Clinical trial NCT02586805
Conditions: Hereditary Angioedema (HAE)
Keywords: DX-2930 Hereditary Angioedema Dyax
Sponsor: Shire
Start date: 2016-03-03; Completion date: 2017-04-13
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of DX-2930 in preventing acute angioedema attacks in patients with Type I and Type II HAE.

Detailed description:

Arms: arm 1: 300 mg DX-2930 administered every 2 weeks by subcutaneous injection. arm 2: 300 mg DX-2930 administered every 4 weeks by subcutaneous injection arm 3: 150 mg DX-2930 administered every 4 weeks by subcutaneous injection arm 4: Placebo administered every 2 weeks by subcutaneous injection.
Interventions: intervention 1: DX-2930 - 300mg/2wk intervention 2: DX-2930 - 300mg/4wk intervention 3: DX-2930 - 150mg/4wk intervention 4: Placebo
Intervention descriptions: intervention 1: 300 mg DX-2930 administered every 2 weeks by subcutaneous injection. intervention 2: 300 mg DX-2930 administered every 4 weeks by subcutaneous injection. To maintain the study blind, subjects will be given placebo injections every other 2 weeks when they are not receiving drug. intervention 3: 150 mg DX-2930 administered every 4 weeks by subcutaneous injection. To maintain the study blind, subjects will be given placebo injections every other 2 weeks when they are not receiving drug. intervention 4: Placebo administered every 2 weeks by subcutaneous injection.

Protocol documents:
SAP_004.pdf: 
STATISTICAL ANALYSIS PLAN
Protocol Title:
HELP StudyTM: A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Efficacy and Safety Study to Evaluate 
DX-2930 for Long-Term Prophylaxis Against Acute Attacks of 
Hereditary Angioedema (HAE)
Protocol Number:
DX-2930-03
Protocol Version/Date:
Amendment 2.0 21 April 2016
Indication:
Prevention of angioedema attacks in subjects with HAE
Study Phase
III
SAP Author
, MPH (Rho, Inc.)
SAP Analysis Type
Final Analysis
SAP Version/Date
Original SAP 1.0 24 May 2016
Confidentiality Statement
This document is the proprietary and confidential property of Dyax Corp., an indirect,
wholly-owned subsidiary of Shire plc.
PPD


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TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS................................................................................................ 5
2.
INTRODUCTION.................................................................................................................. 7
2.1
Purpose of the Statistical Analysis Plan....................................................................... 7
2.2
Background .................................................................................................................. 7
2.3
Study Rationale ............................................................................................................ 7
3.
STUDY OBJECTIVES.......................................................................................................... 8
3.1
Primary Objectives....................................................................................................... 8
3.2
Secondary Objectives................................................................................................... 8
3.3
Tertiary Objectives....................................................................................................... 8
4.
STUDY DESIGN.................................................................................................................... 9
4.1
General Description...................................................................................................... 9
4.2
Discussion of Study Design, Including the Choice of Control Group ....................... 10
4.3
Method of Assigning Subjects to Treatment Regimens............................................. 11
4.4
Blinding...................................................................................................................... 11
4.5
Sample Size Determination........................................................................................ 11
5.
EFFICACY AND SAFETY ENDPOINTS ........................................................................ 13
5.1
Efficacy Endpoints ..................................................................................................... 13
5.1.1
Primary Efficacy Endpoint ............................................................................. 13
5.1.2
Secondary Efficacy Endpoints........................................................................ 13
5.1.3
Exploratory Efficacy Endpoints ..................................................................... 13
5.2
Safety Endpoints......................................................................................................... 13
5.3
Other Endpoints.......................................................................................................... 13
6.
EFFICACY AND SAFETY VARIABLES ........................................................................ 14
6.1
Study Activities Schedule .......................................................................................... 14
6.2
Efficacy Assessments................................................................................................. 14
6.3
Safety Assessments .................................................................................................... 15
6.3.1
Adverse Events............................................................................................... 15
6.3.2
Vital Signs ...................................................................................................... 17
6.3.3
Physical Examination ..................................................................................... 17
6.3.4
Electrocardiogram (ECG)............................................................................... 17
6.3.5
Clinical Laboratories ...................................................................................... 17
6.3.6
Concomitant Therapies................................................................................... 19
6.4
Other Assessments ..................................................................................................... 19
6.4.1
Pharmacokinetic Assessment.......................................................................... 19
6.4.2
Pharmacodynamic Assessment....................................................................... 19
6.4.3
Plasma Anti-Drug Antibody Testing.............................................................. 19
6.4.4
Quality of Life Assessments........................................................................... 19
7.
STATISTICAL ANALYSIS................................................................................................ 21
7.1
General Methodology................................................................................................. 21
7.2
Analysis Populations.................................................................................................. 22
7.2.1
Intent-to-treat (ITT) Population...................................................................... 22
7.2.2
Safety Population............................................................................................ 22
7.3
Subject Disposition..................................................................................................... 22
7.4
Protocol Deviations.................................................................................................... 22
7.5
Demographic and Other Baseline Characteristics...................................................... 23


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7.6
Medical History.......................................................................................................... 23
7.7
Treatment Compliance and Extent of Exposure......................................................... 23
7.8
Analysis of Efficacy................................................................................................... 23
7.8.1
Primary Efficacy Analysis.............................................................................. 23
7.8.2
Secondary Efficacy Analyses ......................................................................... 25
7.8.3
Exploratory Efficacy Analyses....................................................................... 25
7.9
Analysis of Safety ...................................................................................................... 28
7.9.1
Adverse Events............................................................................................... 28
7.9.2
Clinical Laboratory Evaluation....................................................................... 30
7.9.3
Vital Signs ...................................................................................................... 30
7.9.4
Electrocardiography........................................................................................ 31
7.9.5
Physical Examinations.................................................................................... 31
7.9.6
Prior and Concomitant Medications............................................................... 31
7.10
Other Analyses ........................................................................................................... 32
7.10.1
Analysis of Pharmacokinetic Data.................................................................. 32
7.10.2
Analysis of Pharmacodynamic Data............................................................... 32
7.10.3
Analysis of Immunogenicity Data.................................................................. 32
7.10.4
Analysis of Quality of Life Data .................................................................... 32
8.
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES........ 33
8.1
Changes in the Conduct of the Study......................................................................... 33
8.2
Change from the Analyses Planned in the Protocol ................................................... 33
8.2.1
Efficacy Evaluation Period............................................................................. 33
8.2.2
ITT and Safety Population Definitions........................................................... 33
8.2.3
Adverse Events............................................................................................... 33
8.2.4
Laboratory Parameters.................................................................................... 33
8.2.5
Vital Sign Parameters..................................................................................... 34
9.
STATISTICAL/ANALYTIC ISSUES................................................................................ 35
9.1
Adjustment for covariates .......................................................................................... 35
9.2
Handling of Dropouts or Missing Data ...................................................................... 35
9.3
Interim Analysis and Data Monitoring....................................................................... 35
9.4
Multicenter Studies..................................................................................................... 35
9.5
Multiple Comparisons/Multiplicity............................................................................ 35
9.6
Examination of Subgroups......................................................................................... 36
9.7
Sensitivity Analyses ................................................................................................... 36
10. APPENDICIES..................................................................................................................... 39
10.1
Appendix I List of Statistical Outputs........................................................................ 39
10.1.1
List of Planned Tables .................................................................................... 39
10.1.2
List of Planned Figures................................................................................... 48
10.1.3
List of Planned Listings.................................................................................. 50
10.2
Definitions and Programming Conventions............................................................... 51
10.2.1
Age ................................................................................................................. 51
10.2.2
BMI................................................................................................................. 51
10.2.3
Study Day ....................................................................................................... 51
10.2.4
Durations of Events ........................................................................................ 51
10.2.5
Baseline .......................................................................................................... 51
10.2.6
Analysis Periods ............................................................................................. 51
10.2.7
HAE Attack Characteristics............................................................................ 52
10.2.8
Unique HAE Attacks...................................................................................... 52


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10.2.9
HAE Attack Rate............................................................................................ 52
10.2.10
Time to First HAE Attack............................................................................... 53
10.2.11
Adverse Events............................................................................................... 53
10.2.12
GLM Model Sample SAS Code ..................................................................... 53
10.2.13
GEE Model Sample SAS Code ...................................................................... 54
10.2.14
Angioedema Quality of Life........................................................................... 54
10.3
Treatment Period Dosing Schedule............................................................................ 56
10.4
Study Activity Schedule............................................................................................. 57


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1.
LIST OF ABBREVIATIONS
AE
Adverse event
AE-QoL
Angioedema Quality of Life Questionnaire
AESI 
Adverse event of special interest
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
ATC
Anatomic therapeutic chemical
BLQ
Below the limit of quantification
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C1-INH
C1-inhibitor
CI
Confidence interval
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CSR
Clinical study report
DMID
Division of Microbiology and Infectious Diseases
DSMB
Data Safety Monitoring Board
EC
Ethics committee
ECG
Electrocardiogram
EQ5D
EuroQoL Group 5-Dimension
eCRF
Electronic case report form
EDC
Electronic data capture
FWER
Family-wise type I error rate
GEE
Generalized estimating equations
GLM
Generalized linear model
HAARP
HAE Attack Assessment and Reporting Procedures
HAE
Hereditary angioedema 
HIPAA
Health Insurance Portability and Accountability Act
HR
Heart rate
ICH
International Conference on Harmonisation
IMP
Investigational medicinal product
INR
International normalized ratio
IP
Investigational product
IRB
Institutional review board
ITT
Intent-to-treat
IWRS
Interactive web-based randomization system
KM
Kaplan-Meier


