Clinical trial NCT04674761
Conditions: Alagille Syndrome
Keywords: ALGS Alagille syndrome
Sponsor: Albireo
Start date: 2021-03-19; Completion date: 2022-09-09
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Double-blind, randomized, placebo-controlled, Phase 3 study to investigate the efficacy and safety of odevixibat compared to placebo in Patients with Alagille Syndrome.

Detailed description:
Approximately 35 sites will be initiated for this study in North America, Europe, Middle East, and Asia Pacific.

Arms: arm 1: Capsules for oral administration once daily for 24 weeks. arm 2: Capsules for oral administration (to match active) once daily for 24 weeks.
Interventions: intervention 1: Odevixibat intervention 2: Placebo
Intervention descriptions: intervention 1: Odevixibat is a small molecule and selective inhibitor of IBAT. intervention 2: Placebo identical in appearance to experimental drug (odevixibat).

Protocol documents:
Prot_000.pdf: 
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SAP_001.pdf: 
Confidential Property of Albireo
This document is a confidential communication of Albireo. Acceptance of this document constitutes the agreement by the 
recipient that no information contained herein will be published or disclosed without written authorization from Albireo.
Page 1 of 73
Statistical Analysis Plan
Protocol title:
A Phase 3 Double-blind, Randomized, Placebo-controlled 
Study of the Safety and Efficacy of Odevixibat (A4250) in 
Patients with Alagille Syndrome (ASSERT)
Protocol number:
A4250-012
Protocol Version/Date:
V2.0 / 28August 2020
IND Number:
145988
Study phase:
Phase 3
Date of issue:
27 Sep 2022
EudraCT number
2020-004011-28


Statistical A nal ysis Pla n
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Si g n at ure P a ge
Statisticia n, Bi ostatistics
[ Date]
Fir ma Cli nical Researc h
Se ni or Direct or, Bi ostatistics   
  [ Date]
Al bire o P har ma, I nc 
Me dical Direct or    
             [ Date]
Al bire o P har ma, I nc 
P P D
P P D
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Statistical Analysis Plan  
 
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Product Code-Study NumberA4250-012 
 
27Sep2022 
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Table of Contents 
 
STATISTICAL ANALYSIS PLAN ............................................................................................... 1 
SIGNATURE PAGE ....................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES ........................................................................................................................... 6 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
VERSION HISTORY ................................................................................................................... 10 
1 
INTRODUCTION ........................................................................................................... 12 
1.1 
STUDY DESIGN .............................................................................................................. 12 
1.2 
OBJECTIVE AND ENDPOINTS ..................................................................................... 13 
1.3 
ESTIMANDS .................................................................................................................... 15 
2 
SAMPLE SIZE DETERMINATION ............................................................................ 18 
2.1 
SAMPLE SIZE AND POWER ......................................................................................... 18 
2.2 
BLINDED SAMPLE SIZE RE-ESTIMATION ............................................................... 18 
3 
ANALYSIS POPULATIONS ......................................................................................... 20 
4 
STATISTICAL ANALYSES .......................................................................................... 21 
4.1 
GENERAL CONSIDERATIONS ..................................................................................... 21 
4.2 
PATIENT DISPOSITIONS .............................................................................................. 22 
4.3 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS ................................................................................. 23 
4.4 
EXTENT OF EXPOSURE ................................................................................................ 24 
4.5 
PRIMARY ENDPOINT ANALYSIS ............................................................................... 25 
4.5.1 
Definition of Endpoint ...................................................................................................... 25 
4.5.2 
Estimand ............................................................................................................................ 25 
4.5.2.1 Main Analysis ................................................................................................................... 26 
4.5.2.2 Sensitivity Analyses .......................................................................................................... 26 
4.5.2.3 Supplementary Analyses ................................................................................................... 29 
4.5.3 
Subgroup Analyses ............................................................................................................ 29 


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4.6 
SECONDARY ENDPOINTS ANALYSIS ...................................................................... 29 
4.6.1 
Definition of Key Secondary Endpoint ............................................................................. 29 
4.6.2 
Estimand ............................................................................................................................ 29 
4.6.2.1 Main Analysis ................................................................................................................... 30 
4.6.2.2 Sensitivity Analysis ........................................................................................................... 30 
4.6.2.3 Supplementary Analysis .................................................................................................... 30 
4.6.3 
Subgroup Analyses ............................................................................................................ 31 
4.6.4 
Other Secondary Endpoints ............................................................................................... 31 
4.6.4.1 Continuous Endpoints ....................................................................................................... 32 
4.6.4.2 Categorical Endpoints ....................................................................................................... 32 
4.6.4.3 Biomarkers ........................................................................................................................ 33 
4.6.4.4 Exit Interview .................................................................................................................... 33 
4.7 
MULTIPLICITY ADJUSTMENT FOR PRIMARY AND KEY SECONDARY 
ENDPOINTS ..................................................................................................................... 34 
4.8 
SAFETY ANALYSES ...................................................................................................... 34 
4.8.1 
Adverse Events .................................................................................................................. 34 
4.8.2 
Additional Safety Assessments ......................................................................................... 39 
4.8.2.1 Laboratory Variables ......................................................................................................... 39 
4.8.2.2 Vital Signs ......................................................................................................................... 41 
4.9 
OTHER ANALYSES ........................................................................................................ 41 
4.9.1 
Pharmacokinetics (PK) Analyses ...................................................................................... 41 
4.9.2 
Blinded Analysis ............................................................................................................... 41 
4.9.2.1 Pruritus Responder Definitions ......................................................................................... 41 
5 
SUPPORTING DOCUMENTATION ........................................................................... 43 
5.1 
APPENDIX 1 CHANGES TO PROTOCOL-PLANNED ANALYSES .......................... 43 
5.2 
APPENDIX 2 DERIVED VARIABLES .......................................................................... 44 
5.3 
APPENDIX 3 DATA HANDLING CONVENTIONS .................................................... 47 
5.4 
APPENDIX 4 DEFINITION OF REGION VARIABLE ................................................. 49 
5.5 
APPENDIX 5 HANDLING OF MISSING OR INCOMPLETE DATES ........................ 50 
5.6 
APPENDIX 6 SAMPLE SAS CODES ............................................................................. 51 
5.7 
APPENDIX 7 NORMAL REFERENCE RANGES FOR VITAL SIGNS [9] ................. 53 
5.8 
APPENDIX 8 SI AND US CONVENTIONAL UNITS OF CLINICAL 
LABORATORY VALUES ............................................................................................... 54 


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5.9 
APPENDIX 9 CLASSIFICATION OF HEPATIC FUNCTION ..................................... 55 
5.10 
APPENDIX 10 PT TERMS OF POSSIBLE SEQUELAE OF FSV DEFICIENCY ........ 56 
6 
REFERENCES ................................................................................................................ 73 
 


Statistical Analysis Plan  
 
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List of Tables  
Table 1 - Major changes in statistical analysis plan ........................................................................ 10 
Table 2 - Objectives and endpoints ................................................................................................. 13 
Table 3 - Summary of estimands for the primary and the key secondary efficacy endpoints ........ 16 
Table 4 – Blinded sample size re-estimation ................................................................................... 19 
Table 5 - Populations for analyses................................................................................................... 20 
Table 6 – Selections for AEIs .......................................................................................................... 35 
Table 7 – Liver monitoring.............................................................................................................. 40 
Table 8 - Major statistical changes in protocol amendment(s)........................................................ 43 
Table 9 – Derivation rules for the derived variable ......................................................................... 44 
Table 10.1 - Analysis visit windows (general) ................................................................................ 47 
Table 10.2 - Analysis visit windows (GIC/GIS, PedsQL, xanthoma and selected lab tests) .......... 47 
Table 10.3 - Analysis visit windows (abdominal ultrasound and elastography, AFP) ................... 48 
Table 10.4 - Analysis visit windows for scratching score (or itching score), sleep parameters ..... 48 
Table 11 – Country code and region ............................................................................................... 49 
Table 12.1 - Heart rate by age (beats/minute) reference ................................................................. 53 
Table 12.2 - Normal respiratory rate by age (breaths/minute) reference ........................................ 53 
Table 12.3 - Normal blood pressure by age (mm Hg) reference ..................................................... 53 


Statistical Analysis Plan  
 
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List of Abbreviations 
The following abbreviations will be used within this SAP 
Abbreviation or Special Terms 
Explanation 
AE(s) 
Adverse Event(S) 
AFP 
Alfa-fetoprotein 
AEIs 
Adverse Events of  Interest 
ALGS 
Alagille Syndrome 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ANCOVA 
Analysis of Covariance 
AR(1) 
First-Order Autoregressive 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
BMI 
Body Mass Index 
CaGIC 
Caregiver Global Impression of Change 
CaGIS 
Caregiver Gobal Impression of Symptom 
CDC 
Centers for Disease Control and Prevention 
CGIC 
Clinical Global Impression of Change 
CGIS 
Clinical Global Impression of Symptom 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization  
CS 
Compound Symmetry  
CSR 
Clinical Study Report  
DILI 
Drug-Induced Liver Injury 
DSMB 
Data and Safety Monitoring Board 
EAIR 
Exposure Adjusted Incidence Rate 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of Treatment 
EOS 
End of Study 
EU 
European Region  
FAS 
Full Analysis Set  
FDA 
United States Food and Drug Administration 
FSV 
Fat-Soluble Vitamin  
GIC  
Global Impression of Change  


Statistical Analysis Plan  
 
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Abbreviation or Special Terms 
Explanation 
GIS 
Global Impression of Symptoms 
GGT 
Gamma-Glutamyl Transferase  
HTN 
Hypertension 
HSAC 
Hepatic Safety Adjudication Committee  
ICE 
Intercurrent Event 
ICF  
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDMS 
Isotope Dilution Mass Spectrometry 
INR  
International Normalized Ratio  
IWRS  
Interactive Web Response System  
LFT  
Liver Function Test  
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo  
MedDRA  
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of Diet in Renal Disease 
MH 
Medical History 
MI 
Multiple Imputation  
MMRM  
Mixed-Effect Model for Repeated Measures 
MNAR 
Missing Not at Random 
ObsRO  
Observer Reported Outcome  
p-C4  
3ODVPD Į-Hydroxy-4-Cholesten-3-One Concentration  
PedsQL  
Pediatric Quality of Life Inventory  
PFIC 
Progressive Familial Intrahepatic Cholestasis 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Symptoms 
PK 
Pharmacokinetics  
PP  
Per Protocol  
PRO  
Patient Reported Outcome  
PT 
Preferred Term 
RoW  
Rest of World  
SAE(s)  
Serious Adverse Event(s)  
SAP  
Statistical Analysis Plan  
SAF  
Safety Analysis Set  
SAS  
Statistical Analysis System  
SD  
Standard Deviation  
SI 
International System of Unit 
SMQs 
Standardised MedDRA Queries 


Statistical Analysis Plan  
 
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Abbreviation or Special Terms 
Explanation 
SOC 
System Organ Class  
SSR 
Sample Size Re-estimation 
TEAE(s)  
Treatment Emergent Adverse Event(s)  
TFLs 
Tables, Figures and Listings 
UDCA 
Ursodeoxycholic Acid 
ULN  
Upper Limit of Normal  
UN 
Unstructured Covariance Matrix  
US  
United States  
WHO 
World Health Organization 
WHO-DD 
World Health Organization-Drug Dictionary 
  


Statistical Analysis Plan  
 
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Product Code-Study NumberA4250-012 
 
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Version History 
This statistical analysis plan (SAP) for Study A4250-012 is based on protocol version 2.0 dated 28-
Aug-2020. This section summarizes major changes to the statistical analysis features in the SAP. 
This SAP will be approved before the database lock. 
Table 1 - Major changes in statistical analysis plan 
SAP 
Version 
Approval 
Date 
Change 
Rationale 
1.0 
14Oct2021 
NA 
Original version 
2.0 
27Sep2022 
Section 2.1, Section 3 table 5, Section 4.1, 
Section 4.2, Section 4.7 (in SAP version 1.0) 
and Section 4.8: Remove analyses for 
exploratory cohort (18 years old) 
 
There were no subjects enrolled in the 
exploratory cohort. 
Section 1.3 Table 3 and Section 4.5.2: Update 
primary estimand and secondary estimand. 
Keep one estimand with two strategies for 
addressing different intercurrent events. 
Incorporate the comments from the 
FDA’s Meeting Request – Written 
Responses question 2(a) - 2(c), dated 
09MAR2022.  
 
 
Section 1.3 Table 3 and Section 4.5.2: remove 
“Change in anti-pruritus medication 
exceeding a specified duration or dose” as an 
ICE event and add rationale in section 4.5.2. 
Incorporate the comments from the 
FDA’s Meeting Request – Written 
Responses question 2(d), dated 
09MAR2022.  
 
 
Section 1.3 Table 3 and Section 4.5.2.2.5: 
Add a sensitivity analysis for the primary 
endpoint utilizing the 28-day baseline data for 
the patients for whom it is available. 
Incorporate the comments from the 
FDA’s Meeting Request – Written 
Responses question 2(e), dated 
09MAR2022.  
 
 
Section 1.3 Table 3 and Section 4.5.2.2.6: 
Add a sensitivity analysis evaluating 
scratching at Month 6 (Weeks 21 to 24) 
adjusting for baseline scratching in the 
analysis. 
Incorporate the comments from the 
FDA’s Meeting Request – Written 
Responses question 2(f), dated 
09MAR2022.  
 
 
Section 4.5.2.2.1: For the multiple imputation 
(MI) sensitivity analysis assuming data is 
missing not at random (MNAR), update to 
Control-based MI by imputing missing data 
after all types of treatment discontinuations 
based on the outcomes of the placebo patients. 
Incorporate the comments from the 
FDA’s Meeting Request – Written 
Response to Question 2(g), dated 
09MAR2022.  
 
 
Section 4.5.2.2.1 and Section 5.6: Provide 
details and the sample SAS codes for control-
based imputation including “Only imputed 
values within the range of 0 to 4 will be used.”  
Incorporate the comments from the 
FDA’s Meeting Request – Written 
Response to Question 2(h), dated 
09MAR2022.  
 
 
Section 4.5.2.2.2: Add details on the tipping 
point analysis. 
Incorporate the comments from the 
FDA’s Meeting Request – Written 
Response to Question 2(h), dated 
09MAR2022.  


