Clinical trial NCT04526197
Conditions: Wilson Disease
Keywords: Cytochrome P450 Healthy ALXN1840 Celecoxib CYP2C9
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2020-07-07; Completion date: 2020-11-03
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This was a Phase 1, randomized, 2-period, 2-sequence, cross-over study designed to determine the effect of ALXN1840 on the metabolism of celecoxib, a sensitive cytochrome P450 2C9 (CYP2C9) substrate, in healthy male and female participants. The safety and tolerability of ALXN1840 were determined along with ALXN1840 pharmacokinetics (PK) in plasma as measured via total molybdenum with the coadministration of celecoxib.

Detailed description:
The study was conducted as a randomized, 2-period, 2-sequence, cross-over study to determine the effect of a single dose of ALXN1840 (perpetrator) on the single-dose celecoxib (victim) kinetics in healthy male and female participants.

The study had a Screening period (Day -28 to Day -2), two 11-day study periods (Day 1 to Day 11) with a minimum of 14 days between doses of celecoxib, and an End of Study Visit (Day 15 ± 2 days) after Period 2 dosing. Participants only reported to the clinical research unit (CRU) on the day prior to the first dose because they were kept in the CRU during the wash-out period due to coronavirus disease 2019.

All participants received a single dose of celecoxib alone (Treatment A) and celecoxib coadministered with ALXN1840 (Treatment B) during the study, 1 in each treatment period. Based on randomization, participants were administered either Treatments A-B or Treatments B-A in each study period.

The PK profile of ALXN1840 and celecoxib was determined by blood sampling following single-dose administration. In addition to PK sampling, safety and tolerability were assessed by monitoring adverse events, vital signs, 12-lead electrocardiograms, physical examinations, and laboratory parameters.

Arms: arm 1: Participants received 1 treatment during each study period in the following sequence:

* Treatment A: Celecoxib.
* Treatment B: Celecoxib plus ALXN1840. arm 2: Participants received 1 treatment during each study period in the following sequence:

* Treatment B: Celecoxib plus ALXN1840.
* Treatment A: Celecoxib.
Interventions: intervention 1: ALXN1840 intervention 2: Celecoxib
Intervention descriptions: intervention 1: ALXN1840 was administered orally as a single dose as 4 x 15 milligram (mg) enteric-coated tablets with 240 milliliters (mL) of water (fasting), for a total dose of 60 mg. intervention 2: Celecoxib was administered orally as a single dose as one 200-mg tablet with 240 mL of water (fasting).

Protocol documents:
Prot_000.pdf: 
A Phase 1, Randomized, 2-Period, 2-Sequence, Cross-over 
Study to Determine the Effect of ALXN1840 on the 
Metabolism of a CYP2CP Substrate in Healthy Participants 
Unique Protocol ID: 
NCT Number: 
Date of Protocol:  
ALXN1840-HV-105 
NCT04526197 
28 April 2020 


PPD


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INVESTIGATOR’S AGREEMENT 
I have read the study protocol and agree to conduct the study in accordance with this protocol, all 
applicable government regulations, the principles of the ICH E6 Guidelines for Good Clinical 
Practice, and the principles of the World Medical Association Declaration of Helsinki. I also 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol.  
 
 
 
 
____________________________________ 
Printed Name of Investigator 
 
_____________________________________ 
Signature of Investigator 
 
_______________ 
Date


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
1. 
PROTOCOL SUMMARY ............................................................................................7 
1.1. 
Synopsis ........................................................................................................................7 
1.2. 
Schema ........................................................................................................................10 
1.3. 
Schedule of Activities .................................................................................................11 
2. 
INTRODUCTION ......................................................................................................14 
2.1. 
Study Rationale ...........................................................................................................14 
2.2. 
Background .................................................................................................................16 
2.3. 
Benefit/Risk Assessment ............................................................................................16 
2.3.1. 
Risk Assessment .........................................................................................................16 
2.3.2. 
Benefit Assessment .....................................................................................................17 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................17 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................18 
4. 
STUDY DESIGN .......................................................................................................19 
4.1. 
Overall Design ............................................................................................................19 
4.2. 
Scientific Rationale for Study Design ........................................................................20 
4.3. 
Justification for Dose ..................................................................................................20 
4.4. 
End of Study Definition ..............................................................................................22 
5. 
STUDY POPULATION .............................................................................................23 
5.1. 
Inclusion Criteria ........................................................................................................23 
5.2. 
Exclusion Criteria .......................................................................................................24 
5.3. 
Lifestyle Considerations .............................................................................................26 
5.4. 
Screen Failures ............................................................................................................28 
6. 
STUDY INTERVENTION ........................................................................................29 
6.1. 
Study Intervention Administered ................................................................................29 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................29 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................30 
6.4. 
Study Intervention Compliance ..................................................................................30 
6.5. 
Concomitant Therapy .................................................................................................31 


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6.5.1. 
Allowed Medicine and Therapy .................................................................................31 
6.5.2. 
Disallowed Medicine and Therapy .............................................................................31 
6.6. 
Dose Modification ......................................................................................................32 
6.7. 
Intervention After the End of the Study .....................................................................32 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................33 
7.1. 
Discontinuation of Study Intervention ........................................................................33 
7.2. 
Participant Discontinuation/Withdrawal From the Study ...........................................33 
7.3. 
Lost to Follow-up .......................................................................................................34 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................35 
8.1. 
Efficacy Assessments .................................................................................................35 
8.2. 
Safety Assessments .....................................................................................................35 
8.2.1. 
Physical Examinations ................................................................................................35 
8.2.2. 
Vital Signs ..................................................................................................................36 
8.2.3. 
Vital signs will be measured in a semi-supine position after 5 minutes rest. 
Electrocardiograms .....................................................................................................36 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................36 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................37 
8.2.6. 
Pregnancy ...................................................................................................................37 
8.3. 
Adverse Events and Serious Adverse Events .............................................................37 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................37 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................38 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................38 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................38 
8.3.5. 
Adverse Events of Special Interest .............................................................................38 
8.3.6. 
Retained and Biobanked Sample ................................................................................39 
8.4. 
Treatment of Overdose ...............................................................................................39 
8.5. 
Pharmacokinetics ........................................................................................................39 
8.6. 
Pharmacodynamics .....................................................................................................40 
8.7. 
Genetics ......................................................................................................................40 
8.8. 
Biomarkers ..................................................................................................................40 
8.9. 
Immunogenicity ..........................................................................................................40 


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8.10. 
Health Economics and Medical Resource Utilization ................................................40 
9. 
STATISTICAL CONSIDERATIONS .......................................................................41 
9.1. 
Statistical Hypotheses .................................................................................................41 
9.2. 
Sample Size Determination ........................................................................................41 
9.3. 
Populations for Analyses ............................................................................................41 
9.4. 
Statistical Analyses .....................................................................................................41 
9.4.1. 
Efficacy Analyses .......................................................................................................42 
9.4.2. 
Safety Analyses ..........................................................................................................42 
9.4.3. 
Other Analyses ............................................................................................................42 
9.4.3.1. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................42 
9.5. 
Interim Analyses .........................................................................................................44 
9.6. 
Data Monitoring Committee .......................................................................................44 
9.7. 
Safety Review Committee ..........................................................................................44 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................45 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................45 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................45 
10.1.2. 
Financial Disclosure ...................................................................................................45 
10.1.3. 
Informed Consent Process ..........................................................................................46 
10.1.4. 
Data Protection ...........................................................................................................46 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................47 
10.1.6. 
Data Quality Assurance ..............................................................................................47 
10.1.7. 
Source Documents ......................................................................................................48 
10.1.8. 
Study and Site Start and Closure ................................................................................48 
10.1.9. 
Publication Policy .......................................................................................................48 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................50 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................52 
10.3.1. 
Definition of AE .........................................................................................................52 
10.3.2. 
Definition of SAE .......................................................................................................52 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................53 
10.3.4. 
Reporting of SAEs ......................................................................................................54 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................56 
10.5. 
Appendix 5: Abbreviations .........................................................................................58 
11. 
REFERENCES ...........................................................................................................61 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................11 
Table 2:  
Potential Risks and Mitigation Strategy .....................................................................16 
Table 3: 
Study Design ...............................................................................................................20 
Table 4: 
Healthy Participant Lifestyle Considerations .............................................................26 
Table 5: 
Details of Study Interventions Administered .............................................................29 
Table 6: 
Populations for Analyses ............................................................................................41 
Table 7: 
Protocol-Required Safety Laboratory Assessments ...................................................50 
Table 8: 
List of Abbreviations and Definitions of Terms .........................................................58 
 
LIST OF FIGURES 
Figure 1: 
Study ALXN1840-HV-105 Schematic .......................................................................10 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, Randomized, 2-Period, 2-Sequence, Cross-over Study to Determine 
the Effect of ALXN1840 on the Metabolism of a CYP2C9 Substrate in Healthy Participants. 
Short Title: Phase 1 Study of ALXN1840 on the Metabolism of a CYP2C9 Substrate in Healthy 
Participants. 
Rationale:  
ALXN1840 is considered to have potential for moderate drug-drug interactions (DDI) due to 
inhibition of cytochrome P450 2C9 (CYP2C9) according to in vitro studies using human liver 
microsomes and simulations performed to assess the potential for DDI risks. This study has been 
designed to determine the effect of ALXN1840 enteric-coated (EC) tablets at a single dose of 
60 mg (4 × 15 mg) on the metabolism of celecoxib, a sensitive CYP2C9 substrate, at a single 
dose of 200 mg. A single dose of 60 mg ALXN1840 as a perpetrator is considered appropriate 
due to lack of potential for time-dependent inhibition (TDI) under the maximum observed 
ALXN1840 concentration in plasma after repeated daily dosing at steady state. A single dose of 
200 mg celecoxib as a victim is considered appropriate due to the linear pharmacokinetics (PK) 
of celecoxib within the approved therapeutic dose range.  
The 60 mg dose of ALXN1840 is the maximum allowed daily dose in the on-going Phase 3 
Study WTX101-301 in patients with Wilson disease (WD). The 200 mg celecoxib single dose 
has been selected based on the drug interaction study with fluconazole as described in the 
Celebrex® United States Prescribing Information (USPI) (Celebrex®) and Diflucan® USPI 
(Diflucan®).  


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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To determine the effect of ALXN1840 on the 
PK of celecoxib, a sensitive CYP2C9 
substrate 
• 
PK parameters of celecoxib (maximum 
observed plasma concentration [Cmax], area 
under the plasma concentration (AUC) versus 
time curve from time 0 to the last quantifiable 
concentration [AUCt], and AUC versus time 
curve from time 0 to infinity [AUC∞]) with 
and without the coadministration of 
ALXN1840 
Secondary 
 
• 
To determine the effect of ALXN1840 on the 
PK of plasma molybdenum (Mo) with the 
coadministration of celecoxib 
• 
To determine the safety and tolerability of 
ALXN1840, with the coadministration of 
celecoxib  
• 
PK parameters for plasma total Mo (Cmax, 
AUCt, and AUC∞) with the coadministration 
of celecoxib  
• 
Safety assessed by incidence of 
treatment-emergent adverse events (TEAEs) 
and treatment-emergent serious adverse 
events (TESAEs), physical examination, vital 
signs measurements, clinical laboratory and 
12-lead electrocardiogram (ECG) results 
Abbreviations: AUC∞ = area under the plasma concentration versus time curve from time 0 to infinity; 
AUCt = area under the plasma concentration versus time curve from time 0 to the last quantifiable concentration; 
Cmax = maximum observed plasma concentration of the drug; CYP2C9 = Cytochrome P450 2C9; 
ECG = electrocardiogram; Mo = molybdenum; PK = pharmacokinetics; TEAE = treatment-emergent adverse 
event; TESAE = treatment-emergent serious adverse event. 
 
Overall Design 
This is a Phase 1, randomized, 2-period, 2-sequence, cross-over study designed to determine the 
effect of ALXN1840 on the metabolism of celecoxib, a sensitive CYP2C9 substrate, in healthy 
male and female participants. The safety and tolerability of ALXN1840 will be determined along 
with ALXN1840 PK in plasma as measured via total Mo with the coadministration of celecoxib.  
Disclosure Statement: This is an open-label, 2-period, 2-sequence, cross-over study in healthy 
participants with randomization to 2 treatment sequences. 
Number of Participants: 
It is planned that approximately 38 participants will be enrolled at a single site. 
Intervention Groups and Duration: 
The study has a Screening Period (Day -28 to Day -2), two 11-day study periods (Day 1 to 
Day 11) with a minimum of 14 days between doses of celecoxib, and an End of Study (EOS) 
Visit (Day 15 ± 2 days) after Period 2 dosing. Participants will report to the clinical research unit 
(CRU) on the day prior (Day -1) to both dosing periods. 
In each study period, participants will receive one of the 2 treatments noted below:  
• Treatment A: One 200 mg celecoxib capsule with 240 mL water (fasting). 
• Treatment B: One 200 mg celecoxib capsule + 4 × 15 mg ALXN1840 EC tablets 
with 240 mL water (fasting). 


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Participants will receive each treatment as a single dose administration in the sequence as 
defined below. 
Sequence 
number 
Treatment sequence 
Malea 
Femalea 
Total 
Study Period 1 
Study Period 2 
1 
A 
B 
8 to 11 
8 to 11 
19 
2 
B 
A 
8 to 11 
8 to 11 
19 
Total 
16 to 22 
16 to 22 
38 
a In an effort to achieve balance between males and females in each sequence, there will be no less than 16 and no 
more than 22 of either sex (ie, a maximum split in either direction of approximately 60%:40%). Randomization will 
be stratified by sex. 
Treatment A – One 200 mg celecoxib capsule with 240 mL water (fasting) 
Treatment B – One 200 mg celecoxib capsule + 4 × 15 mg ALXN1840 enteric-coated tablets with 240 mL water 
(fasting) 
The time between dosing celecoxib alone or in combination with ALXN1840 in each treatment 
sequence will be a minimum of 14 days. Based on the estimated mean ALXN1840 half-life of 
approximately 2 days in healthy participants (under oral dose of 60 mg), a 14-day period 
between doses of celecoxib is considered sufficient to eliminate, on average, approximately more 
than 99.2% of the plasma total Mo before the next dose of celecoxib is administered. The mean 
elimination half-life (±SD) of celecoxib after chronic dosing is 11.2 (± 3.5) hours (Celebrex®), 
A 14-day period between doses of celecoxib is sufficient to eliminate, on average, more than 
99.2% of the plasma celecoxib before the next dose of celecoxib is administered.  
Participants will return to the CRU on Day 15 (± 2 days) following Period 2 dosing for the EOS 
Visit with follow-up procedures, and to determine if any adverse events (AEs) have occurred 
since the last study visit. If participants withdraw from the study early, they will be seen and 
assessed by the Principal Investigator, and whenever possible, they are to undergo the procedures 
associated with the EOS Visit. Participants may be replaced at the discretion of Alexion. 
Participants may be asked or required to stay in the CRU between Periods 1 and 2, and/or before 
the EOS visit, for their own safety, and also to maintain the integrity of the conduct of the study. 
Data Monitoring Committee:  
There will not be a Data Monitoring Committee, but provision is included for an ad hoc Safety 
Review Committee, if needed. 


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1.2. 
Schema 
Figure 1: 
Study ALXN1840-HV-105 Schematic  
 
Participants will be admitted on Day -1 of each period for Check in procedures. Eligible participants will be 
randomized on Day 1 immediately prior to dosing in Period 1. 
Participants will receive treatment (A or B) based on randomization on Day 1 of each period. 
Blood samples for PK analysis of total Mo (as a measure of ALXN1840) and celecoxib will be collected in each 
period on Day 1 at pre-dose, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours (Day 2) and then at 24 hour intervals on Days 3, 4, 5, 
6, 7, 8, 9, 10, and Day 11. The nominal 336-hour sample for Period 1 will be collected pre-dose in Period 2. 
Participants will be discharged on Day 11 of each period after completion of all procedures and review of all safety 
data. The end of study visit (EOS) will occur on Day 15 ± 2 of Period 2, with the collection of 336-hour PK sample 
for Period 2. 
Participants may be asked or required to stay in the CRU between Periods 1 and 2, and/or before the EOS visit, for 
their own safety, and also to maintain the integrity of the conduct of the study. 
 


