Clinical trial NCT05569252
Conditions: Pseudoxanthoma Elasticum
Keywords: Pseudoxanthoma Elasticum DS-1211b
Sponsor: Daiichi Sankyo
Start date: 2022-10-20; Completion date: 2023-11-21
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed to evaluate the safety, tolerability, pharmacodynamics (PD) of DS-1211b, and pharmacokinetics (PK) in individuals with Pseudoxanthoma elasticum (PXE). PXE is a rare disease that is associated with significant risks of visual impairments and comorbidity from peripheral and cardiovascular diseases, and adversely impacts the quality of life in afflicted individuals.

Detailed description:
DS-1211b, a potent small-molecule inhibitor of tissue-nonspecific alkaline phosphatase, is being developed for the treatment ectopic calcification diseases such as PXE. This study will assess DS-1211b (low-, middle-, and high-dose tablets) administered once daily for 12 weeks in individuals with PXE.

Arms: arm 1: Participants who will be randomized to receive a DS-1211 tablet once daily for 12 weeks. arm 2: Participants who will be randomized to receive a DS-1211b tablet once daily for 12 weeks. arm 3: Participants who will be randomized to receive a DS-1211b tablet once daily for 12 weeks. arm 4: Participants who will be randomized to receive a placebo tablet once daily for 12 weeks.
Interventions: intervention 1: DS-1211b intervention 2: Placebo
Intervention descriptions: intervention 1: DS-1211b tablet administered once daily in the morning either in the fasted state or with a meal intervention 2: Placebo tablet administered once daily in the morning either in the fasted state or with a meal

Protocol documents:
Prot_SAP_000.pdf: 
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Page 1 
CLINICAL STUDY PROTOCOL 
A PHASE 2, 12-WEEK, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY OF DS-1211B 
IN INDIVIDUALS WITH PSEUDOXANTHOMA 
ELASTICUM 
DS1211-A-U201 
 
IND NUMBER 135092  
 
VERSION 3.0, 16 JAN 2023 
VERSION 2.0, 03 OCT 2022 
VERSION 1.0, 22 OCT 2021 
 
DAIICHI SANKYO 
211 MT. AIRY ROAD 
BASKING RIDGE, NJ 07920 United States 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo.  The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo. 
 


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INVESTIGATOR AGREEMENT 
A Phase 2, 12-Week, Randomized, Double-Blind, Placebo-Controlled Study of DS-1211b in 
Individuals with Pseudoxanthoma Elasticum 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with 
the Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential 
and should not be disclosed, other than to those directly involved in the execution or the 
ethical review of the study, without written authorization from the Sponsor.  It is, 
however, permissible to provide information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Council for 
Harmonisation guidelines on Good Clinical Practice (ICH E6), and applicable regional 
regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant 
regulatory authorities, my subjects’ study records in order to verify the data that I have 
entered into the case report forms.  I am aware of my responsibilities as a Principal 
Investigator as provided by the Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study 
at any time for whatever reason; such a decision will be communicated to me in writing.  
Conversely, should I decide to withdraw from execution of the study, I will communicate 
my intention immediately in writing to the Sponsor. 
Print Name 
Signature 
Title 
Date (DD MMM YYYY) 


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SUMMARY OF CHANGES 
Please refer to the comparison document for Protocol Version 3.0 (dated 16 Jan 2023) versus 
Protocol Version 2.0 (dated 03 Oct 2022) for actual changes in text.  The Summary of Changes 
below is a top-line summary of major changes in the current DS1211-A-U201 clinical study 
protocol (Version 3.0) by section. 
Amendment Rationale: 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (section numbers and/or paragraph/bullet numbers) refer to the current protocol 
version, which incorporates the items specified in this Summary of Changes document. 
Minor edits, such as update to language that does not alter original meaning, update to version 
numbering, formatting, change in font color, corrections to typographical errors, use of 
abbreviations, moving verbiage within a section or table, change in style, or change in case, 
are not noted in the table below. 
Section # and Title 
Description of Change 
Brief Rationale 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
SUMMARY OF CHANGES ...........................................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................5 
LIST OF ABBREVIATIONS ........................................................................................................15 
1. 
INTRODUCTION ........................................................................................................17 
1.1. 
Background ...................................................................................................................17 
1.2. 
Study Rationale .............................................................................................................17 
2. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS .................................18 
2.1. 
Study Objectives ...........................................................................................................18 
3. 
STUDY DESIGN ..........................................................................................................20 
3.1. 
Overall Design ..............................................................................................................20 
3.2. 
Discussion of Study Design ..........................................................................................20 
3.3. 
Schedule of Events ........................................................................................................22 
4. 
STUDY POPULATION ...............................................................................................28 
4.1. 
Inclusion Criteria ...........................................................................................................28 
4.2. 
Exclusion Criteria..........................................................................................................28 
5. 
STUDY TREATMENT(S) ...........................................................................................30 
5.1. 
Assigning Subjects to Treatments and Blinding ...........................................................30 
5.1.1. 
Treatment Group(s)/Sequences .....................................................................................30 
5.1.2. 
Method of Treatment Allocation ...................................................................................30 
5.1.3. 
Blinding .........................................................................................................................30 
5.1.4. 
Emergency Unblinding Procedure ................................................................................30 
5.2. 
Study Drug(s) ................................................................................................................31 
5.2.1. 
Description ....................................................................................................................31 
5.2.2. 
Labeling and Packaging ................................................................................................31 
5.2.3. 
Preparation ....................................................................................................................31 
5.2.4. 
Administration ..............................................................................................................31 
5.2.5. 
Storage...........................................................................................................................31 
5.2.6. 
Drug Accountability ......................................................................................................31 
5.3. 
Control Treatment .........................................................................................................32 
5.4. 
Dose Interruptions and Reductions ...............................................................................32 


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5.5. 
Method of Assessing Treatment Compliance ...............................................................32 
5.6. 
Prior and Concomitant Medications..............................................................................32 
5.7. 
Subject Withdrawal/Discontinuation ............................................................................33 
5.7.1. 
Reasons for Withdrawal ................................................................................................33 
5.7.2. 
Withdrawal Procedures .................................................................................................33 
5.7.3. 
Subject Replacement .....................................................................................................34 
5.7.4. 
Subject Rescreening Procedures ...................................................................................34 
6. 
STUDY PROCEDURES ..............................................................................................35 
6.1. 
Screening .......................................................................................................................35 
6.2. 
Randomization ..............................................................................................................35 
6.3. 
Treatment Period ...........................................................................................................35 
6.4. 
End of Treatment...........................................................................................................35 
7. 
EFFICACY ASSESSMENTS .......................................................................................36 
7.1. 
Assessments for Efficacy Endpoint(s) ..........................................................................36 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) ...................................................36 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ........................37 
8.1. 
Pharmacokinetic (PK) Assessment(s) ...........................................................................37 
8.2. 
Pharmacodynamic Assessment(s) .................................................................................37 
8.3. 
Biomarker Assessment(s)..............................................................................................37 
8.4. 
Immunogenicity ............................................................................................................37 
8.5. 
Pharmacogenetic (Inherited Genetic) Analysis .............................................................38 
9. 
SAFETY EVALUATION AND REPORTING ...........................................................39 
9.1. 
Assessment of Safety Endpoint(s) ................................................................................39 
9.2. 
Adverse Event Collection and Reporting ......................................................................39 
9.3. 
Combined Elevations of Aminotransferases and Bilirubin and Adverse Events 
of Special Interest ..........................................................................................................40 
9.4. 
Adverse Event ...............................................................................................................41 
9.4.1. 
Definition of Adverse Event .........................................................................................41 
9.4.2. 
Serious Adverse Event ..................................................................................................41 
9.4.3. 
Severity Assessment .....................................................................................................42 
9.4.4. 
Causality Assessment ....................................................................................................42 
9.4.5. 
Action Taken Regarding Study Drug(s) .......................................................................42 
9.4.6. 
Other Action Taken for Adverse Event ........................................................................42 