Statistical A nal ysis Pla n  
 
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Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2 
 
2 7 Se p 2 0 2 2 
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S A P 
Versi o n 
A p pr o v al 
D ate
 C h a n ge
  
R ati o n ale
 
 
  
Secti o n 4. 5. 2. 1 a n d Secti o n 5. 6: A d d a 
s u p p orti ve a nal ysis a n d a sa m ple S A S c o de t o 
esti mate t he a vera ge treat me nt effect at M o nt h 
4 t o 6 usi n g t he sa me mi xe d-effect m o del f or 
re peate d meas ures ( M M R M) t hat is pr o p ose d 
f or t he c urre nt pri mar y e n d p oi nt. 
I nc or p orate t he c o m me nts fr o m t he 
F D A’s Meeti n g Re q uest – Writte n 
Res p o nse t o Q uesti o n 4, date d 
0 9 M A R 2 0 2 2.   
 
  
A ge calc ulati o n i n Ta ble 9: 
Clar ificati o n o n t he calc ulati o n of a ge 
d ue t o t he data c ollecti o n f or site 
. 
 
  
Secti o n 4. 5. 3 a n d Secti o n 4. 6. 3: Re m o ve t he 
a ge stratificati o n a n d baseli ne direct bilir u bi n 
fr o m t he m o deli n g f or s u b gr o u p. 
D ue t o t he s mall sa m ple size of t he 
st u d y. 
 
  
Ta ble 5 a n d secti o n of pr ot oc ol de viati o ns.  
Clarificati o n o n t he defi niti o ns of per 
pr ot oc ol a nal ysis set ( P P S) a n d 
i m p orta nt pr ot oc ol de viati o n. 
 
  
Secti o n 4. 4: u p date t he f or m ula f or a vera ge 
dail y d ose  
 
C orrect t he a vera ge dail y d ose 
( u g/ k g/ da y) b y di vi di n g t he wei g ht i n 
t he f or m ula.  
 
 
Secti o n 4. 4: m o dif y t he f or m ula f or treat me nt 
c o m plia nce rate. 
C o nsi deri n g t he d ose i nterr u pti o n as 
n o n-c o m plia nce  
 
  
W orst wee kl y sc ore i n Ta ble 9: a d di n g 
baseli ne defi niti o n as t he first d ose date t o 1 4 
da ys pri or t o t he first d ose date a n d t his is t he 
baseli ne defi niti o n f or t he a nal ysis pr o p ose d 
i n t he S A P.  
T o be c o nsiste nt wit h t he baseli ne 
defi niti o n f or m o nt hl y scratc hi n g 
sc ore.  
 
 
  
Secti o n 4. 6. 4. 2: a d d cli nicall y mea ni n gf ul 
t hres h ol d f or pr urit us res p o n der a nal ysis.  
Res ults fr o m bli n de d ps yc h o metric 
a nal ysis. 
 
  
Ta ble 6: u p date defi niti o n of A EIs 
I nc or p orate t he c om me nts fr o m t he 
F D A’s Meeti n g Re q uest – ‘ A d diti o nal 
C o m me nts’, date d 0 9 M A R 2 0 2 2.   
C CI


Statistical Analysis Plan  
 
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1 
Introduction 
The purpose of this SAP is to provide detailed descriptions of the statistical methods, data 
derivations, and data displays for study protocol A4250-012 “A Phase 3 Double-blind, Randomized, 
Placebo-controlled Study of the Safety and Efficacy of Odevixibat (A4250) in Patients with Alagille 
Syndrome (ASSERT)”. The table of contents and templates for the Tables, Figures and Listings 
(TFLs) will be produced in a separate document.  
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been based on ICH E3, E9 and E9(R1) guidelines [1, 2, 3]. All 
data analyses and generation of TFLs will be performed using SAS® version 9.4 or higher. The 
SAP will be finalized and signed off prior to locking the database and unblinding. 
1.1 
Study Design 
This is a phase 3, double-blind, randomized, placebo-controlled study to investigate the efficacy 
and safety of 120 g/kg/day odevixibat compared to placebo in patients with Alagille syndrome 
(ALGS).  
Figure 1 – Study Design 
 
The study includes a screening period of up to 56 days, followed by a 24-week treatment period, 
and a Safety Follow-up Period. Eligible patients will be randomized 2:1 to receive odevixibat 120 
g/kg/day or placebo. An Interactive Web Response System (IWRS) will be used to assign patients 
to treatment. The randomization codes were computer generated by a qualified randomization 
vendor. An experimental cohort of approximately 45 patients <18 years of age at randomization 
with a genetically confirmed diagnosis of ALGS will be enrolled. Patients <18 years of age will be 
randomized according to an age stratification factor, i.e., <10, and 10 to <18 years of age. The 
protocol included an additional exploratory cohort of patienWV  \HDUV RI DJH ZLWK a genetically 
confirmed diagnosis of ALGS, not to exceed 18 patients in total, who were also to be randomized 
2:1 favoring active treatment. A separate randomization scheme was provided for this cohort. 
There were no subjects enrolled in this cohort at the time enrollment completed for the study. 


Statistical Analysis Plan  
 
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Patients who complete the Week 24/EOT visit in this study will be invited to participate in an 
open-label extension study in which all patients will receive active treatment. Patients who enroll 
in the open-label extension study will not participate in the Safety Follow-up Period. 
There will be two treatment groups in this study, odevixibat 120 g/kg/day and placebo. 
Odevixibat and placebo will be supplied as capsules for oral administration. The number of 
capsules provided to the patient will be based on body weight at randomization (Study Day 1) and 
can be adjusted depending on the patient’s weight (Protocol Table 2) at each study visit.  
1.2 
Objective and Endpoints 
The primary, key secondary, and secondary efficacy objectives, and safety objectives and 
endpoints are listed in Table 2.  
Table 2 - Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
Efficacy  
 
 
 
x 
To demonstrate the efficacy of 
repeated daily doses of 120 g/kg/day 
odevixibat in relieving pruritus in 
patients with ALGS 
x 
Change from baseline in scratching score to 
Month 6 (Weeks 21 to 24) as measured by 
the Albireo Observer reported outcome 
(ObsRO) caregiver instrument 
Key Secondary 
Efficacy 
 
 
 
x 
To assess the impact of odevixibat on 
serum bile acid levels in patients with 
ALGS 
x 
Change in serum bile acid levels from 
baseline to the average of Week 20 and Week 
24 
Secondary 
Efficacy 
 
 
 
 
x 
Change from baseline in pruritus score to 
Month 6 (Weeks 21 to 24) as measured by 
the Albireo Patient reported outcome (PRO) 
instrument 
 
 
x 
Percentage of patients achieving a clinically 
meaningful decrease in pruritus (pruritus 
responders) as measured by the Albireo 
ObsRO/PRO instruments 
 
 
x 
Change from baseline through Week 24 in 
patient reported and observer reported itching 
and scratching severity scores, respectively, 
for the morning assessment and for the 
evening assessment. These endpoints will be 
assessed combining age groups, and by age 
group, 0 to <8, 8 to <12, and 12 to <18 
 
 
x 
Change from baseline to Week 24 in sleep 
parameters as measured with the Albireo 
ObsRO/PRO instruments (e.g., tiredness and 
number of awakenings) 


Statistical Analysis Plan  
 
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Objectives 
Endpoints 
 
 
x 
Change from baseline to Week 24 in 
Pediatric Quality of Life Inventory (PedsQL) 
subdomain scores 
 
 
x 
Assessment of Global Symptom Relief from 
baseline to Weeks 4, 12, and 24 as measured 
by patient, caregiver, and clinician Global 
Impression of Symptoms (GIS) (PGIS, 
CaGIS, CGIS) items 
 
 
x 
Assessment of Global Symptom Relief as 
measured by patient, caregiver, and clinician 
Global Impression of Change (GIC) (PGIC, 
CaGIC, CGIC) items at Weeks 4, 12, and 24 
 
 
x 
Patient impression of treatment effect as 
recorded during exit interviews at Week 24 
 
 
x 
Change from baseline to Week 24 in 
xanthomatosis as assessed by the Clinician 
Xanthoma Scale 
 
 
x 
Change in serum bile acid levels from 
baseline through Week 24 
 
 
x 
Change from baseline to Week 24 in serum 
alanine aminotransferase (ALT) 
concentration 
 
 
x 
Change from baseline to Week 24 in serum 
aspartate aminotransferase (AST) 
concentration 
 
 
x 
Change from baseline to Week 24 in gamma-
glutamyl transferase concentration 
 
 
x 
Change from baseline to Week 24 in total 
bilirubin concentration 
 
 
x 
Change from baseline in biochemical 
markers and measures of bile acid synthesis 
DXWRWD[LQ 3ODVPD Į-hydroxy-4-cholesten-
3-one concentration (p-C4)) 
 
 
x 
Change from baseline in total cholesterol 
concentration 
Safety 
 
 
 
x 
To evaluate the safety and tolerability 
of odevixibat in patients with ALGS 
x 
Occurrence of treatment emergent adverse 
events (TEAEs) including severity and 
relatedness to study drug at all visits  
 
 
x 
The incidence of treatment emergent serious 
adverse events (SAEs), based upon 
information from patient reports, including 
the description, incidence, and severity of an 
SAE 
 
 
x 
Trends evaluated for the following 
assessments: physical examinations, 
concomitant medications, vital signs, 
laboratory test results (including clinical 
chemistry, hematology, urinalysis, alfa-
fetoprotein, vitamins A and E, 25-hydroxy 


Statistical Analysis Plan  
 
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Objectives 
Endpoints 
vitamin D and International Normalized 
Ratio [INR]) 
1.3 
Estimands 
Estimand attributes and analyses for the primary efficacy endpoint and the key secondary efficacy 
endpoint are summarized in Table 3. More details are provided in Section 4. 


Statistical Analysis Plan 
 
 
 
 
 
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Table 3 - Summary of estimands for the primary and the key secondary efficacy endpoints 
ENDPOINT 
CATEGORY 
(ESTIMAND) 
ESTIMAND  
ANALYSIS  
AND  
MSSING DATA HANDLING 
VARIABLE 
POPULATION 
POPULATION-
LEVEL SUMMARY 
INTERCURREN
T EVENT (ICE) 
STRATEGY FOR 
ADDRESSING 
ICE 
Primary objective: To demonstrate the efficacy of repeated daily doses of 120 μg/kg/day odevixibat in relieving pruritus in patients <18 years of with ALGS. 
Primary  
efficacy endpoint 
(Estimand) 
Change from 
baseline in 
average AM and 
PM scratching 
score to Month 6  
(Weeks 21 to 24)  
FAS 
The difference 
between treatment 
with odevixibat and 
placebo in mean 
change in scratching 
score from baseline to 
Month 6 (Weeks 21 to 
24)  
Premature 
discontinuation of 
study drug 
treatment prior to 
Week 24  
Treatment Policy 
(include data after 
ICE) 
Main analysis (PRIMARY ANALYSIS):  
A MMRM modelling change from baseline 
for each four-week average AM and PM 
scratching score, with baseline age 
stratification, baseline average AM and PM 
scratching score, baseline direct bilirubin, 
treatment group, time (in months), and 
treatment-by-time interaction in the model. No 
imputation is implemented. (section 4.5.2.1) 
Sensitivity analysis 1: 
MMRM with control-based multiple 
imputation (MI)  (section 4.5.2.2.1) 
Sensitivity analysis 2: 
Tipping point analysis (section 4.5.2.2.2) 
Sensitivity analysis 3: 
MMRM based on worst weekly scratching 
score for a month (section 4.5.2.2.3) 
Sensitivity analysis 4: 
MMRM based on worst weekly scratching 
score for a month with control-based MI  
(section 4.5.2.2.4) 
Sensitivity analysis 5: 
MMRM for the endpoint with the baseline 
pruritus score calculated based on 28 days 
prior to first dose date. (section 4.5.2.2.5) 
Sensitivity analysis 6: 
MMRM for the scratching score 
Undergoes biliary 
diversion surgery 
or liver transplant 
Hypothetical 
(exclude data after 
ICE) 
 
 


Statistical Analysis Plan 
 
 
 
 
 
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ENDPOINT 
CATEGORY 
(ESTIMAND) 
ESTIMAND  
ANALYSIS  
AND  
MSSING DATA HANDLING 
VARIABLE 
POPULATION 
POPULATION-
LEVEL SUMMARY 
INTERCURREN
T EVENT (ICE) 
STRATEGY FOR 
ADDRESSING 
ICE 
at Month 6 (Weeks 21 to 24) adjusting for 
baseline scratching in the analysis. (section 
4.5.2.2.6) 
Supplementary analysis: 
The same MMRM utilized for the main 
analysis will also be used for the PP analysis 
set (section 4.5.2.3) 
Key secondary objective: To assess the impact of odevixibat on serum bile acid levels in patients <18 years of age with ALGS. 
Key secondary 
efficacy endpoint: 
(Estimand) 
Change in serum 
bile acid levels 
from baseline to 
the average of 
Week 20 and 
Week 24  
FAS 
The difference 
between treatment 
with odevixibat and 
placebo in mean 
change in serum bile 
acid levels from 
baseline to the average 
of Week 20 and Week 
24  
Premature 
discontinuation of 
study drug 
treatment prior to 
Week 24  
Treatment Policy 
Main analysis (PRIMARY ANALYSIS):  
The MMRM utilized for the primary efficacy 
endpoint will also be used for assessment of 
the key secondary endpoint (section 4.6.2.1)  
Sensitivity analysis 1: 
MMRM with control-based MI  (section 
4.6.2.2.1) 
Sensitivity analysis 2: 
Tipping point analysis (section 4.6.2.2.2) 
Supplementary analysis 1: 
Rank transform analysis of covariance 
(ANCOVA) (section 4.6.2.3.1) 
Supplementary analysis 2:  
The same MMRM utilized for the main 
analysis will also be used for the PP analysis 
set (section 4.6.2.3.2) 
 
Undergoes biliary 
diversion surgery 
liver transplant 
Hypothetical 
 
 