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1.3. 
Schedule of Activities  
Table 1: 
Schedule of Activities 
Study Procedures 
Sa 
C-Ib 
Treatment Periods 1 and 2 
EOS or ETc 
Days → -28 
to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
15 (±2) 
Hours → 
 
 
Pre-
dose 0d 1 
2 
3 
4 
5 
6 
8 
12 24  48 
72 
96 120 144 
168 
192 
216 
240 
336e 
Eligibility 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Urine alcohol test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C 
screen 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Administrative 
Medical 
history/demographicsf 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Weight 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and BMI  
x 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Discussion/documentation 
of contraception method 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of Study Interventioni  
Treatment A: celecoxib or 
Treatment B: celecoxib + 
ALXN1840 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood Sample 
Celecoxib and ALXN1840 
PK  
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pharmacogenetic sample 
CYP2C9 genotyping 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: 
Schedule of Activities (Continued) 
Study Procedures 
Sa 
C-Ib 
Treatment Periods 1 and 2 
EOS or ETc 
Days → -28 
to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
15 (±2) 
Hours → 
 
 
Pre-
dose 0d 1 
2 
3 
4 
5 
6 
8 
12 24  48 
72 
96 120 144 
168 
192 
216 
240 
336e 
Laboratory Assessments 
 
Chemistryj, hematology, 
coagulation  
x 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
x 
Follicle stimulating 
hormonek  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals signs measurements  
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
x 
12-Lead ECGl 
x 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retained sample (safety)m 
 
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring and 
concomitant therapies 
review 
 
a Within 28 days prior to Day 1 of the first dose of study drug in Dosing Period 1. Note that Screening only occurs once.  
b Participants will be admitted to the CRU at least 10 hours prior to study intervention. 
c Participants are required to return to the CRU approximately Day 15 (± 2 days) following the final dose of study medication for an EOS evaluation. 
Participants may be asked or required to stay in the CRU between Periods 1 and 2, and/or before the EOS visit, for their own safety, and also to maintain the 
integrity of the conduct of the study. In the event of early termination/discontinuation (ET), the procedures listed at the EOS are performed prior to participant 
discharge.   
d Hour 0 corresponds to the time of celecoxib ± ALXN1840 administration. Unless stated otherwise, times listed are in relation to celecoxib ± ALXN1840 
dosing. 
e The nominal 336-hour sample for Period 1 to be collected pre dose in Period 2. 
f Parameters include age and sex. Race and ethnicity will be collected where permitted by local regulations. 
g A full physical examination will be performed at Screening, Check-in for each period, and at the end of the study or upon ET. A symptom-driven physical 
examination may be performed at other times, at the PI’s discretion. 
h Randomization will occur before dosing. 
i Each dose administration will be separated by at least 14 days between celecoxib alone or in combination with ALXN1840 doses. There will be a minimum of 
14 days between Day 1 of Period 1 and Day 1 of Period 2.  
j Samples for chemistry will be obtained following a fast of at least 6 hours at Screening, and at Check-in. In case of dropouts, rechecks, and post dose 
chemistry, fasting is not required (Section 10.2). 
k Only needed if claiming exemption from contraception requirement due to menopause. 


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l Triplicate 12-lead ECG will be taken at screening, pre-dose, and at 4 hours post-dose (before lunch) on Day 1. ECGs will be conducted before PK blood 
sampling if these 2 events are scheduled to occur at the same time. 
m A single 15 mL sample will be retained for evaluation in the event of an unexpected safety finding; retained samples may be destroyed after completion of the 
clinical study report. The retained serum sample will only be collected pre-dose on Day 1 of Period 1.  
 
Abbreviations: AE = adverse event; BMI = body mass index; C-I = Check-in; CRU = clinical research unit; ECG = electrocardiogram; EOS = End of Study; 
ET = Early Termination; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; HR = heart rate; PI = Principal Investigator; 
PK = pharmacokinetics; S = Screening. 


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2. 
INTRODUCTION 
ALXN1840 (bis-choline tetrathiomolybdate; formerly known as WTX101) is a novel, 
first-in-class, copper (Cu)-protein binding agent in development for the treatment of Wilson 
disease (WD) and primary biliary cholangitis (PBC). 
2.1. 
Study Rationale 
This study is being conducted to determine the effect of ALXN1840 at a single dose of 60 mg on 
the metabolism of celecoxib, a sensitive cytochrome P450 2C9 (CYP2C9) substrate, at a single 
dose of 200 mg (Celebrex®). ALXN1840 is considered to have the potential for weak to 
moderate drug-drug interactions (DDI) due to inhibition of CYP2C9, according to in vitro 
studies conducted using human liver microsomes and simulations performed to assess DDI risks 
(Study CYP0840-R2, Study 1907124 and Study AXP/1/B). This study has been designed and 
will be conducted in accordance with the current regulatory guidance issued by the US Food and 
Drug Administration (FDA) “Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- 
and Transporter-Mediated Drug Interactions” (2020), European Medicines Agency (EMA) 
Committee for Medicinal Products for Human Use “Guideline on the Investigation of Drug 
Interaction” (2012), and the Japan Pharmaceuticals and Medical Devices Agency (PMDA) 
“Guideline on drug interaction for drug development” (2019). 
Based on a mean ALXN1840 maximum observed plasma concentration (Cmax) value of 3.92 μM 
with a single dose of 60 mg enteric-coated (EC) tablet under fasting conditions in healthy 
participants (Study WTX101-102), a steady state plasma total Mo Cmax of 13.03 μM can be 
estimated, considering accumulation ratio of 3.33 with linear pharmacokinetics (PK). In the 
Phase 2 Study WTX101-201, conducted in patients with WD, the observed highest plasma total 
molybdenum (Mo) concentration was 20.3 µM after repeated doing of ALXN1840 at 60 mg; the 
dose was escalated to 120 mg at Week 4. Assuming all tetrathiomolybdate (the active ingredient 
in ALXN1840) in human plasma is free (a conservative approximation since 90% - 95% of the 
total Mo in plasma is bound to copper and albumin by forming tripartite complexes), there is no 
potential that ALXN1840 may induce cytochrome P450 (CYP) isoforms or inhibit 
p-glycoprotein, breast cancer resistance protein, or the organic anion and organic cation uptake 
transporters. However, as the estimated in vivo steady-state plasma levels of total Mo after 
dosing ALXN1840 at 60 mg (13.03 µM) daily may exceed the drug concentration required to 
produce 50% of the maximal inhibition (IC50 value = 6.9 µM) of CYP2C9 in vitro, a moderate 
potential for inhibition of CYP2C9 was theoretically and conservatively anticipated 
(Study 030519b, Study 030709c, Study MC05063, and Study CYP0840-R2). 
Subsequent in vitro studies in human liver microsomes (HLM) have shown a potential inhibitory 
effect (competitive and time-dependent) of ALXN1840 (and possibly its degradation products) 
on CYP2C9-mediated metabolism (Study CYP0840-R2 and Study 1907124). The IC50 value for 
the inhibitory effect on CYP2C9 was observed at 6.9 µM (3.0 µg/mL) with the estimated Ki 
values of 6.07 µM (2.6 µg/mL; Study CYP0840-R2 and Study AXP/1/B). Furthermore, the study 
(Study 1907124) specifically examining the inactivation potential of ALXN1840 on CYP2C9 
catalytic activity in vitro using HLM and the FDA recommended CYP2C9 probe substrate 
diclofenac 4'-hydroxylation with the time-dependent probe inhibitor tienilic acid as active control 
(US Food and Drug Administration), demonstrated potential for time-dependent inhibition (TDI) 


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at ALXN1840 concentrations ≥ 30 µM. Because the maximum observed plasma total Mo 
concentration in the Phase 2 Study WTX101-201, conducted in patients with WD, was 20.3 µM 
after repeated doing of ALXN1840 at 60 mg and then dose-escalated to 120 mg at Week 4, the 
observed in vitro TDI potential at ALXN1840 concentration of ≥ 30 µM is not anticipated in 
vivo, even considering total Mo of 20.3 µM is 100% active and free ALXN1840 (a most 
conservative case). Assuming 10% of the total Mo is in the form of free and active ALXN1840, 
which is still conservative given that most of this 10% are likely ALXN1840 degradants such as 
molybdate, then the highest anticipated individual free and active ALXN1840 concentration is at 
2.03 μM in patients with WD, when dosed at 120 mg daily at steady state. Overall, this, implies a 
negligible possibility for observing in vivo TDI with repeated daily doses of ALXN1840 at 60 
mg or up to 120 mg in patients with WD. 
Finally, a validated Simcyp® physiologically based pharmacokinetic model, developed using 
data from Study WTX101-HV-106, predicted a weak CYP2C9 inhibition potential for 
simulations of single dose ALXN1840 exposures at 120 or 240 mg. The predicted geometric 
mean of the AUC ratio of celecoxib was 1.5 for the highest simulated single dose of 240 mg 
ALXN1840 (Study AXP/1/B), indicating weak inhibitory potential in vivo (weak for AUC ratio 
of ≥ 1.25- to < 2-fold), per the 2020 FDA guidance on “Clinical Drug Interaction Studies — 
Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions”. For the highest 
simulated single dose of 240 mg ALXN1840, the maximum in vivo estimated free plasma 
concentration available to interact with CYP2C9 is estimated at 4.1 µM, after accounting for the 
formation of tetrathiomolybdate-Cu-albumin tripartite complexes (TPC), which is higher than 
the 2.03 µM noted above. 
Overall, based on in vitro and in silico study results, the maximum total daily doses in clinical 
studies (currently 60 mg in Phase 3 Study WTX101-301, but previously up to 120 mg in Phase 2 
Study WTX101-201) are not anticipated to reach steady-state ALXN1840 concentrations 
associated with TDI. According to the FDA guidance (US FDA “Clinical Drug Interaction 
Studies - Cytochrome P450 Enzyme - and Transporter-Mediated Drug Interactions” [2020]), a 
single dose study design using the highest anticipated clinically relevant dose will be appropriate 
and justified if there is no TDI. Therefore, single dose of ALXN1840 at 60 mg, which is the 
highest allowed dose in the on-going Phase 3 Study WTX101-301 conducted for treating patients 
with WD, is justified to be tested as a potential perpetrator for the CYP2C9 metabolism of a 
sensitive substrate celecoxib.  
CYP2C9 is the most abundant drug metabolizing cytochrome P450 2C subfamily enzyme in the 
human liver, and accounts for approximately 20% of total hepatic P450 protein with mass 
spectrometry quantitation. Common substrates of CYP2C9 include, but are not limited to, 
numerous NSAIDs, oral hypoglycemic agents, including tolbutamide and sulfonylureas, 
angiotensin II blockers, rifampicin and S-warfarin. In all, CYP2C9 covers the metabolism of 
approximately 15% of drugs that involve CYP450 enzymes (Daly, 2017; Dean, 2012). 
The potentially weak to moderate inhibitory effects of a single 60 mg ALXN1840 dose on a 
single dose 200 mg celecoxib metabolism is anticipated to have a very limited safety concern 
based on the Celebrex® USPI (Celebrex®).  
Further details of the currently available drug metabolism, pharmacokinetics, and safety data are 
available in the Investigator’s Brochure (IB) for ALXN1840 (Edition 10, 25 Feb 2020). 


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2.2. 
Background 
ALXN1840 is in development for the treatment of WD and PBC due to its improved stability 
properties over ammonium tetrathiomolybdate, the latter of which has previously been studied in 
patients with WD and other indications. Ammonium tetrathiomolybdate as well as 
bis-choline tetrathiomolybdate non-clinical and clinical data reported to date support therapeutic 
efficacy and with an appropriate safety profile for ALXN1840. 
ALXN1840 rapidly forms irreversible TPC, which stabilize free and potentially toxic Cu leading 
to a reduction in the non-ceruloplasmin-bound Cu (NCC) concentrations or NCC corrected for 
TPC [NCCcorrected]) (Weiss, 2017). 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ALXN1840 are 
provided in the IB for ALXN1840.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) for ALXN1840 may be found in the IB and for celecoxib in the 
prescribing information (Celebrex®). 
2.3.1. 
Risk Assessment 
Details of the potential risks and mitigation strategy are provided in Table 2.  
Table 2:  
Potential Risks and Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
ALXN1840 
Dose-dependent elevations in 
transaminases (ALT and AST) 
Generally mild to moderate in 
severity, asymptomatic and 
reversible with dose adjustments 
were reported, usually after 
3 – 6 weeks of treatment in patients 
with WD 
 
Regular monitoring of liver 
function tests  
Anemia 
Anemia has been observed in 
patients with WD, PBC and cancer, 
and attributed to overtreatment and 
resultant Cu depletion 
Monitoring complete blood count  
Low white blood cell count 
(leukopenia, bone marrow toxicity)  
Leukopenia and bone marrow 
toxicity (myelosuppression) have 
been observed in patients with WD 
and attributed to overtreatment and 
resultant Cu depletion 
 
Monitoring complete blood count  
Study Procedures 
Risks associated with the study 
design and procedures  
Participants will undergo repeated 
blood draws to measure the PK of 
the study intervention and 
metabolism. Blood draws may 
result in ecchymosis, redness and 
minor pain to the site. On rare 
Blood draws are optimized for PK. 
A cannula may be placed to 
minimize needle sticks 


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2.3.2. 
Benefit Assessment 
This is a healthy volunteer study, and there is no direct benefit to study participants.  
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures implemented to minimize risk to participants, the potential 
risks identified in association with ALXN1840 and celecoxib are justified by the anticipated 
benefits that may be afforded to patients with WD and PBC. 
occasion, infection or 
thrombophlebitis can occur  
Celecoxib 
As per prescribing information 
Celecoxib prescribing information 
(Celebrex®) 
Participants will be monitored for 
adverse réactions and by regular 
laboratory assessments. Participants 
may be discontinued for significant 
drug related adverse events  
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; Cu = copper; 
IB = Investigator’s Brochure; PBC = primary biliary cholangitis; PK = pharmacokinetics; 
WD = Wilson Disease. 


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• 
To determine the effect of ALXN1840 on the 
PK of celecoxib, a sensitive CYP2C9 
substrate 
• 
PK parameters of celecoxib (Cmax, area under 
the plasma concentration (AUC) versus time 
curve from time 0 to the last quantifiable 
concentration [AUCt], and AUC versus time 
curve from time 0 to infinity [AUC∞]) with 
and without the coadministration of 
ALXN1840 
Secondary 
 
• 
To determine the effect of ALXN1840 on the 
PK of plasma Mo with the coadministration of 
celecoxib 
• 
To determine the safety and tolerability of 
ALXN1840, with the coadministration of 
celecoxib  
• 
PK parameters for plasma total Mo (Cmax, 
AUCt, and AUC∞) with the coadministration 
of celecoxib 
• 
Safety assessed by incidence of treatment-
emergent adverse events (TEAEs) and 
treatment-emergent serious adverse events 
(TESAEs), physical examination, vital signs 
measurements, clinical laboratory and 12-lead 
electrocardiogram (ECG) results  
Abbreviations: AUC∞ = area under the plasma concentration versus time curve from time 0 to infinity; 
AUCt = area under the plasma concentration versus time curve from time 0 to the last quantifiable concentration; 
Cmax = maximum observed plasma concentration of the drug; CYP2C9 = cytochrome P450 2C9; 
ECG = electrocardiogram; PK = pharmacokinetics; TEAE = treatment-emergent adverse event; 
TESAE = treatment-emergent serious adverse event. 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
The study is being conducted as a randomized, 2-period, 2-sequence, cross-over study to 
determine the effect of a single dose of ALXN1840 (perpetrator) on the single dose celecoxib 
(victim) kinetics in healthy male and female participants.  
The study has a Screening period (Day -28 to Day -2), two 11-day study periods (Day 1 to 
Day 11) with a minimum of 14 days between doses of celecoxib, and an End of Study (EOS) 
Visit (Day 15 ± 2 days) after Period 2 dosing. Participants will report to the clinical research unit 
(CRU) on the day prior (Day -1) to both dosing periods. 
All participants will receive 1 treatment in each study period; treatment order will be defined 
based on randomization:  
• Treatment A: One 200 mg celecoxib capsule with 240 mL water (fasting). 
• Treatment B: One 200 mg celecoxib capsule + 4 × 15 mg ALXN1840 EC tablets 
with 240 mL water (fasting). 
Based on randomization, participants will be administered either Treatment A or Treatment B in 
each period. A wash-out period of at least 14 days must separate dose administration in Period 1 
and Period 2. Participants will remain institutionalized from the day prior to dosing until Day 11 
following dose administration for each period. 
The PK profile of ALXN1840 and celecoxib will be determined by blood sampling following 
single dose administration over approximately 5 half-lives or more for both study interventions. 
Blood sampling for PK assessments will occur at pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 
120, 144, 168, 192, 216, 240, and 336 hours post-dose to ensure full assessment of exposure over 
time. The nominal 336-hour sample for Period 1 is pre-dose sample for Period 2. In addition to 
PK sampling, safety and tolerability will be assessed by monitoring AEs, vital signs, 12-lead 
electrocardiograms (ECGs), and laboratory parameters. 
Following scheduled procedures on Day 11, participants will be discharged from the unit. If 
there are any participants with clinically significant abnormalities at the time of discharge, the 
Investigator should notify the Medical Monitor prior to discharge, and participants may be asked 
to remain institutionalized for further clinical monitoring.  
Participants may be asked or required to stay in the CRU between Periods 1 and 2, and/or before 
the EOS visit, for their own safety, and also to maintain the integrity of the conduct of the study. 
The End of Study (EOS) Visit will occur approximately 4 days after discharge from Period 2, 
after collection of the nominal 336-hour PK sample.  
This study will include approximately 38 participants; the overall study population will include a 
minimum of 40% of each sex.  
Participants will be randomized to one of two sequences as described in Table 3. 