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9.4.7. 
Adverse Event Outcome ...............................................................................................43 
9.5. 
Serious Adverse Events Reporting–Procedure for Investigators ..................................43 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ...............................................................................................44 
9.7. 
Exposure In Utero During Clinical Studies ..................................................................44 
9.8. 
Clinical Laboratory Evaluations ...................................................................................45 
9.9. 
Vital Signs .....................................................................................................................45 
9.10. 
Electrocardiograms .......................................................................................................45 
9.11. 
Physical Examinations ..................................................................................................45 
9.12. 
Other Examinations .......................................................................................................45 
10. 
OTHER ASSESSMENTS .............................................................................................46 
10.1. 
COVID-19 Assessments ...............................................................................................46 
11. 
STATISTICAL METHODS .........................................................................................47 
11.1. 
General Statistical Considerations ................................................................................47 
11.2. 
Analysis Sets .................................................................................................................47 
11.3. 
Study Population Data ..................................................................................................47 
11.4. 
Efficacy Analyses..........................................................................................................47 
11.5. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses ...........................................47 
11.5.1. 
Pharmacokinetic Analyses ............................................................................................47 
11.5.2. 
Pharmacodynamic Analyses .........................................................................................48 
11.5.3. 
Biomarker Analyses ......................................................................................................48 
11.5.4. 
Pharmacogenetic (Inherited Genetic) Analyses ............................................................48 
11.6. 
Safety Analyses .............................................................................................................48 
11.6.1. 
Adverse Event Analyses ...............................................................................................48 
11.6.2. 
Clinical Laboratory Evaluation Analyses .....................................................................49 
11.6.3. 
Vital Sign Analyses .......................................................................................................49 
11.6.4. 
Electrocardiogram Analyses .........................................................................................49 
11.7. 
Other Endpoint Analysis ...............................................................................................49 
11.8. 
Interim Analyses ...........................................................................................................49 
11.8.1. 
Data Monitoring Committee .........................................................................................49 
11.9. 
Sample Size Determination ...........................................................................................50 
11.10. 
Statistical Analysis Process ...........................................................................................50 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................51 


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12.1. 
Monitoring and Inspections ..........................................................................................51 
12.2. 
Data Collection..............................................................................................................51 
12.3. 
Data Management .........................................................................................................52 
12.4. 
Study Documentation and Storage ................................................................................52 
12.5. 
Recordkeeping...............................................................................................................53 
13. 
FINANCING AND INSURANCE ...............................................................................54 
13.1. 
Finances.........................................................................................................................54 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................54 
14. 
PUBLICATION AND PUBLIC DISCLOSURE OF CLINICAL TRIAL 
INFORMATION ...........................................................................................................55 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ................................56 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance........................................56 
15.2. 
Subject Confidentiality..................................................................................................56 
15.3. 
Informed Consent ..........................................................................................................56 
15.4. 
Regulatory Compliance .................................................................................................57 
15.5. 
Protocol Deviations .......................................................................................................58 
15.6. 
Supply of New Information Affecting the Conduct of the Study .................................58 
15.7. 
Protocol Amendments ...................................................................................................59 
15.8. 
Study Termination .........................................................................................................59 
15.9. 
Data and Safety Monitoring Board ...............................................................................59 
16. 
REFERENCES ..............................................................................................................60 
17. 
APPENDICES ..............................................................................................................62 
17.1. 
CYP Inhibitors and Inducers .........................................................................................62 
17.2. 
Highly Effective Contraception ....................................................................................64 
 


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LIST OF TABLES 
Table 2.1: Description of Objectives, Outcome Measures, and Endpoints .................................18 
Table 3.1: Schedule of Events .....................................................................................................22 
Table 3.2: Intraday Schedule for Select Assessments During Visits 2 to 5 .................................27 
Table 17.1: CYP3A4 Inhibitors/Inducers ......................................................................................62 
Table 17.2: CYP2C19 Inhibitors/Inducers ....................................................................................63 
 


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LIST OF FIGURES 
Figure 3.1: Study Schema .............................................................................................................20 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ABCC6 
ATP-binding cassette subfamily C member 6 
AE 
adverse event 
AESI 
adverse events of interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCinf  
area under the plasma concentration-time curve up to infinity  
AUClast  
area under the plasma concentration-time curve up to the last quantifiable 
time  
AUCtau   
area under the plasma concentration-time curve during dosing interval   
BSAP 
bone-specific alkaline phosphatase 
BUN 
blood urea nitrogen 
Ca 
calcium 
Cmax  
maximum plasma concentration  
COVID-19  
coronavirus disease 2019 
CRF 
case report form 
eCRF 
electronic case report form 
CRO 
contract research organization 
Ctrough  
trough plasma concentration  
EC 
Ethics Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EIU 
exposure in utero 
ENPP1 
ectonucleotide pyrophosphatase/phosphodiesterase 1 
EU 
European Union 
 
 
GCP 
Good Clinical Practice  
 
 
HPP 
hypophosphatasia 
ICF 
informed consent form 
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ABBREVIATION 
DEFINITION 
ICH 
International Council for Harmonisation 
ICMJE 
International Council of Medical Journal Editors 
 
 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
 
 
LLN 
lower limit of normal  
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
magnesium 
MOA 
mechanism of action 
 
 
 
 
PD 
pharmacodynamic 
Pi 
inorganic phosphate 
PK 
pharmacokinetic 
PLP 
pyridoxal 5’-phosphate 
PPi 
inorganic pyrophosphate 
PXE 
pseudoxanthoma elasticum 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAVER 
serious adverse event report 
 
 
SoE 
schedule of events 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
Tmax  
time to reach maximum plasma concentration  
TMF 
trial master file 
TNAP 
tissue-nonspecific alkaline phosphatase 
ULN 
upper limit of normal  
 
  
VEGF 
vascular endothelial growth factor 
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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Study participants must satisfy all of the following criteria to be included in the study: 
1. Sign and date the ICF prior to the start of any study-specific qualification procedures. 
2. Are male or female participants aged 18 to 75 years at screening. 
3. Have an established diagnosis of PXE, with typical ocular and dermatological clinical 
features1,2: 
a. Ocular findings – angioid streaks or peau d’orange 
b. Skin findings – characteristic PXE papules and plaques or diagnostic 
histopathological changes in lesional skin 
4. Are fully vaccinated for coronavirus disease 2019 (COVID-19) per current Center for 
Disease Control and Prevention guidelines 
5. For women of childbearing potential (not postmenopausal as a result of either natural or 
postsurgery cessation of menses), must have a negative serum pregnancy test at screening 
and must be willing to use an effective method of birth control, as detailed in 
Section 17.2 upon entering study screening, during the treatment period, and up until the 
time of the follow-up visit.  
6. Are willing and able to comply with scheduled visits, drug administration plan, 
laboratory tests, other study procedures, and study restrictions. 
4.2. 
Exclusion Criteria 
Individuals who meet any of the following criteria at screening will be disqualified from entering 
the study: 
1. Have a history of bone fracture in the past 6 months. 
2. Have a history of active metabolic bone disease that significantly affect the interpretation 
of study biomarker results, excluding osteopenia or osteoporosis without fragility 
fracture. 
3. Have a history of calcium pyrophosphate deposit disease such as chondrocalcinosis, 
pseudogout, and pyrophosphate arthropathy.  
4. Have a history of hypophosphatasia. 
5. Have a history of untreated hyperparathyroidism.  
6. Participated in another interventional research study in the past 60 days. 
7. Are participating or have participated within the last 12 months in PXE trials (eg, trials 
with PPi, PPi analogues such as bisphosphonate, or ENPP1 and its analogues) or in 
clinical trials relating to bone mineralization. 