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 1 8 of 7 3 
 
2  
S a m ple Size Deter mi n ati o n 
2. 1  
S a m ple Size a n d P o wer 
F ort y-fi ve ( 4 5) patie nts < 1 8 years of a ge were ra n d o mize d at  a n e x peri me ntal-t o-c o ntr ol 
all ocati o n of 2 t o 1 i n or der t o o btai n a p pr o xi matel y 3 6 c o m pleters, ass u mi n g a n a p pr o xi mate 
dr o p- o ut rate of 2 0 %. At a 1-si de d si g nifica nce le vel of al p ha 1-si de d = 0. 0 2 5, ass u mi n g a p o ole d 
sta n dar d de viati o n ( S D) of 1. 0, a n d a differe nce bet wee n t he treat me nt gr o u ps of 1. 2 i n mea n 
c ha n ge i n pr urit us sc ore fr o m base li ne t o M o nt h 6 fa v ori n g t he e x peri me ntal ar m, t he p o wer of t he 
st u d y is 0. 9 0 9, usi n g t he e xact met h o d ( Pr oc P ower, S A S v. 9. 4, Car y, N C). T he ke y sec o n dar y 
e n d p oi nt is als o p o were d f or a st a n dar dize d treat me nt effect (t reat me nt effect/ S D) of 1. 2. 
2. 2  
Bli n de d S a m ple Size Re- Esti m ati o n 
Bli n de d sa m ple size re-es ti mati o n ( S S R) is classifie d as a well- u n derst o o d a da pti ve feat ure i n t he 
F D A g ui da nce [ 4] beca use it d oes n ot i n v ol ve treat me nt u n bli n di n g a n d ca n be c o n d ucte d wit h o ut 
w orr yi n g a b o ut i ntr o d uci n g bias  i nt o a trial. T his o ne-sa m ple varia nce S S R met h o d [ 5] is base d o n 
n o n-c o m parati ve bli n de d data f or w hic h n o al p ha a dj ust me nt is re q uire d. If t he p o ole d S D was 
o veresti mate d i n t he ori gi nal sa m p le size calc ulati o n, t he sa m ple size will n ot be de crease d. If t he 
p o ole d S D was u n deresti mate d i n t he ori gi nal sa m ple size calc ulati o n, t he sa m ple size will 
 
at a 
si g nifica nce le vel of al p ha 1-si de d = 0. 0 2 5, ass u mi n g t he sa me 1. 2 treat me nt difference i n mea n 
c ha n ge i n pr urit us sc ore fr o m baseli ne t o M o nt h 6 ( Wee k 2 1 t o 2 4) as t he ori gi nal sa m ple size 
calc ulati o n.  
After a mi ni m u m of 1 8 patie nts i n t he e x peri me ntal c o h ort ha ve c om plete d t he Wee k 1 6 visit, t he 
p o ole d S D of c ha n ge fr o m baseli ne t o M o nt h 4 ( Wee ks 1 3 t o 1 6 assess me nts) a n d a vaila ble 
c ha n ge fr o m baseli ne t o M o nt h 6 ( Wee k 2 1 t o 2 4 ) i n a vera ge m o nt hl y scratc hi n g sc ore will be 
calc ulate d b y a n i n de pe n de nt bli n de d statisticia n  fr o m C o ntract Researc h Or ga nizati o n ( C R O), 
Fir ma Cli nical. T he i n de pe n de nt bli n de d statisticia n will pr o vi de t he f oll o wi n g state me nt t o t he 
S p o ns or: “ T he o bser ve d p o ole d S D at Wee k 1 6 a n d Wee k 2 4 a vaila ble data is x. x x x. T his 
esti mate is base d o n x x s u bjects wit h n o n- missi n g o utc o me at Wee k 1 3 t o 1 6 a n d x x s u bjects wit h 
n o n- missi n g o utc o mes at Wee k 2 1 t o 2 4.” T he pr ocess of t he bli n de d S S R will be d oc u me nte d 
b y Fir ma Cli nical i n t he Bli n di n g a n d U n bli n di n g Pla n f or Pr ot oc ol A 4 2 5 0- 0 1 2 pri or t o perf or mi n g t he 
bli n de d S S R . 
 patie nts are e x pecte d t o c o m plete Visit Wee k 2 4 at t he ti me of t he bli n de d S S R. Base d o n 
scratc hi n g data fr o m St u d y A 4 2 5 0- 0 0 5 i n t he pr o gressi ve fa milial i ntra he patic c h olestasis ( P FI C) 
i n dicati o n, t he M o nt h 6 p o ole d S D fr o m t he  
 patie nts is ap pr o xi matel y  
 of t he p o ole d 
S D base d o n M o nt h 4 data fr o m t he  
 patie n ts a n d M o nt h 6 ( Wee k 2 1 t o 2 4) data fr o m t he 
 patie nts. T heref ore, a m ulti plicati o n fact or  
 is a p plie d w he n calc ulati n g t he sta n dar d 
effect size at Wee k 2 4 i n Ta ble 4 . T he S p o ns or will deter mi ne t he n u m ber of c o m pleters per t he 
sa m ple size calc ulati o n liste d i n Ta ble 4 . T he n u m ber of a d diti o nal patie nts t o be e nr olle d will be 
base d o n t he act ual dr o p o ut rate.  
C CI
C CI
C CI
C CI
C CI
C CI


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Table 4 – Blinded sample size re-estimation  
 
 
Observed Pooled SD at Week 16 &  
Week 24 available data 
Standard effect size at 
Week 24 
N 
Power 
 
 
36 
 
! WR  
 WR  
39 
 
! WR  
 WR  
42 
 
! WR  
 WR  
45 
 WR  
! WR  
 WR  
48 
 WR  
! WR  
 WR  
51 
 WR  
>1.25 to  
 WR  
54 
 WR  
>1.35 
<0.83 
54 
<0.80 
Assuming a significance level of alpha1-sided = 0.025 and 1.2 treatment difference in mean change in scratching 
score from baseline to Month 6 
N: Number of completers. 
 


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3 
Analysis Populations 
The following populations for analyses are defined:  
Table 5 - Populations for analyses 
Population 
Description 
Randomized 
All patients from the screened population who have been allocated to a 
randomized intervention by IWRS regardless of whether the intervention 
was received or not. 
 
 
Full Analysis Set (FAS) 
All randomized patients who received at least 1 dose of study drug 
treatment. Patients will be analyzed in the treatment group they were 
randomized to even if they received the incorrect study drug.  
The FAS will be utilized for efficacy analyses. 
 
 
Per Protocol Analysis Set (PPS) 
The PPS is a subset of the FAS and will consist of all randomized patients 
for whom no important protocol deviation (i.e., no major protocol deviation 
which may affect the study efficacy outcomes) is documented. In addition, 
patients meet following criteria will be excluded from PPS.   
x 
Overall treatment compliance is less than 70%  
x 
Treatment duration is less than 50% of the days with eDiary data 
collected during weeks 21 to 24 
The PPS will provide supportive data for the efficacy analyses. 
The algorithm for PPS will be defined and allocation of patients to the PPS 
will be performed before the database lock and un-blinding of the study. 
 
 
Safety Analysis Set (SAF) 
All patients who received at least 1 dose of study drug. Patients will be 
analyzed according to the treatment they actually received for the first dose. 
The SAF will be utilized for safety analyses. 
 
A listing for each analysis set will be provided. The reason for exclusion from PPS will be 
summarized by treatment groups and will be included in a listing.    
 
 


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4 
Statistical Analyses 
4.1 
General Considerations 
All personnel involved with the analysis of the study and the independent blinded statistician who 
performs the blinded SSR will remain blinded until database lock except the unblinded Data 
Safety Monitoring Board (DSMB) statistician/programmers from Firma who are independent 
from both the Firma study team and Albireo. All statistical procedures will be completed using 
SAS® version 9.4. 
In general, continuous data will be summarized using descriptive statistics, including the number 
of observations available (n), mean, SD, median, minimum, and maximum. The letter “n” will be 
presented without a decimal point. Minimum and maximum values will be presented to the same 
precision as in the database. Mean and median will be presented to 1 more decimal place than the 
minimum and maximum. SD will be presented to 1 more decimal place than the mean and 
median. 
Categorical and ordinal data will be summarized using the count (frequencies) and percentage of 
patients. Percentages will be rounded to 1 decimal place. Descriptive summaries of change from 
baseline in categorical variables will be provided using shift tables, as applicable. 
For summary purposes, if not otherwise specified, the baseline value of a parameter is defined as 
the last available assessment of that parameter prior to the first intake of study drug. Derived 
variables used for the analyses are provided in Appendix 2. All summaries will be presented by 
treatment group, unless otherwise specified.  
For summary tables, if not otherwise specified, the following 2 presentations will be used: 
• For baseline related tables and protocol deviations: by treatment group (odevixibat and 
placebo) and overall (2 treatment groups combined) will be presented.  
• For the safety and efficacy related tables: by treatment group (odevixibat and placebo) will be 
presented. 
The analysis window details for the derivation of study weeks are outlined in Appendix 3.  
Age is the stratification factor for the study. Since the purpose of stratification in the 
randomization is to balance the treatments in each stratum and following the intend-to-treat 
principle, for any analysis based on the FAS where strata is used for covariate adjustment of the 
modeling (with the exception of subgroup analyses), the strata of age that is recorded in the 
randomization system (IWRS) will be used. For all other analyses based on the FAS and all 
subgroup analyses, the actual age will be used to categorize the age groups.  
Selected patient data, including derived data, will be presented in individual patient data listings. 
All listings will be sorted by treatment group, patient number, date/time and visit. Each patient’s 
sex and age at randomization will be stated on each listing. Data listings will be based on all 
randomized patients. 


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4.2 
Patient Dispositions 
The number (%) of patients in the following categories will be provided:  
x Patients randomized 
x Patients dosed 
x Patients not dosed 
x Patients completing treatment 
x Patients discontinuing treatment early (including reason for discontinuation of treatment) 
x Patients completing Study A4250-012 
- 
Patients discontinuing treatment 
- 
Patients enrolled into Study A4250-015 
- 
Patient did not enroll into Study A4250-015 
x Patients withdrawing early from the study (including withdrawal reason) 
Additionally, patients enrolled, included in the SAF, in the FAS, and in the PP analysis set will be 
summarized by region (Appendix 4).  
Summary table for patients with premature discontinuation of study drug treatment, undergoing 
biliary diversion surgery and liver transplantation will be provided. 
Protocol deviations 
Important protocol deviations (IPD) will be identified by study team according to the criteria 
defined prior to database lock. IPDs will include following categories: 
x Failure to meet following inclusion or exclusion criteria  
o Inclusion criteria (2) Patient must have a history of significant pruritus and a 
caregiver reported observed scratching or a patient -reported pruritus score at an 
average of > 2 
o Inclusion criteria (3) Patient must have an elevated baseline serum bile acid level.  
x Non-compliance in study procedure 
o Missing pruritus score at month 6 due to insufficient eDiary data collected during 
weeks 21-24   
The number of patients with protocol deviations due to COVID-19 and number of protocol 
deviation due to COVID-19 will be summarized in the FAS.  
In addition, a listing will be provided with all protocol deviations identified based on data 
recorded on protocol deviation logs (on randomized patients) prior to database lock. 
 
 


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4.3 
Demographics and Baseline Characteristics, Prior or Concomitant Medications 
Demographics, baseline and disease characteristics  
The following demographics, baseline and disease characteristics, medical and surgical history 
will be summarized using descriptive statistics in the FAS. 
Demographic, baseline, and disease characteristics  
x Age in years as quantitative variable and Age in years as categorical variables (Age group 
1: 0 to <10, 10 to <18; Age group 2: 0 to <2, 2 to <12, 12 to <18) based on actual age.  
x Age group (0 to <10, 10 to <18) from IWRS for randomization 
x Gender (Male, Female) 
x Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific, Islander, White, Other, Not reported) 
x Race group (White, Non-White (including race as not reported)) 
x Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported) 
x Ethnicity group (Hispanic or Latino (including ethnicity as not reported), Not Hispanic or 
Latino) 
x Country and region (Appendix 4) 
x Use of ursodeoxycholic acid (UDCA) 
x Use of anti-pruritus medication 
x Baseline values: height (or length depending on age), weight as quantitative and 
FDWHJRULFDO  DQG ! NJ YDULDEOH, body mass index (BMI), Z-score (height, weight, 
and BMI), pruritus score (i.e., AM, PM, average AM and PM scratching score from 
ObsRO), serum bile acid as quantitative and categorical  median and < median based on 
overall randomization population) variable, estimated glomerular filtration rate (eGFR), 
ALT, AST, gamma-glutamyl transferase (GGT), total bilirubin, direct bilirubin as 
quantitative and categorical (>3 and 3 mg/dL), alkaline phosphatase (ALP), INR, 
cholesterol, triglycerides, vitamin A, vitamin E, and 25-hydroxy vitamin D. 
x Disease characteristics include  
x Genetic testing results for ALGS if performed at screening (e.g., mutation in JAG1 vs 
NOTCH2; per protocol, testing is only performed at screening if not available in the 
patient’s medical record), years since ALGS diagnosis 
x Child-Pugh classification (mild (Class A), moderate (Class B), or severe hepatic 
impairment (Class C)), and hepatic impairment classification (no impairment, mild, 
moderate, or severe) per NCI Organ Dysfunction Working Group [6]. Details of the 
classification are described in Appendix 9. 
eGFR will be calculated based on the modified/bedside Schwartz equation. The values of eGFR 
will be provided by the central laboratory vendor.  


