/Baseline 
PA 5 Week 2 
 
PA 5 Week 4 
PA 5 Week 8 
PA 5 Week 12 
Study Day 
-14 
0 
518a 
532a 
546a 
560a 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
Informed 
Consent/Assent for 
Protocol 
Amendment 5b 
X 
 
 
 
 
 
Assess eligibility 
X 
X 
 
 
 
 
Afternoon Dose 
Escalation (ADE) 
eligibility 
assessment 
followed by shift 
in visit schedule 
 
 
 
 
 
X 
Physical Exam 
X 
X 
 
X 
 
X 
Body Weight & 
Height 
X 
X 
 
X 
 
X 
Vital Signsc 
X 
X 
 
X 
 
X 
CBC with 
Differentiald 
X 
X 
 
X 
 
X 
Coagulationd 
X 
X 
 
X 
 
X 
Chemistry Paneld 
X 
X 
 
X 
 
X 
Lipid Paneld,e 
 
X 
 
X 
 
X 
Cholestasis 
Biomarkersd,e 
 
X 
 
X 
 
X 
Fat Soluble 
Vitaminsd,e,f 
 
X 
 
X 
 
X 
Urinalysisd 
Xi 
Xi 
 
Xi 
 
Xi 


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Study Period 
Treatment Period (continued) 
Long-Term Optional Follow-up Treatment Period 
FTP Study Week 
Screening  PA5 
(Week -2) 
PA 5 Day 0/Baseline 
PA 5 Week 2 
 
PA 5 Week 4 
PA 5 Week 8 
PA 5 Week 12 
Study Day 
-14 
0 
518a 
532a 
546a 
560a 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
Urine Pregnancy 
Test (if indicated)g 
X 
X 
 
X 
 
X 
Clinician Scratch 
Scale 
 
X 
 
X 
 
X 
Clinician 
Xanthoma Scale 
 
X 
 
X 
 
X 
Subject 
eDiary/Caregiver 
eDiary 
Xj 
 
 
Xj 
 
 
PedsQL 
 
X 
 
 
 
 
Palatability 
Questionnaire 
 
 
 
X 
 
X 
Study Drug 
Supplied 
 
X 
 
X 
 
X 
Assess Study Drug 
Compliance 
 
 
 
X 
 
 
Review Study 
Diaries and Assess 
Compliance 
 
X 
 
 
 
X 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Follow-up Phone 
Contacth 
 
 
X 
 
X 
 
a 
Calculation of Study Day includes subject’s participation through the first 72 weeks. 
b 
Once necessary approvals are received for Protocol Amendment 5 and associated consent/assent are available, site will consent/assent subject for Protocol Amendment 5 at the Protocol 
Amendment 5 screening visit.  
c 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
 
d 
See Section 16.2 for detailed list of laboratory analytes. 
e 
Subjects are required to fast at least 4 hr (only water permitted) prior to collection. 
f 
Blood samples must be drawn before administration of vitamin supplementation. 
g 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
h 
Subjects must be available to receive a phone call from study staff. 
i 
Oxalate will be part of the UA.  
j 
During the Re-entry for Protocol Amendment 5, daily completion of the study diary for 2 consecutive weeks following the Protocol Amendment 5 screening visit  and the Protocol 
Amendment 5 Week 4 visit.  .   
 


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CONFIDENTIAL 
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Study Period 
Treatment Period (continued) 
Long-Term Optional Follow-up Treatment Period 
FTP Study Week 
Screening  PA5 
(Week -2) 
PA 5 Day 0/Baseline 
PA 5 Week 2 
 
PA 5 Week 4 
PA 5 Week 8 
PA 5 Week 12 
Study Day 
-14 
0 
518a 
532a 
546a 
560a 
Window (in days) 
(±14) 
(±2) 
(±2) 
(±2) 
(±2) 
(±2) 
 
Clinic Visit 
 
Phone Contact 


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16.1.6 Schedule of Procedure F-G: Re-entry under Protocol Amendment 5  
Schedule of Procedures F – Extension of Long-term Optional Follow-up Treatment Period, 
for subjects ineligible for afternoon dose escalation 
 
Below study activities repeat in repeating 12-week periodsh 
Repeating Period Week (RPx) 
RPx Week 4 
RPx Week 8 
RPx Week 12 
Scheduling Considerations 
 
 
 
Window (in days) 
(±7) 
(±7) 
(±14) 
Physical Exam 
 
 
X 
Body Weight & Height 
 
 
X 
Vital Signsa 
 
 
X 
CBC with Differentialb 
 
 
X 
Coagulationb 
 
 
X 
Chemistry Panelc 
 
 
X 
Lipid Panelb,c 
 
 
X 
Cholestasis Biomarkersb,c 
 
 
X 
Fat Soluble Vitaminsb,c,d 
 
 
X 
Urinalysisb 
 
 
Xi 
AFP Sample 
 
 
Xj 
Serum or Urine Pregnancy Test (if 
indicated)f 
 
 
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 
 
ADE Eligibility Assessment 
 
 
Xk 
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 hr (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 
At indicated visits during treatment period, oxalate will be part of the UA. 
j 
Sample will be drawn at every other clinic visit starting with RP1 Week 12.  
k      Starting at Week 12 RP2 subjects should be re-assessed for ADE eligibility 
 
 
 
Clinic Visit 
 
Phone Contact 
 


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Schedule of Procedures G – Extension of Long-term Optional Follow-up Treatment Period, for subjects eligible for afternoon 
dose escalation 
  
Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in repeating 12-week periods 
after completion of the ADE periodi 
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 
Urinalysisb 
Xj 
 
 
Xj 
 
 
Xj 
 
 
Xj 
AFP Sample 
 
 
 
 
 
 
 
 
 
Xk 
Plasma Sample 
for LUM001e 
X 
 
 
X 
 
 
X 
 
 
Xe 
Serum or Urine 
Pregnancy Test 
(if indicated)f 
X 
 
 
X 
 
 
X 
 
 
X 


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Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in repeating 12-week periods 
after completion of the ADE periodi 
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) 
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 
Suppliedg 
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 Contacth 
 
X 
X 
 
X 
X 
 
X 
X 
 


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Study Period 
 
 
 
Follow-up Treatment Period 
Afternoon Dose Escalation (ADE) 
 
Study activities repeat in repeating 12-week periods 
after completion of the ADE periodi 
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) 
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 hr (only water permitted) prior to collection. 
d 
Blood samples must be drawn before administration of vitamin supplementation. 
e 
Pharmacokinetic sample will additionally be collected at the three scheduled clinic visits following completion of the afternoon dose escalation period. 
f 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
g 
Study drug may be dispensed at unscheduled clinic visits. 
h 
Subjects must be available to receive a phone call from study staff. 
i 
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. 
j 
At indicated visits during treatment period, oxalate will be part of the UA. 
k 
Sample will be drawn at every other clinic visit starting with RP1 Week 12.  
 
 
 
Clinic Visit 
 
Phone Contact 


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08 February 2019 
 
 
16.1.7 Schedule of Procedures H – Study Termination and End of Treatment 
Procedures 
Schedule of Procedures H – 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 
 
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 
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 hr (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 UA. 
 
 
 
Clinic Visit 
 
Phone Contact 


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16.2 List of Laboratory Analytes 
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 
Activated partial 
thromboplastin time (aPTT) 
(sec) 
Prothrombin time (PT) (sec) 
INR 
Clinical Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Phosphate 
Glucose 
Blood urea                     
nitrogen (BUN) 
Creatinine 
Uric Acid 
Total bilirubin 
Direct bilirubin 
(conjugated) 
Indirect bilirubin 
(unconjugated) 
Alkaline 
phosphatase (ALP) 
AST (SGOT) 
ALT (SGPT) 
GGT 
Lipid Panel1 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Triglycerides (TG) 
 
Cholestasis 
Biomarkers1 
Serum bile acids 
7α hydroxy-4-
colesten-3-one (C4) 
 
Fat Soluble 
Vitamins1 
25-hydroxy 
vitamin D 
Retinol 
Retinol binding 
protein  
Tocopherol (α) 
 
Marker of 
hepatocellular 
carcinoma 
Alpha-fetoprotein 
(AFP) 
Urinalysis 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Occult blood and 
cells 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic 
examination2 
Oxalate3 
 
LUM001 Drug 
Levels 
LUM001 in plasma 
1 
Blood samples for the analysis of fat soluble vitamins should be drawn prior to administration of vitamin 
supplementation and approximately 4 hours after food or formula. Other biomarkers [eg, autotaxin, 
lysophosphatidic acid (LPA), FGF-19, FGF-21] may be measured.  At the discretion of the sponsor, samples 
will be collected and appropriately stored for subsequent analysis, as needed. 
2 
Will be performed on abnormal findings unless otherwise specified. 
3 
At the specified time points on the Schedule of Procedures (Section 16.1), oxalate will be part of the urinalysis. 
 
 


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


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


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


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All caregivers will also be required to answer the following question on the ItchRO(Obs) 
morning report: 
 
 
 
 
 
 


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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.  
 
 
If the caregiver selects “None observed or reported” the evening 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 answer the following question on the ItchRO(Obs) evening report: 
 
 
 
 
 


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


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


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16.6 Pediatric Quality of Life Inventory (PedsQL™) 
The PedsQL Generic Cores Scale is composed of 23 items to assess pediatric HRQoL 
measurements across 4 domains:  Physical Functioning (8 items), Emotional Functioning (5 
items), Social Functioning (5 items), and School Functioning (5 items).  Each item consists of a 
5-level Likert item survey (0-4).  Each PedsQL™ age-appropriate form should take less than 
four minutes to complete.   
Pediatric HRQoL measurement instruments must be sensitive to cognitive development and must 
include both child self-report and parent proxy-report.  Accordingly, the PedsQL consists of 
developmentally appropriate forms for children ages 1-12 months, 13- 24 months, 2-4, 5-7, 8-12, 
and 13-18 years.  Pediatric self-report is measured in children and adolescents ages 5-18 years, 
and parent proxy-report of child HRQOL is measured for children and adolescents ages 12 
months to 18 years. 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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16.6.1 Parent Report for Infants (ages 1-12 months) 
 
  
 


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


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16.6.3 Parent Report for Toddlers (ages 2-4) 
 
 
 
 


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


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16.6.5 Parent Report for Children (ages 8-12) 
 
 


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16.6.6 Parent Report for Teenagers (ages 13-18) 
 


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


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


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


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


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


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


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


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


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


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


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16.6.17 Family Impact Module v 2.0 
 
 
 
 


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16.7 
Caregiver Impression of Change (CIC) 
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s perception of 
the subject’s xanthoma severity at the end of study drug treatment compared to his/her xanthoma 
severity prior to the start of treatment with study drug.  The CIC will be completed by all 
caregivers at the Week 48 and Week 72 visit.  For subjects who enter the 52-week and long-term 
optional follow-up treatment periods, the CIC will be completed as outline 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.   
 
CIC 
 
How would you rate the change in your child’s xanthoma severity since the start of the study? 
 
 
Much better (1) 
Better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Worse (6) 
Much worse (7) 


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16.7.1 Caregiver Global Therapeutic Benefit (CGTB) 
 
 
 


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


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16.9 Palatability Questionnaire  
 
 


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16.10 Protocol History 
Document 
Date 
Global/Country/Site Specific 
Original Protocol 
13 Sep 2013 
 
Amendment 1 
05 Nov 2013 
Global 
Amendment 2 
28 Feb 2014 
Global 
Amendment 3 
17 Sep 2014 
Global 
Amendment 4 
04 Nov 2015 
Global 
Amendment 5 
16 May 2017 
Global 
 
16.10.1 Protocol Amendment 5 Summary of Changes 
 
Protocol Number: 
LUM001-303 
 
Protocol Title: 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
 
Amendment: 
5 
 
Date: 
16 May 2017 
 
The LUM001-303 protocol is being amended to allow continued participation in the long-term 
optional follow-up treatment period, beyond what was previously described in Protocol 
Amendment 4. Study treatment in the long-term optional follow-up treatment period will 
continue until the first of the following occurs: (i) the subjects are eligible to enter another 
LUM001 study, (ii) LUM001 is available commercially, or (iii) the sponsor stops the program or 
development in this indication. 
This amendment also describes the way in which eligible subjects who had previously 
discontinued from the study may re-enter and receive study treatment in the long-term optional 
follow-up treatment period (after Week 124).   


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Additional objectives for the long-term optional follow-up treatment period have been added, as 
follows:  
• Exploration of a twice daily (BID) dosing regimen and higher daily dosing of LUM001; 
• Assessment of alpha-fetoprotein (AFP) levels, a marker of hepatocellular carcinoma; 
• Assessment of the palatability of the LUM001 formulation in all subjects, by-proxy in 
subjects <4 years old and by patient questionnaire in children ≥4 years old; 
• Obtain safety and efficacy data in subjects treated long term in LUM001. 
 
Lastly, this amendment updates the contraceptive requirements to align with the Heads of 
Medicine Clinical Trials Facilitation Group Recommendations Related to Contraception and 
Pregnancy Testing (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf ). 
The following changes have been made to the Protocol Amendment 4 (4 November 2015). Note 
that correction of typos and grammatical errors are not captured in the below table.  


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New text indicated in bold; deleted text indicated in strikethrough. 
Section 
Description of Change 
Cover page, 
Sponsor; 
Title Page, Sponsor; 
Sponsor Signature 
Page, Sponsor;  
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, MSc 
 
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. 


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Section 
Description of Change 
Synopsis, 
Objectives; 
Section 3, Study 
Objectives 
Objectives of Optional Follow-up Treatment  Period (after Week 72) the long-term 
optional follow-up treatment period for subjects who are eligible for Protocol 
Amendment 5: 
• 
To offer eligible subjects in the LUM001-303 study continued study treatment at 
Week 72 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. 
• 
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 4 5 parts: a dose escalation period, a dose optimization period, a 
stable dosing period, and an optional 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.   
 
A minimum period of 7 days must elapse between increases in dose. 
 
Dose Optimization Period 
Study drug dose level will be increased or decreased in a double-blind manner. Increases 
in dose will be based on effect on pruritus efficacy (sBA and ItchRO[Obs] score) and 
safety assessments. 
 
Long-term optional Follow Up Treatment Period (Protocol Amendment 5): 
The long-term optional follow up treatment period is 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 560 µg/kg/day (280 µg/kg BID), based on efficacy (sBA and ItchRO score) and 
safety assessments. Subjects’ participation in the long-term optional follow-up 
treatment period will continue until the first of the following occur: 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. 
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 study. 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). 
6. 
Subjects are expected to have consistent caregiver(s) for the duration of the 
study. 
7. 
Subjects above the age of assent and caregivers and children Caregiver (and age 
appropriate subjects) must be able to read and understand English.  


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Section 
Description of Change 
Synopsis, Exclusion 
Criteria; 
Section 7.2, 
Exclusion Criteria 
4. 
History of non-adherence during the subject’s participation in the LUM001-302 
protocol study, or earlier in the LUM001-303 study. Non-adherence is defined by 
dosing compliance of less than 80% in the LUM001-302 protocol study or earlier in the 
LUM001-303 study. 
Eligible subjects for the 52-week optional follow-up treatment period: 
Subjects will be considered eligible for the 52-week optional 52-week follow-up 
treatment period if they have completed the protocol through the Week 72 visit with no 
safety concerns. Subjects who were discontinued due to safety reasons can be re 
challenged if blood tests do not satisfy are back to relatively normal values for this 
patient population and the subject does not meet any of the protocol’s stopping rules; 
the decision will be made by the investigator in consultation with the sponsor medical 
monitor. … 
 
Protocol Amendment 5: Eligible Subjects for the long-term optional follow-up 
treatment period: 
 
Inclusion Criteria: 
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 124 or the ET 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 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 study. 
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: 
All exclusion criteria mentioned for the original study LUM001-303 apply upon re-
entry into the long-term optional follow-up period. 
Synopsis, Treatment 
Groups 
After Week 124 and/or implementation of this amendment, whichever occurs first, 
subjects will be considered for a long-term optional follow-up treatment period, if 
eligible, receiving up to 560 μg/kg/day (given as twice daily doses of 280 μg/kg), or to 
a maximum possible daily dose of 50 mg/day. 


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Synopsis, Study 
Drug Dosage and 
Administration; 
Section 10.1, Study 
Drug 
Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Synopsis, Long-
term Optional 
Follow-up 
Treatment Period; 
Section 5.5.1.6, 
Long-term Optional 
Follow-up 
Treatment Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects will receive a grape-flavored solution containing LUM001, administered 
orally once a day (QD) or 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 doses should be taken approximately at the same time each day for the 
duration of the treatment period. 
 
Subjects who weight 10 kg or more will receive a 1.0 mL grape-flavored solution 
containing LUM001. Subjects who weigh less than 10 kg will receive 0.5 mL grape 
flavored solution containing LUM001.  The volume, either 1.0 mL or 0.5 mL 
administered will not change during the course of the study. Dosing will occur over a 124-
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. 
 
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 for entry into the 
long-term optional follow-up treatment period. All subjects will be re-initiated at the 
same LUM001 dose they last received during LUM001-303. The appropriate amount 
of study drug will be dispensed at the Protocol Amendment 5 Day 0/baseline visit, 
but daily dosing will not begin until the following day, Protocol Amendment 5, Study 
Day 1.  Eligibility assessment for afternoon dose escalation will then occur in all 
subjects based on efficacy (ItchRO[Obs] and sBA) and safety assessments following 
approximately 12 weeks of dose re-initiation as follows: 
• 
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) 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 in order to limit the amount of 
propylene glycol in the diluent administered. 
o 
The afternoon dose will be initiated at half the dose level of the 
morning dose and will continue at this dose for a period of 4 weeks. 
If this dose level is tolerated, the afternoon dose will then be doubled 
to match the morning dose. 
• 
Subjects with abnormal sBA level AND ItchRO(Obs) score ≥1.5 who had 
normal sBA level and ItchRO(Obs) score <1.5 prior to dose interruption will 
remain on the maximum tolerated morning dose (the dose they received last 
during LUM001-303) for an additional 2 weeks until their efficacy and safety 
assessments are repeated for eligibility assessment for afternoon dose 
escalation. 
• 
The sBA value used for determination of afternoon dose escalation eligibility 
will be the most recent available value collected within the prior 16 weeks. 
The ItchRO(Obs) score used for afternoon dose escalation 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 280 µg/kg BID, ie, 560 µg/kg/day (up to a 
maximum possible daily dose of 50 mg/day). 


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Section 
Description of Change 
 
 
 
 
 
Synopsis, Study 
Drug Dosage and 
Administration; 
Section 10.1, Study 
Drug 
Administration 
• 
Subjects who do not wish to enter the long-term optional follow-up treatment 
period, will be contacted via telephone by the study site approximately 30 
days after the last dose of study drug. 
 
Study Drug Administration under Protocol Amendment 5 
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 re-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). 


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Section 
Description of Change 
Synopsis, Rationale 
for Dose and 
Schedule Selection; 
Section 4.5, 
Rationale for Dose 
and Schedule of 
Administration 
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. 
Under Protocol Amendment 5, 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 280 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.  
If a subject experiences intolerance (such as gastrointestinal symptoms like 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. 
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 [PND] 21 
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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Synopsis, Study 
Visit Schedule and 
Procedures; Section 
5.5, Overall Study 
Duration and 
Follow-up 
 
 
 
 
Synopsis, Study 
Visit Schedule and 
Procedures; 
Section 8.1.7, 
Optional Follow-up 
Treatment Period 
 
 
 
 
 
 
 
Synopsis, Study 
Visit Schedule and 
Procedures; 
Section 8.1.8, Long-
term Optional 
Follow-up 
Treatment Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarified titles of study design schemes, updated figures and updated text to reflect the 
addition of the extended follow-up treatment period beyond what was previously 
described in Protocol Amendment 4. 
 
For an individual subject, the study participation period will consist of a 4-week dose 
escalation period, followed by 8-weeks of dose optimization and a 60-week stable dosing 
period. Subjects who complete 72 weeks of treatment may be eligible to receive treatment 
for up to 52 weeks during the optional follow-up treatment period. Planned participation 
for each subject enrolled in the optional follow-up treatment study is 128 weeks, inclusive 
of a 4 week follow-up phone call.  . 
 
With the exception of the Week 120 and Week 124 visit (Study Termination), additional 
study drug will be supplied at each clinic visit during the follow-up treatment period, 
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. 
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. 
 