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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group(s)/Sequences 
The study will consist of 4 treatment groups in which study drug will be administered in a 
double-blind, placebo-controlled parallel-group study design (see Figure 3.1). 
5.1.2. 
Method of Treatment Allocation 
Eligible subjects will be randomized in a 1:1:1:1 ratio into the 4 treatment groups (DS-1211b 
 or placebo).  The randomization schedule will be generated by an 
independent biostatistician.  Prior to treatment, a randomization number will be assigned to each 
eligible subject.  The randomization assignment will be implemented by an automatic voice or 
web response system. 
5.1.3. 
Blinding 
This study will be a double-blind study.  Blinding will be applied to all personnel related to the 
study (subjects, Investigators, and the Sponsor), with the exception of the independent 
biostatistician and other staff involved in the preparation, release, and shipment of investigational 
medicinal products. 
The independent biostatistician will generate the randomization schedule in accordance with the 
operating procedure for allocating study drug.  Until the study is unblinded, the study drug 
randomization schedule will be kept securely. 
5.1.4. 
Emergency Unblinding Procedure 
In the case of an emergency where, in the opinion of the Investigator, discontinuation of study 
drug is not sufficient and the study treatment must be unblinded in order to evaluate further a 
course of medical treatment, the Investigator can perform the unblinding, after discussion with 
the Medical Monitor, if possible.  Entry of the Adverse Event case report form (CRF) page 
should be completed before unblinding except in cases where immediate treatment of the subject 
is required.  If immediate treatment is required, the Adverse Event CRF page is to be completed 
within 24 hours of the unblinding.   
In the event of an emergency unblinding, the subject will be informed about his/her treatment 
assigned.  Information about the treatment assignment must be restricted to designated study site 
staff/personnel who are providing immediate care to the subject.  Any documentation of the 
treatment assignment must be maintained separately (ie, a secured file).  The information must 
not be included in the subject’s source files to ensure the treatment assignment will remain 
blinded to the Contract Research Organization (CRO) monitor and other study personnel not 
involved with the subject’s immediate care.   
When an emergency unblinding has occurred, an automatic notification (via e-mail) will be sent 
to the Investigator and selected Daiichi Sankyo study personnel from the interactive response 
technology (IRT) vendor.  The notification will not contain any unblinding information.  This 
will trigger the follow-up process to document the unblinding by completing the Emergency 
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In addition, the Investigator or designee shall contact Sponsor as soon as possible if there is a 
problem with the shipment. 
Drug Accountability will be conducted via the IRT or local site procedures for study drug, 
placebo, and commercial product as appropriate.  The record must be kept current and should 
contain the dates and quantities of study drug received, subject’s identification number (with or 
without initials) and supply number as applicable, the person for whom the study drug was 
dispensed, the date and quantity of study drug dispensed and remaining, and the initials of the 
dispenser. 
The pharmacist (or qualified designee) is responsible for study drug accountability, 
reconciliation, and record maintenance (ie, Receipt of Shipment Form, dispensation/return 
record, and certificate of destruction/return receipt). 
At the end of the study (or as directed), all unused or partially used study drug will be returned or 
destroyed as per local laws or site policy and only after the CRO monitor has completed a final 
inventory. If applicable, the return of study drug must be documented, and the documentation 
must be included in the return shipment. 
Please see the Pharmacy Manual for more details. 
5.3. 
Control Treatment 
See Section 5.2.1. 
5.4. 
Dose Interruptions and Reductions 
Study subjects should adhere to the protocol-prescribed daily morning dosing schedule 
throughout the entire study.  In case the subject misses the morning dose 
 he/she is 
allowed to take the dose later the same day.  
No subject is allowed to take more than one dose per day, regardless of the number of days of 
missed doses. 
Dose modifications are not allowed in this study. Dose interruptions need to be documented. 
After any dose interruption, the subject should resume the assigned once daily study drug as soon 
as possible. 
5.5. 
Method of Assessing Treatment Compliance 
Compliance will be assessed by tablet count (returned versus dispensed).  Administration of 
study drug will be recorded in the CRF/Drug Accountability Record.  Subjects to be asked 
whether all tablets were taken orally or if any tablets were disposed/thrown away.  
5.6. 
Prior and Concomitant Medications 
Medications used within 30 days prior to screening will be recorded.  COVID-19 vaccine doses 
received prior to the study will be documented as prior medication, regardless of date of 
administration. COVID-19 vaccine dose administered during the study will be recorded as a 
concomitant medication. 
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5.7.3. 
Subject Replacement 
Subject replacement is not planned in this study. 
5.7.4. 
Subject Rescreening Procedures 
Rescreening is permitted for any subject who fails to meet eligibility criteria upon initial 
screening and later has changes in his/her medical condition or other circumstances that in the 
opinion of the Investigator (in consultation with the Sponsor) warrant reconsideration of study 
eligibility.  The subject identification number must be new at the time of rescreening.  The initial 
screening information and the reason why the subject is ineligible for the initial evaluation will 
be recorded on the screening log.  Data from the initial evaluation will be entered into the clinical 
database for a subject who is rescreened. 


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6. 
STUDY PROCEDURES 
See SoE (Table 3.1, Table 3.2), for screening, treatment, end of treatment, and follow-up study 
procedures. 
6.1. 
Screening 
Individuals with an established diagnosis of PXE will be screened between Day -30 through 
Day -1.  Rescreening will be allowed. 
6.2. 
Randomization 
This will be a double-blind (subject and Investigator) randomized study. 
Individuals who complete the screening process and meet the eligibility requirements will be 
randomized on Study Day 1. 
More information on the method of assigning subjects is found in Section 5.1.2. 
6.3. 
Treatment Period 
Approximate visit durations are expected to be: 
 
Visits 1, 6, and 7: a few hours  
 
Visit 3 and 4: more than 6 hours  
 
Visits 2 and 5: more than 10 hours  
Visits 1 through 5 are fasting visits (overnight fast [≥8 hours]).  Study participants will be 
allowed to eat after the first blood collection.  
Visits 6 and 7 will be conducted as in-home visits unless requested by the study participant or 
Investigator. 
Study participants should withhold the intake of vitamin B6 or vitamin B6-containing 
supplements on the day of the study visits (Visits 1 to 7).  Vitamin B6 or vitamin B6-containing 
supplements can be resumed after all study-related procedures are completed. 
6.4. 
End of Treatment 
Visit 5 (Day 84) is the end of treatment visit.  Any study participant who discontinues early will 
complete early discontinuation assessment using the procedures outlined in the end of treatment 
visit and the follow-up assessments (Visits 6 and 7). 
 