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LS
Least squares
LTP
Long-term prophylaxis
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model repeated measures
OLE
Open-label extension
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PT
Prothrombin time
PT
Preferred term
QOL
Quality of life
RBC
Red blood cell 
RR
Respiratory rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Standard deviation
SMQ
Standardized MedDRA Queries
SOC
System organ class
TEAE
Treatment-emergent adverse event
VAS
Visual analog scale
WBC
White blood cell
WHO-DD
World Health Organization-Drug Dictionary


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2.
INTRODUCTION
2.1
Purpose of the Statistical Analysis Plan
This statistical analysis plan (SAP) is being developed after review of DX-2930-03 protocol, but 
before database lock and unblinding of treatment assignment. This SAP contains detailed 
information to aid in the implementation of the statistical analysis and reporting of the study data 
for use in the clinical study report (CSR). This SAP is being written with due consideration of 
the recommendations outlined in the most recent International Conference on Harmonisation 
(ICH) E9 Guideline, entitled Guidance for Industry: Statistical Principles for Clinical Trials, and 
the most recent ICH E3 Guideline, entitled Guidance for Industry: Structure and Content of 
Clinical Study Reports.
This SAP describes the analysis sets that will be used for analysis, as well as subject 
characteristics, efficacy, safety, pharmacokinetic (PK), pharmacodynamic (PD), and quality of 
life (QoL) parameters. The details of the specific statistical methods as stated in the protocol will 
be provided and any changes from the protocol-specified analyses will be documented in the 
SAP prior to database lock. If additional analyses are required to supplement the planned 
analyses described in this SAP after the database lock, they may be completed and will be 
described in the CSR. Table, figure, and listing specifications are provided in separate 
documents.
2.2
Background
DX-2390-03 is a Phase 3, randomized, double-blind, placebo-controlled, multicenter clinical 
study evaluating the safety and efficacy of DX-2930 as a treatment for the prevention of 
hereditary angioedema (HAE) attacks. Details of the study design, rationale, and procedures are 
documented in Protocol DX-2390-03 Amendment 2.0.
2.3
Study Rationale
DX-2930 is a fully human IgG1 recombinant monoclonal antibody that binds specifically to 
active plasma kallikrein. DX-2930 is being developed for prophylactic treatment of angioedema 
attacks in patients with HAE, a serious and life-threatening disease.


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3.
STUDY OBJECTIVES
3.1
Primary Objectives
To evaluate the efficacy of DX-2930 in preventing HAE attacks.
3.2
Secondary Objectives
To evaluate the safety of repeated subcutaneous administrations of DX-2930.
3.3
Tertiary Objectives
•
To evaluate the pharmacodynamic (PD) effects of chronically administered DX-2930
•
To assess the immunogenicity of chronically administered DX-2930
•
To evaluate the pharmacokinetics (PK) of chronically administered DX-2930
•
To evaluate the effect of DX-2930 on health related quality of life (QoL) 


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4.
STUDY DESIGN
4.1
General Description
This study is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate 
the efficacy and safety of DX-2930 in preventing acute angioedema attacks in subjects with Type I 
and Type II HAE. This double-blind study is planned to be followed by an open-label extension 
(OLE) that is described in a separate protocol (Protocol DX-2930-04).
A figure showing dosing is in Appendix 10.3. A table showing the Study Activities Schedule for the 
study is provided in Appendix 10.4.
Long-Term Prophylactic (LTP) Therapy Washout: 
Following informed consent, subjects will undergo screening assessments. Screened subjects who are 
on long-term prophylactic therapy for HAE are required to undergo a minimum 2-week washout 
period prior to the start of the run-in period. This LTP washout is permitted as long as the 
Investigator determines that doing so would not place the subject at any undue safety risk and the 
subject is at least 18 years of age. The Investigator must confirm the subject has successfully 
completed the 2-week washout period before they can enter the run-in period.
Run-In Period: 
Screened subjects who are either not on long-term prophylactic therapy for HAE, or have completed 
the required washout period, will enter a run-in period of 4 weeks to determine the baseline HAE 
attack rate. Only subjects meeting a minimum baseline rate of at least 1 investigator-confirmed HAE 
attack per 4 weeks will be eligible for enrollment and randomization. Subjects who experience 3 or 
more investigator-confirmed attacks before the end of the 4 weeks can exit the run-in period early 
and proceed to enrollment and randomization. Subjects without at least 1 investigator-confirmed 
attack after 4 weeks of run-in will have their run-in period extended for another 4 weeks, during 
which time they need to have at least 2 investigator-confirmed attacks to proceed to enrollment and 
randomization. To be eligible for enrollment, subjects who have their run-in extended must 
complete the full 8-week run-in period prior to entering the treatment period. Subjects who do 
not meet the minimum attack rate during run-in or are otherwise determined to be ineligible due 
to screening assessments will be considered screen failures. Subjects who fail screening will not 
be allowed to rescreen into the study.
Treatment Period: 
After verification of eligibility, subjects will be randomized 2:1 to receive repeated subcutaneous 
(SC) administrations of DX-2930 or placebo in a double-blind fashion. Subjects who are 
randomized to DX-2930 will be assigned in a 1:1:1 ratio to 1 of 3 dose regimens: 300 mg every 2 
weeks, 300 mg every 4 weeks, or 150 mg every 4 weeks. Randomization into all treatment 
groups will be stratified by the baseline attack rate observed during the run-in period into the 
following groups: 1 to < 2 attacks per 4 weeks, 2 to < 3 attacks per 4 weeks, and ≥ 3 attacks per 4 
weeks.
Each subject will undergo a treatment period consisting of 13 doses of blinded Investigational 
Medicinal Product (IMP), for a period of 26 weeks from the date of first dose on Day 0 through 


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two weeks after the final dose. Subjects randomized to one of the 4 treatment arms will either 
receive a DX-2930 or placebo dose according to the dosing schedule in Appendix 10.3. 
Open-Label Extension (OLE) Study: 
Subjects who complete the treatment period will be offered the option of enrolling in an open-
label extension (OLE) study that will be described in a separate protocol (DX-2930-04). 
Follow-up Period: 
Subjects who do not participate in the OLE will undergo safety and additional evaluations (i.e., 
PK and PD) during an 8 week follow-up period. Subjects (or caregivers) will be instructed to 
inform the site of any HAE attacks they experience for up to 30 days after the final follow-up 
visit. 
4.2
Discussion of Study Design, Including the Choice of Control Group
This study is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to 
evaluate the efficacy and safety of DX-2930 in preventing acute angioedema attacks in subjects 
with Type I and Type II HAE. The following is a discussion of the rationale behind the design of 
the trial.

Primary endpoint selection: The objective of this study is to evaluate the efficacy of DX-
2930 in preventing HAE attacks. The number of HAE attacks is a direct way to evaluate 
efficacy.

Dose selection: The dose rationale is based on the pharmacodynamic bioactivity, PK, safety, 
and efficacy of DX-2930 from the Phase 1 clinical studies and nonclinical studies. Together, 
these attributes provide the rationale for the selected doses and regimens to achieve drug 
levels likely to prevent a majority of HAE attacks. Based on these considerations, 300 mg 
every 2 weeks, 300 mg every 4 weeks, and 150 mg every 4 weeks were identified as the 
dosing regimens for evaluation. The 3 proposed dose-regimen combinations provide a 6-fold 
range of steady-state trough concentrations and leverage both the biomarker and efficacy data 
generated in study DX-2930-02. Evaluation of the DX-2930 plasma concentrations at the 
time of attacks reported by DX-2930-treated subjects in DX-2930-02 suggests that the 3 
planned dosing regimens will provide a meaningful range of clinical response.

Control group selection: This trial incorporates a placebo comparator to evaluate and 
interpret the efficacy of DX-2930. The use of placebo is justified because 1) placebo does not 
represent a reduction in current standard of care for subjects due to the availability of acute 
attack treatments and 2) none of the therapies currently used for the prevention of HAE 
attacks are suitable for use as an active comparator.

Study population: Subjects 12 years of age and older with a confirmed diagnosis of HAE 
(Type I or II) who experience at least 1 investigator-confirmed attack per 4 weeks during the 
run-in period. HAE diagnosis will be confirmed through documented clinical history 
consistent with HAE and diagnostic testing conducted during the screening visit. 


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
Baseline symptom severity: To be eligible to participate in the study, subjects had to meet a 
minimum baseline HAE attack rate of at least 1 investigator-confirmed HAE attack per 4 
weeks during the run-in period. 

