Conditions: Healthy
Keywords: Electrocardiogram Cardiac Repolarization ALXN1840 Optimized QT Correction QT Interval Correction Thorough QT QT Correction by Fridericia Individual QT Correction Wilson Disease
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 57
Healthy volunteers: yes

Brief summary:
This study will evaluate the effect of a supratherapeutic dose of ALXN1840 on the heart rate (HR)-corrected QT interval (QTc) in healthy adult participants. Moxifloxacin will be used as the active control.

Detailed description:
This is a randomized, 3-treatment, 3-period, 6-sequence, crossover, placebo- and active-controlled, double-blind for ALXN1840, open-label for moxifloxacin, in healthy adult participants. Participants will be domiciled in the clinic for 7 days during Treatment Period 1 and for 6 days during Treatment Period 2 and 3. A single oral dose of each treatment (ALXN1840, matching ALXN1840 placebo, or moxifloxacin) will be administered on Day 1 of each period following an overnight fast of at least 10 hours. There will be a minimum 14-day washout between study intervention administrations for each treatment period. Cardiodynamic, pharmacokinetic, and safety assessments will be performed at certain times during the study. An end-of-study visit will occur 14 days (±2 days) after the last dose.

Arms:
arm 1: On Day 1 of each period, participants will receive a single dose of the following study interventions:

Period 1: ALXN1840.

Period 2: Placebo-matching ALXN1840.

Period 3: Moxifloxacin. arm 2: On Day 1 of each period, participants will receive a single dose of the following study interventions:

Period 1: ALXN1840.

Period 2: Moxifloxacin.

Period 3: Placebo-matching ALXN1840. arm 3: On Day 1 of each period, participants will receive a single dose of the following study interventions:

Period 1: Placebo-matching ALXN1840.

Period 2: ALXN1840.

Period 3: Moxifloxacin. arm 4: On Day 1 of each period, participants will receive a single dose of the following study interventions:

Period 1: Placebo-matching ALXN1840.

Period 2: Moxifloxacin.

Period 3: ALXN1840. arm 5: On Day 1 of each period, participants will receive a single dose of the following study interventions:

Period 1: Moxifloxacin.

Period 2: ALXN1840.

Period 3: Placebo-matching ALXN1840. arm 6: On Day 1 of each period, participants will receive a single dose of the following study interventions:

Period 1: Moxifloxacin.

Period 2: Placebo-matching ALXN1840.

Period 3: ALXN1840.

Interventions: intervention 1: ALXN1840 intervention 2: Placebo intervention 3: Moxifloxacin
Intervention descriptions: intervention 1: ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose). intervention 2: Placebo will be administered orally. intervention 3: Moxifloxacin (400 milligrams) will be administered orally.

Protocol document:
Prot_000.pdf: 
A Randomized, Three-Treatment, Three-Period, Six-
Sequence, Crossover, Placebo- and Active-Controlled, 
Double-Blind for ALXN1840 (Open-Label for Moxifloxacin) 
Thorough QT/QTc (TQT) Study to Evaluate the Effect of 
ALXN1840 on Cardiac Repolarization in Healthy Adult 
Participants 
Unique Protocol ID: 
NCT Number: 
Date of Protocol:  
ALXN1840-HV-107 
NCT04560816 
01 September 2020 


Alexion Pharmaceuticals, Inc. 
ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
Title Page 
CLINICAL STUDY PROTOCOL 
IND 119,006 
 
A RANDOMIZED, THREE-TREATMENT, THREE-PERIOD, 
SIX-SEQUENCE, CROSSOVER, PLACEBO- AND 
ACTIVE-CONTROLLED, DOUBLE-BLIND FOR ALXN1840 
(OPEN-LABEL FOR MOXIFLOXACIN) THOROUGH QT/QTC (TQT) 
STUDY TO EVALUATE THE EFFECT OF ALXN1840 ON CARDIAC 
REPOLARIZATION IN HEALTHY ADULT PARTICIPANTS 
PROTOCOL NO. ALXN1840-HV-107 
 
Sponsor: 
Alexion Pharmaceuticals, Inc. 
121 Seaport Boulevard 
Boston, MA 02210 
Medical Monitor and 
Sponsor Contact: 
 
 
Telephone: 
 
Version of Protocol: 
Amendment 1 
Date of Protocol:  
01 Sep 2020 
 
 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Alexion Pharmaceuticals, Inc. 
The study will be conducted according to the International Council for Harmonisation 
Guideline E6(R2): Good Clinical Practice. 
PPD
PPD
PPD


PPD


Alexion Pharmaceuticals, Inc. 
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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
Page 3 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree to conduct the study as outlined in protocol amendment 1 titled “A Randomized, 
Three-Treatment, Three-Period, Six-Sequence, Crossover, Placebo- and Active-Controlled, 
Double-Blind for ALXN1840 (Open-Label for Moxifloxacin) Thorough QT/QTc (TQT) 
Study to Evaluate the Effect of ALXN1840 on Cardiac Repolarization in Healthy Adult 
Participants” in accordance with the guidelines and all applicable government regulations, 
including US Title 21 of the Code of Federal Regulations Part 54. I have read and understand 
all sections of protocol amendment 1. 
 
 
Principal Investigator 
PPD 
 
Date 
PPD


Alexion Pharmaceuticals, Inc. 
ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
12 Jun 2020 
Amendment 1  
01 Sep 2020 
Amendment 1 (01 Sep 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
This amendment has been prepared to correct and align information regarding pregnancy and 
contraception with the latest Alexion-approved language, and to clarify ECG procedures. 
Additional, minor edits for clarification and consistency were also made. 
Changes to the Protocol 
Section # and Name 
Description of Change 
Brief Rationale and/or 
Clarifications 
Protocol Synopsis 
Section 3.1, Schedule of Events 
Section 6.1.1, Continuous Holter 
Electrocardiograms 
Addition of text regarding ECG 
extraction on Day -1 of Treatment 
Period 1 
To clarify the ECG procedures 
Protocol Synopsis 
Section 3, Study Design 
Section 6.1.1, Continuous Holter 
Electrocardiograms 
Deletion of text referring to activity 
prior to extraction on Day -1 of 
Treatment Period 1 
To clarify the ECG procedures 
Section 3.1, Schedule of Events 
12-lead Holter measurement at time 
0 on Day 1 removed 
12-lead Holter extraction for 
Day -1 will be performed at 
time point -0.25 instead of 
timepoint 0 
Protocol Synopsis 
Section 4.1, Inclusion Criteria 
Inclusion criterion 5 changed from 6 
months to 6 weeks 
To align with Alexion 
standards 
Inclusion criterion 6 updated to 
include female partners of male 
participants and breastfeeding 
females, add details regarding ova 
donation, and change reference 
from 1 menstrual cycle to 6 weeks 
To correct and align with 
Alexion-approved language. 
Order of text in inclusion criterion 7 
updated for clarity 
Exclusion criterion 12 updated to 
include language regarding a 
positive serum pregnancy test 
Section 6.2.1, Pharmacokinetic and 
Pharmacodynamic Sample 
Collection 
Window for collection of samples 
for PK evaluation added 
To include the time window for 
PK sample collection 
Section 6.3.1.5, Collection of 
Pregnancy Information 
Addition of text on reporting of 
pregnancy 
To clarify reporting 
requirements for pregnancy 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
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Section 6.3.1.5.2, Female 
Participants who Become Pregnant 
Section 9.3.1, Definition of 
Adverse Event 
Definition of adverse events revised 
To align with latest Alexion-
approved language 
Section 9.3.2, Definition of Serious 
Adverse Event 
Definition of suspected unexpected 
serious adverse reaction (SUSAR) 
added. 
To align with latest Alexion-
approved language 
All 
Minor editorial updates and 
corrections 
For clarification, and to ensure 
accuracy and consistency 
throughout the protocol. 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
Page 6 
TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................... 1 
SIGNATURE PAGE ............................................................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ..................................................... 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................. 4 
TABLE OF CONTENTS ........................................................................................................ 6 
PROTOCOL SYNOPSIS ....................................................................................................... 9 
1. 
INTRODUCTION ............................................................................................. 19 
1.1 
BACKGROUND ..............................................................................................19 
1.1.1 
ALXN1840 Pharmacology ...........................................................................20 
1.1.2 
ALXN1840 Safety ........................................................................................22 
1.2 
RATIONALE FOR THE STUDY ....................................................................24 
1.3 
RATIONALE FOR DOSE SELECTION.........................................................25 
2. 
STUDY OBJECTIVES ...................................................................................... 28 
2.1 
PRIMARY OBJECTIVE ..................................................................................28 
2.2 
SECONDARY OBJECTIVES .........................................................................28 
2.3 
EXPLORATORY OBJECTIVE .......................................................................28 
3. 
STUDY DESIGN ................................................................................................ 28 
3.1 
SCHEDULE OF EVENTS ...............................................................................30 
4. 
STUDY POPULATION..................................................................................... 33 
4.1 
INCLUSION CRITERIA .................................................................................33 
4.2 
EXCLUSION CRITERIA ................................................................................35 
4.3 
OTHER SCREENING CONSIDERATIONS ..................................................38 
4.4 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY .........................38 
4.4.1 
Reasons for Withdrawal ...............................................................................38 
4.4.2 
Handling of Withdrawals ..............................................................................39 
4.4.3 
Replacements ................................................................................................39 
5. 
STUDY INTERVENTION ................................................................................ 39 
5.1 
STUDY INTERVENTION ADMINISTERED ................................................39 
5.2 
STUDY INTERVENTION ...............................................................................40 
5.2.1 
Study Intervention Packaging and Storage ...................................................41 
5.2.2 
Study Intervention Accountability ................................................................41 
5.3 
METHOD OF ASSIGNING PARTICIPANTS TO TREATMENT GROUPS .41 
5.4 
BLINDING .......................................................................................................41 
5.4.1 
Blinding Procedures .....................................................................................41 
5.4.2 
Breaking the Blind ........................................................................................42 
5.5 
TREATMENT COMPLIANCE .......................................................................42 
5.5.1 
Prior and Concomitant Medications .............................................................42 


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5.5.1.1 
Prior Medications..................................................................................... 42 
5.5.1.2 
Concomitant Medications ........................................................................ 43 
6. 
STUDY PROCEDURES ................................................................................... 43 
6.1 
CARDIODYNAMIC ASSESSMENTS AND ENDPOINTS ..........................43 
6.1.1 
Continuous Holter Electrocardiograms ........................................................43 
6.1.1.1 
Thorough QT Plus Electrocardiogram Technique ................................... 44 
6.1.1.2 
Expert-Precision QT Analysis ................................................................. 45 
6.1.2 
Cardiodynamic Electrocardiogram Analysis ................................................46 
6.2 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS ......................46 
6.2.1 
Pharmacokinetic and Pharmacodynamic Sample Collection .......................47 
6.2.2 
Pharmacokinetic and Pharmacodynamic Sample Analyses .........................48 
6.3 
SAFETY ASSESSMENTS AND ENDPOINTS ..............................................48 
6.3.1 
Adverse Events and Serious Adverse Events ...............................................48 
6.3.1.1 
Time Period and Frequency for Collecting AE and SAE Information .... 49 
6.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events ........ 49 
6.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events ..................... 49 
6.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events ........... 49 
6.3.1.5 
Collection of Pregnancy Information ...................................................... 50 
6.3.2 
Clinical Laboratory Testing ..........................................................................52 
6.3.3 
Vital Sign Measurements ..............................................................................53 
6.3.4 
Safety Electrocardiograms ............................................................................54 
6.3.5 
Physical Examinations ..................................................................................54 
7. 
STATISTICAL ANALYSIS PLANS................................................................. 55 
7.1 
SAMPLE SIZE CALCULATIONS..................................................................55 
7.2 
ANALYSIS SETS ............................................................................................55 
7.3 
STATISTICAL ANALYSIS .............................................................................56 
7.3.1 
Cardiodynamic Analyses ..............................................................................56 
7.3.1.1 
By-Time Point Analysis (Primary Analysis) ........................................... 56 
7.3.1.2 
Categorical Analyses ............................................................................... 57 
7.3.1.3 
Assay Sensitivity ..................................................................................... 58 
7.3.2 
Pharmacokinetic Analyses ............................................................................58 
7.3.3 
Pharmacokinetic Concentration/QTc Analysis (Exploratory Analysis) .......58 
7.3.4 
Safety Analyses ............................................................................................59 
7.4 
HANDLING OF MISSING DATA ..................................................................60 
7.5 
INTERIM ANALYSES ....................................................................................60 
8. 
REFERENCE LIST........................................................................................... 61 
9. 
APPENDICES .................................................................................................... 63 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS ..................................................63 


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9.2 
APPENDIX 2: STUDY GOVERNANCE .......................................................65 
9.2.1 
Data Quality Assurance ................................................................................65 
9.2.2 
Investigator Obligations ...............................................................................65 
9.2.2.1 
Confidentiality ......................................................................................... 65 
9.2.2.2 
Institutional Review ................................................................................. 66 
9.2.2.3 
Participant Consent .................................................................................. 66 
9.2.2.4 
Financial Disclosure and Obligations ...................................................... 66 
9.2.2.5 
Investigator Documentation ..................................................................... 67 
9.2.2.6 
Study Conduct ......................................................................................... 68 
9.2.2.7 
Case Report Forms and Source Documents ............................................ 68 
9.2.2.8 
Adherence to Protocol ............................................................................. 68 
9.2.2.9 
Reporting Adverse Events ....................................................................... 68 
9.2.2.10 
Investigator’s Final Report ...................................................................... 69 
9.2.2.11 
Records Retention .................................................................................... 69 
9.2.2.12 
Publications.............................................................................................. 69 
9.2.3 
Study Management .......................................................................................69 
9.2.3.1 
Monitoring ............................................................................................... 69 
9.2.3.2 
Management of Protocol Amendments and Deviations .......................... 70 
9.2.3.3 
Study Termination .................................................................................... 71 
9.2.3.4 
Final Report ............................................................................................. 71 
9.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .....72 
9.3.1 
Definition of Adverse Event .........................................................................72 
9.3.2 
Definition of Serious Adverse Event ............................................................73 
9.3.3 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events
 ......................................................................................................................74 
9.3.4 
Reporting of Serious Adverse Events ...........................................................75 
9.4 
APPENDIX 4: PROTOCOL AMENDMENT HISTORY ...............................77 
 


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PROTOCOL SYNOPSIS 
PROTOCOL NO.: ALXN1840-HV-107 Amendment 1 
TITLE: A Randomized, Three-Treatment, Three-Period, Six-Sequence, Crossover, 
Placebo- and Active-Controlled, Double-Blind for ALXN1840 (Open-Label for 
Moxifloxacin) Thorough QT/QTc (TQT) Study to Evaluate the Effect of ALXN1840 on 
Cardiac Repolarization in Healthy Adult Participants 
STUDY PHASE: 1 
STUDY SITE: One clinical site in the United States 
OBJECTIVES: 
Primary: The primary objective of this study is to evaluate the effect of a supratherapeutic 
dose of ALXN1840 on the heart rate (HR)-corrected QT interval (QTc) with the intent to 
exclude a 10 ms effect. 
Secondary: The secondary objectives of the study are: 
• To demonstrate assay sensitivity of the study to detect an effect on the mean QT/QTc 
interval of approximately 5 ms using moxifloxacin as a positive control. 
• To evaluate the safety and tolerability of a single oral supratherapeutic dose of 
ALXN1840 in healthy participants. 
• To assess the pharmacokinetics (PK) of ALXN1840 following administration of a single 
oral supratherapeutic dose in healthy participants. 
• To evaluate the effects of a single oral supratherapeutic dose of ALXN1840 on HR, PR 
and QRS intervals, treatment-emergent T-wave morphology abnormalities, and 
appearance of U-waves. 
STUDY DESIGN: This is a randomized, 3-treatment, 3-period, 6-sequence, crossover, 
placebo- and active-controlled, double-blind for ALXN1840, open-label for moxifloxacin, in 
healthy adult participants. Moxifloxacin will be used as the active control. 
Approximately 54 participants will be randomized to ensure there will be 45 evaluable 
participants with data from all treatment periods. To ensure sequences are balanced within 
sex, participant randomization will be stratified by sex. Study interventions will be given in 
randomized sequences: ABC, ACB, BAC, BCA, CAB, and CBA, with each treatment 
administered with 240 mL of water following an overnight fast of at least 10 hours. No food 
will be allowed for at least 4 hours postdose. Water can be allowed as desired except for 
1 hour before and after drug administration. Treatment A is a single oral dose of ALXN1840 
120 mg administered as 15-mg enteric-coated tablets (supratherapeutic dose); Treatment B is 
a single oral dose of enteric-coated placebo tablets matching ALXN1840; and Treatment C is 
a single oral dose of moxifloxacin 400 mg tablet. 
Cardiodynamic assessment will be performed for approximately 25 hours on Day –1 of 
Treatment Period 1 and Day 1 to Day 2 of each treatment period. Blood samples for PK will 
be collected predose and at specified times up to 96 hours after the Day 1 dose in each 
treatment period. 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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Twelve-lead electrocardiograms (ECGs) will be extracted from a continuous (Holter) 
recording by the central laboratory. To support high quality data for extraction, 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. Blood for plasma PK will be collected as close as 
possible to nominal time but after completion of ECG extraction period with actual times for 
blood sample collections recorded. 
Participants will be domiciled in the clinic for 7 days in Treatment Period 1 and for 6 days in 
Treatment Periods 2 and 3, starting on Day –2 for Treatment Period 1 and on the day before 
dosing (Day –1) for Treatment Periods 2 and 3, until safety procedures have been completed 
and reviewed on Day 5. There will be a washout of at least 14 days between dose 
administration in each period. 
All participants (including participants who terminate the study early) will return to the study 
site 14 days (±2 days) after the last administration of study intervention for follow-up 
procedures and to determine if any adverse event (AE) has occurred since the last study visit. 
Duration of participant participation from the Screening Visit to the End-of-Study (EOS) 
Visit will be approximately 70 days. This includes up to 29 days for the Screening Period, 
study intervention administration on Day 1 of each treatment period, a minimum of a 14-day 
washout between study intervention administration in each treatment period, and 14 days 
(±2 days) for the EOS Visit. 
STUDY POPULATION: 
Inclusion Criteria: Each participant must meet all of the following criteria to be enrolled in 
this study: 
1. Participant is a healthy adult male or female, 18 to 50 years of age, inclusive, at 
Screening. 
2. Participant is a continuous nonsmoker and or an individual who has not used tobacco or 
nicotine-containing products (eg, electronic vapor cigarettes, cigarettes, cigars, chewing 
tobacco, snuff, nicotine gum, nicotine patches) for at least 3 months prior to the first dose 
of study intervention and for the duration of the study. A cotinine test performed during 
Screening and Check-in must be consistent with continuous nonsmoking status. 
3. Participant must weigh at least 60 kg for males or 52 kg for females and have a body 
mass index ≥18.0 and ≤30.0 kg/m2 at Screening. 
4. Participant must have a medical assessment with no clinically significant or relevant 
abnormalities as determined by medical history, physical examination, vital signs, 
12-lead ECG, and clinical laboratory evaluation (hematology, serum chemistry, 
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. 
5. Female participants of nonchildbearing potential must have undergone 1 of the following 
sterilization procedures and have official documentation of these occurring more than 
6 weeks prior to the first dose of study intervention: 
a. Hysteroscopic sterilization;  
b. Bilateral tubal occlusion, including Essure®; 


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c. Bilateral tubal ligation or bilateral salpingectomy; 
d. Hysterectomy; 
e. Bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose of study 
intervention and have serum follicle-stimulating hormone levels consistent with 
postmenopausal status. 
6. Female participants or female partners of male participants of childbearing potential 
(including breastfeeding females), if heterosexually active, must use highly effective 
contraception starting at least 6 weeks before the first dose of study intervention and 
continuing for at least 3 months after the end of systemic exposure of the study 
intervention. Female participants must not donate ova for at least 3 months after the end 
of systemic exposure of the study intervention. Highly effective contraceptive methods 
for females are as follows:  
a. Progestogen-only hormonal contraception associated with inhibition of ovulation as 
follows:  
i. Oral  
ii. Injectable  
iii. Implantable  
b. Intrauterine device 
c. Intrauterine hormone-releasing system 
d. Male partner vasectomized (with documented evidence of azoospermia if possible) 
e. Abstinence (note: 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 interventions. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical study and the preferred and 
usual lifestyle of the participant).  
7. Male participants, if heterosexually active and 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. Male participants 
must not donate sperm for at least 3 months after the end of systemic exposure of the 
study intervention. 
Female spouses or partners of male participants who are of childbearing potential must 
use highly effective contraception as previously defined, starting at least 6 weeks before 
(the male participant’s) first dose of study intervention and continuing until at least 3 
months after the end of their male partner’s systemic exposure to the study intervention.  
 
For male participants who have had a vasectomy (with documented evidence of 
azoospermia if possible) and agree to use a male condom for the stated time period, no 


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additional contraceptive method is required by their female partner. Male condom is 
required even with documented medical assessment of surgical success of a vasectomy. 
8. Participant has no clinically significant history or presence of ECG findings as judged by 
the Investigator at Screening and Check-in, including each criterion as follows: 
a. Normal sinus rhythm (HR between 45 beats per minute [bpm] and 100 bpm 
inclusive) 
b. QT interval corrected for HR using Fridericia’s formula (QTcF) ≤ 450 ms 
c. QRS interval ≤ 110 ms; and confirmed by manual over read if > 110 ms 
d. 120 ms ≤ PR interval ≤ 220 ms 
Exclusion Criteria: Participants meeting any of the following criteria will be excluded from 
the study: 
1. Participant has a significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, hematological, psychiatric, or neurologic disorders. 
2. Participant has a history of gastric bypass, other surgical procedure, or medical condition 
that may significantly alter absorption, metabolism, or excretion of drugs. 
3. Participant has had lymphoma, leukemia, or any malignancy within the past 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have been 
resected with no evidence of metastatic disease for 3 years; or has a history of breast 
cancer within the past 10 years. 
4. Participant has abnormal blood pressure, defined as a supine blood pressure 
<90/50 mm Hg or >140/90 mm Hg at Screening and predose vital signs; if either systolic 
or diastolic components of blood pressure meet these criteria, then the participant must be 
excluded. Blood pressure should be taken after a minimum of 5 minutes in the supine 
position. 
5. Participant has serum potassium, calcium, or magnesium levels outside the normal range 
at Screening and/or Check-in, confirmed by repeat. 
6. Participant has serum copper and/or ceruloplasmin values below the lower limit of 
normal at Screening. 
7. Female participant has hemoglobin <10.8 g/dL and male participant has hemoglobin 
<12.5 g/dL at Screening or Check-in. 
8. Participant has history of alcoholism or history of regular alcohol consumption within 
24 months prior to the study, defined as an average weekly intake of >7 units. One unit is 
equivalent to 1 pint of beer, 1 glass of wine, or 1 measure (single shot) of spirits. 
9. Participant has clinically significant multiple or severe drug allergies, food allergies, or 
allergies to study intervention, this class of drug, its derivatives, or to medical products 
that may be used in the study (eg, allergy to ALXN1840, any sulfur containing drugs, 
moxifloxacin, fluoroquinolone antibiotics, latex, band-aids, adhesive dressing, medical 
tape). 
10. Participant has alanine aminotransferase, aspartate aminotransferase, serum creatinine, or 
total bilirubin greater than upper limit of normal (ULN) for the testing laboratory. 


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Participant’s with confirmed Gilbert’s syndrome may be included with total bilirubin 
>ULN if the participant has a measured direct bilirubin <ULN. 
11. Participant has used any prescribed or over-the-counter medication (including dietary 
supplements, herbal remedies, and medications known to prolong the QTc interval) 
without the approval of the Investigator Alexion within 14 days (or 5 half-lives, 
whichever is longer) before the first dose of study intervention and during the study.  
12. Female participant is pregnant, as evidenced by a positive serum pregnancy test at 
screening or check-in, or lactating. 
13. Participant has positive urine drug or alcohol results at Screening or Check-in. 
14. Participant has presence of hepatitis B surface antigen 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. 
15. Participant has positive syphilis or human immunodeficiency virus (HIV)-1 and HIV-2 
antigen/antibody immunoassay at Screening. 
16. Participant has been on a diet incompatible with the on-study diet (including an extreme 
diet which resulted in a significant weight change for any reason), in the opinion of the 
Investigator, within the 29 days prior to the first dose of study intervention, and 
throughout the study. 
17. Participant has donated blood or has had a significant blood loss of more than 500 mL 
within 56 days prior to the first dose of study intervention. 
18. Participant has donated plasma within 7 days prior to the first dose of study intervention. 
19. Participant is currently enrolled or has had past participation (within the last 30 days 
before signing of consent, 5 half-lives of the study intervention, or twice the duration of 
the biological effect of the study intervention [whichever is longer]) in this or any other 
clinical study involving an investigational study intervention or any other type of medical 
research. 
20. Participant has participated in a previous clinical study where the participant received 
ALXN1840. 
21. Participant has history or presence of: 
a. Hypokalemia, in the opinion of the Investigator 
b. Risk factors for torsades de pointes (eg, heart failure, cardiomyopathy, or family 
history of long QT syndrome) 
c. Sick sinus syndrome, second- or third-degree atrioventricular block, myocardial 
infarction, pulmonary congestion, cardiac arrhythmia, prolonged QT interval, or 
conduction abnormalities 
d. Repeated or frequent syncope or vasovagal episodes 
e. Hypertension, angina, bradycardia (if assessed as clinically significant by the 
Investigator), or severe peripheral arterial circulatory disorders. 


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STUDY INTERVENTION: 
• Treatment A: A single oral dose of ALXN1840 120 mg administered as 15-mg 
enteric-coated tablets (supratherapeutic dose) 
• Treatment B: A single oral dose of enteric-coated placebo tablets matching ALXN1840 
• Treatment C: A single oral dose of moxifloxacin 400 mg tablet  
STUDY PROCEDURES: 
Cardiodynamic Assessments and Endpoints: Twelve-lead ECGs will be extracted from 
approximately 25-hour continuous (Holter) recordings on Day –1 of Treatment Period 1 and 
on Days 1 and 2 in each treatment period. Participants should be resting supinely for at least 
15 minutes before and 5 minutes after each time point for ECG extraction, which should 
precede PK blood samples, when applicable.  
Electrocardiograms will be extracted from the continuous recording by a central ECG 
laboratory (ERT, Rochester, NY) on Day –1 of Treatment Period 1 and each of these days at 
the following time points: Day 1 at predose (–45, –30, and –15 minutes) and 0.5, 1, 2, 3, 4, 5, 
6, 7, 8, 10, 12, and 24 (Day 2) hours postdose, for a total of 15 (3 predose and 12 postdose) 
time points in each treatment period. For HR-corrected QTc calculation in case of a 
substantial HR effect due to ALXN1840, ECG extraction from the Holter recording on Day -
1 of Treatment Period 1 will include continuous ECG extraction for optimized QT interval 
(QTcI) calculation, and if needed, ECG extraction at timepoints that precisely match the 
extraction timepoints for Day 1 of Periods 1, 2 and 3 for individual HR-corrected QT interval 
(QTcS) calculation. 
The following ECG parameters will be measured and calculated: HR, PR interval, QTcF, 
QRS interval, treatment-emergent T-wave morphology abnormalities, and appearance of 
U-waves. 
The primary endpoint is placebo-corrected change from Baseline QTcF (ΔΔQTcF) for 
ALXN1840 using the by-time point analysis. The secondary endpoints are the ΔΔQTcF for 
moxifloxacin; the change from Baseline in HR, QTcF, PR, QRS (ΔHR, ΔQTcF, ΔPR and 
ΔQRS); the placebo-corrected change from Baseline HR, PR, and QRS (ΔΔHR, ΔΔPR and 
ΔΔQRS); categorical outliers for QTcF, HR, PR, and QRS; and the frequency of 
treatment-emergent changes of T-wave morphology and U-wave presence. The exploratory 
endpoint is the ΔΔQTcF for ALXN1840 using the concentration-QTc analysis by 
concentration of total Mo or PUF Mo (as surrogate measures of ALXN1840 PK) in plasma. 
For all continuous ECG parameters from each period, Baseline is defined as the average of 
the measured ECG intervals from the 3 predose time points (–45, –30, and –15 minutes 
before dosing) on Day 1 for the respective period. For T-wave morphology and U-wave 
presence, Baseline includes findings observed in any replicates from the 3 predose time 
points (–45, –30, and –15 minutes) on Day 1 in each period. 
Pharmacokinetic Assessments and Endpoints: Blood samples for PK analysis of total 
molybdenum (Mo) and PUF Mo (as surrogate measures of ALXN1840 PK) will be collected 
at the following time points: within 1.5 hour before dosing and postdose at 0.5, 1, 2, 3, 4, 5, 
6, 7, 8, 10, 12, 24, 48, and 96 hours in each period. Only samples collected predose and 
following ALXN1840 administration will be analyzed for plasma total Mo and PUF Mo. 