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Table 3: 
Study Design  
Sequence 
Number 
Treatment Sequence 
Malea 
Femalea 
Total 
Study Period 1 
Study Period 2 
1 
A 
B 
8 to 11 
8 to 11 
19 
2 
B 
A 
8 to 11 
8 to 11 
19 
Total 
16 to 22 
16 to 22 
38 
aIn an effort to achieve balance between males and females in each sequence, there will be no less than 16 and no 
more than 22 of either sex (ie, a maximum split in either direction of approximately 60%:40%). Randomization will 
be stratified by sex. 
Treatment A -One 200 mg celecoxib capsule with 240 mL water (fasting) 
Treatment B – One 200 mg celecoxib capsule + 4 × 15 mg ALXN1840 enteric-coated tablets with 240 mL water 
(fasting) 
At the Investigator’s discretion, additional participants may be screened to allow for a full 
enrollment of the study, with a minimum of 40% for each sex. Therefore, it is possible that all 
eligible participants may not be included. Participants not included in the study will be 
discharged without dosing on Day 1. 
4.2. 
Scientific Rationale for Study Design 
This study is being conducted in healthy participants so that the assessments are not confounded 
by disease activity, comorbidities, or concomitant medications. The inclusion and exclusion 
criteria for this study are consistent with Phase 1 clinical pharmacology studies that assess the 
medication of interest and to minimize assignment bias. 
A 2-way crossover study design was adopted to control the variability within and between 
participants. Given the desire to evaluate the impact of sequence of administration, the study is 
being conducted as a 2-sequence, 2-period cross-over study. Blood sampling for PK assessment 
will include measures for ALXN1840 and celecoxib. Blood sampling timepoints support 
evaluation of time to reach maximum observed plasma concentration (Tmax) and Cmax and include 
a minimum of 5 half-lives between each study intervention. 
The interval between dose administration in each period will be at least 14 days, based on the 
estimated mean half-life for ALXN1840 of approximately 2 days as previously reported in the 
bioavailability studies (Studies WTX101-101 and WTX101-102), where healthy participants 
took an oral dose at 60 mg. Therefore, a minimum of 14 days between dose administration is 
considered sufficient to eliminate, on average, approximately more than 99.2% of the plasma 
total Mo before a second dose of celecoxib. The approximately 4-day interval after Period 2 dose 
administration will also ensure that the participants will have eliminated measurable 
concentrations of ALXN1840 at the EOS Visit regardless of the randomized dosing sequence. 
The mean elimination half-life (±SD) of celecoxib after chronic dosing is 11.2 (± 3.5) hours 
(Celebrex®), therefore a minimum of 14-day interval between single dose administrations is 
sufficient to eliminate greater than 99.2% of plasma celecoxib.  
4.3. 
Justification for Dose 
ALXN1840 
The maximum tolerated dose (MTD) of ALXN1840 is unknown. To date, the 60 mg single dose 
and repeated daily doses have shown a good safety profile and were well tolerated throughout 


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the Phase 1 to Phase 3 clinical studies. The 60 mg dose is well within the dose range 
demonstrated to have a good safety profile in studies in healthy volunteers and patients with WD. 
The 60 mg dose is well within the dose range to have an acceptable safety profile in humans as 
demonstrated in the completed bioavailability studies that were conducted in healthy male and 
female participants (Study WTX101-101 and Study WTX101-102) with a median (range) body 
weight of 80.8 kg (57.6 to 107.0 kg) as well as the completed Study WTX101-201, conducted in 
patients with WD.  
Tetrathiomolybdate reacts with albumin-bound Cu in the liver or blood to form a stable tripartite 
complex which is excreted into the bile. Tetrathiomolybdate which does not bind to Cu and 
albumin, is not metabolized by the liver but undergoes hydrolysis to form molybdate anion, 
which is excreted in the urine. Therefore, findings from the human microsome study 
(Study CYP0840-R2) are considered an over-estimation of the effect to be observed in vivo. 
Given that in vitro inhibition was observed with the ALXN1840 parent drug and no apparent 
accumulation of free ALXN1840 as part of the plasma ultrafiltrate (PUF) Mo or non-TPC-bound 
Mo after ALXN1840 repeated dosing (preliminary results from Study WTX101-201), a single 
dose of ALXN1840 is considered to be sufficient to assess the inhibition potential of CYP2C9 
using celecoxib as the substrate. Single dose administration of the ALXN1840 tablet under fasted 
conditions resulted in a peak drug concentration of total Mo at approximately 4.54 hours, with a 
half-life of approximately 51 hours (Study WTX101-102).  
Celecoxib 
Peak plasma levels of celecoxib occur approximately 3 hours after an oral dose under fasting 
conditions. Absolute bioavailability studies have not been conducted for this drug. Celecoxib 
exhibits a dose proportional increase in exposure after oral administration up to 200 mg twice 
daily and less than proportional increase at higher doses. It has extensive distribution and high 
protein binding with a half-life of approximately 11 hours (Celebrex®). 
Celecoxib metabolism is predominantly mediated via CYP2C9 in the liver. Concomitant 
administration of fluconazole 200 mg and celecoxib 200 mg resulted in a 2-fold increase in 
celecoxib plasma concentration. This increase is due to the inhibition of celecoxib metabolism 
via CYP2C9 by fluconazole. For celecoxib, the selected dose in this study is 200 mg, which has 
been selected based on the drug interaction study with fluconazole in the Celebrex® US package 
insert (Celebrex®) and Diflucan® USPI (Diflucan®). A single dose is considered appropriate due 
to the linear PK of celecoxib within the approved therapeutic dose range.  
Celecoxib is formulated into capsules at 50, 100, 200, and 400 mg dose strengths. Celecoxib may 
be administered initially up to a dose of 400 mg twice daily with adequate safety and tolerability. 
The dose of 200 mg represents the highest dose within the linear range of the drug to allow DDI 
assessment (linear PK is thought to be limited by poor absorption above 200 mg). Even though 
ALXN1840 is considered theoretically and conservatively to have potential for moderate 
inhibition of CYP2C9 in vitro, because this study is being conducted as a single dose study, 
without risk of accumulation, no dose adjustment is being made to the dose of celecoxib. A dose 
of 200 mg is not expected to result in sufficiently high exposure to cause an increase in safety 
risk. 


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4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Activities (SoA). 
The end of the study is defined as the date the last participant completes the last visit as shown in 
the SoA (Table 1). 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participants must be 18 to 50 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Participants who are healthy as determined by medical evaluation including medical 
history, physical examination, vital signs, 12-lead ECG, and clinical laboratory 
evaluation (hematology, biochemistry, coagulation, and urinalysis) that are reasonably 
likely to interfere with the participant’s participation in or ability to complete the study, 
or to potentially confound interpretation of study results, as assessed by the Investigator.  
3. Adequate venous access in the left or right arm to allow collection of a number of blood 
samples.  
Weight 
4. Body weight ≥ 45 to ≤ 100 kg and body mass index (BMI) within the range of 18 to 
< 30 kg/m2 at Screening.  
Sex 
5. Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a. Male Participants: 
• Male participants, if heterosexually active with a female spouse or partner of 
childbearing potential or a pregnant or breastfeeding spouse or partner, must agree to 
use barrier contraception (male condom) for the duration of the study and for at least 
3 months after the end of systemic exposure of the study intervention (ie, 3 months 
after the EOS Visit). Male participants must also agree to not donate sperm for at 
least 3 months after the end of systemic exposure of the study intervention (ie, 
3 months after the EOS Visit).  
• Female spouses or partners of male participants who are of childbearing potential 
must use highly effective contraception as defined below and in Section 10.4 , 
starting at least 1 menstrual cycle before (the male participant’s) first study 
intervention administration and continuing until at least 3 months after the end of 
their male partner’s systemic exposure to the study intervention (ie, 3 months after the 
EOS Visit).  
• Barrier contraception is required even with documented medical assessment of 
surgical success of a vasectomy. For male participants who have had a vasectomy 


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(with documented evidence of azoospermia if possible) and agree to use a barrier 
method (male condom) for the stated time period, no additional contraceptive method 
is required by their female partner. 
b.  Female Participants: 
• Female participants or female partners of male participants of childbearing potential, 
(including breastfeeding females), if heterosexually active, must be willing to follow 
protocol-specified contraception guidance starting at least 1 menstrual cycle before 
first study intervention administration and continuing for at least 3 months after the 
end of systemic exposure of the study intervention (ie, 3 months after the EOS Visit). 
Female participants must not donate ova for at least 3 months after the EOS (ie, 3 
months after the EOS Visit). 
• Female participants who are documented as being of non-childbearing potential as 
defined in Section 10.4 are exempt from contraception requirements.  
• Highly effective contraceptive methods for female participants and female partners of 
male participants are described in Section 10.4.  
• Women of childbearing potential must have a negative highly sensitive serum 
pregnancy test at screening. Additional urine pregnancy testing will be standard for 
the protocol unless serum testing is required by site policies, local regulation, or 
IRB/IEC and should be performed per the time points specified in the SoA (Table 1). 
Informed Consent 
6. Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions  
1. History or presence of/significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrinological, hematological, or neurological disorders. 
Participants with a history of gastric bypass, other surgical procedure, or medical condition 
that may significantly alter absorption of drugs.  
2. Clinically significant multiple or severe drug allergies, food allergies, or allergies to study 
product or class of product or its derivatives.  
3. Lymphoma, leukemia, or any malignancy within 5 years of Screening, except for basal cell 
or squamous epithelial carcinomas of the skin that have been resected with no evidence of 
metastatic disease for 3 years. 
4. Breast cancer within the past 10 years. 
5. Serum creatinine > upper limit of normal (ULN) of the reference range of the testing 
laboratory at Screening or on Check-in Period 1.  


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6. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin > ULN 
of the testing laboratory at Screening and Check-in. Participants with confirmed Gilbert’s 
syndrome may be included with total bilirubin > ULN but below 3 × ULN if participant has a 
measured direct bilirubin < ULN.  
7. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the 
exception of Gilbert’s syndrome or asymptomatic gallstones). 
8. QTc > 450 msec for male participants or > 470 msec for female participants 
NOTE A: The QTc is the interval between the start of the Q-wave and the end of the T-wave 
in an ECG (QT interval) corrected for heart rate according to Bazett’s formula (QTcB), 
Fridericia’s formula (QTcF), and/or another method. It is machine-read with Investigator 
review. 
NOTE B: The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study; QTcF is preferred; 
however, QTcB may be used if QTcF cannot be measured. 
Prior/Concomitant Therapy 
9. Use or intended use of prescription medications (excluding oral contraceptives) within 
14 days or 5 half-lives of the drug (whichever is longer) prior to dosing on Day 1, except 
with prior approval of Alexion. Participants may not have a medical condition that requires 
chronic medicinal therapy. 
10. Use of nonprescription/ over-the-counter medications, including COX-2 inhibitors, herbal 
remedies and supplements, within 7 days prior to dosing on Day 1 and/or intended use at any 
point over the duration of the study.  
Prior/Concurrent Clinical Study Experience 
11. Participation in a study resulting in loss of blood or donation of blood products in excess of 
500 mL within 60 days prior to Day 1. 
12. Exposure to more than 4 new investigational drugs within 12 months prior to dosing.  
13. Current enrollment or past participation within the last 90 days before signing of consent in 
this or any other clinical study involving an investigational study intervention or any other 
type of medical research. For participants recently participating in clinical studies involving 
an investigational product with a prolonged half-life, participants may not participate in this 
study within 5 half-lives of the last dose administration. 
Diagnostic assessments 
14. Presence of hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to 
first dose of study intervention. Presence of HBsAg or positive hepatitis C antibody or 
ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study 
intervention.  
• NOTE: Participants with positive hepatitis C antibody due to prior resolved disease 
can be enrolled if a confirmatory negative hepatitis C RNA test is obtained.  
• NOTE: The RNA test is optional and participants with negative hepatitis C antibody 
test are not required to also undergo hepatitis C RNA testing. 


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15. Positive pre-study alcohol or drugs of abuse screen. 
16. Positive human immunodeficiency virus (HIV) antibody test.  
17. Ongoing use of tobacco products or nicotine delivery systems. 
Other Exclusions 
18. Regular alcohol consumption within 6 months prior to the study defined as: an average 
weekly intake of > 14 units/week for males or > 7 units/week for females. One unit is 
equivalent to 8 g of alcohol: a half pint (~240 mL) of beer, one ~4 oz glass (125 mL) of wine 
or 1 (25 mL) measure of spirits. 
19. Regular use of known drugs of abuse, based on the assessment of the investigator. 
20. Prior exposure to ALXN1840 or other tetrathiomolybdate salt. 
21. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy 
that, in the opinion of the Investigator or Medical Monitor, contraindicates participation in 
the study.  
22. History of asthma or history of allergy to NSAIDs. 
5.3. 
Lifestyle Considerations 
Participants must be able and willing to adhere to the following lifestyle restrictions 
Table 4: 
Healthy Participant Lifestyle Considerations  
Items Participants Must Not 
Consume or Do 
When Participants Must Stop 
When Participants Can Restart 
Tobacco in any form (eg, smoking 
or chewing) or other nicotine-
containing products in any form 
(eg, gum, patch, electronic 
cigarettes or vaporized inhalation 
device) 
From Screening 
After the final study visit 
Alcohol 
48 hours before check-in to the 
CRU (Day -1) and until discharge 
(Day 11), and 48 hours before the 
EOS Visit 
Discharge from the clinical research 
unit and completion of EOS visit 
Meals/snacks/water 
 
Breakfast will be omitted on the 
Day of dosing (Day 1). With the 
exception of the day of dosing, 
water/fluids may be consumed ad 
libitum. On the day of dosing, 
participant must refrain from water 
intake from 1 hour before to one 
hour after with the exception of the 
240 mL water provided for dose 
administration. On Day -1, 
Check-in for Period 1 and 2, the 
evening meal must be completed no 
later than 2100 hours. Participants 
will continue fasting for 
approximately 4 hours after dosing 
Standard meals will be provided 
during institutionalization 


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Table 4: 
Healthy Participant Lifestyle Considerations (Continued) 
Items Participants Must Not 
Consume or Do 
When Participants Must Stop 
When Participants Can Restart 
Not consume any other substances 
known to be potent inhibitors or 
inducers of CYP450 enzymes. This 
includes food or drink products 
containing cranberry, pomegranate, 
star fruit, grapefruit, pomelos, 
exotic citrus fruits or Seville 
oranges (including marmalade and 
juices made from these fruits). Red 
wine should also not be consumed 
Within 7 days before the planned 
first study intervention 
administration 
After collection of the final PK 
sample for each study period 
Caffeine-containing or xanthine-
containing products (eg, tea, coffee, 
cola drinks, and chocolate)  
During each dosing period, 
24 hours before the planned first 
study intervention administration 
and each outpatient/ follow-up visit 
After collection of the final PK 
sample for each study period 
Strenuous physical activity 
Starting 72 hours prior to each 
blood collection for clinical 
laboratory tests. Participants may 
participate in light recreational 
activities during studies (eg, 
watching television, reading) 
After study completion/last visit. 
Participants should not start new 
physical training activities during 
the study until study completion 
(last visit) 
Any prescription medication. For 
details, see Section 5.2  
Note: If participants have a medical 
need to take any medication or have 
any medications prescribed to them 
by a doctor, they should follow the 
medical advice but inform the 
Investigator as soon as possible 
afterwards. Participants should be 
informed not to stop taking any 
medication that has been prescribed 
by their docto  
14 days or 5 half-lives prior to 
dosing on Day 1 
After the final study visit 
Any nonprescription/ 
over-the-counter medication, 
including herbal remedies and 
supplements. For details, see 
Section 5.2.  
Use of nonprescription/ 
over-the-counter medications, 
within 7 days prior to dosing on 
Day 1 and/or intended use at any 
point over the duration of the study. 
With Investigator approval, 
participants may take up to 
1000 mg/day of acetaminophen 
After the final study visit 
Any herbal remedy or dietary 
supplement containing St John’s 
Wort 
2 weeks before the planned first 
study intervention administration 
After study completion/last visit 
Blood and plasma donation 
Participation in a study resulting in 
loss of blood or donation of blood 
products in excess of 500 mL 
within 60 days prior to Day 1 
(Section 5.2) 
1 month after study completion/last 
visit 