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7. 
EFFICACY ASSESSMENTS 
Not applicable as the study evaluation is based on MOA-related biomarker assessments. 
7.1. 
Assessments for Efficacy Endpoint(s) 
Not applicable. 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) 
Not applicable. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic (PK) Assessment(s) 
Venous blood samples will be collected for PK analysis of DS-1211a at the timepoints detailed 
in Table 3.1 and Table 3.2. 
Fasting is not required except for the predose samples, which will be collected after an overnight 
fast (≥ 8 hours).  Whenever electrocardiograms (ECGs) are performed, ECGs should be 
performed prior to blood collections.  The windows for PK blood sample collection are as 
follows: 120 minutes at the predose timepoint and by ±10% of the nominal sampling time 
thereafter.  The actual dosing time and sampling times will be captured on the electronic Case 
Report Form (eCRF). 
Plasma will be harvested and analyzed for the quantification of DS-1211a using a validated 
liquid chromatography-tandem mass spectrometry method.   
8.2. 
Pharmacodynamic Assessment(s) 
Venous blood samples will be collected for the measurement of ALP, PPi, and PLP following 
the sampling schedule in Table 3.1 and Table 3.2.  
The windows for PD blood sample collection and details on assessment times and deviations are 
as follows: 120 minutes at the predose timepoint, and by ± 10% of the nominal sampling time 
thereafter.  Changes of biomarker levels from baseline will be calculated on the basis of plasma 
concentration-time data. 
Biomarker samples will be analyzed by using a qualified analytical method for each marker.  
8.3. 
Biomarker Assessment(s) 
The estimated creatinine clearance (in millimeters per minute) will be calculated by using the 
Cockcroft-Gault equation. 
8.4. 
Immunogenicity 
Not applicable. 
CCI




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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
The safety endpoints include the following: 
 
AEs 
 
ECG findings 
 
Clinical laboratory test results 
 
Physical examination/assessment findings 
 
Hypophosphatasia (HPP) monitoring: 
 Plasma ALP, PLP, PPi, Pi, and Mg 
 Ca (serum and urinary) 
 
 
 
Nephrotoxicity monitoring: Serum and urine creatinine, BUN, urine total protein, 
urine albumin, urine KIM-1, and urine NGAL 
9.2. 
Adverse Event Collection and Reporting 
All AEs (see Section 9.4.1 and Section 9.4.2 for definitions) occurring after the subject signs the 
Informed Consent Form and up to 14 (± 5) days after the last dose of study medication (ie, the 
follow-up period), whether observed by the Investigator or reported by the subject, will be 
recorded on the Adverse Event CRF page.  All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up. 
Medical conditions (including clinically significant laboratory values/vital signs that are out of 
range) that were diagnosed or known to exist prior to the consent date will be recorded as 
medical history, and not an Adverse Event.  Exacerbation of a pre-existing medical occurrence 
and symptom including increase in severity of the symptom will be recorded as an AE on the 
Adverse Event section. 
All AEs and serious adverse events (SAEs) are to be reported according to the procedures in 
Section 9.5.   
All clinical laboratory results, vital signs, and ECG results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or ECG findings (i.e., not part of a reported diagnosis) should be reported as AEs 
if they are symptomatic, lead to study drug discontinuation, dose reduction, require corrective 
treatment, or constitute an AE in the Investigator’s clinical judgment. 
At each visit, the Investigator or designee will determine whether any AEs have occurred by 
evaluating the subject.  Adverse events may be directly observed, reported spontaneously by the 
subject or by questioning the subject at each study visit.  Subjects should be questioned in a 
general way, without asking about the occurrence of any specific symptoms.  The Investigator 
must assess all AEs to determine seriousness, severity, and causality in accordance with the 
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definitions in Section 9.4.  The Investigator’s assessment must be clearly documented in the 
site’s source documentation with the Investigator’s signature.   
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE.   
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization).  A procedure is 
not an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to 
signing the Informed Consent Form) procedures or treatments requiring hospitalization for pre-
existing conditions that do not worsen in severity should not be reported as SAEs (see Section 
9.4.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an SAE. 
COVID-19 assessments are detailed in Section 10.1.  
9.3. 
Combined Elevations of Aminotransferases and Bilirubin and 
Adverse Events of Special Interest 
Combined elevations of aminotransferases and bilirubin, either serious or nonserious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law case 
(ALT or AST ≥3 × ULN with simultaneous total bilirubin [TBL] ≥ 2 × ULN) should always be 
reported to the Sponsor by using a special collection eCRF with the Investigator’s assessment of 
seriousness, causality, and a detailed narrative.14  These events should be reported within 
24 hours of Investigator’s awareness of the event. 
If the subject discontinues study drug because of liver enzyme abnormalities, the subject should 
have additional clinical and laboratory evaluations in order to determine the nature and severity 
of the potential liver injury. 
There are no adverse events of special interest (AESIs) for this study.  Hypophosphatasia and 
nephrotoxicity will be monitored using laboratory alerts and review of AEs reported during this 
study.  Details of HPP and nephrotoxicity monitoring during the conduct of the study are 
described in the Medical Monitoring Plan.  
If the laboratory alerts indicate deterioration of the subject’s renal function, the Investigator will 
be contacted to obtain relevant subject medical history, Investigator’s assessment of clinical 
significance of the results, clinical course, and outcome. Based on the discussion between the 
Investigator and the Sponsor, further evaluation may be warranted including temporary 
discontinuation of the investigational product.  
 


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9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical 
product and that does not necessarily have to have a causal relationship with this treatment.  An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product (ICH E2A Guideline.  
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 
1994). 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered adverse events. 
9.4.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that at any dose: 
 
Results in death, 
 
Is life-threatening, 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
 
Results in persistent or significant disability/incapacity, 
 
Is a congenital anomaly/birth defect, or 
 
Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  Examples include 
allergic bronchospasm, convulsions, and blood dyscrasias or development of drug dependency or 
drug abuse. 
Note:  
 
Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE.   
 
Preplanned (prior to signing the Informed Consent Form) procedures or treatments 
requiring hospitalizations for pre-existing conditions that do not worsen in severity 
are not SAEs. 


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9.4.3. 
Severity Assessment 
The following definitions should be used to assess intensity of adverse events: 
 
Mild: Awareness of sign or symptom, but easily tolerated, ie, does not interfere with 
subject’s usual function. 
 
Moderate: Discomfort enough to cause interference with usual activity. 
 
Severe: Incapacitating with inability to work or do usual activity, ie, interferes 
significantly with subject’s usual function. 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event while the 
event itself, however, may be of relatively minor medical significance (such as severe headache).  
This is not the same as "seriousness," which is based on patient/event outcome at the time of the 
event. 
9.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an adverse event and the study drug 
on the basis of his/her clinical judgment and the following definitions.  The causality assessment 
must be made on the basis of the available information and can be updated as new information 
becomes available. 
 
Related: 
 The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study or its chemical group or is 
predicted by known pharmacology. 
 
Not Related: 
 The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the subject’s clinical state or other factors (eg, 
disease under study, concurrent diseases, and concomitant medications).  
9.4.5. 
Action Taken Regarding Study Drug(s) 
 
Dose Not Changed: No change in study drug dosage was made. 
 
Drug Withdrawn: The study drug was permanently stopped. 
 
Drug Interrupted: The study drug was temporarily stopped. 
 