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Samples collected predose and after placebo and moxifloxacin administration will be saved 
for analysis, if needed. 
The following plasma PK parameters will be calculated as endpoints for total Mo and 
PUF Mo using noncompartmental methods with Phoenix® WinNonlin® (Certara USA Inc., 
Princeton, New Jersey) Version 8.0 or higher or SAS® (SAS® Institute Inc., Cary, North 
Carolina) Version 9.4 or higher, as applicable. Calculations will be based on the actual 
sampling times elapsed from the reference dosing time in the period as recorded during the 
study. 
• Time delay between the time of dosing and time of appearance of Mo concentration in 
plasma (Tlag) 
• Maximum observed concentration in plasma (Cmax) 
• Time to reach maximum observed concentration in plasma (Tmax) 
• Area under the concentration in plasma versus time curve (AUC) from time 0 to the last 
quantifiable concentration (AUC0-t) 
• AUC from time 0 to 96 hours postdose (AUC0-96) 
• AUC from time 0 extrapolated to infinity (AUC0-inf) 
• Apparent terminal-phase elimination rate constant (λz) 
• Terminal elimination half-life (t1/2) 
• Apparent total clearance from plasma after oral administration of ALXN1840 (CL/F) 
• Apparent volume of distribution during the terminal phase (Vz/F) 
Pharmacokinetic samples may be used for the quantification of pharmacodynamic endpoints 
such as total Cu, PUF Cu, labile bound Cu, ceruloplasmin, and ceruloplasmin-bound Cu. 
Additional PK parameters may be calculated if deemed appropriate. 
Safety Assessments and Endpoints: Safety and tolerability will be assessed by the 
following endpoints: monitoring and recording of AEs, clinical laboratory test results 
(hematology, serum chemistry, and urinalysis), vital sign measurements, 12-lead safety ECG 
results, and physical examination findings. 
For all safety assessments, the Investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (eg, active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance 
will be documented and an AE will be reported on the AE page of the participant’s eCRF. 
The Investigator will monitor the participant until the result has reached the reference range 
or the result at Screening, or until the Investigator determines that follow-up is no longer 
medically necessary. 
STATISTICAL ANALYSIS PLANS: 
Sample Size: A sample size of approximately 54 participants was chosen to obtain 
45 evaluable participants to complete the study. Assuming a 1-sided 5% significance level 
and a within-participant standard deviation of 8 ms for ΔQTcF for all treatment groups and a 
true mean difference of 3 ms in ΔQTcF between ALXN1840 and placebo, based on the 


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calculation of the sample size for a TQT study, a sample size of 45 evaluable participants will 
provide a power of 90% to demonstrate that the upper bound of all the 2-sided 90% CIs on 
ΔΔQTcF will fall below 10 ms for up to 12 postdose time points. To account for a drop-out 
rate of approximately 16%, 54 participants will be enrolled. 
Based on the calculation of the sample size for a TQT study, as the test is performed at 3 time 
points separately (1, 2, and 3 hours), a 1-sided 5% significance level (with adjusted 1-sided 
significance levels of 5%, 2.5%, and 1.67%) is used along with a within-participant standard 
deviation of 8 ms for ΔQTcF and a true effect of moxifloxacin of 10 ms, a sample size of 
45 evaluable participants will provide greater than 98% power to demonstrate assay 
sensitivity of excluding a mean difference of 5 ms in ΔQTcF between moxifloxacin and 
placebo groups.  
Analysis Sets: The analysis populations are as follows: 
• The Safety Set will include all participants who receive at least 1 dose of study 
intervention (ALXN1840, moxifloxacin, or placebo) and for whom any postdose data are 
available. 
• The QT/QTc Set will include all participants in the Safety Set with measurements at 
Baseline as well as on-treatment with at least 1 postdose time point with a valid ΔQTcF 
value. The QT/QTc Set will be used for the by-time point, assay sensitivity, and 
categorical analyses of the cardiodynamic ECG parameters. 
• The PK Set will include all participants who receive at least 1 dose of ALXN1840 and 
have evaluable PK data for total Mo and PUF Mo (as surrogate measures of ALXN1840 
PK) in plasma. The PK Set will be used for PK analysis. 
• The PK/QTc Set will include all participants who are in both the QT/QTc and PK Sets 
with at least 1 pair of postdose PK and QTcF data from the same time point as well as 
participants in the QT/QTc Set who received placebo. The PK/QTc Set will be used for 
the exploratory concentration-QTc analysis. 
Cardiodynamic Analyses: Cardiodynamic analyses will be based on the QT/QTc Set. The 
primary analysis will be based on by-time point analysis to evaluate the effect of ALXN1840 
on the ΔΔQTcF at each postdosing time point (“by-time point” analysis) using the 
intersection union test (IUT). The effect of ALXN1840 on placebo-corrected change from 
Baseline in HR, PR, and QRS (ΔΔHR, ΔΔPR, and ΔΔQRS) will also be evaluated using the 
IUT. 
The statistical hypothesis to be tested for the primary assessment of QT prolongation for the 
ALXN1840 treatment is: 
H0: ∪{μD(i) – μP(i)} ≥10, i = 1,2,…,12 
H1: ∩{μD(i) – μP(i)} <10, i = 1,2,…,12 
where μD(i) and μP(i) are the least squares (LS) mean of ΔQTcF for ALXN1840 and placebo at 
postdose time point i, respectively. 
The by-time point analysis for QTcF will be based on a mixed-effects model for repeated 
measures (MMRM) with change from Baseline QTcF (ΔQTcF) as the dependent variable; 
period, sequence, time (ie, postdose time point: categorical), treatment (supratherapeutic dose 
of ALXN1840, moxifloxacin, and placebo), and time-by-treatment interaction as fixed effects 


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and Baseline QTcF and sex as covariates. An unstructured covariance matrix will be used to 
model within-participant error. If the model with unstructured covariance matrix fails to 
converge, other covariance structure such as Toeplitz with heterogeneity (TOEPH), 
auto-regressive with heterogeneity (ARH), compound symmetry with heterogeneity (CSH), 
TOEP, AR, and CS will be considered in decreasing complexity in parameterization. The 
final model selection will be based on Akaike information criterion (AIC). The degrees of 
freedom estimates will be determined by the Kenward-Roger method. The model will also 
include a participant-specific random effect. Least squares mean difference and 2-sided 90% 
CI will be calculated for the contrast of ALXN1840 versus placebo at each postdose time 
point, separately. If the upper bound of the 2-sided 90% CI of LS mean ΔΔQTcF lies below 
10 ms at all 12 postdose time points, ALXN1840 will be concluded not to have a significant 
effect on QT interval prolongation. 
For HR, PR, and QRS, the analysis will be based on the change from Baseline postdosing 
(ΔHR, ΔPR, and ΔQRS). The same (by-time point analysis) model will be used as described 
for QTcF. The LS mean, SE, and 2-sided 90% CI from the statistical modeling for both 
change from Baseline and placebo-corrected change from Baseline values will be listed in 
the tables and graphically displayed. 
An analysis of categorical outliers will be performed for changes in HR, PR, QRS, QTcF, 
T-wave morphology, and U-wave presence. The results for categorical outliers, T-wave 
morphology, and U-wave presence will be summarized in frequency tables with counts 
(percentages) for both number of participants and number of time points. For categorical 
outliers, the number (percentage) of participants as well as time points who had absolute 
QTcF values >450 and ≤480 ms, >480 and ≤500 ms, or >500 ms, and changes from predose 
Baseline (∆QTcF) of >30 and ≤60 ms, or >60 ms; increase in PR from predose Baseline 
>25% to a PR >200 ms; increase in QRS from predose Baseline >25% to a QRS >120 ms; 
decrease in HR from predose Baseline >25% to a HR <50 bpm; and increase in HR from 
predose Baseline >25% to a HR >100 bpm will be determined. For T-wave morphology and 
U-wave presence, treatment-emergent changes will be assessed; ie, changes not present at 
Baseline. For each category of T-wave morphology and of U-waves, the category will be 
deemed as present if observed in any replicates at the time point. 
Assay sensitivity will also be evaluated using by-time point analysis of the effect on ΔΔQTcF 
of moxifloxacin using a similar model as for the primary analysis. The analysis to show assay 
sensitivity will be based on the change from Baseline postdosing QTcF of moxifloxacin. For 
the 3 predefined time points (1, 2, and 3 hours postdose), the contrast in treatment 
ΔΔQTcF = moxifloxacin versus placebo will be tested against the 1-sided null hypothesis 
ΔΔQTcF ≤5 ms on the 5% level. Multiplicity will be controlled by using a Hochberg 
procedure. If after this procedure the LS mean of ΔΔQTcF is significantly larger than 5 ms 
for at least 1 time point of these 3 time points, assay sensitivity will be considered to have 
been demonstrated. In addition, 2-sided 90% CIs will be obtained for the contrast at all time 
points and used in the figures. 
Other QT interval corrections such as QTcI may be performed, if justified, with details to be 
included in the Statistical Analysis Plan. 
Pharmacokinetic Analyses: Pharmacokinetic analyses will be based on the PK Set. Plasma 
total Mo and PUF Mo (as surrogate measures of ALXN1840 PK) and time deviation data 


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will be presented in a data listing by participant. 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), 
geometric mean, geometric CV, median, minimum, and maximum. Mean concentration 
versus scheduled time profiles will be presented in figures on both linear and 
semilogarithmic scales. Individual concentration versus actual time profiles will be presented 
similarly. 
Pharmacokinetic parameters derived from plasma total Mo and PUF Mo using 
noncompartmental methods will be presented in data listings and summarized separately 
using the following descriptive statistics: number of participants, arithmetic mean, standard 
deviation, arithmetic CV, geometric mean, geometric CV, median, minimum, and maximum. 
Geometric mean and geometric CV will be presented for Cmax and AUCs only. 
Pharmacokinetic Concentration/QTc Analysis: Pharmacokinetic concentration/QTc 
analysis will be based on the PK/QTc Set. The relationship between total Mo or PUF Mo (as 
surrogate measures of ALXN1840 PK) concentrations in plasma and ∆∆QTcF will be 
explored graphically and using a linear mixed-effects modeling approach with ∆∆QTcF as 
the dependent variable, total Mo or PUF Mo concentration in plasma as the exploratory 
variate (0 for placebo), centered Baseline QTcF (ie, Baseline QTcF for individual participant 
minus the population mean Baseline QTcF for all participants in the same treatment period) 
as an additional covariate, treatment (active = 1 or placebo = 0) and time (ie, postdose time 
point) as fixed effects, and a random intercept and slope per participant. The degrees of 
freedom estimates will be determined by the Kenward-Roger method. From the model, the 
slope (ie, the regression parameter for the total Mo or PUF Mo concentration in plasma) and 
the treatment effect-specific intercept (defined as the difference between active and placebo) 
will be estimated together with 2-sided 90% CI. The estimates for the time effect will be 
reported with degrees of freedom and SE. 
The geometric mean of the individual Cmax values for total Mo or PUF Mo (as surrogate 
measures of ALXN1840 PK) concentrations in plasma for participants in the active drug 
group will be determined. The predicted effect and its 2-sided 90% CI for ΔΔQTcF (ie, slope 
estimate × concentration + treatment effect-specific intercept) at this geometric mean Cmax 
will be obtained. 
Safety Analyses: Safety analyses will be based on the Safety Set. Adverse events will be 
coded by preferred term and system organ class using the Medical Dictionary for Regulatory 
Activities. All AE data will be presented in a data listing. Treatment-emergent AEs will be 
summarized by treatment and overall, as well as by severity and relationship to study 
intervention. Serious AEs and AEs leading to early discontinuation will also be presented in 
data listings. 
Actual values and changes from Baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead safety ECG results will be summarized by treatment at each time 
point using descriptive statistics (number of participants, mean, SD, median, minimum, and 
maximum). Shift tables will be generated for clinical laboratory test results. Clinical 
laboratory test results, vital sign measurements, 12-lead safety ECG results, and physical 
examination findings will be presented in data listings. 
DATE OF PROTOCOL AMENDMENT 1: 01 Sep 2020 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
Wilson disease (WD) is a rare, autosomal recessive disorder of impaired copper (Cu) 
transport that results in pathological Cu accumulation. It is caused by mutations in the 
adenosine triphosphate (ATP7B) gene, located on chromosome 13. The gene is highly 
expressed in the liver and encodes a trans-membrane protein adenosine triphosphatase 2 
(ATPase2) involved in Cu transport (Pfeiffer 2007). The physiological role of ATP7B is to 
incorporate Cu in ceruloplasmin and to excrete excess Cu into bile. In WD, mutations in the 
ATP7B gene result in deficient production of ATPase2, which in turn leads to impaired 
biliary excretion of Cu and impaired incorporation of Cu into ceruloplasmin, a serum 
ferroxidase, which, in healthy humans, contains greater than 95% of the Cu found in plasma 
(Hellman 2002). Consequently, there is an increase of Cu in liver, brain, and other tissues 
with resultant organ damage and dysfunction (Pfeiffer 2007). Wilson disease genetic 
prevalence is approximately 1 per 30,000 population worldwide. An estimated 50% of people 
with an identified mutation will become symptomatic, diagnosed, and treated. Typical 
clinical presentation of WD is in adolescence to early adulthood. Initial signs and symptoms 
of WD are predominantly hepatic (approximately 40%), neurologic (approximately 40%), or 
psychiatric (approximately 20%), but patients often develop combined hepatic and 
neuropsychiatric disease. Untreated or inadequately treated patients have progressive 
morbidity, and mortality is usually secondary to hepatic cirrhosis. Liver transplantation is the 
only effective therapy for WD-associated acute liver failure; other causes of death associated 
with WD include hepatic malignancy and neurologic deterioration with severe inanition.  
Current treatment goals for WD focus on compensating for impaired Cu metabolism, 
reducing free Cu, and maintaining normal Cu levels to improve patients’ symptoms. The 
current treatments for WD are general chelator therapies that non-specifically chelate Cu and 
promote urinary Cu excretion. In addition, zinc, which blocks dietary uptake of Cu, is used 
mainly for maintenance treatment. Zinc impairs the absorption of Cu by the induction of 
metallothionein in the gastrointestinal (GI) tract. The currently available drugs have high 
rates of treatment discontinuation due to tolerability and efficacy issues. These therapies 
require frequent dosing (2 to 4 times per day) and must be taken in a fasted state. While 
ALXN1840 is also to be taken in a fasted state, it requires only once daily dosing. The 
adverse event (AE) profiles and complicated dosing regimens of currently available 
treatments leads to poor compliance and high rates of treatment failure, a major concern in 
WD, which requires life-long treatment.  


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ALXN1840 (bis-choline tetrathiomolybdate) is a novel, first-in-class, Cu-binding agent in 
development for the treatment of WD. ALX1840 preclinically has been shown to directly 
target and remove Cu from intracellular Cu stores, rapidly form stable Cu-tetrathiomolybdate 
(TTM) complexes, and promote biliary excretion of Cu to reduce Cu overload. ALXN1840 
acts by improving control of Cu due to the rapid formation of the virtually irreversible 
TTM-Cu-albumin tripartite complexes (TPCs) leading to a rapid de-coppering without 
mobilization of free Cu that could cause tissue toxicity, including neurological deterioration. 
It is hoped that improved long-term compliance with ALXN1840 treatment through 
improved tolerability and the convenience of a simplified once daily dosing regimen 
compared with current therapeutic options (multiple daily dosing) could be achieved. 
Additional information regarding ALXN1840 can be found in the Investigator’s Brochure 
(IB; Alexion Pharmaceuticals, Inc 2020). 
1.1.1 
ALXN1840 Pharmacology 
In the in vitro human ether a-go-go-related gene (hERG)-IKr Assay (Study A0889), results 
indicated that ALXN1840 is devoid of activity to block the delayed rectifying potassium 
currents responsible for cardiac repolarization at concentrations up to 1618 μM, which is 
several magnitudes above the expected total Mo plasma exposure in patients.  
The PK of ALXN1840 were evaluated in 2 Phase 1 studies in healthy participants and in 
1 Phase 1 study in patients with WD. 
Study WTX101-101 assessed the relative exposure of an ALXN1840 uncoated capsule (UC) 
with and without co-administration of a long-acting proton-pump inhibitor (PPI) under fasted 
conditions, the former also under fed conditions. Study WTX101-102 assessed the PK of an 
ALXN1840 enteric-coated tablet under fed and fasting conditions compared with the UC 
administered with a PPI under fasted conditions. 
Total plasma molybdenum (Mo) concentrations are used as a surrogate PK measure for TTM 
as direct quantification of TTM in biological matrices is not possible due to its rapid 
conversion to molybdate in aqueous solution and the almost immediate formation of a drug-
protein TPC. 
In Study WTX101-101, based on total plasma Mo, administration of the UC + PPI under 
fasted conditions resulted in a 30% increase in exposure compared with the UC alone. 
Administration of the UC + PPI fed results in a 22% decrease in exposure compared with the 
UC + PPI fasted. The mean terminal elimination half-life (t1/2) for total Mo was essentially 


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the same for all 3 treatments, with an overall mean of approximately 51 hours or slightly over 
2 days.  
There was a decrease in the between-participant variability when the UC was administered 
with a PPI. The between-participant coefficients of variation for maximum observed 
concentration in plasma (Cmax), area under the concentration in plasma versus time curve 
(AUC) from time 0 to the last quantifiable concentration (AUC0-t), and AUC from time 0 
extrapolated to infinity (AUC0-inf) were approximately 50% lower after administration of the 
UC + PPI under fasted or fed conditions compared with the UC fasted and comparable for 
both PPI treatments.  
Study WTX101-102 evaluated the relative exposure of ALXN1840 from an enteric-coated 
tablet under fed and fasting conditions compared with the non-coated capsule (also referred 
to as UC administered with a PPI) under fasting conditions to confirm the in vivo 
performance characteristics of the enteric-coated tablet in humans, including the absorption 
profile and food effect. There was a slight decrease in the plasma total Mo after 
administration of the enteric-coated tablet fasted, compared with the UC + PPI fasted. 
Similar trends were observed with respect to Cmax, AUC0-t, and AUC0-inf. Nevertheless, 
examination of the individual participant data indicated that while a similar pattern was 
observed with some of the individual participants, the majority had a total Mo 
concentration-time profile that was comparable for the enteric-coated tablet and UC + PPI 
when both were administered under fasted conditions. However, administration of the 
enteric-coated tablet fed resulted in a 60% to 75% decrease in absorption, which was 
consistent among the majority of participants.  
There were no apparent relationships between apparent total clearance from plasma after oral 
administration (CL/F) and body size (weight, body mass index) in either Study WTX101-101 
or Study WTX101-102, suggesting that a fixed dose, rather than a dose based on body size, 
ie, mg/kg or mg/m², may be appropriate for ALXN1840.  
In the Phase 2 Study WTX101-201, preliminary results showed that, based on total Mo 
measures, exposure in patients with WD at the 30 mg dose appeared consistent with previous 
healthy participant data, although half-life estimates in this study were shorter than estimated 
in previous studies. However, plasma concentration sample collection was restricted to 
12 hours, so a full profile including the terminal decay portion was not collected as in the 
previous studies, which could lead to underestimation of half-life. Other parameters appeared 
consistent with previous data, allowing for the limited scope of the PK sample collections 
and small number of participants and variability. There was no evidence that sex, age, or 


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weight had a major impact on PK parameters of ALXN1840 (Alexion Pharmaceuticals, 
Inc. 2020).  
Further dose-exposure information is provided in Section 1.3. 
1.1.2 
ALXN1840 Safety 
ALXN1840 has been evaluated in 108 healthy participants in Phase 1 studies, 28 patients 
with WD in the Phase 2 Study WTX101-201, 108 patients with WD in the ongoing Phase 3 
Study WTX101-301 as of the cut-off date for analysis, 29 Dec 2019, and 163 patients in 
5 oncology studies. In addition, 5 patients received ALXN1840 in a named patient program 
in Canada and Sweden that closed in mid-2014. 
A review of AEs that were reported in patients treated with ALXN1840 during the Phase 2 
Study WTX101-201 and the ongoing Phase 3 Study WTX101-301 was performed to identify 
potential adverse drug reactions. In patients with WD who received multiple daily doses of 
ALXN1840, the most commonly experienced drug effects were increased alanine 
aminotransferase, aspartate aminotransferase, and gamma glutamyl transferase (without 
increased bilirubin). Increases occurred 4 to 10 weeks after daily dosing at 30 mg/day or 
higher. All were asymptomatic. Liver function tests normalized within 1 to 2 weeks of dose 
reduction or treatment interruption. Other side effects observed with ALXN1840 with 
potential significance for the participating healthy participants were thrombocytopenia, 
neutropenia, and anemia. In all cases, treated patients recovered after dose reduction. 
Rash (location non-specific) was also commonly reported in patients during Phase 2 and 3 
clinical studies. The majority of the events of rash were mild in severity and the patients 
recovered with no modification to study intervention.  
ALXN1840 administered once daily or twice daily (total daily dose 120 mg to 300 mg) to 
patients in oncology studies had an acceptable safety profile and was effective in lowering 
Cu, as evidenced by decreased plasma concentrations of potentially toxic Cu, measured as 
labile bound Cu and/or non-ceruloplasmin-bound Cu/corrected non-ceruloplasmin-bound Cu. 
The maximum tolerated dose (MTD) was 300 mg in this patient population, in which total 
body Cu was expected to be within normal limits at Baseline. Overall, ALXN1840 was 
generally well tolerated in oncology studies, and the main drug-related AEs were changes in 
hematologic parameters, fatigue, sulfur burps, and other GI symptoms. Changes in 
hematology parameters, namely anemia, leukopenia and thrombocytopenia, are a 
consequence of myelosuppression from over-decoppering. Myelosuppression is monitorable 
and has been shown to be reversible with correction of Cu deficiency. Only occasional 


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reports of liver function test abnormalities were noted (Lin 2013; Lowndes 2008). These 
findings were similar to those reported by Askari et al (Askari 2010) in patients with primary 
biliary cirrhosis in whom the most common AEs were related to symptoms of over-
decoppering with no reports of liver function test abnormalities (Alexion Pharmaceuticals, 
Inc. 2020). 
Cardiac safety events as defined by ICH E14 guidance (DHHS 2005) that have occurred in 
previous ALXN1840 studies as of 28 Dec 2019 are described in Table 1. Cardiac safety 
events included 3 participants with syncope and 1 participant with seizure. All participants 
recovered completely from the events. Single ECGs were collected as part of the healthy 
participant study with no evidence of concern. Nevertheless, no intensive cardiac monitoring 
or ECG analyses have been performed to date as part of the program. The proposed thorough 
QT (TQT) study is to evaluate the impact of ALXN-1840 on QT prolongation and other ECG 
wave form or interval changes that may place the participant at risk for a cardiac safety 
event. 
Table 1 
Adverse Events That Can Signal Potential Proarrhythmic Effects 
per ICH E14 Guidance 
 
Phase 1 
N=108 
Phase 2 
N=28 
Phase 3 
N=108 
Total Phase 2-3 
N=136 
Adverse Events 
Participant/Event 
Participant/Event 
Participant/Event 
Participant/Event 
Syncope 
1/1 
1/2 
1/1 
2/3 
Seizures 
0/0 
0/0 
1/1 
1/1 
Ventricular tachycardia 
0/0 
0/0 
0/0 
0/0 
Ventricular fibrillation 
and flutter 
0/0 
0/0 
0/0 
0/0 
Torsade de pointes 
0/0 
0/0 
0/0 
0/0 
Sudden death 
0/0 
0/0 
0/0 
0/0 
Phase 1 includes Studies WTX101-101, WTX101-102, WTX101-104, and WTX101-106; Phase 2 includes 
Study WTX101-201; Phase 3 includes Study WTX101-301. Phase 2-3 includes Studies WTX101-201 and 
WTX101-301. Participants originally enrolled in Study WTX101-201 who then entered the extension of 
Study WTX101-301 have all of their data, irrespective of which study it occurred in, presented as if it 
occurred in Study WTX101-201. 
Data cut-off: 29 Dec 2019 
Additional information regarding the safety of ALXN1840 can be found in the IB (Alexion 
Pharmaceuticals, Inc. 2020).  


Alexion Pharmaceuticals, Inc. 
ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
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1.2 
RATIONALE FOR THE STUDY 
The International Council for Harmonisation (ICH) E14 guidance, as adopted in the US Food 
and Drug Administration (FDA) Guidance for Industry, E14 Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs 
(DHHS 2005), emphasizes the need to obtain clear and robust data through “thorough” 
studies that assess the effect of new chemical entities on electrocardiogram (ECG) 
parameters. Specifically, “thorough” studies are defined as studies dedicated to evaluating a 
compound’s effect on cardiac repolarization, as measured by the corrected QT interval (QTc). 
Although many Phase 1, 2, and 3 studies may be conducted with a new compound, they 
typically utilize insufficient sample sizes, infrequent sampling of ECG data, or inadequate 
controls to overcome the variance in cardiac repolarization due to spontaneous change. 
Based on existing nonclinical and clinical data (Alexion Pharmaceuticals, Inc 2020), no QT 
interval effect is expected from treatment with ALXN1840, so only a single supratherapeutic 
dose will be tested in this 3-way crossover study. The study will consist of 3 periods with 
1 single-dose treatment administration per period of ALXN1840 120 mg, matching 
ALXN1840 placebo, or moxifloxacin 400 mg.  
The study will employ moxifloxacin as the positive control, which has been shown to result 
in reproducible QT interval prolongation and can thus verify the sensitivity of the assay for 
the study. Following single-dose administration, moxifloxacin has a time to reach maximum 
observed concentration in plasma (Tmax) between 1 and 3 hours postdose (Merck and 
Co. 2016). Holter monitoring for a period of 24 hours postdose is adequate to assess both the 
ALXN1840 (Tmax approximately 4 to 8 hours based on total Mo and plasma ultrafiltrate Mo 
[PUF Mo]) and moxifloxacin. This is also in keeping with the ICH E14 guideline that the 
TQT monitoring is carried out during the entire dosing interval, which is daily dosing in the 
clinical setting. Time points were chosen to help ensure QT interval assessment at Tmax for 
both drugs as well as additional time points to evaluate for hysteresis. A washout of 14 days 
between treatment administration is considered adequate given a half-life of the TPC of 
approximately 51 hours and a half-life of moxifloxacin of 12 hours (±1.3 hours). 
Healthy participants are most appropriate to evaluate a QT/QTc interval effect of ALXN1840 
as healthy participants are not anticipated to have underlying cardiac conduction 
abnormalities, cardiac comorbidities, concomitant medications, or other disease-specific 
abnormalities that may impact interpretation of the data. 


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
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1.3 
RATIONALE FOR DOSE SELECTION 
This study will be conducted as a single-dose study because the free and active ALXN1840 
itself has an anticipated short half-life (as part of the PUF Mo) and the primary non-reactive 
product, the TPC which is composed of TTM-Cu-protein (where the protein is believed to be 
most commonly albumin), represents a stable protein complex and therefore is not 
anticipated to impact the QT interval. Based on crystal structure of TTM-Cu isolated from 
the lysosome of LEC rats treated with TTM, the Cu-S bonds of approximately 2.28 angstrom 
between TTM-Cu crystal may be consistent with a covalent bond (George 2003); a similar 
type bond may occur between TTM and Cu in the TPC. The dissociation constant of 
TTM-Cu has been measured at 2.32 × 10-20 M, making this a very high affinity complex 
(Smirnova 2018); this is supported by failure to dissociate TTM-Cu-albumin TPC with 
trichloroacetic acid precipitation (Mills 1981). Additionally, the stability of the TPC is 
supported clinically with an improvement in neurologic status as measured by the Unified 
Wilson Disease Rating Scale Parts 2 and 3 over time despite, in some cases such as WD, an 
initial overall increase in plasma total Cu with ALXN1840 treatment (Weiss 2017). 
Therefore, only the active, free ALXN1840 component in PUF Mo is relevant, while the TPC 
is expected to behave in a similar fashion to a protein adduct or biologic and is not 
considered relevant for TQT assessment. 
Following ALXN1840 administration, the majority of the active drug moiety TTM rapidly 
binds Cu and protein to form the TPC of TTM-Cu-protein (where the protein is believed to 
be most commonly albumin) in the blood or target organ(s) and presents as such in the 
systemic circulation. If TPC is not rapidly formed, TTM spontaneously undergoes serial 
hydrolysis to form molybdate, the most common form of the nutrient Mo, and is excreted in 
the urine. Total Mo concentration has been measured as a surrogate of ALXN1840 
pharmacokinetics (PK); however, total Mo concentration cannot distinguish whether the Mo 
is protein bound (mostly as TPC), free active drug as ALXN1840, intermediate hydrolysis 
products, or molybdate which is both a hydrolysis product of TTM and may be present from 
food intake as an essential micronutrient. To better characterize the amount of 
non-TPC-bound drug and its degradation products, PUF Mo has also been measured, which 
represents the free parent drug (TTM), short-lived intermediate hydrolysis products, and 
molybdate (which may have originated from the TTM or from food intake as a 
micronutrient). While it is not feasible to separate and quantify ALXN1840 directly in the 
plasma, total Mo and PUF Mo provide surrogate measures of total Mo PK and free Mo PK 
that can be used to inform study design and dose selection. 


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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Single-dose administration of the enterically-coated ALXN1840 under fasting conditions in 
healthy participants resulted in a peak total Mo concentration at approximately 4.54 hours, 
with a half-life of approximately 51 hours. Data from the recently completed 
Study WTX101-HV-106 at the 60-mg dose have demonstrated a total Mo Tmax of 
approximately 6 hours with only up to 14% of the total Mo represented as PUF Mo, which 
also peaked at approximately 6 hours postdose. By 24 hours, PUF Mo had declined to 
approximately 3% to 5% of the total Mo, near or within the range of endogenous Mo 
concentrations as measured in participants at Baseline in the ongoing Study WTX101-301 
(mean: 1.9 ng/mL; range: 0 to 6.3 ng/mL), which suggests minimal to no accumulation of the 
free active ALXN1840 (or other free Mo hydrolysis products) when dosed daily in the 
clinical setting. ALXN1840 PK parameters in Study WTX101-HV-106 showed less than 
dose-proportional increases from 15 mg to 60 mg (4 × 15 mg) in both Japanese and 
non-Japanese subjects. These findings are consistent with the Phase 2 Study WTX101-201 in 
patients with WD. Because PUF Mo declined to approximately 3% to 5% of the total Mo by 
24 hours with minimal to no accumulation and because total Mo and the PUF Mo peaked by 
4 to 6 hours dominated largely by the TPC, a single dose is adequate for the conduct of this 
TQT study.  
There were no apparent relationships between clearance and body size (weight, body mass 
index) in Study WTX101-101, Study WTX101-102, or Study WTX101-HV-106, suggesting 
that a fixed dose, rather than a dose based on body size, ie, mg/kg or mg/m², may be 
appropriate for ALXN1840. Additional information regarding ALXN1840 pharmacology can 
be found in the IB (Alexion Pharmaceuticals, Inc 2020). 
A single dose of ALXN1840 120 mg is a reasonable dose to be tested in healthy participants 
based on existing safety data from healthy participants following a single-dose administration 
of ALXN1840 60 mg and existing patient experience to date in oncology with the MTD of 
bis-choline TTM at 300 mg/day. 
Single dose administration of ALXN1840 60 mg has been shown to have an adequate safety 
profile and be well tolerated in healthy male and female participants in Phase 1 
bioavailability studies, Study WTX101-101 and Study WTX101-102. In addition, 
preliminary data from Study WTX101-HV-106 have also shown ALXN1840 to be well 
tolerated in Japanese and non-Japanese healthy male and female participants at a single dose 
of 15 mg/day or 60 mg/day. No MTD has been identified in healthy participants. 
In the Phase 2 Study WTX101-201 conducted in patients with WD, the ALXN1840 doses 
were 15 mg/day for 6 patients (21%), 30 mg/day for 13 patients (46%), and 60 mg/day for 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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9 patients (32%) at Week 24 when the primary endpoint assessment was conducted, or at the 
last dose received for patients with early discontinuation. The 15 mg/day to 60 mg/day dose 
range has been demonstrated to be efficacious with a favorable safety profile in treating 
patients with WD (Weiss 2017). Based on these Phase 2 study results, the ongoing Phase 3 
Study WTX101-301 in patients with WD has been testing the efficacy and safety of 
ALXN1840 at a dose titration range from 15 mg/day to 60 mg/day. 
As indicated in Section 1.1.2, ALXN1840 administered once daily or twice daily (total daily 
dose 120 mg to 300 mg) to patients in oncology studies had an acceptable safety profile, with 
an MTD of 300 mg/day. 
In summary, ALXN1840 (bis-choline tetrathiomolybdate) has been well tolerated in 
repeat-dose studies up to 300 mg/day in oncology patients and has been well tolerated with 
an acceptable safety profile following single-dose administration up to 60 mg/day in healthy 
participants. Therefore, 120 mg is considered a reasonable single supratherapeutic dose to be 
tested in this TQT study in healthy participants. A single dose of 120 mg was chosen as it 
represents a 4-fold increase over the anticipated therapeutic dose of 30 mg and represents a 
2-fold increase over the highest dose being tested in Study WTX101-301 in patients with 
WD. Given a lack of accumulation and approximate dose proportionality for PUF Mo 
following single-dose administration within the clinically relevant range of 15 mg to 60 mg 
(Study WTX101-HV-106), the dose of 120 mg is considered sufficient to test the effects of 
supratherapeutic doses of ALXN1840 on potential QT prolongation.  
To mitigate risk against any safety concerns as this is the highest single dose tested in healthy 
participants to date, only participants with normal Cu and ceruloplasmin levels will be 
enrolled in the study. Additionally, the study will be conducted in a minimum of 2 groups 
with the first group (Group 1) including no more than 18 participants representing 
6 participants per treatment. After review of first period (Period 1, Day 5) safety data from 
Group 1, the remaining group(s) will be initiated. Participants will also undergo safety 
assessments including safety laboratory tests at 24 and 96 hours postdose as well as vital sign 
and safety ECG assessments through Day 5. Participants will remain in-house until Day 5 
safety assessments have been completed and reviewed by the Investigator to ensure 
participants can be safely discharged. 
The positive-control group will receive moxifloxacin 400 mg, a commercially available 
fluoroquinolone antimicrobial indicated for the treatment of adults (≥18 years of age) with 
various infections caused by susceptible bacterial strains. Moxifloxacin at this dose is known 
to prolong the QT/QTc interval, with an expected change from Baseline in placebo-corrected 


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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Page 28 
QTc of 5 to 10 ms using a time-averaged analysis, or 10 to 15 ms using a time-matched 
analysis (Merck and Co. 2016). 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the effect of a supratherapeutic dose of 
ALXN1840 on the heart rate (HR)-corrected QT interval with the intent to exclude a 10 ms 
effect. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are: 
• 
To demonstrate assay sensitivity of the study to detect an effect on the mean QT/QTc 
interval of approximately 5 ms using moxifloxacin as a positive control. 
• 
To evaluate the safety and tolerability of a single oral supratherapeutic dose of 
ALXN1840 in healthy participants. 
• 
To assess the PK of ALXN1840 following administration of a single oral 
supratherapeutic dose in healthy participants. 
• 
To evaluate the effects of a single oral supratherapeutic dose of ALXN1840 on HR, PR 
and QRS intervals, treatment-emergent T-wave morphology abnormalities, and 
appearance of U-waves. 
2.3 
EXPLORATORY OBJECTIVE 
The exploratory objective of this study is to evaluate the effects of plasma total Mo and PUF 
Mo (as surrogate measures of ALXN1840 PK) concentrations on QT/QTc. 
3. 
STUDY DESIGN 
This is a randomized, 3-treatment, 3-period, 6-sequence, crossover, placebo- and 
active-controlled, double-blind for ALXN1840, open-label for moxifloxacin, in healthy adult 
participants. Moxifloxacin will be used as the active control. 
Approximately 54 participants will be randomized to ensure there will be 45 evaluable 
participants with data from all treatment periods. To ensure sequences are balanced within 


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
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sex, participant randomization will be stratified by sex. Study intervention will be given in 
randomized sequences: ABC, ACB, BAC, BCA, CAB, and CBA, with each intervention 
administered with 240 mL of water following an overnight fast of at least 10 hours. No food 
will be allowed for at least 4 hours postdose. Water can be allowed as desired except for 
1 hour before and after drug administration: 
• 
Treatment A: A single oral dose of ALXN1840 120 mg administered as 15-mg 
enteric-coated tablets (supratherapeutic dose) 
• 
Treatment B: A single oral dose of enteric-coated placebo tablets matching ALXN1840 
• 
Treatment C: A single oral dose of moxifloxacin 400 mg tablet 
Cardiodynamic assessment will be performed for approximately 25 hours on Day –1 of 
Treatment Period 1 and Day 1 to Day 2 of each treatment period. Blood samples for PK will 
be collected predose and at specified times up to 96 hours after the Day 1 dose in each 
treatment period. 
Twelve-lead ECGs will be extracted from a continuous (Holter) recording by the central 
laboratory. To support high quality data for extraction, 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. Blood for plasma PK will be collected as close as possible to nominal 
time but after completion of ECG extraction period with actual times for blood sample 
collections recorded. 
Participants will be domiciled in the clinic for 7 days in Treatment Period 1 and for 6 days in 
Treatment Periods 2 and 3, starting on Day –2 for Treatment Period 1 and on the day before 
dosing (Day –1) for Treatment Periods 2 and 3, until safety procedures have been completed 
and reviewed on Day 5. There will be a washout of at least 14 days between dose 
administration in each period. 
All participants (including participants who terminate the study early) will return to the study 
site 14 days (±2 days) after the last administration of study intervention for follow-up 
procedures and to determine if any AE has occurred since the last study visit. 
Duration of participation for each participant from the Screening Visit to the End-of-Study 
(EOS) Visit will be approximately 70 days. This includes up to 29 days for the Screening 
Period, study intervention administration on Day 1 of each treatment period, a minimum of a 
14-day washout between study intervention administration in each treatment period, and 
14 days (±2 days) for the EOS Visit.  