Long-term Optional Follow-up Treatment Period 
Subjects who either complete 124 weeks of treatment and/or are considered eligible 
for Protocol Amendment 5 may be eligible to receive treatment under Protocol 
Amendment 5. Subjects who are eligible for re-entry into the long-term optional 
follow-up treatment period will continue to receive study drug until the first of the 
following occurs:  
i. 
The subjects 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 5 is implemented at the site, and the subject consents to 
enter the long-term optional follow-up period, the subject will be re-initiated at the 
same LUM001 dose they last received during LUM001-303 for approximately 12 
weeks. The appropriate amount of study drug will be dispensed at the Protocol 
Amendment 5 Day 0/baseline visit, but daily dosing will not begin until the following 
day, Protocol Amendment 5, Study Day 1. At the Week 12 visit, a determination 
about afternoon dose escalation will be made based on efficacy (ItchRO[Obs] and 
sBA) and safety assessments. Study activities will proceed as follows: 
• 
Protocol Amendment 5 Screening: Screening evaluations 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 urine pregnancy test. The electronic diary will be issued and caregivers 
and age-appropriate subjects will be asked to complete the diary twice daily 
during the 2 weeks following the screening visit. Eligibility criteria will be 
confirmed prior to the Baseline Visit. Concomitant medications and any 
adverse events will be recorded. 
• 
Protocol Amendment 5 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. Screen 
failures are eligible for rescreening on a case by case basis following 


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discussions between the investigator and the medical monitor. 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. 
• 
Protocol Amendment 5 Day 0/Baseline Clinic Visit: Physical exam, body 
weight and height, vital signs, and blood and urine samples for clinical 
laboratory testing, including fasting lipid panel and cholestasis biomarkers. 
Blood will also be collected for determination of baseline fat-soluble vitamins. 
The clinician scratch scale, clinician xanthoma scale, and PedsQL 
questionnaire will be administered. ItchRO compliance will be assessed. 
Female subjects who are of childbearing potential will have a urine pregnancy 
test prior to dispensing study drug. Study drug will be dispensed and 
concomitant medications and adverse events will be collected.  
• 
Protocol Amendment 5 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 and cholestasis biomarkers. Blood will also be 
collected for determination of baseline fat-soluble vitamins. Caregivers and 
age-appropriate subjects will be asked to complete the diary twice daily 
during the 2 weeks following the Week 4 visit. The clinician scratch scale and 
the clinician xanthoma scale 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. The 
electronic diary will be issued and caregivers and age-appropriate subjects 
will be asked to complete the diary twice daily during the 2 weeks following 
the Week 4 visit. Study drug compliance will be assessed and study drug will 
be dispensed. Concomitant medications and adverse events will be collected.  
• 
Protocol Amendment 5 Week 8 Telephone Contact: Collection of concomitant 
medications and any adverse events. 
• 
Protocol Amendment 5 Week 12: Physical exam, body weight and height, 
vital signs, and blood and urine samples for clinical laboratory testing, 
including fasting lipid panel and cholestasis biomarkers. Blood will also be 
collected for determination of baseline fat-soluble vitamins. ItchRO 
compliance will be assessed, and the clinician scratch scale and clinician 
xanthoma scale 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 will 
be assessed for afternoon dose escalation eligibility. The sBA value used for 
determination of afternoon dose escalation eligibility will be the most recent 
available value collected within the prior 12 weeks. The ItchRO(Obs) score 
used for afternoon dose escalation eligibility will be derived from the most 
recent available 7-day interval of ItchRO(Obs) collected within the prior 8 
weeks.  
Subjects who are eligible for re-entry into the long-term optional follow-up 
treatment period will be consented and initiate treatment at the same dose level they 
last received during LUM001-303 (Synopsis Figure 4). After approximately 12 weeks 
of treatment, subjects will be evaluated for eligibility for afternoon dose escalation at 
Week 12. Once a decision about afternoon dose escalation has been made, the 
subject will then either: 
- 
continue receiving the same dose of LUM001 QD (Synopsis Figure 5) if they 
do not meet the criteria for afternoon dose escalation OR 
- 
initiate the afternoon dose escalation (Synopsis Figure 6).   
 


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Subjects not eligible for ADE (subjects with normal sBA level AND ItchRO(Obs) 
score <1.5; Synopsis Figure 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 1 (not pictured in Synopsis Figure 5): subject deemed 
ineligible for afternoon dose escalation and continues QD dosing. 
• 
Repeating Period Week 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. ItchRO compliance will be assessed, the electronic diary 
will be issued, the clinician scratch scale, clinician xanthoma scale, 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. Urine samples 
for clinical laboratory testing will be collected at every other visit. 
• 
Subjects who do not qualify for afternoon dose escalation 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 (RP) beginning with RP2 within 
Schedule F. If, in the course of the afternoon dose escalation re-evaluation, a 
subject is found to qualify for afternoon dose escalation, then the subject 
will move into Schedule G as outlined in Section 16.1. During the follow-up 
treatment period, subjects will return to the clinic every 12 weeks. 
  
If the subject is eligible for afternoon dose escalation,( ie, who has sBA level above 
normal AND/OR ItchRO(Obs) score ≥1.5), the subject will begin BID dosing 
(afternoon dose escalation) as follows: 
• 
On afternoon dose escalation Day 0, morning dosing will continue at 
280 µg/kg or the maximum tolerated dose. However, the volume of the 
morning dose will be reduced by half. Of note: Morning dosing must have 
been stable for ≥4 weeks prior to initiation of afternoon dose escalation.  
• 
On afternoon dose escalation Day 0, the afternoon dose will be initiated at 
half the maximum tolerated morning dose and will continue at this dose 
level for a period of 4 weeks.  If this dose level is tolerated, the afternoon 
dose then will be doubled (ie, at afternoon dose escalation Week 4) to a 
maximum of 280 µg/kg/day (ie, up to a maximum 560 µg/kg/day or 
maximum tolerated dose). 
The following procedures will occur during the ADE period: 
• 
Afternoon dose escalation 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 


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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. 
• 
Afternoon dose escalation Week 1 and Week 2 Telephone Contact: 
Collection of concomitant medications and any adverse events. 
Subject/caregiver will be reminded of dosing instructions. 
• 
Afternoon dose escalation 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. Concomitant medications and any adverse events 
will be collected. 
• 
Afternoon dose escalation Week 5 and Week 6 Telephone Contact: 
Collection of concomitant medications and any adverse events. 
Subject/caregiver will be reminded of dosing instructions. 
• 
Afternoon dose escalation 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. 
 
Thereafter, subjects will have study activities repeated in recurring 12-week periods 
as described within Synopsis Figure 6, until study completion or termination. 
If any subject experiences intolerance, the investigator, in consultation with the 
sponsor medical monitor, may lower the dose at any time during the entire follow-up 
treatment period.  If the subject is on a twice daily dosing regimen, dose lowering 
should first be attempted with the afternoon dose.  At the investigator’s discretion, 
and in consultation with the sponsor medical monitor, subjects who were previously 
down titrated may be re-challenged during the follow-up treatment period. During 
the long-term optional Follow-Up Treatment Period, subjects will return to the clinic 
every 12 weeks. 
Safety and clinical laboratory evaluations and a physical exam (including collection 
of vital signs, height and weight measurements) will be completed at each clinic visit. 
In addition, the clinician scratch scale will be administered and study drug 
compliance will be assessed. The PedsQL will be administered at Protocol 
Amendment 5 Day 0/Baseline visit and every 24 weeks thereafter. 
Subjects/caregivers will receive follow-up phone calls as outlined in the repeating 12 
week periods. Concomitant medications and any AEs will be evaluated and recorded 
at all clinic visits and at scheduled telephone contacts. 
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 
afternoon dose escalation visits. Plasma samples will be obtained for LUM001 


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pharmacokinetics at the afternoon dose escalation Day 0, afternoon dose escalation 
Week 4, afternoon dose escalation Week 8 visits, and at the 3 scheduled clinic visits 
following completion of the afternoon dose escalation period.  
Twice-daily completion of the electronic diary will be required by caregivers and age 
appropriate subjects during the 2 consecutive weeks following the Protocol 
Amendment 5 Week 4 visit 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 follow-up 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 the following assessments as outlined for the EOT/ET visit: 
physical exam, body weight and height, vital signs, and blood and urine samples for 
clinical laboratory samples, including fasting lipid panel and pharmacokinetic 
sampling of LUM001. Blood will also be collected for determination of fat-soluble 
vitamins and AFP.  Female subjects who are of child-bearing potential will have a 
urine pregnancy test.  Study drug compliance will be assessed. Concomitant 
medications and adverse events will be collected. The clinician-administered pruritus 
scale, the PedsQL, the Patient Impression of Change, the Caregiver Impression of 
Change, clinician xanthoma scale, and palatability questionnaire will also be 
completed.  
At completion of the long-term optional 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 terminated early. Concomitant medications and adverse events 
noted during this phone call will be recorded. 
Synopsis, Drug 
Level Evaluations 
Additionally, for subjects in which afternoon dose escalation is initiated, samples will 
also be drawn at 4 hours following the morning dose on afternoon dose escalation 
Day 0, afternoon dose escalation Week 4, afternoon dose escalation Week 8, and at 
the 3 scheduled clinic visits following completion of the afternoon dose escalation 
treatment period. 
Synopsis, Safety 
and Tolerability 
Alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma, will be measured 
every 6 months throughout the remainder of the study. 
Synopsis, 
Palatability Data; 
 
Section 12.2.6, 
Palatability 
Analyses 
 
Section 16.9, 
Palatability 
Questionnaire 
Palatability data will be collected at each clinic visit in the long-term follow-up 
treatment period, with the exception of the afternoon dose escalation visits.  A 
palatability questionnaire will be completed by the subject and/or caregiver 
(dependent on age). Assessments over time will be evaluated. 
 
Added palatability questionnaire 
Section 8.5.6, 
Palatability 
A palatability questionnaire (see Section 16.9) will be completed by the subject 
and/or caregiver (dependent on age) at clinic visits at time points as outlined in the 
Schedule of Procedure in Section 16.1. 


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Synopsis, Statistical 
Considerations;  
 
Section 12.2.7, 
Interim Analyses 
Interim Analysis 
There may be one or more interim analysis (IA) conducted during the conduct of the 
study in order to guide the future of the development program. The IA may result in 
an interim report or publication. 
Section 4.5, 
Rationale for Dose 
and Schedule of 
Administration 
Updated Sample Daily Exposure (mg/day) in Pediatric Subjects table. 
 
In the current LUM001 development program, the safety, tolerability and efficacy of 
LUM001 is being assessed for the first time in children with cholestatic liver disease 
associated with ALGS, 12 months to 18 years. The starting dose in these clinical trials, 14 
µg/kg/day, is equivalent to less than the well-tolerated 1 mg dose (~17µg/kg, 60 kg body 
weight) used in Study 014, where LUM001 was tested at doses up to 5 mg/day for 14 
days in 39 hyperlipidemic pediatric subjects. At the 1 mg dose in Study014, only two out 
of eight subjects reported moderate or severe GI-associated AEs during 14 days. On a 
weight basis, 23 subjects received a dose ≥14 µg/kg/day.  The highest starting dose in 
Study 014 was 168 µg/kg/day. 
Section 5.5, Overall 
Study Duration and 
Follow-up 
For an individual subject, the study participation period will consist of a 4-week dose 
escalation period, followed by an 8-weeks of week dose optimization and period, a 60-
week stable dosing periodSubjects who complete 72 weeks of treatment may be 
eligible to receive treatment for up to 52 weeks during the follow-up treatment 
period (see Figure 4 and Figure 5). Planned participation for each subject enrolled in 
the optional follow-up treatment study is 128 weeks, inclusive of a 4 week follow-up 
phone call (see Figure 3).  , an optional 52-week 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. 
Section 5.5.1, 
Treatment 
Study drug will be dispensed to subjects/caregivers at the study site. 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. 
Long-term Exposure 
Period 
Moved text describing individual study procedures to be performed during this period to 
Section 8.1.7. 
Section 5.6, Study 
Termination 
A subject is considered to have completed the study period(s) based on the version of 
the protocol they participated under. For subjects who consent to the long-term 


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optional follow-up treatment period, the subject is considered to have completed the 
study if they participated in the EOT visit per Scheduled H. 
Section 6.1, 
Enrollment 
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 5 after the subject consents and the investigator has 
determined the subject meets study entry eligibility criteria per Protocol 
Amendment 5. However, any subject who consents to Protocol Amendment 5 and 
does not meet criteria per the investigator is considered a screen failure for the long-
term optional follow-up period under Protocol Amendment 5. Screen failures are 
eligible for rescreening on a case by case basis following discussions between the 
investigator and the medical monitor. Final consent and eligibility determined for 
subjects rescreened will be collected in the case report form. 
Section 8.1.9, 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 H). 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 Patient Impression of 
Change, the Caregiver Impression of Change, and the Caregiver Global Therapeutic 
Benefit assessments, as defined for Early Termination (see Schedule of Procedures, 
Section 16.1). 
Section 8.1.10, 
Safety Follow-up 
Period 
Text moved from former Section 8.1.7. 
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 8.3, 
Physical 
Examination, 
Weight and Height, 
Vital Signs; Section 
8.5.1, Itch Reported 
Outcome 
(ItchRO™); Section 
8.5.2, Clinician 
Scratch Scale; 
Section 8.5.3, 
Clinician Xanthoma 
Scale; Section 8.5.4, 
Pediatric Quality of 
Life Inventory 
(PedsQL); Section 
8.5.5, Caregiver 
Impression of 
Change 
Edited text to indicate all assessments will be performed as outlined in the Schedule of 
Procedures in Section 16.1. 


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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 
enrollmentuntil 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); or 
d. 
A sexual partner who is surgically sterilized. 
 
Male Contraception: 
Contraception is required for all sexually-active male subjects and their partners. 
All male subjects agree not to donate sperm, and to use 1 of the following approved 
methods of contraception until 30 days following study discharge: 
 
a. 
Male condom with spermicide 
b. 
Intrauterine device with spermicide (use by female sexual partner) 
c. 
Female condom with spermicide (use by female sexual partner) 
d. 
Contraceptive sponge with spermicide (use by female sexual partner) 
e. 
Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with 
spermicide, or a cervical cap with spermicide) (use by female sexual partner) 
f. 
Oral, implantable, transdermal, or injectable hormonal contraceptive (use 
by female sexual partner). 
Section 8.6.2, 
Fasting 
Requirements 
On these visit days study drug should be administered as usual (1 mL, 5 mL, or 0.5 mL25 
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 10.1, Study 
Drug 
Administration 
The dose may also be down-titrated, at the investigator’s discretion and in 
consultation with the sponsor medical monitor, for subjects experiencing intolerance 
(eg, gastrointestinal symptoms such as diarrhea, abdominal pain, cramping) to a 
given dose.  If the subject is on twice daily dosing regimen, dose reduction should 
first be attempted with the afternoon dose.  Subjects who were previously down-
titrated may be re-challenged during the long-term exposure period. 
… 
Each subject dose for subjects who weigh 10 kg or more will be Subjects will receive a 
grape-flavored solution containing LUM001, administered orally  as a 1.0 mL solution 
containing study drug (LUM001) QD or BID using the syringe provided.  Each subject 
dose for subjects who weigh less than 10 kg will be administered orally as a 0.5 mL 


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solution containing study drug (LUM001)using the syringe provided.  Study drug The 
first dose should be taken at least 30 minutes prior to the first meal of the day (qAM, ac) 
and should be administered 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 doses should be 
taken approximately at the same time each day for the duration of the treatment period.  
See Sections 5.5.1, 5.5.1.1, and 5.5.1.2 See Section 5.5.1 for information regarding dosing 
during the dose escalation and stable dosing treatment periods, respectively. 
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 10.3, 
Concomitant 
Medications 
A concomitant medication is any non-protocol specified drug or substance (including 
over-the-counter medications, herbal medications and vitamin supplements) administered 
during participation in the study (from baseline/Day 0 of LUM001-303 entry until the 
30-day post-treatment follow-up visitcompleting the final required assessment while 
enrolled in LUM001-303).   
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) dosing will can be suspended. Continued dosing with study drug may be 
considered or continued as per the investigator’s judgment and following discussion 
with the Sponsor Medical Monitor.  The Investigator and Sponsor Medical Monitor 
sponsor medical monitor.  If suspended, the investigator and sponsor medical 
monitor will evaluate the subject’s safety data and make a decision to either restart 
dosing at the same level, restart dosing at a lower dose level, or discontinue dosing.   
Section 10.5.2, 
Safety Monitoring 
Rules 
Of note: the INR re-test should be conducted by the central laboratory, but may also 
be conducted at a local laboratory on an as needed basis. 
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 


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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 monitoring for liver 
chemistry tests given that subjects with ALGS may have abnormal liver enzyme 
levels at baseline. 
Section 11.4.1, 
Pregnancy 
Reporting 
If a subject becomes pregnant or a pregnancy is suspected in either a subject or in the 
partner of a male study participant during the study… 
Section 12.2.4.1, 
Safety Assessments 
Serum alpha-fetoprotein (AFP) 
Section 12.2.5.2, 
Laboratory Tests 
Changes within a treatment group for selected safety measures will be assessed at Weeks 
8, 12, 24, 36, 48, and at the final study evaluation visit ((Week 72)60, 72,and at 
additional time points during the 52-week and long-term optional treatment 
periods… 
Section 12.2.5.6, 
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, 
Schedule of 
Procedures E-H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Added Overall Scheme and Corresponding Schedule of Procedures 
Added Schedule of Procedures E - Long-term Optional Follow-up Treatment Period: 
 
Protocol Amendment 5 Screening (Week -2) and on LUM001. Includes Evaluation of 
Eligibility for Afternoon Dose Escalation Dosing Regimen at Protocol Amendment 5, 
Week 12. 
• 
Any subject who re-enters the study under Protocol Amendment 5. The subject 
returns to their last previously administered dose for 12 weeks and then moves to 
either Schedule F or G, depending on afternoon dose eligibility.  
• 
Proceed to Schedule H for Early Termination or End of Treatment Procedures. 
 
Added Schedule of Procedures F-G: Re-entry under Protocol Amendment 5: 
 
Schedule of Procedures F – Extension of Long-term Optional Follow-up Treatment 
Period, for subjects ineligible for ADE. 
 
Schedule of Procedures G – Extension of Long-term Optional Follow-up Treatment 
Period, for subjects eligible for ADE. 
 
Added Schedule of Procedures H - Study Termination and End of Treatment Procedures 
Section 16.2, List of 
Laboratory Analytes 
Added alpha-fetoprotein (AFP) under marker of hepatocellular carcinoma 
Section 8.5.4, 
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. 
 
 


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16.10.2 Protocol Amendment 4 Summary of Changes 
Protocol Number: 
LUM001-303 
 
Protocol Title: 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
 
Amendment: 
4 
 
Date: 
04 Nov 2015 
 
The LUM001-303 protocol is being amended to include an Optional Follow-up Treatment 
Period (After Week 72) that is intended to offer the opportunity to eligible subjects treated in 
the LUM001-303 study to continue on treatment after Week 72 until the first to occur of the 
following: (i) up to 52 weeks of additional treatment (Week 124), or (ii) in the event that a new 
study opens to enrollment. 
 
The following changes have been made to Protocol Amendment 4. Note that correction of 
typos and grammatical errors are not captured in the below table.  
New text indicated in bold; deleted text indicated in strikethrough. 
Section 
Description of Change 
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: medmonitorLUM303@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 


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Section 
Description of Change 
Study Synopsis, 
Objectives; 
Section 3, Study 
Objectives 
The primary objective of the study (up to and including Week 72) is to:  
• 
Evaluate the long-term safety and tolerability of LUM001 in pediatric subjects 
with ALGS. 
Secondary objectives of the study (up to and including Week 72) are to: 
• 
… 
Objectives of Optional Follow-up Treatment Period (after Week 72): 
• 
To offer eligible subjects in the LUM001-303 study continued treatment 
after Week 72 until the first of the following occur: (i) up to 52 weeks of 
additional treatment (Week 124), or (ii) in the event that a new study opens 
to enrollment. 
• 
To obtain safety and efficacy data in subjects treated long term on 
LUM001 including genotyping characteristics. 
Study Synopsis, 
Study Design; 
Section 5.1, 
Study Design 
This is a multicentre, double-blind study of LUM001 in children ≥12 months of age 
diagnosed with ALGS who have completed participation in the LUM001-302 study. All 
subjects will receive active drug (LUM001) in the study. The study is divided into 34 
parts: a dose escalation period, a dose optimization period, and a stable dosing period, 
and an optional 52-week follow-up period for eligible subjects who choose to stay on 
treatment with LUM001. Subjects’ participation in the optional follow-up 
treatment period will continue until the first of the following occur: i) completion of 
52 weeks of additional treatment or ii) in the event that a new study of LUM001 is 
76 weeks, including a 4 week follow-up opens to enrollment. 
Planned participation for each subject enrolled in the optional follow-up treatment 
study is 76128 weeks, inclusive of a 4 week follow-up phone call. 
… 
Optional Follow-up Treatment Period: 
At Week 72, all subjects will be assessed by the investigator to determine their 
willingness and eligibility to roll-over into the optional 52-week, follow-up 
treatment period to receive study drug at the dose they were receiving at Week 72. 
Study Synopsis, 
Study 
Population; 
Section 7.2, 
Exclusion 
Criteria 
Eligible subjects for 52-week optional follow-up treatment period: 
Subjects will be considered eligible for the 52-week optional follow-up treatment 
period if they have completed the protocol through the Week 72 visit with no safety 
concerns. Subjects who were discontinued due to safety reasons can be 
re-challenged if blood tests do not satisfy the protocol’s stopping rules; the decision 
will be made by the investigator in consultation with the Sponsor Medical Monitor. 
Subjects who have undergone a surgical disruption of the enterohepatic circulation 
will not be eligible to enter into the follow-up treatment period. Subjects who were 
discontinued for other reasons will be considered on an individual basis. 
Study Synopsis, 
Study Drug 
Dosage and 
Administration 
Section 5.1, 
Study Design; 
Section 5.5.1.1, 
Dose Escalation 
Period; Section 
5.5.1.3, Stable 
Dosing Period 
… Dosing will occur over a 72124-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.  
… 
Dose Escalation Period 
… 
The primary anticipated adverse reaction or intolerance is gastrointestinal in nature (e.g., 
diarrhea, abdominal pain, cramping, etc.).  In the absence of GI intolerance, escalation to 
the next dose level for an individual patient may occur at the investigator’s discretion, 
following a scheduled phone call or visit (see Schedule of Procedures, Section ). 