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Items Participants Must Not 
Consume or Do 
When Participants Must Stop 
When Participants Can Restart 
Participants must comply with the 
appropriate contraceptive 
requirements as stated in 
Section 10.4 
Start times for contraceptives vary 
according to method used (see 
applicable contraceptive method in 
Section 10.4) 
See Section 10.4 
Abbreviations: CYP450 = cytochrome P450; PK = pharmacokinetics. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details (eg, failed eligibility criteria), and any AEs, including any serious adverse 
events (SAEs) and any related concomitant medication, occurring during the screening period. 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a 
reason that is expected to resolve or has resolved, may be rescreened based on discussion and 
agreement between the Investigator and the Medical Monitor. 
 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Intervention Administered 
Details of the study interventions administered in the study are provided in Table 5. 
ALXN1840 and celecoxib will be administered at the morning of Day 1. 
Table 5: 
Details of Study Interventions Administered 
ARM Name 
Study Intervention 
Comparator 
Intervention 
Name 
ALXN1840 (formerly WTX101) 
Celecoxib 
Type  
Drug 
Drug 
Dose 
Formulation 
Tablet  
Capsule 
Unit Dose 
Strength(s) 
15 mg ALXN1840  
200 mg 
Dosage Level(s) 
Single dose 60 mg administered as 
4 × 15 mg ALXN1840 tablets 
Administered as a single dose (1 × 200 mg 
capsule) 
Route of 
Administration 
Oral 
Oral  
Use 
experimental/study intervention 
comparator/reference  
IMP and NIMP 
IMP  
IMP 
Sourcing 
Provided centrally by Alexion 
Provided by the site 
Packaging and 
Labeling 
ALXN1840 will be provided in treatment 
kits that will each have a unique 
identification number and be packaged and 
labelled in accordance with all applicable 
regulatory requirements. At a minimum, the 
treatment kit label will provide the 
following information: study Sponsor 
identification, batch number, directions for 
use, required storage conditions, caution 
statements (including “New Drug-Limited 
by Federal Law to Investigational Use” 
language), study identification, and expiry 
date 
Celecoxib will be provided as per the 
prescribing information 
Current/Former 
Name(s) or 
Alias(es) 
Sponsor’s name - Bis-choline 
tetrathiomolybdate  
USAN - Tiomolibdate choline  
Celebrex 
Abbreviations: IMP = investigational medicinal product; NIMP = noninvestigational medicinal product; 
USAN = United States adopted name 
6.2. 
Preparation/Handling/Storage/Accountability 
1. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer the study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 


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(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized site staff. 
2. The Investigator and/or delegated staff (ie, Pharmacist) is responsible for study 
intervention accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
a. This responsibility includes the reporting of any product complaints to 
 within 1 business day. A product complaint is 
defined as any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, usability, safety, effectiveness, or 
performance of a product or clinical study material and/or its packaging components 
after it is has been released for distribution to an end customer that affects the 
performance of such product. 
3. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
a. The ALXN1840 treatment kits should be stored at refrigerated conditions, 2°C to 8°C 
(36°F to 46°F). 
b. Celecoxib should be stored according to the details in the package labeling. 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
• This is an open-label, 2-period cross over study where, in order to minimize selection 
bias in treatment assignment, each participant will be randomized to one of 
2 treatment sequences (Treatment A and B). The randomization will be stratified by 
sex so that an approximately equal number of males and females will be assigned to 
each treatment sequence. 
• Eligible participants who meet all inclusion and no exclusion criteria included in the 
study will be assigned unique study participant numbers for enrollment. Study 
participant numbers will not be reallocated once assigned.  
• To achieve balance between the number of males and females in the 2 sequences, the 
maximum split in either direction will be approximately 60%:40% (16 to 22 of each 
sex in each sequence). 
6.4. 
Study Intervention Compliance 
When participants are dosed at the site, participants will receive study intervention directly from 
the Investigator or designee, under medical supervision. The date and time of the dose will be 
recorded in the source documents and/or in the case report form (CRF). If the primary 
documentation is other than the electronic case report form (eCRF), all primary documentation 
should be filed on site as source documents. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
PPD


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than the person administering the study intervention. Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested. 
For additional information on study intervention compliance and management, refer to the 
Pharmacy Manual. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over -the -counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest that the participant is receiving 
from 14 days prior to the first dose of study intervention until EOS visit must be recorded along 
with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Allowed Medicine and Therapy 
• Paracetamol/acetaminophen at doses of a maximum 1,000 mg per day is permitted for 
use as an exception with the approval of the Investigator.  
• As per the ALXN1840 IB, in this study, Investigators should use caution in the 
co-administration of drugs known to be substrates of CYP2C9. Common substrates of 
CYP2C9 include ibuprofen, which is permitted in this study. Therefore, the 
Investigator must use ibuprofen with caution during the conduct of the study. With 
the exception of the day of dosing in each period, ibuprofen may be used with the 
Investigator’s approval; however, doses may not exceed 1,200 mg in any 24-hour 
period. 
• Topical skin products without significant systemic absorption are permitted for use 
during the study at the Investigator’s discretion.  
• Concomitant medications are not allowed unless medically indicated and with 
agreement between Alexion and the Investigator. 
• Concomitant procedures are not allowed unless medically indicated and/or permitted 
by Alexion or the Investigator. 
6.5.2. 
Disallowed Medicine and Therapy 
Participants must refrain from use or intended use of any prescription medications (excluding 
oral contraceptives) within 14 days or 5 half-lives of the drug (whichever is longer) prior to 
dosing on Day 1 and for the duration of the study (ie, until completion of the EOS visit).  
Participants may not have a medical condition that requires chronic medicinal therapy. Use of 
nonprescription/over-the-counter medications, including COX-2 inhibitors, herbal remedies and 


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supplements, is not permitted within 7 days prior to dosing on Day 1 and for the duration of the 
study (ie, until completion of the EOS Visit). 
6.6. 
Dose Modification 
Not applicable. ALXN1840 and celecoxib will be administered as single doses in the prescribed 
parts of the study. 
6.7. 
Intervention After the End of the Study 
This is a healthy volunteer study and no follow-up intervention is planned. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) the study intervention. If the study intervention is definitively discontinued, the 
participant should remain in the study to be evaluated for safety follow-up. See the SoA 
(Table 1) for data to be collected at the time of discontinuation of study intervention and 
follow-up. 
Discontinuation of study intervention for abnormal liver function should be considered by the 
investigator if transaminase elevations (ie, AST or ALT) exceeds 3 × ULN or if the Investigator 
believes that it is in best interest of the participant. 
If a clinically significant finding is identified (including, but not limited to QTcF ≥ 500 ms or 
QTcB ≥ 500 ms), the Investigator or qualified designee will determine if the participant can 
continue in the study and if any change in participant management is needed. Review of the ECG 
printed at the time of collection must be documented. Any new clinically relevant finding should 
be reported as an AE. 
Participant should be considered for discontinuation from intervention if any of the following 
occur during the study: 
• Serious hypersensitivity reaction; 
• Severe uncontrolled infection; 
• Use of disallowed medication (Section 6.5.2); 
• Pregnancy or planned pregnancy (see Section 10.4); or 
• Alexion or the Investigator deems it is necessary for the participant. 
See the SoA (Table 1) for samples and data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal From the Study 
• All efforts should be made to ensure participants are willing to comply with study 
participation prior to conducting the screening procedures. The study staff should 
notify Alexion and their site monitor of all study withdrawals as soon as possible. The 
reason for participant discontinuation must be recorded in the source documents and 
CRF. 
• A participant may withdraw from the study at any time at his/her own request or may 
be withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an Early Termination (ET) 
Visit should be conducted, as shown in the SoA (Table 1). See the SoA for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 


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• The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
• If the participant withdraws consent for disclosure of future information, Alexion may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site 
study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific site or of the study as a whole are handled as described in 
Section 10.1.8  


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Table 1). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screen failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management 
(eg, blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol specified 
criteria and were performed within the time frame defined in the SoA. 
• Abnormal laboratory parameters may be repeated once during the Screening Period to 
ensure an accurate assessment of eligibility.  
• Unscheduled blood samples may be taken at the discretion of the Investigator for 
assessment of safety issues. 
8.1. 
Efficacy Assessments 
No efficacy assessments will be obtained during this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1). 
For study Periods 1 and 2, when multiple procedures are scheduled to occur at the same time, the 
following order of events should be strictly adhered to whenever possible: Vital signs, ECG, 
blood sampling, study intervention administration, and meal.  
Collection of samples for PK assessment should occur as close as possible to the scheduled time.  
8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. It will be 
performed at Screening, Check-in for each period, and at the EOS or upon ET. 
Height, BMI (at Screening only) and weight will also be measured and recorded as 
outlined in the SOA (Table 1). 
• A symptom-driven physical examination may be performed at other times, at the 
study physician’s discretion. 


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• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs 
• Oral temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure 
(mm Hg) will be assessed. 
• Routine blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques should be used if repeat measurements are 
necessary due to abnormal results. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, cell 
phones). Ideally, the same arm for each participant should be used for measurements. 
8.2.3. 
Vital signs will be measured in a semi-supine position after 5 minutes rest. 
Electrocardiograms 
• Participants will be resting in the supine position for at least 15 minutes prior to and 
5 minutes after each nominal time point for ECG extraction. Triplicate 12-lead ECG 
will be conducted as outlined in the SoA (see Table 1) to obtain heart rate, PR, QRS, 
QT, and QTc intervals. Heart rate and interval data will be recorded in the eCRF. QT 
corrected for heart rate using Fridericia’s formula should be recorded as the QTc 
reading (unless unavailable and then QTcB may be recorded). Refer to Section 7 for 
QTc withdrawal criteria and any additional QTc readings that may be necessary. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Section 10.2 for the list of clinical laboratory tests to be performed and the  SoA 
(Table 1) for the timing and frequency.  
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. At the Investigator’s discretion, all abnormal values may be repeated to confirm 
results. The laboratory reports must be filed with the source documents.  
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study after the last dose of the study intervention should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or Medical Monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and Alexion 
notified. 
− All protocol required laboratory assessments, as defined in Section10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Table 1). 
− All laboratory values from nonprotocol specified laboratory assessments also 
must be recorded in the CRF.  


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8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
Not applicable. 
8.2.6. 
Pregnancy 
• Pregnancy data from female participants and female spouses/partners of male 
participants will be collected from the first dose of the study intervention through 
90 days post the last dose and at the time points specified in the SoA. Any female 
participant who becomes pregnant while participating in the study will be 
discontinued from the study intervention. If a pregnancy is reported, the Investigator 
must immediately inform Alexion within 24 hours of awareness of the pregnancy and 
follow the procedures outlined in Section 10.4. 
• For all Alexion products, both in development or post approval, exposure during 
pregnancy must be recorded and the pregnancy followed until the outcome of the 
pregnancy is known (ie, spontaneous miscarriage, elective termination, normal birth, 
or congenital abnormality), even if the participant discontinues study intervention or 
withdraws from the study. The corresponding infant must be followed for 3 months 
postpartum. 
• Pregnancy is not considered an AE (Section 10.4) unless there is a suspicion that the 
study intervention may have interfered with the effectiveness of a contraceptive 
medication. However, complications of pregnancy and abnormal outcomes of 
pregnancy are AEs and may meet the criteria for a SAE (eg, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly) (Section 8.3). Elective abortions without complications should not be 
reported as AEs. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
Adverse events will be reported to the Investigator or qualified designee by the participant (or, 
when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in 
Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs will be collected from the signing of the ICF until the EOS or ET Visit.  


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All SAEs will be recorded and reported to Alexion or the designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The Investigator will 
submit any updated SAE data to Alexion within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has exited the study, and he/she considers the event to be reasonably related to the 
study intervention, the Investigator must promptly notify Alexion. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow-up with each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is provided in Section 10.3.  
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to Alexion of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
• Alexion has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. Alexion will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
• Suspected unexpected serious adverse reactions (SUSARs) must be reported 
according to local regulatory requirements and Alexion policy and forwarded to 
Investigators as necessary. 
• An Investigator who receives an Investigator Safety Report describing an SAE or 
other specific safety information (eg, summary or listing of SAEs) from Alexion will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Adverse Events of Special Interest 
There are no adverse events of special interest for this study. 


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8.3.6. 
Retained and Biobanked Sample 
A single biobanked serum sample will be collected pre-dose to serve as a retained safety sample 
during the study. At the end of the study, pre-dose safety samples will be biobanked to support 
assay development and determination of normal Cu and Mo levels in healthy participants. 
Samples may be stored and used for up to 5 years following completion of the study. 
8.4. 
Treatment of Overdose 
For this study, any dose of ALXN1840 or celecoxib greater than that specified in the protocol 
will be considered an overdose. 
Alexion does not recommend specific treatment for an overdose.  
Overdoses are medication errors that are not considered AEs unless there is an untoward medical 
occurrence resulting from the overdose. 
In the event of an overdose or suspected overdose, the Investigator or treating physician should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for any AE/SAE. 
• Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis).  
• Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
• Whole blood samples will be collected for the measurement of plasma concentrations 
of total Mo and celecoxib as specified in the SoA (Table 1). Additional samples may 
be collected at additional time points during the study if warranted and agreed upon 
between the Investigator and Alexion. Collection of samples for PK evaluation should 
occur as close as possible to the scheduled time and actual time of collection should 
be documented on the eCRF. Samples collected within ± 10% of the scheduled time, 
or 30 minutes whichever is larger, will not be considered a protocol deviation. In the 
event of a safety occurrence and after agreement between the Investigator and 
Medical Monitor, up to 3 additional PK sampling timepoints may be added.  
• Instructions for the collection and handling of biological samples will be provided by 
Alexion. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• Samples will be used to evaluate the effect of ALXN1840 on the PK of celecoxib. 
Samples collected for analyses of plasma concentrations may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 


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• Excess/additional samples may be stored for up to 5 years and used for 
pharmacodynamic (PD) development and research to understand the pathways 
associated with the mechanism of action of ALXN1840; however, samples will not 
be used for genetic analyses (ie RNA or DNA analyses).  
8.6. 
Pharmacodynamics 
Plasma samples collected for PK may be used for analyzing the PD of ALXN1840 including, but 
not limited to plasma total Cu, ceruloplasmin (Cp), Cp-bound Cu (CpC), and potentially toxic Cu 
measured as labile-bound Cu (LBC) and PUF Cu and/or assessed via NCC/NCCcorrected. 
8.7. 
Genetics 
Blood samples for genetic testing of CYP2C9 polymorphism will be collected at clinical 
Check-in (Day -1). This study proposes to collect genetic polymorphism data to characterize 
potential impact of ALXN1840 on phenotypic CYP2C9 metabolism of celecoxib and evaluate 
the potential effect of genetic polymorphism on the between-participant variability of celecoxib 
PK. As this is an exploratory assessment, the study will not specifically select target participants 
with a certain proportion of CYP2C9 genotypes.  
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study.  
8.9. 
Immunogenicity 
Not applicable. 
8.10. 
Health Economics and Medical Resource Utilization 
Health economic and medical resource utilization parameters are not evaluated in this study. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary objective is to determine the effect of ALXN1840 on the PK of celecoxib. There is 
no formal null hypothesis to be statistically tested and used to drive declaration of study success 
or failure.  
To assure the study has enough participants, to estimate the inhibitory effect of ALXN1840 on 
the metabolism of celecoxib, the sample size was determined using the conservative 90% 
confidence interval (CI) and 80% to 125% no-effect boundary approach described in the FDA 
Guidance “Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and 
Transporter-Mediated Drug Interactions” (2020). This guidance notes the 80 to 125 % 
boundaries represent a very conservative standard for drugs that have wide safety “margins” and 
“the totality of evidence should be taken into consideration when determining the clinical impact 
of the DDI on the substrate drug”. Therefore, if the estimated inhibition effect of ALXN1840 on 
celecoxib PK lies outside this no-effect boundary, this should not be interpreted as a failed study. 
9.2. 
Sample Size Determination 
A default of no-effect boundary (80% to 125%) approach will be employed to assess whether 
there is an inhibition effect on the metabolism of celecoxib in the presence of ALXN1840. For a 
2-period crossover study design, assuming the true ratio of the means (celecoxib + ALXN1840 
vs celecoxib alone) on the PK parameters is 1 (Cmax; area under the plasma concentration versus 
time curve from zero to infinity [AUC∞]) and the intra-participant coefficient of variation (CV) is 
0.30 (Dennison, 2018), a total sample size of 32 participants can achieve 90% power with two 
1-sided tests, each with a type I error rate of 5% (two-sided type I error rate of 10%). The intra-
participant CV is estimated using residual mean-square error (MSE) term in the ANOVA model. 
The CV is estimated as 100% × √ (exp (MSE) - 1) for the log-transformed PK parameters. 
Assuming a 15% dropout rate, approximately 38 participants will be enrolled.  
9.3. 
Populations for Analyses 
The following populations are defined (Table 6): 
Table 6: 
Populations for Analyses 
Population 
Description 
Enrolled Set 
All participants who sign the ICF 
Safety Set 
All participants who receive at least 1 dose of study intervention 
Pharmacokinetic/Pharmacodynamic 
(PK/PD) Analysis Set 
All participants who have sufficient plasma samples to have evaluable PK 
data for celecoxib and total Mo (as a measure of ALXN1840) in plasma 
Abbreviation: ICF = informed consent form; Mo = molybdenum. 
9.4. 
Statistical Analyses 
Statistical methods described in this section will be further elaborated in a separate Statistical 
Analysis Plan (SAP). The SAP will be developed and approved before database lock and will 
describe the participant populations to be included in the analyses, and procedures for accounting 
for missing data. 