Stratified randomization: Randomization to treatment is stratified by the baseline HAE 
attack rate observed during the run-in period. The three levels of HAE attack rate strata are 1-
<2 attacks per 4 weeks, 2-<3 attacks per 4 weeks and 3 or more attacks per 4 weeks.

Safety monitoring: Adverse events (AE), clinical laboratories and vital signs will be 
monitored throughout the study.
4.3
Method of Assigning Subjects to Treatment Regimens
Subjects will be randomized after confirmation of study eligibility in a 2:1 ratio to receive 
repeated SC administrations of DX-2930 or placebo in a double-blind fashion via an Interactive 
Web-based Randomization System (IWRS). Subjects who are randomized to DX-2930 will be 
assigned in a 1:1:1 ratio to 1 of 3 dose regimens: 300 mg every 2 weeks, 300 mg every 4 weeks, 
or 150 mg every 4 weeks. Randomization into all treatment groups will be stratified by the 
baseline attack rate observed during the run-in period into the following groups: 1 to < 2 attacks 
per 4 weeks, 2 to < 3 attacks per 4 weeks, and ≥ 3 attacks per 4 weeks.
4.4
Blinding
Subjects will be randomized to receive 300 mg DX-2930 every 2 weeks, 300 mg DX-2930 every 
4 weeks, 150 mg DX-2930 every 4 weeks or placebo every 2 weeks in a double-blind fashion. 
The appearance of the placebo will be indistinguishable from DX-2390. Subjects, caregivers for 
subjects under 18 years of age, Investigators and site personnel will be blinded to the treatment 
administered until the study is complete. The Sponsor will be blinded to the treatment 
administered until all subject involvement in the treatment period is complete, the database has 
locked, and primary statistical analyses have been conducted.
An Unblinded Data Team Charter will be developed to document which roles will have access to 
which data and their responsibilities. The Unblinded Data Team is independent from the blinded 
study team and is not involved in the day-to-day conduct of the study. 
4.5
Sample Size Determination
Power analysis and sample size estimation was based on 1000 computer simulations using a 
generalized linear model for count data assuming a Poisson distribution with Pearson chi-square 
scaling of standard errors to account for potential overdispersion. The active treatment dose in 
each active treatment arm to placebo ratio was set at 1:1.5. A 10% missing data/dropout rate for 
both active treatment and placebo was also built into the empirical sample size simulations.


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For a treatment effect of 60% reduction in attacks as compared to placebo, assuming a placebo 
attack rate of 0.3 attacks per week over a 26 week period for an average total of 7.8 attacks 
during the treatment period, a sample size of 24 actively treated subjects for the primary active 
treatment arm and 36 placebo subjects would provide at least 95% power (at alpha=0.025, 
one-sided). A 60% reduction is well below the smallest expected reduction in attacks, for in the 
DX-2930-02 study, we observed reductions of attacks of near 100%. These sample sizes will 
also provide adequately sized safety population for evaluation. Up to 120 subjects 
(approximately 80 subjects in the 3 active treatment groups and 40 in the placebo group) may be 
enrolled to account for potential early drop-outs during the study.


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5.
EFFICACY AND SAFETY ENDPOINTS
5.1
Efficacy Endpoints
5.1.1
Primary Efficacy Endpoint

Number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
Day 182).
5.1.2
Secondary Efficacy Endpoints

Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period.  

Number of moderate or severe investigator-confirmed HAE attacks during the treatment
period.  
5.1.3
Exploratory Efficacy Endpoints

Time to first HAE attack after Day 14.

Number of high-morbidity investigator-confirmed HAE attacks during the treatment period.

Number of investigator-confirmed HAE attacks resulting in an emergency department visit 
and/or admission to hospital during the Treatment Period.

Achievement of a reduction from the baseline in the investigator-confirmed HAE attack rate
(i.e., responder analysis).

Characteristics of investigator-confirmed HAE attacks, including attack duration, severity, 
location, and medication use. 

Percentage of attack free days.
5.2
Safety Endpoints
The safety and tolerability of DX-2390 will be evaluated through the assessment of adverse 
events, clinical laboratory testing, vital sign measurements, electrocardiogram (ECG) recordings, 
concomitant medications and physical examination findings.
5.3
Other Endpoints
Additional endpoints of interest in this study are the plasma concentration of DX-2930, 
pharmacodynamic biomarker assays, anti-drug antibodies and quality of life data as collected 
with the EuroQoL Group 5-Dimension (EQ5D) Questionnaire and the Angioedema Quality of 
Life (AE-QoL) Questionnaire.


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6.
EFFICACY AND SAFETY VARIABLES
6.1
Study Activities Schedule
Please refer to Appendix 10.4 for details of assessments performed at each visit.
6.2
Efficacy Assessments
The collection, reporting and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP). Site personnel will be trained 
on HAARP prior to screening subjects at their site.
During the study, subjects (or caregivers, in the event the subject is < 18 years old) will be 
instructed to notify and report details of an attack to the study site within 72 hours of the onset of 
an HAE attack. In the event that a subject is incapacitated following an attack, this information 
can be provided to the site by a family member or other individual with detailed knowledge of 
the event. If desired by the subject, memory aids may be provided to assist in tracking any HAE 
attacks subjects experience. Weekly communication between the subjects and the site personnel, 
including reports of HAE attacks must be documented in the electronic case report form (eCRF).
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack:

Date and time symptoms of an attack were first experienced

Description of symptoms experienced, including location(s)

Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits

Any medications used to treat the attack

If the attack resolved, date and time the subject was no longer experiencing symptoms
Site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP. 
Sites personal will also record the severity of the attack, if the attack required acute treatment, if 
the attack resulted in an emergency department visit or hospitalization, if the attack was 
hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or associated 
with syncope or near-syncope) and whether the attack was peripheral, abdominal or laryngeal.
In this study HAE attacks will be captured as AEs. All AEs, regardless of seriousness, severity, 
or causal relationship to study drug, will be recorded on the AE page of the eCRF. Any AE 
reported to the site meeting criteria for a serious adverse event must be reported to the Sponsor 
using the SAE Reporting Form in the electronic data capture (EDC) system within 24 hours of 
becoming aware of the event. For all serious adverse events that are reported as HAE attacks, the 
Principal Investigator or physician designee will review the event within 24 hours of initial 
notification and, in accordance with HAARP, evaluate if it represented a confirmed HAE attack.
For all non-serious AEs that are reported as HAE attacks, the Principal Investigator or physician 
designee will review the event within 3 days of initial notification and, in accordance with 


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HAARP, evaluate if it represented a confirmed HAE attack. If necessary for the evaluation, the 
Investigator or designee may contact the subject for additional information. Any subject-reported 
attack not confirmed by the Investigator must have an alternate AE diagnosis recorded. All 
subject-reported and investigator-confirmed HAE attacks will be recorded in the eCRF.
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured.
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with an 
attack in at least one of the following locations: 

Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region.

Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea.

Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx.
Despite the presence of these symptoms, the Investigator may still clinically determine that the 
event did not represent an HAE attack if there are features that strongly refute such a diagnosis. 
For example, the reported event is accompanied by symptoms that are not consistent with an 
HAE attack (e.g., urticaria), the reported event persists well beyond the typical time course of an 
HAE attack, or there is a likely alternate etiology for the event (e.g., the subject’s abdominal 
symptoms are attributable to a viral gastroenteritis outbreak in the household). 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.
6.3
Safety Assessments
6.3.1
Adverse Events
Adverse events will be collected from signing of the informed consent through the last study 
visit. For a detailed definition on AEs, Serious AEs (SAEs), severity of AEs, and relatedness of 
AEs and SAEs, please refer to the protocol.
An AE is treatment-emergent if the onset time is after first administration of IMP or, in the event 
that onset time precedes first IMP administration, the AE increases in severity after first 
administration of IMP.
In this study, the severity of AEs will be assessed according to Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table, Draft, November 2007 (US National 
Institutes of Health: National Institute of Allergy and Infectious Diseases) and the Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Table, Draft, November 2007 
(US National Institutes of Health: National Institute of Allergy and Infectious Diseases). For 
abnormalities not specifically found in the Toxicity Tables, the following general scale will be 
used to estimate grade of severity:


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
GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required

GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required

GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 

GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable
Any treatment-emergent ECG abnormality that is considered by the Investigator as clinically 
significant and requiring intervention/therapy will be assessed as a severe AE.
The causal relationship between the study IMP and the AE will be assessed as Not Related or 
Related.
6.3.1.1
Adverse Events of Special Interest
Adverse events of special interest (AESI) will be captured and monitored during this study. 
AESI include hypersensitivity reactions and events of disordered coagulation. 
Hypersensitivity Reactions
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the reactions 
are suspected to be related to study drug.
Events of Disordered Coagulation
Bleeding AESI
Although aPTT prolongation due to plasma kallikrein inhibition is an artifactual in vitro
phenomenon, as a precautionary measure in evaluating the safety of DX-2930, bleeding events 
will be reported as AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with a clinical event of 
bleeding. Coagulation testing (aPTT, PT, INR) should be performed when possible, and when 
temporally reasonable, with any reports of bleeding or for clinical conditions possibly indicative 
of bleeding.
Hypercoagulable AESI
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology. 