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Section 
Description of Change 
If a subject experiences intolerance due to gastrointestinal symptoms (eg, diarrhea, 
abdominal pain, cramping) at any time during the study, the investigator, in 
consultation with the Sponsor Medical Monitor, may lower the dose to a previously 
tolerated dose. 
Optional Follow-up Treatment Period: 
At Week 72, 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 three following possible scenarios 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 same dose level. 
• 
For subjects who are eligible to roll over into the follow-up treatment 
period having ≥7 days since the last dose of LUM001, will be dose escalated 
up to 280 µg/kg/day or the highest tolerated dose following a  4-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 30 days after the last dose of 
study drug. 
Study Synopsis, 
Rationale for 
Dose and 
Schedule 
Selection  
…The dose may also be down-titrated, at the investigator’s discretion and in 
consultation with the Sponsor Medical Monitor, for subjects experiencing 
intolerance to a given dose. During the follow-up treatment period, the dose will be 
escalated for those subjects who had been off treatment for ≥7 days. The dose will 
be escalated over the first 4 weeks up to 280 µg/kg/day or to the highest tolerated 
dose starting at 35 µg/kg/day. This escalation regimen is supported by the safety 
profile observed in completed and ongoing clinical studies of LUM001 and allows 
for subjects to reach 280 µg/kg/day or a highest tolerated dose within a 4-week 
period. 
Study Synopsis, 
Study Visit 
Schedule and 
Procedures; 
Section 5.5, 
Overall Study 
Duration and 
Follow-up; 
Section 5.5.1.4, 
Optional 
Follow-up 
Treatment 
Period; Section 
8.1.8, Optional 
Follow-up 
Treatment 
Period (post 
Week 72 to 
Week 124);  
Statistical 
Considerations, 
Section 12; 
Section 
For an individual subject, the study participation period will consist of a 4-week dose 
escalation period, followed by 8-weeks of dose optimization and a 60-week stable dosing 
period. Subjects who complete 72 weeks of treatment may be eligible to receive 
treatment for up to 52 weeks during the optional follow-up treatment period. 
Planned participation for each subject enrolled in the optional follow-up treatment 
study is 76128 weeks, inclusive of a 4 week follow-up phone call.  Study activities will 
be conducted as described in the Schedule of Procedures (Section 16.1). 
 
Study Scheme (as described belowUp to and including Week 72):  
 


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Section 
Description of Change 
12.2.3.1, 
Efficacy 
Variables 
Follow-up Treatment Scheme  
(no interruption in LUM001 dosing, or interruption <7 days)  
 
 
Follow-up Treatment Scheme  
(interruption in LUM001 dosing ≥7 days): 
 
… 
Week 72 / Study Termination: At the Study Termination Visit, Week 72: Subjects will 
be evaluated by the investigator to determine whether they are eligible to roll over 
into the optional 52-week treatment period. Eligible subjects must have documented 
consent in order to continue in the optional follow-up treatment period. 
… 
Follow-up Period: For subjects who do not roll over into the 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. This call will be made for all subjects who complete the 
study, as well as any subject who terminates from the study early.  Concomitant 
medications and any adverse events noted during this phone call will be recorded. 
 


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Section 
Description of Change 
Optional Follow-up Treatment Period (post Week 72 to Week 124):  
Subjects who are eligible to roll over into the follow-up treatment period will 
continue to receive study drug at the dose they were receiving at Week 72 for up to 
52 weeks or until a new study opens to enrollment, whichever occurs first. 
Subjects who are eligible to roll over into the follow-up treatment period with no 
LUM001 dosing interruption or an interruption of <7 days will be maintained at the 
same dose level.  
Subjects with ≥7 days since last dose of LUM001 will be dose escalated up to 
280 µg/kg/day or to the highest tolerated dose starting at 35µg/kg/day. This 
escalation regimen is supported by the safety profile observed in completed and 
ongoing clinical studies of LUM001 and allows for subjects to reach 280 µg/kg/day 
or a highest tolerated dose within a 4-week period. The dose escalation (DE) period 
will proceed as follows: 
• 
DE Week -2 Clinic Visit: obtain consent, obtain weight, and draw labs.   
• 
DE Day 0 Clinic Visit: PI evaluates laboratory results, study drug is 
dispensed and subject begins at 35 µg/kg/day dose level. 
• 
DE Week 73 Telephone Contact: subject escalates to 70 µg/kg/day dose 
level if prior dose level was tolerated.  
• 
DE Week 74 Clinic Visit: subject escalates to 140 µg/kg/day dose level if 
prior dose level was tolerated. 
• 
DE Week 75 Telephone Contact: subject escalates to 280 µg/kg/day dose, if 
prior dose level was tolerated. 
• 
DE Week 76 Clinic Visit: subject continues in Follow-up Treatment Period 
at 280 µg/kg/day, or highest tolerated dose. 
If any subject experiences intolerance, the investigator, in consultation with the 
Sponsor Medical Monitor, may lower the dose to a previously tolerated dose at any 
time during the entire follow-up treatment period. At the investigator’s discretion 
and in consultation with the Sponsor Medical Monitor, subjects who were 
previously down titrated may be re-challenged during the optional follow-up 
treatment period.  
During the follow-up treatment period, subjects will return to the clinic every 
3 months, at Weeks 84, 96, 108, 120, and 124.  
Safety and clinical laboratory evaluations and a physical exam (including collection 
of vital signs, height and weight measurements) will be completed at each clinic 
visit. In addition, the clinician scratch scale will be administered and study drug 
compliance will be assessed. The PedsQL will be administered at DE Day 0 (for 
subjects requiring dose escalation) and at Weeks 84, 96, 108, 120, and 124. The 
Caregiver Impression of Change (CIC) assessment will be completed at Weeks 108, 
120, and 124. Subjects/caregivers will receive follow-up phone calls at Weeks 76, 80, 
88, 92, 100, 104, 112, and 116. Concomitant medications and any AEs will be 
evaluated and recorded at all clinic visits and at scheduled telephone contacts.  
Twice daily completion of the electronic diary will be required by caregivers and 
age appropriate subjects during the 2 consecutive weeks following the Week 84, 96, 
108, and 120 clinic visits. Electronic diaries will be provided to subjects and 
caregivers at these visits and re-training on the use of the diary will occur, as 
appropriate.  
At the physician investigator’s discretion, withdrawal of concomitant medications 
used for the treatment of pruritus may occur during the long-term exposure period.  


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Section 
Description of Change 
With the exception of the Week 120 and Week 124 visit (Study Termination), 
additional study drug will be supplied at each clinic visit during the follow-up 
treatment period. Used and unused study drug will be collected at every visit. 
… 
Efficacy Evaluations 
The primary evaluation for the durability of the therapeutic effect will be the mean 
change from Baseline (Day 0) to Week 48 in: 
… 
Secondary evaluations for the durability of the therapeutic effect will be the mean change 
from Baseline (Day 0) to Week 48 and the change from Week 12 to Week 48 in: 
… 
Additional exploration of evaluations of safety, including behavior during the dose 
escalation and durability of therapeutic effect optimization phases will be specified in 
the statistical analysis plan. 
… 
Efficacy 
…Special attention will be paid to change from baseline for those on placebo at baseline, 
and to durability of effect during the first 12 weeks for those on active study drug at 
baseline and to durability during the stable dosing period for all subjects at all dose 
levels.  
 
Rationale for removing durability of effect from efficacy evaluations: 
The efficacy evaluation of durability of effect of LUM001 in subjects was removed as 
this cannot be assessed as this study is not placebo-controlled and an effect has not yet 
been established (through historical control for example). 
Section 5.5.2, 
Follow-up 
Study drug will be discontinued at Week 72 if the subject chooses not to participate 
in the optional follow-up treatment period. 
… 
This call For those patients that choose to roll over in to the follow-up treatment 
period, a follow-up phone call will take place at Week 128, 30 days after the last 
dose of study drug. Follow-up phone calls will be made for all subjects who complete 
the study, as well as any subject who terminates from the study early.   
Section 5.6, 
Study 
Termination 
Subjects will be dosed to complete a cumulative LUM001 exposure of at least one year. 
Section 8.1.5, 
Week 72 
Week 72/Study Termination (End of Study) 
At the Week 72/Study Termination Visit, a physical exam (including collection of vital 
signs, height and weight measurements) will be performed. 
… 
Study drug will be discontinued at this visit.  
Section 8.1.6, 
Early 
Termination 
Any subject who withdraws from the study prior to completion of all treatment period 
clinic visits up to Week 72 or who is not eligible or willing to roll into the 52-week 
optional treatment period should undergo the procedures specified for the Week 
72/Study Termination Visit. 


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Section 
Description of Change 
Section 8.1.7, 
Follow-up 
Period (30 days 
After Last 
Dose) 
Subjects who complete the study or who discontinued early due to reasons other 
than safety may be eligible for participation in an optional follow-up treatment 
period. 
Section 8.2, 
Genetic Testing 
JAGGED1 and NOTCH2 mutations are predictive of ALGS. For subjects who do 
not have complete documentation of a JAGGED1 or NOTCH2 mutation, blood 
samples for genotyping will be collected at the screening visit. The appropriate 
genetic counseling in accordance with local laws will be provided to any subject and 
their legal caregivers at a study visit following the receipt of results of genetic 
testing, at no cost to the subject. Subjects for whom prior genotyping was 
performed may need to have an optional repeat analysis performed if the original 
information collected at screening was insufficient for complete documentation of 
the diagnosis of ALGS including the type of mutation recorded. For those 
participants for which the type of mutation cannot be documented, genetic testing 
may be conducted and the results recorded. 
Section 8.3, 
Physical 
Examination, 
Weight and 
Height, Vital 
Signs 
… 
For subjects who enter into the 52-week optional follow-up treatment period, 
physical examinations will also be conducted at Weeks 84, 96, 108, 120, and 124. 
For subjects with interruptions in LUM001 dosing of ≥7 days, additional physical 
examinations will be conducted during the DE period at DE -2, DE Day0, DE Week 
74, and DE Week 76. 
… 
Section 8.5.1, 
Itch Reported 
Outcome 
(ItchRO™) 
…  
For subjects who enter the 52-week optional follow-up treatment period, daily 
completion of the diary will also be during the 2 weeks following the Weeks 84, 96, 
108, and 120 clinic visits. 
… 
Section 8.5.2, 
Clinician 
Scratch Scale 
… 
For subjects who enter the optional follow-up treatment period, the clinician 
scratch scale will also be administered at Weeks 84, 96, 108, 120, and 124. For 
subjects with interruptions in LUM001 dosing of ≥7 days, assessments will be 
conducted during the DE period at DE -2, DE Day 0, DE Week 74, and DE Week 
76.    
Section 8.5.3, 
Clinician 
Xanthoma Scale 
… 
For subjects who enter the 52-week optional follow-up treatment period, the 
clinician’s assessment of  xanthomatosis will also be administered at Weeks  84, 96, 
108, 120, and 124. 
For subjects with interruptions in LUM001 dosing of ≥7 days, the assessment will 
also be conducted during the DE period at DE Week 76.  … 
Section 8.5.4, 
Pediatric 
Quality of Life 
Inventory 
(PedsQL) 
… 
For subjects who enter the 52-week optional follow-up treatment period, the 
PedsQL will also be administered at Weeks 84, 96, 108, 120, and 124. For subjects 
with interruptions in LUM001 dosing of ≥7 days, the PedsQL will also be 
administered at DE Day 0…. 
For subjects who enter the optional follow-up treatment period, the 
multidimensional fatigue and family impact questionnaires will also be 
administered at Weeks 84, 96, 108, 120, and 124. … 


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Section 
Description of Change 
Section 8.5.5, 
Caregiver 
Impression of 
Change 
… 
For subjects who enter the 52-week optional follow-up treatment period, the CIC 
will also be administered at Weeks 108, 120, and 124. 
Section 11.3; 
Monitoring and 
Recording of 
Adverse Events 
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. 
Section 11.3.1; 
Serious Adverse 
Events 
The collection of SAEs will begin after the subject signs the informed consent form and 
stop at the end of the subject’s follow-up period which is defined as Week 76 for 
subjects who do not roll over into the 52-week optional treatment follow-up period, 
Week 124 for subjects who do roll over into the optional treatment follow-up 
period, or 30 days after the last dose of study drug for those subjects that terminate prior 
to the Week 72 76 or Week 124 visit.    
Section 11.3.2; 
Non-serious 
Adverse Events 
The recording of non-serious AEs will begin after the subject signs the informed consent 
form and will stop at the end of the subject’s follow-up period, which is defined as Week 
76 for subjects who do not roll over into the 52-week optional treatment follow-up 
period, Week 124 for subjects who do roll over into the 52-week optional treatment 
follow-up period, or 30 days after the last dose of study drug for those subjects that 
terminate prior to the Week 76 or Week 124 visit.   
Section 16.1; 
Schedule of 
Procedures 
Added: 
Two new Schedules of Procedures for the Optional Follow-up Treatment Period (Week 
72-Week 124) for: 
• 
Subjects with no interruption in LUM001 dosing or interruption <7 days 
• 
Subjects with interruption in LUM001 dosing ≥7 days 
Section 16.7, 
Caregiver 
Impression of 
Change (CIC) 
The Caregiver Impression of Change (CIC) is designed to assess the caregiver’s 
perception of the subject’s xanthoma severity at the end of study drug treatment 
compared to his/her xanthoma severity prior to the start of treatment with study drug.  
The CIC will be completed by all caregivers at the Week 48 visit.  and Week 72 visit.  
For subjects who enter the 52-week optional follow-up treatment period, the CIC 
will also be administered at Weeks 108, 120, and 124. 


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16.10.3 Protocol Amendment 3 Summary of Changes 
 
Protocol Number: 
LUM001-303 
Protocol Title: 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
3  
Date: 
September 17, 2014 
 
The following changes have been made to protocol amendment 3.  The following table provides 
a summary list of changes to the protocol: 
 
Section 
Description of Change 
Synopsis (Section 1), Study Design 
Overall Study Duration and Follow-up (Section 5.5) 
Changed treatment (duration) period to collect 
additional long-term safety data from 48 weeks to 76 
weeks, including a 4 week follow-up. Treatment 
period changed from 48 weeks to 72 weeks. 
Synopsis (Section 1), Study Visit Schedule and 
Procedures 
Study Design (Section 5.1) 
 
Changed stable dosing period from 36 weeks to 
60 weeks and study duration to 76 weeks, including a 
4 week follow-up. 
Added study visits at Weeks 60 and 72. 
Changed Study Termination (End of Study) from 
Week 48 to Week 72. 
Added PedsQL evaluation at Week 72. 
Added Caregiver Impression of Change evaluation at 
week 72. 
Changed Study Termination from Week 48 to Week 
72. 
Synopsis (Section 1), Number of Subjects 
Number of Subjects (Section 5.4) 
Statistical Considerations (Section 12) 
Changed from 42 to 18 
Synopsis (Section 1), Drug Level Evaluations 
Added evaluation at week and 72 
Synopsis (Section 1), Study Population 
Subject Eligibility (Section 7) 
Clarified that core LUM001 treatment protocol refers 
to Study LUM001-302 for eligibility in this study 


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Section 
Description of Change 
Synopsis (Section 1), Efficacy Evaluations 
Efficacy Evaluations (Section 12.2.3.1) 
Modification of biochemical markers of cholestasis 
and liver disease to include deletion of alkaline 
phosphatase (ALP) and modification of bilirubin 
(total and direct) to total bilirubin in secondary 
evaluations for the durability of the therapeutic effect 
as mean change from Baseline (Day 0) to Week 48 
and the change from Week 12 to Week 48. 
Number of Study Centers (Section 5.3) 
Changed from 14 to 3 
Stable Dosing Period (Sections 5.5.1.3, 8.1.4) 
Changed stable dosing period from 36 weeks to 
60 weeks and study duration to 72 weeks 
Study Termination (Section 8.1.5) 
Changed Study Termination (End of Study) from 
Week 48 to Week 72 
Early Termination (Section 8.1.6) 
Changed Study Termination (End of Study) from 
Week 48 to Week 72 
Physical Examination, Weight and Height, Vital 
Signs (Section 8.2) 
Added assessments at Weeks 60 and 72 
Clinician Scratch Scale (Section 8.4.2) 
Added assessments at Weeks 60 and 72 
Clinician Xanthoma Scale (Section 8.4.3) 
Added assessments at Weeks 60 and 72 
Pediatric Quality of Life Inventory PedsQL (Section 
8.4.4) 
Added assessment at Week 72; clarified that age at 
baseline visit will be used as the age for the 
determination of the appropriate questionnaire to be 
used for the duration of the study, regardless of 
subsequent birthdays during the study. 
Caregiver Impression of Change (Section 8.4.5) 
Added assessment at Week 72 
Schedule of Procedures (Section 16.1) 
Modified to reflect changes listed above 
Administrative Changes 
To correct typographical and grammatical errors; 
replaced core LUM001 treatment protocol with Study 
LUM001-302 


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16.10.4 Protocol Amendment 2 Summary of Changes 
 
Protocol Number: 
LUM001-303 
Protocol Title: 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
Amendment: 
2 
Date: 
February 28, 2014 
 
The following changes have been made to protocol amendment 2.  The following table provides 
a summary list of changes to the protocol: 
 
Section 
Description of Change 
Inclusion Criteria (Synopsis and Section 7.1) 
Lowered eligibility age from 2 years of age to 
12 months to 18 years 
Synopsis (Section 1), Number of Subjects 
(Section 5.4) 
Changed from 60 to 42 
Synopsis (Section 1), Treatment (Section 5.5.1), 
Study Drug Administration (Section 10.1) 
Text has been revised to indicate that subjects who 
weigh 10 kg or more will receive a 1.0 mL solution 
containing LUM001 or placebo. Subjects who weigh 
less than 10 kg will receive a 0.5 mL solution 
containing LUM001 or placebo. The volume 
administered will not change during the course of the 
study. 
Section 4.5, (Rationale for Dose and Schedule of 
Administration) 
Edited age criteria from 2 to 18 years to 12 months 
to18 years 
Study Drug Description (Section 9.1) 
Tabular descriptions of the composition of the 
LUM001 0.5 mL solution and the 0.5 mL placebo 
solution have been included.  Correction made to 
maximum LUM001 dose. 
Section 11.4.2 (dosing errors) 
Clarified that dosing errors are captured in eCRF and 
in paper dosing diaries 
Section 16.6 (PedsQL) 
Added PedQL for infants 


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16.10.5 Protocol Amendment 1 Summary of Changes 
 
Protocol Number: 
LUM001-303 
 
Protocol Title: 
A MULTICENTRE EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND DURABILITY OF THE THERAPEUTIC 
EFFECT OF LUM001, AN APICAL SODIUM-DEPENDENT BILE 
ACID TRANSPORTER INHIBITOR (ASBTI), IN THE TREATMENT 
OF CHOLESTATIC LIVER DISEASE IN PEDIATRIC SUBJECTS 
WITH ALAGILLE SYNDROME 
 
Amendment: 
1 
 
Date: 
November 5, 2013 
 
 
The following changes have been made to the original protocol: 
 
Minor changes have been made to the text to improve the clarity of the protocol and/or minor 
inconsistencies. 
 