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Summary statistics will be computed and displayed by study group and by visit, where 
applicable. Descriptive statistics for continuous variables will include number of non-missing 
values, arithmetic mean, standard deviation, median, minimum, and maximum. Categorical 
variables will be summarized using percentages and frequency counts.  
All statistical analyses will be conducted using SAS® for Windows® Version 9.3 or higher. 
9.4.1. 
Efficacy Analyses 
No efficacy analyses will be performed for this study. 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Set.  
Safety analyses will include an analysis of all AEs, ECGs, clinical laboratory data, physical 
examinations, and vital sign measurements using descriptive statistics. Data will be summarized 
by study groups.  
No inferential statistical analyses are planned for the safety parameters of this study. The 
incidence of AEs and SAEs will be summarized by System Organ Class (SOC) and Preferred 
Term for each treatment and overall, and by relationship to study intervention. Adverse events 
will also be summarized by treatment and overall by severity. Serious AEs and AEs resulting in 
withdrawal from the study will be listed. Participants having multiple AEs within a category 
(eg, overall, SOC, Preferred Term) will be counted once in that category. For severity tables, a 
participant’s most severe event within a category will be counted.  
Changes from baseline in vital sign measurements and laboratory assessments (eg, chemistry, 
blood cell count with differential, and urinalysis) will be summarized by study groups. 
Laboratory parameter values will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE). Shift tables by treatment will be produced 
for these laboratory parameters. These tables will summarize the number of participants with 
each baseline grade relative to the reference ranges and changes to the worst highest grade 
assessed post-dose during the study.  
Electrocardiogram parameters will be measured at the specified time points, including heart rate, 
PR, RR, QRS, QT, and corrected QTcF intervals. The average of the triplicate ECG readings at 
the time points collected will be calculated, and changes from pretreatment baseline values will 
be assessed by each treatment.  
All concomitant medications will be coded and summarized using the World Health 
Organization (WHO) Drug Dictionary. 
9.4.3. 
Other Analyses 
9.4.3.1. 
Pharmacokinetic and Pharmacodynamic Analyses 
Pharmacokinetic analyses will be performed using the PK/PD Analysis Set. 
Blood samples for PK analysis of total Mo (as a measure of ALXN1840) and celecoxib will be 
collected at the following time points: pre-dose and post-dose at 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 
96, 120, 144, 168, 192, 216, 240, and 336 hours in each period.  


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The following plasma PK parameters will be calculated as endpoints for total Mo and celecoxib 
using noncompartmental methods with Phoenix® WinNonlin® (Certara USA Inc., Princeton, 
New Jersey) Version 8.0 or higher or SAS Version 9.3 or higher (SAS Institute Inc., Cary, North 
Carolina), as applicable. Calculations will be based on the actual sampling times recorded during 
the study. 
• Time delay between the time of dosing and time of appearance of drug concentration 
in plasma (Tlag; for plasma total Mo with ALXN1840 administration) 
• Maximum observed concentration in plasma (Cmax) 
• Time to Cmax (Tmax)   
• Area under the plasma concentration (AUC) versus time curve from time 0 to the last 
quantifiable concentration (AUCt) 
• AUC versus time curve from time 0 to infinity (AUC∞)  
• AUC extrapolated from time t to infinity as a percentage of AUC∞ (%AUCextrap)  
• Apparent terminal-phase elimination rate constant (λz) 
• Terminal elimination half-life (t½) 
• Apparent oral clearance (CL/F) 
• Apparent volume of distribution (Vd/F) 
Additional plasma PK parameters may be calculated if deemed appropriate. 
Plasma concentrations of total Mo and celecoxib and time deviation data will be presented in a 
data listing by participant. Plasma concentration data will be summarized separately by analyte 
and time point for each treatment using the following descriptive statistics: number of 
participants, arithmetic mean, SD, coefficient of variation (CV), median, minimum, and 
maximum. Mean plasma concentration versus scheduled time profiles will be presented in 
figures on both linear and semilogarithmic scales. Individual plasma concentration versus actual 
time profiles will be presented similarly. 
Pharmacokinetic parameters derived from plasma concentrations of total Mo and celecoxib will 
be presented in data listings and summarized separately using the following descriptive statistics: 
number of participants, arithmetic mean, SD, arithmetic CV, median, minimum, maximum, and 
95% CI. Geometric mean and geometric CV will be presented for Cmax and AUCs only. 
The effect of ALXN1840 on celecoxib PK will be assessed using a linear mixed‐effect model 
(SAS PROC MIXED) with treatment condition, sequence, and period as fixed effects and 
participant nested within sequence as a random effect. The model will be fitted to the natural‐
log‐transformed PK parameters Cmax, AUC∞ and AUCt for estimation of effects and construction 
of CIs for the test treatment (Treatment B: 200 mg celecoxib + 60 mg ALXN1840) compared 
with the reference treatment (Treatment A: 200 mg celecoxib). The within-participant CV for the 
corresponding PK parameters will be estimated using the mean squared error from the statistical 
model. Confidence intervals (90%) will be constructed for the least-squares geometric mean ratio 
(GMR) estimates between the test and reference treatments for above PK parameters using the 


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natural log-transformed data. The GMR estimates and the associated 90% confidence limits will 
be exponentiated back to the original scale.  
Analyses of other PK data including, but not limited to PUF Mo may be conducted. 
Pharmacodynamic data of ALXN1840 including, but not limited to, plasma total Cu, Cp, CpC, 
and potentially toxic Cu measured as LBC and PUF Cu and/or assessed via NCC/NCCcorrected 
may be analyzed and reported. 
Details of the PK/PD analyses will be described in the PK/PD data analysis plan or included in 
the SAP, which will be finalized before database lock. 
9.5. 
Interim Analyses  
No interim analyses are planned for this study. 
9.6. 
Data Monitoring Committee 
There will not be a Data Monitoring Committee, but provision is included for an ad hoc Safety 
Review Committee (SRC), if needed. 
9.7. 
Safety Review Committee 
To ensure participant safety, ad hoc SRC meetings may be held to discuss urgent issues should 
the need arise. The ad hoc SRC must convene within 24 hours in the case of a TESAE or the 
withdrawal of any participant due to an adverse reaction. 
The ad hoc SRC, consisting of the Investigator, Alexion Safety Physician and Alexion Medical 
Monitor will evaluate the study data, if needed, for participant safety and make recommendations 
on termination of the study.  


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval and, where 
applicable, competent authority approval before implementation of changes made to 
the study design, except for changes necessary to eliminate an immediate hazard to 
study participants.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 


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10.1.3. 
Informed Consent Process 
• It is the responsibility of the Investigator to obtain signed (written or electronic 
signature) informed consent from all study participants prior to any study-related 
procedures including screening assessments. 
• The Investigator or his/her representative will explain the nature of the study 
(including but not limited to the objectives, potential benefits and risk, 
inconveniences, and the participant’s rights and responsibilities) to the participant, 
defined according to local and country regulations where the study is taking place, 
and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants, or 
their legally authorized representative, will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
European Union (EU) General Data Protection Regulation (GDPR), ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was screened in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF(s). 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A copy of the signed (written or electronic) documentation (ie, a complete set of 
participant information sheets and fully executed signature pages) must be provided 
to the participant or the participant’s legally authorized representative, as applicable. 
This document may require translation into the local language. Signed (written or 
electronic) consent forms must remain in each participant’s study file and must be 
available for verification at any time. 
• The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee 
will explain to each participant the objectives of the exploratory research. If sharing 
exploratory research results with the Investigator is not planned, the ICF should 
mention it. Participants or legally authorized representative will be told that they are 
free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate signature will be required to document a 
participant’s agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not 
provide this separate signature. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by Alexion. Any participant records 
or datasets that are transferred to Alexion will contain the identifier only; participant 


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names or any information which would make the participant identifiable will not be 
transferred.  
• The participant must be informed that his/her personal study-related data will be used 
by Alexion in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data 
to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
Alexion, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialregister.eu), as appropriate, and in accordance with national, regional, and local 
regulations. 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on a printed or electronic 
CRF unless transmitted to Alexion or designee electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Alexion or its designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 2 years after the last marketing 
application approval, or if not approved, 2 years following the discontinuance of the 
test article for investigation, unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of Alexion. No records may be transferred to another 
location or party without written notification to Alexion.  


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10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The Investigator or designee will prepare and maintain adequate 
and accurate source documents (eg, medical records, ECGs, AE and concomitant medication 
reporting, raw data collection forms) designed to record all observations and other pertinent data 
for each participant. 
Data reported in the CRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. Source documents are filed at the Investigator’s site. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant signs the informed consent.  
Alexion or its designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of Alexion. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Alexion or the Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Alexion ‘s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate therapy and/or follow-up. 
10.1.9. 
Publication Policy 
• Where possible, primary manuscripts reporting results of the primary efficacy 
endpoint or the final results will be submitted for publication within 12 – 18 months 
of the primary evaluation date or end of study, whichever is earlier.  
• Investigators who participate as authors in manuscripts derived from 
Alexion-sponsored studies will agree to the prerequisites as outlined in the Alexion 
author engagement agreement prior to engaging in manuscript development.  
• The Investigator agrees to submit proposals for new manuscripts (whether or not the 
proposed analyses are derived from protocol-specified endpoints) to Alexion for 


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review and consideration. All manuscripts or abstracts emanating from approved 
proposals are to be submitted to Alexion for review before submission to the 
journal/society. This allows Alexion to protect proprietary information and to provide 
comments.  
− The proprietary nature of some development work may preclude publication. In 
some cases, it may be necessary to delay a publication to allow Alexion to ensure 
protection of intellectual property.  
• In general, primary publications, including congress and journal publications, 
containing the protocol-specified results of a study should occur prior to the 
publication of individual study site results or case reports. Alexion’s policy prohibits 
duplicate publication, whereby the same results must not be published in multiple 
peer-reviewed journal manuscripts.  
− Encore congress publications may be appropriate to allow communication of 
research findings to relevant audience and geographical regions. 
• Alexion will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, Alexion will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements and per the Alexion 
Publication Policy. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 7 will be performed by the local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.  
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. Investigators must 
document their review of each laboratory safety report and indicate whether out of 
range results are clinically significant (“CS”) or not clinically significant (“NCS”). 
• Women of childbearing potential should only be enrolled after a negative serum 
pregnancy test result at screening. Additional urine pregnancy testing will be standard 
for the protocol unless serum testing is required by site policies, local regulation, or 
IRB/IEC and should be performed per the time points specified in the 
SoA(Table 1).Screening pregnancy criteria are detailed in Section 5.1. 
Table 7: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
Red blood cell count 
Hemoglobin 
Hematocrit 
RBC Indices: 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
% Reticulocytes 
WBC count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical Chemistry 
BUN 
Potassium 
Bicarbonate 
Sodium 
Glucose 
AST 
ALT 
Chloride 
Alkaline phosphatase 
Direct bilirubin 
Total bilirubin 
Albumin 
Creatinine 
Creatine phosphokinase 
Coagulation 
INR  
Partial thromboplastin time 
Prothrombin time 
Routine Urinalysis 
Specific gravity 
pH 
Glucose 
Protein 
Blood 
Bilirubin 
Urobilinogen 
Nitrite 
Leukocyte esterase by dipstick 
Microscopic examination 
Other Screening 
Tests 
Urine alcohol and urine drug screen (to include at minimum: amphetamines, 
barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, methamphetamine, 
3,4methylenedioxy-methamphetamine, methadone, and tetrahydrocannabinol 
[cannabinoids])  


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Table 7: 
Protocol-Required Safety Laboratory Assessments (Continued) 
Laboratory 
Assessments 
Parameters 
 
Human immune deficiency virus (HIV)-1 and HIV-2 antibodies, HbsAg, anti-HBC IgG + 
IgM (if IgG positive), and anti- HCV with confirmation by HCV RNA  
Serum or urine hCG pregnancy test (as needed for women of childbearing potential) 
 FSH (postmenopausal females only) 
Note: All events of ALT ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or 
ALT ≥ 3 × ULN and international normalized ratio (INR) > 1.5, if INR measured which may indicate severe liver 
injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
FSH = follicle-stimulating hormone; HbsAg = hepatitis B surface antigen; HbA1C = hemoglobin A1C;  
HBC = hepatitis B core antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cell; 
RNA = ribonucleic acid; WBC = white blood cell. 
Investigators must document their review of each laboratory safety report. 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study 
intervention, whether or not considered related to the study intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
 
Events Not Meeting the AE Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): The condition that leads to the procedure is 
the AE. Situations in which an untoward medical occurrence did not occur (eg, hospitalization for elective 
surgery if planned before the signing the ICF, admissions for social reasons or for convenience).  
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of 
the study that do not worsen.  
• 
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what 
is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result 
of a medication error.  
• 
Cases of pregnancy that occur during maternal or paternal exposure to study intervention are to be reported 
within 24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will be collected for 
regulatory reporting and safety evaluation.  
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it 
was more severe. 


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An SAE is defined as any untoward medical occurrence that, at any dose: 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 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 participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should usually be considered 
serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
Recording of AE and/or SAE 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to Alexion 
in lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by Alexion. In this 
case, all participant identifiers, with the exception of the participant number, will be redacted on the copies 
of the medical records before submission to Alexion. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Intensity 
 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to one of the following categories from National Cancer Institute CTCAE v5.0, published 27 Nov 2017:  
• 
Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
• 
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Grade 3: Severe (incapacitating, with inability to perform normal activities) 
• 
Grade 4: Life-threatening 
• 
Grade 5: Fatal 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the study intervention and each occurrence 
of each AE or SAE. An Investigator causality assessment must be provided for all AEs (both nonserious and 
serious). This assessment must be recorded in the CRF and on any additional forms, as appropriate. The 
definitions for the causality assessments are as follows: 


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Assessment of Causality 
− 
Not related: There is no reasonable possibility the study intervention caused the AE.  
 
The AE has a more likely alternative etiology; it may be due to underlying or concurrent 
illness, complications, concurrent treatments, or effects of another concurrent drug.  
 
The event does not follow a reasonable temporal relationship to administration of the study 
intervention. 
− 
Related: There is a reasonable possibility the study intervention caused the AE. 
 
The AE has a temporal relationship to the administration of the study intervention. 
 
The event does not have a likely alternative etiology.  
 
The event corresponds with the known pharmaceutical profile of the study intervention. 
 
There is improvement on discontinuation and/or reappearance on rechallenge. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure (IB) in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to 
include in the initial report to Alexion. However, it is very important that the Investigator always make an 
assessment of causality for every event before the initial transmission of the SAE data to Alexion. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send an SAE 
follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by Alexion to elucidate the nature and/or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide Alexion with a copy of any post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of the 
information. 
10.3.4. 
Reporting of SAEs  
SAE Reporting to Alexion GDS via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours 
awareness. 
• 
SAEs will be reported using the Safety Reporting Form and submitted to Alexion Global Drug Safety 
(GDS). The Investigator must complete, sign, and date the SAE pages, verify the accuracy of the 
information recorded on the SAE pages with the corresponding source documents, and send a copy via 
email or facsimile to the contact information provided below: 
− 
Email: 
 or Fax: 
 
• 
Additional follow-up information, if required or available, should be entered into the CRF and sent to 
Alexion GDS within 24 hours of the Investigator or study site staff becoming aware of this additional 
information via the reporting process outlined above.  
• 
For all SAEs, the Investigator must provide the following: 
− 
Appropriate and requested follow-up information in the time frame detailed above 
− 
Causality of the SAE(s) 
− 
Treatment of/intervention for the SAE(s) 
− 
Outcome of the SAE(s) 
− 
Medical records and laboratory/diagnostic information 
PPD
PPD


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SAE Reporting to Alexion GDS via Paper Safety Reporting Form 
• 
All paper forms and follow-up information submitted to Alexion GDS must be accompanied by a cover 
page signed by the Investigator.  
• 
Paper source documents and/or reports should be kept in the appropriate section of the study file. 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information  
 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD): female participants with a Cu-containing IUD  
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
o 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days.) 
• 
Highly Effective Methodsb That Are User Dependent 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
Oral 
o 
Injectable 
• 
Sexual abstinence 
o 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
• 
Female participants of non-childbearing potential are exempt from contraception requirements. Non-
childbearing potential for female patients is defined as any of the following: 
o Prior to first menses 
o Postmenopausal, as documented by amenorrhea for at least 1 year prior to the Day 1 visit and follicle 
stimulating hormone (FSH) serum levels consistent with postmenopausal status 
o Permanent sterilization at least 6 weeks prior to the Day 1 visit: 
− 
Hysteroscopic sterilization 
− 
Bilateral tubal ligation or bilateral salpingectomy 
− 
Hysterectomy 
− 
Bilateral oophorectomy 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom should not be used together (due to risk of failure with friction) 


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• 
Collection of pregnancy information 
o If a female participant or a male participant’s female spouse/partner becomes pregnant during the 
conduct of this study, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and 
Outcome Form" to Alexion Global Drug Safety (GDS) via fax or email (see Section 10.3 [Appendix 3] 
for contact information). When the outcome of the pregnancy becomes known, the form should be 
updated and submitted to Alexion GDS. If additional follow up is required, the Investigator will be 
requested to provide the information. 
o Exposure of an infant to an Alexion product during breastfeeding must also be reported (via the 
“Pregnancy/Breastfeeding Reporting and Outcome Form”) and any AEs experienced by the infant must 
be reported to Alexion GDS or designee via email or facsimile (see Section 10.3 for contact 
information). 
 