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6.3.2
Vital Signs
Vital signs will be assessed by the Investigator or his/her qualified designee according to the 
Study Activities Schedule (Appendix 10.4). Routine vital sign assessments will be taken with the 
subject in the sitting or supine position after 5 minutes at rest and will include body temperature, 
heart rate (HR), blood pressure (BP) and respiratory rate (RR). BP should be determined using 
the same arm and the same equipment for each assessment. There is a ±15 minute window for all 
vital signs.
At study visits in which IMP is administered, vital signs will be obtained prior to dosing, 1 hour 
after dosing, and 2 hours after dosing for the first 4 doses with the ability to eliminate the 2 hour 
vitals for the remaining doses based on the discretion of the Investigator and the absence of 
safety signals.
6.3.3
Physical Examination
A physical examination including height, weight and calculation of Body Mass Index (BMI) will 
be performed by the Investigator or his/her qualified designee according to the Study Activities 
Schedule (Appendix 10.4). Height and weight will be collected at the screening visit only.
6.3.4
Electrocardiogram (ECG)
A standard 12-lead ECG (single recording) will be performed at screening, baseline prior to 
Dose 1, Day 56, and Day 144±1 day (to capture the estimated Cmax), and Day 182. The ECG 
assessment at Cmax on Day 144±1 day may be performed via at-home nurse or technician in lieu 
of a subject visit to the study site. For subjects that do not rollover into OLE (DX-2930-04), an 
ECG will be performed on Day 238. The date and time of each ECG and its results will be 
documented in the source documents and eCRF. Electrocardiograms will be sent to a central 
reading vendor for assessment.
6.3.5
Clinical Laboratories
Laboratory testing will be performed according to the Study Activities Schedule (Appendix 
10.4).
Laboratory testing includes general safety parameters (hematology, coagulation, urinalysis, and 
serum chemistry), serology, pregnancy tests, C1-INH functional assay, C4 assay, C1q assay, PK 
samples, PD samples, and plasma anti-drug antibody testing. All laboratory tests will be 
performed using established and validated methods. 
6.3.5.1
Hematology
•
Hemoglobin
•
Hematocrit
•
Red blood cell (RBC) count
•
White blood cell (WBC) count with differential


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•
Mean corpuscular volume (MCV)
•
Mean corpuscular hemoglobin (MCH)
•
Mean corpuscular hemoglobin concentration (MCHC)
•
Absolute platelet count
6.3.5.2
Coagulation
•
Prothrombin time (PT)
•
Activated partial thromboplastin time (aPTT)
•
International Normalized Ratio (INR)
6.3.5.3
Chemistry
•
Albumin
•
Alkaline phosphatase
•
Alanine aminotransferase (ALT; SGPT)
•
Aspartate aminotransferase (AST; SGOT)
•
Bilirubin (total and direct)
•
Blood urea nitrogen (BUN)
•
Calcium
•
Carbon dioxide (CO2)
•
Chloride
•
Creatinine
•
Creatine phosphokinase (CPK)
•
Glucose
•
Phosphate
•
Magnesium
•
Potassium
•
Sodium
•
Total protein
•
Uric acid
6.3.5.4
Urinalysis
•
Bilirubin
•
Glucose
•
Ketones
•
Blood 


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•
Nitrite
•
pH
•
Protein
•
Specific gravity
•
Microscopy (if indicated by macroscopic findings)
6.3.6
Concomitant Therapies
The Sponsor representatives and Investigator at the site conducting the trial will review and 
evaluate prior and concomitant medication usage on an ongoing basis. All prescription, over-the-
counter medications, herbals, and supplements that are being taken or have been taken by 
subjects from the time of screening through the duration of the study will be regarded as 
concomitant medications and must be documented in the source documents and eCRF.
6.4
Other Assessments
6.4.1
Pharmacokinetic Assessment
Blood samples for the measurement of plasma DX-2930 concentration will be obtained at 
pre-dose on Days 0, 56±3, 98±3, 140±3, and 182±3. Additional samples will be collected on 
Days 210±3 and 238±3 during the follow-up period for any subjects not entering OLE.
6.4.2
Pharmacodynamic Assessment
To evaluate the PD effects of DX-2930 upon plasma kallikrein activity, blood samples will be 
obtained at pre-dose on Days 0, 56±3, 98±3, 140±3, and 182±3. Additional samples will be 
collected on Days 210±3 and 238±3 during the follow-up period for any subjects not entering 
OLE.
6.4.3
Plasma Anti-Drug Antibody Testing 
Plasma samples for testing for formation of antibodies to DX-2930 will be obtained at pre-dose 
on Days 0, 56±3, 98±3, 140±3, and 182±3. Additional samples will be collected on Days 238±3 
during the follow-up period for any subjects not entering OLE.
6.4.4
Quality of Life Assessments
Quality of life data will be obtained using the EuroQoL Group 5-Dimension (EQ5D) 
Questionnaire at pre-dose on Days 0, 98±3, and 182±3 and using Angioedema Quality of Life 
(AE-QoL) Questionnaire at pre-dose on Days 0, 28 ±3, 56 ±3, 98±3, 126 ±3, 154 ±3, and 182±3. 
An additional quality of life assessment will be conducted on Day 238±3 for subjects not 
entering OLE.


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ED-5D-5L
The EQ-5D-5L consists of 2 parts: descriptive questions and a visual analog scale (VAS).  The 
descriptive questions comprise 5 dimensions: Mobility, Self-care, Usual activities, 
Pain/discomfort, and Anxiety/depression. Each dimension is divided into 5 levels of perceived 
problems: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The VAS records the subject’s self-rated health on a 20-cm vertical VAS with 
endpoints labelled “the best health you can imagine” and “the worst health you can imagine”. 
AE-QoL
The AE-QoL consists of 4 domains (functioning, fatigue/mood, fears/shame and nutrition) and 
17 questions. Details of how to compute scores for the domains and the total score are included 
in Appendix 10.2.14. 


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7.
STATISTICAL ANALYSIS
7.1
General Methodology
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, 
, 
, USA).
Unless otherwise specified, summary tabulations will be presented by treatment group (DX-2930 
300 mg every 2 weeks, DX-2930 300 mg every 4 weeks, DX-2930 150 mg every 4 weeks, and 
Placebo). All data listings will be sorted by treatment group, site, and subject number, and will 
include the subject’s age, sex, and race.  
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. Where applicable, estimates from statistical model of least 
squares means, treatment differences, standard errors, p-values, and 95% confidence intervals 
(CI) for least squares mean treatment differences will be provided. Time-to-event data will be 
summarized using Kaplan-Meier (KM) estimates of the 25th, 50th (median), and 75th percentiles 
with associated two-sided 95% CI, as well as percentage of censored observations. Plots of the 
KM curves and supporting data listings detailing each subject’s contribution to the analysis will 
be provided. 
Formal statistical hypothesis testing will be performed on the primary and rank ordered 
secondary efficacy endpoints with the global family-wise type I error rate (FWER) strongly 
controlled at two-sided 0.05 using a Bonferroni-based general gatekeeping procedure as 
described in Section 9.5.
For the summary statistics of all numerical variables unless otherwise specified, minimum and 
maximum will be displayed to the same level of precision as reported. Mean and median will be 
displayed to one level of precision greater than the data collected. Standard deviation will be 
displayed to two levels of precision greater than the data collected. P-values will be rounded to 3 
decimal places, p-values <0.0005 will be displayed as <0.001.
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts.  The denominator for all percentages will be the number 
of subjects for that treatment group within the population of interest, unless otherwise specified.
See Section 10.2 for detailed descriptions of analysis definitions and programming conventions.   
PPD
PPD


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7.2
Analysis Populations
The analysis populations will be defined as follows: 
7.2.1
Intent-to-treat (ITT) Population 
The ITT Population will include all randomized subjects who received any study drug. The 
primary efficacy analyses will be carried out with the ITT Population. Subjects will be analyzed 
according to their randomized treatment assignment regardless of the treatment actually received.
7.2.2
Safety Population 
The Safety Population will include all subjects who received any study drug. All safety analyses 
will use the Safety Population. Subjects will be analyzed according to the treatment actually 
received, regardless of the treatment assigned. 
7.3
Subject Disposition
The number of subjects screened, randomized, treated with study drug, completed the study and 
discontinued prematurely by reason will be summarized overall and by randomized treatment 
assignment for all subjects. For each analysis population, the number of subjects included in the 
population, completing the study and those that discontinued prematurely by reason, will be 
summarized by treatment group, overall DX-2930, and overall. Listings of all disposition data 
will be provided.
7.4
Protocol Deviations
Protocol deviations will be collected at both the site and subject level. 
Deviations at the site level will be applied to all subjects who were enrolled at that site at the 
time of the deviation. Deviation types for site level deviations are: Use of incorrect equipment, 
use of incorrect forms, use of expired laboratory samples, use of equipment with expired 
maintenance, study procedure completed by non-authorized personnel, site personnel did not 
complete training prior to completing study procedure, amendment implementation without 
approval/notification or IRB/EC, temperature excursion for IP and other. 
Deviation types for subject level deviations are: eligibility criteria, informed 
consent/assent/HIPAA, concomitant medication, investigational product, study visit (missed/out 
of window), study procedure (missed/out of window), site personnel/assessor error, 
randomization, safety reporting, IRB/EC reporting, EQ-5D, Angioedema Quality of Life, lab 
collection, and other (not otherwise defined).
Summary tables of protocol deviation type by treatment group, overall DX-2930, and overall 
will be provided for the ITT Population. All protocol deviations will be included in a subject 
listing. 