Not Applicable: Subject died, study treatment had been completed prior to adverse 
event, or reaction/event occurred prior to start of treatment. 
9.4.6. 
Other Action Taken for Adverse Event 
 
None. 


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 No treatment was required. 
 
Medication required. 
 Prescription and/or over-the-counter medication was required to treat the adverse 
event. 
 
Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged because of the AE, whether or not 
medication was required. 
 
Other. 
9.4.7. 
Adverse Event Outcome 
 
Recovered/Resolved 
 The subject fully recovered from the adverse event with no residual effect 
observed. 
 
Recovering/Resolving 
 The adverse event improved but has not fully resolved. 
 
Not recovered/Not resolved 
 The adverse event itself is still present and observable. 
 
Recovered/Resolved with sequelae 
 The residual effects of the adverse event are still present and observable. 
 Include sequelae/residual effects. 
 
Fatal 
 Fatal should be used when death is a direct outcome of the adverse event. 
 
Unknown 
9.5. 
Serious Adverse Events Reporting–Procedure for Investigators 
All SAEs will be reported in the CRF. 
The following types of events should be reported by the Investigator in Electronic Data Capture 
(EDC) or on a Serious Adverse Event Report (SAVER) form if EDC is unavailable within 
24 hours of awareness: 
 
SAEs (see Section 9.4.2 for definition) 
 
Hepatic events meeting combination abnormalities (ALT or AST ≥3 × ULN with 
simultaneous TBL ≥2 × ULN) (potential Hy’s Law case), both serious and 
nonserious. 
Although pregnancy is not an AE, all pregnancies must be reported within 24 hours of the 
Investigator being aware of it (see Section 9.7). 


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All events (serious and nonserious) must be reported with Investigator’s assessment of the 
event’s seriousness, severity, and causality to the blinded study drug.  For SAEs, a detailed 
narrative summarizing the course of the event, including its evaluation, treatment, and outcome 
should be provided.  Specific or estimated dates of event onset, treatment, and resolution should 
be included when available.  Medical history, concomitant medications, and laboratory data that 
are relevant to the event should also be summarized in the narrative.  For fatal events, the 
narrative should state whether an autopsy was or will be performed and include the results if 
available.  Source documents (including medical reports) will be retained at the study site and 
should not be submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to nonurgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
In the event that eCRF is unavailable, report SAEs by faxing the paper SAVER Form to the CRO 
using the provided fax cover sheet and the appropriate fax number provided for your country. 
Once eCRF becomes available, please enter SAEs reported on the SAVER Form into eCRF as 
soon as possible.  Please refer to eCRF Completion Guide for additional instructions. 
Contact study medical monitor for questions regarding SAE reporting.  
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform Investigators, Institutional Review Boards/Ethics 
Committees (IRBs/ECs), and regulatory authorities of any suspected unexpected serious Adverse 
reactions (SUSARs) occurring in other study sites or other studies of the investigational drug, as 
appropriate per local reporting requirements.  Daiichi Sankyo and/or CRO will comply with any 
additional local safety reporting requirements.  The section of “Reference Safety Information” in 
the current Investigator’s Brochure should be referred to judge “Unexpected.”  
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the study 
drug, unless delegated to the Sponsor, it is the Investigator’s responsibility to inform the IRB per 
Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s or CRO’s responsibility to report 
SUSARs to all ECs. 
9.7. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or within 
30 days of discontinuing the study drug.  Although pregnancy is not technically an adverse 
event, all pregnancies must be followed to conclusion to determine their outcome.  This 
information is important for both drug safety and public health concerns.  It is the responsibility 
of the Investigator, or designee, to report any pregnancy in a female subject using the Exposure 
In Utero (EIU) Reporting form within 24 hours of learning of the pregnancy.  Please contact 
your study monitor to receive the EIU Reporting Form upon learning of a pregnancy.  The 
Investigator should make every effort to follow the subject until completion of the pregnancy and 
complete the EIU Reporting Form with complete pregnancy outcome information, including 


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normal delivery and induced abortion.  The adverse pregnancy outcome, either serious or 
nonserious, should be reported in accordance with study procedures.  If the outcome of the 
pregnancy meets the criteria for immediate classification as a SAE (ie, postpartum 
complications, spontaneous or induced abortion, stillbirth, neonatal death, or congenital 
anomaly, including that in an aborted fetus), the Investigator should follow the procedures for 
reporting SAEs outlined in Section 9.5.  
9.8. 
Clinical Laboratory Evaluations 
The clinical laboratory tests including hematology, coagulation, blood chemistry, and urinalysis 
will be performed as per the SoE (Table 3.1).   
9.9. 
Vital Signs 
Vital signs will be measured and recorded as per the SoE (Table 3.1). 
Blood pressure and pulse rate will be measured after the subject has rested in a recumbent 
position for 5 minutes or more. 
Information will be entered in the case report form on whether or not the parameter was 
measured, on what date the measurement is performed, and what the measurement results were 
for the following items: systolic blood pressure, diastolic blood pressure, pulse rate, respiratory 
rate, and body temperature.   
9.10. 
Electrocardiograms 
Twelve-lead ECGs in triplicate will be performed and recorded for every subject as per the SoE 
(Table 3.1).  Vital signs will be collected after ECG measurements, and blood collection should 
occur after the vital signs (if indicated at the same timepoint).  
The ECG will be measured after the subject has rested in a recumbent position for 5 minutes or 
more.  Whether or not measurement is performed, on what date the measurement is performed, 
and what the results and findings are for the following parameters will be recorded: heart rate, 
PR interval, RR interval, QRS amplitude, and QT interval. 
9.11. 
Physical Examinations 
Physical examinations/assessments should be performed as per the SoE (Table 3.1).  
Height and body weight will be performed only at Screening.  
The physical examination will include an evaluation mainly of the respiratory, cardiovascular, 
gastrointestinal, dermatological, neurological, and musculoskeletal systems, as well as the eyes, 
ears, nose, and throat.  The physical assessment may be expanded further to note any 
observations related to the subject’s physical signs and symptoms.  The physical assessment will 
be performed by a visiting nurse for the in-home visit (Visit 7). 
 
9.12. 
Other Examinations 
Not applicable. 


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10. 
OTHER ASSESSMENTS 
10.1. 
COVID-19 Assessments 
All confirmed or suspected COVID-19 infection events during the study must be recorded in the 
eCRF.  Investigator should make every effort to collect or perform all required diagnostic tests to 
fully diagnose the suspected concomitant illnesses to confirm the definitive diagnosis if possible. 
The subject’s consent may be required for some of the diagnostic tests as required by the local 
legal or regulatory needs or customary practices. 
In the case of a moderate to severe COVID-19 infection or COVID-19 infection requiring 
treatment, study drug interruption should be considered by the Investigator in consultation with 
the medical monitor.  
In an effort to ensure appropriate safety reporting of COVID-19 cases in accordance with Health 
Authority guidelines, the following process should be followed for cases that have occurred in 
the context of a clinical trial: 
 
All confirmed or suspected COVID-19 events must be recorded in the eCRF.  
 Subjects who test positive for COVID-19 should be reported as “Confirmed 
COVID-19,” either as an AE or SAE.  
 Subjects whose medical history and clinical manifestations, signs, and possible 
exposure are consistent with COVID-19 but for whom no polymerase chain 
reaction or antibody test for COVID-19 is available should be reported as 
“Suspected COVID-19,” either as an AE or SAE.  
 