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10.5. 
Appendix 5: Abbreviations 
A list of abbreviations and terms are used in this study protocol is provided in Table 8. 
Table 8: 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
λz 
apparent terminal-phase elimination rate constant  
AE 
adverse event  
ALT 
alanine aminotransferase  
ANOVA 
Analysis of Variance  
AST 
aspartate aminotransferase  
AUC 
area under the plasma concentration versus time curve 
AUCt 
area under the plasma concentration versus time curve from time 0 to the last 
quantifiable concentration  
AUC∞ 
area under the plasma concentration versus time curve from zero to infinity  
BMI 
body mass index 
BUN 
blood urea nitrogen 
CYP 
cytochrome P450  
CYP2C9 
cytochrome P450 2C9 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL/F 
apparent oral clearance  
Cmax 
maximum observed plasma concentration  
CONSORT 
Consolidated Standards of Reporting Trials  
Cp 
ceruloplasmin  
CpC 
ceruloplasmin-bound copper 
CRF 
case report form  
CRU 
clinical research unit  
CTCAE 
Common Terminology Criteria for Adverse Events  
CTFG 
Clinical Trial Facilitation Group 
Cu 
copper  
CV 
arithmetic coefficient of variation 
DDI 
Drug-Drug Interactions 
EC 
enteric-coated  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of Study  
ET 
Early Termination 
EU 
European Union 
FDA 
Food and Drug Administration 


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GCP  
Good Clinical Practice  
GDS 
Global Drug Safety  
GMR 
geometric mean ratio 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus  
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
human immunodeficiency virus 
HLM 
human liver microsomes 
IB 
Investigator’s Brochure  
IC50 value 
drug concentration required to produce 50% of the maximal inhibition 
ICF 
informed consent form  
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
LAM 
lactational amenorrhoea method 
LBC 
labile-bound copper 
Mo 
molybdenum  
MSE 
mean-square error 
MTD 
maximum tolerated dose 
NCC 
non-ceruloplasmin-bound copper  
NCCcorrected 
corrected NCC 
NCS 
not clinically significant 
PBC 
primary biliary cholangitis 
PD 
Pharmacodynamic(s) 
PI 
Principal Investigator 
PK 
pharmacokinetic(s)  
PMDA 
Pharmaceuticals and Medical Devices Agency 
PUF 
plasma ultrafiltrate  
QT 
interval between the start of the Q wave and the end of the T wave in an ECG  
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula  
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan  
SoA 
Schedule of Activities 
SOC 
System Organ Class 


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SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life  
TDI 
time-dependent inhibition 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
Tmax 
time to reach maximum observed plasma concentration  
TPC 
Tetrathiomolybdate-Cu-albumin tripartite complex formed after ALXN1840 
administration 
ULN 
upper limit of normal 
USPI 
United States Package Insert 
UWDRS 
Unified Wilson Disease Rating Scale  
Vd/F 
apparent volume of distribution  
WD 
Wilson Disease  
WHO 
World Health Organization 


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11. 
REFERENCES 
Celebrex®. CELEBREX ® (celecoxib) capsules (USPI).Pfizer; Revised May, 2019.  
Daly AK, Rettie AE, Fowler DM, Miners JO. Pharmacogenomics of CYP2C9: Functional and 
Clinical Considerations. J Pers Med. 2017;8(1). 
Dean L. Celecoxib Therapy and CYP2C9 Genotype. In: Pratt VM, McLeod HL, Rubinstein WS, 
Scott SA, Dean LC, Kattman BL, et al., editors. Medical Genetics Summaries. Bethesda 
(MD)2012. 
Dennison J, Puri A, Warrington S, Endo T, Adeloye T, Johnston A. Amenamevir: Studies of 
Potential CYP2C8- and CYP2B6-Mediated Pharmacokinetic Interactions With Montelukast and 
Bupropion in Healthy Volunteers. Clin Pharmacol Drug Dev. 2018;7(8):860-870. 
Diflucan®. DIFLUCAN ® (fluconozole) tablet (USPI). Pfizer; Revised Feb, 2019. . 
US Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers, Revised Dec 2019. 
Weiss K, Askari F, Czlonkowska A, et al. Bis-choline tetrathiomolybdate in patients with 
Wilson's disease: an open-label, multicentre, phase 2 study. Lancet Gastroenterol Hepatol. 
2017;12:869-876. 
 

SAP_001.pdf: 
A Phase 1, Randomized, 2-Period, 2-Sequence, Cross-over 
Study to Determine the Effect of ALXN1840 on the 
Metabolism of a CYP2CP Substrate in Healthy Participants 
Unique Protocol ID: 
NCT Number: 
Date of SAP:  
ALXN1840-HV-105 
NCT04526197 
04 September 2020 


Alexion Pharmaceuticals, Inc. 
Final Statistical Analysis Plan, Version 1.0 
ALXN1840-HV-105 
Date Issued: 04Sep2020 
 
Alexion Confidential                                                                                                                                           Page 1 of 23 
 
 
 
 
 
 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
 
ALXN1840-HV-105 
 
A Phase 1, Randomized, 2-Period, 2-Sequence, Cross-over Study to 
Determine the Effect of ALXN1840 on the Metabolism of a CYP2C9 
Substrate in Healthy Participants 
 
04Sep2020 
 
Final Statistical Analysis Plan 
 
Version 1.0 
 
Prepared by: 
 
PPD 
3900 Paramount Parkway 
Morrisville, NC 27560 USA 
 
 
 
 


Alexion Pharmaceuticals, Inc. 
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ALXN1840-HV-105 
Date Issued: 04Sep2020 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................... 4 
1. 
INTRODUCTION ............................................................................................. 6 
2. 
OBJECTIVES ................................................................................................... 6 
2.1. PRIMARY OBJECTIVE........................................................................................... 6 
2.2. SECONDARY OBJECTIVE ...................................................................................... 6 
3. 
INVESTIGATIONAL PLAN ............................................................................ 6 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................... 6 
3.2. SCHEMA ............................................................................................................. 8 
3.3. STUDY ENDPOINTS.............................................................................................. 8 
3.3.1. Primary Endpoints....................................................................................... 8 
3.3.2. Secondary Endpoints ................................................................................... 8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ........................................... 9 
4.1. STATISTICAL HYPOTHESES ................................................................................ 10 
4.2. SAMPLE SIZE .................................................................................................... 10 
4.3. RANDOMIZATION, STRATIFICATION, AND BLINDING ............................................ 10 
4.4. ANALYSIS SET .................................................................................................. 11 
4.4.1. Enrolled Set............................................................................................... 11 
4.4.2. Pharmacokinetic/Pharmacodynamic Analysis Set ....................................... 11 
4.4.3. Safety Set................................................................................................... 11 
5. 
PARTICIPANT DISPOSITION ..................................................................... 11 
5.1. DISPOSITION ..................................................................................................... 11 
5.2. PROTOCOL DEVIATIONS .................................................................................... 12 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................... 12 
6.1. DEMOGRAPHICS AND BASELINE CHARACTERISTICS............................................. 12 
6.2. URINE ALCOHOL AND DRUG SCREEN ................................................................. 12 
6.3. MEDICAL HISTORY ........................................................................................... 12 
6.4. INCLUSION AND EXCLUSION CRITERIA ............................................................... 13 
6.5. GENETICS......................................................................................................... 13 
7. 
TREATMENTS AND MEDICATIONS ......................................................... 13 
7.1. PRIOR AND CONCOMITANT MEDICATIONS .......................................................... 13 
7.2. NON-PHARMACOLOGIC THERAPIES AND PROCEDURES ........................................ 13 
7.3. STUDY TREATMENTS ........................................................................................ 13 
8. 
SAFETY ANALYSIS ...................................................................................... 14 
8.1. ADVERSE EVENTS ............................................................................................. 14 
8.1.1. Incidence of Adverse Events ....................................................................... 15 


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8.1.2. Relationship of Adverse Events to Study Drug............................................. 15 
8.1.3. Intensity of Adverse Event .......................................................................... 15 
8.1.4. Serious Adverse Events .............................................................................. 16 
8.1.5. Adverse Events Leading to drug withdrawal ............................................... 16 
8.2. CLINICAL LABORATORY EVALUATIONS.............................................................. 16 
8.2.1. Chemistry .................................................................................................. 17 
8.2.2. Hematology ............................................................................................... 17 
8.2.3. Coagulation............................................................................................... 17 
8.2.4. Urinalysis.................................................................................................. 17 
8.3. VITAL SIGN MEASUREMENTS ............................................................................ 17 
8.4. PHYSICAL EXAMINATION .................................................................................. 18 
8.5. ELECTROCARDIOGRAM...................................................................................... 18 
8.6. OTHER SAFETY DATA ....................................................................................... 18 
8.6.1. Liver Function Results ............................................................................... 18 
8.6.2. Serology .................................................................................................... 18 
8.6.3. Pregnancy Test .......................................................................................... 19 
8.6.4. Follicle Stimulating Hormone .................................................................... 19 
8.6.5. Discussion/documentation of contraception method .................................... 19 
8.6.6. Retained Sample ........................................................................................ 19 
9. 
PHARMACOKINETICS AND PHARMACODYNAMIC ANALYSIS ......... 19 
9.1. PHARMACOKINETIC SAMPLING .......................................................................... 19 
9.2. BLQ VALUES / MISSING VALUES....................................................................... 20 
9.3. PHARMACOKINETIC/PHARMACODYNAMIC DATA PRESENTATION CONVENTIONS ... 20 
9.4. PHARMACOKINETIC PARAMETERS...................................................................... 20 
9.5. PHARMACOKINETIC STATISTICAL ANALYSIS....................................................... 21 
9.6. GENETIC VARIANT ANALYSES FOR CYP2C9 ...................................................... 22 
9.7. PHARMACODYNAMIC PARAMETERS ................................................................... 22 
9.8. PHARMACODYNAMIC STATISTICAL ANALYSIS .................................................... 22 
10. 
INTERIM ANALYSIS .................................................................................... 23 
11. 
CHANGES IN THE PLANNED ANALYSIS ................................................. 23 
12. 
REFERENCES................................................................................................ 23 


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List of Abbreviations 
Abbreviation Term 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC  
area under the plasma concentration versus time curve 
AUCt  
area under the plasma concentration versus time curve from time 0 to 
the last quantifiable concentration 
AUC∞  
area under the plasma concentration versus time curve from zero to 
infinity 
AUEC 
area under the effect versus time curve 
AUECt 
area under the effect versus time curve from time 0 to last quantifiable 
concentration time 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CL/F 
apparent oral clearance 
Cmax 
maximum observed plasma concentration  
CRF 
case report form 
CRU 
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cu 
Copper 
CV 
coefficient of variation 
EC 
enteric-coated 
ECG 
electrocardiogram 
eDISH 
evaluation of drug-induced serious hepatotoxicity 
Emax 
maximum observed PD concentration in plasma 
EOS 
End of Study 
ET 
early termination 
FSH 
Follicle stimulating hormone 
GMR 
geometric mean ratio 
ICF 
informed consent form 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MSE 
mean-square error 
Mo 
molybdenum 
PBC 
primary biliary cholangitis 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula  
RBC 
red blood cell 
SAE 
serious adverse event 


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Abbreviation Term 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TEmax 
time to reach maximum observed pharmacodynamic concentration in 
plasma 
Tlag 
time delay between the time of dosing and time of appearance of drug 
concentration in plasma 
Tmax 
time to reach maximum observed concentration in plasma  
t1/2 
terminal elimination half-life 
Vd/F 
apparent volume of distribution 
WD 
Wilson disease 
% AUCextrap 
AUC extrapolated from time t to infinity as a percentage of total AUC∞ 
λz 
apparent terminal-phase elimination rate constant 
 
 
 


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1. Introduction 
This document outlines the statistical methods to be implemented during the analysis of 
data collected within the scope of Alexion Pharmaceuticals, Inc., protocol ALXN1840-
HV-105 (A Phase 1, Randomized, 2-Period, 2-Sequence, Cross-over Study to Determine 
the Effect of ALXN1840 on the Metabolism of a CYP2C9 Substrate in Healthy 
Participants), original version, dated 28 Apr 2020. The purpose of this statistical analysis 
plan is to define the planned statistical analysis of the study data consistent with the study 
objectives. 
ALXN1840 (bis-choline tetrathiomolybdate; formerly known as WTX101) is a novel, first-
in-class, copper (Cu)-protein binding agent in development for the treatment of Wilson 
disease (WD). 
2. Objectives 
2.1. Primary Objective 
The primary objective of this study is to determine the effect of ALXN1840 on the 
pharmacokinetics (PK) of celecoxib, a sensitive CYP2C9 substrate. 
2.2. Secondary Objective 
The secondary objectives of this study are to determine the effect of ALXN1840 on the PK 
of plasma molybdenum (Mo) with the coadministration of celecoxib and to determine the 
safety and tolerability of ALXN1840, with the coadministration of celecoxib. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
The study is being conducted as a randomized, 2-period, 2-sequence, cross-over study to 
determine the effect of a single dose of ALXN1840 (perpetrator) on the single dose 
celecoxib (victim) kinetics in healthy male and female participants. 
The study has a Screening period (Day -28 to Day -2), two 11-day study periods (Day 1 to 
Day 11) with a minimum of 14 days between doses of celecoxib, and an End of Study 
(EOS) Visit (Day 15 ± 2 days) after Period 2 dosing. Participants will report to the clinical 
research unit (CRU) on the day prior (Day -1) to both dosing periods. 
All participants will receive 1 treatment in each study period; treatment order will be 
defined based on randomization: 
• 
Treatment A: One 200 mg celecoxib capsule with 240 mL water (fasting). 
• 
Treatment B: One 200 mg celecoxib capsule + 4 × 15 mg ALXN1840 enteric-
coated (EC) tablets with 240 mL water (fasting). 


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Based on randomization, participants will be administered either Treatment A or Treatment 
B in each period. A wash-out period of at least 14 days must separate dose administration 
in Period 1 and Period 2. Participants will remain institutionalized from the day prior to 
dosing until Day 11 following dose administration for each period. 
The PK profile of ALXN1840 and celecoxib will be determined by blood sampling 
following single dose administration over approximately 5 half-lives or more for both 
study interventions. Blood sampling for PK assessments will occur at pre-dose, 1, 2, 3, 4, 
5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 336 hours post-dose to ensure 
full assessment of exposure over time. The nominal 336-hour sample for Period 1 is pre-
dose sample for Period 2. In addition to PK sampling, safety and tolerability will be 
assessed by monitoring adverse events (AEs), vital signs, 12-lead electrocardiograms 
(ECGs), and laboratory parameters. 
Following scheduled procedures on Day 11, participants will be discharged from the unit. 
If there are any participants with clinically significant abnormalities at the time of 
discharge, the Investigator should notify the Medical Monitor prior to discharge, and 
participants may be asked to remain institutionalized for further clinical monitoring. 
Participants may be asked or required to stay in the CRU between Periods 1 and 2, and/or 
before the EOS visit, for their own safety, and also to maintain the integrity of the conduct 
of the study. 
The EOS Visit will occur approximately 4 days after discharge from Period 2, after 
collection of the nominal 336-hour PK sample. 
This study will include approximately 38 participants; the overall study population will 
include a minimum of 40% of each sex. 
Participants will be randomized to one of two sequences as described in Table 1. 
Table 1: Study design 
Sequence 
Number  
Treatment Sequence 
Malea  
Femalea  
Total  
Study Period 
1  
Study Period 
2  
1  
A  
B  
8 to 11  
8 to 11  
19  
2  
B  
A  
8 to 11  
8 to 11  
19  
Total  
16 to 22  
16 to 22  
38  
aIn an effort to achieve balance between males and females in each sequence, there will be no less than 
16 and no more than 22 of either sex (ie, a maximum split in either direction of approximately 
60%:40%). Randomization will be stratified by sex. 
Treatment A -One 200 mg celecoxib capsule with 240 mL water (fasting) 
Treatment B – One 200 mg celecoxib capsule + 4 × 15 mg ALXN1840 EC tablets with 240 mL water 
(fasting) 
At the Investigator’s discretion, additional participants may be screened to allow for a full 
enrollment of the study, with a minimum of 40% for each sex. Therefore, it is possible that 
all eligible participants may not be included. Participants not included in the study will be 
discharged without dosing on Day 1. 