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3.1 
SCHEDULE OF EVENTS 
Phase Screening 
Same Schedule for Treatment Periods 1, 2, and 3 
EOS 
 
Day –29 to –2 
Check-in 
(Day -2 for 
Period 1; Day -1 
for Periods 2 
and 3 
1 
2 
3 
4 
5 15 ±2 
–2 
–1 
Procedure(a) 
Hours 
– 
– 
– 
-0.75 -0.5 -0.25 
0 
0.5 
1 
2 
3 
4 
5 
6 
7 
8 
10 12 24 48 72 96 
– 
Admission to clinic(b) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic(c) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Outpatient visit(d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history(e) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology(f) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH(g) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum copper and 
ceruloplasmin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, and BMI(h) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical examination(i) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital sign measurements(j) 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
12-lead safety ECG(k) 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
Clinical laboratory testing(l) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Urinalysis 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug/alcohol/cotinine 
screen(m) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test(n) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization (Period 1 
only) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
administration(o)  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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12-lead Holter ECG(p) 
 
 
X 
X 
X 
XErro
r! 
Referen
ce 
source 
not 
found. 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PK blood sample(r) 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Fasting period(s) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Non-fasting period(s) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events(t) 
X 
Nonpharmacologic therapies 
and procedures 
X 
Prior/concomitant 
medications 
X 
Abbreviations: AEs, adverse events; BMI, body mass index; ECG, electrocardiogram; EOS, end of study; FSH, follicle-stimulating hormone; PK, pharmacokinetic. 
Notes: 
(a) When procedures overlap or occur at the same time point, all blood draws should follow vital signs or ECGs, and PK sampling should be timed to occur last and as 
close to the scheduled time window as possible. 
(b) Participants will be asked to arrive at the study site on Day –2 of Treatment Period 1 and on the day before the start of dosing (Day –1) of Treatment Periods 2 and 3. 
The assessments scheduled for Day –2 of Treatment Period 1 will not be repeated on Day –1 of Treatment Period 1. 
(c) Discharge from the study site will occur after the 96-hour PK samples and after completion and review by the Investigator of all 96-hour safety assessments 
(including safety laboratory test results) on Day 5 of each study period. There will be a washout of at least 14 days between dose administration in each period. 
(d) The EOS Visit will occur 14 days (±2 days) after the last dose of study intervention in Period 3 or upon early discontinuation. 
(e) A full medical history will be performed at Screening only. Any subsequent changes to health status will be assessed at each Check-in. 
(f) A complete list of serology assessments is provided in Section 6.3.2. 
(g) Females only. Further details are provided in Section 6.3.2. 
(h) Height and weight will be measured and BMI calculated at Screening only. Only weight will be measured at Check-in and EOS. 
(i) A full physical examination will be performed at Screening. A brief physical examination will be performed at Check-in and EOS. Further details are provided in 
Section 6.3.5. 
(j) Predose vital signs on Day 1 may be obtained up to 1.5 hours before dosing. Further details on vital sign measurements are provided in Section 6.3.3. 
(k) Predose ECG on Day 1 may be obtained up to 1.5 hours before dosing. Further details on safety ECG recordings are provided in Section 6.3.4. 
(l) Further details on clinical laboratory assessments, including a complete list of assessments, are provided in Section 6.3.2. 
(m) Further details on drug/alcohol/cotinine screening are provided in Section 6.3.2.  
(n) Women only.  
(o) The time of study intervention (ALXN1840, placebo, or moxifloxacin) dosing will be called “0” hour in each period. Further dosing details are provided in 
Section 5.1. 


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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(p) Continuous 12-lead Holter ECG will be performed on Day -1 of Treatment Period 1 only to record the baseline ECG, which will allow extraction of ECG recordings 
that match the time points of Day 1 of Periods 1, 2 and 3. Further details on Holter ECG monitoring are provided in Section 6.1.1. On Day -1, participants shall 
follow the Day 1 supine positioning schedule. Participants shall assume supine positioning starting at least 15 minutes before the Day 1 timepoints for ECG 
extraction and continue to remain in the supine position until 5 minutes after the timepoint.  
(q)  The –0.25-hour predose ECG time point of Day 1, Treatment Period 1 will be used as the 24-hour ECG time point of Day -1, Treatment Period 1. 
(r) Predose samples on Day 1 may be obtained up to 1.5 hours before dosing. Further details on the collection of blood samples for PK analysis are provided in 
Section 6.2.1. 
(s) Further details on fasting and nonfasting periods are provided in Section 5.1. 
(t) Further details on collection and reporting of AEs are provided in Section 6.3.1 and Appendix 3. 


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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4. 
STUDY POPULATION 
Approximately 54 healthy male and female participants will be enrolled at 1 center in the 
United States. 
4.1 
INCLUSION CRITERIA 
Each participant must meet all of the following criteria to be enrolled in this study: 
 Participant is a healthy adult male or female, 18 to 50 years of age, inclusive, at 
Screening. 
 Participant is a continuous nonsmoker and or an individual who has not used tobacco or 
nicotine-containing products (eg, electronic vapor cigarettes, cigarettes, cigars, chewing 
tobacco, snuff, nicotine gum, nicotine patches) for at least 3 months prior to the first dose 
of study intervention and for the duration of the study. A cotinine test performed during 
Screening and Check-in must be consistent with continuous nonsmoking status. 
 Participant must weigh at least 60 kg for males or 52 kg for females and have a body 
mass index ≥18.0 and ≤30.0 kg/m2 at Screening. 
 Participant must have a medical assessment with no clinically significant or relevant 
abnormalities as determined by medical history, physical examination, vital signs, 
12-lead ECG, and clinical laboratory evaluation (hematology, serum chemistry, 
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. 
 Female participants of nonchildbearing potential must have undergone 1 of the following 
sterilization procedures and have official documentation of these occurring more than 
6 weeks prior to the first dose of study intervention: 
 Hysteroscopic sterilization;  
 Bilateral tubal occlusion, including Essure®; 
 Bilateral tubal ligation or bilateral salpingectomy; 
 Hysterectomy; 
 Bilateral oophorectomy; 


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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or be postmenopausal with amenorrhea for at least 1 year prior to the first dose of study 
intervention and have serum follicle-stimulating hormone levels consistent with 
postmenopausal status. 
 Female participants or female partners of male participants of childbearing potential 
(including breastfeeding females), if heterosexually active, must use highly effective 
contraception starting at least 6 weeks before the first dose of study intervention and 
continuing for at least 3 months after the end of systemic exposure of the study 
intervention. Female participants must not donate ova for at least 3 months after the end 
of systemic exposure of the study intervention. Highly effective contraceptive methods 
for females are as follows:  
a. Progestogen-only hormonal contraception associated with inhibition of ovulation as 
follows:  
i. Oral  
ii. Injectable  
iii. Implantable  
b. Intrauterine device 
c. Intrauterine hormone-releasing system 
d. Male partner vasectomized (with documented evidence of azoospermia if possible) 
e. Abstinence (note: 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 interventions. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical study and the preferred and 
usual lifestyle of the participant).  
 Male participants, if heterosexually active and 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. Male participants 
must not donate sperm for at least 3 months after the end of systemic exposure of the 
study intervention.  


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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Female spouses or partners of male participants who are of childbearing potential must 
use highly effective contraception as previously defined, starting at least 6 weeks before 
(the male participant’s) first dose of study intervention and continuing until at least 3 
months after the end of their male partner’s systemic exposure to the study intervention.  
For male participants who have had a vasectomy (with documented evidence of 
azoospermia if possible) and agree to use a male condom for the stated time period, no 
additional contraceptive method is required by their female partner. Male condom is 
required even with documented medical assessment of surgical success of a vasectomy. 
 Participant has no clinically significant history or presence of ECG findings as judged by 
the Investigator at Screening and Check-in, including each criterion as follows: 
a. Normal sinus rhythm (HR between 45 beats per minute [bpm] and 100 bpm 
inclusive) 
b. QT interval corrected for HR using Fridericia’s formula (QTcF) ≤ 450 ms 
c. QRS interval ≤ 110 ms; and confirmed by manual over read if > 110 ms 
d. 120 ms ≤ PR interval ≤ 220 ms 
4.2 
EXCLUSION CRITERIA 
Participants meeting any of the following criteria will be excluded from the study: 
 Participant has a significant history of or current cardiovascular, respiratory, hepatic, 
renal, GI, endocrine, hematological, psychiatric, or neurologic disorders. 
 Participant has a history of gastric bypass, other surgical procedure, or medical condition 
that may significantly alter absorption, metabolism, or excretion of drugs. 
 Participant has had lymphoma, leukemia, or any malignancy within the past 5 years, 
except for basal cell or squamous epithelial carcinomas of the skin that have been 
resected with no evidence of metastatic disease for 3 years; or has a history of breast 
cancer within the past 10 years. 
 Participant has abnormal blood pressure, defined as a supine blood pressure 
<90/50 mm Hg or >140/90 mm Hg at Screening and predose vital signs; if either systolic 
or diastolic components of blood pressure meet these criteria, then the participant must be 


Alexion Pharmaceuticals, Inc. 
ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
Page 36 
excluded. Blood pressure should be taken after a minimum of 5 minutes in the supine 
position. 
 Participant has serum potassium, calcium, or magnesium levels outside the normal range 
at Screening and/or Check-in, confirmed by repeat. 
 Participant has serum Cu and/or ceruloplasmin values below the lower limit of normal at 
Screening. 
 Female participant has hemoglobin <10.8 g/dL and male participant has hemoglobin 
<12.5 g/dL at Screening or Check-in. 
 Participant has history of alcoholism or history of regular alcohol consumption within 
24 months prior to the study, defined as an average weekly intake of >7 units. One unit is 
equivalent to 1 pint of beer, 1 glass of wine, or 1 measure (single shot) of spirits. 
 Participant has clinically significant multiple or severe drug allergies, food allergies, or 
allergies to study intervention, this class of drug, its derivatives, or to medical products 
that may be used in the study (eg, allergy to ALXN1840, any sulfur containing drugs, 
moxifloxacin, fluoroquinolone antibiotics, latex, band-aids, adhesive dressing, medical 
tape). 
 Participant has alanine aminotransferase, aspartate aminotransferase, serum creatinine, or 
total bilirubin greater than upper limit of normal (ULN) for the testing laboratory. 
Participant’s with confirmed Gilbert’s syndrome may be included with total bilirubin 
>ULN if the participant has a measured direct bilirubin <ULN. 
 Participant has used any prescribed or over-the-counter medication (including dietary 
supplements, herbal remedies, and medications known to prolong the QTc interval) 
without the approval of the Investigator or Alexion within 14 days (or 5 half-lives, 
whichever is longer) before the first dose of study intervention and during the study.  
 Female participant is pregnant, as evidenced by a positive serum pregnancy test at 
screening or check-in, or lactating. 
 Participant has positive urine drug or alcohol results at Screening or Check-in. 
 Participant has presence of hepatitis B surface antigen 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 


Alexion Pharmaceuticals, Inc. 
ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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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. 
 Participant has positive syphilis or human immunodeficiency virus (HIV)-1 and HIV-2 
antigen/antibody immunoassay at Screening. 
 Participant has been on a diet incompatible with the on-study diet (including an extreme 
diet which resulted in a significant weight change for any reason), in the opinion of the 
Investigator, within the 29 days prior to the first dose of study intervention, and 
throughout the study. 
 Participant has donated blood or has had a significant blood loss of more than 500 mL 
within 56 days prior to the first dose of study intervention. 
 Participant has donated plasma within 7 days prior to the first dose of study intervention. 
 Participant is currently enrolled or has had past participation (within the last 30 days 
before signing of consent, 5 half-lives of the study intervention, or twice the duration of 
the biological effect of the study intervention [whichever is longer]) in this or any other 
clinical study involving an investigational study intervention or any other type of medical 
research. 
 Participant has participated in a previous clinical study where the participant received 
ALXN1840. 
 Participant has history or presence of: 
a. Hypokalemia, in the opinion of the Investigator 
b. Risk factors for torsades de pointes (eg, heart failure, cardiomyopathy, or family 
history of long QT syndrome) 
c. Sick sinus syndrome, second- or third-degree atrioventricular block, myocardial 
infarction, pulmonary congestion, cardiac arrhythmia, prolonged QT interval, or 
conduction abnormalities 
d. Repeated or frequent syncope or vasovagal episodes 
e. Hypertension, angina, bradycardia (if assessed as clinically significant by the 
Investigator), or severe peripheral arterial circulatory disorders 


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4.3 
OTHER SCREENING CONSIDERATIONS 
• 
Participants must be willing to remain at the study site from Day –2 through Day 5 of 
Treatment Period 1 and Day –1 through Day 5 in Treatment Periods 2 and 3. 
• 
Participants must refrain from strenuous activity or contact sports from 24 hours before 
the first dose of study intervention through the end of the study. 
• 
Participant must refrain from ingesting grapefruit or grapefruit juice, pomegranate or 
pomegranate juice, pomelo fruit or pomelo juice, alcohol, or xanthine-containing 
products (eg, tea, coffee, chocolate, cola) within 72 hours before the first dose of study 
intervention through the end of the study. 
4.4 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY 
4.4.1 
Reasons for Withdrawal 
Participants can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment. 
The Investigator may withdraw a participant from the study if the participant: 
1. Is noncompliant with the protocol; 
2. Experiences a serious AE (SAE) or intolerable AE(s) that in the investigator’s opinion 
requires withdrawal from the study; 
3. Has laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from Baseline values; 
4. Has postdose safety ECG result (confirmed by repeat within 1 hour) that reveals a new 
QTc duration >500 ms or an increase from Baseline of >60 ms; 
5. Develops, during the course of the study, symptoms or conditions listed in the exclusion 
criteria; 
6. Requires a medication prohibited by the protocol; or 
7. Requests an early discontinuation for any reason. 
The Investigator can also withdraw a participant upon the request of Alexion, or if Alexion 
terminates the study. Upon occurrence of an SAE or intolerable AE, the Investigator will 


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confer with Alexion. If a participant is discontinued because of an AE, the event will be 
followed until it is resolved, stable, or judged by the Investigator to be not clinically 
significant. 
4.4.2 
Handling of Withdrawals 
Participants are free to withdraw from the study at any time upon request. Participation in the 
study may be stopped at any time at the discretion of the Investigator or at the request of 
Alexion. 
When a participant withdraws from the study, the reason(s) for withdrawal shall be recorded 
by the Investigator on the relevant page of the electronic case report form (eCRF). Whenever 
possible, any participant who withdraws from the study prematurely will undergo all EOS 
assessments. Any participant who fails to return for final assessments will be contacted by 
the study site in an attempt to have them comply with the protocol. The status of participants 
who fail to complete final assessments will be documented in the eCRF. 
4.4.3 
Replacements 
At the discretion of Alexion, and in consultation with the Investigator, any participant who 
withdraws before completing the study may be replaced to retain the target of 45 evaluable 
participants. Any replacement participant will be assigned to receive the same treatment as 
the participant he or she is replacing. 
5. 
STUDY INTERVENTION 
5.1 
STUDY INTERVENTION ADMINISTERED 
On Day 1 of each period, participants will receive 1 of the following study interventions 
according to the randomization schedule: 
• 
Treatment A: A single oral dose of ALXN1840 120 mg administered as eight 15-mg 
enteric-coated tablets (supratherapeutic dose)  
• 
Treatment B: A single oral dose of 8 enteric-coated placebo matching tablets of 
ALXN1840 
• 
Treatment C: A single oral dose of moxifloxacin 400 mg tablet 


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The possible sequences are as follows:  
 
Period 1 
Period 2 
Period 3 
Sequence 1 
A 
B 
C 
Sequence 2 
A 
C 
B 
Sequence 3 
B 
A 
C 
Sequence 4 
B 
C 
A 
Sequence 5 
C 
A 
B 
Sequence 6 
C 
B 
A 
 
All doses of study intervention will be administered with 240 mL of room temperature water 
under fasting conditions. Water is permitted as desired except for the period 1 hour before 
and 1 hour after administration of study intervention. During fasting periods, participants will 
fast overnight (nothing to eat or drink except water) for at least 10 hours before each study 
intervention administration. Participants will remain fasting and will maintain an upright 
(seated or standing) position for 4 hours after dosing with study intervention (not including 
the time when the participant is required to be supine for Holter ECG extractions). During 
nonfasting periods, participants should receive standardized meals scheduled at the same 
time in each period of the study. 
5.2 
STUDY INTERVENTION 
The study interventions that will be used are as follows: 
Product 
Supplied Formulation 
ALXN1840 
15-mg enteric-coated tablet 
Placebo 
Enteric-coated tablet 
Moxifloxacin (positive control) 
400-mg tablet 
 
ALXN1840 tablets will be supplied by Alexion. The ALXN1840 tablet contains the 
following inactive excipients: tribasic calcium phosphate, National Formulary (NF), 
anhydrous sodium carbonate NF, sodium starch glycolate NF, magnesium stearate NF, 
Opadry 03K19229 clear, and acryl-EZE.  
Placebo tablets will be supplied by Alexion. The placebo tablet contains only inactive 
excipients.  
Moxifloxacin (generic formulation, Torrent Pharmaceuticals Limited) will be sourced by the 
PPD pharmacy. 
Further information on ALXN1840 can be found in the IB (Alexion Pharmaceuticals, 
Inc. 2020). 


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5.2.1 
Study Intervention Packaging and Storage 
Alexion Pharmaceuticals, Inc. will provide the Investigator and study site with adequate 
quantities of ALXN1840. The study site will provide moxifloxacin in its 
commercially-available form. An unblinded study site pharmacist will prepare the study 
interventions for each participant according to the schedule of events (Section 3.1). Detailed 
instructions for the preparation of study interventions will be provided in a separate 
pharmacy manual. 
All study interventions must be stored according to the labeled instructions in a secure 
cabinet or room with access restricted to necessary clinic personnel. The study site will be 
required to keep a temperature log to establish a record of compliance with storage 
conditions. 
5.2.2 
Study Intervention Accountability 
The Investigator will maintain accurate records of receipt of all study interventions, including 
dates of receipt. Accurate records will be kept regarding when and how much study 
intervention is dispensed and used by each participant in the study. Reasons for departure 
from the expected dispensing regimen must also be recorded. At the completion of the study, 
and to satisfy regulatory requirements regarding drug accountability, all study interventions 
will be reconciled and retained or destroyed according to applicable regulations. 
5.3 
METHOD OF ASSIGNING PARTICIPANTS TO 
TREATMENT GROUPS 
A randomization schedule will be generated containing randomization numbers (in sequential 
order), which will be assigned before the first dose of study intervention is administered on 
Day 1 of Treatment Period 1. 
After meeting all of the inclusion criteria and none of the exclusion criteria, participants will 
be randomized to 1 of the 6 pre-specified treatment sequences. To ensure that the sequences 
are balanced within sex, randomization will be stratified by sex. 
5.4 
BLINDING 
5.4.1 
Blinding Procedures 
This study will employ a double-blind study design. The ALXN1840 and matching placebo 
will be identical in appearance and will be administered in a double-blind manner. 


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Moxifloxacin, as the positive control, will not be blinded. The unblinded pharmacist will be 
responsible for dispensing the study intervention in a manner consistent with maintaining the 
blind; moxifloxacin doses will be prepared in an open-label manner. 
Access to the randomization code will be strictly controlled according to the standard 
operating procedures of PPD. The ECG core laboratory will be blinded to all study 
interventions. 
5.4.2 
Breaking the Blind 
The Medical Monitor will be responsible for maintaining the blind throughout the study. If a 
participant becomes seriously ill or pregnant during the study, the blind will be broken only if 
knowledge of the administered study intervention will affect that participant’s available 
treatment options. In the event of a medical emergency requiring identification of the study 
intervention administered to an individual participant, the Investigator will make every 
attempt to contact the Medical Monitor to explain the need for opening the code within 
24 hours of opening the code. The Investigator will be responsible for documenting the time, 
date, reason for the code break, and the names of the personnel involved. 
5.5 
TREATMENT COMPLIANCE 
All doses of the study intervention will be administered in the study site under direct 
observation of study site personnel and recorded in the eCRF. Study site personnel will 
confirm that the participant has received the entire dose of study intervention. 
The date and time of study intervention dosing will be recorded on the appropriate page of 
the eCRF. If a participant is not administered study intervention, the reason for the missed 
dose will be recorded. 
5.5.1 
Prior and Concomitant Medications 
Restrictions for prior and concomitant medications and therapies are provided in Sections 4.1 
and 4.2. Prior and concomitant medications and therapies will be coded using the World 
Health Organization Drug Dictionary. 
5.5.1.1 
Prior Medications 
Information regarding prior medications taken by the participant within the 30 days before 
signing the informed consent form (ICF) will be recorded in the participant’s eCRF. 


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5.5.1.2 
Concomitant Medications 
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 
receives during the study 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. 
If a concomitant medication is taken, except for those specified in the protocol, a joint 
decision will be made by the Investigator and Alexion to continue or discontinue the 
participant based on the time the medication was administered, its pharmacology and PK, 
and whether the use of the medication will compromise the safety of the participant or the 
interpretation of the data. The Investigator is responsible for ensuring that details regarding 
the medication are adequately recorded in the eCRF. 
6. 
STUDY PROCEDURES 
Before performing any study procedures, all potential participants will sign an ICF as 
outlined in Section 9.2.2.3. Participants will undergo study procedures at the time points 
specified in the schedule of events (Section 3.1). 
The total amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. 
6.1 
CARDIODYNAMIC ASSESSMENTS AND ENDPOINTS 
6.1.1 
Continuous Holter Electrocardiograms 
Twelve-lead ECGs will be extracted from approximately 25-hour continuous (Holter) 
recordings on Day –1 of Treatment Period 1 and Days 1 and 2 in each treatment period. 
Participants should be resting supinely for at least 15 minutes before and 5 minutes after each 
time point for ECG extraction, which should precede blood samples. The actual times of 
dosing, supine rest, and PK sampling will be communicated to the central ECG laboratory 
(ERT, Rochester, NY) by the site. 


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Electrocardiograms will be extracted by a central ECG laboratory (ERT, Rochester, NY) 
from the continuous Holter recording of Day 1 of the Treatment Periods 1, 2, and 3 at the 
following 15 (3 predose and 12 postdose) time points: predose at –45, –30, and –15 minutes; 
and postdose at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours. For HR-corrected QTc 
calculation in case of a substantial HR-effect due to ALXN1840, ECG extraction from the 
Holter recording of Day -1 of Treatment Period 1 will include continuous ECG extraction for 
optimized QT interval (QTcI) calculation, and if needed, ECG extraction at the 15 timepoints 
that precisely match the extraction timepoints for Day 1 of Periods 1, 2 and 3 for individual 
QT interval (QTcS) calculation. The following ECG parameters will be measured and 
calculated: HR, PR interval, QTcF, QRS interval, treatment-emergent T-wave morphology 
abnormalities, and appearance of U-waves. 
All ECG data will be collected using Welch Allyn (Mortara) Surveyor Central. The raw data 
from the Surveyor system will be saved to the archive database (hScribe). The data will be 
burned onto a hard drive and sent to ERT. The ECGs to be used in the analyses will be 
selected by pre-determined time points, as defined in the schedule of events (Section 3.1), 
and will be read centrally by ERT. 
The following principles will be followed in ERT’s core laboratory: 
• ECG analysts will be blinded to the participant, visit, and treatment allocation. 
• Baseline and on-treatment ECGs for a particular participant will be over-read on the same 
lead and will be analyzed by the same reader. 
• The primary analysis lead will be lead II. If lead II is not analyzable, then the primary 
lead of analysis will be changed to another lead for the entire participant data set. 
6.1.1.1 
Thorough QT Plus Electrocardiogram Technique 
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the “TQT Plus method”, a computer-assisted and statistical process utilized 
by ERT. The method enables the extraction of ECGs with the lowest HR variability and noise 
within the protocol-specified extraction time window (eg, the HR and QT changes from beat 
to beat in the range of <10%). At each protocol-specified time point, 10 ECG replicates will 
be extracted from a 5-minute ECG window (typically, the last 5 minutes of the 15-minute 
period when the participant is maintained in a supine or semi-recumbent quiet position). 


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6.1.1.2 
Expert-Precision QT Analysis 
Expert-precision QT analysis will be performed on all analyzable (non-artifact) beats in the 
10 ECG replicates. Statistical quality control procedures are used to review and assess all 
beats and identify “high” and “low” confidence beats using several criteria, including: 
• 
QT or QTc values exceeding or below certain thresholds (biologically unlikely) 
• 
RR values exceeding or below certain thresholds (biologically unlikely) 
• 
Rapid changes in QT, QTc, or RR from beat to beat 
Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” will be performed using the COMPAS software. 
All low-confidence beats will be reviewed manually and adjudicated using pass-fail criteria. 
The final quality control assessment will be performed by a cardiologist. The beats found 
acceptable by manual review will be included in the analysis. The median QT, QTc, and RR 
value from each extracted replicate will be calculated, and the mean of all available medians 
from a nominal time point will be used as the participant’s reportable value at that time point. 
Categorical T-wave morphology analysis and the measurement of PR and QRS intervals will 
be performed manually in 3 of the 10 ECG replicates at each time point. Each fiducial point 
(onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) will be 
electronically marked. 
For T-wave morphology and U-wave presence, treatment-emergent changes will be assessed, 
ie, changes not present at Baseline. For each category of T-wave morphology and of 
U-waves, the category will be deemed as present if it is observed in any replicates at the time 
point. For Baseline, the category will be deemed as present if it is observed in any replicates 
from all time points that constitute Baseline. The T-wave morphology categories are 
described in Table 2. 
Table 2: 
Categories for T-Wave Morphology and U-Wave Presence 
(Assessed Manually) 
Category 
Description 
Normal T-wave 
Any positive T-wave not meeting any criterion below 
Flat T-wave 
T amplitude <1 mm (either positive or negative), including a flat 
isoelectric line 
Notched T-wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on ascending or 
descending arm of the positive T-wave 


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Category 
Description 
Biphasic 
T-wave that contains a second component with an opposite phase that is 
at least 0.1 mV deep (both positive/negative and negative/positive and 
polyphasic T-waves included) 
Normal T-wave (-) 
T amplitude that is negative, without biphasic T-wave or notches 
Notched T-wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on descending or 
ascending arm of the negative T-wave 
U-waves 
Presence of abnormal U-waves 
 
6.1.2 
Cardiodynamic Electrocardiogram Analysis 
The primary endpoint is placebo-corrected change from Baseline QTcF (ΔΔQTcF) for 
ALXN1840 using the by-time point analysis. The secondary endpoints are the ΔΔQTcF for 
moxifloxacin; the change from Baseline in HR, QTcF, PR, QRS (ΔHR, ΔQTcF, ΔPR and 
ΔQRS); the placebo-corrected change from Baseline HR, PR, and QRS (ΔΔHR, ΔΔPR and 
ΔΔQRS); categorical outliers for QTcF, HR, PR, and QRS; and the frequency of 
treatment-emergent changes of T-wave morphology and U-wave presence. The exploratory 
endpoint is the ΔΔQTcF for ALXN1840 using the concentration-QTc analysis by 
concentrations of total Mo or PUF Mo (as surrogate measures of ALXN1840 PK) in plasma. 
For all continuous ECG parameters from each period, Baseline is defined as the average of 
the measured ECG intervals from the 3 predose time points (−45, −30, and −15 minutes 
before dosing) on Day 1 for the respective period. For T-wave morphology and U-wave 
presence, Baseline includes findings observed in any replicates from the 3 predose time 
points (−45, −30, and −15 minutes) on Day 1 in each period. 
To enable HR-corrected evaluation of QTc via methods such as QTcI and/or QTcS 
calculation, if justified by a substantial change in HR due to ALXN1840, participants will 
undergo 12-lead Holter ECG monitoring on Day -1 of Treatment Period 1. 
6.2 
PHARMACOKINETIC ASSESSMENTS AND ENDPOINTS 
Blood samples for PK analysis of total Mo and PUF Mo (as surrogate measures of 
ALXN1840 PK) will be collected at the following time points: within 1.5 hour before dosing 
and postdose at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 96 hours in each period. Only 
samples collected predose and after ALXN1840 administration will be analyzed for plasma 
total Mo and PUF Mo. Samples collected predose and after placebo or moxifloxacin 
administration will be saved for analysis, if needed. 


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The following plasma PK parameters will be calculated as endpoints for total Mo and 
PUF Mo, using noncompartmental methods with Phoenix® WinNonlin® (Certara USA Inc., 
Princeton, New Jersey) Version 8.0 or higher or SAS® (SAS® Institute Inc., Cary, North 
Carolina) Version 9.4 or higher, as applicable. Calculations will be based on the actual 
sampling times elapsed from the reference dosing time in the period as recorded during the 
study. 
• 
Time delay between the time of dosing and time of appearance of Mo concentration in 
plasma (Tlag) 
• 
Maximum observed concentration in plasma (Cmax) 
• 
Time to reach maximum observed concentration in plasma (Tmax) 
• 
Area under the concentration in plasma versus time curve (AUC) from time 0 to the last 
quantifiable concentration (AUC0-t) 
• 
AUC from time 0 to 96 hours postdose (AUC0-96) 
• 
AUC from time 0 extrapolated to infinity (AUC0-inf) 
• 
Apparent terminal-phase elimination rate constant (λz) 
• 
Terminal elimination half-life (t1/2) 
• 
Apparent total clearance from plasma after oral administration of ALXN1840 (CL/F) 
• 
Apparent volume of distribution during the terminal phase (Vz/F) 
Additional PK parameters may be calculated if deemed appropriate. 
6.2.1 
Pharmacokinetic and Pharmacodynamic Sample Collection 
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. Details for the collection, processing, storage, and shipping of PK 
samples will be provided to the study site separately. 