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7.5
Demographic and Other Baseline Characteristics
Baseline and demographic variables will be descriptively summarized by treatment group, 
overall DX-2930, and overall for each analysis population. 
Demographic variables to be presented include age (years), age category (<18, 18 to <40, 40 to 
<65, ≥65 years), sex (male, female), ethnicity (Hispanic, Non-Hispanic), race (American Indian 
or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, 
White and Other), race group (White, Other) geographical region (US, Canada, Europe and 
Jordan), height (cm), weight (kg), weight group (<50, 50 to <75, 75 to <100, ≥100 kg), BMI 
(kg/m2) and BMI group (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2). 
A separate table will be created for baseline characteristics and will include age at onset of 
angioedema symptoms, HAE type (Type I, Type II, Unspecified), history of laryngeal attacks, 
primary attack locations, number of attacks in the last 1, 3, and 12 months, baseline HAE attack 
rate (attacks/4 weeks) and baseline HAE attack rate strata (1 to <2, 2 to <3, ≥3 attacks/4 weeks). 
All baseline and demographic data will be presented in subject listings.
7.6
Medical History
Medical history will be coded using Medical Dictionary for regulatory Activities (MedDRA) 
version 18.1 and summarized by system organ class (SOC) and preferred term (PT) by treatment 
group, overall DX-2930 and overall for each analysis population. Tabulations will be presented 
sorted by SOC in alphabetical order and by PT within each SOC by descending frequency.  All 
medical history will be presented in subject listings.
7.7
Treatment Compliance and Extent of Exposure
All planned study drug administrations will be recorded in the case report form, including 
whether a full, partial, or no dose was given; date and time of dose; and location of the injection. 
Regardless of treatment assignment, all subjects are to receive two injections of blinded study 
drug given in the same upper arm, with at least 2 cm separation between each injection site. 
It is anticipated that all subjects will be compliant with treatment because the study drug will be 
administered by qualified site personnel. Treatment compliance and the extent of exposure will 
be described by the percentage of planned doses received by the subject, total number of doses 
received by the subject, and the number and percentage of subjects that received at least 80% of 
planned doses, summarized by treatment group for each analysis population. Listings of study 
administrations by subject will also be provided.
7.8
Analysis of Efficacy
All efficacy analyses will be performed on the ITT Population.
7.8.1
Primary Efficacy Analysis
The primary efficacy endpoint, number of investigator-confirmed HAE attacks during the 
treatment period (Day 0 through Day 182), will be compared for each active treatment group 


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(DX-2930) to the placebo group using a generalized linear model (GLM) for count data 
assuming a Poisson distribution with a log link function and Pearson chi-square scaling of 
standard errors to account for potential overdispersion. The model will include fixed effects for 
treatment group (categorical) and the normalized baseline attack rate (continuous), and the 
logarithm of time in days each subject was observed during the treatment period will be used as 
an offset variable in the model. See Section 10.2.9.1 for the calculation of the normalized 
baseline attack rate.
From this model, the least squares mean rate and standard error for each treatment group as well 
as, the mean rate ratios relative to the placebo group and corresponding 95% confidence intervals 
for each active treatment group will be estimated. These estimates will be reported as mean event 
rates per unit of time (week and monthly) by transforming the estimates using the exponential 
function and scaling by the unit of time. 
The primary endpoint will be tested by the following hypothesis:
H0: λDX-2930 / λplacebo = 1 versus H1: λDX-2930 / λplacebo ≠ 1
λDX-2930 refers to the mean investigator-confirmed HAE attack rate in the DX-2930 group and 
λPlacebo refers to the mean investigator-confirmed HAE attack rate in the placebo group. The null 
hypothesis is that the mean investigator-confirmed HAE attack rate ratio is 1 (no difference 
between treatment groups), versus the alternative hypothesis that the HAE attack rate ratio is not 
1. Estimated attack rate ratios less than one would indicate that subjects treated with DX-2930, 
on average, have a lower incidence of investigator-confirmed HAE attacks during the treatment
period. The hypothesis will be tested using the model-based least squares means estimate of the 
treatment difference using a Wald-based chi-square test.
The percentage difference in mean investigator-confirmed HAE attack rate of each active 
treatment group from the attack rate of placebo will be calculated as 100% * (mean rate ratio –
1). Similarly, the estimated upper and lower confidence limits for the mean rate ratio can be 
transformed by subtracting 1 and multiplying by 100% to calculate 95% confidence intervals for 
the percentage change.  The mean rate ratios and corresponding 95% confidence intervals will be 
estimated from the generalized linear model as described previously. 
In order to maintain the overall Type I error at 0.05, a conservative Bonferroni-based procedure 
will be used for the comparisons of each of the active treatment groups with the placebo group 
with equal weights for each test set at 1.67% significance level (α/3). See Section 9.5 for more 
information.
Unadjusted monthly investigator-confirmed HAE attack rates will be calculated for the 
pretreatment, run-in and treatment periods.  See Section 10.2.9 for details.  The pretreatment 
period, run-in period, treatment period, treatment period change from baseline, and treatment 
period change from run-in period in the monthly investigator-confirmed HAE attack rate will be 
summarized by treatment group. This summary will include the total number of investigator-
confirmed HAE attacks reported and the subject-time in months each subject contributed to the 
pretreatment, run-in period, and treatment period. Figures by treatment group (one for each 


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treatment group) plotting the on-study investigator-confirmed HAE attacks reported during the 
treatment period relative to randomization for each subject will be created.  
In addition to the data summaries for the primary analysis of the primary efficacy endpoint 
described above, the number of investigator-confirmed HAE attacks per month (defined as 28 
days) will be summarized descriptively by month (per 28 day interval) and treatment group. The 
summary will include the number, change from pretreatment, and percent change from 
pretreatment of investigator-confirmed HAE attacks. Investigator-confirmed HAE attacks will be 
grouped into 28-day intervals using the start date of the HAE attack. The date of the first 
exposure to study drug will be used as the start of the first interval and end of the interval will be 
the date of first exposure to study drug plus 28 days. Each successive interval will start the last 
day of the prior interval plus 1 day and end 28 days later. See Section 10.2.6.1 for the definition 
of the pretreatment period.
All HAE attacks will be presented in listings.
7.8.2
Secondary Efficacy Analyses
The rank ordered secondary efficacy endpoints are as follows:
1. Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period.
2. Number of moderate or severe investigator-confirmed HAE attacks during the treatment
period. 
The secondary endpoints will be analyzed using the same method as described for the primary 
efficacy endpoint. Data summaries will parallel those described for the primary analysis of the 
primary efficacy endpoint.
To adjust for the potential of inflated overall type-I error rate, the rank ordered secondary 
endpoints will be tested in a fixed sequence for each active treatment group to placebo group 
comparison using a general gatekeeping approach consistent with the logical restrictions of the 
rank ordering of the endpoints. Secondary endpoints will not be declared statistically significant 
unless the primary endpoint for that active treatment group to placebo group comparison is found 
to be statistically significant. See Section 9.5 for more information.
7.8.3
Exploratory Efficacy Analyses
Exploratory analyses will include data summaries for the following:

Time to first HAE attack after Day 14, i.e., duration that a subject is attack free after Day 14

Number of high-morbidity investigator-confirmed HAE attacks during the treatment period.

Number of investigator-confirmed HAE attacks resulting in an emergency department visit 
or admission to the hospital.

Number of investigator-confirmed HAE attacks resulting in an emergency department visit.

Number of investigator-confirmed HAE attacks resulting in admission to the hospital.


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
Achievement of a reduction from pretreatment in the investigator-confirmed HAE attack rate
(i.e., responder analysis).

Characteristics of investigator-confirmed HAE attacks, including attack duration, severity, 
and rescue mediation use. 