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3.2. Schema 
Figure 1: 
Study ALXN1840-HV-105 Schematic  
 
Participants will be admitted on Day -1 of each period for Check in procedures. Eligible participants will be 
randomized on Day 1 immediately prior to dosing in Period 1. 
Participants will receive treatment (A or B) based on randomization on Day 1 of each period. 
Blood samples for PK analysis of total Mo (as a measure of ALXN1840) and celecoxib will be collected in 
each period on Day 1 at pre-dose, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours (Day 2) and then at 24 hour intervals on 
Days 3, 4, 5, 6, 7, 8, 9, 10, and Day 11. The nominal 336-hour sample for Period 1 will be collected pre-dose 
in Period 2. Participants will be discharged on Day 11 of each period after completion of all procedures and 
review of all safety data. The end of study visit (EOS) will occur on Day 15 ± 2 of Period 2, with the 
collection of 336-hour PK sample for Period 2. 
Participants may be asked or required to stay in the CRU between Periods 1 and 2, and/or before the EOS 
visit, for their own safety, and also to maintain the integrity of the conduct of the study. 
3.3. Study Endpoints 
3.3.1. Primary Endpoints 
The primary endpoints include following PK parameters of celecoxib with and without the 
coadministration of ALXN1840 
• 
Cmax: maximum observed plasma concentration 
• 
AUCt: area under the plasma concentration (AUC) versus time curve from time 0 
to the last quantifiable concentration 
• 
AUC∞: AUC versus time curve from time 0 to infinity 
3.3.2. Secondary Endpoints 
The secondary endpoints include following PK parameters for plasma total Mo with the 
coadministration of celecoxib and safety assessed parameters 
• 
The PK parameters 
• 
Cmax 
• 
AUCt 
• 
AUC∞ 


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• 
The safety parameters 
• 
Incidence of treatment-emergent adverse events (TEAEs) and treatment-
emergent serious adverse events (TESAEs) 
• 
Physical examination (PE) 
• 
Vital signs measurements 
• 
Clinical laboratory results 
• 
12-lead ECG results 
4. General Statistical Considerations 
All data captured on the case report form (CRF), laboratory safety variables, and PK 
assessments will be listed on an individual basis by treatment sequence and participant. 
Summary tables will be presented by treatment and overall, unless otherwise specified. 
All pre- and post- dose assessments including repeated and/or unscheduled assessments 
will be included in the data listing.  
Continuous variables will be described using the following descriptive statistics: number of 
non-missing values (n), arithmetic mean, standard deviation (SD), median, Q1, Q3, IQR, 
minimum, and maximum, unless otherwise specified.  Categorical variables will be 
summarized using percentages and frequency count.  
For the summary statistics of all continuous variables unless otherwise specified, minimum 
and maximum will be presented to the same number of decimal places as the raw data, 
mean, median, Q1, Q3, and IQR will be presented to one more decimal places than the raw 
data, and SD will be presented to two more decimal places than the raw data.  
Percentages will be suppressed when the count is zero and will be presented to one decimal 
place. The denominator for all percentages will be the number of participants in the 
treatment sequence for the population of interest, unless otherwise specified. 
Baseline is defined as the last non-missing assessment (including repeated and 
unscheduled assessments) prior to treatment on Day 1 (dose day for each period), unless 
otherwise specified. If there are repeated assessments at a time point, the first non-missing 
assessment will be included in the summary tables. If the original scheduled measurement 
at that time point is missing, the next available repeated measurement will be used in the 
summary tables. 
For safety laboratory evaluations, for the purpose of summarization, any numeric values 
recorded below the lower limit or above the upper limit of quantification will be set to the 
respective limit for all related summaries. In listings, original results containing inequality 
sign will be displayed, unless otherwise specified. 
Study day will be calculated as follows: 
• 
If assessment date is on or after the dose of treatment, then  


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Study Day = Assessment Date –Day 1 Date + 1 
• 
Otherwise,  
Study Day = Assessment Date – Day 1 Date 
All statistical analyses detailed in this statistical analysis plan (SAP) will be conducted 
using SAS® Version 9.4 or higher (SAS Institute, Inc., Cary, North Carolina) and Phoenix® 
WinNonlin® Version 8.0 or higher (Certara USA, Inc., Princeton, New Jersey). 
4.1. Statistical Hypotheses  
The primary objective is to determine the effect of ALXN1840 on the PK of celecoxib. 
There is no formal null hypothesis to be statistically tested and used to drive declaration of 
study success or failure. 
To assure the study has enough participants, to estimate the inhibitory effect of 
ALXN1840 on the metabolism of celecoxib, the sample size was determined using the 
conservative 90% confidence interval (CI) and 80% to 125% no-effect boundary approach 
described in the FDA Guidance “Clinical Drug Interaction Studies —Cytochrome P450 
Enzyme- and Transporter-Mediated Drug Interactions” (2020). This guidance notes the 80 
to 125 % boundaries represent a very conservative standard for drugs that have wide safety 
“margins” and “the totality of evidence should be taken into consideration when 
determining the clinical impact of the DDI on the substrate drug”. Therefore, if the 
estimated inhibition effect of ALXN1840 on celecoxib PK lies outside this no-effect 
boundary, this should not be interpreted as a failed study. 
4.2. Sample Size 
A default of no-effect boundary (80% to 125%) approach will be employed to assess 
whether there is an inhibition effect on the metabolism of celecoxib in the presence of 
ALXN1840. For a 2-period crossover study design, assuming the true ratio of the means 
(celecoxib + ALXN1840 vs celecoxib alone) on the PK parameters is 1 (Cmax; AUC∞) and 
the intra-participant coefficient of variation (CV) is 0.30 (Dennison, 2018), a total sample 
size of 32 participants can achieve 90% power with two 1-sided tests, each with a type I 
error rate of 5% (two-sided type I error rate of 10%). The intra-participant CV is estimated 
using residual mean-square error (MSE) term in the analysis of variance (ANOVA) model. 
The CV is estimated as 100% × √ (exp (MSE) - 1) for the log-transformed PK parameters. 
Assuming a 15% dropout rate, approximately 38 participants will be enrolled. 
4.3. Randomization, Stratification, and Blinding 
This is a randomized, open-label, 2-period, 2-sequence, cross-over study. The 
randomization will be stratified by sex. In an effort to achieve balance between males and 
females in each sequence, there will be no less than 16 and no more than 22 of either sex 
(ie, a maximum split in either direction of approximately 60%:40%).  


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4.4. Analysis Set 
4.4.1. Enrolled Set 
The enrolled set will include all participants who sign the informed consent form (ICF). 
4.4.2. Pharmacokinetic/Pharmacodynamic Analysis Set 
The PK analysis set will include all participants who have sufficient plasma samples to 
have evaluable PK data for celecoxib and/or total Mo (as a measure of ALXN1840) in 
plasma.  
The Pharmacodynamic (PD) analysis set will include all participants who have sufficient 
plasma samples to have evaluable PD data for total Cu or PUF Cu. 
4.4.3. Safety Set 
The safety set will include all participants who receive at least 1 dose of study intervention.  
5. Participant Disposition 
5.1. Disposition 
Using the enrolled set, the screen failure of participants will be summarized with counts 
and percentages by overall. Summary table will include the following: 
• 
Number of participants in the enrolled set (ie, all participants who signed the 
ICF) 
• 
Number of participants who were screen failures 
• 
Number of participants who were randomized 
• 
Number of participants who failed screen due to COVID-19 related reasons 
• 
Reason for screen failure that was not due to eligibility 
Based on the randomized participants, the analysis sets will be summarized with counts 
and percentages by treatment and overall. Summary table will include the following: 
• 
Number of participants included in PK/PD analysis set 
• 
Reason for exclusion from the PK/PD analysis set 
• 
Number of participants included in safety set 
• 
Reason for exclusion from the safety set 
Using the randomized participants, PK analysis set, and safety set respectively, the 
disposition of participants will be summarized with counts and percentages by treatment 
and overall. Summary table will include the following: 
• 
Number of participants who completed the study 


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• 
Number of participants who discontinued the study 
• 
Reasons for discontinuation 
• 
Number of participants who discontinued the treatment 
• 
Reasons for treatment discontinuation 
• 
Number of participants who were discontinued due to COVID-19  
Screen failure data, participant disposition data, and analysis set will be presented in 
separate data listings for the participants who randomized. 
5.2. Protocol Deviations 
The protocol deviations will be summarized by treatment and overall for the safety set.  
All protocol deviations will be presented in a data listing based on randomized 
participants.  
6. Demographics and Baseline Characteristics 
6.1. Demographics and Baseline Characteristics 
Age, sex, race, ethnicity, height, and body mass index (BMI) will be collected at 
Screening; weight will be collected at Screening and Check-in for each period.  
Demographic characteristics including age, sex, race, ethnicity, weight (kg), height (cm), 
and BMI (kg/m2) will be summarized by treatment sequence and overall for the safety set. 
Weight measurements collected at Check-in to Dosing Period 1 will be used as baseline for 
the summary. 
Demographic characteristics will be presented in a data listing for the safety set. 
6.2. Urine Alcohol and Drug screen 
Urine alcohol test and urine drug screen will be performed at Screening and Check-in for 
each period.  
Urine alcohol and drug screen results in the safety set will be presented in a data listing for 
the safety set. 
6.3. Medical History 
Medical history will be collected at Screening.  
Medical history results will be presented in a data listing for the safety set with each 
verbatim term be mapped to a system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary for Drug Regulatory Activities (MedDRA, Version 23.0 or later). 


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6.4. Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria will be confirmed at Screening and Check-in for each 
period. 
Admission criteria deviations are defined as any violation of protocol-defined 
inclusion/exclusion criteria.  
Admission criteria deviations will be presented in a data listing for the participants who 
randomized. 
6.5. Genetics 
Blood samples for genetic testing of CYP2C9 polymorphism will be collected at clinical 
Check-in (Day -1) for Period 1. 
Genetic testing results will be listed and summarized by treatment sequence and overall for 
the safety set. 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
Prior medications are defined as medications that were started and ended prior to the first 
dose of treatment. Concomitant medications are defined as medications that were 
administered after the first dose of treatment. Medications initiated prior to the first dose of 
treatment and were continued after the first dose of treatment will be counted as both prior 
and concomitant medications. 
Prior concomitant medications will be summarized by treatment sequence and overall for 
the safety set. Concomitant medications will be summarized by treatment and overall for 
the safety set. The anatomical therapeutic chemical code coding scheme of the World 
Health Organization Drug Dictionary Version March 2019 or later will be used to group 
medications into relevant categories for the tabulation.  
All prior and concomitant medications will be presented in a data listing for the safety set. 
7.2. Non-Pharmacologic Therapies and Procedures 
Non-pharmacologic therapies and procedures will be coded using the MedDRA Version 
23.0 or later and will be presented in a data listing for the safety set. 
7.3. Study Treatments 
Study treatments will be administered in each study period at the morning of Day 1 and all 
participants will receive 1 treatment in each study period. Study treatments are as follow 
• 
Treatment A: One 200 mg celecoxib capsule with 240 mL water (fasting). 


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• 
Treatment B: One 200 mg celecoxib capsule + 4 × 15 mg ALXN1840 EC tablets 
with 240 mL water (fasting). 
Any dose of ALXN1840 or celecoxib greater than that specified in the protocol will be 
considered an overdose. 
Study treatment administration data will be presented in a data listing for the safety set. 
8. Safety Analysis 
All safety analyses will be performed on the safety set. 
Safety analyses will include an analysis of all AEs, ECGs, clinical laboratory data, 
physical examinations, and vital sign measurements using descriptive statistics. Summaries 
will be presented by treatment and overall, unless otherwise stated. Shift tables will be 
summarized with count and percentages of participants in each category. Percentages will 
be based on the number of participants with both non-missing baseline and relevant 
post-baseline results. 
No inferential statistical analyses are planned for the safety parameters of this study. 
8.1. Adverse Events 
An AE is any untoward medical occurrence in a participant, temporally associated with the 
use of study intervention, whether or not considered related to the study intervention. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention.  
Adverse events will be analyzed in terms of TEAEs which are defined as any AEs that 
begin or worsen on or after the first dose of treatment until the EOS or early termination 
(ET). If the onset date/time of an AE is missing and AE end date is on or after the first 
dose of treatment, the AE will be defined as treatment-emergent. 
All AEs will be listed from the time the participant signs ICF until the EOS or ET Visit. 
A treatment-related TEAE is defined as TEAE which was considered to be related to the 
treatment. 
All AEs will be coded by SOC and PT using the MedDRA Version 23.0 or later.  
All summary tables will include number and percentage of participants and number of 
events, unless otherwise stated. For the number of AEs, each occurrence will be counted 
once. Percentages will be based upon the number of participants in the safety set.  
In the summary tables where both SOC and PT are presented, the default ordering of SOC 
will be alphabetical and the default ordering for PT will be most prevalent (using 
percentage) PT within each SOC based on Total column. For PTs with the same number of 
participants, they should be further sorted by number of events and then alphabetically. 


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In the by- participant analyses, a participant having the same event more than once within 
the same level of summarization will be counted only once within the same treatment 
using the most intense or worst highest event (for by toxicity grade summary) or the most 
related event (for by relationship summary). 
 In summaries of AEs by treatment, AEs will be summarized according to the most recent 
treatment received prior to the AE onset, regardless of when the AE ended. For example, 
an AE that started on or after administration of the treatment on Day 1 in Dosing Period 1 
but before the administration of treatment on Day 1 in Dosing Period 2 will be summarized 
for the treatment in Period 1; an AE that started on or after administration of treatment on 
Day 1 in Dosing Period 2 will be summarized for the treatment in Period 2. The AEs that 
started before administration of treatment on Day 1 in Dosing Period 1 will not be 
summarized unless if the AE meets the TEAE definition, in that case, the AEs will be 
summarized for the treatment received prior to the AEs worsened. 
8.1.1. Incidence of Adverse Events 
An overview summary of TEAEs will be provided and will include the following 
• 
Participants with at least 1 TEAE 
• 
Participants with at least 1 TEAE related to study drug 
• 
Participants with at least 1 TESAE 
• 
Participants with at least 1 TESAE related to study drug 
• 
Participants who drug withdrawn due to TEAE 
• 
Participants who drug withdrawn due to TEAE related to study drug 
The frequency of TEAEs will be tabulated by SOC and PT. 
8.1.2. Relationship of Adverse Events to Study Drug 
The relationship between the study intervention and each occurrence of each AE or SAE is 
assessed by the Investigator. The relationship will be classified as Related or Not Related. 
The frequency of TEAEs will be tabulated by SOC, PT and by relationship.  
8.1.3. Intensity of Adverse Event 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories from National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0, published 27 
Nov 2017:  
• 
Grade 1: Mild (awareness of sign or symptom, but easily tolerated)  
• 
Grade 2: Moderate (discomfort sufficient to cause interference with normal 
activities)  


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• 
Grade 3: Severe (incapacitating, with inability to perform normal activities)  
• 
Grade 4: Life-threatening  
• 
Grade 5: Fatal  
The frequency of TEAEs will be tabulated by SOC and PT and by intensity. 
8.1.4. Serious Adverse Events 
Serious adverse events (SAEs) will be analyzed in terms of TESAEs which are defined as 
any SAEs that begin or worsen on or after the first dose of treatment until the EOS or ET.  
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires participant hospitalization or prolongation of existing hospitalization 
• 
Results in persistent disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Other situations 
The frequency of TESAEs will be tabulated by SOC and PT, and by SOC and PT and 
by relationship. 
Treatment-emergent SAEs will be listed separately. 
8.1.5. Adverse Events Leading to drug withdrawal 
Treatment-emergent AEs leading to drug withdrawal will be listed separately. 
8.2. Clinical Laboratory Evaluations 
Laboratory assessments (including chemistry, hematology, and coagulation) will be 
performed at Screening, Check-in for each period, Day 2 for each period, Day 5 for each 
period, Day 10 for each period, and EOS or ET. 
Urinalysis will be performed at Screening and Check-in for each period. 
Summary statistics and change from baseline for chemistry, hematology, and coagulation 
will be presented by treatment and by visit. Laboratory parameter values will be graded 
according to the National Cancer Institute CTCAE. Shift tables will be produced for 
chemistry, hematology, and coagulation. Shift from baseline grade relative to the reference 
ranges tables will be presented by treatment and by visit. Shift from changes to the worst 
highest grade assessed post-dose during the study tables will be presented by treatment. 
Last recheck values collected prior the dose of treatment will be used as baseline and all 
rechecks will be deleted from post-dose observations in calculating summary statistics. 