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Listings will be created to present all the demographic, baseline, and disease characteristics for all 
randomized patients. 
Medical surgical history 
Medical and surgical history includes date of diagnosis of ALGS, prior medications for ALGS, 
historical (2 years prior to Screening) liver function test (LFT) values (AST, ALT, and total 
bilirubin), previous genetic testing for ALGS, and historical biopsy data.  
Medical and surgical history will be coded to a preferred term (PT) and associated primary 
System organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 25.0. The frequencies and percentages of patients with reported medical and surgical 
history will be presented by SOC and PT for the SAF. The summary table will be sorted 
alphabetically for SOC and PT. Medical and surgical history will also be listed. 
Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version March 2022.  
x Prior medications are any medications taken by the patient within 3 months prior to first 
intake of study drug that is recorded on the eCRF. Prior medications can be discontinued 
before the first intake of study drug or can be ongoing during the treatment period. 
x Concomitant medications are any medications received by the patient concomitantly on or 
after the first intake of study drug. 
Prior and concomitant medications will be summarized descriptively using frequency tables by 
Anatomical Therapeutic Chemical (ATC) and PT for the SAF. ATC class 4 and PT will be 
presented alphabetically. All prior and concomitant medications will be listed. Details for 
imputing missing or partial start and/or stop dates of non-study medications are described in 
Appendix 5. 
4.4 
Extent of Exposure 
The extent of exposure will be assessed by the duration of treatment exposure, average daily dose, 
and compliance. Exposure will be summarized with descriptive statistics (n, mean, median, SD, 
minimum, and maximum) and presented using the SAF. In addition, duration of treatment 
exposure will be summarized categorically: <= 4 weeks, >4 – <= 8 weeks, >8 – <= 12 weeks, >12 
– <= 16 weeks, >16 – <= 20 weeks, >20 – <= 24 weeks, and >24 weeks. 
Duration of exposure (in weeks) = (Date of last study drug intake – Date of first study drug intake 
+ 1)/7. Investigators are allowed to interrupt the study drug to allow adverse events to resolve, if 
necessary. Any drug interruption will not be considered when calculating the treatment duration. 
Average daily dose (ug/kg/day) = Sum of (number of capsules taken per day* dose strength of the 
capsules per weight category * dose duration under this dose amount/weight) / (Date of last study 
drug intake – Date of first study drug intake + 1). Intake dose and the corresponding dose duration 
is collected on the dosing administration page of the eCRF.    


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Treatment Compliance = 100 × sum of (number of capsules actually taken) / sum of (number of 
capsules planned to be taken per day * dose duration under this planned dose amount). The 
denominator is calculated as the prescribed number of capsules (based on body weight at each 
visit; refer to Protocol Table 2 and 3 for the details) multiplied by the treatment period (regardless 
drug interrupted).   
Subgroup analysis based on the Age group 1 (i.e., 0 to <10 years vs. 10 to <18 years which 
categorized based on the actual age) will be provided for the exposure and compliance rate. In 
addition, treatment compliance will be summarized quantitatively and categorically: <80%, 
between 80% and 120%, and >120%. 
4.5 
Primary Endpoint Analysis 
4.5.1 Definition of Endpoint 
The primary endpoint is the change from baseline in average AM and PM scratching score to 
Month 6 (Weeks 21 to 24) as measured by the Albireo ObsRO caregiver instrument. It is based on 
the worst scratching score (item 1) of the ObsRO AM and ObsRO PM scores (Protocol Appendix 
2). The detailed derivation of baseline scores and monthly scores is provided in Appendix 2. 
Change from baseline is calculated as the monthly score minus the baseline score. 
4.5.2 Estimand  
 
The primary objective of this study is to assess the efficacy of repeated daily doses of 
120 g/kg/day odevixibat in relieving pruritus in patients with ALGS. The estimand includes all 
data collected through the end of the study following an ICE due to premature discontinuation of 
study treatment prior to Week 24 (i.e., treatment policy strategy), while excluding data following 
ICEs of biliary diversion surgery or liver transplant (i.e., hypothetical strategy).  
On the one hand, premature treatment discontinuation could occur due to an AE, tolerability issue, 
lack of efficacy, or other reasons. As stated in the guidance for industry E9(R1) Statistical 
Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials, 
the clinical and regulatory interest of hypothetical scenarios assuming the patient could tolerate 
treatment or did not have an AE is limited and would usually depend on a clear understanding of 
why and how the intercurrent event or its consequences would be expected to be different in 
clinical practice than in the clinical trial. Therefore, the estimand will utilize the treatment policy 
strategy for premature treatment discontinuation ICEs and include all data collected after this type 
of ICEs. This reflects the patients’ outcomes in practice if they are unable to continue receiving 
the investigational drug. Of note, protocol section 7.1.4 specifies that for patients who prematurely 
discontinue study drug treatment during the treatment period, all efforts will be made to have 
patients continue to complete all scheduled study visits for assessments following completion of 
the EOT visit.  
On the other hand, only a small number of patients, if any, are expected to have biliary diversion 
surgery or liver transplant during the placebo-controlled portion of the trial. As biliary diversion 
surgery may be viewed as a “rescue” treatment for pruritus, it may be reasonable for the primary 
analysis of pruritus outcomes to utilize a hypothetical strategy (which assumes that the biliary 
diversion surgery did not occur) for this ICE. A similar strategy may be reasonable for liver 


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transplantation, although transplantation may be indicated for reasons other than pruritus. The 
proposed primary analysis method will model outcomes following biliary diversion surgery or 
liver transplantation informed by the patients’ outcomes prior to the surgery/transplant and by the 
trajectories of other patients in the trial.  
 
Although not permitted by the study protocol, a significant change in anti-pruritus medication 
may also be considered as an ICE as it can affect the patient’s scratching score and thus introduce 
noise into the measure of treatment effect. However, due to large number of various anti-pruritic 
medications with different pharmacokinetic and pharmacodynamic properties, it would be 
challenging from a clinical standpoint to define significant changes in anti-pruritus medication 
based on duration and dose collected in concomitant medication only. Therefore, change in anti-
pruritus medication will not be considered as an intercurrent event in this study and all efficacy 
data after change in anti-pruritus medication will be included in the analyses.    
4.5.2.1 Main Analysis 
The primary efficacy analysis for the primary endpoint will be performed on the FAS and will be 
based on a MMRM excluding data after ICEs of biliary diversion surgery or liver transplant and 
data collected after treatment discontinuation will be included.  
The change from baseline for each 4-weeks (monthly) average AM and PM scratching score will 
be analyzed with the SAS PROC MIXED using a restricted maximum likelihood (REML) with 
baseline age stratification, baseline average AM and PM scratching score, baseline direct 
bilirubin, treatment group, time (in months, this is a categorical variable, i.e., 1-4 weeks, 5-8 
weeks, 9-12 weeks, 13-16 weeks, 17-20 weeks, and 21-24 weeks), and treatment-by-time 
interaction in the model. Baseline direct bilirubin is expected to be associated with the treatment 
effect. Unstructured covariance matrix (UN) will be used in the analysis. If this analysis fails to 
converge, the following structures will be tested in this order: Toeplitz (equal variances and a 
separate correlation for each level of separation between the time points), AR(1) (first-order 
autoregressive, equal variances and exponentially decreasing correlations), compound symmetry 
(CS) (equal variances and equal pairwise correlations across fixed time points). The first 
(co)variance structure yielding convergence will be used as the primary analysis. The Kenward-
Roger approximation will be used to estimate denominator degrees of freedom. The primary 
comparison will be the difference of the least square mean (lsmean) estimate between odevixibat 
and placebo at Month 6 (Weeks 21 to 24). The difference of the lsmean estimate between 
odevixibat and placebo at other Months will be estimated and tested. Average treatment effect 
between odevixibat and placebo at Month 4 to 6 will be also estimated and tested. 
4.5.2.2 Sensitivity Analyses 
4.5.2.2.1 Sensitivity analysis 1 – Control-based MI    
To assess the robustness of the primary analysis results based on MAR assumption, a sensitivity 
analysis based on MI for missing average AM and PM monthly scratching scores will be 
conducted.  
The following procedures in MI will be followed: 


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1. Intermediate missing values are imputed by the Markov Chain Monte Carlo (MCMC) 
imputation model, so only monotone missing values exist after imputation. Only imputed 
values within the range of 0 to 4 will be used since the rating of the questionnaire is from 0 
to 4. 
2. The monotone missing values are imputed chronologically by month using SAS Proc MI 
regression method including baseline age stratification and baseline direct bilirubin in the 
model. For all patients with missing average scratching score for any reason, their missing 
average scratching score will be imputed from all placebo patients in a visit-by-visit (i.e., 
Month by Month) manner, regardless of study treatment assignment. This is done by each 
imputed data set from step 1. Only imputed values within the range of 0 to 4 will be used.  
3. After the imputation, all data are pooled and the MMRM analysis is performed on each of 
the 200 imputed datasets.  
4. The same MMRM model as in the primary analysis is used to compare the treatment effect 
at Month 6 (Weeks 21 to 24). This is done by the imputation IDs from step 1.  
5. The results from step 4 will be combined using Rubin’s method [14]. 
4.5.2.2.2 Sensitivity analysis 2 - Tipping point analysis 
A tipping-point analysis will be used to explore whether missing data could have adversely 
impacted findings from the analysis of change from baseline in scratching score to Month 6 
(Weeks 21 to 24) regardless of treatment adherence. The goal of a tipping-point analysis is to 
explore how the overall results may be impacted by different assumptions about the magnitude of 
change from baseline in scratching score to Month 6 (Weeks 21 to 24) for those with missing 
Month 6 (Weeks 21 to 24) data, which are sensitivity parameters (defined for each treatment 
group) that are systematically varied.  
The tipping-point analysis will be implemented as follows: 
1. 100 imputed datasets will be created using multiple imputation (MI) based on MAR, the 
same steps 1-2 in section 4.5.2.2.1 will be used to impute the missing average AM and PM 
score except that in step 2 the imputation will be done within each treatment group. 
2. At each missing visit, the baseline score will be subtracted from imputed score to obtain 
imputed change from baseline (CHG). 
3. For each patient with a missing Month 6 (Weeks 21 to 24) value, the following steps will 
be performed for adjusting the imputed CHG with mean zero and add the constant for the 
tipping steps: 
a. The average imputed CHG will be computed based on the 100 imputed datasets 
from step 2 per patient. 
b. The average imputed CHG will be subtracted from the imputed CHG per subject 
per imputed dataset and this is resulting in the imputed CHG among the imputed 
datasets for a subject having a mean of zero at month 6.   
c. $ FRQVWDQW ǻ2 and ǻ3 Zill be added to the imputed value for the odevixibat arm 
and the placebo arm for each of the imputed datasets. 
4. Combine imputed CHG at month 6 in step 3 and other visit in step 2 with the observed 
CHG to get the completed 100 datasets for analyses in step 4 and 5.  


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5. Results from the same MMRM model as used in the primary analysis fit to the imputed 
datasets will be combined using Rubin’s method [14]. Treatment effect estimates, p-value 
and limits from the 95% confidence interval (CI) will be retained. 
6. The above steps will be UHSHDWHG XVLQJ GLIIHUHQW YDOXHV IRU ǻ2 DQG ǻ3 
To characterize the extent of departures from assumptions that change the interpretation of the 
results in terms of their statistical or clinical significance, with particular interest to identify the 
region in the sensitivity parameter space that leads the results to no longer be statistically 
significant, a map of treatment effects and p-values obtained in Step 6 above will also be 
presented, so as to allow assessment of the differences in posited scenarios for missing outcomes, 
that would lead to a change in conclusion from the study results.  
4.5.2.2.3 Sensitivity analysis 3 - Worst weekly scratching score for a month   
The worst weekly scratching score for baseline (14-day period) and each month (28-day period) is 
defined in Appendix 2; please also refer to the analysis window in Appendix 3. 
The MMRM utilized for the main analysis for the sensitivity analysis of the primary endpoint will 
also be used for the change from baseline in scratching score to Month 6 (Weeks 21 to 24) based 
on worst weekly scratching score for a month. The baseline worst weekly scratching score will be 
used as the covariate instead of the baseline average AM and PM scratching score in the MMRM.   
4.5.2.2.4 Sensitivity analysis 4 - Worst weekly scratching score for a month with control-based 
MI 
The MMRM utilized for the main analysis and with control-based MI utilized for the sensitivity 
analysis of the primary endpoint will also be used for the change from baseline in scratching score 
to Month 6 (Weeks 21 to 24) based on worst weekly scratching score for a month. The baseline 
worst weekly scratching score will be used as the covariate instead of the baseline average AM 
and PM scratching score in the MMRM.   
4.5.2.2.5 Sensitivity analysis 5 - Primary endpoint with different definition of baseline   
The MMRM utilized for the main analysis will be used for the change from baseline in scratching 
score to Month 6 (Weeks 21 to 24) with the baseline score redefined as following: 
The baseline scratching score for this analysis is calculated by averaging the four-baseline weekly 
average AM and PM scores in the 28 days preceding start of treatment for whom it is available. 
The baseline score will be unrounded and can only be calculated if 2 or more weekly scores can 
be calculated. 
4.5.2.2.6 Sensitivity analysis 6 - Monthly scratching score    
The MMRM utilized for the main analysis of the primary endpoint will be used for the monthly 
scratching score at Month 6 (week 21 to 24) to evaluate scratching at a landmark time - the end of 
the randomized treatment period.       