The usual protocol mandated SAE reporting requirements should be followed for 
confirmed or suspected COVID-19 as done for any other AE, ie, the Investigator 
should assess whether any seriousness criteria are met per protocol, and appropriate 
protocol reporting requirements should be followed.  
 In the event that the Investigator assesses that a COVID-19 case does not meet 
any seriousness criteria as outlined in the protocol, it should be reported as a non-
serious adverse event in the CRF.  
 
All study drug interruption or discontinuation due to the COVID-19 event must be 
recorded on the AE and drug administration eCRFs.  
 
For both serious or nonserious COVID-19-related AEs, the following information 
should be provided as applicable:  
 Date and laboratory results confirming the COVID-19 diagnosis (including viral 
antigen test and/or antiviral antibody serological test).  
 Clinical course of the case including presenting signs, symptoms, exposure, 
actions taken with the investigational products, medications used for treatment or 
prophylaxis of COVID-19, and outcome in relevant eCRF (eg, concomitant 
medication, AE).  
 Findings from diagnostic imaging (including computed tomography scan or other 
chest imaging).  


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11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
Continuous variables will be summarized by the number of subjects, mean, standard deviation, 
median, and minimum and maximum values, unless otherwise specified.  Categorical variables 
will be summarized by using frequency counts and percentages.  In general, data will be 
summarized by treatment group. 
Raw data will be presented with the exact precision with which they were collected. 
There is no multiplicity adjustment. 
11.2. 
Analysis Sets 
 
All Enrolled Subjects will include all subjects who sign the informed consent form. 
 
The Intent-to-treat Analysis Set will consist of all randomized subjects. 
 
Safety Analysis Set will include all subjects who received at least 1 dose of study 
drug. 
 
Per-protocol Analysis Set consists of all randomized subjects who received at least 1 
dose of the study drug according to an automatic voice or web response system 
assignment and do not have important protocol deviations.  Important protocol 
deviations are defined in the statistical analysis plan (SAP). 
 
Pharmacokinetic Analysis Set will include all subjects who receive at least 1 
dose of study drug and have at least 1 measurable pharmacokinetic result. 
 
Biomarker Analysis Set will consist of all subjects who receive at least 1 dose of 
study drug and have at least 1 measurable biomarker assessment. 
11.3. 
Study Population Data 
Disposition and reasons for ending the treatment and discontinuing from the study will be 
summarized and listed for subjects in the enrolled analysis set.  
Demographic and other baseline characteristics will be summarized for the Intent-to-treat 
Analysis Set.  
11.4. 
Efficacy Analyses 
Not applicable. 
11.5. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses 
11.5.1. 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be based on Pharmacokinetic Analyses Set.  
The following PK parameters will be calculated by noncompartmental methods from the 
DS-1211a concentration-time data: maximum plasma concentration, minimum plasma 


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concentration, time to reach maximum plasma concentration, and if appropriate area under the 
plasma concentration-time curve (AUC), terminal elimination half-life, The apparent total body 
clearance, and apparent volume of distribution at steady state.  The PK analysis will be 
conducted in compliance with DSI Noncompartmental Analysis Guidelines. 
Plasma concentration of DS-1211a and PK parameters will be summarized by treatment group 
using descriptive statistics, including the mean, geometric mean, standard deviation, coefficient 
of variation percentage or median.  
Finally, plasma concentration data for DS-1211a collected from the study may also be analyzed 
by means of nonlinear mixed-effect modeling.  Results from the analysis will be reported in a 
separate standalone report. 
11.5.2. 
Pharmacodynamic Analyses 
See Section 11.5.3. 
11.5.3. 
Biomarker Analyses 
All biomarker analyses will be based on Biomarker Analysis Set.  Observed values at each 
assessment and the absolute change and percentage change from baseline will be numerically 
summarized for primary and exploratory biomarkers by treatment group over time.  The 95% 
confidence interval will be presented for percentage change from baseline in ALP, PPi, and PLP. 
The baseline of biomarker data is defined as the last nonmissing assessment collected prior to the 
first dose of study medication. 
Difference in primary and exploratory biomarkers between active doses and placebo will be 
summarized by descriptive statistics. 
11.5.4. 
Pharmacogenetic (Inherited Genetic) Analyses 
11.6. 
Safety Analyses 
Safety analysis will be performed by using the Safety Analysis Set and subjects will be analyzed 
according to their actual treatment received.  The baseline value for clinical laboratory, vital 
sign, and ECG values is defined as the last nonmissing value prior to the first dose of study 
medication. 
11.6.1. 
Adverse Event Analyses 
Treatment-emergent adverse events (TEAEs) are defined as events that start on or after the first 
dose of study drug or start prior to but then worsen after the first dose of study drug.  Treatment-
emergent adverse events will be analyzed by treatment group. 
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The number and percentage of subjects reporting TEAEs will be calculated overall, by system 
CCI


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organ class, by preferred term, and by treatment group.  TEAEs will be further summarized by 
severity and relationship to study drug.  Similarly, the number and percentage of subjects 
reporting treatment-emergent SAEs will be tabulated, as well as TEAEs leading to 
discontinuation of study treatments. 
A by-subject AE (including treatment emergent) data listing including but not limited to 
verbatim term, preferred term, system organ class, severity Common Toxicity Criteria for 
Adverse Event grade, and relationship to study treatment will be provided.  Deaths, other SAEs, 
and other significant AEs, including those leading to discontinuation of study treatments, will be 
listed. 
AEs due to COVID-19 will be summarized and listed. 
11.6.2. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results by scheduled time of 
evaluation and by treatment group for the safety population, as well as for the change from 
baseline.  In addition, mean change from baseline will be presented by treatment group for the 
maximum and minimum post-treatment values and the values at the end of treatment visit. 
The number and percentage of subjects with laboratory interval values meeting Hy’s law criteria 
will be summarized.  Laboratory results from HPP and nephrotoxicity monitoring will be 
analyzed. 
11.6.3. 
Vital Sign Analyses 
Descriptive statistics will be provided for the vital sign measurements by scheduled time of 
evaluation and by treatment group for the safety population, as well as for the change from 
baseline.  
11.6.4. 
Electrocardiogram Analyses 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation and by treatment group for the safety population, as well as for the change from 
baseline.  In addition, the number and percentage of subjects with ECG interval values meeting 
the criteria will be tabulated (eg, QTc ≤ 450 ms, > 450 to ≤ 480 ms, > 480 ms to ≤ 500 ms, and > 
500 ms).  Data from ECG will also be presented in the data listings. 
11.7. 
Other Endpoint Analysis 
Not applicable. 
11.8. 
Interim Analyses 
Not applicable. 
11.8.1. 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will not be involved in the management of this clinical 
study.   