The following table provides a summary list of changes to the protocol: 
 
Section 
Description of Change 
Exclusion Criteria 3 (Synopsis and Section 7) 
History or presence of gallstones or kidney stones added 
Dose Escalation Period (Synopsis and Section 
5.5.1.1) 
Clarification added regarding dose escalation for subjects 
who may be unable to begin LUM001-303 the same day 
of the last day of  their LUM001 treatment protocol 
Abbreviations 
Removal of unused abbreviations 
Study Scheme (Synopsis, Figure 4 and protocol 
titles in Sections 8.1.3 and 8.1.4) 
Updated “Dose Optimization Period to Weeks 5-12”, and 
“Stable Dosing Period to Weeks 13-48” 
Section 8.1.1 and Schedule of Events 
Addition of Medical History 
Schedule of Events 
Subscript “c” added with clarity around dose escalation.  
Window visit updated during dose escalation period.  
Correction made to Week 8 (was Day 63, corrected to 
Day 56) 
 

SAP_001.pdf: 
 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Final Version 1.0    |    Date: 10-Apr-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
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Sponsor 
Mirum Pharmaceuticals, Inc. 
Protocol Title: 
A Multicentre Extension Study to Evaluate the Long-Term Safety 
and Durability of the Therapeutic Effect of LUM001, an Apical 
Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the 
Treatment of Cholestatic Liver Disease in Pediatric Subjects with 
Alagille Syndrome 
Protocol Number: 
LUM001-303 
Premier Research PCN: 
LUME2941 
Document Version: 
FINAL Version 1.0 
Document Date:  
10-Apr-2020 
 
 
 


 
Statistical Analysis Plan  
 
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PCN Number LUME2941 
 
 
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Approvals 
Role 
Signatures 
Date (dd-Mmm-yyyy) 
Sr. Director, 
Biostatistics 
Premier Research 
Print Name: Jana Steinmetz 
 
Sign Name: 
 
 
 
 
 
Mirum 
Pharmaceuticals, 
Inc. Representative 
Print Name: Thomas Jaecklin, MD 
 
Sign Name: 
 
 
 
 
 
Print Name:  Will Garner, PhD 
 
Sign Name:  
 
 


 
Statistical Analysis Plan  
 
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Table of Contents 
Approvals ........................................................................................................................................ 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 6 
1. 
Overview ............................................................................................................................. 7 
2. 
Study Objectives and Endpoints ......................................................................................... 9 
2.1. 
Study Objectives ........................................................................................................... 9 
2.2. 
Study Endpoints ............................................................................................................ 9 
2.2.1. Safety Endpoints ......................................................................................................... 10 
2.2.2. Efficacy Endpoints ...................................................................................................... 10 
2.2.3. Other Endpoints .......................................................................................................... 19 
3. 
Overall Study Design and Plan ......................................................................................... 19 
3.1. 
Overall Design ............................................................................................................ 19 
3.2. 
Sample Size and Power ............................................................................................... 21 
3.3. 
Study Population ......................................................................................................... 21 
3.4. 
Treatments................................................................................................................... 21 
3.4.1. Dose Escalation Period ............................................................................................... 22 
3.4.2. Dose Optimization Period ........................................................................................... 23 
3.4.3. Stable Dosing Period................................................................................................... 24 
3.4.4. Optional Follow-up Treatment Period ........................................................................ 24 
3.4.5. Follow-up .................................................................................................................... 24 
3.4.6. Long-term Optional Follow-up Treatment Period ...................................................... 24 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................. 25 
3.6. 
Blinding and Unblinding............................................................................................. 25 
3.7. 
Schedule of Procedures ............................................................................................... 27 
3.7.1. Schedule of Procedures A: Baseline – Week 12 ......................................................... 28 
3.7.2. Schedule of Procedures B – Stable Dosing: Week 16 – Week 72 / Study 
Termination ................................................................................................................. 30 
3.7.3. Schedule of Procedures C – 52-Week Optional Follow-Up Treatment Period for 
those subjects < 7 days from last dose of MRX (Protocol Amendment 4)................. 32 
3.7.4. Schedule of Procedures D – 52-Week Optional Follow-up Treatment Period: 
DE-2 –Week 176 for Subjects with ≥7days from last dose of MRX (Protocol 
Amendment 4). Includes Evaluation of Eligibility for Afternoon Dose 
Escalation Dosing Regimen  ....................................................................................... 34 


 
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3.7.5. Schedule of Procedures E – Long-term Optional Follow-up Treatment Period: 
Protocol Amendment 5 Screening (Week -2) and on MRX. Includes Evaluation 
of Eligibility for Afternoon Dose Escalation Dosing Regimen at Protocol 
Amendment 5, Week 12.............................................................................................. 37 
3.7.6. Schedule of Procedures F – Extension of Long-term Optional Follow-up 
Treatment Period, for subjects ineligible for afternoon dose escalation ..................... 39 
3.7.7. Schedule of Procedures G – Extension of Long-term Optional Follow-up 
Treatment Period, for subjects eligible for afternoon ................................................. 41 
3.7.8. Schedule of Procedures H – End of Treatment (EOT) / Early Termination (ET) 
Visit and Post-Treatment Safety Follow Up ............................................................... 44 
4. 
Statistical Analysis and Reporting .................................................................................... 46 
4.1. 
Introduction ................................................................................................................. 46 
4.2. 
Interim Analysis .......................................................................................................... 47 
4.3. 
Data Monitoring .......................................................................................................... 47 
5. 
Analysis Populations ......................................................................................................... 47 
6. 
General Issues for Statistical Analysis .............................................................................. 48 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 48 
6.1.1. Baseline ....................................................................................................................... 48 
6.1.2. Study Day.................................................................................................................... 48 
6.1.3. Adjustments for Covariates......................................................................................... 48 
6.1.4. Multiple Comparisons ................................................................................................. 48 
6.1.5. Handling of Dropouts or Missing Data ....................................................................... 49 
6.1.6. Investigative Sites ....................................................................................................... 50 
6.1.7. Analysis Visit Windows.............................................................................................. 51 
6.1.8. Variable Definitions .................................................................................................... 53 
6.1.9. Derived Variables ....................................................................................................... 54 
6.1.10. Data Adjustments/Handling/Conventions................................................................... 58 
7. 
Study Subjects and Demographics.................................................................................... 61 
7.1. 
Disposition of Subjects and Withdrawals ................................................................... 61 
7.2. 
Protocol Violations and Deviations ............................................................................ 62 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 62 
7.4. 
Prior Medications ........................................................................................................ 63 
7.5. 
Treatment Compliance ................................................................................................ 63 
8. 
Efficacy Analysis .............................................................................................................. 63 
8.1. 
Primary Efficacy Analysis .......................................................................................... 63 
8.2. 
Secondary, Exploratory and Other Efficacy Analyses................................................ 64 


 
Statistical Analysis Plan  
 
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9. 
Safety and Tolerability Analysis ....................................................................................... 64 
9.1. 
Treatment Exposure .................................................................................................... 64 
9.2. 
Adverse Events ........................................................................................................... 65 
9.2.1. Adverse Events Leading to Withdrawal ..................................................................... 66 
9.2.2. Deaths and Serious Adverse Events............................................................................ 66 
9.2.3. Adverse Events of Special Interest ............................................................................. 66 
9.3. 
Clinical Laboratory Evaluations ................................................................................. 66 
9.4. 
Physical Examination.................................................................................................. 67 
9.5. 
Vital Signs ................................................................................................................... 68 
9.6. 
Concomitant Medication ............................................................................................. 68 
9.7. 
Safety Data Graphical Presentations ........................................................................... 68 
10. 
Other Analysis................................................................................................................... 68 
10.1. Pharmacokinetic Analysis ........................................................................................... 68 
10.2. Palatability .................................................................................................................. 68 
10.3. Serum Alpha-fetoprotein............................................................................................. 68 
11. 
Changes from Planned Analysis ....................................................................................... 69 
12. 
References ......................................................................................................................... 70 
13. 
Tables, Listings, and Figures ............................................................................................ 71 
13.1. Planned Table Descriptions ........................................................................................ 71 
13.2. Planned Listing Descriptions ...................................................................................... 76 
13.3. Planned Figure Descriptions ....................................................................................... 80 
14. 
Tables, Listings, and Listing Shells .................................................................................. 82 
14.1. Standard Layout for all Tables, Listings, and Figures ................................................ 82 
Appendix 1:  Premier Research Library of Abbreviations ........................................................... 83 
Appendix 2: Listing of Safety and Efficacy Laboratory Analytes................................................ 87 
Appendix 3: Listing Fat Soluble Vitamin Deficiency Events....................................................... 88 
 
 
 


 
Statistical Analysis Plan  
 
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List of Tables 
Table 1: Secondary Efficacy Endpoints ........................................................................................ 11 
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 – Primary Analysis ................................................................. 52 
Table 5: Analysis Visit Windows – Supporting Subgroup Analysis (Data Assessed after an 
Extended Drug Interruption) ................................................................................................. 53 
 
 
 


 
Statistical Analysis Plan  
 
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1. 
Overview 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Mirum 
Pharmaceuticals Inc. (Mirum) protocol LUM001-303, A Multicenter Extension Study to 
Evaluate the Long-Term Safety and Durability of the Therapeutic Effect of LUM001, an Apical 
Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi), in the Treatment of Cholestatic 
Liver Disease in Pediatric Patients with Alagille Syndrome, dated 08-Feb-2019 
(Amendment 5.1). 
The original LUM001-303 protocol, dated 13-Sep-2013, planned for a 48-week treatment period. 
This treatment period included 3 parts: a 4-week double-blind dose escalation period, at doses up 
to a target dose of 140 µg/kg/day; a 8-week dose optimization period where dosing may be 
increased or decreased to 35, 70, 140 or 280 µg/kg/day; and a 36-week stable dosing period 
where participants continue to receive the Week 12 dose, or the highest tolerated dose below the 
Week 12 dose from dose optimization period. 
There have been 6 protocol amendments to date. The summary list of changes to each of the 
protocol amendments are describe in the final amendment, Protocol Amendment 5.1. Several of 
the protocol amendments included optional long-term extensions. 
Protocol Amendment 1, dated 05-Nov-2013, changed the exclusion criteria 3 by adding history 
or presence of gallstones or kidney stones, clarification added regarding dose escalation, and 
included other minor changes to improve the clarity of the protocol and/or correct minor 
inconsistencies and typographical errors. 
Protocol Amendment 2, dated 28-Feb-2014, lowered eligibility age from 2 years of age to 12 
months to 18 years, changed the number of participants from 60 to 42, revised text regarding 
volume administrated (i.e. participants who weigh 10 kg or more will receive 1.0 mL solution, 
and participants who weigh less than 10 kg will receive 0.5 mL solution). Additionally, 
clarification was included that dosing errors will be captured in eCRF and in paper dosing 
diaries, PedQL for infants was added, and other corrections of minor inconsistencies and 
typographical errors were applied. 
Protocol Amendment 3, dated 17-Sep-2014, changed treatment duration to collect additional 
long-term safety data from 48 weeks to 76 weeks including 4 weeks follow-up. The treatment 
period was changed from 48 weeks to 72 weeks. The stable dosing period was changed from 36 
to 60 weeks, study visits at Weeks 60 and 72 were added, study termination changed from week 
48 to 72, and PedsQL evaluation at week 72 and Caregiver Impression of Change evaluation 
were added. Assessments were added at Weeks 60 and 72. The number of participants was 
changed from 42 to 18, the number of centers changed from 14 to 3 and other corrections of 
minor inconsistencies and typographical errors were applied. 
Protocol Amendment 4, dated 04-Nov-2015, added an Optional Follow-up treatment period 
(after week 72) that offers opportunity to eligible participants treated in the study to continue on 
treatment after week 72 until the first of (i) up to 52 weeks of additional treatment  (Week 124) 
or  (ii) in the event that a new study opens to enrollment.  


 
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Protocol Amendment 5, dated 16-May-2017, allowed continued participation in the long-term 
optional follow-up treatment period, beyond what was previously added in Protocol Amendment 
4. Study treatment in the long-term optional follow-up treatment period will continue until the 
first of the following occurs: (i) the participants are eligible to enter another LUM001 study, (ii) 
LUM001 is available commercially, or (iii) the sponsor stops the program or development in this 
indication. This amendment also describes the way in which eligible participants who had 
previously discontinued from the study may re-enter and receive study treatment in the long-term 
optional follow-up treatment period (after Week 124). Additional objectives for the long-term 
optional follow-up treatment period were added, as follows: 
• 
Exploration of a twice daily (BID) dosing regimen and higher daily dosing of LUM001; 
• 
Assessment of alpha-fetoprotein (AFP) levels, a marker of hepatocellular carcinoma; 
• 
Assessment of the palatability of the LUM001 formulation in all participants, by-proxy in 
participants <4 years old and by patient questionnaire in children ≥4 years old; 
• 
Obtain safety and efficacy data in participants treated long term in LUM001. 
A list of detailed changes to the protocol is included in the final amendment, Protocol 
Amendment 5.1. 
The final protocol amendment, Amendment 5.1, dated 08-Feb-2019, reflects the change of 
sponsorship from Lumena Pharmaceuticals LLC to Mirum Pharmaceuticals, Inc. 
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 (MRX) and that label will be used 
hereinafter within this document. 


 
Statistical Analysis Plan  
 
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2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
The primary objective of the study (up to and including Week 72) is to: 
• 
Evaluate the long-term safety and tolerability of MRX in pediatric participants with ALGS. 
 
Secondary objectives of the study (up to and including Week 72) are to: 
• 
Evaluate the long-term effect of MRX on serum bile acid levels. 
• 
Evaluate the long-term effect of MRX on pruritus associated with ALGS. 
• 
Explore the long-term effect of MRX on other biochemical markers of cholestasis and liver 
disease. 
• 
Evaluate the long-term effect of MRX on xanthomas. 
• 
Explore an expanded dosing range to identify the doses necessary to achieve the optimal 
benefit-to-risk ratio for this patient population. 
 
Objectives of the long-term optional follow-up treatment period for participants who are eligible 
for Protocol Amendment 5: 
• 
To offer eligible participants in the LUM001-303 study continued study treatment until the 
first of the following occur: (i) the participants 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. 
• 
To explore twice a day (BID) dosing regimen and higher daily dosing of MRX. 
• 
To obtain safety and efficacy data in participants treated long-term on MRX. 
• 
To assess the level of alpha-fetoprotein (AFP), a marker of hepatocellular carcinoma. 
• 
To assess palatability of the MRX formulation. 
2.2. 
Study Endpoints 
Safety and efficacy endpoints are examined overall and for each of the 5 treatment phases: 
• Dose Escalation Period (Day 1 – Week 4), 
• Dose Optimization Period (Week 5 – Week 12), 
• Stable Dosing Period (Week 13 – Week 72),  
• Optional Follow-up Treatment Period (Week 73 – Week 124) 
• Long-term Optional Follow-up Treatment Period (Week 125 – EOT/ET). 
Unless otherwise specified, summaries will be provided by treatment sequence where applicable 
from the LUM001-302 core study (e.g., PBO-MRX), and overall. 


 
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2.2.1. Safety Endpoints 
The following assessments will be used to monitor safety: 
• 
Adverse events (AEs) and serious adverse events (SAEs). 
• 
Clinical laboratory results. 
• 
Vital signs. 
• 
Physical exam findings, including body weight and height. 
• 
Concomitant medication usage. 
• 
Serum alpha-fetoprotein (AFP). 
Physical examination findings include body weight and height, along with BMI. Vital signs 
include heart rate, respiratory rate, body temperature, and blood pressure. Note that the z-scores 
for body weight, height and BMI are considered as efficacy but are derived from safety 
variables. Z-scores are derived as described in Section 6.1.9. 
Safety laboratory tests and units that will be used for reporting are listed in Appendix 2. Note 
that bilirubin (total and direct), ALP, GGT, and ALT are considered as both safety and efficacy 
laboratory tests. 
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
The primary evaluation will be the mean change from Baseline (Day 0) to Week 48 in: 
• 
Fasting serum bile acid level (sBA). 
2.2.2.2. 
Secondary Endpoints 
Secondary evaluations will be the mean change from Baseline (Day 0) to Week 48 in: 
• 
Biochemical markers of cholestasis and liver disease [ALT, AST, ALP, GGT and total 
and direct bilirubin]. 
• 
Pruritus as measured by the ItchRO instruments (ItchRO(Obs)TM, caregiver 
instrument/ItchRO(Pt) TM patient instrument). 
During the first 12 weeks of the study, the electronic diary (ItchRO) will be completed twice 
daily (AM & PM). During the stable dosing period (Weeks 13-48), twice daily completion of the 
electronic diary (ItchRO) for 4 consecutive weeks will be required following the Week 24 and 
Week 44 clinic visits. For participants who continue in the follow-up treatment period, twice 
daily completion of the electronic diary (ItchRO) for 2 consecutive weeks will be required 
following the Week 84, 96, 108, and 120 clinic visits. For participants who continue to long-term 
optional follow-up, twice daily completion of electronic diary (ItchRO) for 2 consecutive weeks 
will be required following Protocol Amendment 5 screening visit, Week 4 visit and for repeating 
Week 12 visits.  
• 
Xanthomas as measured by clinician xanthoma scale.  
 


 
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Efficacy variables will be presented for each time point at which they are measured (see 
Section 3.7).  
For the secondary ItchRO endpoint, only the weekly average morning severity score will be 
summarized. 
The secondary efficacy endpoints for this study are summarized in Table 1. 
Table 1: Secondary Efficacy Endpoints 
Efficacy 
Parameter(s) 
Variable(s) 
Mean Change 
From MRX BL* 
Week  
Through Week 
ItchRO(Obs),  
 
Weekly average morning severity 
score 
0  
48 
Liver enzymes 
(ALP, ALT, AST, GGT, 
total bilirubin, direct 
bilirubin) 
Laboratory test level 
0  
48 
Clinician xanthoma scale 
5-point scale 
0  
48 
sBA 
Laboratory test level 
0  
48 
* The observation obtained at first dose of MRX (either in LUM001-302 or in LUM001-303) 
2.2.2.3. 
Sensitivity Endpoints 
All efficacy endpoints for this study, are described in Table 2 and Table 3, for continuous and 
categorical endpoints, respectively. Note that data for participants who early terminated from the 
study will be imputed in a last-observation-carried-forward (LOCF) sensitivity analysis approach 
(see Section 6.1.5.2). 
Table 2: Analysis of Continuous Efficacy Endpoints (including Sensitivity) 
Efficacy 
Parameter(s) 
Variable(s) 
Mean Change 
From MRX BL* 
Week 
To Week 
ItchRO(Obs) 
 
Weekly morning average 
severity score 
 
0 
1) Baseline to Week 12: 
2, 4, 8, 12 
2) Stable Dosing: 
24, 44, 48 
3) 52-week optional follow-up: 
84, 96, 108, 120, 122/LOCF 
4) Long-term optional follow-up: 
Protocol Amendment 5 screening 
visit, Week 4 visit, Week 12 visit 
(for repeating visits) 
sBA 
Laboratory test level 
0 
1) Baseline to Week 12: 


 
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Efficacy 
Parameter(s) 
Variable(s) 
Mean Change 
From MRX BL* 
Week 
To Week 
2, 4, 8, 12,  
2) Stable Dosing: 
24, 36, 48, 60, 72/LOCF 
3) 52-week optional follow-up: 
84, 96, 108, 120, 124/LOCF, 
including Dose Escalation visit (DE) 
-2, DE 0, DE74, DE 76 for 
participants with ≥7 days from last 
dose 
4) Long-term optional follow-up: 
Protocol amendment 5 screening visit, Day 0 
(Baseline), Week 4 visit, Week 12 visit (for 
repeating visits), including Afternoon Dose 
Escalation (ADE) ADE 0, ADE Week 4, ADE 
Week 8 for participants eligible for afternoon 
dose escalation, EOT/ET 
Liver enzymes 
(ALP, ALT, AST 
GGT, total bilirubin, 
direct bilirubin) 
Laboratory test level 
0 
1) Baseline to Week 12: 
2, 4, 8, 12,  
2) Stable Dosing: 
24, 36, 48, 60, 72/LOCF 
3) 52-week optional follow-up: 
84, 96, 108, 120, 124/LOCF, 
including Dose Escalation visit (DE) 
-2, DE 0, DE74, DE 76 for 
participants with ≥7 days from last 
dose 
4) Long-term optional follow-up: 
Protocol amendment 5 screening visit, Day 0 
(Baseline), Week 4 visit, Week 12 visit (for 
repeating visits), including Afternoon Dose 
Escalation (ADE) ADE 0, ADE Week 4, ADE 
Week 8 for participants eligible for afternoon 
dose escalation, EOT/ET 
Clinician Scratch 
Score (CSS) 
Score 
0 
1) Baseline to Week 12: 
2, 4, 8, 12,  
2) Stable Dosing: 
24, 36, 48, 60, 72/LOCF 
3) 52-week optional follow-up: 
84, 96, 108, 120, 124/LOCF, 
including Dose Escalation visit (DE) 
-2, DE 0, DE74, DE 76 for 
participants with ≥7 days from last 
dose 
4) Long-term optional follow-up: 
Protocol amendment 5 screening visit, Day 0 
(Baseline), Week 4 visit, Week 12 visit (for 


 
Statistical Analysis Plan  
 
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Efficacy 
Parameter(s) 
Variable(s) 
Mean Change 
From MRX BL* 
Week 
To Week 
repeating visits), including Afternoon Dose 
Escalation (ADE) Week 4, ADE Week 8 for 
participants eligible for afternoon dose 
escalation, EOT/ET 
Clinician Xanthoma 
Scale 
Score 
0 
1) Stable Dosing: 
16 (for participants who undergo a 
dose change at Week 12), 24, 36, 48, 
60, 72/LOCF 
2) 52-week optional follow-up: 
84, 96, 108, 120, 124/LOCF, 
including Dose Escalation visit (DE) 
76 for participants with ≥7 days from 
last dose 
3) Long-term optional follow-up: 
Protocol amendment 5 screening visit, Day 0 
(Baseline), Week 4 visit, Week 12 visit (for 
repeating visits), including Afternoon Dose 
Escalation (ADE) Week 4, ADE Week 8 for 
participants eligible for afternoon dose 
escalation 
PedsQL 
Total Scale Score (Parent); 
Total Scale Score (Child); 
Multidimensional Fatigue 
Scale Score (Parent); 
Multidimensional Fatigue 
Scale Score (Child) 
Family Impact Total Scale 
Score; 
Psychosocial Health 
Summary Score (Parent); 
 
0 
1) Stable Dosing: 
24, 48, 72/LOCF 
2) 52-week optional follow-up: 
84, 96, 108, 120, 124/LOCF, 
including Dose Escalation visit (DE) 
0 for participants with ≥7 days from 
last dose 
3) Long-term optional follow-up: 
Protocol amendment 5 Day 0 (Baseline), 
Week 12 visit (for repeating visits), including 
Afternoon Dose Escalation (ADE) 0, ADE 
Week 4, ADE Week 8 for participants eligible 
for afternoon dose escalation, EOT/ET 
Caregiver Impression 
of Change 
 
Score 
-- 
Summary statistics at Week:  
48, 72/LOCF, 108, 120, 124/LOCF 
 
 
 
Height and Weight 
z-Score 
Z-Score  
0 
2, 4, 8, 12, 16 (only for participants who 
undergo a change in dose at Week 12), 24, 36, 
48, 60, 72/LOCF, 84, 96, 108, 120, 
124/LOCF, Protocol amendment 5 screening 
visit, Day 0 (Baseline), Week 4 visit, Week 12 
visit (for repeating visits), including 


 
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Efficacy 
Parameter(s) 
Variable(s) 
Mean Change 
From MRX BL* 
Week 
To Week 
Afternoon Dose Escalation (ADE) 0, ADE 
Week 4, ADE Week 8 for participants eligible 
for afternoon dose escalation, EOT/ET 
* The observation obtained at first dose of MRX (either in LUM001-302 or in LUM001-303) 
 
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 
 
 
Descriptive summaries at Week: 
1) Baseline to Week 12: 
2, 4, 8, 12,  
2) Stable Dosing: 
24, 36, 48, 60, 72/LOCF 
3) 52-week optional follow-up: 
84, 96, 108, 120, 124/LOCF, including 
Dose Escalation visit  (DE) -2, DE 0, DE74, 
DE 76 for participants with ≥7 days from 
last dose 
4) Long-term optional follow-up: 
Protocol amendment 5 screening visit, Day 0 
(Baseline), Week 4 visit, Week 12 visit (for 
repeating visits), including Afternoon Dose 
Escalation (ADE) Week 4, ADE Week 8 for 
participants eligible for afternoon dose escalation, 
EOT/ET 


 
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Efficacy 
Parameter(s) 
Scale and Responder Criteria 
 or Variables 
Endpoint 
Clinician Xanthoma Scale 
improved, stable or worsened. 
  