Percentage of attack free days
The exploratory efficacy endpoints are considered supportive and any statistical tests comparing 
treatments will be made without adjustment for multiplicity. The resulting p-values from these 
supportive analyses will be interpreted descriptively as summarizing the weight of evidence for a 
treatment effect.
Time to first HAE attack after Day 14
The time to first HAE attack (days) will be calculated from the date of Day 14 visit to the date of 
the first attack after Day 14 visit. Subjects who do not have an attack will be censored at the date 
of discontinuation or completion of the study (Day 182 for subjects who do not roll-over into the 
OLE). Time to the first HAE attack after Day 14 will be summarized using Kaplan-Meier 
methods. A log-rank test comparing each active treatment group to the placebo group will be 
included. 
Number of high-morbidity investigator-confirmed HAE attacks
A high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation < 24 
hours), hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal. If the length of hospitalization can’t be 
determined due to missing dates and times, then that hospitalization will be conservatively 
counted as being greater than 24 hours. The number of high-morbidity investigator-confirmed 
HAE attacks during the treatment period will be analyzed using the same method as for the 
primary efficacy endpoint. Data summaries will parallel those described for the primary analysis 
of the primary efficacy endpoint.
Number of investigator-confirmed HAE attacks resulting in an emergency department visit or 
admission to the hospital
For each HAE attack, the site records if the attack resulted in a visit to the emergency department
or admission to the hospital. The number of investigator-confirmed HAE attacks resulting in an 
emergency department visit or admission to the hospital during the treatment period will be 
analyzed using the same method as for the primary efficacy endpoint. Data summaries will 
parallel those described for the primary analysis of the primary efficacy endpoint.
Number of investigator-confirmed HAE attacks resulting in an emergency department visit
For each HAE attack, the site records if the attack resulted in a visit to the emergency 
department. The number of investigator-confirmed HAE attacks resulting in an emergency 
department visit during the treatment period will be analyzed using the same method as for the 


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primary efficacy endpoint. Data summaries will parallel those described for the primary analysis 
of the primary efficacy endpoint.
Number of investigator-confirmed HAE attacks resulting in admission to the hospital
For each HAE attack, the site records if the attack resulted in hospitalization. The number of 
investigator-confirmed HAE attacks resulting in admission to the hospital during the treatment 
period will be analyzed using the same method as for the primary efficacy endpoint. Data 
summaries will parallel those described for the primary analysis of the primary efficacy 
endpoint.
Achievement of reduction from pretreatment in the investigator-confirmed HAE attack rate (i.e., 
responder analysis)
There will be five classes of responders based on percent reduction in the investigator-confirmed 
HAE attack rate from the pretreatment attack rate: 50% or more reduction, 60% or more 
reduction, 70% or more reduction, 80% or more reduction and 90% or more reduction. For each 
subject, a treatment period HAE attack rate and pretreatment HAE attack rate will be calculated. 
See Section 10.2.9 for details. The percentage reduction will be calculated as the pretreatment
HAE attack rate minus the treatment period HAE attack rate divided by the pretreatment HAE 
attack rate. Summary statistics will be presented for each of the five classes of responders by 
treatment. The five classes of responders are nested and not mutually exclusive.
Characteristics of investigator-confirmed HAE attacks, including attack duration, severity, 
location and mediation use
Attack characteristics, as described below, will be summarized by treatment group and overall 
DX-2930 for the pretreatment period and treatment period.
HAE Attack Duration
For each subject, the mean, minimum and maximum duration of all investigator-confirmed HAE 
attacks will be calculated in hours and summarized. See Section 10.2.7.1 for details. The subject-
level average attack duration will be categorized into 12 hour intervals and tabulated by category 
(<12 hours, 12-24 hours, >24-48 hours, and >48 hours).  
HAE Attack Severity
For each subject, the mean and maximum severity of all investigator-confirmed HAE attacks will 
be calculated using a numerical rating and summarized. See Section 10.2.7.2 for details. The 
number and percentage of subjects, as well as the number of events, will be tabulated by attack
severity (mild, moderate, and severe).  
HAE Attack Location
The number and percentage of subjects with attacks, as well as the number of events, will be 
tabulated by attack location (peripheral, abdominal, and laryngeal). 


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Rescue Medication Use
The number and percentage of subjects with rescue medication use for an HAE attack, as well as 
the number of events, will be tabulated by rescue medication by type (ecallantide, icatibant, 
nano-filtered C1-INH, plasma-derived C1-INH, recombinant C1-INH, fresh frozen plasma, and 
other).
Supportive Treatment Use
The number and percentage of subjects with supportive treatment use for an HAE attack, as well 
as the number of events, will be tabulated by supportive treatment by type (IV fluids, pain 
medication, oxygen, anti-emetic, and other). 
Percentage of HAE attack free days
The percentage of HAE attack free days will be calculated by counting the number of days in the 
treatment period without an HAE attack and dividing by the number of days the subject was in 
the treatment period. If an HAE attack was 8 hours or less on a particular day that day will be 
considered attack-free. Summaries of the percentage of HAE attack free days will be provided by 
treatment group.
7.9
Analysis of Safety
All safety analyses will be performed on the Safety Population. No inferential statistics are 
planned.
7.9.1
Adverse Events
Adverse events (AEs) will be coded using the MedDRA coding dictionary version 18.1. 
Treatment-emergent AEs (TEAEs) are defined as AEs with onset at the time of or following the 
start of treatment with study medication, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.  
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.  
Related AEs are AEs classified as related to study drug by the investigator.  Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator.
For this analysis, AEs will be classified to one of three analysis periods:

Pretreatment Period AEs will include AEs starting at or after informed consent to those 
starting before the first exposure to study drug (AEs starting prior to treatment on Day 0).


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
Treatment Period AEs will include all AEs starting at or after the first exposure to study drug 
to those starting before or at the subject’s last visit date during the treatment period (AEs 
starting at or after treatment on Day 0 to the Day 182 visit). 

Follow-up Period AEs will include all AEs starting at or after the subject’s last visit date of 
the treatment period (AEs starting after the Day 182 visit). 
For AEs with partial onset times, non-missing date parts will be used to determine if the AE falls 
within the period. If a determination cannot be made using the non-missing date parts as to if the 
AE falls within the period, the AE will be conservatively counted as a treatment-period AE. 
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE,  
any severe AE, and any related severe AE will as well as the total number of events for each 
category will be summarized by treatment group. The number of deaths due to an AE, 
hospitalization due to an AE and study discontinuation due to an AE will be summarized by 
treatment group and overall DX-2930. This tabulation will be repeated for each of the analysis 
periods.
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized for each treatment group and overall DX-2930 by SOC, and PT for each analysis 
period. This tabulation will be repeated for related AEs, SAEs, related SAEs, severe AEs, and 
related severe AEs for treatment period and follow-up period AEs. This tabulation will be 
repeated for SAEs for pretreatment period. Tabulations will be presented sorted by SOC in 
alphabetical order and by PT within each SOC by descending frequency in the overall DX-2930 
group and then the placebo group.
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized for each treatment group and overall DX-2930 by PT for treatment period AEs only. 
This tabulation will be repeated for related AEs and serious AEs for treatment period AEs. 
Tabulations will be presented sorted by PT by descending frequency in the overall DX-2930 
group and then the placebo group.
All AEs will be provided in subject listings. Listings will be presented separately for each 
analysis period. In addition, subject listings of AEs causing discontinuation of study medication, 
AEs leading to death, SAEs, related AEs, severe AEs, and AEs of special interest (AESIs) will 
be produced. 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events). Standardized MedDRA 
Queries (SMQ) for each AESI will be performed using the study data. The number and percentage 
of subjects with an AESI, as well as the total number of AESIs, will be summarized for each 
treatment group and overall DX-2930 by SOC and PT. Separate summary tables will be created for 
each AESI and for those events with the SMQs classified as related, serious, related serious, 
severe, and related severe. A listing detailing the PT within the SMQ will be provided.


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7.9.2
Clinical Laboratory Evaluation
Laboratory test results will be presented in conventional units. 
Baseline is defined as the last non-missing value prior to the first exposure to study drug.
Continuous laboratory test results (serum chemistry, hematology, and urine pH) will be summarized 
as described below. 
Actual values and changes from baseline in clinical laboratory tests for hematology, coagulation, 
chemistries, and urinalysis will be summarized for each treatment group and overall DX-2930 by 
study visit. If more than one laboratory result is reported per study visit per parameter, the last non-
missing result will be selected for analysis. All laboratory results will be presented in subject 
listings.
Laboratory test results will be classified according to the reference ranges and clinical significance as 
determined by the investigator. The number of subjects with a non-missing result, and the number 
and percentage of subjects with a clinically significant result less than the lower limit of normal, non-
clinically significant result less than the lower limit of normal, within the normal range, non-
clinically significant result more than the upper limit of normal, and clinically significant result more 
than the upper limit of normal will be summarized for each treatment group and overall DX-2930 by 
study visit. If more than one laboratory result is reported per study visit per parameter, the result 
yielding the most severe classification will be selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized for treatment group 
and overall DX-2930 by study visit. If more than one laboratory result is reported per study visit per 
parameter, the result yielding the most severe classification will be selected for analysis. 
Subjects with clinically significant abnormal laboratory test results will be listed. This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the investigator for a subject across study visit to identify any trends.
7.9.3
Vital Signs
Baseline is defined as the last non-missing value prior to the first exposure to study drug.
Actual values and changes from baseline in vital signs will be summarized for each treatment 
group and DX-2930 overall by study visit and study time point. All vital sign data will be 
presented in subject listings.
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage of 
subjects with a non-clinically significant result and clinically significant result will be summarized 
for each treatment group and overall DX-2930 by study visit and study time point. If more than one 
vital sign result is reported per study visit and study time point per parameter, the result yielding the 
most severe classification will be selected for analysis. Subjects with clinically significant vital sign 
values will be listed. This listing will include all results of the vital sign parameter that was 
determined by the investigator to be clinically significant for a subject across study time points to 
identify any trends.