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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
12.1. 
Monitoring and Inspections 
The Sponsor/CRO monitor and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (eg, CRFs, source data, and other pertinent documents). 
 The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH Good Clinical Practice (GCP) and local regulations on the conduct of 
clinical research will be accomplished through a combination of onsite visits by the monitor and 
review of study data remotely.  The frequency of the monitoring visit will vary based on the 
activity at each study site.  The monitor is responsible for inspecting the CRFs and ensuring 
completeness of the study essential documents.  The monitor should have access to subject 
medical records and other study-related records needed to verify the entries on the CRFs.  
Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the Investigator and will ensure that appropriate action (s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study site may be selected for 
audit by representatives from the Sponsor.  Audit of study site facilities (eg, pharmacy, drug 
storage areas, laboratories) and review of study-related records will occur in order to evaluate the 
study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  The Investigator should respond to audit findings.  In the event that a regulatory 
authority informs the Investigator that it intends to conduct an inspection, the Sponsor shall be 
notified immediately. 
12.2. 
Data Collection 
DSI or a designee will supply eCRFs.  An eCRF must be completed for each subject who signs 
an ICF and undergoes any screening procedure.  If a subject is not treated, the reason must be 
recorded on the eCRF.  All data collected during the study will be recorded in this individual, 
subject-specific eCRF.  Instructions will be provided for the completion of the eCRF and any 
corrections made will be automatically documented via the EDC software’s “audit trail.” 
Completion of the eCRF should be kept current to enable the monitor to review the subject’s 
status throughout the course of the study.  All information and other material to be used by 
subjects and investigative staff must use vocabulary and language that are clearly understood.  
The eCRF will be completed, reviewed, and signed off or e-signed by the Investigator/designee.  
The Investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature.  These signatures will indicate that the Investigator inspected or reviewed 
the data on the eCRF, the data queries, and the site notifications, and agrees with the content. 


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12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor/CRO.  Data will be vetted both electronically and manually for CRFs and the data will 
be electronically vetted by programmed data rules within the application.  Queries generated by 
rules and raised by reviewers will be generated within the EDC application.  During this review, 
subject data will be checked for consistency, completeness, and any apparent discrepancies.  
CRFs queries will be raised and resolved within the EDC application. 
Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
Serious adverse events and nonserious AEs potentially meeting Hy's Law in the clinical database 
will be reconciled with the safety database. 
All AEs will be coded by using MedDRA.  Prior and concomitant medications will be coded by 
using the World Health Organization Drug Reference List. 
Data that may potentially unblind the treatment assignment will be handled with special care 
during the data cleaning and review process.  These data will be handled in such a way that, prior 
to unblinding, any data that may unblind study team personnel will be presented as blinded 
information or otherwise will not be made available. 
12.4. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or corrections on 
CRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects and the date and outcome of screening/rescreening 
process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s CRF data 
are obtained.  These include, but are not limited to, hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, CRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IRB/EC 
correspondence and approvals, approved and signed informed consent forms, Investigator’s 
Agreement, clinical supplies receipts, distribution and return records), and other Sponsor 


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correspondence pertaining to the study must be kept in appropriate study files at the study site 
(Trial Master File).  Source documents include all recordings and observations or notations of 
clinical activities and all reports and records necessary for the evaluation and reconstruction of 
the clinical study.  These records will be retained in a secure file for the period required by the 
institution or study site policy.  Prior to transfer or destruction of these records, the Sponsor must 
be notified in writing and be given the opportunity to further store such records. 
12.5. 
Recordkeeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  Essential documents contained in the Trial Master File include: 
 
Subject files containing completed CRFs, informed consent forms, and supporting 
copies of source documentation (if kept). 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the EC/IRB and the Sponsor. 
 
Records related to the study drug(s) including acknowledgment of receipt at study 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
All study-related essential documentation will be retained by the Investigator until at least 3 
years (or as applicable for local requirements) after the last approval of a marketing application 
in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or at least 3 years (or as applicable for local requirements) have lapsed since the 
formal discontinuation of clinical development of the investigational drug.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the Sponsor to 
inform the Investigator/institution as to when these documents no longer need to be retained. 
Subject’s medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice.  
No study document should be destroyed without prior written agreement between Sponsor and 
the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify Sponsor in writing of the new responsible 
person and/or the new location. 


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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical study 
agreement with the CRO on behalf of DSI.  This agreement will include the financial 
information agreed upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 


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14. 
PUBLICATION AND PUBLIC DISCLOSURE OF CLINICAL 
TRIAL INFORMATION 
Daiichi Sankyo is committed to meeting the highest standards of publication and public 
disclosure of information arising from clinical trials sponsored by the company.  We will comply 
with applicable United States (US), European Union (EU), and Japanese policies for public 
disclosure of the clinical trial protocol and clinical trial results, and for sharing of clinical trial 
data.  We follow the principles set forward in “Good Publication Practice for Communicating 
Company-Sponsored Medical Research (GPP3)”, and publications will adhere to the 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” established by the International Council of Medical Journal Editors (ICMJE).   
In order to ensure that we are in compliance with the public disclosure policies and the ICMJE 
recommendations, and to protect proprietary information generated during the study, all 
publications (manuscripts, abstracts, or other public disclosure) based on data generated in this 
study must be accepted, reviewed, and approved in writing by the Sponsor prior to submission.  


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the International Council for Harmonization (ICH) 
consolidated Guideline E6 for GCP (CPMP/ICH/135/95), and applicable regulatory 
requirement(s) including the following: 
 
European Commission Directive (2001/20/EC Apr 2001) and/or; 
 
European Commission Directive (2005/28/EC Apr 2005) and/or; 
 
US Food and Drug Administration GCP Regulations: Code of Federal Regulations 
Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 
Other applicable local regulations. 
15.2. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
For EU study sites, the Sponsor will observe the rules laid down in the European Data Protection 
Directive 95/46/EC on the protection of individuals with regard to the processing of personal 
data and the free movement of such data. 
The Investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identifier as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB/EC 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data.  The Investigator is obligated to inform the subject that his/her study-related 
records will be reviewed by the above-named representatives without violating the 
confidentiality of the subject. 
15.3. 
Informed Consent  
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent in writing from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study drugs are administered.  Subjects should be given the opportunity to ask 
questions and receive satisfactory answers to their inquiries and should have adequate time to 
decide whether or not to participate in the study.  The written ICF should be prepared in the local 
language(s) of the potential subject population. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 


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have their origin in the Declaration of Helsinki.  The consent form and any revision(s) should be 
approved by the EC or IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records.  
The ICF should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the Investigator).  The original signed ICF 
should be retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject.  The date and time (if applicable) that informed consent was 
given should be recorded on the CRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an impartial 
witness should be present during the entire informed consent discussion.  This witness should 
sign the ICF after the subject has consented to the subject’s participation and, if possible, signed 
the ICF.  By signing the ICF, the witness attests that the information in the ICF and any other 
written information was adequately explained to and apparently understood by the subject and 
that informed consent was freely given by the subject. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, etc) 
are provided in the Sponsor’s ICF template for the Investigator to prepare the documents to be 
used at his or her study site. 
For study sites in the US, an additional consent (or section of the main consent) is required for 
the Health Insurance Portability and Accountability Act.  
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator Brochure, any subject 
written instructions to be given to the subject, available safety information, subject recruitment 
procedures (eg, advertisements), information about payments and compensation available to the 
subjects, and documentation evidencing the Investigator’s qualifications should be submitted to 
the EC or IRB for ethical review and approval according to local regulations, prior to the study 
start.  The written approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Sponsor will appoint a Coordinating Investigator.  Among other possible duties, the 
Coordinating Investigator will be responsible for reviewing and approving the Final Clinical 
Study Report and testifying to the accuracy of the description of the study conduct.  Because the 
Coordinating Investigator should have personal knowledge of the conduct of the study, he or she 
will normally be chosen from among those Investigators who have enrolled and treated at least 
one subject.  However, where an Investigator has special knowledge of the field or of the trial, 
the Coordinating Investigator can be chosen prior to enrollment of the first subject.  In all cases, 
the Coordinating Investigator must be chosen prior to locking the database.   
The Investigator and/or Sponsor must submit and, where necessary, obtain approval from the EC 
or IRB for all subsequent protocol amendments and changes to the ICF.  The Investigator should 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study site and 
other AE reports received from the Sponsor/CRO in accordance with local procedures. 