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6.2.2 
Pharmacokinetic and Pharmacodynamic Sample Analyses 
Pharmacokinetic samples will be analyzed using validated inductively coupled plasma-mass 
spectrometry (ICP-MS) methods for total Mo and PUF Mo in human plasma. Assay results 
and validation details will be provided in a separate bioanalytical report. 
Pharmacokinetic samples may be used for the quantification of pharmacodynamic (PD) 
endpoints such as total Cu, PUF Cu, labile bound Cu, ceruloplasmin, and ceruloplasmin-
bound Cu. 
6.3 
SAFETY ASSESSMENTS AND ENDPOINTS 
Safety and tolerability will be assessed by the following endpoints: monitoring and recording 
of AEs, clinical laboratory test results (hematology, serum chemistry, and urinalysis), vital 
sign measurements, 12-lead safety ECG results, and physical examination findings. 
For all safety assessments, the Investigator will determine whether results are clinically 
significant, which is defined as any variation in a result that has medical relevance and may 
result in an alteration in medical care (eg, active observation, diagnostic measures, or 
therapeutic measures). If clinical significance is noted, the result and reason for significance 
will be documented and an AE will be reported on the AE page of the participant’s eCRF. 
The Investigator will monitor the participant until the result has reached the reference range 
or the result at Screening, or until the Investigator determines that follow-up is no longer 
medically necessary. 
6.3.1 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 9.3. 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 intervention(s) (see 
Section 4.4). Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs 
are outlined in Appendix 3. 


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6.3.1.1 
Time Period and Frequency for Collecting AE and SAE 
Information 
Adverse events will be assessed from the time of signing the informed consent until EOS and 
should be followed until they are resolved, stable, or judged by the Investigator to be not 
clinically significant. 
All SAEs will be recorded and reported to Alexion or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 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 the conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he or she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must 
promptly notify Alexion. 
6.3.1.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. Care 
will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
6.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits or contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up. Further 
information on follow-up procedures is provided in Appendix 3. 
6.3.1.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
• 
Prompt notification by the Investigator to Alexion of a 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. 


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• 
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), 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 a 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, if appropriate according to local 
requirements. 
6.3.1.5 
Collection of Pregnancy Information 
Pregnancy data will be collected during this study for all female participants and female 
spouses/partners of male participants. Exposure during pregnancy (also referred to as 
exposure in utero) can be the result of either maternal exposure or transmission of drug 
product via semen following paternal exposure. If a female participant or a male participant’s 
female partner becomes pregnant from the first dose of study drug up to 3 months post the 
last dose of study drug, the Investigator must submit the Pregnancy/Breastfeeding Reporting 
and Outcome Form to Alexion Global Drug Safety (GDS) via facsimile or email within 24 
hours of awareness of the pregnancy: 
 or Fax: 
 
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. 
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. 
Pregnancy is not regarded as an AE 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 an SAE (eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, 
neonatal death, or congenital anomaly). Elective abortions without complications should not 
be reported as AEs.  
PPD
PPD


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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 the study intervention or withdraws from the study. The 
corresponding infant must be followed for 3 months postpartum. 
Any female participant who becomes pregnant while participating in the study will be 
discontinued from study intervention. 
6.3.1.5.1 
Male Participants with Partners who Become Pregnant 
• 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate 
Pregnancy/Breastfeeding Reporting and Outcome Form and submit it to Alexion within 
24 hours of learning of the partner’s pregnancy. The female partner will also be followed 
to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to Alexion. Generally, the follow-up will be no longer than 3 
months following the delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
6.3.1.5.2 
Female Participants who Become Pregnant 
• 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to Alexion within 24 hours of learning of 
a participant’s pregnancy.  
• 
The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to Alexion. Generally, follow-up will not be required for 
longer than 3 months beyond the delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure. 


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• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. A spontaneous abortion (occurring at less than 22 weeks gestational 
age) or stillbirth (occurring at greater than 22 weeks gestational age) is always considered 
to be an SAE and will be reported as such. Any poststudy pregnancy related SAE 
considered reasonably related to the study intervention by the Investigator will be 
reported to Alexion as described in Section 6.3.1.4. While the Investigator is not 
obligated to actively seek this information in former study participants, he or she may 
learn of an SAE through spontaneous reporting. 
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
6.3.2 
Clinical Laboratory Testing 
Clinical laboratory testing will occur at Screening; at Check-in (Day –2 of Treatment 
Period 1 and Day –1 of Treatment Periods 2 and 3), Day 2, and Day 5 of each period; and at 
the EOS Visit. Clinical laboratory tests will be performed by the PPD Central Laboratory. 
Blood and urine samples will be collected under fasting conditions and will be prepared 
using standard procedures. 
Repeat clinical laboratory tests may be performed at the discretion of the Investigator, if 
necessary, to evaluate inclusion and exclusion criteria or clinical laboratory abnormalities. 
The clinical laboratory that will perform the tests will provide the reference ranges for all 
clinical laboratory parameters. Abnormal clinical laboratory values will be flagged as either 
high or low (or normal or abnormal) based on the reference ranges for each laboratory 
parameter. 
The following clinical laboratory assessments will be performed: 
Hematology 
Absolute neutrophil count, total leukocytes, and leukocyte 
differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), hematocrit, hemoglobin, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, mean corpuscular 
volume, platelet count, red blood cell count, and red cell distribution 
width 
Coagulation 
Activated partial thromboplastin time, prothrombin time, and 
international normalized ratio (Screening only) 


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Serum Chemistry 
Alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bilirubin (total and direct), blood urea nitrogen, 
calcium, bicarbonate, chloride, cholesterol (total, high-density 
lipoprotein, and calculated low-density lipoprotein), creatinine, 
gamma-glutamyltransferase, globulin, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total protein, 
triglycerides, and creatine kinase 
Screening only: serum Cu and ceruloplasmin 
Urinalysis 
Appearance, bilirubin, color, glucose, ketones, leukocytes, reflex 
microscopy (performed if dipstick is positive for protein or the blood 
value is 1+ or greater; and includes bacteria, casts, crystals, epithelial 
cells, red blood cells, and white blood cells), nitrites, occult blood, 
pH, protein, specific gravity, turbidity, and urobilinogen 
Serology 
Hepatitis B surface antigen, hepatitis C virus antibody; HIV-1 and 
HIV-2 antigen/antibody immunoassay; and syphilis (Screening only) 
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. 
Other analyses 
• All participants: Urine drug screen (alcohol, amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, 
cotinine, methamphetamines, methylenedioxymethamphetamine, 
and opiates [including heroin, codeine, and oxycodone]) 
• Female participants: Follicle-stimulating hormone, serum 
pregnancy test (human chorionic gonadotropin) 
6.3.3 
Vital Sign Measurements 
Vital signs will be measured at Screening and at the following time points in each period: 
Day –1; on Day 1 within 1.5 hours prior to study intervention; and at 2, 24, 48, 72, and 
96 hours postdose; and at EOS after the participant has been in the supine position for at least 
5 minutes.  
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
body temperature.  
If vital signs are abnormal, 2 additional repeats should be performed with an average of the 
3 reported in the eCRF and to support eligibility. 


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6.3.4 
Safety Electrocardiograms 
Since an ECG recorder that stores all digital ECGs on a digital flash card performs the 
recording of ECGs for the endpoint analysis, no ECG is available for immediate assessment 
of safety at the site. Therefore, after the participant has been in the supine position for at least 
5 minutes, standard digital 12-lead safety ECGs will be recorded on site at Screening, Day -2 
of Treatment Period 1, and at the following time points in each period: Day –1; on Day 1 
within 1.5 hours before dosing (in triplicate, approximately 1 minute apart); at 4, 6, 8, 12, 24, 
and 96 hours postdose; and at EOS (single ECGs) to detect any immediate ECG effects on 
participant safety. A single repeat measurement is permitted at Screening for eligibility 
determination. 
The Mortara Eli 250c machine will be used for safety ECG collection. Measurements of the 
following intervals will be automatically measured and reported by the Mortara Eli 250c: RR 
interval, PR interval, QRS width, QT interval, and QTcF. The safety ECGs will be evaluated 
on site by the Investigator. The Investigator will document his or her assessment on the ECG; 
assessments will include comments on whether the tracings are normal or abnormal, rhythm, 
presence of arrhythmia or conduction defects, morphology, any evidence of myocardial 
infarction, or ST-segment, T-wave, and U-wave abnormalities.  
Any postdose ECG with a QTc >500 ms or an increase from Baseline of >60 ms (as defined 
by automatically measured intervals) should be confirmed by a second ECG within 1 hour. If 
results are confirmed by repeat measurement, the participant will be discontinued from the 
study (Section 4.4.1). 
6.3.5 
Physical Examinations 
A full physical examination will be performed at Screening. A brief physical examination 
will be performed at Day –1 in each period and at EOS. A full physical examination will 
include, at minimum, assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, 
heart, cardiovascular system, abdomen, lymph nodes, and musculoskeletal 
system/extremities. A brief physical examination will include, at minimum, assessment of 
skin, lungs, cardiovascular system, and abdomen (liver and spleen). Interim physical 
examinations may be performed at the discretion of the Investigator, if necessary, to evaluate 
AEs or clinical laboratory abnormalities. 


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7. 
STATISTICAL ANALYSIS PLANS 
7.1 
SAMPLE SIZE CALCULATIONS 
A sample size of approximately 54 participants was chosen to obtain 45 evaluable 
participants to complete the study. Assuming a 1-sided 5% significance level and a 
within-participant standard deviation of 8 ms for ΔQTcF for all treatment groups and a true 
mean difference of 3 ms in ΔQTcF between ALXN1840 and placebo, based on the 
calculation of the sample size for a TQT study (Zhang 2008), a sample size of 45 evaluable 
participants will provide a power of 90% to demonstrate that the upper bound of all the 
2-sided 90% CIs on ΔΔQTcF will fall below 10 ms for up to 12 postdose time points. To 
account for a drop-out rate of approximately 16%, 54 participants will be enrolled. 
Based on the calculation of the sample size for a TQT study (Zhang 2008), as the test is 
performed at 3 time points separately (1, 2, and 3 hours), a 1-sided 5% significance level 
(with adjusted 1-sided significance levels of 5%, 2.5%, and 1.67%) is used along with a 
within-participant standard deviation of 8 ms for ΔQTcF and a true effect of moxifloxacin of 
10 ms, a sample size of 45 evaluable participants will provide greater than 98% power to 
demonstrate assay sensitivity of excluding a mean difference of 5 ms in ΔQTcF between 
moxifloxacin and placebo groups. 
7.2 
ANALYSIS SETS 
The analysis populations are as follows: 
• 
The Safety Set will include all participants who receive at least 1 dose of study 
intervention (ALXN1840, moxifloxacin, or placebo) and for whom any safety data are 
available. 
• 
The QT/QTc Set will include all participants in the Safety Set with measurements at 
Baseline as well as on-treatment with at least 1 postdose time point with a valid ΔQTcF 
value. The QT/QTc Set will be used for the by-time point, assay sensitivity, and 
categorical analyses of the cardiodynamic ECG parameters. 
• 
The PK Set will include all participants who receive at least 1 dose of ALXN1840 and 
have evaluable PK data for total Mo and PUF Mo (as surrogate measures of ALXN1840 
PK) in plasma. The PK Set will be used for PK analysis. 
• 
The PK/QTc Set will include all participants who are in both the QT/QTc and PK Sets 
with at least 1 pair of postdose PK and QTcF data from the same time point as well as 


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participants in the QT/QTc Set who received placebo. The PK/QTc Set will be used for 
the exploratory concentration-QTc analysis. 
7.3 
STATISTICAL ANALYSIS 
Details of all statistical analyses will be described in a statistical analysis plan. All data 
collected will be presented in data listings. Data from participants excluded from an analysis 
population will be presented in the data listings, but not included in the calculation of 
summary statistics. 
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of participants, mean, 
median, standard deviation, minimum, and maximum). 
Baseline demographic and background variables will be summarized for all participants. The 
number of participants who enroll in the study, the number and percentage of participants in 
each analysis set, and the number and percentage of participants who complete the study will 
be presented. Frequency and percentage of participants who withdraw or discontinue from 
the study, and the reason for withdrawal or discontinuation, will also be summarized. 
7.3.1 
Cardiodynamic Analyses 
7.3.1.1 
By-Time Point Analysis (Primary Analysis) 
Cardiodynamic analyses will be based on the QT/QTc Set. The primary analysis will be 
based on by-time point analysis to evaluate the effect of ALXN1840 on the ΔΔQTcF at each 
postdosing time point (“by-time point” analysis) using the intersection union test (IUT). The 
effect of ALXN1840 on placebo-corrected change from Baseline in HR, PR, and QRS 
(ΔΔHR, ΔΔPR, and ΔΔQRS) will also be evaluated using the IUT. 
The statistical hypothesis to be tested for the primary assessment of QT prolongation for the 
ALXN1840 treatment is: 
H0: ∪{μD(i) – μP(i)} ≥10, i = 1,2,…,12 
H1: ∩{μD(i) – μP(i)} <10, i = 1,2,…,12 
where μD(i) and μP(i) are the least squares (LS) mean of ΔQTcF for ALXN1840 and placebo at 
postdose time point i, respectively. 


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The by-time point analysis for QTcF will be based on a mixed-effects model for repeated 
measures (MMRM) with change from Baseline QTcF (ΔQTcF) as the dependent variable; 
period, sequence, time (ie, postdose time point: categorical), treatment (supratherapeutic dose 
of ALXN1840, moxifloxacin, and placebo), and time-by-treatment interaction as fixed effects 
and Baseline QTcF and sex as a covariates. An unstructured covariance matrix will be used to 
model within-participant errors. If the model with unstructured covariance matrix fails to 
converge, other covariance structure such as Toeplitz with heterogeneity (TOEPH), auto-
regressive with heterogeneity (ARH), compound symmetry with heterogeneity (CSH), TOEP, 
AR, and CS will be considered in decreasing complexity in parameterization. The final 
model selection will be based on Akaike information criterion (AIC). The degrees of freedom 
estimates will be determined by the Kenward-Roger method. The model will also include a 
participant-specific random effect. Least squares mean difference and 2-sided 90% CI will be 
calculated for the contrast ALXN1840 versus placebo at each postdose time point, separately. 
If the upper bound of the 2-sided 90% CI of LS mean ΔΔQTcF lies below 10 ms at all 
12 postdose time points, ALXN1840 will be concluded not to have a significant effect on QT 
interval prolongation. 
For HR, PR, and QRS, the analysis will be based on the change from Baseline postdosing 
(ΔHR, ΔPR, and ΔQRS). The same (by-time point analysis) model will be used as described 
for QTcF. The LS mean, SE, and 2-sided 90% CI from the statistical modeling for both 
change from Baseline and placebo-corrected change from Baseline values will be listed in 
the tables and graphically displayed. 
Other QT interval corrections such as QTcI may be performed, if justified, with details to be 
included in the Statistical Analysis Plan. 
7.3.1.2 
Categorical Analyses 
An analysis of categorical outliers will be performed for changes in HR, PR, QRS, QTcF, 
T-wave morphology, and U-wave presence. The results for categorical outliers, T-wave 
morphology, and U-wave presence will be summarized in frequency tables with counts 
(percentages) for both number of participants and number of time points. For categorical 
outliers, the number (percentage) of participants as well as time points who had absolute 
QTcF values >450 and ≤480 ms, >480 and ≤500 ms, or >500 ms, and changes from predose 
Baseline (∆QTcF) of >30 and ≤60 ms, or >60 ms; increase in PR from predose Baseline 
>25% to a PR >200 ms; increase in QRS from predose Baseline >25% to a QRS >120 ms; 
decrease in HR from predose Baseline >25% to a HR <50 bpm; and increase in HR from 
predose Baseline >25% to a HR >100 bpm will be determined. For T-wave morphology and 


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U-wave presence, treatment-emergent changes will be assessed; ie, changes not present at 
Baseline. For each category of T-wave morphology and of U-waves, the category will be 
deemed as present if observed in any replicates at the time point. 
7.3.1.3 
Assay Sensitivity 
Assay sensitivity will also be evaluated using by-time point analysis of the effect on ΔΔQTcF 
of moxifloxacin using a similar model as for the primary analysis. The analysis to show assay 
sensitivity will be based on the change from Baseline postdosing QTcF of moxifloxacin. For 
the 3 predefined time points (1, 2, and 3 hours postdose), the contrast in treatment 
ΔΔQTcF = moxifloxacin versus placebo will be tested against the 1-sided null hypothesis 
ΔΔQTcF ≤5 ms on the 5% level. Multiplicity will be controlled by using a Hochberg 
procedure (Hochberg 1998). If after this procedure the LS mean of ΔΔQTcF is significantly 
larger than 5 ms for at least 1 time point of these 3 time points, assay sensitivity will be 
considered to have been demonstrated. In addition, 2-sided 90% CIs will be obtained for the 
contrast at all time points and used in the figures. 
7.3.2 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be based on the PK Set. Plasma total Mo and PUF Mo (as 
surrogate measures of ALXN1840 PK) and time deviation data will be presented in a data 
listing by participant. 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), geometric mean, geometric CV, median, 
minimum, and maximum. Mean concentration versus scheduled time profiles will be 
presented in figures on both linear and semilogarithmic scales. Individual concentration 
versus actual time profiles will be presented similarly. 
Pharmacokinetic parameters derived from plasma total Mo and PUF Mo using 
noncompartmental methods will be presented in data listings and summarized separately 
using the following descriptive statistics: number of participants, arithmetic mean, standard 
deviation, arithmetic CV, geometric mean, geometric CV, median, minimum, and maximum. 
Geometric mean and geometric CV will be presented for Cmax and AUCs only. 
7.3.3 
Pharmacokinetic Concentration/QTc Analysis (Exploratory 
Analysis) 
Pharmacokinetic concentration/QTc analysis will be based on the PK/QTc Set. The 
relationship between total Mo or PUF Mo (as surrogate measures of ALXN1840 PK) 


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concentrations in plasma and ∆∆QTcF will be explored graphically and using a linear 
mixed-effects modeling approach with ∆∆QTcF as the dependent variable, total Mo or PUF 
Mo concentration in plasma as the exploratory variate (0 for placebo), centered Baseline 
QTcF (ie, Baseline QTcF for individual participant minus the population mean Baseline 
QTcF for all participants in the same treatment period) as an additional covariate, treatment 
(active = 1 or placebo = 0) and time (ie, postdose time point) as fixed effects, and a random 
intercept and slope per participant (Garnett 2018). The degrees of freedom estimates will be 
determined by the Kenward-Roger method. From the model, the slope (ie, the regression 
parameter for the total Mo or PUF Mo concentration in plasma) and the treatment 
effect-specific intercept (defined as the difference between active and placebo) will be 
estimated together with 2-sided 90% CI. The estimates for the time effect will be reported 
with degrees of freedom and SE. 
The geometric mean of the individual Cmax values for total Mo or PUF Mo (as surrogate 
measures of ALXN1840 PK) concentrations in plasma for participants in the active drug 
group will be determined. The predicted effect and its 2-sided 90% CI for ΔΔQTcF (ie, slope 
estimate × concentration + treatment effect-specific intercept) at this geometric mean Cmax 
will be obtained. 
7.3.4 
Safety Analyses 
Safety analyses will be based on the Safety Set. Adverse events will be coded by preferred 
term and system organ class using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 22 or higher. All AE data will be presented in a data listing. 
Treatment-emergent AEs will be summarized by treatment and overall, as well as by severity 
and relationship to study intervention. Serious AEs and AEs leading to early discontinuation 
will also be presented in data listings. 
Actual values and changes from Baseline for clinical laboratory test results, vital sign 
measurements, and 12-lead safety ECG results will be summarized by treatment at each time 
point using descriptive statistics (number of participants, mean, SD, median, minimum, and 
maximum). 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 postdose during the study. Clinical laboratory test results, 
vital sign measurements, 12-lead safety ECG results, and physical examination findings will 
be presented in data listings. 


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7.4 
HANDLING OF MISSING DATA 
For descriptive statistics of safety and PD laboratory data values that are below the lower 
limit of quantification (LLOQ) will be treated as LLOQ and those above the upper limit of 
quantification (ULOQ) will be treated as ULOQ. Missing concentrations will be excluded 
from the calculations. 
For the PK analysis, results below the LLOQ values will be treated as zero with the 
exception that a value below the LLOQ between 2 quantifiable concentrations will be set as 
missing. Missing concentrations will be treated as missing from the PK parameter 
calculations. If consecutive concentrations below the LLOQ are followed by quantifiable 
concentrations in the terminal phase, those concentrations after the concentrations that are 
below the LLOQ will be treated as missing. 
7.5 
INTERIM ANALYSES 
No formal interim analyses will be performed in this study. 


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8. 
REFERENCE LIST 
Alexion Pharmaceuticals, Inc. ALXN1840 Investigator’s Brochure, Version 10.0. 
Boston (MA); 25 Feb 2020. 
Askari F, Innis D, Dick RB, et al. Treatment of primary biliary cirrhosis with 
tetrathiomolybdate: results of a double-blind trial. Transl Res. 2010;155(3):123-130. 
Avelox® (moxifloxacin hydrochloride) Tablets. [package insert]. July 2016. Merck and Co. 
Whitehouse Station (NJ). 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research, Center for Biologics Evaluation and Research (US). 
Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs. October 2005 [cited 02 Dec 2019] 
[20 screens]. Available from: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/UCM073153.pdf. 
Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modeling. 
J Pharmacokinet Pharmacodyn. 2018;45(3):383-97. [Published correction appears in 
J Pharmacokinet Pharmacodyn. 2018;45(3):399]. 
George GN, Pickering IJ, Harris HH et al. Tetrathiomolybdate causes formation of hepatic 
copper-molybdenum clusters in an animal model of Wilson's disease. J Am Chem Soc. 
2003;125(7):1704-5. 
Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annu Rev Nutr. 
2002;22:439-58. 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75(4):800-2. 
Lin J, Zahurak M, Beer TM, et al. A non-comparative randomized phase II study of 2 doses 
of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically 
recurrent hormone-naïve prostate cancer. Urol Oncol. 2013;31(5):581-8. 
Lowndes SA, Adams A, Timms A, et al. Phase I study of copper binding agent ATN-224 in 
patients with advanced solid tumors. Clin Cancer Res. 2008;14(22):7526-34. 


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Mills CF, El-Gallad TT, Bremner I. Effects of molybdate, sulfide, and tetrathiomolybdate on 
copper metabolism in rats. J Inorg Biochem. 1981;14(3):189-207. 
Pfeiffer RF. Wilson's Disease. Semin Neurol. 2007;27(2):123-32. 
Smirnova J, Kabin E, Jarving I, et al. Copper(I)-binding properties of decoppering drugs for 
the treatment of Wilson disease. Alpha-lipoic acid as a potential anti-copper agent. Sci Rep. 
2018;8(1):1463. 
Weiss KH, Askari FK, Czlonkowska A, et al. Bis-choline tetrathiomolybdate in patients with 
Wilson's disease: an open-label multicentre, phase II study. Lancet Gastroenterol Hepatol. 
2017;2(12):869-76. 
Zhang J, Machado SG. Statistical issues including design and sample size calculation in 
thorough QT/QTc studies. J Biopharm Stat. 2008;18(3):451-67. 


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9. 
APPENDICES 
9.1 
APPENDIX 1: LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ΔHR 
change from Baseline in heart rate 
ΔPR 
change from Baseline in PR interval 
ΔQRS 
change from Baseline in QRS interval 
ΔQTcF 
change from Baseline in the QT interval corrected for heart rate 
using Fridericia’s formula 
ΔΔHR 
placebo-corrected change from Baseline in heart rate 
ΔΔPR 
placebo-corrected change from Baseline in PR interval 
ΔΔQRS 
placebo-corrected change from Baseline in QRS interval 
∆∆QTcF 
placebo-corrected change from Baseline in the QT interval 
corrected for heart rate using Fridericia’s formula 
AE 
adverse event 
ATP 
adenosine triphosphatase 
ATPase2 
adenosine triphosphatase 2 
AUC 
area under the concentration in plasma versus time curve 
AUC0-96 
area under the concentration in plasma versus time curve from 
time 0 to 96 hours postdose 
AUC0-inf 
area under the concentration in plasma versus time curve from 
time 0 extrapolated to infinity 
AUC0-t 
area under the concentration in plasma versus time curve from 
time 0 to the last quantifiable concentration 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration in plasma  
Cu 
copper 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
FDA 
Food and Drug Administration 
GDS 
Global Drug Safety 
GI 
gastrointestinal 
HR 
heart rate 
IB 
Investigator’s brochure 


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Abbreviation 
Term 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
IUT 
intersection union test 
LLOQ 
lower limit of quantification 
LS 
least squares 
MMRM 
mixed-effects model for repeated measures 
Mo 
molybdenum 
ms 
millisecond 
MTD 
maximum tolerated dose 
NF 
National Formulary 
PD 
pharmacodynamic 
PK 
pharmacokinetic(s) 
PPI 
proton-pump inhibitor 
PUF Mo 
plasma ultrafiltrate molybdenum 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QTcI 
optimized HR-corrected QT interval 
QTcS 
individual HR-corrected QT interval 
SAE 
serious adverse event 
Tmax 
time to maximum observed concentration in plasma  
TPC 
tripartite complex 
TQT 
thorough QT 
TTM 
tetrathiomolybdate 
UC 
uncoated capsule 
ULN 
upper limit of normal 
ULOQ 
upper limit of quantification 
WD 
Wilson disease 


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9.2 
APPENDIX 2: STUDY GOVERNANCE 
9.2.1 
Data Quality Assurance 
This study will be conducted using the quality processes described in applicable procedural 
documents. The quality management approach to be implemented will be documented and 
will comply with current ICH guidance on quality and risk management. All aspects of the 
study will be monitored for compliance with applicable government regulatory requirements, 
current Good Clinical Practice, the protocol, and standard operating procedures. The monitor 
will maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
Investigator and staff. Electronic CRFs and electronic data capture will be utilized. The 
electronic data capture system is validated and compliant with US Title 21 Code of Federal 
Regulations (CFR) Part 11. Each person involved with the study will have an individual 
identification code and password that allows for record traceability. 
Important protocol deviations, should they occur during the study, will be presented in 
Section 10.2 of the clinical study report. 
9.2.2 
Investigator Obligations 
The following administrative items are meant to guide the Investigator in the conduct of the 
study and may be participant to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments. 
9.2.2.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant (or the participant’s legal guardian), except as necessary for 
monitoring and auditing by Alexion, its designee, the FDA, or the IRB. 
The Investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from Alexion or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 


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9.2.2.2 
Institutional Review 
Federal regulations and ICH guidelines require that approval be obtained from an IRB before 
participation of human participants in research studies. Before study onset, the protocol, ICF, 
advertisements to be used for the recruitment of study participants, and any other written 
information regarding this study that is to be provided to the participant or the participant’s 
legal guardian must be approved by the IRB. Documentation of all IRB approvals and of the 
IRB compliance with the ICH harmonised tripartite guideline E6(R2): Good Clinical Practice 
will be maintained by the study site and will be available for review by Alexion or its 
designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
9.2.2.3 
Participant Consent 
Written informed consent in compliance with US Title 21 CFR Part 50 shall be obtained from 
each participant before he or she enters the study or before performing any unusual or 
nonroutine procedure that involves risk to the participant. If any institution-specific 
modifications to study-related procedures are proposed or made by the study site, the consent 
should be reviewed by Alexion or its designee or both before IRB submission. Once 
reviewed, the Investigator will submit the ICF to the IRB for review and approval before the 
start of the study. If the ICF is revised during the course of the study, all active participating 
participants must sign the revised form. 
Before recruitment and enrollment, each prospective participant or his or her legal guardian 
will be given a full explanation of the study and will be allowed to read the approved ICF. 
Once the Investigator is assured that the participant/legal guardian understands the 
implications of participating in the study, the participant/legal guardian will be asked to give 
his or her consent to participate in the study by signing the ICF. A copy of the ICF will be 
provided to the participant/legal guardian. 
9.2.2.4 
Financial Disclosure and Obligations 
The Investigator is required to provide financial disclosure information to allow Alexion to 
submit the complete and accurate certification or disclosure statements required under US 
Title 21 CFR Part 54. In addition, the Investigator must provide to Alexion a commitment to 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year after the completion of the study. 
Neither Alexion nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither Alexion nor PPD is financially responsible for 
further treatment of the disease under study. 
9.2.2.5 
Investigator Documentation 
Prior to beginning the study, the Investigator will be asked to comply with ICH 
E6(R2) Section 8.2 and US Title 21 of the CFR by providing essential documents, including 
but not limited to, the following: 
• IRB approval 
• An original investigator-signed investigator agreement page of the protocol 
• Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572 
• Curriculum vitae for the Principal Investigator and each Subinvestigator listed on Form 
FDA 1572. Current licensure must be noted on the curriculum vitae. Curriculum vitae 
will be signed and dated by the Principal Investigators and Subinvestigators at study 
start-up, indicating that they are accurate and current. 
• Financial disclosure information to allow Alexion to submit complete and accurate 
certification or disclosure statements required under US Title 21 CFR Part 54. In 
addition, the Investigators must provide to Alexion a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• An IRB-approved ICF, samples of study site advertisements for recruitment for this 
study, and any other written information about this study that is to be provided to the 
participant or legal guardians 
• Laboratory certifications and reference ranges for any local laboratories used by the study 
site, in accordance with US Title 42 CFR Part 493 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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9.2.2.6 
Study Conduct 
The Investigator agrees to perform all aspects of this study in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ICH E6(R2): Good Clinical 
Practice; the protocol; and all national, state, and local laws or regulations. 
9.2.2.7 
Case Report Forms and Source Documents 
Site personnel will maintain source documentation, enter participant data into the eCRF as 
accurately as possible, and will rapidly respond to any reported discrepancies. 
Electronic CRFs and electronic data capture will be utilized. The electronic data capture 
system is validated and compliant with US Title 21 CFR Part 11. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and any subsequent investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records, as well as 
the time and date of any modifications. There may be an internal quality review audit of the 
data and additional reviews by the clinical monitor. 
Each eCRF is presented as an electronic copy, allowing data entry by study site personnel, 
who can add and edit data, add new participants, identify and resolve discrepancies, and view 
records. This system provides immediate direct data transfer to the database, as well as 
immediate detection of some discrepancies, enabling study site coordinators to resolve and 
manage discrepancies in a timely manner. 
Paper copies of the eCRFs and other database reports may be printed and signed by the 
Investigator. This system provides study site personnel, monitors, and reviewers with access 
to hardcopy audits, discrepancy reviews, and investigator comment information. 
9.2.2.8 
Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol, in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 
9.2.2.9 
Reporting Adverse Events 
By participating in this study, the Investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the Investigator agrees to 
submit annual reports to his or her IRB as appropriate. The Investigator also agrees to 


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provide Alexion with an adequate report, if applicable, shortly after completion of the 
investigator’s participation in the study. 
9.2.2.10 
Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform the 
institution; the Investigator/institution should provide the IRB with a summary of the study’s 
outcome and Alexion and regulatory authorities with any reports required. 
9.2.2.11 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents 
should be retained for a longer period, however, if required by applicable regulatory 
requirements or by an agreement with Alexion. Alexion is responsible for informing the 
Investigator/institution when these documents no longer need to be retained. 
9.2.2.12 
Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, Alexion will be responsible 
for these activities and will work with the Investigators to determine how the manuscript is 
written and edited, the number and order of authors, the publication to which it will be 
submitted, and any other related issues. Alexion has final approval authority over all such 
issues. 
Data are the property of Alexion and cannot be published without their prior authorization, 
but data and any publication thereof will not be unduly withheld. 
9.2.3 
Study Management 
9.2.3.1 
Monitoring 
9.2.3.1.1 
Monitoring of the Study 
The clinical monitor, as a representative of Alexion, is obligated to follow the study closely. 
In doing so, the monitor will visit the Investigator and study site at periodic intervals in 
addition to maintaining necessary telephone and email contact. The monitor will maintain 


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current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the Investigator and 
staff. 
All aspects of the study will be carefully monitored by Alexion or its designee for 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and standard operating procedures. 
9.2.3.1.2 
Inspection of Records 
The Investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the Investigator agrees to allow Alexion, their representatives, the 
FDA, or other regulatory agencies access to all study records. 
The Investigator should promptly notify Alexion and study site(s) of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to 
Alexion. 
9.2.3.2 
Management of Protocol Amendments and Deviations 
9.2.3.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent 
immediate hazard to the participant, must be reviewed and approved by Alexion or designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB for 
approval before participants are enrolled into an amended protocol. 
9.2.3.2.2 
Protocol Deviations 
The Investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The Investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
participants without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to Alexion for agreement, and to the 
regulatory authorities, if required. 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. An important deviation (sometimes referred to as a major 


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ALXN1840 
Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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or significant deviation) is a subset of protocol deviations that leads to a participant being 
discontinued from the study, or significantly affects the participant’s rights, safety, or 
well-being and/or the completeness, accuracy, and reliability of the study data. An important 
deviation can include nonadherence to inclusion or exclusion criteria or nonadherence to 
FDA regulations or ICH E6(R2) guidelines. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. The Investigator will be notified in writing by the monitor of deviations. 
The IRB should be notified of all protocol deviations, if appropriate, in a timely manner. 
9.2.3.3 
Study Termination 
Although Alexion has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last participant completes the last 
visit (including the EOS Visit and any additional long-term follow-up). Any additional 
long-term follow-up that is required for monitoring of the resolution of an AE or finding may 
be appended to the clinical study report. 
9.2.3.4 
Final Report 
Regardless of whether the study is completed or prematurely terminated, Alexion will ensure 
that clinical study reports are prepared and provided to regulatory agency(ies) as required by 
the applicable regulatory requirement(s). Alexion will also ensure that clinical study reports 
in marketing applications meet the standards of the ICH harmonised tripartite guideline E3: 
Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review complete study results. 
Upon completion of the clinical study report, the Investigator(s) will be provided with the 
final approved clinical study report, as appropriate. 