Number and % of participants at Week: 
1) Stable Dosing: 
 16 (for participants who undergo a dose 
change at Week 12), 24, 36, 48, 60, 
72/LOCF 
2) 52-week optional follow-up: 
84, 96, 108, 120, 124/LOCF, including 
Dose Escalation visit (DE) 76 for 
participants with ≥7 days from last dose 
3) Long-term optional follow-up: 
Protocol amendment 5 screening visit, Day 0 
(Baseline), Week 4 visit, Week 12 visit (for 
repeating visits), including Afternoon Dose 
Escalation (ADE) Week 4, ADE Week 8 for 
participants eligible for afternoon dose escalation,  
2.2.2.4. 
Efficacy Parameter Descriptions 
Itch Reported Outcome (ItchRO) 
The primary assessment of pruritus will be the pruritus severity as assessed using the Itch 
caregiver reported outcome measure (ItchRO[Obs]TM) administered as a twice daily electronic 
diary. Children ≥9 years of age will complete the patient instrument: ItchRO(Pt)™. Children 
between the ages of 5 and 8 years of age will complete the patient instrument with the assistance 
of their caregiver: ItchRO (Pt). Participants and caregivers will be trained on the use of the 
electronic diary during their participation in LUM001-302 protocol. There is no ItchRO(Pt) 
report for participants under the age of 5 years. 
Age at screening (from lead-in study 302) will be used as the age for the determination of the 
appropriate ItchRO instrument to be used for the study and this same instrument will be used for 
the duration of the study (regardless of subsequent birthdays after the screening visit). 
Given the age range of the study population and the small sample size, the primary ItchRO score 
will be derived from the ItchRO(Obs) instrument. The itch score from the ItchRO(Pt) will not be 
analyzed.  
For the ItchRO instrument, the caregiver and/or subject indicate the itch severity (Item 1) in the 
morning and in the evening each day during the following periods: 
• Screening through first 12 weeks during the dose escalation and dose optimization 
periods. 
• 4 consecutive weeks that follow the Week 24 and Week 44 clinic visits during the 
stable dosing period. 


 
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• 2 consecutive weeks that follow the Week 74, Week 84, Week 96, Week 108, Week 
120 clinic visits during the 52-week optional follow-up treatment period. 
• 2 consecutive weeks that following Protocol Amendment 5 screening visit, Week 4 
visit and Week 12 visit (repeating visits) for the long-term optional follow-up 
treatment period 
Completion of the ItchRO instrument occurs as outlined in the Schedule of Procedures in 
Section 3.7. For the ItchRO(Obs) instrument, caregivers also indicate the frequency of itch 
(Item 3). 
Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score 
of 4, with 4 representing more severe (Item 1) or more frequent (Item 3) itching. The weekly 
average morning severity score from ItchRO(Obs) is calculated and used in the analysis of 
pruritus. 
The weekly average morning severity scores are calculated as the average of the morning scores 
over a defined study week consisting of the 7 days before the scheduled clinic visit (i.e., Baseline 
[Day 0], Weeks 2, 4, 8, 12, 24, 44, 48, 84, 88, 96, 108, 120, and Protocol Amendment 5 
screening visit, Week 4 visit and Week 12 visit). For the change from baseline calculations in 
weekly average ItchRO scores, baseline is defined in Section 6.1.1. Post-baseline weekly average 
ItchRO scores are only computed if at least 4 of the 7 daily ItchRO scores for the 7-day period 
are available. 
In deriving weekly average morning severity post-baseline ItchRO score, each visit date will be 
determined based on the varying eDiary collection periods (as applicable):  (A) Week 2, 4, 8, and 
12, (B) Week 24 and 44 (C) Week 86, 98, 110, 122 and (D) Week 6 and 14.   
A. Week 2, 4, 8, and 12:  The scheduled visit date is used. 
B. Week 28 and 48: Each scheduled visit date will be determined based on the date of 
the associated scheduled clinic visit (i.e., Week 24 and 44) plus 28 days.   
C. Week 86, 98, 110, 122:  Each scheduled visit date will be determined based on the 
date of the associated scheduled clinic visit (i.e., Week 84, 96, 108 and 120) plus 14 
days.   
D. Long term optional follow-up: Week 6 and 14: Each scheduled visit date will be 
determined based on the date of the associated scheduled clinic visit (i.e., Week 4 and 
12) plus 14 days. Week 12 visits will be repeated until EOT/ET. 
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.  


 
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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. This assessment will be completed at Baseline (Day 0) and at all 
clinic visits thereafter (Weeks 2, 4, 8, 12, 24, 36, 48, 60 and 72). For participants who enter into 
the 52-week optional and long-term optional follow-up treatment periods, the clinician scratch 
scale will be administered as outlined in the Schedule of Procedures in Section 3.7. 
The clinician scratch score uses a 5-point scale, in which 0 designates no evidence of scratching, 
and 4 designates cutaneous mutilation with bleeding, haemorrhage and scarring (see Table 3 for 
complete scale descriptions). 
Clinician Xanthoma Scale 
The clinician’s assessment of the 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 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). 
A clinician’s assessment of xanthomatosis will be made by the principle investigator or 
appropriate designee using the clinician xanthoma scale. This assessment will be completed at 
Baseline (Day 0) and at Weeks 24, 36, 48, 60 and 72. For participants who enter into the 52-
week optional and long-term optional follow-up treatment periods, the clinician’s assessment of 
xanthomatosis will be administered as outlined in the Schedule of Procedures in Section 3.7. 
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).  
The CIC will be completed by all caregivers at the Week 48 and Week 72 visit. For participants 
who enter into the 52-week optional follow-up treatment periods, the CIC will be administered 
as outlined in the Schedule of Procedures in Section 3.7. 
Pediatric Quality of Life (PedsQL) 
The PedsQL13 is a questionnaire that will be administered to participants and or caregivers at the 
Baseline (Day 0) and Weeks 24, 48 and 72 clinical visits using the age-appropriate PedsQL 
module. For participants who enter the 52-week optional follow-up treatment period, the PedsQL 


 
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will also be administered at Weeks 84, 96, 108, 120, and 124. For participants with interruptions 
in MRX dosing of ≥7 days, the PedsQL will also be administered at DE Day 0. 
In addition to the core generic PedsQL module, the multidimensional fatigue and family impact 
questionnaires will also be administered at the Baseline (Day 0) and Weeks 24, 48 and 72 
clinical visits using the age appropriate module, see Section 16.6. For participants who enter into 
the 52-week optional and long-term optional follow-up treatment periods, the multidimensional 
fatigue and family impact questionnaires will be administered as outlined in the Schedule of 
Procedures in Section 3.7. 
The PedsQL13 is a validated, modular instrument designed to measure health-related quality of 
life (HRQoL) in infants, children and adolescents. The PedsQL questionnaire is administered to 
participants and/or caregivers depending on age using age-appropriate PedsQL modules. The 
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 Study LUM001-302 baseline will be used as the age for the determination of the 
appropriate module to be used for the study, and this same module will be used for the duration 
of the study (regardless of subsequent birthdays after the baseline visit).  
With the exception of the 5-7 year age group (Young Child) subject report, each item of the 
PedsQL consists of a 5-level Likert-type item survey (0-4), where 0=Never, 1=Almost never, 
2=Sometimes, 3=Often, and 4=Almost always. Items of the PedsQL Young Child subject report 
are scored on a 3-point scale, where 0=Not at all, 2=Sometimes, and 4=A lot.  
The PedsQL Generic Core Scale is composed of items to assess pediatric HRQoL measurements 
across 6 subscales: Physical Functioning, Physical Symptoms (only applicable for infants, 1-24 
months), Emotional Functioning, Social Functioning, Cognitive Functioning [only applicable for 
infants, 1-24 months], and School Functioning (only applicable for children, 2 18 years).  
The Total Scale Score, Physical Health Summary Score and Psychosocial Health Summary 
Score are computed individually for both the parent and subject reports of the PedsQL Generic 
Core Scale. The Total Scale Score is computed from all items. The Physical Health Summary 
Score is computed from the items of the Physical Functioning domain, and the Physical 
Symptoms domain (infants only). The Psychosocial Health Summary Score is computed from 
items of the Emotional, Social, and School Functioning domains, and the Cognitive Functioning 
domain (infants only). 
The PedsQL Multidimensional Fatigue Scale is composed of items across 3 subscales: General 
Fatigue, Sleep/Rest Fatigue, and Mental Fatigue. Respondents use the scale to indicate how 
frequently certain fatigue-related symptoms and complaints trouble them. The Multidimensional 
Fatigue Scale Score is computed from all items of the PedsQL Multidimensional Fatigue Scale. 


 
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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. 
Palatability 
A palatability questionnaire 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 3.7. 
2.2.3. Other Endpoints 
Other endpoints of this study include the following: 
• Analysis of MRX plasma concentrations. 
Pharmacokinetics 
 
Pharmacokinetic blood samples are collected at baseline and then approximately 4 hours post-
dosing at one additional time point – at Week 12, 24, 36, 48, 72, and 4 hours post-dose during 
afternoon dose escalation in the long term follow-up at Day 0, Week, Week 8 and 3 clinic visits 
following completion of the afternoon dose escalation as selected by the site/investigator. 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is a multicenter, double-blind study of MRX in children >12 months of age diagnosed with 
ALGS who have completed participation in the LUM001-302 protocol. While all participants 
will receive active drug (MRX) in this study, the investigator, participants and study personnel 
were blinded to individual subject dose. The study is divided into 5 parts: a dose escalation 
period, a dose optimization period, a stable dosing period, an optional 52- week follow-up 
period, and a long-term optional follow-up treatment period for eligible participants who choose 
to stay on treatment with MRX. 
Dose Escalation Period (Day 1 – Week 4): 
All participants entering the extension study will participate in a 4-week double-blind dose 
escalation period during which: 
• 
Participants who were randomized to receive placebo during the LUM001-302 study will 


 
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receive weekly dose increases of MRX up to a target dose of 140 μg/kg/day. 
• 
Participants who were randomized to receive active drug during the LUM001-302 study 
will continue to receive the dose of MRX that they were taking at Week 13 of the 
LUM001-302 study. The MRX doses for these participants will remain blinded and will 
not be altered during the dose-escalation period. 
A minimum period of 7 days must elapse between increases in dose. 
Dose Optimization Period (Week 5 – Week 12): 
Following completion of the 4-week dose escalation period, participants will enter an 8-week 
dose-optimization period. During this period, the investigator will have the option to adjust MRX 
dosing with the objective of achieving optimal control of pruritus at a dose level that is tolerated 
by the subject and up to a maximum daily dose of 280 μg/kg MRX or 20 mg total dose. Study 
drug dose level will be increased or decreased in a double-blind manner. Increases in dose will 
be based on effect on efficacy (sBA and ItchRO[Obs] score) and safety assessments. Reductions 
in dose will be based on tolerability. At the investigator’s discretion, the doses for participants 
who were previously down-titrated may be re-challenged during the dose optimization period. 
Each subject will receive one of the following dose levels: 
• 
MRX 35 μg/kg/day. 
• 
MRX 70 μg/kg/day. 
• 
MRX 140 μg/kg/day. 
• 
MRX 280 μg/kg/day. 
A minimum period of 7 days must elapse between increases in dose. 
Stable Dosing Period (Week 13 – 72): 
Following completion of the 8-week dose optimization period, all participants will enter the 
stable dosing period lasting 60 weeks. During the remainder of the study, participants will be 
dosed with the Week 12 dose, or the highest tolerated dose below the Week 12 dose. However, if 
a subject experiences intolerance due to gastrointestinal symptoms, the investigator, in 
consultation with the medical monitor, may lower the dose to a previously tolerated dose. 
Optional Follow-up Treatment Period (Week 73 – 124): 
At Week 72, all participants will be assessed by the investigator to determine their willingness 
and eligibility to roll-over into the optional 52-week, follow-up treatment period to receive study 
drug at the dose they were receiving at Week 72. 
• 
For participants who are eligible to roll over into the follow-up treatment period, those 
with <7 days since the last dose of MRX, will be maintained at the same dose level. 
• 
For participants who are eligible to roll over into the follow-up treatment period having 
≥7 days since the last dose of MRX, will be dose escalated up to 280 μg/kg/day or the 
highest tolerated dose following a 4 week dose escalation beginning at 35 μg/kg/day. 
• 
For participants 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 30 days after the last dose of study drug. 


 
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Long-term optional Follow Up Treatment Period (Week 125 – EOT/ET): 
The long-term optional follow up treatment period is for eligible participants who choose to stay 
on treatment with MRX. During this long-term optional follow-up treatment period, participants 
may have their dose of MRX increased to a maximum of 560 μg/kg/day (280 μg/kg BID), based 
on efficacy (sBA and ItchRO score) and safety assessments. Participants’ participation in the 
long-term optional follow-up treatment period will continue until the first of the following occur: 
i) the participants are eligible to enter another LUM001 study, (ii) MRX is available 
commercially, or (iii) the sponsor stops the program or development in this indication. 
3.2. 
Sample Size and Power 
Approximately 18 participants meeting the study’s inclusion and exclusion criteria may be 
enrolled in the study. Because this is an extension study for participants who participated in the 
LUM001- 302 study, the sample size is not based on statistical considerations. 
3.3. 
Study Population 
The study population is males and females, between the ages of 12 months and 18 years 
(inclusive), diagnosed with ALGS. 
3.4. 
Treatments  
For an individual subject, the study participation period will consist of a 4-week dose escalation 
period, an 8-week dose optimization period, a 60-week stable dosing period, an optional 52-week 
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. The 
Week 13 visit from the LUM001-302 study will also serve as the Baseline Visit for the 
LUM001-303 extension protocol. Eligible participants will be enrolled in the extension study at 
the Baseline Visit (Day 0). Dosing with study drug will begin on Day 1, following the Baseline 
Visit on (Day 0). 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. 
 
 
 
 
 
 
 
 


 
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Figure 1 Study Design for LUM001-303 (Up to and including Week 72) 
 
3.4.1. Dose Escalation Period 
For participants randomized to placebo in the LUM001-302 study, or those who complete the 
LUM001-302 more than 7 days prior to enrollment into this study, the MRX dose during the first 
4 weeks of the study will be increased at weekly intervals to 140 μg/kg/day, or to a maximum 
tolerated dose below 140 μg/kg/day (10 mg maximum total dose). For participants who were 
randomized to receive active drug in the LUM001-302 study MRX doses will remain the same 
as the dose taken at Week 13 of the LUM001-302 study. Study treatment for each subject will 
remain blinded and will be prepared by the unblinded central pharmacist according to a specified 
dose-escalation regimen. This regimen will represent a real dose escalation for participants 
previously randomized to placebo and a mock dose escalation for participants previously 
randomized to active study treatment. 
 
 
 
 
 
 
 
 


 
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Table 1 Dose Escalation regimens 
 
If a subject experiences intolerance due to gastrointestinal symptoms (e.g., diarrhea, abdominal 
pain, cramping) at any time during the study, the 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 
replacement study medication will be provided to the subject/caregiver.  
3.4.2. Dose Optimization Period 
Following the dose escalation period, the MRX dose for each subject may be increased or 
decreased by the investigator as clinically indicated with the objective of achieving control of 
pruritus at a dose level that is tolerated by the subject. Dose optimization will occur in a blinded, 
titrated manner with four dose levels available as treatment options: 35, 70, 140 or 280 
μg/kg/day. Adjustments may occur at weekly intervals. Once an optimal MRX dose is achieved, 
the dose will be fixed for the duration of the period. However, if at any time during the study, a 
subject experiences intolerance due to gastrointestinal symptoms, the physician investigator, in 
consultation with the medical monitor, may lower the dose to a previously tolerated dose.  
The maximum daily dose of MRX in this period is 280 μg/kg/day, up to a maximum daily dose 
of 20 mg. Blinded investigators may request dose adjustment for any subject based on an 
assessment of tolerability and effect on pruritus. Caregivers and age-appropriate participants will 
be asked whether they wish to take a higher dose of the study medication to achieve greater relief 


 
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of itching. If so, the dose may be adjusted upward, within the permitted dose range. However, 
the subject, caregiver, physician investigator, or the medical monitor may recommend against 
further escalation if there are safety or tolerability concerns. Doses of MRX will not be increased 
above 280 μg/kg/day or 20 mg per day during this period. 
3.4.3. Stable Dosing Period 
At the end of the Dose Optimization Period, participants will continue dosing to complete 72 
weeks of cumulative MRX exposure in this study. If, at any time during the study, a subject 
experiences intolerance due to gastrointestinal symptoms, the physician investigator, in 
consultation with the medical monitor, may lower the dose to a previously tolerated dose. To 
ensure the safety of participants participating in this study, a DMC will review serious adverse 
event data, other key subject safety and study data at specified intervals for the duration of the 
study. 
3.4.4. Optional Follow-up Treatment Period 
Participants who are eligible to roll over on to the optional follow-up treatment period with no 
MRX dosing interruption or an interruption of <7 days will continue to receive study drug at the 
dose they were receiving at Week 72 for up to 52 weeks of additional treatment or in the event 
that a new study opens to enrollment, whichever occurs first.  
Participants who are eligible to roll over into the follow-up treatment period with no MRX 
dosing interruption or an interruption of <7 days will be maintained at the same dose level. 
Participants with ≥7 days since last dose of MRX will be dose escalated up to 280 μg/kg/day or 
to the highest tolerated dose starting at 35 μg/kg/day. This escalation regimen is supported by the 
safety profile observed in completed and ongoing clinical studies of MRX and allows for 
participants to reach 280 μg/kg/day or a highest tolerated dose within a 4-week period.  
3.4.5. Follow-up  
Study drug will be discontinued at Week 72 if the subject chooses not to participate in the 
optional follow-up treatment period. A safety follow-up phone call will be made by the study site 
at 30 days after the last dose of study drug. Follow-up phone calls will be made for all 
participants who complete the study, as well as any subject who terminates from the study early. 
Concomitant medications and any adverse events noted during this phone call will be recorded. 
3.4.6. Long-term Optional Follow-up Treatment Period 
Upon completion (or early termination) of the 52-week optional follow-up treatment period 
and/or implementation of this amendment, participants will be assessed by the investigator to 
determine their willingness and eligibility for entry into the long-term optional follow-up 
treatment period. All participants will be re-initiated at the same MRX dose they last received 
during LUM001-303. Eligibility assessment for afternoon dose escalation will then occur in all 
participants based on efficacy (ItchRO[Obs] and sBA) and safety assessments following 
approximately 12 weeks of dose re-initiation as follows: 


 
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• Participants with normal sBA level AND ItchRO(Obs) score <1.5 will be maintained at the 
same dose level and will continue morning dosing only. 
• Participants with sBA level above normal AND/OR ItchRO(Obs) score ≥1.5 will start BID 
dosing (afternoon dose escalation) 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 in order to limit the amount of propylene glycol in the diluent 
administered. 
o The afternoon dose will be initiated at half the dose level of the morning dose and 
will continue at this dose for a period of 4 weeks. If this dose level is tolerated, 
the afternoon dose will then be doubled to match the morning dose. 
• Participants with abnormal sBA level AND ItchRO(Obs) score ≥1.5 who had normal 
sBA level and ItchRO(Obs) score <1.5 prior to dose interruption will remain on the 
maximum tolerated morning dose (the dose they received last during LUM001-303) for 
an additional 2 weeks until their efficacy and safety assessments are repeated for 
eligibility assessment for afternoon dose escalation. 
• The sBA value used for determination of afternoon dose escalation eligibility will be the 
most recent available value collected within the prior 16 weeks. The ItchRO(Obs) score 
used for afternoon dose escalation 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 280 μg/kg BID, i.e.., 560 μg/kg/day (up to a maximum 
possible daily dose of 50 mg/day). 
• Participants who do not wish to enter the long-term optional follow-up treatment period, 
will be contacted via telephone by the study site approximately 30 days after the last dose 
of study drug. 
 