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As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation.  If changes to 
the initial protocol and other relevant study documents are made, this representative will also 
ensure that any revised documents required for submission are submitted to regulatory 
authorities and implementation of these changes happen only after approval by the relevant 
regulatory bodies. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authority(ies) in any area of the world, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately.   
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP noncompliance that the Investigator becomes aware of. 
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRBs/ECs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject.  Sponsor must be 
notified of all intended or unintended deviations to the protocol (eg, inclusion/exclusion criteria, 
dosing, missed study visits) on an expedited basis. 
The Investigator or a person designated by the Investigator should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment and had at least 1 
administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the EC or IRB of deviations from the protocol in 
accordance with local procedures. 
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all Investigators involved in the clinical study, 
ECs/IRBs, and regulatory authorities of such information, and when needed, will amend the 
protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study.  


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If the subject information is revised, it must be reapproved by the IEC/IRB.  The Investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The Investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the Investigator by Daiichi Sankyo or the CRO.  Also, the Sponsor will 
ensure the timely submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all study sites in all regions of the 
world.  Such amendments will be incorporated into a revised protocol document.  Changes made 
by such amendments will be documented in a Summary of Changes document.  These protocol 
amendments will undergo the same review and approval process as the original protocol.   
A local protocol amendment will affect study conduct at a particular study site(s) and/or in a 
particular region/country.  Sponsor approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities, unless implementation is allowed without this approval by local 
regulations. 
15.8. 
Study Termination 
The Sponsor has the right to terminate the study at any time and the study termination may also 
be requested by (a) competent authority/ies. 
15.9. 
Data and Safety Monitoring Board 
Not applicable. 
 


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16. 
REFERENCES 
1. Uitto J, Jiang Q, Váradi A, et al. Pseudoxanthoma elasticum: diagnostic features, 
classification, and treatment options. Expert Opin Orphan Drugs. 2014; 2(6):567-77. 
2. Plomp AS, Toonstra J, Bergen AAB, et al. Proposal for updating the pseudoxanthoma 
elasticum classification system and a review of the clinical findings. Am J Med Genet 
Part A 2010; 152A:1049–1058. 
3. Jansen RS, Küçükosmanoglu A, de Haas M, et al. ABCC6 prevents ectopic 
mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. 
Proc Natl Acad Sci USA. 2013; 110(50):20206-11. 
4. Jansen RS, Duijst S, Mahakena S, et al. ABCC6-mediated ATP secretion by the liver is 
the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic 
circulation-brief report. Arterioscler Thromb Vasc Biol. 2014; 34(9):1985-9.  
5. Sheen CR, Kuss P, Narisawa S, et al. Pathophysiological role of vascular smooth muscle 
alkaline phosphatase in medial artery calcification. J Bone Miner Res. 2015; 30(5):824-
36. 
6. Azpiazu D, Gonzalo S, Villa-Bellosta R. Tissue non-specific alkaline phosphatase and 
vascular calcification: a potential therapeutic target. Curr Cardiol Rev. 2019; 15(2):91-5. 
7. Ziegler SG, Ferreira CR, MacFarlane EG, et al. Ectopic calcification in pseudoxanthoma 
elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase. Sci Transl 
Med. 2017; 9(393):eaal1669. 
8. Pomozi V, Brampton C, van de Wetering K, et al. Pyrophosphate supplementation 
prevents chronic and acute calcification in ABCC6-deficient mice. Am J Pathol. 2017; 
187(6):1258-72. 
9. Li Q, Huang J, Pinkerton AB, Millan JL, et al. Inhibition of tissue-nonspecific alkaline 
phosphatase attenuates ectopic mineralization in the Abcc6-/- mouse model of PXE but 
not in the Enpp1 mutant mouse models of GACI. J Invest Dermatol. 2019; 139(2):360-8. 
10. Germain DP. Pseudoxanthoma elasticum. Orphanet J Rare Dis. 2017; 12(1):85. 
11. Finger RP, Charbel Issa P, Ladewig M, et al. Intravitreal bevacizumab for choroidal 
neovascularisation associated with pseudoxanthoma elasticum. Br J Ophthalmol. 2008; 
92(4):483-7. 
12. DS-1211b Investigator’s Brochure. Most current version. 
13. Maruyama S, Zamora C.  A Phase 1, Double-blind, Placebo controlled, Randomized, 
Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of DS-1211b in Healthy Subjects- Version 1.0.  Daiichi Sankyo. 
Clinical Study Report. 12 May 2020; Study No.: DS1211-A-U102.  
14. Food and Drug Administration [Internet]. Guidance for industry: drug-induced liver 
injury: premarketing clinical evaluation. July 2009 [cited 13 Oct 2021]. Available from: 
https://www.fda.gov/media/116737/download.  


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15. Heads of Medicines Agencies. Clinical Trial Facilitation Group (CTFG) [Internet]. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
September 2014 [cited 13 Oct 2021]. Available from: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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17. 
APPENDICES 
17.1. 
CYP Inhibitors and Inducers  
Table 17.1 lists the generic names of strong CYP3A4 inhibitors and inducers. Table 17.2 lists the 
generic names of CYP2C19 inhibitors and inducers. 
Table 17.1: 
CYP3A4 Inhibitors/Inducers 
Inhibitor/Inducer Type 
Generic Drug Name 
Allowance 
Strong Inhibitor 
Ketoconazole 
Voriconazole 
Itraconazole 
Clarithromycin 
Telithromycin 
Indinavir 
Ritonavir 
Nelfinavir 
Saquinavir 
Mibefradil 
Idelalisib 
Tucatinib 
Ribociclib 
Grapefruit Juice 
Use is prohibited during the study. 
 
Strong Inducer 
Rifampin (rifampicin) 
Phenytoin 
Fosphenytoin 
Phenobarbital 
Carbamazepine 
Apalutamide 
Enzalutamide 
Lumacaftor 
Lumacaftor-ivacaftor 
Mitotane 
Primidone 
St John’s Wort 
Use is prohibited during the study. 
 
Note: Moderate and weak CYP3A4 inhibitors and inducers are allowed (https://drug-
interactions.medicine.iu.edu/MainTable.aspx) 


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Table 17.2: 
CYP2C19 Inhibitors/Inducers 
Inhibitor/Inducer Type 
Generic Drug Name 
Allowance 
Strong Inhibitors 
Fluvoxamine 
Fluconazole 
Ticlopidine 
 
Use is prohibited during the 
study. 
 
 
Moderate Inhibitors 
Esomeprazole 
Fluoxetine 
 
Use is allowed. 
 
Weak Inhibitors 
Armodafinil 
Citalopram 
Cimetidine 
Felbamate 
Isoniazid 
Luliconazole 
Modafinil 
Omeprazole 
Pantoprazole 
Oral contraceptives 
 
Use is allowed. 
 
Strong Inducers 
Rifampin (rifampicin) 
Apalutamide 
Use is prohibited during the 
study. 
 


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17.2. 
Highly Effective Contraception 
Methods considered to be highly effective contraception include:15  
 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
Complete sexual abstinence (evaluate in relation to the preferred and usual lifestyle 
choice of the study participant) 
 


CCI