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9.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING 
9.3.1 
Definition of Adverse Event 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment . 
• 
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, serum 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). 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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9.3.2 
Definition of Serious Adverse Event 
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 were more severe. 
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. 
 
A suspected unexpected serious adverse reaction (SUSAR) is defined as: 
A serious event that is not listed in the IB and that the Investigator identifies as related to 
investigational product or procedure. United States Title 21 CFR 312.32 and European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs. Alexion has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent with 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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A suspected unexpected serious adverse reaction (SUSAR) is defined as: 
global regulations and the associated detailed guidances. Suspected unexpected serious adverse 
reactions will be reported to the national competent authority and IRBs/IECs where applicable.  
 
9.3.3 
Recording and Follow-Up of Adverse Events and/or Serious 
Adverse Events 
AE and SAE Recording 
• 
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 eCRF. 
• 
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 eCRF 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 1 of the following categories from National Cancer Institute CTCAE v 5.0, 
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 eCRF and 
on any additional forms, as appropriate. The definitions for the causality assessments are as 
follows: 
• 
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.  


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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Assessment of Causality 
 
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 IB and/or product information, for marketed products, 
in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he or 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 a 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 postmortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of 
the information. 
9.3.4 
Reporting of Serious Adverse Events  
SAE Reporting to Alexion via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 
24 hours awareness. 


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
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SAE Reporting to Alexion via Paper Safety Reporting Form 
• 
SAEs will be reported using the Safety Reporting Form and submitted to Alexion 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 serious event(s) 
 
Treatment of/intervention for the SAE(s) 
 
Outcome of the serious event(s) 
 
Medical records and laboratory/diagnostic information 
• 
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. 
 
PPD
PPD


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Protocol No. ALXN1840-HV-107 Amendment 1, 01 Sep 2020 
Clinical Study Protocol 
 
 
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9.4 
APPENDIX 4: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
12 Jun 2020 
Amendment 1 
01 Sep 2020 
 

SAP_001.pdf: 
A Randomized, Three-Treatment, Three-Period, Six-
Sequence, Crossover, Placebo- and Active-Controlled, 
Double-Blind for ALXN1840 (Open-Label for Moxifloxacin) 
Thorough QT/QTc (TQT) Study to Evaluate the Effect of 
ALXN1840 on Cardiac Repolarization in Healthy Adult 
Participants 
Unique Protocol ID: 
NCT Number: 
Date of SAP:  
ALXN1840-HV-107 
NCT04560816 
03 September 2020 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
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Ale xi o n C o nfi de ntial  
 
S T A TI S TI C A L A N A L Y SI S  P L A N  
P H A S E I  
 
D A T E O F P L A N:  
0 3 -Se p -2 0 2 0  
 
B A S E D O N:  
Pr ot oc ol A me n d me nt 1  
 
S T U D Y D R U G:  
A L X N 1 8 4 0  
P R O T O C O L N U M B E R:  
A L X N 1 8 4 0 -H V -1 0 7  
S T U D Y TI T L E:  
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C o ntr olle d, D o u ble -Bli n d f or A L X N 1 8 4 0 ( O pe n -La b el f or M o xifl o x aci n) T h or o u g h Q T/ Q Tc 
( T Q T) St u d y t o E v al uate t he Effect of A L X N 1 8 4 0 o n Car diac Re p olarizati o n i n Healt hy A d ult 
Partici pa nts  
S P O N S O R:  
Ale xi o n P har mace uticals, I n c.  
1 2 1 Sea p ort B o ule var d  
B ost o n, M A 0 2 2 1 0  
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
SI G N A T U R E P A G E  
 
 
 
Date  
 
 
 
Date  
 
 
 
 
 
Date  
0 3 - S e p - 2 0 2 0  |  0 8 : 2 9 : 3 1  E D T
0 3 - S e p - 2 0 2 0  |  1 4 : 5 8 : 3 0  E D T
0 3 - S e p - 2 0 2 0  |  0 8 : 4 7 : 4 6  E D T
P P D


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
T E C H NI C A L S U M M A R Y R E P O R T  
N a me of S p o ns or/ C o m p a n y:  
Ale xi o n P har mace uticals, I nc.   
I n di vi d u al St u d y T a ble Referri n g 
t o P art of t he D ossier: 
V ol u me:  
( F or N ati o n al A ut h ority Use 
O nly) : 
N a me of Fi nis he d Pr o d uct:  
A L X N 1 8 4 0  
P a ge:  
 
N a me of Acti ve I n gre die nt : 
Bis -c h oli ne tetrat hi o m ol y b dat e  
 
 
Title of St u d y:  
A Ra n d o mize d, T hree -Treat me nt, T hree -P eri o d, Si x -Se q ue nce, Cr oss o ver, Place b o - a n d Acti ve -C o ntr olle d, 
D o u ble -Bli n d f or A L X N 1 8 4 0 ( O pe n -La b el f or M o xifl o xaci n) T h or o u g h Q T/ Q T c ( T Q T) St u d y t o E val uate t he 
Effect of A L X N 1 8 4 0 o n Car diac Re p olarizati o n i n Healt h y A d ult P artici pa nts  
I n vesti g at ors: 
St u d y Ce nter(s): O ne cli nical site i n t he U nite d States  
St u die d peri o d:  
D urati o n of partici pa nt p artici pati o n 
fr o m t he Scree ni n g Visit t o t he 
E n d -of -St u d y ( E o S) Visit will be 
a p pr o xi matel y 7 0 da ys  
P h ase of de vel o p me nt:  
P hase 1  
O bjecti ves:  
Pri mar y:  
T he pri mar y o bj ecti ve of t his st u d y is t o e val uate t he effect of a s u prat hera pe utic d ose of A L X N 1 8 4 0 o n t he heart 
rate ( H R)-c orrecte d Q T i nter val ( Q T c) wit h t he i nte nt t o e xcl u de a 1 0  ms effect.  
Sec o n dar y: T he sec o n dar y o bjecti ves of t he st u d y are:  
 
T o d e m o nstrate assa y se nsiti vit y of t he st u d y t o detect a n effect o n t he mea n Q T/ Q T c i nter val of 
a p pr o xi matel y 5 ms usi n g m o xifl o xaci n as a p ositi ve c o ntr ol.  
 
T o e val uate t he safet y a n d t olera bilit y of a si n gle oral s u prat hera pe utic d ose of A L X N 1 8 4 0 i n healt h y 
partici pa nts.  
 
T o assess t he p har mac o ki netics ( P K) of A L X N 1 8 4 0 f oll o wi n g a d mi nistrati o n of a si n gle oral 
s u prat hera p e utic d ose i n healt h y partici pa nts.  
 
T o e val uate t he effects of a si n gle oral s u prat hera pe utic d ose of A L X N 1 8 4 0 o n H R, P R a n d Q R S i nter vals, 
treat me nt-e mer ge nt T -wa ve m or p h ol o g y a b n or malities, a n d a p peara nce of U wa ves.  
 
E x pl orat or y: T he e x pl orat or y o bj ecti ve of t his st u d y is t o e val uate t he effects of plas ma t otal m ol y b de n u m ( M o) 
a n d plas ma ultrafiltrate ( P U F) M o (as a s urr o gate meas ure of A L X N 1 8 4 0) plas ma c o nce ntrati o ns o n Q T/ Q T c.  
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 4  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
M et h o d ol o g y:  
T his is a ra n d o mize d, 3 -treat me nt, 3-peri o d, 6 -se q ue nce, cr oss o ver, place b o- a n d acti ve -c o ntr olle d, d o u ble -bli n d 
f or A L X N 1 8 4 0, o pe n-la bel f or m o xifl o xaci n, i n healt h y a d ult partici pa nts. M o xifl o xaci n will be use d as t he 
acti ve c o ntr ol.  
St u d y i nter ve nti o ns will be gi ve n i n ra n d o mize d se q ue nces: A B C, A C B, B A C, B C A, C A B, a n d C B A, wit h eac h 
treat me nt a d mi nistere d wit h 2 4 0 m L of water f oll o wi n g a n o ver ni g ht fast of at least 1 0 h o urs. N o f o o d will be 
all o we d f or at least 4 h o urs p ost d ose. W ater ca n be all o we d as desire d e xce pt f or 1 h o ur bef ore a n d after dr u g 
a d mi nistrati o n. Treat me nt A is a si n gle oral d ose of A L X N 1 8 4 0 1 2 0 m g a d mi nistere d as 1 5 -m g e nteric -c oate d 
ta blets (s u prat hera p e utic d ose); Treat me nt B is  a si n gle oral d ose of e nteric -c oate d place b o ta blets matc hi n g 
A L X N 1 8 4 0; a n d Treat me nt C is a si n gle oral d ose of m o xifl o xaci n 4 0 0 m g ta blet.  
Car di o d y na mic assess me nt will be perf or me d f or a p pr o xi matel y 2 5 h o urs o n D a y – 1 of  Treat me nt P eri o d 1 a n d  
Da y 1 t o  Da y 2  of eac h treat me nt p eri o d. Bl o o d sa m ples f or P K will be c ollecte d pre d ose a n d at s pecifie d ti mes u p 
t o 9 6 h o urs after t he Da y 1 d ose i n eac h treat me nt peri o d. 
 
T wel ve -lea d electr ocar di o gra ms ( E C Gs) will be e xtracte d fr o m a c o nti n u o us ( H olter) rec or di n g b y t he ce ntral 
la b orat or y. T o s u p p ort hi g h q ualit y data f or e xtracti o n, partici pa nts will be resti n g i n t he s u pi ne p ositi o n f or at 
least 1 5 mi n utes pri or t o a n d 5 mi n utes after eac h n o mi nal ti me p oi nt f or E C G e xtracti o n. Bl o o d f or plas ma P K 
will b e c ollecte d as cl ose as p ossi ble t o n o mi nal ti me b ut aft er c o m pleti o n of E C G e xtracti o n wit h act ual ti mes f or 
bl o o d sa m ple c ollecti o ns rec or de d.  
 
P artici pa nts will be d o mic ile d i n t he cli nic f or 7 da ys i n Treat me nt P eri o d 1 a n d f or 6 da ys i n Treat me nt P eri o ds 2 
a n d 3, starti n g o n Da y – 2 f or Treat me nt P eri o d 1 a n d o n t he da y bef ore d osi n g ( Da y – 1) f or Treat me nt P eri o ds 2 
a n d 3, u ntil safet y pr oce d ures ha ve bee n c o m plete d a n d re vi e we d o n Da y 5.T here will be a was h o ut of at least 1 4 
da ys bet wee n d ose a d mi nistrati o n i n eac h peri o d.  
 
All partici pa nts (i ncl u di n g partici pa nts w h o ter mi nate t he st u d y earl y) will ret ur n t o t he st u d y site 1 4 da ys ( ± 2 
da ys) after t he last a d mi nistrati o n  of st u d y i nter ve nti o n f or f oll o w -u p pr oce d ures a n d t o deter mi ne if a n y a d verse 
e ve nt ( A E) has occ urre d si nce t he last st u d y visit.  
D urati o n of partici pa nt p artici pati o n fr o m t he Scree ni n g Visit t o t he E n d -of -St u d y Visit will be a p pr o xi matel y 7 0 
da ys. T his  i ncl u des u p t o 2 9 da ys f or t he Scree ni n g P eri o d, st u d y i nter ve nti o n a d mi nistrati o n o n Da y 1 of eac h 
treat me nt p eri o d, a mi ni m u m of a 1 4-da y was h o ut bet wee n st u d y i nter ve nti o n a d mi nistrati o n i n eac h treat me nt 
peri o d, a n d 1 4  da ys ( ± 2  da ys) f or t he E O S Visit . 
N u m ber of P artici p a nts ( pl a n ne d a n d a n al yze d):  
A p pr o xi matel y 5 4 partici pa nts will be ra n d o mize d t o e ns ure t here will be 4 5 e val ua ble partici pa nts wit h data 
fr o m all treat me nt peri o ds. T o e ns ure se q ue nces are bala nce d wit hi n se x, partici pa nt ra n d o mizati o n will be 
stratifie d b y se x. 
Di a g n osis a n d m ai n criteri a f or i ncl usi o n:  
 
P artici pa nt is a healt h y a d ult male or fe male, 1 8 t o 5 0 years of a ge, i ncl usi ve, at Scree ni n g.  
 
P artici pa nt is a c o nti n u o us n o ns m o ker a n d or a n i n di vi d ual w h o has n ot use d t o bacc o or n ic oti ne-
c o ntai ni n g pr o d ucts (e g, electr o nic va p or ci garettes, ci garettes, ci gars, c he wi n g t o bacc o, s n uff, nic oti ne 
g u m, nic oti ne patc hes) f or at l east 3 m o nt hs pri or t o t he first d ose of st u d y i nter ve nti o n a n d f or t he 
d urati o n of t he st u d y. A c oti ni ne test  perf or me d d uri n g Scree ni n g a n d C hec k -i n m ust b e c o nsiste nt wit h 
c o nti n u o us n o ns m o ki n g stat us.  
 
P artici pa nt m ust wei g h at least 6 0 k g f or males or 5 2 k g f or fe males a n d ha ve a b o d y mass i n de x ≥1 8. 0 
a n d ≤3 0. 0 k g/ m 2 at Scree ni n g.  
 
P artici pa nt m ust ha ve a me dic al assess me nt wit h n o cli nicall y si g nifica nt or rele va nt a b n or malities as 
deter mi ne d b y me dical hist or y, p h ysical e xa mi nati o n, vital si g ns, 1 2 -lea d E C G, a n d cli nical la b orat or y 
e val uati o n ( he mat ol o g y, ser u m c he mistr y, c oa g ulati o n, a n d uri nal ysis) t hat are reas o na bl y li kel y t o 
i nterfere wit h t he partici pa nt’s partici pati o n i n or a bilit y t o c o m plete t he st u d y, or t o p ote ntiall y 
c o nf o u n d i nter pretati o n of st u d y res ults, as assesse d b y t he I n vesti gat or.  
 
P artici pa nt has n o cli nicall y si g nifica nt hist or y or prese nce of E C G fi n di n gs as j u d ge d b y t he 
I n vesti gat or at Scree ni n g a n d C hec k-i n 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 5  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
Test pr o d uct, d ose a n d m o d e of a d mi nistr ati o n, b atc h n u m ber:  
A si n gle oral d ose of A L X N 1 8 4 0 1 2 0 m g a d mi nistere d as 1 5 -m g e nteric - c oate d ta blets (s u prat hera pe utic)  
D ur ati o n of tre at me nt: 
T he st u d y c o nsists 3 treat me nt peri o ds, st u d y i nter ve nti o n a d mi nistrati o n o n Da y 1 of eac h treat me nt peri o d, a 
mi ni m u m of a 1 4 -da y was h o ut bet wee n st u d y i nter ve nti o n a d mi nistrati o n i n eac h treat me nt peri o d, a n d 1 4  da ys 
( ± 2 da ys) f or t he E O S Visi t. 
Refere nce t her a p y, d ose a n d m o de of a d mi nistr ati o n, b atc h n u m b er:  
A si n gle oral d ose of e nteric -c oate d place b o ta blets matc hi n g A L X N 1 8 4 0  
A si n gle oral d ose of m o xifl o xaci n 4 0 0 m g ta blet  
Criteri a f or e v al u ati o n:  
C ar di o dy n a mic Assess me nts a n d E n d p oi nts : 
 
T wel ve -lea d E C Gs will be e xtracte d fr o m a p pr o xi matel y 2 5-h o ur c o nti n u o us ( H olter) rec or di n gs o n Da y – 1 of 
Treat me nt P eri o d 1 a n d o n Da ys 1 a n d 2 i n eac h treat me nt peri o d. P artici pa nts s h o ul d be resti n g s u pi nel y f or at 
least 1 5 mi n utes bef ore a n d 5 mi n ute s after eac h ti me p oi nt f or E C G e xtracti o n, w hic h s h o ul d prece de P K bl o o d 
sa m ples, w he n a p plica ble.  
 
Electr ocar di o gra ms will be e xtracte d fr o m t he c o nti n u o us rec or di n g b y a ce ntral E C G la b orat or y ( E R T, 
R oc hester, N Y) o n Da y – 1 of Treat me nt P eri o d 1 a n d ea c h of t hese da ys at t he f oll o wi n g ti me p oi nts: Da y 1 at 
pre d ose ( – 4 5, – 3 0, a n d – 1 5 mi n utes) a n d 0. 5, 1, 2, 3, 4, 5, 6, 7, 8, 1 0, 1 2, a n d 2 4 ( Da y 2) h o urs p ost d ose, f or a 
t otal of 1 5 ( 3 pre d ose a n d 1 2 p ost d ose) ti me p oi nts i n eac h tr eat me nt peri o d. F or H R -correcte d Q T c calc ulati o n i n 
case of a s u bsta ntial H R effect d u e t o A L E X N 4 0, E C G e xtra cti o n fr o m t he H olter rec or di n g  Da y -1 of Treat me nt 
P eri o d 1 will i ncl u de c o nti n u o us E C G e xtracti o n f or o pti miz e d Q T i nter val ( Q T cI) calc ulati o n, a n d  if nee de d,  
E C G e xtracti o n at ti me p oi nts t hat precisel y matc h t he e xtracti o n ti me p oi nts f or Da y 1 of P eri o ds 1, 2 a n d 3 f or 
i n di vi d ual H R-c orrecte d Q T i nter val ( Q T c S) calc ulati o n.  
T he f oll o wi n g E C G para meters will be meas ure d a n d calc ulate d: H R, P R i nter val, Q T i nte r val c orrecte d f or heart 
rate ( Q T c), Q R S i nter val, treat me nt-e mer ge nt T -wa ve m or p h ol o g y a b n or malities, a n d a p peara nce of U -wa ves.  
T he pri mar y e n d p oi nt is place b o -c orrecte d c ha n ge fr o m Bas eli ne Q T c ( Δ Δ Q T c, c orrecti o n met h o d will be data 
dri ve n) f or A L X N 1 8 4 0  usi n g t he b y -ti me p oi nt a nal ysis. T he sec o n dar y e n d p oi nts are t he Δ Δ Q T c f or 
m o xifl o xaci n; t he c ha n ge fr o m B aseli ne i n H R, Q T c, P R, Q R S ( Δ H R, Δ Q T c, Δ P R a n d Δ Q R S); t he place b o -
c orrecte d c ha n ge fr o m B aseli ne H R, P R, a n d Q R S ( Δ Δ H R, Δ Δ P R a n d Δ Δ Q R S); cate g oric a l o utliers f or Q T c, 
H R, P R, a n d Q R S; a n d t he fre q ue nc y of treat me nt -e mer ge nt c ha n ges of T -wa ve m or p h ol o g y a n d U -wa ve 
prese nce. T he e x pl orat or y e n d p oi nt is t he Δ Δ Q T c f or A L X N 1 8 4 0 usi n g t he c o nce ntrati o n -Q T c a nal ysis b y 
c o nce ntrati o n of t otal M o a n d P U F M o ( as s urr o gate meas ur es of A L X N 1 8 4 0 P K) i n plas ma.  
F or all c o nti n u o us E C G para meters fr o m eac h peri o d, Baseli ne is defi ne d as t he a vera ge of meas ure d E C G 
i nter vals fr o m t he 3 pre d ose ti me p oi nts ( −4 5, −3 0, a n d −1 5 mi n utes bef ore d osi n g) o n Da y 1 f or t he res pecti ve 
peri o d. F or T -wa ve m or p h ol o g y a n d U -wa ve prese nce, Bas eli ne i ncl u des fi n di n gs o bser ve d i n a n y re plicates 
fr o m t he 3 pre d ose ti me p oi nts ( −4 5, −3 0, a n d −1 5 mi n utes) o n Da y 1 i n eac h peri o d. 
 
P h ar m ac o ki netic a n d P h ar m ac o dy n a mic Assess me nts a n d E n d p oi n ts: 
 
Bl o o d sa m ples f or P K a nal ysis of t otal M o a n d P U F M o (as s urr o gate meas ures of A L X N 1 8 4 0 P K) will be 
c ollecte d at t he f oll o wi n g ti me p oi nts: wit hi n 1. 5 h o ur bef ore d osi n g a n d p ost d ose at 0. 5, 1, 2, 3, 4, 5, 6, 7, 8, 1 0, 
1 2, 2 4, 4 8, a n d 9 6  h o urs i n eac h  peri o d. O nl y sa m ples c ollect e d pre d ose a n d f oll o wi n g A L X N 1 8 4 0 
a d mi nistrati o n will be a nal yze d f or plas ma t otal M o a n d P U F M o. Sa m ples c ollecte d pre d ose a n d after place b o or 
m o xifl o xaci n a d mi nistrati o n will b e sa ve d f or a nal ysis, if nee de d.  
T he f oll o wi n g p las ma P K para meters will b e calc ulate d as e n d p oi nts f or t otal M o a n d P U F M o usi n g 
n o nc o m part me ntal met h o ds wit h P h oe ni x ® Wi n N o nli n ® ( Certara U S A I nc., Pri ncet o n, N e w J erse y) Versi o n 8. 0 
or hi g her or S A S ( S A S I nstit ute I nc., Car y, N ort h Car oli na) Versi o n 9. 4 or hi g her, as a p plica ble. Calc ulati o ns will 
be base d o n t he act ual sa m pli n g ti mes rec or de d d uri n g t he st u d y.  
 
Ti me dela y bet wee n t he ti me of d osi n g a n d ti me of a p peara nce of M o c o nce ntrati o n i n plas ma ( T la g) 
 
Ma xi m u m o bser ve d plas ma c o nce ntrati o n ( C
ma x ) 
 
Ti me t o reac h ma xi m u m o bser ve d plas ma c o nce ntrati o n ( T
ma x ) 
 
Area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve ( A U C) fr o m ti me 0 t o t he last q ua ntifia ble 
c o nce ntrati o n ( A U C 0 -t) 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 6  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
 
A U C fr o m ti me 0 t o 9 6 h o urs p ost d ose ( A U C 0 -9 6) 
 
A U C fr o m ti me 0 e xtra p olate d t o i nfi nit y ( A U C0 -∞) 
 
A p pare nt ter mi nal -p hase eli mi nati o n rate c o nsta nt ( λz)  
 
T er mi nal eli mi nati o n half -life (t1/ 2) 
 
A p pare nt t otal cleara nce fr o m plas ma after oral a d mi nistrati o n of A L X N 1 8 4 0 ( C L/ F)  
 
 
P har mac o ki netic sa m ples ma y be use d f or t he q ua ntificati o n of p har mac o d y na mic ( P D) e n d p oi nts s uc h as t otal 
C u, P U F C u, la bile -b o u n d C u, cer ul o plas mi n, a n d cer ul o plas mi n -b o u n d C u.  
 
S afety : 
 
Safet y a n d t olera bilit y will be assesse d b y t he f oll o wi n g e n d p oi nts: m o nit ori n g a n d rec or di n g of a d verse e ve nts 
( A Es), cli nical la b orat or y test res ults ( he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis), vital si g n meas ure me nts, 
1 2 -lea d safet y E CG res ults, a n d p h ysical e xa mi nati o n fi n di n gs.  
F or all safet y assess me nts, t he I n vesti gat or will deter mi ne w het her res ults are cli nicall y si g nifica nt, w hic h is 
defi ne d as a n y variati o n i n a res ult t hat has me dical rele va nc e a n d ma y res ult i n a n alterati o n i n me dical care (e g, 
acti ve o bser vati o n, dia g n ostic meas ures, or t hera pe utic meas ures). If cli nical si g nifica nce is n ote d, t he res ult a n d 
reas o n f or si g nifica nce will be d oc u me nte d a n d a n A E will b e re p orte d o n t he A E pa ge of t he partici pa nt’s 
electr o nic ca se re p ort f or m (e C R F). T he I n vesti gat or will m o nit or t he partici pa nt u ntil t he res ult has reac he d t he 
refere nce ra n ge or t he res ult at Scree ni n g, or u ntil t he I n vesti gat or deter mi nes t hat f oll o w-u p is n o l o n ger 
me dicall y necessar y.   
St atistic al met h o ds:  
T he statistical h y p ot hesis t o be teste d f or t he pri mar y assess me nt of Q T pr ol o n gati o n f or t he A L X N 1 8 4 0 
treat me nt is: 
H 0: ∪{ μ D(i) –  μ P(i) } ≥1 0, i = 1, 2, …, 1 2  
H 1: ∩{ μD(i) –  μ P(i) } < 1 0, i = 1, 2, …, 1 2  
w here μ D(i) a n d μ P(i)  are t he least s q uares ( L S) mea n of Δ Q T c  f or A L X N 1 8 4 0 a n d place b o at p ost d ose ti me p oi nt i, 
res pecti vel y. 
T he b y -ti me p oi nt a nal ysis f or Q T c will be base d o n a mi xe d m o del f or re peate d meas ures ( M M R M) wit h c ha n ge 
fr o m Baseli ne Q T c ( Δ Q T c) as t he de p e n de nt varia ble; peri o d, se q ue nce, ti me (ie, p os t d ose ti me p oi nt: 
cate g orical), treat me nt (s u prat hera p e utic d ose of A L X N 1 8 4 0, m o xifl o xaci n, a n d place b o), ti me -b y -treat me nt 
i nteracti o n as fi xe d effects, a n d B aseli ne Q T c a n d se x as c o variates. A n u nstr uct ure d c o varia nce matri x will be 
s pecifie d f or t he repeate d meas ures at p ost d ose ti me p oi nts f or partici pa nt wit hi n eac h treat me nt peri o d. If t he 
m o del wit h u nstr uct ure d c o varia nce matri x fails t o c o n ver ge, ot her c o varia nce str uct ure s uc h as T oe plitz wit h 
heter o ge neit y ( T O E P H), a ut o -re gressi ve wit h heter o ge neit y ( A R H), c o m p o u n d s y m metr y wit h heter o ge neit y 
( C S H), T oe plitz ( T O E P), a ut o-re gressi ve ( A R), a n d c o m p o u n d s y m metr y ( C S) will be c o nsi dere d i n decreasi n g 
c o m ple xit y i n para meterizati o n. T he fi nal m o del selecti o n will be base d o n A kai ke i nf or mati o n criteri o n ( AI C). 
T he de grees of free d o m esti mates will be deter mi ne d b y t he Ke n war d -R o ger met h o d. T he m o del will als o i ncl u de 
a partici pa nt -s pecific ra n d o m effect. 
Least -s q uares mea n differe nce a n d 2-si de d 9 0 % c o nfi de nce i nter val ( CI) will be calc ulate d f or t he c o ntrast 
A L X N 1 8 4 0 vers us place b o at eac h p ost d ose ti me p oi nt, se paratel y. If t he u p per b o u n d of t he 2 -si de d 9 0 % CI of 
L S mea n Δ Δ Q T c lies bel o w 1 0  ms at all 1 2  p ost d ose ti me p oi nts, A L X N 1 8 4 0 will be c o ncl u de d n ot t o ha ve a 
si g nifica nt effect o n Q T i nter val pr ol o n gati o n.  
 