3.5. 
Method of Assigning Participants to Treatment Groups 
This trial is an open-label extension of LUM001-302, and all participants will receive MRX at 
various dose regimens. 
3.6. 
Blinding and Unblinding 
Although all participants are treated are on MRX, dose optimization will occur in a blinded, 
titrated manner. This regimen will represent a real dose escalation for participants previously 
randomized to placebo and a mock dose escalation for participants previously randomized to 
active study treatment in the LUM001-302 core study.  
If in the event of an emergency situation when knowledge of the treatment assignment during the 
double-blind, randomized drug withdrawal period will impact the clinical management of the 
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 


 
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within 24 hours. If the blinding is prematurely broken, it is the responsibility of the investigator 
to promptly document and explain any unblinding to the sponsor. 
Breaking of the blind should not occur except in the event of a medical emergency where the 
identity of the drug must be known in order to properly treat the subject, or when causality must 
be determined prior to submitting a regulatory safety report for a SAE as defined in the protocol. 
Any unblinding event carried out in connection with submission of a regulatory safety report will 
be conducted by the sponsor as described in the protocol. 
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Schedule of Procedures, Section 3.7) before unblinding, as knowledge of the 
treatment arm could influence subject assessment. 
An administrative letter (dated 21-Nov-2019) has been accepted by all sites that allows for 
unblinding of subjects’ doses from LUM001-301, as that database has now locked. 
 


 
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3.7. 
Schedule of Procedures 
Overall Scheme and Corresponding Schedule of Procedures. The following schematic shows the study flow and corresponding Schedule of 
Procedures (A –G). Study Termination and End of Treatment Procedures are outlined in Schedule H. 
 
 
 
 


 
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3.7.1. Schedule of Procedures A: Baseline – Week 12 
 


 
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a Evaluations and procedures completed for the Week 13 Visit of LUM001-302 study will also serve as the evaluations for the Baseline Visit for this extension study. 
b Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
c See Section 16.2 in the protocol for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins should be drawn prior to administration of vitamin supplementation. 
d Participants are required to fast at least 4 hr (only water permitted prior to collection). 
e Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
f Participants 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 the first 12 weeks of the study, the eDiary (ItchRO) will be completed twice daily (AM & PM). Compliance will be assessed at each visit/phone contact. 
i Participants should be dosed for at least 7 days at each dose level. 
 
Clinic Visit 
Phone Contact 
 


 
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3.7.2. Schedule of Procedures B – Stable Dosing: Week 16 – Week 72 / Study Termination 
 
 


 
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a 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
b 
See Section 16.2 in the protocol for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins should be drawn prior to administration of vitamin supplementation. 
c 
Participants are required to fast at least 4 hr (only water permitted prior to collection). 
d 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
e 
Participants must be available to receive a phone call from study staff. 
f 
A Week 16 Clinic Visit will be completed for all participants who undergo a change in dose at Week 12; Participants who do not undergo a dose change at Week 12 will be contacted by 
phone at Week 16. 
g 
Participants who withdraw early should complete all evaluations at this visit. 
h 
Participants who roll directly into the Week 76 visit will not have a follow-up visit until after Week 124. 
i 
Follow-up visit is only for participants who exit the study at the Study Termination Visit. 
j 
At the indicated visits during the treatment period, oxalate will be part of the urinalysis 
k 
During the stable dosing period, twice daily completion of the eDiary (ItchRO) for 4 consecutive weeks will be required following the Week 24 and Week 44 clinic visits. 
 
Clinic Visit 
Phone Contact 
 
 
 
 
 


 
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3.7.3. Schedule of Procedures C – 52-Week Optional Follow-Up Treatment Period for those participants < 7 days from last dose 
of MRX (Protocol Amendment 4) 
 


 
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a 
Once necessary approvals are received for Protocol Amendment 5 and associated consent/assent documents are available, site will consent/assent subject for Protocol Amendment 5 at the 
next clinic visit. 
b 
Once necessary approvals are received for Protocol Amendment 5 and associated consent/assent has been signed, site will assess subject eligibility for Protocol Amendment 5. Depending on 
the outcome of afternoon dose escalation eligibility assessment, the subject will move into either Schedule of Procedures F or G. Note: It is possible that subject will not necessarily complete 
up through Week 124 before they move to Schedule of Procedures F or G. 
c 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
d 
See Section 16.2 in the protocol for detailed list of laboratory analytes. Blood samples for analysis of fat soluble vitamins should be drawn prior to administration of vitamin supplementation. 
e 
Participants are required to fast at least 4 hr (only water permitted prior to collection). 
f 
Genotyping sample will be drawn at Week 84 or at the time of re-consent for the optional follow-up treatment period; sample will be used to provide a full characterization and 
documentation of the mutation type in support of the diagnosis of ALGS. 
g 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
h 
Participants must be available to receive a phone call from study staff. 
i 
Participants who withdraw early should complete all evaluations at this visit. 
j 
Study termination only for participants who discontinue early and/or decide not to continue into optional follow-up period(s). Participants who choose to stay in the study go straight from this 
visit to the Optional Follow-up Treatment Period (Weeks 72-124). 
k 
Follow-up visit is only for participants who exit the study at the Study Termination Visit. 
l 
At the indicated visits during the treatment period, oxalate will be part of the urinalysis. 
m 
During the stable dosing period, twice daily completion of the eDiary (ItchRO) for 2 consecutive weeks will be required following the Weeks 84, 96, 108, 120 clinic visits. 
 
Clinic Visit 
Phone Contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.7.4. Schedule of Procedures D – 52-Week Optional Follow-up Treatment Period: DE-2 –Week 176 for participants with ≥7days 
from last dose of MRX (Protocol Amendment 4). Includes Evaluation of Eligibility for Afternoon Dose Escalation Dosing Regimen 
 


 
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a 
Calculation of Study Day includes subject’s participation through the first 72 weeks. 


 
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b 
Once necessary approvals are received for Protocol Amendment 5 and associated consent/assent are available, site will consent/assent subject for Protocol Amendment 5 at the next clinic visit. 
c 
Depending on the outcome of afternoon dose escalation eligibility assessment, the subject will move into either Schedule of Procedures For G. Note: It is possible that subject will not 
necessarily complete up through Week 124 before they move to Schedule of Procedures F or G. 
d 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
e 
See Section 16.2 in the protocol for detailed list of laboratory analytes. 
f 
Participants are required to fast at least 4 hr (only water permitted) prior to collection. 
g 
Blood samples must be drawn before administration of vitamin supplementation. 
h 
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. 
i 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
j 
Participants must be available to receive a phone call from study staff. 
k 
Participants who withdraw early should complete all evaluations at this visit. 
l 
Follow-up visit is only for participants who exit the study at the Study Termination Visit. 
m 
At indicated visits during treatment period, oxalate will be part of the UA. 
n 
During the Follow-up Treatment Period, daily completion of the study diary for 2 consecutive weeks following Week 74, Week 84, Week 96, Week 108, and Week 120 visits . 
 
Clinic Visit 
Phone Contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.7.5. Schedule of Procedures E – Long-term Optional Follow-up Treatment Period: Protocol Amendment 5 Screening (Week -2) 
and on MRX. Includes Evaluation of Eligibility for Afternoon Dose Escalation Dosing Regimen at Protocol Amendment 5, Week 
12 
Any subject who re-enters the study under Protocol Amendment 5. The subject returns to their last previously administered dose for 12 weeks and then moves to either 
Schedule F or G, depending on afternoon dose eligibility. Proceed to Schedule H for Early Termination or End of Treatment Procedures. 
 


 
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a 
Calculation of Study Day includes subject’s participation through the first 72 weeks. 
b 
Once necessary approvals are received for Protocol Amendment 5 and associated consent/assent are available, site will consent/assent subject for Protocol Amendment 5 at the Protocol 
Amendment 5 screening visit. 
c 
Blood pressure (BP), heart rate (HR), temperature, respiration rate. 
d 
See Section 16.2 in the protocol for detailed list of laboratory analytes. 
e 
Participants are required to fast at least 4 hr (only water permitted) prior to collection. 
f 
Blood samples must be drawn before administration of vitamin supplementation. 
g 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
h 
Participants must be available to receive a phone call from study staff. 
i 
Oxalate will be part of the UA. 
j 
During the Re-entry for Protocol Amendment 5, daily completion of the study diary for 2 consecutive weeks following the Protocol Amendment 5 screening visit and the Protocol 
Amendment 5 Week 4 visit. . 
Clinic Visit 
Phone Contact 


 
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3.7.6. Schedule of Procedures F – Extension of Long-term Optional Follow-up Treatment Period, for participants ineligible for 
afternoon dose escalation 
 


 
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a 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.  
b 
See Section 16.2 in the protocol for detailed list of   laboratory analytes. 
c 
Participants are required to fast at least 4 hr (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 
Participants 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) participants 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 
At indicated visits during treatment period, oxalate will be part of the UA. 
j 
Sample will be drawn at every other clinic visit starting with RP1 Week 12.  
k 
 Starting at Week 12 RP2 participants should be re-assessed for ADE eligibility 
Clinic Visit 
Phone Contact 
 
 
 
 


 
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3.7.7. Schedule of Procedures G – Extension of Long-term Optional Follow-up Treatment Period, for participants eligible for 
afternoon 
 


 
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a 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.  
b 
See Section 16.2 in the protocol for detailed list of laboratory analytes. 
c 
Participants are required to fast at least 4 hr (only water permitted) prior to collection.  
d 
Blood samples must be drawn before administration of vitamin supplementation. 
e 
Pharmacokinetic sample will additionally be collected at the three scheduled clinic visits following completion of the afternoon dose escalation period.  
f 
Females of childbearing potential, result must be reviewed prior to dispensing study drug. 
g 
Study drug may be dispensed at unscheduled clinic visits. 
h 
Participants must be available to receive a phone call from study staff. 
i 
Study visits will continue in the same pattern until the first of the following occur: (i) participants are eligible to enter another LUM001 study, (ii) LUM001 is available commercially, or 
(iii) the sponsor stops the program or development in this indication. 
j 
At indicated visits during treatment period, oxalate will be part of the UA.  
k 
Sample will be drawn at every other clinic visit starting with RP1 Week 12. 
 
Clinic Visit 
Phone Contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3.7.8. Schedule of Procedures H – End of Treatment (EOT) / Early Termination (ET) Visit and Post-Treatment Safety Follow Up 
 


 
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a 
Blood pressure (BP), heart rate (HR), temperature, respiration rate.  
b 
See Section 16.2 in the protocol for detailed list of laboratory analytes. 
c 
Participants are required to fast at least 4 hr (only water permitted) prior to collection.  
d 
Blood samples must be drawn before administration of vitamin supplementation.  
e 
Females of childbearing potential. 
f 
Participants must be available to receive a phone call from study staff. 
g 
Will take place when the first of the following occur: (i) participants 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 UA. 


 
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4. 
Statistical Analysis and Reporting 
Statistical analysis will be performed following Premier Research’s Standard Operating 
Procedures (SOPs). 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher).  
Continuous (quantitative) variable summaries will include the number of participants (n) with 
non-missing values, mean, standard deviation (SD) and/or standard error (SE) if appropriate, 
median, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
participants who are in the particular category. In general, the denominator for the percentage 
calculation will be based upon the total number of participants in the analysis population for the 
treatment group and overall, unless otherwise specified. 
For purposes of analysis of disposition of participants, there will be 3 treatment phases in 
addition to overall:   
• 
Original Protocol Phase (Day 1 – Week 72), 
• 
52-Week Optional Follow-up Phase (Week 72 – Week 124) 
• 
Long-term Optional Follow-up Phase (Week >124) 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data, unless otherwise specified. Measures of location 
(mean and median) and measures of spread (standard deviations or errors) will be reported to 1 
degree of precision more than the observed data and measures of spread (SD and/or SE) will be 
reported to 2 degrees of precision more than the observed data. 
The minimum and maximum values for derived and select observed values will be reported as 
follows, with measures of location and spread following the above rules. Derived values for 
corrected sodium, along with select laboratory values of autotaxin, FGF-19, and FGF-21, will be 
presented as integers. Derived values for BMI, PedsQL summary and total scale scores, along 
with select laboratory values of sBA, 25-hydroxyvitamin D, and vitamin A, and pH, will be 
presented to 1 decimal place. Derived values of height, weight and BMI z-scores, and ItchRO 
average values, along with select laboratory values of creatinine, α-tocopherol, retinol binding 
protein (RBP), retinol:RBP molar ratio, and ratio of α-tocopherol to the sum of cholesterol and 
triglycerides will be reported to 2 decimal places. 
Percentages will be presented to 1 decimal place, unless otherwise specified. Where the number 
of participants in a particular category is zero, a percentage (i.e., 0.0%) will not be displayed. 


 
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All statistical tests will be conducted using 2-tailed tests at the 0.05 significance level. No 
inference will be drawn from any p-values presented. Where appropriate, corresponding 95% 
confidence intervals (CIs) will be presented. 
4.2. 
Interim Analysis 
There is no planned interim analysis (IA) in this study. However, in preparation for briefing 
documents for the End-of-Phase 2 meeting with FDA on 21May2019 and the pre-New Drug 
Application (NDA) meeting with FDA on 19Nov2019, additional interim analyses were 
performed outside of what is noted in the protocol. In preparation for the NDA submission, 
currently planned in Aug2020, the analysis herein described will be performed using an interim 
data cut date of 01Dec2019. 
Additional analyses may be performed to explore both safety and efficacy measures collected in 
this study. The precise methods and analyses will be determined after the database is locked and 
the blind is broken. Thus, all such analyses will be interpreted cautiously and not used for formal 
inference, although inferential statistics may be used as part of the data summary. 
4.3. 
Data Monitoring 
A Data Monitoring Committee (DMC) will review serious adverse event (SAE) data and other 
key 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. 
Analysis Populations 
The following analysis population is planned for this study:  
• Safety Population (SAF):  
The Safety Population is defined as all participants who were enrolled and received at 
least one dose of the study drug.  
The Safety Population will be used for the analyses of all endpoints. Safety analyses will be 
conducted according to the treatment received. 


 
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6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
All Efficacy Assessments and Safety Assessments Before Drug Interruption 
For all visit-based efficacy analyses, and for visit-based safety data that is collected/assessed 
before an extended (> 28-day) drug interruption period (between protocol amendments), the 
following baseline will be used for change from baseline values: 
• 
MRX Baseline: The observation obtained at first dose of MRX (either in LUM001-302 or 
in LUM001-303) will be used as the baseline MRX observation for all calculations of 
change from baseline MRX. This baseline is applicable only to visit-based analyses. 
For ItchRO weekly average scores, baseline is defined as the average of daily scores in the week 
consisting of the 7 days immediately before the baseline visit. 
Safety Assessments After Drug Interruption 
For visit-based analyses on safety data collected/assessed after an extended drug interruption 
period > 28 days (between protocol amendments), the following baseline definitions will be used 
for change from baseline values.  
• 
MRX Baseline: Same definition as above. 
• 
Baseline (PA Day 0): The last observation obtained before the first re-initiation dose after 
the drug interruption will be used as the baseline (PA Day 0) observation for all 
calculations of change from baseline (PA Day 0).  
6.1.2. Study Day 
Day 1 is defined as the date of first study drug administration. Study day is calculated relative to 
the date of Day 1. 
6.1.3. Adjustments for Covariates 
No adjustments will be made for covariates. 
6.1.4. Multiple Comparisons 
No adjustments will be made for multiple comparisons. 


 
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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 participants 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 are scheduled to undergo all procedures specified for 
the EOT/ET visit. Per the protocol, the ET visits should be scheduled within 7 days of the last 
dose of study drug. However, in the event an ET visit occurs more than 7 days after the date of 
last dose, prior to the respective ET visit (i.e., Week 72/ET, 124/ET, 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 as described in Section 6.1.7. 
The procedures for handling dropouts or missing data, including the handling of missing 
individual daily ItchRO scores, PedsQL scale score items, and adverse event severity and 
relationship to study drug are described in the below subsections. 
Rules for handling missing or partial AE or birth dates are described in Section 6.1.10. 
6.1.5.2. 
LOCF Imputation 
In addition to the time points specified in the protocol, safety and efficacy variables analyzed by 
time point will also be analyzed (as a sensitivity analysis) at the following LOCF time points: 
Week 72/LOCF, Week 124/LOCF time points, where appropriate. Imputed time points are only 
applicable for ItchRO(Obs) weekly morning average scores.  
For participants that discontinue early, these time points are defined as the last post-baseline 
value obtained on or before the date of last dose plus 7 days (prior to the ET visit date). ItchRO 
assessments that occur more than 7 days after the date of last dose (prior to the ET visit date) will 
not be used to derive LOCF average scores. In this event, the LOCF average score will include 
assessments made up to the last 7 days immediately following the date of last dose (see Section 
6.1.7). 
6.1.5.3. 
Missing ItchRO Scores 
In deriving the ItchRO weekly average morning score, each scheduled visit date will be 
determined from the date of the vital signs assessment. If the date of vital signs is missing, then 
the date of the physical examination will be used. If both of these dates are missing for a specific 
scheduled visit then the start date from the participants 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 participants/caregiver failed to complete the morning/evening report, the 
morning/evening score for that day will be treated as missing data. 
On-study compliance for post-baseline ItchRO is defined as having at least 4 of the 7 daily 
scores for a 7-day period. Compliance restrictions are not set for baseline ItchRO average scores. 
If a participants/caregiver is not compliant with reporting ItchRO assessments during the 7-day 
period before a study visit, the weekly average score from the most recent, previous compliant 
7-day period will be used in a LOCF format. Additionally, the same ItchRO assessment day 
(morning/evening daily score) will not be used across different weekly time periods (i.e. no 
overlap). 
6.1.5.4. 
Missing PedsQL Scores 
For PedsQL scale scores, if more than 50% of the items in the scale are missing, the scale score 
is not computed (see Section 6.1.9). 
6.1.5.5. 
Missing Last Dose 
For participants who are missing the date of last dose of study drug, the last known contact date 
will be used in the calculation of treatment duration and study drug exposure. 
6.1.5.6. 
Missing Adverse Event Severity/Relationship 
For analysis purposes, only the following rules will be applied for missing AE severity or 
relationship to study drug. An AE that does not have a recorded relationship to study drug value 
will be considered as “Possibly Related” to study drug. If the severity of an AE is missing, the 
severity will be reported for analysis purposes as “Severity Not Recorded”. 
6.1.5.7. 
Missing Fat-Soluble Vitamin Data 
For analysis purposes, missing FSV lab values will be reported in a ‘Missing’ category in 
summarizing FSV level abnormalities. 
6.1.6. Investigative Sites 
An investigative site is defined as a single principal investigator (including sub-investigators) 
who enrols participants for the study. If an investigator has multiple practice locations, these 
locations are considered a single investigative site. 
Analyses will be based on data pooled across investigative sites.  
There is the potential that a 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. 


 
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6.1.7. Analysis Visit Windows 
Analyses of all visit-based efficacy and safety variables will be performed using the analysis visit 
windows as defined in this section. The below tables address scheduled post-baseline 
assessments; baseline assessments are described in Section 6.1.1. Scheduled visits will be 
selected over unscheduled visits. 
For those participants who discontinue early from the study, the below tables (as appropriate) 
will also be used to assign the appropriate analysis visit to the ET visit. For participants that were 
dose-escalated after an extended  drug interruption (between protocol amendments), the data 
collected/assessed during the dose-escalation period (i.e., DE Week -2 and DE Day 0 for PA3, 
PA4, and PA5) will not be assigned to a post-dose analysis visit. Only the DE Day 0 values will 
be used as baseline values as described in Section 6.1.9. 
The study day will be calculated for each scheduled or ET post-baseline visit (and/or 
assessment), as described below, and compared to the assessment window presented in Table 4 
or Table 5, as appropriate, to define the visit window used for analyses.  
The analysis visit windows only apply to those visits that are applicable to the specific 
assessment. For example, if the scheduled or ET visit falls at Week 15 but a specific assessment 
(e.g., sBA sample or Clinician Xanthoma Scale score) was not scheduled at that visit (see 
Section 3.7, Schedule of Procedures), then that assessment will not be used for analyses. 
Average ItchRO scores, which are derived by anchoring on scheduled in-clinic visit dates, will 
also be assigned to a study week for analysis according to Table 4. For analysis visits past 
Week 48, ItchRO average weekly scores are based on the 2-week period following the scheduled 
in-clinic visit. Thus, the “Analysis Visit” and “Analysis Visit Name” will be adjusted 
accordingly (e.g., “Week 62” rather than “Week 60”).  
If more than 1 visit falls within the same visit window, the data from the visit closest to the target 
day will be used for the analysis visit. If 2 visits within the same visit window are equidistant 
from the target day, the data from the later visit will be used for the analysis visit. 
Efficacy and Visit-Based Safety Assessments Before Drug Interruption 
Analyses of all efficacy variables, regardless of drug interruptions, will be performed using the 
analysis visit windows defined by study day relative to the first dose of study drug as outlined 
below in Table 4. For participants with an extended drug interruption, efficacy assessments after 
the interruption are essentially treated as if the 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 participants 
without such a drug interruption. 