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7.9.4
Electrocardiography
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG not performed, will be summarized for each 
treatment group and overall DX-2930 by study visit. Subjects with clinically significant ECG 
results will be listed. This listing will include all results for a subject across study time points to 
identify any trends.
All ECG data will be provided in subject listings.
7.9.5
Physical Examinations
Physical examination findings by body system will be classified as normal, abnormal not 
clinically significant, abnormal clinically significant or not performed by the investigator and 
will be summarized for each treatment group and DX-2930 overall by study visit. Subjects with 
clinically significant abnormal physical examination findings will be listed. This listing will 
include all results of the body system that was determined by the investigator to be clinically 
significant for a subject across study time points to identify any trends.
All physical examination findings will be provided in subject listings.
7.9.6
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) Version 2015 Q3.
Prior medications are defined as medications with start and stop times at or prior to the time of 
study drug administration. 
Concomitant medications are defined as medications with a start times after the time of study drug 
administration or medications with a start times prior to study drug administration but continuing 
after treatment. 
For medications with partial onset times, non-missing date parts will be used to determine if the 
medication is concomitant or prior medication. If a determination cannot be made using the non-
missing date parts as to when the medication occurred relative to study drug administration then the 
medication will be classified as concomitant medication. 
The number and percentage of subjects with prior or concomitant medications will be summarized 
for each treatment group and overall DX-2930 by therapeutic class and preferred term. Therapeutic 
class will be based on the Therapeutic Subgroup corresponding to level 2 of the Anatomic 
Therapeutic Chemical (ATC) classification system. Tabulations will be presented sorted by 
therapeutic class in alphabetical order and by PT within each therapeutic class by descending 
frequency in the overall DX-2930 group and then the placebo group. A separate similar table will 
be provided for rescue medications. All medications will be presented in subject listings.


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7.10
Other Analyses
Additional analyses of pharmacokinetic (PK) and pharmacodynamic (PD) data will be described 
in a separate PK/PD report.
Additional analysis of quality of life (QoL) data will be described in a separate QoL report.
7.10.1
Analysis of Pharmacokinetic Data
Plasma concentrations of DX-2930 will be summarized for each treatment group by nominal PK 
sampling time and listed by subject using the Safety Population.
Plasma concentrations reported as BLQ (below the limit of quantification) of the assay will be 
reported as zero in the data listings, and BLQ concentrations are treated as zero in the calculation 
of summary statistics.
7.10.2
Analysis of Pharmacodynamic Data
Plasma kallikrein activity will be summarized for each treatment group by nominal PD sampling 
time and listed by subject using the Safety Population.
7.10.3
Analysis of Immunogenicity Data
The number and percentage of positive antibodies will be summarized for each treatment group 
and DX-2930 overall by study visit and overall and listed by subject using the Safety Population.
7.10.4
Analysis of Quality of Life Data
The number and percentage of subjects at each level of the EQ-5D-5L dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) for each treatment group and 
DX-2930 overall by study visit using the Safety Population. In addition, the VAS score for the 
subject’s self-rated health will be summarized for each treatment group and DX-2930 overall by 
study visit using the Safety Population.  
The responses to the AE-QoL for each item will be tabulated for each treatment group and DX-
2930 overall by study visit using the Safety Population. In addition, the domain scores 
(functioning, fatigue/mood, fears/shame, nutrition) and total score will be summarized for each 
treatment group and DX-2930 overall by study visit using the Safety Population.
All QoL data will be provided in subject listings.


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8.
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES
8.1
Changes in the Conduct of the Study
There was no change in the conduct of the study.
8.2
Change from the Analyses Planned in the Protocol
8.2.1
Efficacy Evaluation Period
The phase “Efficacy Evaluation Period” was used in the protocol to describe the time interval for 
which efficacy would be evaluated and was defined as Day 0 through Day 182. This phase was 
changed to treatment period for consistency with the Study Activities Schedule. The definition of 
the duration of the interval remains Day 0 through Day 182.  
8.2.2
ITT and Safety Population Definitions
The definition of the ITT Population specified in the protocol stated that the population will 
include all randomized subjects who are administered at least 1 dose of active IMP or placebo.  
The definition in the SAP was modified from “at least 1 dose of active IMP or placebo” to “any 
exposure to study drug”. This change was made to clarify that a subject did not need to receive 
the full dose to be included in this analysis population, but that subjects receiving partial doses 
would be included.
A similar modification was applied to the definition of the Safety Population.
8.2.3
Adverse Events
The protocol stated that incidence of AEs and rate of study discontinuation among the four 
treatments arms would be compared, the SAP clarified that this comparison would be based on 
descriptive statistics.   
Additionally, the analysis of the incidence of AEs by month from start of study drug was 
omitted. Because subjects are repeatedly exposed to study drug on at least a monthly basis, it is 
not expected that the type or frequency of AE would vary by month.  
8.2.4
Laboratory Parameters
The protocol specified that for laboratory parameters the change from screening would be 
summarized. Instead, a change from baseline will be summarized and a definition of baseline 
was included in the SAP. 
The protocol specified that laboratory parameters would be summarized using shift tables. This 
summary was omitted and replaced with a summary of results based on reference ranges and 
clinical significance as determined by the investigator.


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8.2.5
Vital Sign Parameters
The protocol specified that for vital sign parameters the change from screening would be 
summarized. Instead, a change from baseline will be summarized and a definition of baseline 
was included in the SAP. 


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9.
STATISTICAL/ANALYTIC ISSUES
9.1
Adjustment for covariates
The analysis of the primary and secondary efficacy adjusts for the normalized pretreatment HAE 
attack rate.  No additional covariate adjustment is planned.
9.2
Handling of Dropouts or Missing Data
All available data will be included in the analysis.  The length of time a subject was observed 
during the treatment period will be included as a variable in the generalized linear model to 
adjust for differences in follow-up time.
9.3
Interim Analysis and Data Monitoring
No interim analyses are planned. However, an independent Data Safety Monitoring Board 
(DSMB) will be established to provide ongoing, independent review and assessment of the safety 
data, and to safeguard the interests and safety of the participating subjects in the study. Analysis 
of the data for DSMB review will be conducted according to the DSMB Charter and DSMB 
SAP. Because no formal hypothesis testing for safety assessments is planned, multiplicity 
concerns regarding repeated analyses are not an issue.
9.4
Multicenter Studies
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis.
9.5
Multiple Comparisons/Multiplicity
The global family-wise type I error rate (FWER) for the statistical tests of the primary and rank 
ordered secondary efficacy endpoints (rank specified in Section 7.8.2) will be controlled at 0.05. 
To strongly control the global FWER at this level, a general gatekeeping approach with branches 
for each active treatment group to placebo group comparison will be utilized in which each 
family of statistical tests will be conducted in a sequential manner. Specifically, a three-branch 
general gatekeeping procedure with three families of hypotheses will be defined as follows:
Family 1 (F1): Hypothesis tests for the primary efficacy endpoint, one test for each active 
treatment to placebo comparison ordered by highest total monthly dose (H11, H12, and H13).
Family 2 (F2): Hypothesis tests for the first ranked secondary endpoint, one test for each active 
treatment to placebo comparison ordered by highest total monthly dose (H21, H22, and H23).
Family 3 (F3): Hypothesis tests for the second ranked secondary endpoint, one test for each 
active treatment to placebo comparison ordered by highest total monthly dose (H31, H32, and 
H33).
The 3 sets of hypotheses in F1, F2, and F3 will be tested in a fixed sequence within each active 
treatment group to placebo group comparison or branch. Testing within a branch will continue in 


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sequence until the first test that the null hypothesis cannot be rejected; statistical significance 
cannot be declared for that test or for any of the remaining tests within the branch. 
Within a family, hypotheses will be tested using a conservative Bonferroni-based procedure with 
equal weights for each test set at 1.67% significance level (α/3). If the null hypothesis for a test is 
rejected, α will be propagated entirely to the next test in the sequence, which will then be tested 
at the 1.67% significance level.
To further illustrate this approach, the test for the primary endpoint will be conducted first at the 
1.67% significance level for each active treatment group compared with the placebo group and, 
if significant, the first secondary endpoint will be similarly tested at the 1.67% significance level. 
The testing sequence will continue in order through the remaining secondary endpoints for each 
active treatment group to placebo comparison or branch as long as the null hypothesis is rejected 
at the 1.67% significance level. 
Testing within the last family (F3) will utilize the remaining α by applying the Holm-Bonferroni 
procedure. 
9.6
Examination of Subgroups 
Subgroup analyses are planned for the primary efficacy endpoint and adverse events. Any p-
values that are presented will be descriptive. 
The following subgroups will be used:

Age Group (<18, 18 to <40, 40 to <65, ≥65 years)

Sex (Male, Female)

Race Group (White, Other)

Weight Group (<50, 50 to <75, 75 to <100, ≥100 kg)

BMI Group (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2)

Run-in Period HAE Attack Rate (1 to <2, 2 to <3, ≥3 attacks/month)

Pretreatment Period HAE Attack Rate (1 to <2, 2 to <3, ≥3 attacks/month)

HAE Type (Type I, Type II, Unspecified)

Geographic Region (US, Canada, Jordan, Europe)

Type of Long-term Prophylactic Therapy Prior to Study Randomization (C1-INH, 
Androgens, Anti-fibrinolytics, Not on LTP)
The subgroups will be analyzed using the same method as described for the primary efficacy 
endpoint. Data summaries will parallel those described for the primary analysis of the primary 
efficacy endpoint and the primary analysis of the adverse events.
9.7
Sensitivity Analyses
The following sensitivity analyses will be performed on the primary efficacy endpoint to 
evaluate the robustness of the results. Data summaries will parallel those described for the 
primary analysis of the primary efficacy endpoint.  