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 7  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
T A B L E O F C O N T E N T S  
 
1.  
LI S T O F A B B R E VI A TI O N S .....................................................................................1 0  
2.  
I N T R O D U C TI O N ......................................................................................................1 2  
3.  
S T U D Y O BJ E C TI V E( S) A N D E N D P OI N T( S)  ........................................................1 3  
3. 1.  
St u d y O bjecti ve(s)  ......................................................................................................1 3  
3. 2.  
St u d y E n d p oi nt(s)  .......................................................................................................1 3  
3. 2. 1.  
Pri mar y E n d p oi nt  ........................................................................................................1 3  
3. 2. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................1 4  
3. 2. 2. 1.  
Car di o d y n a mic E n d p oi nts  ..........................................................................................1 4  
3. 2. 2. 2.  
P har mac o ki netic a n d P har mac o d y na mic Ass ess me nt a n d Para meters  ......................1 7  
3. 2. 2. 3.  
Safet y E n d p oi nts  .........................................................................................................1 8  
3. 2. 3.  
E x pl orat or y E n d p oi nts  ................................................................................................1 8  
3. 3.  
Statistical H y p ot heses  .................................................................................................1 8  
3. 3. 1.  
Pri mar y H y p ot h esis  ....................................................................................................1 8  
3. 3. 2.  
Sec o n dar y H y p ot h esis  ................................................................................................1 9  
4.  
S T U D Y D E SI G N  .......................................................................................................2 0  
4. 1.  
Defi niti o n of  St u d y Dr u gs  ..........................................................................................2 0  
4. 2.  
Sa m ple Siz e C o nsi derati o ns  .......................................................................................2 1  
4. 2. 1.  
Sa m ple Siz e J ustificati o ns  ..........................................................................................2 1  
4. 3.  
Ra n d o mizati o n  ............................................................................................................2 1  
4. 4.  
Cli nical Assess me nts  ..................................................................................................2 1  
5.  
P L A N N E D A N A L Y S E S  ............................................................................................2 4  
5. 1.  
I nteri m A nal yses .........................................................................................................2 4  
5. 2.  
Fi nal A nal ysis  .............................................................................................................2 4  
5. 3.  
C ha n ges f r o m A nal ysis S pecifie d i n t he Pr ot oc ol ......................................................2 4  
5. 3. 1.  
Pri mar y E n d p oi nt  ........................................................................................................2 4  
5. 3. 2.  
Sec o n dar y e n d p oi nts  ...................................................................................................2 4  
5. 3. 3.  
E x pl orat or y e n d p oi nt  ..................................................................................................2 5  
5. 3. 4.  
P K e n d p oi nt  ................................................................................................................2 5  
6.  
D A T A H A N D LI N G, P R E S E N T A TI O N C O N V E N TI O N S,  A N D 
D E FI NI TI O N  ..............................................................................................................2 6  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 8  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
6. 1.  
Data Ma na ge me nt  .......................................................................................................2 6  
6. 2.  
Data Prese nt ati o n C o n ve nti o ns  ...................................................................................2 6  
6. 3.  
A nal ysis Sets  ...............................................................................................................2 7  
6. 3. 1.  
Scree ne d Set  ................................................................................................................2 7  
6. 3. 2.  
E nr olle d Set  ................................................................................................................2 7  
6. 3. 3.  
Safet y Set  ....................................................................................................................2 7  
6. 3. 4.  
Q T/ Q Tc Se t .................................................................................................................2 7  
6. 3. 5.  
P K Set  .........................................................................................................................2 7  
6. 3. 6.  
P D Set  .........................................................................................................................2 7  
6. 3. 7.  
P K/ Q Tc Set  .................................................................................................................2 7  
6. 4.  
Baseli ne Defi niti o n  .....................................................................................................2 7  
6. 5.  
Baseli ne E C G Para meters, T -wa ve, U -wa v e  ..............................................................2 8  
6. 5. 1.  
Pre d ose Baseli ne  .........................................................................................................2 8  
6. 6.  
Deri ve d a n d Tra nsf or me d data  ...................................................................................2 8  
6. 6. 1.  
Baseli ne A ge  ...............................................................................................................2 8  
6. 6. 2.  
St u d y Da y  ...................................................................................................................2 8  
6. 6. 3.  
C ha n ge fr o m Baseli ne  .................................................................................................2 8  
6. 6. 4.  
C ha n ge fr o m Pre d os e Baseli ne E C G Para meters  .......................................................2 8  
6. 6. 5.  
Place b o -c orrecte d C ha n ge fr o m Baseli ne E C G Para meters  .......................................2 9  
7.  
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S  ...................................3 0  
7. 1.  
M ultice nter St u dies  .....................................................................................................3 0  
7. 2.  
Ot her Strata a n d C o variates  ........................................................................................3 0  
7. 3.  
E x a mi nati o n of S u b gr o u ps  .........................................................................................3 0  
7. 4.  
M ulti ple C o m paris o ns a n d M ulti plicit y ......................................................................3 0  
7. 5.  
Data ha n dli n g c o n v e nti o ns  .........................................................................................3 0  
7. 5. 1.  
Pre mat ure Wit h dra wal a n d Missi n g Data  ...................................................................3 0  
7. 5. 2.  
Missi n g Dates  .............................................................................................................3 1  
8.  
S T A TI S TI C A L A N A L Y SI S  ......................................................................................3 2  
8. 1.  
Dis p ositi o n of Partici pa nts  ..........................................................................................3 2  
8. 2.  
Pr ot oc ol De viati o ns  ....................................................................................................3 2  
8. 3.  
De m o gra p hic a n d Baseli ne Safet y C haracteristics  .....................................................3 2  
8. 4.  
Me dical Hist or y  ..........................................................................................................3 2  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 9  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
8. 5.  
Pri or a n d C o nc o mita nt Me dicati o n  .............................................................................3 2  
8. 6.  
Treat me nt C o m plia nce  ................................................................................................3 3  
8. 7.  
Car di o d y n a mic A nal yses  ............................................................................................3 3  
8. 7. 1.  
E val uati o n of Q T/ R R C orrecti o n Met h o ds  .................................................................3 3  
8. 7. 2.  
Pri mar y A n al ysis(es)  ..................................................................................................3 4  
8. 7. 3.  
Assa y Se nsiti vit y A nal ysis(es)  ...................................................................................3 5  
8. 7. 4.  
Ot her Car di o d y na mic A n al ysis(es)  .............................................................................3 6  
8. 7. 4. 1.  
Ot her C o nti n u o us Car di o d y na mic E n d p oi nts  .............................................................3 6  
8. 7. 4. 2.  
Cate g orical E n d p oi nts  .................................................................................................3 6  
8. 8.  
P har mac o ki netic a n d P har mac o d y na mic A nal yses  ....................................................3 7  
8. 9.  
P har mac o ki netic C o nce ntrati o n/ Q Tc A nal ysis ( E x pl orat or y A nal ysis)  .....................3 7  
8. 1 0.  
Safet y A nal yses  ..........................................................................................................3 7  
8. 1 0. 1.  
A d verse E v e nts  ...........................................................................................................3 7  
8. 1 0. 2.  
O verall S u m mar y of A d v erse E ve nts  .........................................................................3 7  
8. 1 0. 3.  
A Es b y S yste m Or ga n Class a n d Preferre d Ter m  .......................................................3 8  
8. 1 0. 4.  
A Es b y Preferre d T er m  ...............................................................................................3 8  
8. 1 0. 5.  
A Es b y S yste m Or ga n Class, Preferre d T er m a n d Se verit y  .......................................3 8  
8. 1 1.  
Cli nical La b orat or y E val uati o ns  .................................................................................3 8  
8. 1 2.  
Safet y Electr o car di o gra m  ...........................................................................................3 9  
8. 1 3.  
Vital Si g ns  ..................................................................................................................3 9  
8. 1 4.  
P h ysical E x a mi nati o n  .................................................................................................3 9  
9.  
R E F E R E N C E S  ...........................................................................................................4 0  
LI S T O F T A B L E S  
Ta ble  1:  
List of A b bre viati o ns  ..................................................................................................1 0  
Ta ble  2:  
Cate g ories f or T -Wa ve M or p h ol o g y  ..........................................................................1 9  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
Electr ocar di o gra m W a vef or m Ill ustr ati o n  ..................................................................1 5  
 
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 0  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
1.  
LI S T O F A B B R E VI A TI O N S  
T a ble  1 : 
List of A b bre vi ati o ns  
A b bre vi ati o n  
T er m 
Δ H R  
c ha n ge fr o m B aseli ne i n heart rate  
Δ P R  
c ha n ge fr o m B aseli ne i n P R i nter val  
Δ Q R S  
c ha n ge fr o m B aseli ne i n Q R S i nter val  
Δ Q T c  
c ha n ge fr o m B aseli ne i n t he Q T i nter val c orrecte d  
Δ Q T c F  
c ha n ge fr o m B aseli ne i n t he Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s 
f or m ula 
Δ Q T cI  
c ha n ge fr o m B aseli ne i n o pti mize d H R -c orrecte d Q T i nter val  
Δ Δ H R  
place b o -c orrecte d c ha n ge fr o m Baseli ne i n heart rate  
Δ Δ P R  
place b o -c orrecte d c ha n ge fr o m Bas eli ne i n P R i nter val  
Δ Δ Q R S  
place b o -c orrecte d c ha n ge fr o m Baseli ne i n Q R S i nter val  
Q T c  
place b o -c orrecte d c ha n ge fr o m Baseli ne i n t he Q T i nter val c orrecte d  
Q T c F  
place b o -c orrecte d c ha n ge fr o m Baseli ne i n t he Q T i nter val c orrecte d f or heart rate 
usi n g Fri d ericia’s f or m ula  
Δ Δ Q T cI 
place b o -c orrecte d c ha n ge fr o m Baseli ne i n o pti mize d H R -c orrecte d Q T i nter val  
A Da M  
a nal ysis data m o del  
A E  
a d verse e ve nt  
A R  
a ut o -re gressi ve 
A R H  
a ut o -re gressi ve wit h heter o ge neit y 
A U C  
area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve  
A U C 0 -9 6 
A U C fr o m ti me 0 t o 9 6 h o urs p ost d ose  
A U C 0 -∞ 
A U C fr o m ti me 0 e xtra p olate d t o i nfi nit y  
A U C 0 -t 
A U C fr o m ti me 0 t o t he last q ua ntifia ble c o nce ntrati o n  
C DI S C  
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m  
CI  
c o nfi de nce i nter val  
C L/ F  
a p pare nt t otal cleara nce fr o m plas ma after oral a d mi nistrati o n of A L X N 1 8 4 0  
C ma x  
ma xi m u m o bser ve d plas ma c o nce ntrati o n  
C S  
c o m p o u n d s y m metr y  
C S H  
c o m p o u n d s y m metr y wit h het er o ge neit y  
C T C A E  
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  
C u  
c o p per 
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E O S  
e n d of st u d y  
H R  
heart rate  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I U T 
i ntersecti o n u ni o n test 
L L O Q  
l o wer li mit of q ua ntificati o n 
L S  
least s q uares 
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 1  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
A b bre vi ati o n  
T er m 
M M R M  
mi xe d effects m o del f or re peate d meas ures  
M o  
m ol y b de n u m  
N CI  
Nati o nal Ca ncer I nstit ute  
P B C  
pri mar y biliar y c h ola n gitis  
P D  
p har mac o d y na mic  
P K  
p har mac o ki netic(s)  
P U F M o  
plas ma ultrafiltrate m ol y b de n u m  
Q T c  
c orrecte d Q T i nter val 
Q T c F  
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s f or m ul a  
Q T cI  
o pti mize d H R -c orrecte d Q T i nter val  
Q T c S  
I n di vi d ualize d heart rate c orrecte d Q T i nter val 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
S S S  
s u m of s q uare d sl o pes 
t1/ 2 
ter mi nal eli mi nati o n half-life 
T ma x  
ti me t o reac h ma xi m u m o bser ve d plas ma c o nce ntrati o n 
T O E P  
t oe plitz  
T O E P H  
t oe plitz wit h heter o ge neit y 
T Q T  
t h or o u g h Q T 
U L N  
u p per li mit of n or mal  
U L O Q  
u p per li mit of q ua ntificati o n  
Vz / F 
a p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase  
W D  
Wils o n disease  
λz  
a p pare nt ter mi nal -p hase eli mi nati o n rate c o nsta nt  
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 2  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
2.  
I N T R O D U C TI O N 
T his statistical a nal ysis pla n ( S A P) relates t o Ale xi o n P har mace uticals I n c. Pr ot oc ol A L X N 1 8 4 0 -
H V -1 0 7 “ A Ra n d o mize d, T hree -Treat me nt, T hree -Peri o d, Si x -se q ue nce, Cr oss o ver, Place b o- 
a n d Acti ve-C o ntr olle d, D o u ble -Bli n d f or A L X N 1 8 4 0 ( O pe n -La bel f or M o xifl o x aci n) T h or o u g h 
Q T/ Q Tc ( T Q T) St u d y t o E val uate t he Effect of A L X N 1 8 4 0 o n Car diac Re p olarizati o n i n 
Healt h y A d ult partici pa nts”, A me n d me nt  1.  
A L X N 1 8 4 0 ( bis -c h oli ne tetrat hi o m ol y b date) is a n o vel, first -i n-class, C u -pr otei n -bi n di n g a ge nt 
i n de vel o p me nt f or t he treat me nt of Wils o n Disease ( W D). T o f oll o w t he I nter nati o nal C o u ncil 
f or Har m o nisati o n (I C H) E 1 4 g ui da nce o n cli nical e val uati o n of Q T/ Q Tc i nter val pr ol o n gati o n 
a n d pr oarr h yt h mic p ote ntial f or n o n -a ntiarr h yt h mic dr u gs ( D H H S , 2 0 0 5), St u d y A L X N 1 8 4 0-
H V -1 0 7 is de dicat e d t o e val uati n g A L X N 1 8 4 0’s p ote ntial effect o n electr ocar di o gra m 
para meters, s pecifi call y, A L X N 1 8 4 0’s effect o n car diac re p olarizati o n, as meas ure d b y t he 
c orrecte d Q T i nter val.  
T his d oc u me nt ser ves as a pri mar y S A P f or t his st u d y. T his d oc u me nt d escri be s t he pri mar y, 
sec o n dar y (e x ce pt P K, P D), a n d safet y a nal ys es pla n ne d f or t his st u d y. P K, P D, a n d e x pl orat or y 
a nal ysis of A L X N 1 8 4 0 P K c o nce ntr ati o n o n Q T/ Q Tc will be c o vere d i n a s u p ple me ntal S A P.  
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 3  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
3.  
S T U D Y O B J E C TI V E( S) A N D E N D P OI N T( S)  
3. 1.  
St u d y O bjecti ve(s)  
T he  pri mar y o bje cti ve of t his st u d y is t o e val u ate t he effect of a s u prat hera p e utic d ose of 
A L X N 1 8 4 0 o n t he heart rate ( H R) -c orrect e d Q T i nter val wit h t he i nte nt t o e xcl u de a 1 0  ms 
effect.  
T he sec o n d ar y o bjecti ves of t he st u d y are:  
 T o de m o nstrate assa y s e nsi ti vit y of t he st u d y t o d etect a n effect o n t he mea n Q T/ Q Tc i nter val 
of a p pr o xi matel y 5 ms usi n g m o xifl o x aci n as a p ositi ve c o ntr ol.  
 T o e val uate t he s afet y a n d t olera bilit y of a si n gle oral s u prat hera pe utic d os e of A L X N 1 8 4 0 i n 
healt h y p artici pa nts.  
 T o asses s t he P K of A L X N 1 8 4 0 f oll o wi n g a d mi nistrati o n of a si n gl e oral s u prat hera pe utic 
d ose i n healt h y p artici pa nts.  
 T o e val uate t he effects of a si n gle oral s u prat h era p e utic d ose of A L X N 1 8 4 0 o n H R, P R a n d 
Q R S i nter vals, treat me nt -e mer ge nt T -wa v e m or p h ol o g y a b n or malities, a n d a p peara nce of U - 
wa ves.  
T he e x pl orat or y o bj ecti v e of t his st u d y is t o e val u ate t he effects of t otal M o a n d P U F M o (as a 
s urr o gate meas ure of A L X N 1 8 4 0 P K) c o nce ntrati o ns o n Q T/ Q Tc.  
3. 2.  
St u d y E n d p oi nt(s)  
3. 2. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt is place b o -c orrecte d c ha n ge fr o m Baseli ne Q Tc ( Δ ΔQ Tc) f or A L X N 1 8 4 0 
usi n g t he b y -ti me p oi nt a nal ysis. I n t he a bse nce of a s u bsta ntial effect (Secti o n  3. 2. 2. 1. 1 0 ) o n 
heart rate, t he Fri derici a met h o d will be use d f or heart rate c orrecti o n. If a s u bsta ntial H R effect 
is o bser ve d, ot her c orrecti o n met h o ds s uc h as o pti mize d H R-c orrect e d Q T i nter val ( Q TcI)  ma y 
be e x pl ore d a n d c o m pare d a s dee me d necess ar y a n d a p pr o priate. T h e met h o d t hat re m o ves t he 
H R de pe n de n ce m ost effi cie ntl y will be c h ose n as t he pri mar y c orrecti o n met h o d a n d 
c orres p o n di n g pri mar y e n d p oi nt is Δ Δ Q Tc wit h t his pri mar y c orrecti o n met h o d f o r A L X N 1 8 4 0 
usi n g t he b y -ti me p oi nt a nal ysis.  
T he select e d pri mar y c orrecti o n met h o d will als o be use d f or: 1) Assa y se nsiti vit y; a n d 2) t h e 
relati o ns hi p bet wee n t otal M o or P U F M o (as s urr o gat e meas ures of A L X N 1 8 4 0 P K) 
c o nce ntr ati o ns i n plas ma a n d ∆∆Q Tc.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 4  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
3. 2. 2.  
Sec o n d ar y E n d p oi nts  
3. 2. 2. 1.  
C ar di o d y n a mic E n d p oi nts  
 T he Δ Δ Q Tc f or m o xifl o xaci n;  
 T he c ha n ge fr o m Baseli n e i n H R, Q Tc F, P R, Q R S ( ΔH R, Δ Q Tc F, Δ P R a n d 
Δ Q R S);  
 T he place b o -c orrecte d c h a n ge fr o m Bas eli ne H R, P R, a n d Q R S ( Δ ΔH R, Δ Δ P R 
a n d Δ Δ Q R S);  
 Cate g orical o utliers f or  Q Tc F, H R, P R, a n d Q R S;  
 T he fre q u e nc y of treat me nt -e mer ge nt c ha n ges of T-wa ve m or p h ol o g y a n d U -wa v e 
prese nce.  
 If a s u bsta ntial H R effect ( is o bser ve d after A L X N 1 8 4 0 a d mi nistrati o n,  
o  T he place b o -c orrecte d c h a n ge fr o m b aseli ne i n Δ Q Tc ( Δ ΔQ Tc) usi n g t h e 
b y -ti me p oi nt a nal ysis (e n d p oi nts calc ulate d usi n g c orrecti o n met h o ds t hat 
n ot use d as pri mar y will be c o nsi dere d as sec o n dar y)  
o  T he c h a n ge fr o m Baseli n e i n Q Tc I ( ΔQ TcI)   
o  Cate g orical o utliers f or Q TcI  
Fi g ure  1  is a gra p hic ill ustrati o n of electr o car di o gra m wa ve f or m, descri pti o ns a n d al g orit h ms f or 
car di o d y na mic e n d p oi nts are des cri be d i n Secti o n  3. 2. 2. 1. 1  t o Secti o n  3. 2. 2. 1. 9   


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 5  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
Fi g ure  1 : 
Electr oc a r di o gr a m  W a vef or m Ill ustr ati o n  
 
3. 2. 2. 1. 1.  Q T I nter v al  
 
D urati o n of ve ntric ul ar acti vati o n a n d rec o v er y; i ncl u des t he Q R S, S T se g me nt, a n d T -wa v e.   
3. 2. 2. 1. 2.  Q Tc Fri derici a C orrecti o n  
T he meas ur e d Q T dat a will be c orrecte d f or heart rate usi n g Fri dericia c orrecti o n met h o d, as per 
t he f oll o wi n g f or m ula:  
Fri deri cia’s C orrecti o n  
𝑄𝑇𝑐=
𝑄𝑇 (𝑚𝑠)
[𝑅𝑅(𝑚𝑠)
1 0 0 0
]1 / 3
 
W here R R is t he ti me bet wee n 2 c o ns ec uti ve beats/c ycl es, meas ure d as t he ti me bet wee n t he 
pea ks of 2 c o ns ec uti ve R wa ves  
3. 2. 2. 1. 3.  I n di vi d u alize d Q T  C orrecti o n Met h o ds  
I n case a s u bsta ntial H R effect (Secti o n  3. 2. 2. 1. 1 0 ) is o bser ve d o n-tr eat me nt wit h A L X N 1 8 4 0, 
dr u g -free Q T/ R R data will be c ollecte d o ver a ra n ge of H R see n pri or t o treat me nt t o all o w t he 
ge n erati o n of o pti m ize d Q T c orrecti o n met h o d. Q Tc will be calc ul ate d fr o m Da y  −1 fr o m all 
e val ua ble Q T/ R R pairs i n t he 2 4 -h o ur rec or di n g ( Gar nett  2 0 1 2 ). T h ese dat a will be use d t o 
o btai n t he R R i nter val ( H R) a n d Q T data t o e n a ble deri vati o n of Q TcI as f oll o ws .   
  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 6  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
1.  A n o pti miz e d H R -c orrect e d Q T i nter val ( Q TcI) will be deri ve d fr o m a br oa der ra n ge of H Rs 
b y usi n g all Q T/ R R data o n Da y −1 of Treat me nt Peri o d 1. T he Q T/ R R pairs fr o m eac h 
partici pa nts will be use d f or t hat partici pa nt’s i n di vi d ual c orrecti o n c oeffici e nt, w hic h will be 
deri ve d fr o m a li near re gressi o n m o del: l o g( Q T)  = l o g(a) + b ×l o g( R R). T h e c oeffi cie nt of 
l o g( R R) f or each s u bject, b i, will t he n be use d t o calc ulate Q T cI f or t hat partici pa nt as 
f oll o ws: Q TcI  =  Q T/ R Rbi. 
2.  I n a d diti o n t o Q TcI, if nee de d, i n di vi d ualize d H R-c orrecte d Q T i nter val ( Q Tc S) ma y be 
calc ulate d fr o m Q T/ R R data o btai ne d at s u pi ne resti n g ti me p oi nts o n D a y −1 of Treat me nt 
Peri o d 1. Bas e d o n Q T/ R R pairs fr o m all partici pa nts, t he Q Tc S c orrecti o n c oeffi cie nt will be 
deri ve d fr o m a li near mi x e d -effects m o del: l o g( Q T)  = l o g(a) + b × l o g( R R) a n d se x i ncl u de d 
as a fi x e d effect a n d p artici pa nt i ncl u de d as a ra n d o m effect f or b ot h i nterce pt a n d sl o pe. T he 
c oeffi cie nt of l o g( R R) f or eac h p artici pa nt, b i, will t he n be use d t o calc ul ate Q Tc S f or eac h 
partici pa nt as f oll o ws: Q Tc S  =  Q T/ R R bi.  
3. 2. 2. 1. 4.  P R I nt er v al  
P R i nter val is t he ti me fr o m o nset of atrial acti vati o n t o o nset of ve ntric ular acti vati o n, it i ncl u des 
P -wa ve a n d P R se g me nt.  
3. 2. 2. 1. 5.   Q R S I nter v al  
T he Q R S i nter val is a series of deflecti o ns i n a n el ectr ocar di o gra m t hat r e prese nt electrical 
acti vit y ge n erat e d b y ve ntric ular de p olarizati o n pri or t o c o ntracti o n of t he ve ntricle s, i ncl u di n g 
t he Q-wa v e, R -wa v e, a n d S -wa ve.   
3. 2. 2. 1. 6.  T -w a ve  
T -wa ve re prese nts ve ntri c ular re p olarizati o n.  
3. 2. 2. 1. 7.  C h a n ges i n T -w a ve M or p h ol o g y  
T -wa ve m or p h ol o g y c ha n ge will be assesse d ma n uall y, f oll o wi n gs are cate g ories of T -wa ve 
m or p h ol o g y.  
T a ble  2 : 
C ate g ories f or T -W a v e M or p h ol o g y  
C ate g or y  
Descri pti o n  
N or mal T -wa ve  
A n y p ositi ve T -wa ve n ot meeti n g a n y criteri o n bel o w  
Flat T -wa ve  
T a m plit u de < 1 m m (eit her p ositi ve or ne gati ve) i ncl u di n g a flat 
is oelectric li ne 
N otc he d T -wa ve ( +)  
Prese nce of n otc h(es) of at least 0. 0 5 m V a m plit u de o n asce n di n g or 
desce n di n g ar m of t he p ositi ve T -wa ve  
Bi p hasic  
T -wa ve t hat c o ntai ns a sec o n d c o m p o ne nt wit h a n o p p osite p hase t hat is 
at least 0. 1 m V dee p ( b ot h p ositi ve/ ne gati ve a n d ne gati ve/ p ositi ve a n d 
p ol y p hasic T -wa ves i ncl u de d)  
N or mal T -wa ve ( -) 
T a m plit u de t hat is ne gati ve, wit h o ut bi p hasic T -wa ve or n otc hes  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 7  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
C ate g or y  
Descri pti o n  
N otc he d T -wa ve ( -) 
Prese nce of n otc h(es) of at least 0. 0 5 m V a m plit u de o n desce n di n g or 
asce n di n g ar m of t he ne gati ve T -wa ve  
3. 2. 2. 1. 8.  U -w a ve  
T he U -w a ve is n ot o bser ve d i n all E C Gs a n d w he n o bser ve d, ca n be eit her n or mal or a b n or mal. 
U -wa v e will be assesse d ma n uall y.  
3. 2. 2. 1. 9.  He art R ate  
T he electrical de p olarizati o n of car diac m uscle n or mall y prece d es c o ntracti o n of t he heart 
m uscle. U n der n or mal circ u msta nces,  car diac c o ntracti o ns res ult i n ejecti o n of bl o o d i nt o t he 
arterial s yste m. T he d e p olariz ati o n rate of t he car diac ve ntricles is r eferre d t o as t he ' heart rate', 
w hic h us uall y e q uals t he n u m ber of car diac c o ntracti o ns ( meas ure d as heart beats per mi n ute) 
an d t he n u m ber of p eri p h eral p ulses ( meas ure d as t he p ulse rate).  
3. 2. 2. 1. 1 0.  S u bst a nti al Effect o n He art R ate  
S u bsta ntial effect o n he art rate is defi ne d as t he lar gest L S mea n i n place b o -c orrecte d c h a n ge 
fr o m baseli ne i n Δ H R ( Δ Δ H R) is great er t ha n 1 0 b p m i n t he b y-ti me p oi nt a nal ysis.  
3. 2. 2. 2.  
P h ar m a c o ki netic a n d P h ar m a c o d y n a mic Assess me nt a n d P ar a meters  
T he f oll o wi n g pl as ma P K para met ers will be calc ulate d as e n d p oi nts f or t otal M o a n d P U F M o 
(as a s urr o gate meas ure of A L X N 1 8 4 0) usi n g n o n c o m part me ntal met h o ds wit h P h oe ni x ® 
Wi n N o nli n ® ( Certara U S A I n c., Pri ncet o n, Ne w J erse y) Versi o n 8. 0 or hi g her or S A S Versi o n 
9. 4 or hi g h er ( S A S I nstit ute I n c., Car y, N ort h Car oli na), as a p plica bl e. Calc ulati o ns will be base d 
o n t he act ual sa m pli n g ti mes ela pse d fr o m t he refere nce d osi n g ti m e i n t he peri o d as rec or de d 
d uri n g t he st u d y.  
 Ti me dela y bet wee n t he ti me of d osi n g a n d ti me of a p peara n ce of M o 
c o nce ntr ati o n i n plas ma ( T la g) 
 Ti me ( o bser ve d ti me p oi nt) of last q ua ntifia ble c o nce ntrati o n ( T last) 
 Ma xi m u m o bser ve d c o nce ntrati o n i n plas ma ( C ma x ) 
 Ti me t o reac h ma xi m u m o bser ve d c o n ce ntr ati o n i n plas ma ( T ma x ) 
 Area u n d er t he c o nce ntr ati o n i n plas ma vers us ti me c ur ve ( A U C) fr o m ti me 0 t o 
t he last q ua ntifia ble c o nce ntrati o n ( A U C0 -t) 
 A U C fr o m ti me 0 t o 9 6 h o urs p ost d ose ( A U C 0 -9 6) 
  A U C fr o m ti me 0 e xtra p olate d t o i nfi nit y ( A U C 0 -∞) 
 A p pare nt ter mi nal -p hase eli mi nati o n rate c o nsta nt ( λz) 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 8  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
 Ter mi nal eli mi nati o n half -life (t1/ 2) 
 A p pare nt t otal cle ara n ce fr o m plas ma aft er oral a d mi nistrati o n of A L X N 1 8 4 0 
( C L/ F) 
 A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi n al p hase ( Vz/ F)  
 
A d diti o nal P K para meters ma y be calc ul ate d if dee me d a p pr o priate.  
 