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4.5.2.3 Supplementary Analyses  
x MMRM for the PP analysis set   
The same MMRM utilized for the main analysis will also be used for the PP analysis set.  
4.5.3 Subgroup Analyses 
The following subgroup analyses will be performed by using MMRM model with baseline 
average AM and PM scratching score, treatment group, time and treatment-by-time interaction. 
The approach to selection of the covariance matrix in the model will follow the same approach as 
for the primary endpoint.   
x Age group 1: 0 to <10 and 10 to <18 years (based on actual age) 
x Age group 2: 0 to <2, 2 to <12, 12 to <18 years (based on actual age)  
x Region (US, EU, and rest of the world [RoW]) 
x Sex  
x Race (White vs. Non-White (including race as not reported)) 
x Ethnicity (Hispanic or Latino (including ethnicity as not reported), Not Hispanic or Latino) 
x Baseline serum bile acid  median and < median) 
x The use of UDCA (Y, N) 
x The use of anti-pruritus medication (Y, N) 
x Child-Pugh classification (Class A, B, C) 
x Hepatic impairment classification (no impairment, mild, moderate, or severe) 
x Baseline direct ELOLUXELQ ! DQG  PJG/ and equivalent to >51.3 and  mol/L) 
x Genetic Testing for ALGS (JAG1 vs NOTCH2) 
A forest plot of the subgroup analyses will be provided for the primary endpoint. Statistical 
DQDO\VLV ZLOO EH SHUIRUPHG RQO\ ZKHQ WKH VDPSOH VL]H LV 5 in each treatment group. If the sample 
size is <5 in either treatment group, only summary statistics will be provided; the p-value will not 
be reported.   
4.6 
Secondary Endpoints Analysis  
4.6.1 Definition of Key Secondary Endpoint 
The key secondary endpoint is change in serum bile acid levels from baseline to the average of 
Week 20 and Week 24. Baseline is defined as the average of the last 2 values prior to the first 
dose and the average of Week 20 and Week 24 is defined as the average of values at week 20 and 
week 24 (refer to Appendix 2 and Appendix 3 for details). Change from baseline is calculated as 
the serum bile acid value minus the baseline value.  
4.6.2 Estimand 
The key secondary objective of this study is to assess the impact of odevixibat on serum bile acid 
levels in patients with ALGS. The same estimand used for the primary endpoint is also used in 
assessing this objective. That is, all data collected through the end of the study following an ICE 


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due to premature discontinuation of study treatment prior to Week 24 (i.e., treatment policy 
strategy), will be included while excluding data following ICEs of biliary diversion surgery or 
liver transplant (i.e., hypothetical strategy). 
4.6.2.1 Main Analysis  
The analysis for the key secondary endpoint will be determined from a MMRM modelling change 
from baseline for serum bile acid at each scheduled visit, with baseline age stratification, baseline 
serum bile acid, treatment group, visits (Weeks 4, 8, 12, 16, 20, 24), and treatment-by-visit 
interaction in the model. The approach to selection of the covariance matrix in the model will 
follow the same approach for the primary endpoint. The primary comparison of treatment 
difference in change from baseline to the average of Week 20 and Week 24 will be estimated and 
tested; also, the difference at Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 will be 
estimated and tested.   
4.6.2.2 Sensitivity Analysis 
4.6.2.2.1 Sensitivity analysis 1 – Control-based MI  
To assess the robustness of the main analysis results based on MAR assumption, a sensitivity 
analysis based on MI for missing serum bile acid result at each scheduled visit will be conducted.  
The MI procedures that described for the primary endpoint in section 4.5.2.2.1 will be applied.  
4.6.2.2.2 Sensitivity analysis 2 – Tipping point analysis 
The analysis approach that described for the primary endpoint in section 4.5.2.2.2 will be applied.   
4.6.2.3 
Supplementary Analysis 
4.6.2.3.1 Supplementary analysis 1 – Non-parametric analysis 
The serum bile acid levels are expected to fluctuate. To evaluate the robustness of the deviation 
from the normal and homoscedastic assumptions used in the main analysis, a rank transform 
ANCOVA model with baseline age stratification, baseline serum bile acid, treatment group will 
also be used to evaluate the treatment effect. The ranked ANCOVA method permits adjustment 
for baseline values which increases the efficiency of the statistical test. Change from baseline to 
the average of Week 20 and Week 24 will be ranked ignoring treatment group. The value of mid-
ranks will be used in the case of ties. The baseline serum bile acid data will also be ranked in the 
same manner. This analysis will be performed with missing data at each scheduled visit imputed 
by MI based on MAR (the step 1 in the tipping point analysis) before ranking. The multiple 
estimates of treatment difference from the ranked ANCOVA will then be combined using Rubin’s 
rules. The same ranked ANCOVA will also be performed at each visit (Weeks 4, 8, 12, 16, 20, 
24).  


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4.6.2.3.2 Supplementary analysis 2 – Based on the PP analysis set 
The MMRM utilized for the main analysis in section 4.6.2.1 will also be used for the PP analysis 
set.    
4.6.3 Subgroup Analyses 
The following subgroup analyses will be performed by using MMRM model with baseline serum 
bile acid, treatment group, visit and treatment-by-visit interaction. The approach to selection of 
the covariance matrix in the model will follow the same approach as for the primary endpoint.   
x Age group 1: 0 to <10 and 10 to <18 years (Based on the actual age) 
x Age group 2: 0 to <2, 2 to <12, 12 to <18 years (Based on the actual age) 
x Region (US, EU, and RoW) 
x Sex  
x Race (White vs. Non-White (including race as not reported)) 
x Ethnicity (Hispanic or Latino (including ethnicity as not reported), Not Hispanic or Latino) 
x Baseline serum bile acid  median and < median) 
x The use of UDCA (Y, N) 
x The use of anti-pruritus medication (Y, N) 
x Child-Pugh classification (Class A, B, C) 
x Hepatic impairment classification (no impairment, mild, moderate, or severe) 
x Baseline direct ELOLUXELQ ! DQG  PJG/ DQG HTXLYDOHQW WR ! DQG  PRO/) 
x Genetic Testing for ALGS (JAG1 vs NOTCH2) 
A forest plot of the subgroup analyses will be provided for the key secondary endpoint. Statistical 
DQDO\VLV ZLOO EH SHUIRUPHG RQO\ ZKHQ WKH VDPSOH VL]H LV 5 in each treatment group. If the sample 
size is <5 in either treatment group, only summary statistics will be provided; the p-value will not 
be reported.   
4.6.4 Other Secondary Endpoints 
For all secondary endpoints, all data collected through the end of the study following an ICE due 
to premature discontinuation of study treatment prior to Week 24 (i.e., treatment policy strategy), 
will be included while excluding data following ICEs of biliary diversion surgery or liver 
transplant (i.e., hypothetical strategy). 
The change in secondary endpoints such as serum bile acids, ALT, AST, gamma-glutamyl 
transferase, direct bilirubin, total bilirubin, total cholesterol, PRO and ObsRO sleep parameters 
will be summarized by visit using descriptive statistics.  
In addition to evaluate vital signs (height and weight) in the safety analysis, growth data 
(height/length for age, weight for age, and BMI for age) will be considered as an exploratory 
efficacy endpoint. Growth data will be calculated using the software or methods from the Centers 
for Disease Control and Prevention (CDC) website [12] IRU SDWLHQWV ZLWK DJH  \HDUV ROG DQG
from the World Health Organization (WHO) website [13] for patients with age <2 years old. 


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Change from baseline in growth (i.e., height [cm], weight [kg], BMI [kg/m2] and corresponding 
linear growth compared to a standard growth curve [Z-score, SD from P50 standard growth 
curve], calculated by using the software or methods from the CDC website for patients with age 
>= 2 years old and from the WHO website for patients with age < 2 years old) will be summarized 
by visit using descriptive statistics.  
4.6.4.1 Continuous Endpoints 
Change in ALT, AST, gamma-glutamyl transferase, direct, total bilirubin and total cholesterol, 
change in itching score to Month 6 (Weeks 21 to 24) as measured by the Albireo PRO instrument, 
change in sleep parameters, and change in growth will also be analyzed using the MMRM model. 
The summary of change from baseline based on MMRM model will also be displayed using 
graphical presentations except for itching score as measured by the Albireo PRO instrument. 
MMRM model will include the baseline value of the response variable, baseline age stratification, 
baseline direct bilirubin (for change in itching score), treatment group, visit (in months for itching 
score and sleep parameters, and in weeks for other assessments) and treatment-by-visit 
interaction. The approach to selection of the covariance matrix in the model will follow the same 
approach as for the primary endpoint.  
The change from baseline through Week 24 in the Albireo ObsRO scratching severity scores and 
PRO itching scores for the morning assessment, evening assessment, and average morning and 
evening assessment will also be evaluated by weekly score. These endpoints will be assessed 
combining age groups and by age group (based on the actual age), 0 to <8, 8 to <12, and 12 to 
<18. A line graph of scratching daily severity scores (average AM and PM) from the Albireo 
ObsRO and sBA over time for each patient will be provided. In addition, line plot for mean of 
change from baseline on Albireo ObsRO average AM and PM, AM, and PM scratching weekly 
score will be provided, respectively. 
Patients  \HDUV and caregivers will be asked to complete a quality-of-life questionnaire 
(PedsQL) at Randomization Day 1, Week 12, and Week 24. Details of the questions included on the 
questionnaire are provided in Protocol Appendix 4. Comparisons of the change from baseline at 
Week 12 and Week 24 in the PedsQL total score (calculated as average score of all answered 
items) and domain scores between the treatment groups will be conducted using ANCOVA. The 
model will include terms for baseline, age category based on the age groups defined for the 
PedsQL (5 to <8, 8 to <13, 13 to <18) and treatment. The analysis will be conducted based on the 
total scores reported by child (5 years of age) and by parent (including patients for all age) 
separately. If the sample size based on child reported data (5 years of age) is less than 10, then 
ANCOVA will not be conducted. The PedsQL total score and domain scores of the family impact 
module will be analyzed similarly. 
A Pearson correlation coefficient will be provided to evaluate the relationship between the 
primary endpoint (change from baseline in scratching score to Month 6 (Weeks 21 to 24)) and the 
key secondary endpoint (change in serum bile acid levels from baseline to the average of Week 20 
and Week 24).  
4.6.4.2 Categorical Endpoints 
A clinically meaningful decrease in scratching score will be defined in the psychometric analysis 
report based on psychometric analysis results before database lock. Please refer to the 


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psychometric analysis plan for details. The results of the blinded psychometric analysis across all 
anchors and timepoints supported a threshold from 1.0 to 1.5 points. The upper bound of 1.5 
points reduction will be used for the primary analysis while the lower bound of 1.0-point 
reduction will be used for the sensitivity analysis. The proportion of patients achieving a clinically 
meaningful decrease in scratching score (pruritus responders) at Week 24 (or Week 12) will be 
analyzed using a Cochran-Mantel-Haenszel (CMH) test. Patients with missing data at Week 24 
(or Week 12) will be classified as non-responders. CMH stratified by baseline age stratification 
will be performed to compare the proportion of the responders in pruritus at Week 24 (or Week 
12). In the CMH test, data in a stratum will not be used in the calculation of the p-value if a row 
sum or column sum is 0 in the contingency table. If a row sum or column sum is 0 or a stratum 
has <4 patients, the CMH test will not be stratified.   
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. 
The change from baseline to Week 12, Week 24 and last assessment during treatment in 
xanthomatosis will be summarized by a shift table. Shift tables for the number of patients with 
changes from baseline to the best and to the worst post-baseline value will be provided. 
3DWLHQWV  \HDUV RI DJH FDUHJLYHUV DQG FOLQLFLDQV ZLOO FRPSOHWH *,& 3*,& &D*,& DQG
CGIC) and the GIS measures (PGIS, CaGIS, CGIS) (Protocol Appendix 3) at randomization 
(Study Day 1; PGIS only), Week 4, 12, and 24. The GIC items that assess change in itch (patient 
version), scratching (caregiver and clinician version), and sleep (all version) will be analyzed 
using the proportional odds model with treatment and baseline GIS score as the covariates and 
will consider 3 categories (better, no change, worse). The better category will include answers of 
“Very Much Better”, “Much Better”, and “A Little Better”; no change will include answers of 
“No Change”; worse will include answers of “A Little Worse”, “Much Worse”, and “Very Much 
Worse”. GIC and GIS data at baseline (GIS only), Weeks 4, 12, and 24 will be summarized using 
frequency tables and bar chart figures.  
4.6.4.3 Biomarkers 
Blood samples for autotaxin and p-C4 will be drawn at randomization (Study Day 1), Week 12, 
and Week 24, only for children with body weight >10 kg. For biochemical markers and measures 
of bile acid synthesis, the change from baseline to Week 24 will be analyzed descriptively in 
addition to the actual visit values.  
FGF-19 is collected when a patient meets criteria for close observation due to suspected drug-
induced liver injury (DILI); the results will be provided in a listing.   
4.6.4.4 Exit Interview 
During the exit interview, patients  \HDUV RI DJH and caregivers will be asked to complete the 
exit questionnaire (Protocol Appendix 8). The answers for the first two questions on the 
questionnaire will be summarized using a frequency table for each combination of the answer 
from these two questions by the responses from patients and caregivers. The details of responses 
to the exit interview will be provided in a listing.  


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4.7 
Multiplicity Adjustment for Primary and Key Secondary Endpoints 
Statistical testing for the primary analysis of the primary endpoint will be performed with a 1-
sided Type I error rate of 0.025. The key secondary efficacy endpoint will be assessed for 
statistical significance if and only if the success criterion for the primary endpoint is met. This 
hierarchical testing strategy prevents alpha inflation from the assessment of multiple endpoints. 
Other secondary efficacy endpoints will provide supportive efficacy information regarding the 
differences between treatment with odevixibat and placebo. No alpha adjustments will be 
performed for multiple comparisons when testing other secondary efficacy endpoints. 
4.8 
Safety Analyses 
Safety criteria are as follows: 
x Primary safety analysis is the incidence of TEAEs and TEAEs categorized by causality, 
severity, and seriousness assessments made by the investigator by comparing active arms 
vs. placebo. This includes liver-related mortality and liver decompensation events 
(protocol Section 10.2.2.3) and all-cause mortality. 
x Safety will also be evaluated by the following assessments:  
- 
Physical examinations  
- 
Concomitant medications  
- 
Vital signs  
- 
Laboratory test results (including clinical chemistry, hematology, urinalysis, AFP, 
vitamins A and E, 25-hydroxy vitamin D, and INR)  
- 
Abdominal ultrasound  
- 
Discontinuations due to AEs  
All safety analyses will be performed on the SAF unless otherwise specified, using the following 
common rules: 
x The analysis of the safety variables will be analyzed using descriptive statistics and 
summaries by treatment group for each cohort. 
x No inferential statistical analysis will be planned.  
x For each safety variable, the last value collected prior to first dose of study drug will be 
used as the baseline for all analyses. 
4.8.1 Adverse Events 
General common rules for summarizing adverse events 
All AEs will be classified by SOC and PT using the MedDRA version 25.0.  
AEs will be classified as TEAEs, defined as follows: An AE (classified by preferred term) that occurs 
during the Treatment Period will be considered a TEAE if it has a start date on or after the first dose 
date of study drug, or it has a start date before the date of the first dose date of study drug but 
worsened in severity on or after the date of the first dose date of study drug. 