 
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Table 4: Analysis Visit Windows – Primary Analysis 
Analysis Visit 
Analysis Visit Name 
Target Day of 
Planned Visit 
Assessment Window 
(Study Days1) 
2 
Week 2 
14 
Post-dose ─ 21 
4 
Week 4 
28 
22 ─ 36 
8 
Week 8 
56 
37 ─ 70 
12 
Week 12 
84 
71 ─ 98 
16 
Week 16 
112 
99 ─ 133 
24 
Week 24 
154 
134 ─ 203 
36 
Week 36 
252 
204 ─ 301 
44 
Week 44 
308 
302 ─ 324 
48 
Week 48 
336 
325 – 378 
60 
Week 60 
420 
379 – 462 
72 
Week 72 
504 
463 – 546/511* 
74* 
Week 73 
518 
512 - 525 
76* 
Week 76 
532 
526 - 546 
84 
Week 84 
588 
547 – 630 
96 
Week 96 
672 
631 – 714 
108 
Week 108 
756 
715 – 798 
120 
Week 120 
840 
799 – 852 
124 
Week 124 
868 
853 - 882 
1282 
PA5 Week 4 
896 
883 - 910 
1362 
PA5 Week 12 
952 
911 - 9943/9664 
1483 
RP Week 12 
1036 
995 - 10786 
1404 
ADE Week 4 
980 
967 - 1008 
1484 
ADE Week 8 
1036 
1009 - 1078 
1605 
ADE RP Week 12 
1120 
1079 - 11626 
1Study day relative to the date of first dose of study medication, unless otherwise specified. 
2Related to Long – term optional follow-up all participants 
3Related to Long – term optional follow-up for participants ineligible for afternoon dose escalation 
4Related to Long – term optional follow-up for participants eligible for afternoon dose escalation 
5Related to Long – term optional follow-up for participants after completion of afternoon dose escalation 
6This will include repeated visits until EOT/ET. Assessment windowing will be adjusted as relevant. 
*Dose Escalation period for participants with ≥ 7 days from last dose of MRX 


 
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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 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 (between protocol amendments), as described in Section 5, the analysis visit 
windows defined in Table 5 will be used. The analysis visit windows below are defined by study 
day relative to the date of first re-initiation of study drug after the drug interruption (i.e., PA 
Day 0; see Section 6.1.1). 
Table 5: Analysis Visit Windows – Supporting Subgroup Analysis 
(Data Assessed after an Extended Drug Interruption) 
Analysis 
Visit 
Analysis Visit 
Name 
Target Day of 
Planned Visit 
Assessment Window 
(Study Days1) 
4 
Week 4 
28 
Post-dose ─ 35 
12 
Week 12 
84 
70 ─ 98 
16 
Week 16 
112 
99 – 126 
20 
Week 20 
140 
127 – 209 
34 
Week 34 
238 
210 – 266 
46 
Week 46 
322 
288 – 364 
58 
Week 58 
406 
365 – 448 
70 
Week 70 
490 
449 – 532 
82 
Week 82 
574 
533 – 616 
94 
Week 94 
658 
617 – 700 
106 
Week 106 
742 
701 – 784 
118 
Week 118 
826 
785 – 868 
1 Study day relative to the date of first re-initiation of study drug after the drug interruption 
(i.e., PA Day 0). 
6.1.8. Variable Definitions 
• “Week 48/LOCF” (see Section 6.1.5.2) 
• “Week 72/LOCF” (see Section 6.1.5.2) 
• “Week 124/LOCF” (see Section 6.1.5.2) 


 
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• Treatment-emergent adverse events (TEAEs) are defined in Section 9.2. 
• Concomitant medications are defined in Section 9.6. 
6.1.9. Derived Variables 
• Age (months) at Baseline: 
For participants under 2 years of age, the age in years and months at baseline will be 
used: Age (months) at Baseline = (12 x Age (years) at Baseline) + # of months at 
Baseline 
Otherwise,  
Age (months) at Baseline = Integer of (Baseline Visit Date – Date of birth) / 30.44 
Partial birth dates are imputed for analysis purposes as described in 
Section 6.1.10. 
• Age Group at Baseline: 
1 if age (full years) at baseline < 2 years 
2 if age (full years) at baseline is 2 to 4 years 
3 if age (full years) at baseline is 5 to 8 years 
4 if age (full years) at baseline is 9 to 12 years 
5 if age (full years) at baseline is 13 to 18 years 
• Body mass index (kg/m2) = 
𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑖𝑖𝑖𝑖 𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘𝑘
(ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚) 2 
• Treatment Duration (days) = LASTDAY – FIRSTDAY + 1 day - GAP 
LASTDAY = date of the EOT visit OR the date of last dose for participants that 
withdrew from the study, FIRSTDAY = date of first dose, and GAP = total # of 
days subject was off study between protocol amendments.  
For ET participants, the date of last dose is considered. For participants who are missing 
the date of last dose of study drug, the last known contact date will be used in the 
calculation of treatment duration and study drug exposure. 
• % Compliance = 100 x Number of days at least 1 dose is taken / QD Treatment Duration 
(days) 
where,  
Number of days at least 1 dose is taken = Treatment Duration (days) – Number of 
days a dose was missed [during the specified time period, not including dosing gaps 
due to the subject being off study between protocol amendments] 


 
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Compliance is derived overall (Week 0-EOT) and for the following treatment 
phases: Week 0-72, Week >72-124, and Week >124. Study drug compliance will 
not be calculated for those participants whose date of last dose is unknown.  
• Total Dose Received (µg/kg) = Dose (µg/kg/day) x Treatment Duration (days), for a 
given dose level  
• 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 0-72, Week >72-124, and Week >124. 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 participants who are 
missing the date of last dose of study drug, the last known contact date will be 
used in the calculation of treatment duration and study drug exposure.  
• 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 0-72, Week >72-124, and Week >124. 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. 
• ItchRO Weekly Morning Average Score = Sum of ItchRO daily morning scores (over 
a 7-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) weekly average scores. The baseline weekly morning/evening 
average score is derived using the 7 days immediately before the baseline visit 
date, according to the baseline definitions described in Section 6.1.1. 
• Estimated Total Lipids, mg/dL = cholesterol (mg/dL) + triglycerides (mg/dL) 
• Ratio of Alpha Tocopherol to estimated total lipids, 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. 


 
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• Corrected Sodium, mmol/L = sodium (mmol/L) + [ 0.00216 x Estimated Total Lipids 
(mg/dL)] 
• Retinol:RBP Molar Ratio, mol/mol = 0.0734 x serum retinol (µg/dL) / serum RBP 
(mg/dL) 
• 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. 
• 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. 
• Body Weight, Height and BMI z-Scores: 


 
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Height and weight z-scores are based on a subject’s gender and age at each scheduled visit. 
For participants less than 24 months of age, the World Health Organization (WHO) growth 
charts11 are recommended by the Centers for Disease Control (CDC) and will be used to 
derive z-scores. For participants at least 24 months of age, the CDC growth charts12 will 
be used to derive z-scores.  
• 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: 
• 
Total Scale Score – computed as the sum of the items over the number of items 
answered on the PedsQL Generic Core Scales (up to 45 items) 
• 
Physical Health Summary Score – computed as the sum of the items over the 
number of items answered in the Physical Functioning Scale (and Physical 
Symptoms Scale for infants) from the PedsQL Generic Core Scales (up to 19 
items) 
• 
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) 
• 
Multidimensional Fatigue Scale Score – computed as the sum of the items over 
the number of items answered in the PedsQL Multidimensional Fatigue Scales 
(18 items) 
• 
Family Impact Total Scale Score – computed as the sum of the items over the 
number of items answered in the PedsQL Family Impact module (36 items) 
• 
Parent Functioning Summary Score – computed as the sum of the items over the 
number of items answered in the Physical, Emotional, Social, and Cognitive 
Functioning Scales from the PedsQL Family Impact module (20 items) 
• 
Family Impact Summary Score – computed as the sum of the items over the 
number of items answered in the Daily Activities and Family Relationships Scales 
from the PedsQL Family Impact module (8 items) 


 
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Total scale, physical health summary, psychosocial health summary, and multidimensional 
fatigue scale scores are computed individually for the parent and subject reports. 
6.1.10. Data Adjustments/Handling/Conventions 
Data not subject to analysis according to this plan will not appear in any tables, listings, or 
graphs. 
Participant Age 
Age at screening from the LUM001-302 study will be used as the age for the determination of 
the appropriate ItchRO instrument and the appropriate PedsQL module to be used for the study. 
The same age-appropriate instrument will be used for the duration of the study (regardless of 
subsequent birthdays after the baseline visit).Adverse Event and Concomitant Medication 
Coding 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1. Prior and concomitant medications will be coded using WHO-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 participants with study drug interruptions (for any reason), any concomitant medication that 
starts >14 days after the last dose before the drug interruption and ended before the study drug 
was re-initiated will not be considered (for analysis purposes) as a concomitant medication. 
Medications that treat pruritus include ATC preferred terms of rifampicin, phenobarbital, 
alimemazine, brompheniramine maleate, cetirizine hydrochloride, desloratadine, 
dexchlorpheniramine maleate, dimetindene maleate, ketotifen fumarate, levocetirizine 
dihydrochloride, loratadine, mequitazine, promethazine, promethazine hydrochloride, ornithine 
aspartate, ursodeoxycholic acid, colestyramine, naltrexone, naltrexone hydrochloride, and 
sertraline. 
Treatment-Emergent Adverse Event Definition and Handling of Data 
In general, TEAEs are defined as AEs with a start date on or after the first dose date of study 
drug and started before the last dose of study drug plus 14 days. For participants with >14 days 


 
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of study drug interruption/withdrawal, the definition of a TEAE will consider both the date of the 
last dose before study drug interruption and the actual last dose. For these participants, AEs that 
start >14 days after the last dose (before study drug interruption) and ended before the drug is re-
initiated will not be considered as treatment-emergent. 
Any event which started before the first dose and worsens in severity or changes from non-
serious to serious on or after the first dose date will also be designated as a treatment-emergent 
event. If an event worsens in severity during the study, the lower grade event is marked as “Not 
recovered/not resolved” on the AE CRF and an end date entered. A new event is recorded on the 
AE CRF with a start date that matches the end date, and the term recorded includes “Worsened” 
(e.g., “Worsened Headaches”). If an event becomes serious, the date that the event became 
serious is recorded on the AE CRF as the End Date of that AE and the Start Date of the 
corresponding SAE. 
Adverse event severity grades are reported according to the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. If the CTCAE does not have a grading for a particular 
AE, the severity of the event is reported by the investigator as mild, moderate, or severe. If 
CTCAE is not used and the event is reported as life-threatening then the severity of the event is 
considered as “Life-Threatening (CTCAE Grade 4)” for analysis purposes. Similarly, if CTCAE 
is not used and the event results in death then, for analysis purposes, the severity of the event is 
considered as “Fatal (CTCAE Grade 5)”. 
A treatment-related AE is any AE with a relationship to the study drug of related or possibly 
related. 
An AE that does not have a recorded relationship to study drug will be considered as “Possibly 
Related” to study drug. If severity of an AE is missing, severity of the event will be reported for 
analysis purposes as “Severity Not Recorded”. 
Adverse Events of Special Interest 
The following events have been defined as AEs of special interest (AESI) due to the nature of 
ALGS disease as well as of MRX: 
• Diarrhoea events 
• FSV deficiency events 
• Elevated transaminases events 
• Elevated bilirubin events 
All of these events occur during the natural history of ALGS. MRX is associated with 
gastrointestinal disturbances such as diarrhea. 
The list of PTs used to identify FSV deficiency events are provided in Appendix 3. Diarrhoea 
events include PTs of ‘Diarrhoea’ and ‘loose stool’, “increased stool frequency”. Elevated 
transaminases events include PTs of ‘Alanine aminotransferase increased’ and ‘Aspartate 
aminotransferase increased’. Elevated bilirubin events include the PT of ‘Blood bilirubin 
increased’. 


 
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Partial Date Imputation 
If partial dates occur, the convention for replacing missing dates for the purpose of calculating 
derived variables is as follows: 
Partial ALGS Diagnosis Dates 
For partial original ALGS diagnosis dates: (a) if only the day is missing, and the month and 
year match the first dose date, then the day is assigned the first day of the month (01); 
otherwise the day assigned is 15; and (b) if both the day and month are missing then the 
day/month assigned is the first day of July (01JUL), as long as the date is before the first 
dose date; otherwise, the day/month assigned is the first day of January (01JAN). 
Partial Dates of Birth 
Several of the investigative sites are located in countries that do not permit the reporting of 
complete dates of birth. These sites only report the month and year of date of birth. Complete 
date of birth is required, however, to derive a 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 the below, first dose date is with 
respect to the first dose in LUM001-303. 
For partial AE or prior/concomitant medication start dates: (a) if only the day is missing and 
the month and year match the first dose date  and the end date is on or after the first dose 
date, (or the event is ongoing), then the date is assigned the first dose date; thus, the 
event/medication will be considered as treatment-emergent/concomitant; if the month and/or 
year do not match the first dose date or the end date is before the first dose date, then the day 
is assigned the first day of the month (01); (b) if both the day and month are missing, and the 
year matches the first dose date and the end date is on or after the first dose date (or the event 
is ongoing), then the date is assigned the first dose date; if the year does not match the first 
dose date or the end date is before the first dose date, then the day/month are assigned the 
first day of the year (01 Jan). 
For partial end dates: (a) if only the day is missing, then the day is assigned the last day of 
the month; (b) if both day and month are missing, they are assigned the last day of the year 
(31 Dec). 
Lower and Upper Limit of Quantitation  
In general, for quantitative laboratory values reported as “<” or “≤” the lower limit of 
quantitation (LLOQ), one-half of the reported value (i.e., LLOQ/2) will be used for analysis. The 


 
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exception to this data treatment is for plasma MRX concentrations that are reported as <LLOQ, 
where a value of zero will be used in calculating summary statistics. 
For quantitative laboratory values reported as “>” or “≥” the upper limit of quantitation (ULOQ), 
the reported value (i.e., ULOQ) will be used for analysis. 
Repeat Laboratory Test Results 
For analysis purposes, repeat laboratory test results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non-missing repeat 
laboratory value will be used for data analysis. 
Dose Used in Safety Analysis 
For all safety and tolerability analyses, participants will be analyzed by the treatment received. 
For AE summaries, MRX treatment groups are based on the dose received at the onset of the 
event. 
Treatment Duration and Exposure 
For participants who are missing the date of last study drug, for any reason, the last known 
contact date will be used in the calculation of treatment duration and study drug exposure. Study 
drug compliance will not be calculated for those participants whose date of last study drug 
application is unknown.   
7. 
Study Participants and Demographics 
7.1. 
Disposition of Participants and Withdrawals 
Subject disposition will be presented overall and by treatment phase and treatment group. 
Subject disposition will include tabulations of the number and percentage of participants in each 
of the analysis populations, down-titrated during the study, completed treatment, and 
discontinued treatment early (along with reasons for withdrawal). For the overall summary and 
the Week >72 treatment period, participants that did not consent to the optional long-term 
treatment extensions (PA4 and PA5) are not considered to have completed treatment. Reasons 
for withdrawal will include those collected on the CRF, along with not consenting to PA4 and 
PA5 (separately).  
For the by study phase and treatment group summaries, the number and percentage of 
participants presented will be based on the number of participants in each treatment period. 
The subject disposition tabulation will also include the number of participants screened for 
eligibility (under the original protocol), the number of screen failures (under the original 
protocol), enrolled/randomized/continued, as appropriate for each treatment phase. 
Study drug accountability and compliance listings will be prepared for all participants, showing 
when the planned dosing schedule was not followed, along with the date and type of dosing 


 
Statistical Analysis Plan  
 
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Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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deviation. Other disposition and study conduct information, including major protocol deviations 
will be listed.   
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be tracked, recorded, and reviewed 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 the Sponsor 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 by treatment group and 
overall. 
Summary statistics for age (at baseline), age group, gender, country, weight z-score, height 
z-score, and BMI z-score will be presented. Age group categories are defined as <2, 2-4, 5-8, 9-
12, and 13-18 years of age at baseline. 
These analyses will be conducted for the Safety Population. 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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7.4. 
Prior Medications 
Prior medications will be summarized descriptively by treatment group and overall, using the 
number and percent of participants by ATC class and preferred term. Summaries will be 
presented separately for: (1) prior anti-pruritus medications, (2) prior medications (excluding 
anti-pruritus medications), and (3) therapies to treat pruritus in the past, as collected specifically 
on the Disease History CRF under categories of topical, oral, and other therapies.  Each summary 
will also include tabulations for the following categories: no medication, 1 medication, 2 
medications, and at least 3 medications. 
Prior medications will be presented separately from concomitant medications.  
Prior and concomitant medications will also be presented separately in subject listings. A 
separate listing of prior medications that treat pruritus will also be presented. 
7.5. 
Treatment Compliance 
Treatment compliance will be calculated for each subject and summarized descriptively. This 
analysis will be completed using the Safety Population for each of the following study phases:  
Weeks 0-72, Weeks >72-124, Weeks >124, and overall (Weeks 0-EOT). Participants that 
withdraw early before any given study phase are not included in the analysis of that study phase. 
A listing of all participants and their participation in each study phase will be provided.     
A subject is considered compliant with treatment (for a given day) if any amount of study drug 
was administered.  
Study drug accountability will be presented in a subject listing.  
8. 
Efficacy Analysis 
The primary analysis population for efficacy analysis will be the Safety Population. Analyses for 
the primary and secondary efficacy outcome variables will also be done on the Safety 
Population. All sensitivity analysis will be done on the Safety Population. Efficacy data 
summaries will be provided by treatment group ad overall, unless otherwise specified. 
All efficacy data will be presented in subject listings. 
8.1. 
Primary Efficacy Analysis 
The change from baseline to Week 48 in the serum bile acid will be displayed for each treatment 
group and overall by study visit, 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. 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
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8.2. 
Secondary, Exploratory and Other Efficacy Analyses 
Secondary efficacy variables that are continuous measures will be analyzed similarly to the 
primary efficacy analyses, using summary statistics and ANCOVA model to determine if the 
mean change is statistically significant, where applicable. 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. 
Categorical measures will be presented by level of response with frequencies and percentages. 
Change from baseline in Xanthoma scale will be categorized as improved, stable or worsened 
and will be compared between treatment groups using the chi-square test. 
Change from baseline in ItchRO(Obs) weekly average morning severity score, sBA, C4, 
bilirubin (total and direct), ALT, AST, ALP, GGT, total cholesterol, LDL-C, height, weight and 
BMI z-scores, and PedsQL total scale and multidimensional fatigue scale scores (parent) will be 
displayed graphically over the treatment period. 
Planned efficacy figures are described in Section 13.3. Additional figures may be added post-hoc 
to further examine study data. 
9. 
Safety and Tolerability Analysis 
All safety analyses will be performed on the Safety Population.  
Safety measures including treatment exposure, AEs, clinical laboratory values, physical 
examination findings (including BMI), vital signs, and concomitant treatment usage will be 
summarized descriptively. No inferential statistical tests will be performed, unless otherwise 
specified. 
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, participants will be analyzed by the treatment received. In general, safety 
data summaries will be provided by treatment phase and treatment group. For AE summaries, 
MRX treatment groups are based on the dose received at the onset of the event. 
All safety and tolerability data will be presented by treatment sequence in 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 phases: Weeks 0-72, Weeks >72-124, Weeks >124, and overall (Weeks 0-EOT). These 


 
Statistical Analysis Plan  
 
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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 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 participants with >14 days of study 
drug interruption/withdrawal, the definition of a TEAE considers both the date of the last dose 
prior to drug interruption and the actual last dose (see Section 6.1.9). 
Analysis of TEAEs will be performed by treatment group and overall. TEAEs will be 
summarized overall and by MRX dose at the onset of the event. 
A summary of TEAEs will be presented overall and by treatment group and overall (including 
MRX overall and dose at onset). The summary will include the total number and percent of 
participants reporting: 
• Any TEAEs 
• Any treatment-related TEAE 
• Any serious TEAE 
• Any serious treatment-related TEAE  
• Any TEAE leading to study discontinuation 
• TEAEs resulting in death 
The number and percent of participants reporting TEAEs, grouped by MedDRA system organ 
class (SOC) and preferred term (PT), will be tabulated overall and by maximum severity. These 
adverse event summaries will be repeated for treatment-related AEs. In the case of multiple 
occurrences of the same TEAE within the same subject, each subject will only be counted once 
for each preferred term.  


 
Statistical Analysis Plan  
 
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All AEs will be coded using MedDRA version 22.1. All TEAEs summarized by SOC and PT 
will be sorted in alphabetical order of the SOC and by descending total 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 6.1.9. 
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 
date and study day, end date and study day, event duration, severity, relationship to study drug, 
outcome, action taken with study drug, seriousness, and treatment required.  
9.2.1. Adverse Events Leading to Withdrawal 
AEs that lead to permanent discontinuation of study drug will be tabulated by SOC and PT 
overall by dose at onset of the event. 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: diarrhea events, FSV deficiency events, elevated transaminases, and elevated bilirubin. 
The list of PTs used to identify FSV deficiency events are provided in Appendix 3. 
The incidence of TEAEs of special interest will be summarized in the same manner as AEs that 
lead to permanent discontinuation of study drug.  
9.3. 
Clinical Laboratory Evaluations 
The primary analysis of safety laboratory data will exclude any laboratory samples that were 
collected from a subject after a drug interruption due to the subject being off study (between 
protocol amendments). 