P har mac o ki netic sa m ples ma y b e use d f or t he q ua ntificati o n of P D e n d p oi nts s uc h as 
t otal C u, P U F C u, la bile-b o u n d C u, cer ul o plas mi n, a n d cer ul o plas mi n -b o u n d C u.  
3. 2. 2. 3.  
S afet y E n d p oi nts  
 A d verse E v e nts  
 Cli nical la b orat or y test res ults ( he mat ol o g y, s er u m c he mistr y, a n d uri nal ysis)  
 Vital si g ns meas ur e me nts  
 1 2 -lea d safet y E C G res ults 
 P h ysical e x a mi nati o n fi n di n gs  
3. 2. 3.  
E x pl or at or y E n d p oi nts  
T he e x pl orat or y e n d p oi nt is t he relati o ns hi p bet wee n t otal M o or P U F M o (as s urr o gate m eas ures 
of A L X N 1 8 4 0 P K) c o nce ntrati o ns i n plas ma a n d ∆∆Q Tc.  
3. 3.  
St atistic al H y p ot heses  
3. 3. 1.  
Pri m ar y H y p ot hesis  
T he statistical h y p ot hesis t o be teste d f or t he pri mar y assess me nt  of Q T pr ol o n gati o n f or t h e 
A L X N 1 8 4 0 treat me nt is:  
H 0: ∪{ μ D(i)  –  μ P(i) } ≥1 0, i = 1, 2, …, 1 2  
H 1: ∩{ μ D(i)  –  μ P(i) } < 1 0, i = 1, 2, …, 1 2  
w here μ D(i)  a n d μ P(i)  are t he L S me a n of Δ Q Tc f or A L X N 1 8 4 0 a n d place b o at p ost d ose ti me p oi nt 
i ( 0. 5, 1, 2, 3, 4, 5, 6, 7, 8, 1 0, 1 2, a n d 2 4 h o urs p ost d ose), res pecti vel y.  
If t he u p per b o u n d of t he 2-si de d 9 0 % CI of L S m ea n Δ Δ Q Tc lies bel o w 1 0 ms at all 1 2  p ost d ose 
ti me p oi nts, A L X N 1 8 4 0 will be c o ncl u de d n ot t o ha ve a si g nifica nt effect o n Q T i nter val 
pr ol o n gati o n.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 1 9  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
3. 3. 2.  
Sec o n d ar y H y p ot hesis  
T he sec o n d ar y h y p ot hesis t o be teste d f or t he sec o n dar y assess me nt of Q T pr ol o n gati o n f or t he 
m o xifl o x aci n  
H 0: μM(i) –  μ P(i) ≤ 5, i = 1, 2, 3 
H 1: μM(i) –  μ P(i) > 5 , i = 1 , 2 , 3   
w here μ M(i)  a n d μ P(i)  are t he L S me a n of Δ Q Tc f or m o xifl o x aci n a n d place b o at p ost d ose ti me 
p oi nt i ( 1, 2, a n d 3 h o urs p ost d ose), res pecti vel y. M ulti plicit y will be c o ntr olle d b y usi n g a 
H oc h ber g pr oce d ure ( H o c h ber g , 1 9 8 8 ) wit h a dj uste d 1-si de d si g nifica n ce le vels of 5 %, 2. 5 %, 
a n d 1. 6 7 % f or statistical testi n g, res p ecti vel y, of t he 3 p -val ues ra n ke d fr o m lar gest t o s mallest.  
T he lar gest p -v al ue will be e val uat e d usi n g a 5 % si g nifica n ce testi n g le vel a n d t he s mallest will 
be e val uat e d usi n g a 1. 6 7 % si g nifica nce t esti n g le vel.  Testi n g will start wit h lar gest p -val ue, a n d 
c o nti n ue se q ue ntiall y t hr o u g h t he ra n ke d p -val ues, u ntil t he first si g nifica nt val ue is f o u n d at 
w hic h p oi nt all s maller p -val ues are c o nsi dere d si g nifica nt. If at least 1 test is si g nifica nt at t he 
s pecifie d le v el, assa y se nsiti vit y will be c o n cl u de d. 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 0  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
4.  
S T U D Y D E SI G N  
T his is a ra n d o mize d, 3 -treat me nt, 3-p eri o d, 6 -se q ue nce, cr oss o ver, pl ace b o- a n d 
acti ve-c o ntr olle d, d o u ble -bli n d f or A L X N 1 8 4 0, o pe n -la bel f or m o xifl o x aci n st u d y i n healt h y 
a d ult partici pa nts. M o xifl o x aci n will be use d as t he acti ve c o ntr ol.  
A p pr o xi matel y 5 4 p artici pa nts will be ra n d o mize d t o e ns ure t here will be 4 5 e val ua ble 
partici pa nts wit h  data fr o m all treat me nt peri o ds. T o e ns ure se q u e nces are bala nce d wit hi n se x, 
partici pa nt ra n d o mizati o n will be stratifie d b y s e x. St u d y i nter ve nti o n will be gi v e n i n 
ra n d o mize d se q ue nces: A B C, A C B, B A C, B C A, C A B, a n d C B A, wit h eac h i nter ve nti o n 
a d mi nistere d wit h 2 4 0 m L of water f oll o wi n g a n o ver ni g ht fast of at least 1 0 h o urs. N o f o o d will 
be all o we d f or at least 4 h o urs p ost d ose. Water ca n be all o we d as d esire d e x ce pt f or 1  h o ur 
bef ore a n d aft er dr u g a d mi nistrati o n:  
Car di o d y n a mic  assess me nt will be perf or me d f or a p pr o xi matel y 2 5 h o urs o n Da y – 1 of 
Treat me nt Peri o d 1 a n d Da y  1 t o Da y 2 of eac h tr eat me nt peri o d. Bl o o d sa m ples f or P K will be 
c ollecte d pre d ose a n d at s pecifie d ti mes u p t o 9 6 h o urs after t h e Da y 1 d os e i n eac h tr eat me n t 
peri o d.  
T wel ve -le a d ele ctr ocar di o gra ms will be e xtracte d fr o m a c o nti n u o us ( H olter) rec or di n g b y t he 
ce ntral la b orat or y. T o s u p p ort hi g h q ualit y data f or e xtracti o n, partici pa nts will be resti n g i n t he 
s u pi ne p ositi o n f or at least 1 5 mi n utes pri or t o a n d 5 mi n utes after eac h n o mi nal ti me p oi nt f or 
E C G e xtracti o n . Bl o o d f or plas ma P K will be c ollecte d as cl ose as p ossi ble t o n o mi nal ti me after 
c o m pleti o n of E C G e xtracti o n wit h act ual ti mes f or bl o o d sa m ple c ollecti o ns rec or de d.  
Partici pa nts will be d o micil e d i n t he cli nic f or 7 da ys i n Tr eat me nt Peri o d 1 a n d f or 6 da ys i n 
Treat me nt Peri o ds 2 a n d 3, starti n g o n Da y – 2 f or Treat me nt Peri o d 1 a n d o n t he da y bef ore 
d osi n g ( Da y – 1) f or Treat me nt Peri o ds 2 a n d 3, u ntil safet y pr oce d ures ha v e bee n c o m plete d a n d 
revie we d o n Da y 5 . T h ere will be a was h o ut of at least 1 4 da ys bet wee n d ose a d mi nistrati o n i n 
eac h p eri o d.  
All partici pa nts (i ncl u di n g partici pa nts w h o ter mi nate t he st u d y earl y) will ret ur n t o t he st u d y site 
1 4 da ys ( ± 2 da ys) after t he last a d mi nistrati o n o f st u d y i nter venti o n f or f oll o w -u p pr oce d ures a n d 
t o deter mi ne if a n y A E h as occ urre d si nce t he last st u d y visit. 
D urati o n of partici pati o n f or eac h partici p a nt fr o m t he Scree ni n g Visit t o t he E n d -of -St u d y 
( E O S) Visit will be a p pr o xi matel y 7 0 da ys. T his i ncl u des u p t o 2 9  da ys f or t he Scree ni n g Peri o d, 
st u d y i nter ve nti o n a d mi nistrati o n o n Da y 1 of eac h treat me nt peri o d, a mi ni m u m of a 1 4 -da y 
was h o ut bet wee n st u d y i nter ve nti o n a d mi nistrati o n i n eac h treat me nt peri o d, a n d 1 4  da ys 
( ± 2 da ys) f or t h e E O S Visit.  
4. 1.  
D efi niti o n of St u d y Dr u gs  
Treat me nt A: A si n gle oral d ose of A L X N 1 8 4 0 1 2 0 m g a d mi nistere d as 1 5 -m g e nteric -c oate d 
ta blets (s u prat hera pe utic d ose) 
Treat me nt B: A si n gl e oral d ose of e nteric -c oate d place b o ta blets matc hi n g A L X N 1 8 4 0  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 1  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
Treat me nt C: A si n gl e oral  d ose of m o xifl o x aci n 4 0 0 m g  
4. 2.  
S a m ple Size C o nsi der ati o ns  
4. 2. 1.  
S a m ple Size J ustific ati o ns  
A sa m ple siz e of a p pr o xi matel y 5 4 p artici pa nts w as c h ose n t o o btai n 4 5 e val ua ble partici p a nts t o 
c o m plete t he st u d y. Ass u mi n g a 1 -si de d 5 % si g nifica nce l e vel a n d a wit hi n-pa rtici pa nt S D of 
8  ms f or Δ Q Tc f or all treat me nt gr o u ps a n d a tr u e mea n differe nce of 3  ms i n Δ Q Tc bet w ee n 
A L X N 1 8 4 0 a n d pla ce b o, base d o n t he calc ulati o n of t he sa m ple siz e f or a T Q T st u d y ( Z h a n g , 
2 0 0 8 ), a sa m ple siz e of 4 5 e val ua ble p artici pa nts will pr o vi de a p o wer of 9 0 % t o de m o nstrate 
t hat t he u p per b o u n d of all t he 2-si de d 9 0 % CIs o n Δ Δ Q Tc will fall bel o w 1 0 ms f or u p t o 1 2 
p ost d ose ti me p oi nts. To acc o u nt f o r a dr o p-o ut rat e of a p pr o xi matel y 1 6 %, 5 4 partici pa nts will 
be e nr olle d.  
Base d o n t h e cal c ulati o n of t he sa m ple siz e f or a T Q T st u d y ( Z h a n g , 2 0 0 8 ), as t he test is 
perf or me d at 3 ti me p oi nts se paratel y ( 1, 2, a n d 3 h o urs), a 1 -si de d 5 % si g nifica nce le vel ( wit h 
a dj uste d 1 -si de d si g nifi ca nce le vels of 5 %, 2. 5 %, a n d 1. 6 7 %) is use d al o n g wit h a wit hi n -
partici pa nt S D of 8 ms f or Δ Q Tc a n d a tr u e effect of m o xifl o x aci n of 1 0 ms, a sa m ple siz e of 4 5 
e val ua ble p artici pa nts will pr o vi de > 9 8 % p o wer t o de m o nstrate assa y s e nsiti vit y of e x cl u di n g a 
mea n differe nce of 5 ms i n Δ Q Tc bet w ee n m o xifl o x ac i n a n d place b o gr o u ps. 
4. 3.  
R a n d o miz ati o n  
A ra n d o mizati o n sc he d ul e will be ge nerate d, a n d ra n d o mizati o n n u m bers will be assi g ne d b ef ore 
t he first d ose of st u d y i nter ve nti o n is a d mi nistere d o n Da y 1 of Peri o d 1.  
After me eti n g all i ncl usi o n a n d n o ne of t he e x cl us i o n criteria, partici pa nts will be ra n d o mize d t o 
o ne of t he 6 pre -s pecifie d treat me nt se q ue n ce. T o e ns ure se q u e nces are b al a nce d wit hi n se x, 
ra n d o mizati o n will be stratifie d b y s e x. 
4. 4.  
Cli nic al Assess me nts  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 2  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
P h ase  Scree ni n g  
S a me Sc he d ule f or Tre at me nt Peri o ds 1, 2, a n d 3  
E O S  
 
D a y  – 2 9 t o – 2  
C hec k -i n 
( D a y -2 f or 
Peri o d 1;  D a y -1 
f or Peri o ds 2 
a n d 3  
1  
2  
3  
4  
5  1 5 ± 2  
– 2  
– 1  
Pr oce d ure ( a) 
H o urs  
–  
–  
–  
-0. 7 5  -0. 5  -0. 2 5  
0  
0. 5  
1  
2  
3  
4  
5  
6  
7  
8  
1 0  1 2  2 4  4 8  7 2  9 6  
–  
A d missi o n t o cli nic ( b) 
 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disc har ge fr o m cli nic (c) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
O ut patie nt visit ( d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y
E rr o r! Refe re nce 
s o urce n ot f o u n d. 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gr a p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser ol o g y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m F S H (f) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m c o p per a n d 
cer ul o plas mi n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht, wei g ht, a n d B MI ( g) 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
P h ysical e xa mi nati o n ( h) 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Vital si g n meas ure me nts (i) 
X  
X  
X  
X  
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
X  
X  
X  
X  
X  
1 2 -lea d safet y E C G(j) 
X  
X  
X  
X  
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
X  
 
 
X  
X  
Cli nical la b orat or y testi n g  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
X  
X  
Uri nal ysis  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Dr u g/alc o h ol/c oti ni ne scree n  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m pre g na nc y test ( k) 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Ra n d o mizati o n ( Peri o d 1 
o nl y)  
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St u d y i nter ve nti o n 
a d mi nistrati o n (l)  
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 2 -lea d H olter E C G( m) 
 
 
X  
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
P K bl o o d sa m ple ( n) 
 
 
 
X  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
 
Fasti n g peri o d  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
N o n -f asti n g peri o d 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 3  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
N o n p har mac ol o gic t hera pies 
a n d pr oce d ures  
X  
Pri or/c o nc o mita nt 
me dicati o ns  
X  
A b bre viati o ns: A Es, a d verse e ve nts; B MI, b o d y mass i n de x; E C G, electr ocar di o gra m; E O S, e n d of st u d y; F S H, f ollicle -sti m ulati n g h or m o ne; P K, p har mac o ki netic.  
N otes:  
(a) W he n pr oce d ures o verla p or occ ur at t he sa me ti me p oi nt, all bl o o d dra ws s h o ul d f oll o w vital si g ns or E C Gs, a n d P K sa m pli n g s h o ul d be ti me d t o occ ur last a n d as 
cl ose t o t he sc he d ule d ti me wi n d o w as p ossi ble.  
( b) Partici pa nts will be as ke d t o arri ve at t he st u d y site o n Da y – 2  of Treat me nt Peri o d 1 a n d o n t he da y bef ore t h e start of d osi n g ( Da y – 1) of Treat me nt Peri o ds 2 a n d 3. 
T he assess me nts sc he d ule d f or Da y – 2 of Treat me nt Peri o d 1  will n ot be re peate d o n Da y – 1 of Treat me nt Peri o d 1.  
(c) Disc har ge fr o m t he st u d y site will occ ur after t he 9 6 -h o ur P K sa m ples a n d after c o m pleti o n a n d re vie w b y t he I n vesti gat or of all 9 6 -h o ur safet y assess me nts (i ncl u di n g 
safet y la borat or y test res ults) o n Da y  5 of eac h st u d y peri o d. T h ere will be a was h o ut of at least 1 4 da ys bet wee n d ose a d mi nistrati o n i n eac h peri o d.  
( d) T he E O S Visit will occ ur 1 4 da ys ( ± 2 da ys) after t he last d ose of st u d y i nter ve nti o n i n Peri o d 3 or u p o n earl y disc o nti n uati o n.  
(e) A f ull me dical hist or y will be p erf or me d at Scree ni n g o nl y. A n y s u bse q ue nt c ha n ges t o healt h stat us will be assesse d at eac h C hec k -i n. 
(f) Fe males o nl y.  
( g) Hei g ht a n d wei g ht will be meas ure d a n d B MI calc ulate d at Scre e ni n g o nl y. O nl y wei g ht will be meas ure d at C hec k -i n a n d E O S. 
( h) A f ull p h ysic al e xa mi nati o n will be p erf or me d at Scree ni n g. A brief p h ysical e xa mi nati o n will be p erf or me d at C hec k -i n a n d E O S. 
(i) Pre d ose vital si g ns o n Da y 1 ma y be o btai ne d u p t o 1. 5 h o urs bef ore d osi n g.  
(j) Pre d ose E C G o n Da y 1 m a y be o btai ne d u p t o 1. 5 h o urs bef ore d osi n g.  
( k) W o me n o nl y.  
(l) T he ti me of st u d y i nter ve nti o n ( A L X N 1 8 4 0, place b o, or m o xifl o xaci n) d osi n g will be calle d “ 0” h o ur i n eac h peri o d.  
( m) C o nti n u o us 1 2 -lea d H olter E C G will be p erf or me d o n Da y -1 of Peri o d 1 o nl y t o rec o r d t he b aseli n e E C G, w hic h will all o w e xtracti o n of E C G rec or di n gs t hat matc h 
t he ti me p oi nts of Da y 1 of Peri o ds 1, 2 a n d 3. O n Da y -1, partici pa nts s hall f oll o w t he Da y  1 s u pi ne p ositi o ni n g sc he d ule. Partici pa nts s hall ass u me s u pi ne p ositi o ni n g 
starti n g at least 1 5 mi n utes bef ore t h e Da y 1 ti me p oi nts f or E C G e xtracti o n a n d c o nti n ue t o re mai n i n t he s u pi ne p ositi o n u ntil 5 mi n u tes after t he ti me p oi nt. T he -0. 2 5 
h o ur pre -d ose E C G ti me p oi nt will be use d as t he 2 4 -h o urs E C G ti me p oi nt of Da y -1, Peri o d 1.  
( n) Pr e d ose sa m ples o n Da y 1 ma y be o btai ne d u p t o 1. 5 h o urs bef ore d osi n g.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 4  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
5.  
P L A N N E D A N A L Y S E S  
5. 1.  
I nteri m A n al yses 
N o i nteri m a nal ysis is pla n ne d f or t his st u d y.  
5. 2.  
Fi n al A n al ysis  
T he fi nal a n al ysis will be perf or me d f oll o wi n g t h e data base l oc k after t he last partici pa nt has 
c o m plete d t he fi nal f oll o w -u p assess me nt.  
5. 3.  
C h a n ges fr o m A n al ysis S pecifie d i n t he Pr ot oc ol  
T he ori gi nal c orrecti o n met h o d pr o p ose d f or pri mar y e n d p oi nt is place b o -c orrecte d c ha n ge fr o m 
Baseli ne Q Tc F ( Δ ΔQ Tc F) f or A L X N1 8 4 0  usi n g  t h e b y-ti me p oi nt a nal ysis.  
W hic h c orrecti o n met h o d t o be use d as pri mar y c orrecti o n will be bas e d o n w het her t here is a 
s u bsta ntial H R effect (Secti o n  3. 2. 2. 1. 1 0 ) o n -treat me nt wit h A L X N 1 8 4 0, ot her c orrecti o n 
met h o d s uc h as o pti miz e d H R-c orrecte d Q T i nter val ( Q TcI) ma y  be us e d as a p pr o priate i n t he 
prese nce of s u bsta ntial H R effect.   
T he select e d pri mar y c orrecti o n met h o d will als o be use d f or: 1) Assa y se nsiti vit y; a n d 2) t h e 
relati o ns hi p bet wee n t otal M o or P U F M o (as s urr o gat e meas ures of A L X N 1 8 4 0 P K) 
c o nce ntr ati o ns i n plas ma a n d ∆∆Q Tc.  
5. 3. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt is place b o -c orrecte d c ha n ge fr o m Baseli ne i n Q T c ( Δ ΔQ Tc) f or 
A L X N 1 8 4 0 usi n g t h e b y-ti me p oi nt a nal ysis.  
5. 3. 2.  
Sec o n d ar y e n d p oi nts  
 T he Δ Δ Q Tc f or m o xifl o xaci n  
If a s u bsta ntial H R effect is o bser ve d aft er A L X N 1 8 4 0 a d mi nistrati o n, 
 T he place b o -c orrecte d c h a n ge fr o m b aseli ne i n Δ Q Tc ( Δ ΔQ Tc) usi n g t h e b y -ti me 
p oi nt a nal ysis ( E n d p oi nts calc ula te d usi n g c orrecti o n met h o ds t hat n ot use d as 
pri mar y will be c o nsi dere d as sec o n d ar y)  
 T he c ha n ge fr o m Baseli n e i n Q Tc I ( ΔQ Tc I) 
 Cate g orical o utliers f or Q Tc I 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 5  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
5. 3. 3.  
E x pl or at or y e n d p oi nt  
T he e x pl orat or y e n d p oi nt is t he relati o ns hi p bet wee n t otal M o or P U F M o (as s urr o gate m eas ures 
of A L X N 1 8 4 0 P K) c o nce ntrati o ns i n plas ma a n d ∆∆Q Tc.  
5. 3. 4.  
P K e n d p oi nt  
T he f oll o wi n g e n d p oi nt is a d de d  
 Ti me ( o bser ve d ti me p oi nt) of last q ua ntifia ble c o nce ntrati o n ( T last) 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 6  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
6.  
D A T A H A N D LI N G, P R E S E N T A TI O N C O N V E N TI O N S,  A N D 
D E FI NI TI O N  
6. 1.  
D at a M a n a ge me nt  
St u d y d ata i de ntifie d i n t he sc he d ule f or ti me a n d e ve nts ( Secti o n  4. 4 ) will be c ollecte d, a n d 
s o urce verifie d, o n t he electr o nic dat a ca pt ur e t o ol R A V E. Cli nical la b orat or y testi n g dat a, E C G 
data, a n d P K data are n ot c ollecte d i n t he R A V E a n d are pr o vi d e d fr o m e xter nal la b orat ories. 
Data st ora ge, data tra nsfer a n d cle a ni n g pr o cess will be c o vere d i n t he d ata ma na ge me nt pla n.  
All st u d y data will be f or m ulate d i nt o re g ul at or y c o m plia nt data sets. Data will be ma p pe d t o t he 
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m ( C DI S C) St u d y Data Ta b ulati o n M o del 
( S D T M) a n d ser ve as t he so urce dat a fr o m t he trial. All st u d y a nal yses will be c o m plete d usi n g 
a nal ysis d ata sets t hat are deri ve d fr o m t he S D T M a n d f oll o w t he C DI S C A nal ysis Dat a M o del 
( A Da M) arc hitect ure. 
Data ma ni p ulati o n a n d a nal yses will be perf or me d pri maril y usi n g S A S versi o n 9. 4 or hi g h er 
( S A S I nstit ute I nc., Car y, N ort h Car oli na).  
6. 2.  
D at a Prese nt ati o n C o n ve nti o ns  
C o nti n u o us varia bles (e. g. a ge) are s u m marize d usi n g descri pti ve statistics (t he n u m ber of 
partici pa nts wit h a vaila bl e data, t he mea n, sta n dar d de viati o n ( S D), me dia n a n d mi ni m u m a n d 
ma xi m u m). Cate g orical varia bles (e. g. race) are s u m marize d usi n g c o u nts a n d perce nta ges.  
T he f oll o wi n g c o n ve nti o ns are a p plie d t o all data prese ntati o ns a n d s u m maries.  
 F or c o nti n u o us varia bles, all mea n a n d me dia n v al ues are f or matte d t o o ne m ore 
deci mal place t h a n t he m eas ure d v al ue. Sta n dar d de viati o n val ues are f or m atte d t o  
t w o m ore deci mal places t ha n t he meas ure d val ue. Mi ni m u m a n d ma xi m u m val ues 
are prese nte d wit h t he s a me n u m ber of deci mal places as t h e meas ure d val ue.  
 F or cate g orical varia bl es, t he n u m ber a n d perce nta ge of res p o ns es are pres e nte d i n t he 
f or m X X ( X X. X %) w here t he perce nta ge is i n t he pare nt hes es.  
 Date vari a bles are f or m atte d as D D M M M Y Y Y Y f or prese ntati o n. Ti me is f or matte d 
i n militar y ti me as H H: M M f or pres e ntati o n. 
 W here ver p ossi ble, dat a will be deci mal ali g n e d.  
 P -val ues, if a p plica ble, will be prese nte d t o 4 deci mal places. If t h e p -val u e is less 
t ha n 0. 0 00 1 t he n it will be prese nt e d as < 0. 0 0 0 1. If t he r o u n de d res ult is a val ue of 
1. 0 0 0, it will be dis pla ye d as > 0. 9 9 9 9.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 7  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
6. 3.  
A n al ysis Sets  
6. 3. 1.  
Scree ne d Set  
T he S cree ne d S et will i ncl u de all partici pa nts w h o si g ne d i nf or me d c o nse nt f or m. 
6. 3. 2.  
E nr olle d Set  
T he E nr olle d S et will i ncl u de all partici pa nts w h o are ra n d o mize d.  
6. 3. 3.  
S afet y Set  
T he Safet y Set will i ncl u de all partici pa nts w h o recei ve at least 1 d ose of st u d y i nter ve nti o n 
( A L X N 1 8 4 0, m o xifl o x aci n, or place b o) a n d f or w h o m a n y s afet y dat a are a vaila ble. 
6. 3. 4.  
Q T/ Q Tc Set  
T he Q T/ Q Tc Set will i ncl u de all partici pa nts i n t he Safet y Set wit h meas ure me nts at Baseli ne as 
well as o n -treat me nt wit h at least 1 p ost d ose ti me p oi nt wit h a vali d Δ Q Tc val ue. T he Q T/ Q T c 
Set will be use d f or t he b y -ti me p oi nt, assa y s e nsiti vit y, a n d cate g orical a nal yses of t h e 
car di o d y na mic E C G p ara meters.  
6. 3. 5.  
P K Set  
T he P K Set will i ncl u de all partici pa nts w h o recei ve at least 1 d ose of A L X N 1 8 4 0 a n d ha ve 
e val ua ble P K dat a f or t ot al M o a n d/ or P U F M o (as s urr o gate meas ures of A L X N 1 8 4 0 P K) i n 
plas ma. T he P K Set will be use d f or P K a nal ysis.  
6. 3. 6.  
P D Set  
T he P D Set will i ncl u de all partici pa nts w h o recei ve at least 1 d ose of A L X N 1 8 4 0 a n d ha ve 
e val ua ble P D dat a f or t ot al C u a n d/ or P U F C u i n plas ma. T he P D Set will be u se d f or P D 
a nal ysis.  
6. 3. 7.  
P K/ Q Tc Set  
T he P K/ Q Tc Set will i ncl u de all partici pa nts w h o are i n b ot h t he Q T/ Q Tc a n d P K Sets wit h at 
least 1 pair of p ost d ose P K a n d Q Tc d ata fr o m t he sa me ti me p oi nt as well as partici pa nts i n t he 
Q T/ Q Tc Set w h o recei ve d place b o. T h e P K/ Q Tc Set will be use d f or t he e x pl orat or y 
c o nce ntr ati o n -Q Tc a nal ysis.  
6. 4.  
B aseli ne Defi niti o n  
U nless ot her wise n ote d, Baseli ne assess me nts are defi ne d as t he l ast n o n -missi n g res ult pri or t o 
a d mi nistrati o n of t he first d ose of st u d y i nter ve nti o n (e. g., pri or first d ose i n t he first treat me nt 
peri o d).  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 8  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
6. 5.  
B aseli ne E C G P ar a meters, T -w a ve, U -w a ve  
6. 5. 1.  
Pre d ose B aseli ne  
E C G para meters pre d os e Baseli ne ( H R, P R, Q R S, Q T, a n d Q Tc)  i n eac h p eri o d are d efi ne d as 
t he a vera ge of t h e meas ure d E C G i nter vals fr o m t he 3 pre d ose ti me p oi nts ( −4 5, −3 0, a n d −1 5 
mi n utes bef ore d osi n g) o n Da y 1 i n eac h treat me nt peri o d.  
F or T -wa ve m or p h ol o g y a b n or malit y a n d U -wa ve prese nce i n eac h peri o d, pre d ose Baseli ne will 
be base d o n fi n di n gs o bs er ve d i n t he a n y re plicates fr o m t he 3 pre d os e  ti me p oi nts ( −4 5, −3 0, 
a n d −1 5 mi n utes) o n Da y 1 i n eac h treat me nt peri o d.  
6. 6.  
Deri ve d a n d Tr a nsf or me d d at a  
6. 6. 1.  
B aseli ne A ge  
T he f oll o wi n g f or m ula s h o ul d be f oll o we d f or cal c ulati o n of a ge if n ee d e d:  
A ge ( year) = F L O O R((refere n ce d ate –  date of birt h)/ 3 6 5. 2 5)  
w here F L O O R( ) f u ncti o n ret ur ns t he i nte ger part of t he res ult.  
I n cases w here o nl y t h e m o nt h a n d year are pr o vi de d f or a d ate, t he d a y f or t he date will be 
i m p ute d as 1 5. Missi n g m o nt h will be i m p ute d as J u ne. I n cas es w here t he da y is o bser ve d b ut 
t he m o nt h is missi n g, t he date will be i m p ute d as J u ne 1 5. 
6. 6. 2.  
St u d y D a y  
If t he date of i nterest oc c urs o n or after t he first d ose/ra n d o mizati o n date, t he n st u d y d a y will be 
calc ulate d as ( date of i nterest –  date of first d ose/ra n d o mizati o n) + 1. If t he date of i nterest occ urs 
pri or t o t he first d ose/ra n d o mizati o n date, t he n st u d y da y will be calc ul ate d as ( date of i nterest –  
date of first d ose/r a n d o miz ati o n). T here is n o st u d y da y 0.  
6. 6. 3.  
C h a n ge fr o m B aseli ne  
C ha n ge fr o m Baseli ne is calc ulate d as ( P ost -baseli ne res ul t –  Baseli ne res ult). If eit her t h e 
Baseli ne or t he P ost -baseli ne res ult is missi n g, t he c ha n ge fr o m Baseli ne is set t o missi n g as well.  
6. 6. 4.  
C h a n ge fr o m Pre d ose B aseli ne E C G P ar a meters  
F or car di o d y na mic a nal yses, c ha n ge fr o m pr e d ose Baseli ne E C G p ara m eters ( Δ Q Tc, Δ H R, Δ P R, 
Δ Q R S) is calc ulate d as ( P ost -baseli ne E C G para meter at a s p ecific ti me p oi nt mi n us pre d ose 
Baseli ne E C G p ara m eter) f or eac h tr eat me nt peri o d.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 2 9  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
6. 6. 5.  
Pl ac e b o -c orrecte d C h a n ge fr o m B aseli ne E C G P ar a meters  
I n t he pri mar y a n d s ec o n dar y b y-ti me p oi nt a nal ysis, place b o-c orrecte d c h a n ge fr o m b aseli ne 
E C G meas ures a n d 9 0 % CI (e. g. Δ Δ Q Tc, Δ Δ H R, Δ Δ P R, Δ Δ Q R S) will be esti mate d fr o m 
statistical m o del at eac h ti me p oi nt. 
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 0  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
7.  
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S  
7. 1.  
M ultice nter St u dies  
N/ A  
7. 2.  
Ot her Str at a a n d C o v ari ates  
T his is a cli nical p har mac ol o g y st u d y i n a healt h y a d ult p o p ulati o n. It is n ot e x pecte d t hat a n y of t he 
variet y of Baseli ne de m o gra p hic para meters w o ul d i ntr o d uce a lar ge Q T/ Q Tc res p o nse t o 
A L X N 1 8 4 0 i n certai n s u b -p o p ulati o n defi ne d as a ge, race, etc.  
7. 3.  
E x a mi n ati o n of S u b gr o u ps  
F or e x pl orat or y p ur p os es, pri mar y e n d p oi nt will be e val uat e d b y se x.  
7. 4.  
M ulti ple C o m p aris o ns a n d M ulti plicit y  
T he pri mar y a n al ysis will be base d o n b y -ti me p oi nt a nal ysis t o e val uate t h e effect of 
A L X N 1 8 4 0 o n t he Δ Δ Q Tc at eac h p ost d osi n g  ti me p oi nt (“ b y-ti me p oi nt” a nal ysis) usi n g t he 
i ntersecti o n u ni o n test (I U T) pr oce d ure at o ne-si d e d 0. 0 5 le vel. T he I U T pr oce d ure is 
c o nser vati ve i n t hat t he t y p e I err or rate mi g ht b e s maller t ha n t he i nte n de d 0. 0 5 le vel. T here is 
n o m ulti plicit y a dj ust me nt f or t he pri mar y a nal ysis.  
T he sec o n d ar y h y p ot hesis f or assa y se nsiti vit y will be base d o n b y -ti me p oi nt a nal ysis t o 
e val uate t he effect of m o xifl o x aci n o n t he Δ Δ Q Tc at t he 3 pre defi ne d ti me p oi nts ( 1, 2, a n d 3 
h o urs p ost d ose). M ulti plicit y will be c o n tr olle d b y usi n g a H oc h ber g pr oce d ure, wit h a dj uste d 1-
si de d si g nifica n ce le v els of 5 %, 2. 5 %, a n d 1. 6 7 % f or statistical testi n g, res pecti vel y, of t he 3 p -
val ues ra n k e d fr o m lar gest t o s mallest.  T he lar gest p -val ue will be e val u ate d usi n g a 5 % 
si g nifica n ce testi n g le vel a n d t he s mallest will be e val uate d usi n g a 1. 6 7 % si g nifica n ce testi n g 
le vel.  Testi n g will start wit h lar gest p-val ue, a n d c o nti n ue se q ue ntiall y t hr o u g h t he ra n ke d p -
val ues, u ntil t he first si g nifica nt val ue is f o u n d at w hic h p oi nt all s mall er p-val ues are c o nsi dere d 
si g nifica nt. If at least 1 test is si g nifica nt at t he s pecifie d le vel, ass a y se nsiti vit y will be 
c o ncl u de d.  
7. 5.  
D at a h a n dli n g c o n ve nti o ns  
7. 5. 1.  
Pre m at ure Wit h dr a w al a n d Missi n g D at a  
E ver y eff ort will be ma d e t o c ollect all data. H o we ver, des pite b est eff orts, missi n g or i nc o m plete 
i nf or mati o n ma y o cc ur. All missi n g or partial dat a will be prese nt e d i n t he s u bject data listi n g, as 
t he y are rec or de d o n t he e C R F.  
I n t he e ve nt of missi n g d ose, t he data c ollecte d i n t he ass ociate d peri o d will be e x cl u de d fr o m 
a nal ys es.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 1  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
Partici pa nts l ost t o f oll o w -u p or pre mat ure wit h dra w n will be i ncl u de d i n statistical prese ntati o ns 
u p t o t he p oi nt of t heir last e val uati o n. Missi n g data will n ot be i m p ute d. A nal yses will be base d 
o n o bser ve d val u es.  
7. 5. 2.  
Missi n g D ates  
U nless ot her wise s pecifie d, missi n g date will n ot be i m p ute d. Partial start dates/ti mes will be 
q uerie d.  
F or a d v erse e ve nts, i f i nf or mati o n is n ot a vaila ble t o relia bl y all ocate A E t o a peri o d, t he all ocati o n 
will be a gree d at t he data re vie w meeti n g bef ore data base l oc k. If t here is a n y d o u bt a b o ut 
A L X N 1 8 4 0 treat me nt e mer ge nce, A Es will be classifie d as A L X N 1 8 4 0 treat me nt -e mer ge nt.  
F or c o n c o mita nt me dicati o n, if me dicati o n dates or ti mes are i nc o m plete a n d it is n ot clear 
w het her t he me di cati o n was c o nc o mita nt, it will be ass u me d t o be c o n c o mita nt.  
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 2  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
8.  
S T A TI S TI C A L A N A L Y SI S  
8. 1.  
Dis p ositi o n of P artici p a nts  
T he n u m ber of partici pa nts w h o e nr olle d i n t he st u d y will be prese nte d. T h e n u m ber a n d 
perce nt a ges of  p artici pa nts i ncl u de d i n eac h a n al ysis set will be s u m marize d b y treat me nt 
se q ue nce a n d o verall.  
T he n u m ber a n d p erce nta ge of partici p a nts w h o c o m plete d, or pre mat urel y disc o nti n ue d fr o m t he 
st u d y, al o n g wit h reas o n f or disc o nti n uati o n will be descri b e d b y ra n d o mize d treat me nt se q u e nce 
a n d o verall.  
Pre mat urel y disc o nti n ue d partici pa nts will be prese nte d i n a listi n g. A list of scree ni n g fail ure 
will als o be pr o vi de d.  
8. 2.  
Pr ot oc ol De vi ati o ns  
All i m p orta nt/ n ot i m p orta nt pr ot oc ol vi olati o ns will be deter mi ne d a n d a p pr o priatel y cate g orize d 
pri or t o data base l o c k. T he n u m ber a n d p erce nta ge of partici p a nts wit h a n y i m p orta nt/n ot 
i m p orta nt pr ot oc ol vi olati o ns as well as t he n u m ber a n d perce nta ge of parti ci pa nts wit h 
vi olati o ns wit hi n eac h cate g or y will be prese nt e d b y treat me nt se q ue n ce a n d o verall. A listi n g 
will als o be pr o vi de d.  
8. 3.  
De m o gr a p hic a n d B aseli ne S afet y C h ar acteristics  
I n di vi d ual s u bject de m o gra p hics (i ncl u di n g a ge, se x, race a n d et h nicit y), b o d y meas ure me nt d ata 
( hei g ht, b o d y wei g ht a n d b o d y mass i n de x) will be liste d a n d s u m marize d f or t he Safet y Set b y 
eac h tr eat me nt se q ue n ce a n d o verall. If t he n u m ber of partici pa nts i n a n y of t he Q T/ Q Tc, P K, 
P D, a n d P K/ Q Tc sets are differe nt fr o m t he Safet y Set b y m ore t ha n 5 %, se parate de m o gra p hic 
a n d baseli ne c h aracte risti c ta bles will be pr o d uce d f or t hat set. 
Data c ollecte d f or vir us s er ol o g y, uri ne dr u g s cree n, ser u m c o p per, cer ul o plas mi n a n d ser u m 
pre g na nc y t est (f or w o me n of c hil d beari n g p ote ntial) will be pr o vi de d i n listi n g.  
8. 4.  
Me dic al Hist or y  
Me dical hist or y d ata will be c o de d usi n g t he Me di cal Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) dicti o nar y V ersi o n 2 2. 0 ( or hi g her). Me dical a n d s ur gical hist or y d ata will be liste d 
i n di vi d uall y a n d s u m mariz e d b y treat me nt s e q ue n ce a n d o v erall f or t h e Safet y Set. 
8. 5.  
Pri or a n d C o nc o mit a nt Me dic ati o n  
T he W orl d Healt h Or ga niz ati o n Dr u g Dicti o nar y versi o n fr o m Marc h 2 0 1 8 or later will be use d 
t o c o de t he me dic ati o ns.  
Pri or me dicati o ns are d efi ne d as t hera pi es e n de d b ef ore t h e date a n d ti me of first st u d y 
i nter ve nti o n a d mi nistrati on.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 3  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
C o nc o mita nt me dicati o ns are defi ne d as t h ose eit her wit h start date a n d ti me o n or after t he date 
a n d ti me of first st u d y i nt er ve nti o n a d mi nistrati o n, or t h ose wit h start date a n d ti me pri or t o t he 
first st u d y i nter ve nti o n dr u g a d mi nistrati o n a n d c o ntin ui n g at t he ti me of first st u d y i nter ve nti o n 
a d mi nistrati o n.  
Pri or a n d c o nc o mita nt m e dicati o ns will be s u m marize d f or t he Safet y Set b y se q u e nce gr o u p a n d 
o verall. T he n u m ber a n d perce nt a ge of partici pa nts recei vi n g a n y c o nc o mit a nt me dicati o n will be 
s u mmariz e d, as well as t he n u m ber a n d p erce nta ge recei vi n g a n y c o n c o mita nt me dicati o n b y 
A T C dr u g class a n d ge neric dr u g na me. Partici pa nts re p orti n g us e of m ore t ha n o ne me dicati o n 
at eac h l e vel of s u m mari zati o n (a n y me dicati o n recei ve d, A T C cl ass, a n d ge ner ic dr u g na me) 
will be c o u nte d o nl y o n ce. A T C class ter ms will b e dis pla ye d b y desce n di n g or der of i nci d e nce, 
as well as ge n eric dr u g n a mes wit hi n eac h A T C class.  
Pri or a n d c o nc o mita nt m e dicati o ns will als o be prese nte d i n i n di vi d ual listi n g.  
8. 6.  
Tre at me nt C o m p li a nce 
As per pr ot oc ol, st u d y i nter ve nti o n d osi n g will occ ur wit h t he partici pa nt bei n g i n a faste d state. 
T he date a n d ti me of st u d y i nter ve nti o n d osi n g, a n d n utriti o nal state (fasti n g/ n o n -fasti n g) will be 
pr o vi de d i n listi n g, f or partici pa nts w h o misse d st u d y i nter ve nti o n, t he reas o n f or t he misse d d ose 
will be pr o vi de d i n t he listi n g f or t he Safet y Set.  
8. 7.  
C ar di o d y n a mic A n al yses  
Car di o d y n a mic a nal yses will be base d o n t he Q T/ Q Tc Set. F or car di o d y n a mic a nal ys es, Baseli ne 
refers t o pre d ose Baseli ne.  
E C G para meters ( Q Tc, H R, P R, Q R S) a n d c ha n ge fr o m Bas eli ne ( Δ Q Tc, Δ H R, Δ P R, Δ Q R S) at 
all ti me p oi nts will be s u m marize d usi n g descri pti ve statistics b y treat me nt a n d ti me. C ha n ge 
fr o m Bas eli ne i n E C G para meters will als o be pres e nte d b y treat me nt a n d ti me usi ng fi g ures.  
M o del base d least s q uare mea ns of Δ Δ Q Tc a n d 9 0 % CIs will be pl otte d a gai nst meas ure d ti me 
p oi nts f or A L X N 1 8 4 0 a n d M o xifl o x aci n i n di vi d uall y as well as o v erla yi n g esti mates of t hese 
t w o treat me nts i n o ne fi g ure. 
8. 7. 1.  
E v al u ati o n of Q T/ R R C orrecti o n Me t h o ds 
I n case a s u bsta ntial H R effect is o bser ve d o n-treat me nt wit h A L X N 1 8 4 0, Q TcI will be deri ve d 
a n d c o m pare d t o Q Tc F usi n g e val u ati o n met h o d t hat descri be d b el o w.  
T he relati o ns hi p bet wee n Q Tc ( Q T c F a n d, if deri ve d, Q TcI [ o pti mize d]) a n d R R i nter val will  be 
i n vesti gate d usi n g o n-tr eat me nt data ( A L X N 1 8 4 0, m o xifl o x aci n, a n d place b o) b y a li near 
re gressi o n m o del: Q Tc  = c  +  d ×   R R. Mea n Q Tc a n d R R val ues fr o m all n o mi nal ti me p oi nts 
(i ncl u di n g pre d ose) will be use d. T he R R c oeffici e nt f or eac h s u bject, di, will t he n be use d t o 
calc ulate t he a vera ge s u m of s q uare d sl o pes ( S S S) f or eac h of t h e differe nt Q T/ R R c orrecti o n 
met h o ds. T he c orrecti o n met h o d t hat res ults i n t he a vera ge o n -tr eat me nt sl o pe cl osest t o 0 (t he 
s mallest a vera ge S S S, as descri be d b y T or n øe (T or n øe  C W  2 0 1 1 ) f or A L X N 1 8 4 0 a n d place b o 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 4  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
will be dee me d t he m ost a p pr o priate H R c orrecti o n met h o d. If differe nt met h o ds s h o w l o west 
S S S o n place b o as c o m pare d  t o A L X N 1 8 4 0, pri orit y i n t he c h oice will be gi ve n t o t he place b o 
res ults. I n a d diti o n, a scatter pl ot a n d q ua ntile pl ot of Q Tc ( Q Tc F, a n d Q TcI) a n d R R i nter vals b y 
treat me nt wit h re gressi o n li ne a n d a li near mi x e d-effects li ne ( 9 0 % CI), res p ecti vel y, will  als o be 
gi ve n.    
8. 7. 2.  
Pri m ar y A n al ysis(es)  
T he pri mar y a n al ysis will be base d o n b y -ti me p oi nt a nal ysis t o e val uate t h e effect of 
A L X N 1 8 4 0 o n t he Δ Δ Q Tc at eac h p ost d osi n g ti me p oi nt (“ b y -ti me p oi nt” a nal ysis) usi n g t he 
i ntersecti o n u ni o n test (I U T).  
T he stat istical h y p ot hesis t o be teste d f or t he pri mar y assess me nt of Q T pr ol o n gati o n f or t h e 
s u prat hera p e utic d ose of t he A L X N 1 8 4 0 treat me nt is: 
H 0: ∪{ μ D(i)  –  μ P(i) } ≥1 0, i = 1, 2, …, 1 2  
H 1: ∩{ μD(i)  –  μ P(i) } < 1 0, i = 1, 2, …, 1 2  
w here μ D(i)  a n d μ P(i)  are t he least s q uares ( L S) mea n of Δ Q Tc f or A L X N 1 8 4 0 a n d place b o at 
p ost d ose ti me p oi nt i, res pecti vel y.  
T he b y -ti me p oi nt a nal ysis f or Q Tc will be bas e d o n a mi x e d m o del f or re p eate d meas ures wit h 
c ha n ge fr o m Baseli ne Q Tc as t he de p e n de nt varia ble, peri o d, se q ue n ce, ti me (ie,  p ost d ose ti me 
p oi nt: cate g orical), tr eat me nt (s u prat hera pe utic d ose of A L X N 1 8 4 0, m o xifl o x aci n, a n d place b o), 
ti me-b y -tr eat me nt i nteracti o n as fi x e d effects; a n d Baseli ne Q Tc a n d s e x as c o variates. A n 
u nstr uct ure d c o v aria n ce matri x wi ll be s pecifie d f or t he re p eate d meas ures at p ost d ose ti me 
p oi nts f or partici pa nt wit hi n treat me nt peri o d. If t he m o del wit h u nstr uct ur e d c o vari a nce m atri x 
fails t o c o n ver ge, ot h er c o varia nce str uct ur e s uc h as T oe plitz wit h heter o ge neit y ( T O E P H), a ut o-
re gressi ve wit h heter o ge neit y ( A R H), c o m p o u n d s y m metr y wit h heter o ge n eit y ( C S H), T O E P, 
A R, a n d C S will be c o nsi dere d i n de creasi n g c o m ple xit y i n para meterizati o n. T he fi nal m o del 
selecti o n will be base d o n A kai ke i nf or mati o n criteri o n ( AI C). T h e de grees of fre e d o m esti mates 
will be deter mi ne d b y t he Ke n war d -R o ger met h o d. T he m o del will als o i ncl u de a partici p a nt -
s pecific ra n d o m effect. 
Least -s q uares mea n differe nce a n d 2-si de d 9 0 % CI will be calc ulate d f or t he c o ntrast 
A L X N 1 8 4 0 vers us place b o at eac h p ost d ose ti me p oi nt, se paratel y. If t he u p per b o u n d of t he 2-
si de d 9 0 % CI of L S m ea n Δ Δ Q Tc lies b el o w 1 0 ms at all 1 2  p ost d ose ti me p oi nts, A L X N 1 8 4 0 
will be c o ncl u de d n ot t o ha ve a si g nifica nt effect o n Q T i nter val pr ol o n gati o n.  
Sa m ple c o de f or pri mar y a nal ysis:  
P R O C MI X E D D A T A = E C G M E T H O D = R E M L;  
C L A S S S U BJI D T R E A T TI M E P E RI O D S E Q U E N C E S E X;  
M O D E L Q T c = B A S E T R E A T TI M E T R E A T * TI M E P E RI O D S E Q U E N C E S E X/ D D F M = K R;  
R A N D O M I N T E R C E P T / S U BJ E C T = S U BJI D T Y P E = U N;  
R E P E A T E D TI M E / S U BJ E C T = P E RI O D * S U BJI D T Y P E = U N;  
L S M E A N S T R E A T * TI M E / C L DI F F A L P H A = 0. 1;  
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 5  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
*  E x a m ple f or o btai ni n g p -val ue at a s p ecific ti me p oi nt; 
L S M E S TI M A T E  T R E A T * TI M E  'A L X N 1 8 4 0  V S  P L A C E B O A T P O S T -D O S E 2 4 H R S '  
                       1 0 0 0 0 0 0 0 0 0 0 0  
                       0 0 0 0 0 0 0 0 0 0 0 0  
                      -1 0 0 0 0 0 0 0 0 0 0 0/ T E S T V A L U E = 1 0 A L P H A = 0. 0 5 L O W E R T AI L E D  C L ; 
R U N;  
W here E C G  =  Q T/ Q T c set, S U BJI D  =  s u bj ect n u m ber, T R E A T =  treat me nt (s u prat hera pe utic d ose of A L X N 1 8 4 0, 
m o xifl o xaci n, a n d place b o), TI M E  =  n o mi nal p ost -d ose ti me p oi nt, B A S E  =  baseli ne Q T c  
8. 7. 3.  
Ass a y Se nsiti vit y A n al ysis(es)  
Assa y s e nsiti vit y will als o be e val uat e d usi n g b y -ti me p oi nt a nal ysis of t he effect o n Δ Δ Q Tc of 
m o xifl o x aci n usi n g t he sa me m o del as f or t h e pri mar y a nal ysis.  T he a nal ysis t o s h o w assa y 
se nsiti vit y will be b ase d o n t he c ha n ge  fr o m Baseli ne  i n Q Tc of m o xifl o x aci n. F or t he 3 
pre defi n e d ti me p oi nts ( 1, 2, a n d 3 h o urs p ost d ose), t he c o ntrast i n treat me nt 
Δ Δ Q Tc  =  m o xifl o x aci n vers us place b o will be teste d a gai nst t he 1 -si de d n ull h y p ot hesis Δ Δ Q Tc 
≤5  ms o n  t he 5 % le vel. M ulti plicit y will be c o ntr olle d b y usi n g a H oc h ber g pr oce d ure (H oc h ber g  
1 9 9 8 ) wit h a dj uste d 1 -si de d si g nifica nce le vels of 5 %, 2. 5 %, a n d 1. 6 7 % f or statistical testi n g, 
res pecti vel y, of t h e 3 p-v al ues ra n k e d fr o m lar gest t o s mallest.  T he lar gest p -val ue will be 
e val uate d usi n g a 5 % si g nifica nce t esti n g le vel a n d t he s mallest will be e val uate d usi n g a 1. 6 7 % 
si g nifica n ce testi n g le vel.  Testi ng will start wit h lar gest p -val u e, a n d c o nti n ue se q ue ntiall y 
t hr o u g h t he ra n ke d p-val ues, u ntil t he first si g nifi ca nt val ue is f o u n d at w hic h p oi nt all s maller p -
val ues are c o nsi dere d si g nifica nt.  
If after t his pr oce d ure t he L S mea n of Δ Δ Q Tc is si g nifica ntl y lar ger t h a n 5 ms f or at least 1 ti me 
p oi nt of t hese 3 ti me p oi nts, assa y s e nsiti vit y will be c o nsi dere d t o ha ve b ee n de m o nstrate d. I n 
a d diti o n, 2 -si de d 9 0 % CIs will be o btai ne d f or t he c o ntrast at all ti me p oi nts a n d use d i n t he 
fi g ures. 
Sa m ple c o de f or  pri mar y a nal ysis:  
P R O C MI X E D D A T A = E C G M E T H O D = R E M L;  
C L A S S S U BJI D T R E A T TI M E P E RI O D S E Q U E N C E S E X;  
M O D E L Q T c = B A S E T R E A T TI M E T R E A T * TI M E P E RI O D S E Q U E N C E S E X/ D D F M = K R;  
R A N D O M I N T E R C E P T / S U BJ E C T = S U BJI D T Y P E = U N;  
R E P E A T E D TI M E / S U BJ E C T = P E RI O D * S U BJI D T Y P E = U N ; 
L S M E A N S T R E A T * TI M E/ C L DI F F A L P H A = 0. 1;  
 