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AEs with missing start dates, but with stop dates either overlapping with the treatment period or 
missing, will be considered TEAEs. A TEAE with missing drug-relationship will be considered as 
related. A TEAE with missing severity will be considered as CTCAE grade 3 (severe). Details for 
imputing missing or partial start dates of adverse events are described in Appendix 5. AEs with 
the same AE reference number that is collected on AE page of eCRF are counted as one AE only.  
Adverse events of interest (AEIs)  
Adverse events of interest (AEIs) will be selected for analyses as indicated in Table 6 - Selections 
for AEIs .  
Table 6 – Selections for AEIs  
AEIs  
Selection 
Liver Decompensation 
 
a. 
The following TEAEs will be included: 
PT = International normalised ratio increased and checkbox that event is 
refractory to vitamin supplementation is checked and at least 1 INR value 
(within 2 weeks [+/-] of the AE started date) is >1.5 
PT = Vitamin K increased and checkbox that event is refractory to vitamin 
supplementation is checked and at least 1 INR value (within 2 weeks [+/-] of 
the AE started date and checkbox) is >1.5 
PT = Hepatic failure, Acute on chronic liver failure, or Subacute hepatic 
failure 
b. The following TEAEs occurring as separate events or in the presence of (i.e. 
ongoing medical history or AE) PT of portal hypertension and/or PT of 
hepatic cirrhosis were included: 
PT = Ascites  
PT = Hepatorenal syndrome 
PT = Portopulmonary hypertension 
PT = Oesophageal varices haemorrhage 
PT = Gastric varices haemorrhage  
PT = Intestinal varices haemorrhage 
PT = Hepatic encephalopathy 
 
 
Liver Related 
The following Standardised MedDRA Queries (SMQs) will be included: 
 
x 
Drug related hepatic disorders – comprehensive search SMQ (narrow 
and broad) 
x 
Biliary tract disorders SMQ 
x 
Gallbladder related disorders SMQ 
x 
Gallstone related disorders SMQ     
 
 
FSV Deficiency refractory to 
clinically recommended 
vitamin supplementation 
based on CRF 
Both questions of “Is this an event of fat-soluble vitamin deficiency?” and “Is 
this refractory to clinically recommended vitamin supplementation?” on the AE 
page are checked as “Yes”.  
 
Possible Sequelae of FSV 
Deficiency  
Specified TEAEs with PTs are listed in Appendix 10 
 
  


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AEIs  
Selection 
Clinically Significant Diarrhea 
Clinically significant diarrhea is defined as diarrhea that persists for 3 or more 
days without any other etiology (e.g., infection) as assessed by the investigator, 
diarrhea reported by the investigator as severe in intensity or reported as an SAE 
or diarrhea with concurrent dehydration requiring treatment with oral or 
intravenous rehydration and/or other treatment intervention. Therefore, at least 
one of the following conditions met will be considered as clinically significant 
diarrhea: 
x 
37  'LDUUKRHD RU 'LDUUKRHD KDHPRUUKDJLF DQG ODVW IRU  GD\V DQG WKH
CRF question of “Does this event have a clear etiology (e.g., 
Infection)?” on the AE page is checked as “No”. 
x 
37  'LDUUKRHD RU 'LDUUKRHD KDHPRUUKDJLF DQG &7&$( * 
x 
PT = Diarrhoea or Diarrhoea haemorrhagic and SAE = “Yes”  
x 
PT = Diarrhoea or Diarrhoea haemorrhagic and the CRF question of “Is 
this an event of diarrhea with concurrent dehydration requiring 
treatment with oral or intravenous rehydration and/or other treatment 
intervention?” on the AE page is checked as “Yes” 
Analysis of all adverse events  
An overall summary of the incidence of TEAEs (number of patients with any events and number of 
events, if applicable) will include the following: 
x Overview of the incidence of TEAEs  
x Drug-related TEAEs (AE will be defined as drug-related if causality is either probable, 
possibly, or definitely related)  
x TEAEs by CTCAE grades 1, 2, 3, 4, 5 
x TEAEs leading to study drug discontinuation 
x TEAEs leading to study drug interruption 
x TEAEs leading to study drug dose reduction 
x Serious TEAEs 
x Drug-related serious TEAEs 
x TEAEs leading to death 
x Any hepatic TEAE  
- 
Any TEAE of liver decompensation (as defined in Table 6 - Selections for AEIs, for 
TEAEs listed in b occurring as separate events ) 
- 
Any TEAE of liver decompensation (as defined in Table 6 - Selections for AEIs, for 
TEAEs listed in b in the presence of (i.e. ongoing medical history or AE) PT of portal 
hypertension and/or PT of hepatic cirrhosis)  
- 
Any liver-related TEAE (as defined in Table 6 - Selections for AEIs ) 
x Any Fat-Soluble Vitamin (FSV) Deficiency refractory to clinically recommended vitamin 
supplementation TEAEs (as defined in Table 6 - Selections for AEIs )  
x Possible Sequelae of FSV Deficiency TEAEs (as defined in Table 6 - Selections for AEIs ) 


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x Any Clinically Significant Diarrhea TEAEs (as defined in Table 6 - Selections for AEIs ) 
x Overview of the incidence of TEAEs by age group 1 (0 to <10, 10 to <18, based on the 
actual age)  
x Overview of the incidence of TEAEs by age group 2 (0 to <2, 2 to <12, 12 to <18, based 
on the actual age)  
TEAEs (number of patients with any events and number of events, if applicable) by SOC (as 
applicable) and PT will be tabulated for the following: 
x TEAEs by SOC and PT 
x All TEAEs by PT by descending incidence in odevixibat column 
x TEAEs leading to study drug discontinuation by SOC and PT 
x TEAEs leading to study drug interruption by SOC and PT 
x TEAEs leading to study drug dose reduction by SOC and PT 
x Serious TEAE by SOC and PT 
x Drug-related TEAEs by SOC and PT 
x Drug-related serious TEAE by SOC and PT  
x TEAEs leading to death by SOC and PT  
x &RPPRQ 7($(V 5% odevixibat group) by PT 
x Severe or worse of TEAEs (CTCAE JUDGH   by SOC and PT 
x Hepatic TEAEs  
- 
Any TEAE of liver decompensation (as defined in Table 6 - Selections for AEIs, for 
TEAEs listed in b occurring as separate events ) by SOC and PT 
- 
Any TEAE of liver decompensation (as defined in Table 6 - Selections for AEIs, for 
TEAEs listed in b in the presence of (i.e. ongoing medical history or AE) PT of portal 
hypertension and/or PT of hepatic cirrhosis ) by SOC and PT 
- 
Liver-related TEAEs by SOC and PT 
x FSV Deficiency refractory to clinically recommended vitamin supplementation TEAEs by 
SOC and PT (as defined in Table 6 - Selections for AEIs ) 
x Possible Sequelae of FSV Deficiency TEAEs by SOC and PT (as defined in Table 6 - 
Selections for AEIs ) 
x Clinically Significant Diarrhea TEAEs by SOC and PT (as defined in Table 6 - Selections 
for AEIs ) 
Summary tables for number of patients with any TEAEs by SOC and PT by severity (grade 1 to 
grade 5) and by causality (related [possibly, probably, and definitely] vs unrelated [unlikely and 
unrelated]), will also be provided. AEs with the worst severity will be used in the by-severity 
summaries. Similarly, AEs with the worst causality (most related to treatment) will be used in the 
by-causality summaries. If severity or causality is missing, data will be imputed as grade 3 or 
related, respectively.  


Statistical Analysis Plan  
 
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When a patient has the same adverse event, based on preferred terminology, reported multiple 
times during the study, the patient will only be counted once at the preferred terminology level in 
adverse event frequency tables. Where a patient has multiple adverse events within the same SOC 
during the study, the patient will only be counted once at the SOC level in adverse event 
frequency tables. In the AE summaries, AEs will be sorted by alphabetically for SOC and PT. 
In addition to the frequency summary of TEAE tables, the exposure adjusted incidence rate 
(EAIR) (per 100 patient years at risk) with the 95% confidence interval, based on Poisson 
distribution, will also be provided for each of the following AE tables: 
x TEAEs by SOC and PT 
x Liver-related TEAEs by SOC and PT 
x Liver Decompensation TEAEs (as defined in Table 6 - Selections for AEIs, for TEAEs 
listed in b in the presence of (i.e. ongoing medical history or AE) PT of portal 
hypertension and/or PT of hepatic cirrhosis) by SOC and PT 
x FSV Deficiency refractory to clinically recommended vitamin supplementation TEAEs by 
SOC and PT 
x Possible Sequelae of FSV Deficiency TEAEs by SOC and PT 
x Clinically Significant Diarrhea TEAEs by SOC and PT  
The EAIR (per 100 patient years at risk) will be calculated as follows: 
Number of subjects with event/ Total cumulative time at risk (years) x 100 
where total cumulative time at risk is the sum of individual time at risk. The time at risk for a 
subject with the event of interest will be calculated (in years) as: 
(first event date – date of first dose + 1) / 365.25 
The time at risk for a subject without the event of interest is calculated as: 
(last participation date – date of first dose + 1) / 365.25 
Kaplan-Meier curves may be used for time to event data (time to first liver decompensation 
TEAEs [as defined in Table 6 - Selections for AEIs, for TEAEs listed in b in the presence of (i.e. 
ongoing medical history or AE) PT of portal hypertension and/or PT of hepatic cirrhosis ] onset 
(days), time to first liver-related TEAEs onset (days), time to first FSV deficiency refractory to 
clinically recommended vitamin supplementation TEAEs onset (days), time to first possible 
sequelae of FSV deficiency TEAEs onset (days), time to first clinically significant diarrhea event 
onset (days), and time to all-cause mortality (weeks)). Patient will be censored at the last contact 
date if no event occurs.  
A diarrhea event is defined as a TEAE with PT as Diarrhoea or Diarrhoea haemorrhagic.  
Descriptive summary statistics will be used to summarize the duration of each diarrhea episodes 
(days), the number of episodes per patient and time to onset of diarrhea (days). In addition, the 
summaries will be provided for clinically significant diarrhea TEAEs.    
In order to assess who developed onset of FSV Deficiency refractory to clinically recommended 
vitamin supplementation, a listing merging with concomitant medications and selected lab data 
will be provided.  


Statistical Analysis Plan  
 
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Product Code-Study NumberA4250-012 
 
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Analysis of special situations 
Certain safety events are defined by regulatory authorities as Special Situations and require 
reporting. These Special Situations include: 
x Overdose of study medication  
x Suspected abuse/misuse of study medication 
x Medication error involving the study medication 
x Drug-drug interaction 
x Pregnancy 
Special Situations should be reported on the Special Situations page of eCRF, whether or not they 
result in an AE/SAE. Number (%) of patients experiencing these special situations will be 
provided. 
4.8.2 Additional Safety Assessments 
4.8.2.1 Laboratory Variables 
The following laboratory variables will be analyzed.  
x Hematology:  
- 
Red blood cells and platelets: hemoglobin, hematocrit, red blood cell count, and 
platelet count 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, and eosinophils 
x Clinical chemistry: 
- 
Metabolism: total cholesterol, triglycerides, creatine kinase, albumin 
- 
Electrolytes: sodium, potassium, chloride, calcium 
- 
Renal function: creatinine, blood urea nitrogen, estimated glomerular filtration rate 
- 
Liver function: ALT, AST, Alkaline phosphatase (and isoenzymes as applicable), 
direct bilirubin, total bilirubin, gamma-glutamyl transferase 
- 
Pregnancy test: 6HUXP ȕ-human chorionic gonadotropin (all female patients with 
positive urine pregnancy test)  
x Urinalysis: 
- 
Urinalysis for quantitative analysis: pH, proteins, glucose, blood, ketones, leukocytes, 
and nitrites  
x Other Labs: Vitamin A and E, 25-hydroxy vitamin D, INR, Alfa-fetoprotein (AFP), and 
Prothrombin Time 
Quantitative analyses 


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 4 0 of 7 3 
 
F or all la b orat or y varia bles a b o ve, de scri pti ve statistics f or cli nical la b orat or y val ues (i n SI u nits 
f or all tests, a n d i n c o n ve ntio nal u nits f or se lecte d tests (A p pe n di x 8 ) a n d a bs ol ute c ha n ges fr o m 
baseli ne at eac h p ost- baseli ne visit ( A p pe n di x 3 ) will be prese nte d. T he c ha n ge t o t he last visit 
will als o be s u m marize d. Ce ntral la b orat or y da ta will be use d f or t he s u m mar y. If ce ntral 
la b orat or y data are n ot a vaila ble d ue t o C O VI D- 1 9 or ot her reas o ns, l ocal la b orat or y data will be 
use d if a vaila ble.  
Fi g ure f or A L T, A S T, t otal bilir u bi n, A L P, a n d ga m ma- gl uta m yl tra nsferase will be prese nte d as 
i n di vi d ual patie nt trellis pl ot o ver ti me. 
A n al yses acc or di n g t o refere nce n or m al r a n ge  
S hift ta bles fr o m baseli ne t o t he hi g hest a n d l o we st p ost- baseli ne val ue f or q ua ntitati ve varia bles 
will be prese nte d f or t he cli nical la b orat or y para me ters. T he la b orat or y res ults will be classifie d as 
l o w, n or mal, a n d hi g h base d o n t he n or mal ra n ge t hat pr o vi de d b y ce ntral/l ocal la b orat ories. 
F or A L T, A S T a n d t otal bilir u bi n, a s hift ta ble ba se d o n t he f oll o wi n g classificati o ns ( per DI LI 
g ui da nce a n d C T C A E) will be prese nte d: 
 A L T a n d A S T: 
 3 U L N, > 3 a n d  5 U L N, > 5 a n d  1 0 U L N, > 1 0 U L N  
 T otal Bilir u bi n: 
 2 U L N a n d > 2 U L N 
Li ver m o nit ori n g 
A listi n g of patie nts meeti n g t he criteria f or li ver m o nit ori n g ( Ta ble 7 ) will be pr o vi de d. 
 T a ble 7 – Li ver m o nit ori n g  
L a b or at or y v al ue(s) or  S y m pt o ms  
Criteri o n 
A S T or A L T i n c o m bi nati o n wit h 
t otal bilir u bi n (c o nfir me d wit h 
re peat testi n g wit hi n 4 8 t o 7 2 h o urs) 
T otal bilir u bi n (c o nfir me d wit h 
re peat testi n g wit hi n 4 8 t o 7 2 h o urs) 
I N R 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 4 1 of 7 3 
 