 
Statistical Analysis Plan  
 
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Safety laboratory test results will be summarized using descriptive statistics by laboratory test 
panel (i.e., chemistry, hematology, FSVs, and lipids), by treatment group and analysis visit as 
observed and change from baseline values.  
Specific laboratory tests, and associated units of measure, that will be used for safety reporting 
are listed in Appendix 2. As noted, summary statistics will not be presented for urinalysis results, 
but rather included in subject listings. Bilirubin (total and direct), ALT, AST, ALP, GGT 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, lipid ratio of alpha tocopherol to estimated 
total lipids, corrected sodium, INR, retinol:RBP molar ratio, and vitamin A, a summary of 
abnormalities will be presented. The number and percent of participants within each test level 
category will be presented. For these fat-soluble vitamins, categories may include normal, 
sufficient, insufficient, possibly insufficient, indeterminate, and excess (see Section 6.1.9 for 
specific definitions). Missing lab values will be reported in a ‘Missing’ category. 
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 an extended drug interruption 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). 
FSV level abnormalities (e.g., sufficient, insufficient, excess) will also be analyzed separately as 
a sensitivity analysis using laboratory samples collected after a drug interruption. The number 
and percent of participants within each test level category (see Section 6.1.9 for category 
definitions) will be presented. 
9.4. 
Physical Examination 
BMI will be summarized using descriptive statistics by treatment group 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, along with z-scores for height, 
weight and BMI will be included in subject listings. 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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9.5. 
Vital Signs 
Vital signs (blood pressure, heart rate, body temperature, and respiration rate) will be 
summarized using descriptive statistics by scheduled study visit as both observed values and 
change from baseline values. 
9.6. 
Concomitant Medication 
A concomitant medication is any non-protocol specified drug or substance administered after the 
first dose of study drug. For participants with study drug interruptions (for any reason), any 
concomitant medication that starts >14 days after the last dose before the drug interruption and 
ended before the study drug was re-initiated will not be considered (for analysis purposes) as a 
concomitant medication. 
Concomitant medications will be summarized descriptively by treatment group and overall using 
the number and percent of participants by ATC class and preferred term. Pruritus medications 
that treat pruritus are listed in Section 13.1. 
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. 
9.7. 
Safety Data Graphical Presentations 
Study drug exposure and TEAEs of special interest will be displayed graphically over time, as 
described in Section 13.3. Additional figures may be added post-hoc to further examine study 
data. 
10. 
Other Analysis 
10.1. Pharmacokinetic Analysis 
MRX plasma concentrations will be summarized using descriptive statistics by study visit and 
the last dose of MRX received prior to the blood sample collection. 
10.2. Palatability 
Palatability data will be summarized using descriptive statistics by treatment group and analysis 
visit as observed.  
10.3. Serum Alpha-fetoprotein 
Assessments of serum AFP will be listed for individual participants and summarized using 
descriptive statistics by study visit. 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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11. 
Changes from Planned Analysis 
The protocol defines Baseline (Day 0) and Baseline from LUM001-302, however in 
LUM001-303, the first dose of MRX (either in LUM001-302 or LUM001-303) will be used as 
the baseline visit to harmonize across the ALGS program. 
Other changes from the protocol include: 
- 
Change from Week 12 to Week 48 removed from the secondary endpoints, this change 
analysis will be no longer meaningful with the use of MRX baseline.  
- 
AST, ALP and direct bilirubin added to the secondary endpoints to harmonize across the 
ALGS program. 
- 
The protocol states the ANCOVA analysis will be performed for the primary endpoint, 
however Student t-test will be used. 
 
 
 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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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 LUM001-303  
 
PCN Number LUME2941 
 
 
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13. 
Tables, Listings, and Figures 
All listings, tables, and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (listing number, where applicable). 
13.1. Planned Table Descriptions 
The following are planned summary tables for protocol number LUM001-303. The table 
numbers are place holders only and will be determined when the tables are produced. 
Table Number 
 
Table Title 
14.1  Disposition, Demographic, Disease History, Prior Medications, and Study Drug Compliance 
14.1.1.1 
Subject Disposition: Overall – All Participants 
14.1.1.2 
Subject Disposition by Study Phase – Enrolled Participants 
14.1.2 
Demographics and Baseline Characteristics – Safety Population 
14.1.3 
Disease History and Baseline Disease Characteristics – Safety Population 
14.1.5.1 
Summary of Prior Anti-Pruritus Medications – Safety Population 
14.1.5.2 
Summary of Prior Medications (Excluding Anti-Pruritus Medications) – Safety Population 
14.1.5.3 
Summary of Therapies to Treat Pruritus in the Past – Safety Population 
14.1.6 
Study Drug Compliance – Safety Population 


 
Statistical Analysis Plan  
 
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14.2  Efficacy Data 
14.2.1 
Summary of ItchRO (Obs) Weekly Average Morning Severity Score and Change from Baseline by  
Analysis Visit – Safety Population 
      14.2.2            Summary of sBA (µmol/L) and Change from Baseline by Analysis Visit – Safety Population 
14.2.3 
Summary of ALP (U/L) and Change from Baseline by Analysis Visit – Safety Population 
14.2.4 
Summary of ALT (U/L) and Change from Baseline by Analysis Visit – Safety Population 
14.2.5           Summary of AST (U/L) and Change from Baseline by Analysis Visit – Safety Population 
14.2.6          Summary of GGT (U/L) and Change from Baseline by Analysis Visit – Safety Population 
14.2.6          Summary of Total Bilirubin (mg/dL) and Change from Baseline by Analysis Visit – Safety Population 
14.2.7           Summary of Direct Bilirubin (mg/dL) and Change from Baseline by Analysis Visit – Safety Population 
14.2.8 
Summary of C4 (ng/mL) and Change from Baseline by Analysis Visit – Safety Population 
14.2.9 
Summary of Total Cholesterol (mg/dL) and Change from Baseline by Analysis Visit – Safety Population 
14.2.10 
Summary of LDL-C (mg/dL) and Change from Baseline by Analysis Visit – Safety Population 
14.2.11.1 
Summary of Clinician Scratch Score (CSS) and Change from Baseline by Analysis Visit – Safety 
Population 
14.2.11.2 
Summary of Clinician Scratch Score (CSS) Change from Baseline by Analysis Visit – Categorical Data 
Analysis – Safety Population 
14.2.12 
Summary of Clinician Xanthoma Severity Score and Change from Baseline by Analysis Visit – Safety 
Population 
14.2.12.1      Secondary analysis: Change from Baseline in Clinician Xanthoma Severity Score, Chi-square test – Safety 
Population 
14.2.13 
Summary of Height z-Score and Change from Baseline by Analysis Visit – Safety Population 
14.2.14 
Summary of Weight z-Score and Change from Baseline by Analysis Visit – Safety Population 
14.2.15 
Summary of CIC (Itch-Related Symptoms) and Change from Baseline by Analysis Visit – Safety 
Population 
14.2.16 
Summary of CIC  (Xanthoma Severity) and Change from Baseline by Analysis Visit – Safety Population 
14.2.17 
Summary of PedsQL Total Scale Score (Parent) and Change from Baseline by Analysis Visit – Safety 


 
Statistical Analysis Plan  
 
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Population 
14.2.18 
Summary of PedsQL Multidimensional Fatigue Scale Score (Parent) and Change from Baseline by Analysis 
Visit – Safety Population 
14.2.19 
Summary of PedsQL Family Impact Total Scale Score and Change from Baseline by Analysis Visit – 
Safety Population 
14.2.20 
Summary of PedsQL Psychosocial Health Summary Score (Parent) and Change from Baseline by Analysis 
Visit – Safety Population 
14.2.21 
Summary of PedsQL Total Scale Score (Child) and Change from Baseline by Analysis Visit – Safety 
Population 
14.2.22 
Summary of PedsQL Multidimensional Fatigue Scale Score (Child) and Change from Baseline by Analysis 
Visit – Safety Population 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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14.3  Safety Data 
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 
Summary of Treatment-Emergent Adverse Events by Dose at Onset of TEAE – Safety Population 
14.3.2.2 
Incidence of Treatment-Emergent Adverse Events by Dose at Onset of TEAE – Safety Population 
14.3.2.3 
Incidence of Treatment-Emergent Adverse Events by Maximum Severity and Dose at Onset of TEAE – 
Safety Population 
14.3.2.4 
Incidence of Treatment Related Adverse Events by Dose at Onset of TEAE – Safety Population 
14.3.2.5 
Incidence of Treatment Related Adverse Events by Maximum Severity and Dose at Onset of TEAE – 
Safety Population 
14.3.3  Summary of Deaths, Other Serious and Significant Adverse Events 
14.3.3.1 
Incidence of Treatment-Emergent SAEs by Dose at Onset of TEAE – Safety Population 
14.3.3.2 
Incidence of Treatment Related SAEs by Dose at Onset of TEAE – Safety Population 
14.3.3.3 
Incidence of Adverse Events Leading to Permanent Treatment Discontinuation by Dose at Onset of TEAE – 
Safety Population 
14.3.3.4 
Incidence of Treatment-Emergent Adverse Events of Special Interest – Diarrhoea Events by Dose at Onset 
of TEAE – Safety Population 
14.3.3.5 
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated Transaminases Events by 
Dose at Onset of TEAE – Safety Population 
14.3.3.6 
Incidence of Treatment-Emergent Adverse Events of Special Interest – Fat Soluble Vitamin Deficiency 
Events by Dose at Onset of TEAE – Safety Population 
14.3.3.7 
Incidence of Treatment-Emergent Adverse Events of Special Interest – Elevated Bilirubin Events by Dose 
at Onset of TEAE – Safety Population 
14.3.4  Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
14.3.4.1 
Listing of Serious Adverse Events – Safety Population 
14.3.4.2 
Listing of Adverse Events Leading to Permanent Treatment Discontinuation – Safety Population 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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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 z-score  (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 
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 
 
 
 
 


 
Statistical Analysis Plan  
 
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Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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14.4 Other Data Summaries 
 
14.4.1 Pharmacokinetic Data 
14.4.1 Summary of Plasma Sample Maralixibat Concentrations (ng/mL) by Analysis Visit – Safety Population 
14.4.2 Palatability Data 
14.4.2    Summary of Palatability data by Analysis Visit – Safety Population 
 
13.2. Planned Listing Descriptions 
For the planned interim analysis for protocol number LUM001-303, 3 subject data listings will 
be produced: SAEs, TEAEs leading to permanent treatment discontinuation, and deaths. These 
listings are imbedded within the safety tables. 
All listings will be sorted by treatment phase, treatment received, site, and subject number. 
All calculated variables (e.g., study day, TEAE flag) will be included in the listings. 
In all listings, a blank line will be placed between each 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. 
In data listings, the information for one subject will be kept on one page if at all possible, rather 
than splitting a subject’s information across pages. 
Listing Number 
 
Subject Listing Title 
16.2 
Subject Disposition 
16.2.1 
Analysis Populations and Treatment Assignments – Enrolled Participants  
16.2.2 
Subject Disposition – Enrolled Participants 
16.2.3 
Subject Disposition – Screen Failure 
16.3 
Protocol Deviations/ Participants Excluded from Efficacy Analyses 
16.3.1 
Inclusion and Exclusion Criteria – Enrolled Participants 
16.3.2 
Subject Excluded from Efficacy Analyses – Enrolled Participants 
16.3.3 
Major Protocol Deviations – Safety Population 
16.4 
Demographic Data and Other Baseline Characteristics 
16.4.1 
Demographics and Informed Consent – Safety Population 
16.4.2 
Medical History – Safety Population 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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Listing Number 
 
Subject Listing Title 
16.4.3 
Prior Medications – Safety Population 
16.5 
Study Drug Exposure, Compliance and Changes to MRX Dose 
16.5.1 
Study Drug Exposure – Safety Population 
16.5.2 
Study Drug Accountability and Compliance – Safety Population 
16.5.3 
Maralixibat Chloride Dose Changes – Safety Population 
16.6 
Individual Efficacy Response Data 
16.6.1 
ItchRO (Obs) Weekly Average Morning Severity Score and sBA Results – Safety 
Population 
16.6.2 
Clinician Scratch and Xanthoma Scores – Safety Population  
16.6.3 
Liver Biochemical Enzymes – Safety Population 
16.6.5 
ItchRO Reported Outcomes (Caregiver) Daily Morning Scores – Safety Population 
16.6.6 
CIC, and CIC-Xan – Safety Population 
16.6.7 
Efficacy Laboratory Tests – Safety Population 
16.6.8 
Total sBA – Safety Population 
16.6.9 
Height and Weight Z-Scores – Safety Population 
16.2.10.1.1.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Physical Functioning – 
Safety Population  
16.6.10.1.1.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Physical 
Functioning – Safety Population 
16.6.10.1.2 
Pediatric Quality of Life Inventory (Parent Report for Infants) - Physical Symptoms – 
Safety Population 
16.6.10.1.3.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Emotional Functioning – 
Safety Population  
16.6.10.1.3.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Emotional 
Functioning – Safety Population 
16.6.10.1.4.1 Pediatric Quality of Life Inventory (Parent Report for Infants) - Social Functioning – 
Safety Population 
16.6.10.1.4.2 Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - Social 
Functioning – Safety Population 
16.6.10.1.5 
Pediatric Quality of Life Inventory (Parent Report for Infants) - Cognitive Functioning – 
Safety Population 
16.6.10.1.6 
Pediatric Quality of Life Inventory (Parent Report for Children 2 - 18 Years) - 
Nursery/Day Care/School Functioning – Safety Population 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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Listing Number 
 
Subject Listing Title 
16.6.10.2.1 
Pediatric Quality of Life Inventory (Subject Report) - Physical Functioning – Safety 
Population 
16.6.10.2.2 
Pediatric Quality of Life Inventory (Subject Report) - Emotional Functioning – Safety 
Population 
16.6.10.2.3 
Pediatric Quality of Life Inventory (Subject Report) - Social Functioning – Safety 
Population 
16.6.10.2.4 
Pediatric Quality of Life Inventory (Subject Report) - School Functioning – Safety 
Population 
16.6.10.3.1 
Multidimensional Fatigue Scale (Parent Report) - General Fatigue – Safety Population 
16.6.10.3.2 
Multidimensional Fatigue Scale (Parent Report) - Sleep/Rest Fatigue – Safety Population 
16.6.10.3.3 
Multidimensional Fatigue Scale (Parent Report) - Mental Fatigue – Safety Population 
16.6.10.4.1 
Multidimensional Fatigue Scale (Subject Report) - General Fatigue – Safety Population 
16.6.10.4.2 
Multidimensional Fatigue Scale (Subject Report) - Sleep/Rest Fatigue – Safety Population 
16.6.10.4.3 
Multidimensional Fatigue Scale (Subject Report) - Cognitive Fatigue – Safety Population 
16.6.10.5.1 
Family Impact Module (Parent Report) - Physical Functioning – Safety Population 
16.6.10.5.2 
Family Impact Module (Parent Report) - Emotional Functioning – Safety Population 
16.6.10.5.3 
Family Impact Module (Parent Report) - Social Functioning – Safety Population 
16.6.10.5.4 
Family Impact Module (Parent Report) - Cognitive Functioning – Safety Population 
16.6.10.5.5 
Family Impact Module (Parent Report) – Communication – Safety Population 
16.6.10.5.6 
Family Impact Module (Parent Report) – Worry – Safety Population 
16.6.10.5.7 
Family Impact Module (Parent Report) - Daily Activities – Safety Population 
16.6.10.5.8 
Family Impact Module (Parent Report) - Family Relationships – Safety Population 
16.6.10.6.1 
Pediatric Quality of Life Inventory (Parent Report) - Total Scale and Summary Scores – 
Safety Population 
16.6.10.6.2 
Pediatric Quality of Life Inventory (Subject Report) - Total Scale and Summary Scores – 
Safety Population 
16.7 
Adverse Events 
16.7.1 
Adverse Events – Safety Population 
16.7.2.1 
Adverse Events of Special Interest: Diarrhoea Events – Safety Population 
16.7.2.2 
Adverse Events of Special Interest: Fat Soluble Vitamin Deficiency Events – Safety 
Population 
16.7.2.3 
Adverse Events of Special Interest: Elevated Transaminases Events – Safety Population 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
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Listing Number 
 
Subject Listing Title 
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 
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 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Final Version 1.0    |    Date: 10-Apr-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
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Listing Number 
 
Subject Listing Title 
16.9.1.1 
Vital Signs – Safety Population 
16.9.1.2 
Vital Signs – on Measures After Extended Drug Interruption - Safety Population 
16.9.2 
Physical Examination – Safety Population 
16.9.3 
Telephone Contact Log – Enrolled Participants 
16.10 
Concomitant Medications 
16.10.1 
Concomitant Medications – Safety Population 
16.10.2 
Concomitant Medications that Treat Pruritus – Safety Population 
16.11 
Drug Concentration Data 
16.11 
Plasma Sample Maralixibat Concentrations 
        16.12 Palatability Data 
            16.12              Palatability Data 
 
 
13.3. Planned Figure Descriptions 
The figure numbers and page numbers are place holders only and will be determined when the 
figures are produced. 
Mean (± SE) change from baseline for select efficacy variables will be displayed graphically by 
study week over time. For these line plots over time, study week will be based on the analysis 
visit mapping described in Table 4. Separate methods of displaying this data will be used as 
described below. 
TEAEs of special interest will be displayed in swimmer-type plots. A plot will be displayed for 
each individual AESI (as the preferred term) and present the start and stop study day of each 
event over time. The vertical axis will represent each unique 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. 
Figure Number 
 
Figure Title 
14.2  Efficacy Data 
14.2.1 
Plot of Mean (± SE) Change from Baseline in ItchRO (Obs) Weekly Average Morning Severity Score 
by Treatment Group Over Time - Safety Population 


 
Statistical Analysis Plan  
 
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Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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14.2.2 
Plot of Mean (± SE) Change from Baseline in sBA (umol/L) by Treatment Group Over Time - Safety 
Population 
14.2.3 
Plot of Mean (± SE) Change from Baseline in ALP (U/L) by Treatment Group Over Time - Safety 
Population 
14.2.4 
Plot of Mean (± SE) Change from Baseline in ALT (U/L) by Treatment Group Over Time - Safety 
Population 
14.2.4.1       Plot of Mean (± SE) Change from Baseline in AST (U/L) by Treatment Group Over Time - Safety 
Population 
14.2.5 
Plot of Mean (± SE) Change from Baseline in GGT (U/L) by Treatment Group Over Time - Safety 
Population 
14.2.6 
Plot of Mean (± SE) Change from Baseline in Total Bilirubin (mg/dL) by Treatment Group Over Time - 
Safety Population 
14.2.7 
Plot of Mean (± SE) Change from Baseline in Direct Bilirubin (mg/dL) by Treatment Group Over Time 
- Safety Population (footnote about the cap at 10 mg/dL of direct Bilirubin) 
14.2.8 
Plot of Mean (± SE) Change from Baseline in C4 (ng/mL) by Treatment Group Over Time - Safety 
Population 
14.2.9 
Plot of Mean (± SE) Change from Baseline in Total Cholesterol (mg/dL) by Treatment Group Over 
Time - Safety Population 
14.2.10 
Plot of Mean (± SE) Change from Baseline in LDL-C (mg/dL) by Treatment Group Over Time - Safety 
Population 
14.2.11 
Plot of Mean (± SE) Change from Baseline in Height z-Score by Treatment Group Over Time - Safety 
Population 
14.2.12 
Plot of Mean (± SE) Change from Baseline in Weight z-Score by Treatment Group Over Time - Safety 
Population 
14.2.13 
Plot of Mean (± SE) Change from Baseline in PedsQL Total Score (Parent) by Treatment Group Over 
Time - Safety Population 
14.2.14 
Plot of Mean (± SE) Change from Baseline in PedsQL Multidimensional Fatigue Scale Score (Parent)  
by Treatment Group Over Time - Safety Population 
14.3.1  Display of Study Drug Exposure 
14.3.1 
Study Drug Exposure Over Time by Subject – Safety Population 
14.3.2  Displays of Adverse Events 
14.3.2 
Plot of Treatment-Emergent Adverse Events of Special Interest Over Time by Preferred Term and 
Individual Subject – Safety Population 


 
Statistical Analysis Plan  
 
Sponsor Mirum Pharmaceuticals, Inc.  
 
Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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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. 


 
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Protocol Number LUM001-303  
 
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Appendix 1: Premier Research Library of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse events of special interest 
ALGS 
alagille syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
Aspartate aminotransferase 
ASA 
American statistical association 
ASBTi 
apical sodium dependent bile acid transporter inhibitor 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
BID 
twice-a-day dosing regimen 
BMI 
body mass index 
BP 
blood pressure 
C4 
7-alpha-hydroxy-4-cholesten-3-one 
CDC 
centers for disease control 
ChiLDReN 
Childhood Liver Disease Research Network 
CI 
confidence interval 
CIC 
caregiver impression of change 


 
Statistical Analysis Plan  
 
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Abbreviation 
Definition 
CRF 
case report form 
CSR 
clinical study report 
CSS 
clinician scratch score 
CTCAE 
common terminology criteria for adverse events 
DMC 
data monitoring committee 
eDiary 
electronic diary 
EMA 
European medicines agency 
EOT 
end of treatment 
ET 
early termination 
FDA 
food and drug administration 
FGF-19 
fibroblast growth factor 19 
FGF-21 
fibroblast growth factor 21 
FSV 
fat-soluble vitamin 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
HR 
heart rate 
HRQoL 
health-related quality of life 
IA 
interim analysis 
ICH 
international council for harmonization  


 
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Abbreviation 
Definition 
ID 
identification 
ItchRO 
itch reported outcome 
LLOQ 
lower limit of quantification 
LOCF 
last-observation-carried-forward 
MedDRA 
medical dictionary for regulatory activities 
MRX 
maralixibat 
NDA 
new drug application 
PBO 
placebo 
PedsQL 
pediatric quality of life 
PT 
preferred term 
RBP 
retinol binding protein 
RSS 
royal statistical society 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acid 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
SOP 
standard operating procedure 


 
Statistical Analysis Plan  
 
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Protocol Number LUM001-303  
 
PCN Number LUME2941 
 
 
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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
ULOQ 
upper limit of quantification 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


 
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Protocol Number LUM001-303  
 
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Appendix 2: Listing of Safety and Efficacy Laboratory Analytes 
 
 
 
 
 
 
 


 
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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  
 
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- 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  
 
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- international normalised ratio increased 
- international normalised ratio abnormal 
- haemorrhage 
- melaena                        
- epistaxis 
- haematochezia 
- haemoptysis