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All clinical laboratory tests (including chemistry, hematology, coagulation, and urinalysis) 
will be presented in data listings.  
8.2.1. Chemistry 
Serum chemistry evaluation will include blood urea nitrogen, potassium, bicarbonate, 
sodium, glucose, aspartate aminotransferase, alanine aminotransferase, chloride, alkaline 
phosphatase, direct bilirubin, total bilirubin, albumin, creatinine, and creatine 
phosphokinase. 
8.2.2. Hematology 
Blood hematology evaluation will include platelet count, red blood cell (RBC) count, 
hemoglobin, hematocrit, RBC indices (including mean corpuscular volume, mean 
corpuscular hemoglobin, and % reticulocytes), and white blood cell count with differential 
(including neutrophils, lymphocytes, monocytes, eosinophils, and basophils). 
8.2.3. Coagulation 
Blood coagulation evaluation will include international normalized ratio, partial 
thromboplastin time, and prothrombin time. 
8.2.4. Urinalysis 
Urinalysis evaluation will include specific gravity, pH, glucose, protein, blood, bilirubin, 
urobilinogen, nitrite, leukocyte esterase by dipstick, and microscopic examination. 
8.3. Vital Sign Measurements 
Oral temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure (mm 
Hg) will be performed at Screening, Day 1 (Pre-dose, 1 Hour, 4 Hour, 8 Hour, and 12 
Hour) for each period, Day 2 (24 Hour) for each period, and EOS or ET. 
Weight will be collected at Screening and Check-in for each period. BMI will be collected 
at Screening only. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
Summary statistics and change from baseline for vital signs (temperature, pulse rate, 
respiratory rate, and systolic and diastolic blood pressure) will be presented by treatment 
and overall and by visit and time point.  Last recheck values collected prior to the dose of 
treatment will be as baseline and all rechecks will be deleted from post-dose observations 
in calculating summary statistics.  
Vital sign measurement results, including height, weight, and BMI, will be presented in a 
data listing. 


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8.4. Physical Examination 
A full PE, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, 
and neurological systems will be performed at Screening, Check-in for each period, and 
EOS or ET. A symptom-driven physical examination may be performed at other times, at 
the principal investigator’s discretion. 
General appearance, skin, head/ear/eye/nose/throat, neck, lymph node, chest, heart, 
abdominal cavity, limb, central nervous system, and musculoskeletal will be captured on 
the CRF. 
Physical examination results will be presented in a data listing. 
8.5. Electrocardiogram 
Triplicate 12-lead ECG will be performed at Screening and Day 1 (Pre-dose and 4 Hour 
[before lunch]) for each period. 
Participants will be resting in the supine position for at least 15 minutes prior to and 5 
minutes after each nominal time point for ECG extraction. 
Heart rate, PR interval, QRS interval, RR interval, QT interval, QT interval corrected for 
heart rate using Fridericia’s formula (QTcF), and interpretation of ECG will be captured on 
the CRF. 
The average of the triplicate ECG readings at the time points collected will be calculated. 
Summary statistics and change from baseline of calculated average for heart rate, PR 
interval, QRS interval, RR interval, QT interval, and QTcF interval will be presented by 
time point. Last recheck values collected prior to the dose of treatment will be as baseline 
and all rechecks will be deleted from post-dose observations in calculating summary 
statistics. 
Triplicate 12-lead ECG findings will be presented in a data listing. 
8.6. Other Safety Data 
8.6.1. Liver Function Results 
All events of ALT ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN (> 35% 
direct bilirubin) or ALT ≥ 3 × ULN and international normalized ratio (INR) > 1.5, if 
INR measured which may indicate severe liver injury (possible Hy’s Law), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis).  
Liver function results will be presented in a summary table and eDISH (evaluation of 
drug-induced serious hepatotoxicity) plots. 
8.6.2. Serology 
Serology including HIV, hepatitis B, and hepatitis C screen will be performed at 
Screening. 


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Serology results will be presented in a data listing. 
8.6.3. Pregnancy Test 
Serum or urine pregnancy test for female participants and female spouses/partners of male 
participant will be performed at Screening, Check-in for each period, and EOS or ET.  
Pregnancy test results will be presented in a data listing. 
8.6.4. Follicle Stimulating Hormone 
Follicle stimulating hormone (FSH) will be performed at Screening and only needed if 
claiming exemption from contraception requirement due to menopause. 
FSH results will be presented in a data listing. 
8.6.5. Discussion/documentation of contraception method 
Discussion/documentation of contraception method will be performed at Screening and 
Check-in for each period. The discussion/documentation of contraception method results 
will be kept in the source documents and will not be recorded on the CRF; therefore, the 
discussion/documentation of contraception method results will not be presented in any of 
the tables, listings, or figures. 
8.6.6. Retained Sample 
A single 12 mL sample will be retained for evaluation in the event of an unexpected safety 
finding; retained samples may be destroyed after completion of the clinical study report. 
The retained serum sample will only be collected pre-dose on Day 1 of Period 1. 
Retained sampling results will be presented in a data listing. 
9. Pharmacokinetics and Pharmacodynamic Analysis 
9.1. Pharmacokinetic Sampling 
Whole blood samples will be collected for the measurement of plasma concentrations of 
total Mo, PUF Mo, and celecoxib at the following time points: pre-dose and post-dose at 1, 
2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 336 hours in each 
period. Additional samples may be collected at additional time points during the study if 
warranted and agreed upon between the Investigator and Alexion. Collection of samples 
for PK evaluation should occur as close as possible to the scheduled time and actual time 
of collection should be documented on the eCRF. Samples collected within ± 10% of the 
scheduled time, or 30 minutes, whichever is less, will not be considered a protocol 
deviation. In the event of a safety occurrence and after agreement between the Investigator 
and Medical Monitor, up to 3 additional PK sampling timepoints may be added.  
PK samples will also be used for the PD analysis of total Cu and PUF Cu. 


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9.2. BLQ Values / Missing Values 
For PK and the PD measure Total Cu parameter calculations, concentrations below the 
limit of quantification (BLQ) prior to the first measurable concentration will be set to zero; 
all other BLQ values will be treated as missing. For PUF Cu parameter calculations, all 
BLQ values will be set to zero. 
For PK and PD concentration summaries, BLQ values will be set to zero. 
9.3. Pharmacokinetic/Pharmacodynamic Data Presentation Conventions 
PK and PD concentration data will be summarized using descriptive statistics (number of 
participants (N), number of participants with available data (n), arithmetic mean, SD, 
arithmetic CV, geometric mean (GM), geometric CV, median, minimum and maximum). 
The predose PD concentration will be used as baseline; absolute change from baseline will 
be calculated as: a postdose concentration value – baseline concentration value; percent 
change from baseline will be calculated as: ([a postdose concentration value – baseline 
concentration value] / baseline) ×100%. 
The following conventions will be applied to PK/PD presentations and summaries. 
• 
For continuous variables, all mean and median values are formatted to one more 
decimal place than the measured value. Standard deviation values are formatted to 
two more decimal places than the measured value. Minimum and maximum 
values are presented with the same number of decimal places as the measured 
value. 
• 
Date variables are formatted as DDMMMYYYY for presentation. Time is 
formatted in military time as HH:MM for presentation. 
9.4. Pharmacokinetic Parameters  
The following plasma PK parameters will be calculated for total Mo, PUF Mo, and 
celecoxib using noncompartmental methods with Phoenix® WinNonlin® (Certara USA 
Inc., Princeton, New Jersey) Version 8.0 or higher or SAS Version 9.4 or higher (SAS 
Institute Inc., Cary, North Carolina), as applicable. Calculations will be based on the actual 
sampling times relative to the actual reference ALXN1840 dosing times recorded during 
the study. 
• 
Tlag: time delay between the time of dosing and time of appearance of drug 
concentration in plasma (for plasma total Mo and PUF Mo with ALXN1840 
administration) 
• 
Cmax: maximum observed concentration in plasma 
• 
Tmax: time to reach maximum observed concentration in plasma 
• 
AUCt: AUC from time 0 to the last quantifiable concentration, calculated using 
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• 
AUC∞: AUC versus time curve from time 0 to infinity, calculated using the linear 
trapezoidal rule 
• 
% AUCextrap: AUC extrapolated from time t to infinity as a percentage of total 
AUC∞ 
• 
t1/2: terminal elimination half-life 
• 
λz: apparent terminal-phase elimination rate constant 
For ALXN1840, equivalent Mo dose will be used to calculate total Mo (and PUF Mo 
if applicable) CL/F and Vd/F values: Mo MW of 95.95 Da/ALXN1840 MW of 432.54 
Da x 60 mg ALXN1840 = 13.31 mg Mo dose. For celecoxib, use 200 mg dose for the 
calculation. 
• 
CL/F: apparent oral clearance 
• 
Vd/F: apparent volume of distribution 
Additional plasma PK parameters may be calculated if deemed appropriate.  
9.5. Pharmacokinetic Statistical Analysis 
Plasma concentration data for total Mo, PUF Mo, and celecoxib will be summarized 
separately for each scheduled sampling time using descriptive statistics. Plasma 
concentrations of total Mo, PUF Mo, and celecoxib and time deviation data will be 
presented in a data listing by participant. Mean plasma concentration versus scheduled 
time profiles will be presented in figures on both linear and semilogarithmic scales. 
Individual plasma concentration versus actual time profiles will be presented similarly. 
Pharmacokinetic parameters derived from plasma concentrations of total Mo, PUF Mo, 
and celecoxib will be presented in data listings and summarized separately using the 
following descriptive statistics: N, n, arithmetic mean, SD, arithmetic CV, median, 
minimum, maximum, and 95% confidence interval (CI). Geometric mean and geometric 
CV will be presented for Cmax and AUCs only. 
The effect of ALXN1840 on celecoxib PK will be assessed using a linear mixed‐effect 
model (SAS PROC MIXED) with treatment condition, sequence, and period as fixed 
effects and participant nested within sequence as a random effect. The model will be fitted 
to the natural‐log‐transformed PK parameters Cmax, AUC∞ and AUCt for estimation of 
effects and construction of CIs for the test treatment (Treatment B: 200 mg celecoxib + 
60 mg ALXN1840) compared with the reference treatment (Treatment A: 200 mg 
celecoxib). The within-participant CV for the corresponding PK parameters will be 
estimated using the mean squared error from the statistical model. Confidence intervals 
(90%) will be constructed for the least-squares geometric mean ratio (GMR) estimates 
between the test and reference treatments for the indicated PK parameters using the natural 
log-transformed data. The GMR estimates and the associated 90% confidence limits will 


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be exponentiated back to the original scale. The statistical results will also be graphically 
presented using a forest plot. 
9.6. Genetic Variant Analyses for CYP2C9 
Participants with variant CYP2C9 alleles will be identified in the PK concentration and 
parameter listings, where applicable. The characterization of potential impact of 
ALXN1840 on phenotypic CYP2C9 metabolism of celecoxib and genetic polymorphism 
on the between-participant variability of celecoxib PK are exploratory assessments. Thus, 
this study does not specifically select target participants with a certain proportion of 
CYP2C9 genotypes. Depending on the distribution of CYP2C9 genotypes within 
treatments, the impact of ALXN1840 coadministration on celecoxib PK may be stratified 
by CYP2C9 genotypes to assess the impact on the drug-drug interaction. 
9.7. Pharmacodynamic Parameters 
The following plasma PD parameters will be calculated using noncompartmental methods 
for Total Cu and PUF Cu (measured and absolute change from baseline) concentrations 
with Phoenix® WinNonlin® (Certara USA Inc., Princeton, New Jersey) Version 8.0 or 
higher or SAS Version 9.4 or higher (SAS Institute Inc., Cary, North Carolina), as 
applicable. Calculations will be based on the actual sampling times relative to the actual 
reference ALXN1840 dosing times recorded during the study. 
• Emax:  maximum observed PD concentration in plasma 
• TEmax:  time to reach maximum observed PD concentration in plasma 
• AUECt: area under the effect versus time curve (AUEC) from time 0 to last 
quantifiable concentration time, calculated using the linear trapezoidal rule 
Additional PD parameters may be calculated as necessary. 
9.8. Pharmacodynamic Statistical Analysis 
Plasma concentration data for total Cu and PUF Cu will be summarized separately for each 
scheduled sampling time using descriptive statistics. Individual concentration data will be 
presented in data listings. Individual concentration versus actual time profiles will be 
provided. Additionally, mean concentration versus nominal time profiles will be provided. 
Note that the measured, change from baseline, and percent change from baseline 
concentration data for total Cu and PUF Cu will be listed, summarized, and presented 
graphically on linear scales. 
Parameters for total Cu and PUF Cu in plasma will be summarized separately using 
descriptive statistics (N, n, mean, SD, median, %CV, minimum, and maximum). 
Geometric mean and geometric %CV will be calculated for AUECs and Emax. 


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10. Interim Analysis 
No interim analyses are planned for this study. 
11. Changes in the Planned Analysis 
For the definition of PK/PD analysis set in the protocol was “All participants who have 
sufficient plasma samples to have evaluable PK data for celecoxib and total Mo (as a 
measure of ALXN1840) in plasma”,  in this SAP is changed to “The PK analysis set will 
include all participants who have sufficient plasma samples to have evaluable PK data for 
celecoxib and/or total Mo (as a measure of ALXN1840) in plasma. The Pharmacodynamic 
(PD) analysis set will include all participants who have sufficient plasma samples to have 
evaluable PD data for total Cu or PUF Cu.” 
12. References 
Dennison J, Puri A, Warrington S, Endo T, Adeloye T, Johnston A. Amenamevir: Studies 
of Potential CYP2C8- and CYP2B6-Mediated Pharmacokinetic Interactions With 
Montelukast and Bupropion in Healthy Volunteers. Clin Pharmacol Drug Dev. 
2018;7(8):860-870. 


PPD Biostatistics and Programming 
Statistical Analysis Plan (SAP) Client Approval Form 
 
PPD CONFIDENTIAL AND PROPRIETARY 
SOP-BST-05ar06  
Effective Date:   19 September 2019 
Page 1 of 2 
Client: 
Alexion Pharmaceuticals, Inc. 
Protocol Number: 
ALXN1840-HV-105 
 
Document Description: 
Final Statistical Analysis Plan 
SAP Title: 
A Phase 1, Randomized, 2-Period, 2-Sequence, 
Cross-over Study to Determine the Effect of ALXN1840 
on the Metabolism of a CYP2C9 Substrate in Healthy 
Participants 
SAP Version Number: 
Version 1.0 
Effective Date: 
04 Sep 2020 
 
Author(s): 
For PPD: 
 
For PPD: 
 
 
Approved by: 
 
 
Alexion Pharmaceu
Date (DD-MMM-YYYY) 
 
 
 
Date (DD-MMM-YYYY) 
 
 
 
Date (DD-MMM-YYYY) 
Alexion PharmacS
Alexion Pharmac
04-Sep-2020 | 13:51:58 EDT
04-Sep-2020 | 13:36:22 EDT
08-Sep-2020 | 07:11:07 EDT
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PPD Biostatistics and Programming 
Statistical Analysis Plan (SAP) Client Approval Form 
 
PPD CONFIDENTIAL AND PROPRIETARY 
SOP-BST-05ar06  
Effective Date:   19 September 2019 
Page 2 of 2 
 
Date (DD-MMM-YYYY) 
 Alexion Pharmace
04-Sep-2020 | 14:23:05 EDT
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Certificate Of Completion
Envelope Id: 
Status: Completed
Subject: Please DocuSign: ALXN1840-HV-105 SAP Approval Form.pdf
Source Envelope: 
Document Pages: 2
Signatures: 4
Envelope Originator: 
Certificate Pages: 2
Initials: 0
AutoNav: Enabled
EnvelopeId Stamping: Disabled
Time Zone: (UTC-05:00) Eastern Time (US & Canada)
100 College St.
New Haven, CT  06510
IP Address: 
 
Record Tracking
Status: Original
             04-Sep-2020 | 12:47
Holder: 
             
Location: DocuSign
Signer Events
Signature
Timestamp
Alexion Pharmaceuticals, Inc.
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 04-Sep-2020 | 13:35
Viewed: 04-Sep-2020 | 13:51 
Signed: 04-Sep-2020 | 13:51
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Alexion Pharmaceuticals Inc.
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 04-Sep-2020 | 13:35
Viewed: 04-Sep-2020 | 13:35 
Signed: 04-Sep-2020 | 13:36
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
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Signer Events
Signature
Timestamp
Alexion Pharmaceuticals, Inc.
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 04-Sep-2020 | 13:35
Viewed: 08-Sep-2020 | 07:10 
Signed: 08-Sep-2020 | 07:11
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Alexion Pharmaceuticals, Inc. (Regulated)
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 04-Sep-2020 | 13:35
Viewed: 04-Sep-2020 | 14:22 
Signed: 04-Sep-2020 | 14:23
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
In Person Signer Events
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Timestamp
Agent Delivery Events
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Intermediary Delivery Events
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Certified Delivery Events
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Signature
Timestamp
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Status
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Envelope Sent
Hashed/Encrypted
04-Sep-2020 | 13:35
Certified Delivered
Security Checked
08-Sep-2020 | 07:10
Signing Complete
Security Checked
08-Sep-2020 | 07:11
Completed
Security Checked
08-Sep-2020 | 07:11
Payment Events
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