L a b or at or y v al ue(s) or  S y m pt o ms  
Criteri o n 
S y m pt o ms 
S y m pt o ms 
4. 8. 2. 2  Vit al Si g ns 
Descri pti ve statistics f or vital si g ns [ bl o o d press ure (s yst olic a n d di ast olic), p ulse, re s pirat or y rate, 
te m perat ure, hei g ht ( or le n gt h de pe n di n g o n a ge), b o d y wei g ht ( usi n g a certifie d wei g ht scale), 
a n d B MI] a n d t heir c ha n ges fr o m baseli ne at eac h  p ost- baseli ne visit will be prese nte d. T he 
c ha n ge t o last visit will als o be  s u m marize d. S hift ta bles f or t he n u m ber of patie nts wit h c ha n ges 
fr o m baseli ne t o hi g hest a n d l o west p ost- baseli ne val ue base d o n t he n or mal ra n ges as o utli ne i n 
A p pe n di x 7  will be pr o vi de d.  
If hei g ht is c ollecte d as le n gt h, it will be c o n verte d as f oll o wi n g: 
Hei g ht (c m) = le n gt h (c m) – 0. 7 c m.  
4. 9  
Ot her A n al yses 
4. 9. 1  P h ar m ac o ki netics ( P K) A n al yses 
P K a nal ysis will be s pecifie d  i n a se parate P K S A P. 
4. 9. 2  Bli n de d A n al ysis  
4. 9. 2. 1  Pr urit us Res p o n der Defi niti o ns 
Bli n de d a nal yses of t he Al bire o O bs R O ( or P R O) e Diar y data will be perf or me d w he n 
a p pr o xi matel y 8 5 % or m ore of t h e pla n ne d sa m ple size has c o m ple te d t he Wee k 2 4 ( or Wee k 1 2) 
visit. T he bli n de d a nal ysis will be use d t o esti ma te a t hres h ol d of cli nicall y mea ni n gf ul c ha n ge 
(i.e., res p o n der defi niti o n) i n t he Al bire o O bs R O scratc hi n g sc ore ( or P R O itc hi n g sc ore). T he 
a nal ysis will be perf or me d b y a gr o u p fr o m I Q VI A, i n de pe n de nt fr o m b ot h t he st u d y tea m a n d 
Al bire o. Bli n de d data will be use d  f or t his a nal ysis; data will be c olla pse d acr oss treat me nt 
gr o u ps. 
T he a nal yses will i ncl u de distri b uti o n- a n d a n c h or- base d a nal yses t o e xa mi ne a res p o n der 
defi niti o n f or t he Al bire o O bs R O scratc hi n g sc ore ( or P R O itc hi n g sc ore). Distri b uti o n- base d 
a nal yses will i ncl u de calc ulati o n of t he S D a n d sta n dar d err or of meas ure me nt f or t he baseli ne 
C CI


Statistical Analysis Plan  
 
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Product Code-Study NumberA4250-012 
 
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Albireo ObsRO scratching score (or PRO itching score). Anchor-based analyses will involve 
examining the degree of change on the Albireo ObsRO scratching score (or PRO itching score) 
from baseline to Week 24 (or Week12) for patients who experience change in pruritus according 
to PGIC and symptom items. This will be described in the PAP. 


Statistical Analysis Plan  
 
  Version number: 2.0  
Product Code-Study NumberA4250-012 
 
  27Sep2022 
Confidential 
                                                                                                                                    Page 43 of 73 
 
5 
Supporting Documentation 
 
5.1 
Appendix 1 Changes to Protocol-Planned Analyses 
This section summarizes major statistical changes in the protocol amendment(s). 
Table 8 - Major statistical changes in protocol amendment(s) 
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
V2.0 
28Aug2020 
Definition of the PP analysis set 
is changed for patients without 
major protocol violation to 
patient without important 
protocol violation. Additional 
criteria are added.   
Correct the definition of the PP analysis 
set. 
 
 
 
The covariate of baseline 
conjugated bilirubin in MMRM 
is changed to direct bilirubin.  
 
Align with the routine laboratory 
parameters collected during the study 
 
 
 
The contrast statement for month 
6 (weeks 21 to 24) to assess 
treatment effect is changed to the 
difference of the least square 
mean estimate.   
 
The difference of the least square mean 
estimate will produce the same result as 
the contrast statement for the primary 
endpoint at Month 6 and provide data for 
the preceding visits.  
 
 
 
Add growth as an exploratory 
efficacy endpoint 
 
 
Patients with ALGS have impaired 
growth. To evaluate the effect of 
odevixibat on growth.   
 
 
 


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 4 4 of 7 3 
 
5. 2  
A p pe n di x 2 Deri ve d V ari a bles 
T he ta ble bel o w pr o vi des t he li st of deri ve d varia bles f or de m o gra p hic a n d baseli ne 
c haracteristics, vari o us d urati o n deri vati o ns, dr u g c o m plia nce, baseli ne deri vati o ns a n d ot her 
i m p orta nt pr ot oc ol deri vati o ns a p plica ble f or t his st u d y. 
T a ble 9 – Deri v ati o n r ules f or t he deri ve d v ari a ble 
V ari a bles
 F or m ul a
 
De m o gr a p hic a n d B aseli ne c h ar acteristics 
A ge (i n years) 
F or patie nts n ot fr o m site  
:  
A ge is calc ulate d base d o n date of birt h a n d date of ra n d o mizati o n. It will 
be deri ve d b y S A S Y R DI F f u ncti o n: yr dif ( Date of birt h, Date of 
Ra n d o mizati o n, " A C T/ A C T") 
F or patie nts fr o m site  
:  
O nl y year of birt h was c ollecte d, a n d Ja n uar y 1 was i m p ute d i n t he e D C 
s yste m. F or a nal ysis p ur p ose, a ge is calc ulate d base d o n c ollecte d a ge 
m o nt hs a n d a ge years o n t he C R F. 
Deri v ati o n of D ur ati o n 
St u d y da y at a n y visit 
Date of i nterest – Date of first d ose of st u d y dr u g. O ne da y is a d de d if t his 
 
E xte nt of E x p os ure 
D urati o n of treat me nt e x p os ure 
( da ys) 
Date of last st u d y dr u g i nta ke – Date of fist st u d y dr u g i nta ke + 1 
A vera ge Dail y d ose ( u g/ k g/ da y) 
S u m of ( n u m ber of ca ps ules ta ke n per da y * d ose stre n gt h of t he ca ps ules 
per wei g ht cate g or y * d ose d urati o n u n der t his d ose a m o u nt/ wei g ht) / ( Date 
of last st u d y dr u g i nta ke – Date of first st u d y dr u g i nta ke + 1) 
O ver all St u d y Dr u g C o m pli a nce  
C o m plia nce  
1 0 0 × s u m of ( n u m ber of ca ps ules act uall y ta ke n) / s u m of ( n u m ber of 
ca ps ules pla n ne d t o be ta ke n per da y * d ose d urati o n u n der t his pla n ne d 
d ose a m o u nt) 
Last partici pa nt date 
Last c o ntact date or date of deat h w hic h occ urre d first 
Deri v ati o n f or Effic ac y P ar a meters  
Baseli ne ( ge neral) 
T he baseli ne val ue of a para meter is defi ne d as t he last assess me nt of t hat 
para meter pri or t o t he first i nta ke of st u d y treat me nt, e xce pt as i n dicate d 
bel o w 
Baseli ne f or ser u m bile aci d 
T he baseli ne will be calc ulate d as t he a vera ge of t he last 2 val ues pri or t o 
t he first d ose (ce ntral la b orat or y res ults will be use d o ver l ocal la b orat or y 
res ults). If o nl y o ne n o n- missi n g val ue is a vaila ble, it will be use d as 
baseli ne. 
A vera ge ser u m bile aci d of Wee k 2 0 
a n d Wee k 2 4 
T he a vera ge of val ues t hat i de ntifie d fr o m a nal ysis wi n d o w at Wee k 2 0 a n d 
Wee k 2 4.  
Dail y sc ore f or O bs R O scratc hi n g 
( or P R O itc hi n g) se verit y  
T he dail y sc ore is calc ulate d b y a vera gi n g t he P M sc ore a n d t he ne xt da y 
A M sc ore. T he dail y sc ore is calc ulate d if at least t he P M sc ore or t he ne xt 
da y A M sc ore is c ollecte d. 
C CI
C CI


Statistical Analysis Plan  
 
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Product Code-Study NumberA4250-012 
 
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Variables 
Formula 
Weekly AM (or PM) score for 
ObsRO scratching (or PRO itching) 
severity 
The weekly AM (or PM) score is calculated by averaging the AM (or PM) 
scores in a week. Each week, at least 4 of 7 AM (or PM) assessments need 
to be collected to calculate the weekly AM (or PM) score (i.e., 50% rule). If 
these minimum assessments are not available, the weekly AM (or PM) 
score is considered missing 
Weekly average score for ObsRO 
scratching (or PRO itching) severity 
The weekly average AM and PM score is calculated by averaging of (the 
average of AM scores, the average of PM scores) in a week. Each week, at 
least 7 of 14 AM or PM assessments need to be collected to calculate the 
weekly average AM and PM score (i.e., 50% rule) regardless how many 
AM assessments or how many PM assessments are collected respectively.  
If these minimum assessments are not available, the weekly average AM 
and PM score is considered missing. 
Baseline score for ObsRO 
scratching (or PRO itching) severity 
(general) 
The baseline AM (or PM, or average AM and PM) score is calculated by 
averaging the two-baseline weekly AM (or PM, or average AM and PM) 
scores in the 14 days preceding start of treatment. Baseline score will be 
unrounded.    
Baseline values can only be calculated if both weeks can be calculated. 
Baseline score for ObsRO 
scratching (or PRO itching) severity 
(sensitivity analysis) 
The baseline AM (or PM, or average AM and PM) score is calculated by 
averaging the four-baseline weekly AM (or PM, or average AM and PM) 
scores in the 28 days preceding start of treatment. Baseline score will be 
unrounded.    
Baseline values can only be calculated if 2 or more weeks score can be 
calculated. 
Monthly average score for ObsRO 
scratching or (PRO itching) severity 
The post-baseline monthly (28 days) AM (or PM, or average AM and PM) 
score is calculated by averaging 4 weekly scores within the 4-week interval. 
The monthly AM (or PM, or average AM and PM) score can only be 
calculated if at least 3 of 4 weekly scores within the 4-week interval can be 
calculated. 
Baseline for worst weekly score for 
ObsRO scratching (or PRO itching) 
severity 
The baseline for worst weekly score is calculated by taking the worst daily 
score as the maximum of the PM score and the next day AM score in the 14 
days preceding start of treatment, then calculating the worst weekly score 
by taking the average of the worst daily scores in a week (7 days), and 
finally calculating the worst weekly score for baseline as the maximum of 
the worst weekly scores within the 2-week interval. 
At least one of the PM score or the next day AM score need to be collected 
to calculate the worst daily score. At least 4 of 7 worst daily scores within 
the week are needed to calculate the worst weekly score. The worst weekly 
score for baseline is calculated if at least one worst weekly score within the 
2-week interval can be calculated.   
Worst weekly score for a month for 
ObsRO scratching (or PRO itching) 
severity  
The worst weekly score for a month (28 days) is calculated by taking the 
worst daily score as the maximum of the PM score and the next day AM 
score, then calculating the worst weekly score by taking the average of the 
worst daily scores in a week (7 days), and finally calculating the worst 
weekly score for a month as the maximum of the worst weekly scores 
within the 4-week interval.  
At least one of the PM score or the next day AM score need to be collected 
to calculate the worst daily score. At least 4 of 7 worst daily scores within 
the week are needed to calculate the worst weekly score. The worst weekly 
score for a given month is calculated if at least one worst weekly score 
within the 4-week interval can be calculated.   
The worst weekly score for a month is calculated for each month of post-
baseline 


Statistical Analysis Plan  
 
  Version number: 2.0  
Product Code-Study NumberA4250-012 
 
  27Sep2022 
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                                                                                                                                    Page 46 of 73 
 
Variables 
Formula 
Change from baseline for ObsRO 
scratching or (PRO itching) severity 
score 
The daily, weekly, monthly AM (or PM, or average AM and PM) score 
change from baseline is calculated by subtracting the baseline AM (or PM, 
or average AM and PM) score from the daily, weekly, monthly AM (or PM, 
or average AM and PM) score 
Change from baseline for worst 
weekly score for a month for ObsRo 
scratching (or PRO itching) severity 
Change from baseline in the worst weekly score for a month is calculated 
by subtracting the worst baseline score from the worst weekly score for a 
month 
Average Month 4 to 6 and change 
from baseline 
Average of all available monthly scores through Month 4 to 6. 
Change from baseline through Month 4 to 6 is calculated by subtracting the 
baseline score from the average of monthly scores through Month 4 to 6. 
Baseline and monthly score for 
sleep parameters (such as difficulty 
of falling asleep and staying asleep, 
tiredness, and the number of 
awakening)  
For patient- and observer- reported outcome scores of sleep parameters, the 
same approach above will be used as for scratching (or itching) severity 
score by AM and PM respectively since there is just 1 rating per day. 
PRO and ObsRO Assessment 
Scores for psychometric analyses  
Please refer to psychometric analysis plan  
 
 
Derivation for Safety Parameters  
AE duration (days) 
AE end date – AE start date +1 
TEAE 
An AE (classified by preferred term) that occurs during the Treatment 
Period will be considered a TEAE if it has a start date on or after the first 
dose date of study drug, or it has a start date before the date of the first dose 
date of study drug, but worsened in severity on or after the date of the first 
dose date of study drug 
 
 


Statistical Analysis Plan  
 
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Product Code-Study NumberA4250-012 
 
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5.3 
Appendix 3 Data Handling Conventions 
Analysis windows for time points 
The following analysis windows will decide how the scheduled and/or unscheduled visits will be 
used in the by-visit analyses of efficacy and safety variables. A measurement (scheduled or 
unscheduled) will be used if it is available and measurement date is within the analysis window.   
After applying these time windows, if multiple assessments are associated to the same time point, 
the closest from the targeted study day will be used. In case of ties between observations located 
on different sides of the target day, the earlier assessment will be used. For laboratory parameters, 
central laboratory results will be used over local laboratory results if both are in a same analysis 
window. 
Table 10.1 - Analysis visit windows (general) 
Timing of assessment 
 
Visit Name to 
display for 
Analysis 
Targeted study 
day 
Analysis window in 
study days /  
date of assessment 
Screening  
Baseline 
 
<= -1 
Randomization day 1 
Baseline 
 
1 (pre-dose) 
Week 4  
Week 4 
28 
Post-baseline to 42 
Week 8  
Week 8 
56 
43 to 70 
Week 12  
Week 12 
84 
71 to 98  
Week 16  
Week 16 
112 
99 to 126 
Week 20  
Week 20 
140 
127 to 154 
Week 24  
Week 24 
168 
155 to EOSa / 
155 to EOS-1b 
4 Weeks Post Last Dose of Study Drug  
Follow-up 
 
EOSb 
EOS=date of EOS assessment 
a For patients who rollover to Study A4250-015.  
b For patients who not rollover to Study A4250-015. 
Table 10.2 - Analysis visit windows (GIC/GIS, PedsQL, xanthoma and selected lab tests) 
Timing of assessment 
 
Visit Name to 
display for 
Analysis 
Targeted study 
day 
Analysis window in 
study days / 
date of assessment 
Screening  
Baseline 
 
<= -1 
Randomization day 1  
Baseline 
1 (pre-dose) 
Week 4  
Week 4 
28 
Post-baseline to 56 
Week 12  
Week 12 
84 
57 to 126  
Week 24 
Week 24 
168 
127 to EOSa / 
127 to EOS-1b 
4 Weeks Post Last Dose of Study Drug  
Follow-up 
 
EOSb  
Note  Selected lab tests include hematology, urinalysis, autotaxin, p-C4, Vitamins A & E and 25-hydroxy vitamin D. 
EOS=date of EOS assessment 
a For patients who rollover to Study A4250-015.  
b For patients who not rollover to Study A4250-015. 