* E x a m ple f or o btai ni n g p -val ue at a s p ecific ti me p oi nt; 
L S M E S TI M A T E  T R E A T * TI M E  'M O XI  V S  P L A C E B O A T P O S T -D O S E 1 H R '  
                       0  0 0 0 0 0 0 0 0 0 0 0  
                       0 0 0 0 0 0 0 0 0 0 1  0  
                       0  0 0 0 0 0 0 0 0 0 -1  0/ T E S T V A L U E = 5  A L P H A = 0. 0 5 U P P E R T AI L E D  C L ; 
R U N;  
 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 6  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
8. 7. 4.  
Ot her C ar di o d y n a mic A n al ysis(es)  
8. 7. 4. 1.  
Ot her C o nti n u o us C ar di o d y n a mic E n d p oi nts  
F or H R, P R, Q R S, a n d Q Tc c orrecti o n met h o d n ot selecte d as pri mar y if t h ere is s u bsta ntial H R 
effect, b y -ti me p oi nt a nal ysis will be use d t o e val u ate t he effect of A L X N 1 8 4 0 o n t he Δ Δ H R, 
Δ Δ P R, Δ Δ Q R S a n d Δ Δ Q Tc at eac h p ost d osi n g ti me p oi nt. Si milarl y , M M R M m o del will be 
use d t o m o del c ha n ge fr o m Baseli ne i n Δ H R, Δ P R, Δ Q R S , a n d Δ Q Tc . Fi x e d effects will i ncl u de 
peri o d, se q ue n ce, ti me (i e,  p ost d ose ti me p oi nt: cate g ori cal), treat me nt (s u prat hera pe utic d ose of 
A L X N 1 8 4 0, a n d pla ce b o), ti me -b y -treat me nt i nteracti o n a n d c orres p o n di n g pre d ose Baseli ne 
meas ures of t h at E C G para meter a n d se x as c o vari ates . T he L S mea n, S E, a n d 2 -si de d 9 0 % CI 
fr o m t he statistical m o deli n g f or b ot h c ha n ge fr o m Baseli ne a n d place b o-c orrect e d c ha n ge fr o m 
Baseli ne v al ues will be prese nte d i n t he ta bl es a n d gra p hicall y dis pla ye d.  
8. 7. 4. 2.  
C ate g oric al E n d p oi nts  
A n a nal ysis of cate g orical o utliers (i ncl u di n g all re plicates at all ti me p oi nts) will be perf or me d 
f or c ha n ges i n H R, P R, Q R S, Q Tc, T -wa ve m or p h ol o g y, a n d U -wa ve pres e nce . T h e res ults f or 
cate g orical o utliers will be s u m marize d i n fre q ue n c y t a bles wit h c o u nts ( perce nta ges) f or b ot h 
n u m ber of partici p a nts a n d n u m ber of ti me p oi nts b y treat me nt.  T he fre q u e nc y of partici p a nts 
wit h a n i ncreas e fr o m Baseli ne i n E C G meas ures will be s u m marize d f or eac h treat me nt 
acc or di n g t o t he f oll o wi n g cate g ories:  
 Q Tc F v al ues > 4 5 0 a n d ≤4 8 0 ms, > 4 8 0 a n d  ≤5 0 0 ms, or > 5 0 0 ms;  
 I n crease i n Q T c F fr o m pr e d ose Baseli ne > 3 0 a n d ≤6 0 ms, or > 6 0 ms;  
 Q TcI val u es > 4 5 0 a n d ≤4 8 0 ms, > 4 8 0 a n d ≤5 0 0 ms, or > 5 0 0 ms if t here is s u bsta ntial 
H R effect;  
 I n crease i n Q T cI fr o m pre d ose Baseli ne > 3 0 a n d ≤ 6 0 ms, or > 6 0 ms if t here is 
s u bsta ntial H R effect; 
 I n crease i n P R fr o m pre d ose Bas eli ne > 2 5 % t o a P R > 2 0 0 ms;  
 I n crease i n Q R S fr o m pr e d ose Baseli ne > 2 5 % t o a Q R S > 1 2 0 ms; 
 Decrease i n H R fr o m pre d ose Bas eli ne > 2 5 % t o a H R < 5 0 b p m;  
 I n crease i n H R fr o m pre d ose Bas eli ne > 2 5 % t o a H R > 1 0 0 b p m;  
I n di vi d ual partici pa nt E C G data will be liste d. All i nci de nces of E C G m eas ures t hat fall i nt o 
a b o ve cate g ories will be fla g ge d i n t he i n di vi d ual data listi n g.  
F or T -wa ve m or p h ol o g y, a n d U -w a ve prese nce, s u m marize  t he n u m ber ( %) of partici pa nts wit h at 
least: 1) o ne treat me nt-e mer ge nt T -wa ve c ha n ge; 2) o ne treat me nt -e mer ge nt U-wa ve a b n or malit y, 
wit h data s u m marize d b y treat me nt a n d o verall. I n di vi d ual partici pa nt data o n T-wa ve m or p h ol o g y 


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 7  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
a n d a b n or mal U -wa v e prese n ce will be liste d, treat me nt e mer ge nt T -wa ve m or p h ol o g y a b n or mal 
c ha n ge a n d a b n or mal U -wa ve will be fla g ge d.  
8. 8.  
P h ar m ac o ki netic a n d P h ar m ac o d y n a mic A n al yses  
Details of t he P K a n d P D a nal ys es will be descri be d i n a se parate P K/ P D, a n d Q T/ Q Tc S A P.  
8. 9.  
P h ar m ac o ki net ic C o nce ntr ati o n/ Q Tc A n al ysis ( E x pl or at or y 
A n al ysis)  
Details of t he P K c o nce ntrati o n/ Q Tc a nal ysis will be descri b e d i n a se parat e P K/ P D, a n d 
Q T/ Q Tc S A P.  
8. 1 0.  
S afet y A n al yses  
Safet y A nal yses will be b ase d o n t he Safet y Set.  
8. 1 0. 1.  
A d verse E ve nts  
Treat me nt -e mer ge nt a d v erse e v e nts ( T E A Es) are defi ne d as t h ose A Es wit h o nset after t he first 
d ose of st u d y i nter ve nti o n or e xisti n g e ve nts t hat w orse ne d i n se v erit y after t he first d ose of st u d y 
i nter ve nti o n. 
A d verse e ve nts will be c o de d b y preferre d ter m a n d s yste m or ga n clas s usi n g Me d D R A versi o n 
2 2. 0 or hi g h er  a n d s u m m arize d b y pri mar y S O C a n d P T. A d verse e v e nt se verit y will be 
e val uate d usi n g t he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d v erse 
E ve nts ( C T C A E) versi o n 5. 0 ( p u blis he d 2 7 N o v 2 0 1 7) ( N CI, 2 0 1 7).  
A T E A E will be classifie d t o a s pecific Peri o d if t he A E start date/ti me is o n or after t h e date a n d 
ti me of treat me nt a d mi nistrati o n of t hat Peri o d a n d bef ore t h e start date/ti me of t he ne xt Peri o d.  
All T E A E data will be prese nte d i n a dat a listi n g. Treat me nt -e mer ge nt S A E a n d A Es lea di n g t o 
earl y disc o nti n uati o n will als o be prese nte d i n t he se parat e data listi n gs.  
8. 1 0. 2.  
O ver all S u m m ar y of A d verse E ve nts  
A n o verall s u m mar y of T E A Es will be prese nte d, n u m ber of e v e nts, n u m ber a n d perce nta ge ( %) 
of partici pa nts e x perie n ci n g t he e ve nt will be s u m marize d b y tr eat me nt a n d o verall. T he 
s u m mar y will i ncl u de f oll o wi n g cate g ories: 
 T E A Es  
 Relate d  
 N o n -relat e d 
 Lea di n g t o earl y disc o nti n uati o n  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 8  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
 Lea di n g t o deat h  
 Treat me nt -e mer ge nt S A Es  
 Relate d  
 N o n -relat e d 
 Lea di n g t o earl y disc o nti n uati o n  
 Lea di n g t o deat h  
 T E A Es b y t o xicit y gra de  
 Treat me nt -e mer ge nt S A Es b y t o xicit y gra d e  
8. 1 0. 3.  
A Es b y S yste m Or g a n Cl ass a n d Preferre d Ter m  
T he n u m ber of T E A Es a n d t he n u m ber a n d perce nta ge of partici pa nts wit h e ve nts will be 
prese nte d b y s yste m or ga n class a n d preferre d ter m. Partici pa nts are c o u nt e d o nce i n eac h s yste m 
or ga n class a n d preferre d ter m. Data will be s u m m arize d b y tr eat me nt a n d o verall. S yste m or ga n 
classes will be liste d i n desce n di n g fre q ue n c y as well as preferre d ter ms wit hi n eac h s yst e m 
or ga n class.  
Treat me nt -e mer ge nt S A Es, treat me nt -e mer ge nt n o n -seri o us A Es, relate d T E A Es, relate d 
treat me nt-e mer ge nt S A Es will be s u m marize d usi n g t he sa m e a p pr oac h.  
8. 1 0. 4.  
A Es b y Preferre d Ter m  
T he n u m ber of T E A Es a n d t he n u m ber a n d perce nta ge of partici pa nts wit h e ve nts will be 
prese nte d b y preferre d ter m i n c ol u m n f or o verall. Partici pa nts are c o u nte d o nce i n eac h 
preferre d t er m. Data will be s u m ma rize d b y tr eat m e nt a n d o verall. 
8. 1 0. 5.  
A Es b y S yste m Or g a n Cl ass, Preferre d Ter m a n d Se verit y  
T he n u m ber of T E A Es a n d t he n u m ber a n d perce nta ge of partici pa nts wit h e ve nts will be 
prese nte d b y s yste m or ga n class, preferre d ter m a n d se verit y. If a partici pa nt has m ore t ha n o ne 
occ urre nce of a n A E, t he hi g hest se v erit y re p ort e d will be use d. If se v erit y is missi n g, t he A E 
will be ass u me d t o be se vere.  
8. 1 1.  
Cli nic al L a b or at or y E v al u ati o ns  
Cli nical la b orat or y para meters (i ncl u di n g bl o o d c he mistr y, h ae mat ol o g y, ser u m c he mi str y, a n d 
uri nal ysis) will be gra de d acc or di n g t o t he C T C A E . A bs ol ute ( o bser ve d) val ues a n d c ha n ges 
fr o m Bas eli ne (c o nti n u o us varia bles) will be s u m marize d f or eac h para met er at t he sc h e d ule d 
ti me p oi nt b y tr eat me nt. T he last la b val ue will be use d f or s u mmar y a nal ysis if re peate d 
meas ure me nts are ma d e at a n y ti me p oi nt.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 3 9  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
F or des cri pti ve statistics of cli nical la b orat or y dat a val ues t hat are bel o w t h e l o wer li mit of 
q ua ntificati o n ( L L O Q) will be treate d as L L O Q a n d t h ose a b o ve t he u p per li mit of q ua ntificati o n 
( U L O Q) will be treate d as U L O Q. Missi n g c o n ce ntrati o ns will be e x cl u de d fr o m t he 
calc ulati o ns.  
C o nti n ge nc y ta bles will be prese nt e d f or eac h l a b orat or y para meter t o s u m marize t he s hift fr o m 
t he Bas eli ne cate g or y t o t he w orst P ost-baseli ne m eas ure m e nt b y  tr eat me nt.  
8. 1 2.  
S afet y Electr oc ar di o gr a m  
T he Baseli ne f or s afet y E C G meas ures refers t o pre d ose Baseli ne bef ore eac h treat me nt peri o d.  
1 2 -lea d safet y E C G meas ures i ncl u di n g H R, P R, Q Tc, Q R S a n d c ha n ge fr o m baseli ne i n t h ose 
para meters will be a nal yze d usi n g  descri pti ve s u m mar y statistics b y treat me nt gr o u p. F or E C G 
para meters, t he a v era ge of all t he re plicat es at meas ure d ti me p oi nts will be use d f or statistics 
a nal ys es.  
Listi n gs of 1 2 -lea d s afet y E C G wit h i nter pretati o n, m or p h ol o g y a n al ysis a n d fla g f or cli nicall y 
si g nifica nt will be pr o vi d e d. 
8. 1 3.  
Vit al Si g ns  
Vital si g n data i ncl u di n g s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y rate, a n d 
b o d y te m perat ur e will be liste d f or eac h i n di vi d ual partici pa nt.  
S u m mar y statistics of o bser ve d val u es a n d  c h a n ges fr o m Bas eli ne will be prese nte d f or eac h 
para meter at sc h e d ule d ti me p oi nt b y treat me nt.  
8. 1 4.  
P h ysic al E x a mi n ati o n  
P h ysical e x a mi nati o n data will be liste d i n di vi d uall y, a n d a b n or mal fi n di n gs will be fla g ge d.  


Ale xi o n P har mace uticals, I nc.  
 
A L X N 1 8 4 0 -H V -1 0 7  
Statistical A nal ysis Pla n –  Pr ot oc ol A L X N 1 8 4 0 -H V -1 0 7   
Se p  0 3 , 2 0 2 0 
 
 
 
P a ge 4 0  of 4 0  
 
 
Ale xi o n C o nfi de ntial  
 
9.  
R E F E R E N C E S  
De part me nt of Healt h a n d H u ma n S er vices ( D H H S), F o o d a n d Dr u g A d mi nistrati o n, Ce nter f or 
Dr u g E val uati o n a n d Res earc h, C e nter f or Bi ol o gi cs E val uati o n a n d Researc h ( U S). G ui da nce 
f or I n d ustr y: E 1 4 Cli nical E val uati o n of Q T/ Q Tc I nter val Pr ol o n gati o n a n d Pr oarr h yt h mic 
P ote ntial f or N o n -A nt iarr h yt h mic Dr u gs. Oct o ber 2 0 0 5 [cite d 0 2 Dec 2 0 1 9] [ 2 0  scree ns]. 
Availa ble fr o m: 
htt ps:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui d a nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui da nces/
U C M 0 7 3 1 5 3. p df . 
Gar nett C, Z h u H, Mali k M, et al. Met h o d ol o gies t o c haracterize t he Q T/ c orrecte d Q T i nter val i n 
t he prese n ce of dr u g-i n d uce d heart rat e c ha n ges or ot her a ut o n o mic effects. A m Heart J. 
2 0 1 2; 1 6 3( 6): 9 1 2 -9 3 0.  
Gar nett  C, B o n ate P L, D a n g Q, et al. Scie ntific w hite pa per o n c o n ce ntr ati o n -Q Tc m o deli n g. J 
P har mac o ki net P har mac o d y n. 2 0 1 8; 4 5( 3): 3 8 3 -9 7. [ P u blis he d c orrecti o n a p pears i n 
J P har mac o ki net P har mac o d y n. 2 0 1 8; 4 5( 3): 3 9 9].  
H oc h ber g Y. A s h ar per B o nferr o ni pr o ce d ure f o r m ulti ple tests of si g nifica nce. Bi o metri ka. 
1 9 8 8; 7 5( 4): 8 0 0 -2.  
Tor n øe C W, Gar nett C E, Wa n g Y, Fl oria n J, Li M, G o b b ur u J V. Creati o n of a k n o wle d ge 
ma na ge me nt s yste m f or Q T a nal yses. J Cli n P har mac ol. 2 0 1 1; 5 1( 7): 1 0 3 5 -1 0 4 2.  
Z ha n g  J, Mac h a d o S G. Statistical iss ues i ncl u di n g desi g n a n d sa m ple siz e calc ulati o n i n 
t h or o u g h Q T/ Q Tc st u dies. J Bi o p har m Stat. 2 0 0 8; 1 8( 3): 4 5 1-6 7.  
 
 


C ertifi c at e Of C o m pl eti o n
E n v el o p e I d: 
St at u s: C o m pl et e d
S u bj e ct: Pl e a s e D o c u Si g n: S A P _ 1 0 7 _ V er si o n 1. d o c x
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 4 0
Si g n at ur e s: 3
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 2
I niti al s: 0
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: Di s a bl e d
Ti m e Z o n e: ( U T C- 0 5: 0 0) E a st er n Ti m e ( U S & C a n a d a)
1 0 0 C oll e g e St.
N e w H a v e n, C T  0 6 5 1 0
I P A d dr e s s: 
  
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             0 3- S e p- 2 0 2 0 | 0 8: 2 0
H ol d er: 
             
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
Al e xi o n P h ar m a c e uti c al s I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 0 3- S e p- 2 0 2 0 | 0 8: 2 8
Vi e w e d: 0 3- S e p- 2 0 2 0 | 0 8: 2 8 
Si g n e d: 0 3- S e p- 2 0 2 0 | 0 8: 2 9
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
Al e xi o n P h ar m a c e uti c al s I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 0 3- S e p- 2 0 2 0 | 0 8: 2 8
Vi e w e d: 0 3- S e p- 2 0 2 0 | 1 4: 5 7 
Si g n e d: 0 3- S e p- 2 0 2 0 | 1 4: 5 8
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
Al e xi o n P h ar m a c e uti c al s, I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 0 3- S e p- 2 0 2 0 | 0 8: 2 8
Vi e w e d: 0 3- S e p- 2 0 2 0 | 0 8: 4 7 
Si g n e d: 0 3- S e p- 2 0 2 0 | 0 8: 4 7
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
0 3- S e p- 2 0 2 0 | 0 8: 2 8
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
0 3- S e p- 2 0 2 0 | 1 4: 5 7
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
0 3- S e p- 2 0 2 0 | 1 4: 5 8
C o m pl et e d
S e c urit y C h e c k e d
0 3- S e p- 2 0 2 0 | 1 4: 5 8
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s
P P D
P P D
P P D
P P D
P P D
P P D