Statistical Analysis Plan  
 
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Table 10.3 - Analysis visit windows (abdominal ultrasound and elastography, AFP) 
Timing of assessment 
Visit Name to 
display for 
Analysis 
Targeted study 
day 
Analysis window in 
study days / 
date of assessment 
Screening  
Baseline 
 
<= -1 
Randomization day 1  
Baseline 
1 (pre-dose) 
Week 24 
Week 24 
168 
71 to EOSa / 
71 to EOS-1b 
4 Weeks Post Last Dose of Study Drug  
Follow-up 
 
EOSb  
EOS=date of EOS assessment 
a For patients who rollover to Study A4250-015.  
b For patients who not rollover to Study A4250-015. 
Derivations for scratching score (or itching score), sleep parameters measured by the Albireo 
ObsRO (or PRO) instrument will be derived based on the following analysis window. For analysis 
purposes, diary entries will be assigned to a study day based on the recorded date regardless of 
recorded time. 
Table 10.4 - Analysis visit windows for scratching score (or itching score), sleep parameters 
Analysis Window  
Treatment Period  
Start Study Day  
End Study Day  
Baseline  
Week 0 (randomization) 
Day -14, PM assessment  
Day -28, PM assessment a 
Day 1, AM assessment  
Week 1  
Week 1  
Day 1, PM assessment  
Day 8, AM assessment  
Week 2  
Week 2  
Day 8, PM assessment  
Day 15, AM assessment  
Week X 
Week X  
Day 7*(x-1)+1, PM assessment  
Day 7*x+1, AM assessment  
 a Day -28 is for sensitivity analysis. 
 
 


Statistical Analysis Plan  
 
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Product Code-Study NumberA4250-012 
 
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5.4 
Appendix 4 Definition of Region Variable  
Table 11 – Country code and region 
Country  
Country code  
Region variable  
Belgium 
BEL 
EU 
Canada 
CAN 
RoW 
France 
FRA 
EU 
Germany 
DEU 
EU 
Israel 
ISR 
RoW 
Italy 
ITA 
EU 
Malaysia 
MYS 
RoW 
Netherlands 
NLD 
EU 
New Zealand 
NZL 
RoW 
Poland 
POL 
EU 
Turkey 
TUR 
RoW 
United Kingdom 
GBR 
RoW 
United States 
USA 
US 
 
 
 


Statistical Analysis Plan  
 
  Version number: 2.0  
Product Code-Study NumberA4250-012 
 
  27Sep2022 
Confidential 
                                                                                                                                    Page 50 of 73 
 
5.5 
Appendix 5 Handling of Missing or Incomplete Dates  
Global statement: 
If the imputed date is prior to the date of birth, then impute the missing date as date of birth. 
Imputation rules for missing or partial AE start date are defined below: 
If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the first dose date, then: 
x If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start day as the day of first dose date; 
x If AE end date is prior to first dose date, then impute the AE start day as 1. 
If Day and Month of AE start date are missing: 
If AE start year = first dose year, then: 
x If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then impute the AE start month and day as the month and day of first dose date; 
x If AE end date is prior to first dose date, then impute the AE start month as January and 
the day as 1. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing, then query the site with 
no imputation. Also compare the full (or partial) AE end date to the first dose date. If the AE end 
date is before the first dose date, then the AE should be considered as a pre-treatment AE. 
Otherwise, the AE will be considered as TEAE. 
Imputation rules for missing or partial non-study medication start/stop dates are defined below: 
Missing or partial non-study medication start date: 
x If only day is missing, use the first day of the month. 
x If day and month are both missing, use the first day of the year. 
x If day, month and year are all missing, use the date of the day before the first dose date. 
Missing or partial non-study medication stop date: 
x If only day is missing, use the last day of the month. 
x If day and month are both missing, use the last day of the year. 
x If day, month and year are all missing, assign ‘continuing’ status to stop date 
 
 


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 5 1 of 7 3 
 
5. 6  
A p pe n di x 6 S a m ple S A S C o des 
T he c o variates i n t he m o del will be a dj uste d  acc or di n gl y base d o n t he S A P f or t he c orres p o n di n g 
e n d p oi nts.  
1. M M R M 
2. C oc hr a n- M a ntel- H ae nszel test 
3. A N C O V A m o del 
4. MI  
C CI
C CI
C CI
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 5 2 of 7 3 
 
5. Pr o p orti o n al O d ds M o del  
C CI


Statistical Analysis Plan  
 
  Version number: 2.0  
Product Code-Study NumberA4250-012 
 
  27Sep2022 
Confidential 
                                                                                                                                    Page 53 of 73 
 
5.7 
Appendix 7 Normal Reference Ranges for Vital Signs [9] 
Table 12.1 - Heart rate by age (beats/minute) reference 
 Age  
 Awake Rate  
Infant (< 1 y) 
 100-190  
Toddler (>= 1 – < 3 y)  
 98-140  
Preschool (>= 3 – < 6 y) 
 80-120  
School-age (>= 6 – < 12 y) 
 75-118  
Adolescent (>= 12 – < 15 y) 
 60-100  
>= 15 y 
 60-100 
 
Table 12.2 - Normal respiratory rate by age (breaths/minute) reference 
 Age  
 Respiratory Rate  
Infant (< 1 y) 
 30-53  
Toddler (>= 1 – < 3 y)  
 22-37  
Preschool (>= 3 – < 6 y) 
 20-28  
School-age (>= 6 – < 12 y) 
 18-25  
Adolescent (>= 12 – < 15 y) 
 12-20  
>= 15 y 
 12-20 
 
Table 12.3 - Normal blood pressure by age (mm Hg) reference 
 Age  
 Systolic Pressure  
 Diastolic Pressure  
 
Infant (< 1 y) 
 72-104  
 37-56  
 
 Toddler ((>= 1 – < 3 y)  
 86-106  
 42-63  
 
 Preschooler (>= 3 – < 6 y) 
 89-112  
 46-72  
 
 School-age (>= 6 – < 10 y) 
 97-115  
 57-76  
 
 Preadolescent (>= 10 – < 12 y) 
 102-120  
 61-80  
 
Adolescent (>= 12 – < 15 y) 
 110-131  
 64-83  
 
>= 15 y 
 90-120 
 50-80 
 
 
 
 


Statistical Analysis Plan  
 
  Version number: 2.0  
Product Code-Study NumberA4250-012 
 
  27Sep2022 
Confidential 
                                                                                                                                    Page 54 of 73 
 
5.8 
Appendix 8 SI And US Conventional Units of Clinical Laboratory Values 
 
SERUM CHEMISTRY 
SI UNIT 
CONVENTIONAL UNIT 
Analyte 
 
 
    Alpha Fetoprotein 
IU/mL 
ng/mL 
    Direct bilirubin 
mol/L 
mg/dL 
    Calcium 
mmol/L 
mg/dL 
    Chloride 
mmol/L 
mEq/L 
    Creatinine 
umol/L 
mg/dL 
    Potassium 
mmol/L 
mEq/L 
    Sodium 
mmol/L 
mEq/L 
    Serum bile acid 
mol/L 
g/mL 
    Total bilirubin 
mol/L 
mg/dL 
    Total cholesterol 
mmol/L 
mg/dL 
    Triglycerides 
mmol/L 
mg/dL 
Haematology 
SI Unit 
Conventional Unit 
Analyte 
 
 
    Haematocrit 
L/L 
% 
    Haemoglobin 
g/L 
g/dL 
    Red blood count (RBC) 
x10ˆ12/L 
x10ˆ6/L 
    Platelet count 
x10ˆ9/L 
x10ˆ3/L 
    White blood cell count 
x10ˆ9/L 
x10ˆ3/L 
Fat Soluble Vitamins  
SI Unit 
Conventional Unit 
    Vitamin A 
mol/L 
mg/L 
    Vitamin E 
mol/L 
mg/L 
    Vitamin D (25-dihydroxy) 
nmol/L 
ng/mL 
Urinalysis 
SI Unit 
Conventional Unit 
Analyte 
  
  
    Glucose 
mmol/L 
mg/dL 
 
 
 


Statistical Analysis Plan  
 
  Version number: 2.0  
Product Code-Study NumberA4250-012 
 
  27Sep2022 
Confidential 
                                                                                                                                    Page 55 of 73 
 
5.9 
Appendix 9 Classification of Hepatic Function 
x Categorization of Hepatic Impairment [6] 
 
 
 
Total Bilirubin 
ALT or AST 
No impairment 
 
 
 
Mild 
A (5-6 PT) 
%  ULN 
B2: >1–1.5XULN 
B1: > ULN 
B2: ANY 
Moderate 
B (7–9 PT) 
>1.5–3X ULN 
Any 
Severe 
C (10–15 PT) 
>3X ULN 
Any 
x Child-Pugh Scores [10, 11] 
 
 
 
 
Point 
Encephalopathy (exclusion criteria, as per 
Protocol A4250-012) 
None 
1 
Ascites (exclusion criteria, as per Protocol 
A4250-012) 
Absent 
1 
Bilirubin (baseline) 
<2 mg/dL 
1 
2-3 mg/dL 
2 
>3 mg/dL 
3 
Albumin (baseline) 
>3.5 g/dL 
1 
2.8-3.5 g/dL 
2 
<2.8 g/dL 
3 
Prothrombin time (PT) prolongation 
(baseline) 
Less than 4 seconds above control for PT 
1 
4-6 seconds above control for PT 
2 
More than 6 seconds above control for PT 
3 
Classification 
5 to 6 points : Child-Pugh A (mild liver impairment) 
7 to 9 points : Child-Pugh B (moderate liver impairment) 
10 to 15 points : Child-Pugh C (severe liver impairment) 


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 5 6 of 7 3 
 
5. 1 0  A p pe n di x 1 0 P T Ter ms of P ossi bl e Se q uel ae of F S V Deficie nc y 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 5 7 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 5 8 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 5 9 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 0 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 1 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 2 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 3 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 4 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 5 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 6 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 7 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 8 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 6 9 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 7 0 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 7 1 of 7 3 
 
C CI


Statistical A nal ysis Pla n  
  
  Versi o n n u m ber: 2. 0  
Pr o d uct C o de- St u d y N u m ber A 4 2 5 0- 0 1 2  
  
  2 7 Se p 2 0 2 2 
C o nfi de ntial 
                                                                                                                                    Pa ge 7 2 of 7 3 
 
 
 
C CI


Statistical Analysis Plan  
 
  Version number: 2.0  
Product Code-Study NumberA4250-012 
 
  27Sep2022 
Confidential 
                                                                                                                                    Page 73 of 73 
 
6 
References 
1. ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95- adopted 
December 1995). 
2. ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted March 
1998). 
3. ICH E9 (R1): Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the 
guideline on Statistical Principles for Clinical Trials (EMA/CHMP/ICH/436221/2017 – adopted 
30 January 2020). 
4. US Food & Drug Administration. Adaptive Designs for Clinical Trials of Drugs and Biologics 
Guidance for Industry, December 2019. (https://www.fda.gov/media/78495/download) 
5. Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not affect the 
type I error rate. Stat Med. 2003; 22:3571–81. 
6. Aaron S. Mansfield, Michelle A. Rudek, Diana Vulih, Gary L. Smith, Pamela Jo Harris, and S. 
Percy Ivy (2016). The effect of hepatic impairment on outcomes in phase 1 clinical trials in cancer 
subjects. Clinical Cancer Research 2016 Nov 15, 22 (22): 5472-5479. 
7. European Medicines Agency (EMA). Guideline on Missing Data in Confirmatory Clinical 
Trials (EMA/CPMP/EWP/1776/99 Rev. 1– adopted 24Jun2010) 
8. US Food & Drug Administration. Adjusting for Covariates in Randomized Clinical Trials for 
Drugs and Biological Products. Guidance for Industry, May 2021 Revision 1. 
(https://www.fda.gov/media/148910/download) 
9. Peds cases - Pediatrics for Medical Students - Developed by Chris Novak and Peter Gill for 
PedsCases.com April 21, 2016 (http://www.pedscases.com/pediatric-vital-signsreference-Chart) 
10. FDA Guidance for Industry. Pharmacokinetics in Patients with Impaired Hepatic Function:  
Study Design, Data Analysis, and Impact on Dosing and Labeling. May 2003. Clinical 
Pharmacology. https://www.fda.gov/media/71311/download 
11. Child Pugh Classification for Severity of Liver Disease. 
(https://www.merckmanuals.com/medical-calculators/ChildTurPuScore.htm) 
12. CDC: https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm 
13. WHO: https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas-who.htm 
14. Rubin, D.B., Multiple Imputation for Nonresponse in Surveys. J. Wiley & Sons, New York, 
1987.