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1. The primary analysis will be repeated using the Safety Population. Subjects will be analyzed 
according to the treatment actually received.  This analysis will only be presented if the 
Safety Population is different from the ITT Population or if subjects did not receive treatment 
as randomized.
2. The primary analysis will be repeated counting HAE attacks occurring on Day 14 after 
administration of study drug through Day 182, instead of Day 0 to Day 182.
3. The primary analysis will be repeated counting HAE attacks occurring on Day 7 after 
administration of study drug through Day 182, instead of Day 0 to Day 182.
4. The primary analysis will be repeated using all subject reported HAE attacks instead of 
limiting the analysis to those attacks that were investigator-confirmed.
5. The primary analysis will be repeated using a generalized estimating equations (GEE)
analysis method counting HAE attacks occurring on Day 14 after administration of study 
drug through Day 182 in order to descriptively compare the results from this study with those 
from DX-2930-02 study. The methods for this analysis are listed below.
HAE attack rates for each active treatment group will be compared to the placebo group 
using a mixed-model repeated measures (MMRM) analysis of covariance (ANCOVA) for 
count data (assuming a Poisson distribution with log link function) using GEE. The model 
will include a fixed effect for treatment (categorical), pretreatment period attack rate 
(continuous), and a random effect for subject. 
Repeated measurement analysis will be employed, with a 7-day time period (i.e., 168 hours) 
serving as the discrete unit of measurement. Subject weeks for which completed observation 
is less than the full 168 hours within a week will be treated as a full week if at least 3 or more 
days of data were recorded during the week. Weeks with fewer than 3 days will not be 
included.
In the event that there are 0 events in one of the treatment groups, a small value of 0.000001 
will be added in order to calculate event rates.
Additionally, as applicable, the following sensitivity analyses will be performed on secondary 
and exploratory efficacy endpoints as detailed in Table 1. Data summaries will parallel those 
described for the each of the endpoints.


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Table 1: Sensitivity Analysis for Secondary and Exploratory Efficacy Endpoints
Secondary and Exploratory Efficacy Endpoint
Sensitivity Analysis Item
1
2
3
4
5
Number of HAE attacks requiring acute treatment
x
x
x
x
Number of moderate or severe HAE attacks 
x
x
x
x
Time to first HAE attack
x
x
x
Number of high-morbidity HAE attacks
x
x
x
x
Number of HAE attacks resulting in visit to emergency department 
or admission to the hospital 
x
x
x
x
Number of HAE attacks resulting in visit to emergency department 
x
x
x
x
Number of HAE attacks resulting in admission to the hospital
x
x
x
x
Responder Analysis
x
x
x
x
Characteristics of HAE attacks
x
x
x
x
Percentage of attack-free days
x
x
x
x


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10.
APPENDICIES
10.1
Appendix I List of Statistical Outputs
10.1.1
List of Planned Tables
Table No.
Title
14.1.1.1
Analysis Population by Treatment Group – All Subjects
14.1.1.2
Analysis Populations by Treatment Group and Site – All Subjects
14.1.2.1
Subject Disposition by Treatment Group – ITT Population
14.1.2.2
Subject Disposition by Treatment Group – Safety Population
14.1.3.1
Demographic Characteristics by Treatment Group – ITT Population
14.1.3.2
Demographic Characteristics by Treatment Group – Safety Population
14.1.4.1
Baseline Characteristics by Treatment Group – ITT Population
14.1.4.2
Baseline Characteristics by Treatment Group – Safety Population
14.1.5.1
Medical History by System Organ class, Preferred Term, and Treatment Group – ITT Population
14.1.5.2
Medical History by System Organ class, Preferred Term, and Treatment Group – Safety Population
14.1.6.1
Prior Medications by Treatment Group – Safety Population
14.1.6.2
Concomitant Medications and Therapies (Other than Rescue Medications) by Treatment Group –
Safety Population
14.1.6.3
Rescue Medications by Treatment Group – Safety Population 
14.1.7.1
Summary of Protocol Deviation Type by Treatment Groups – ITT Population
14.1.8.1
Treatment Compliance and Study Drug Exposure by Treatment Group – ITT Population
14.1.8.2
Treatment Compliance and Study Drug Exposure by Treatment Group – Safety Population
14.2.1.1
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Treatment Group – ITT Population
14.2.1.2
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Treatment Group – Safety Population
14.2.1.3
Poisson Regression of Investigator-confirmed HAE Attacks during Day 14 to Day 182 by Treatment 
Group – ITT Population
14.2.1.4
Poisson Regression of Investigator-confirmed HAE Attacks during Day 8 to Day 182 by Treatment 
Group – ITT Population
14.2.1.5
Poisson Regression of All HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group – ITT Population
14.2.1.6
GEE Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 
14 to Day 182) by Treatment Group – ITT Population
14.2.1.7
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Age Group and Treatment Group – ITT Population
14.2.1.8
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Sex and Treatment Group – ITT Population
14.2.1.9
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Race Group and Treatment Group – ITT Population
14.2.1.10
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Weight Group and Treatment Group – ITT Population


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14.2.1.11
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by BMI Group and Treatment Group – ITT Population
14.2.1.12
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Run-in Period HAE Attack Rate Group and Treatment Group – ITT Population
14.2.1.13
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Pretreatment Period HAE Attack Rate Group and Treatment Group – ITT Population
14.2.1.14
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by HAE Type and Treatment Group – ITT Population
14.2.1.15
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Geographic Region and Treatment Group – ITT Population
14.2.1.16
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Type of Long-term Prophylactic Therapy Prior to Study Randomization and Treatment 
Group – ITT Population
14.2.1.17
Summary of Investigator-confirmed HAE Attacks by Treatment Group – ITT Population
14.2.1.18
Mean, Mean Change, and Mean Percent Change from Pretreatment Period in Number of 
Investigator-confirmed HAE Attacks per Month by Treatment Group – ITT Population
14.2.2.1
Poisson Regression of Investigator-confirmed HAE Attacks Requiring Acute Treatment during the 
Treatment Period (Day 0 to Day 182) – ITT Population
14.2.2.2
Poisson Regression of Investigator-confirmed HAE Attacks Requiring Acute Treatment during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population
14.2.2.3
Poisson Regression of Investigator-confirmed HAE Attacks Requiring Acute Treatment during Day 
14 to Day 182 by Treatment Group – ITT Population
14.2.2.4
Poisson Regression of Investigator-confirmed HAE Attacks Requiring Acute Treatment during Day 
8 to Day 182 by Treatment Group – ITT Population
14.2.2.5
Poisson Regression of All HAE Attacks Requiring Acute Treatment during the Treatment Period 
(Day 0 to Day 182) by Treatment Group – ITT Population
14.2.2.6
Mean, Mean Change, and Mean Percent Change from Pretreatment in Number of Investigator-
confirmed HAE  Attacks Requiring Acute Treatment per Month by Treatment Group – ITT 
Population
14.2.2.7
Summary of Investigator-confirmed HAE Attacks Requiring Acute Treatment by Treatment Group –
ITT Population
14.2.3.1
Poisson Regression of Moderate and Severe Investigator-confirmed HAE Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population
14.2.3.2
Poisson Regression of Moderate and Severe Investigator-confirmed HAE Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population
14.2.3.3
Poisson Regression of Moderate and Severe Investigator-confirmed HAE Attacks during Day 14 to 
Day 182 by Treatment Group – ITT Population
14.2.3.4
Poisson Regression of Moderate and Severe Investigator-confirmed HAE Attacks during Day 8 to 
Day 182 by Treatment Group – ITT Population
14.2.3.5
Poisson Regression of All Moderate and Severe HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Treatment Group – ITT Population
14.2.3.6
Summary of Moderate and Severe Investigator-confirmed HAE Attacks by Treatment Group – ITT 
Population
14.2.4.1
Time to First Investigator-confirmed HAE Attack after Day 14 – ITT Population
14.2.4.2
Time to First Investigator-confirmed HAE Attack after Day 14 – Safety Population
14.2.4.3
Time to First Investigator-confirmed HAE Attack after Day 7 – ITT Population


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14.2.4.4
Time to First HAE Attack after Day 14 – ITT Population
14.2.5.1
Poisson Regression of Investigator-confirmed High-Morbidity HAE Attacks  during the Treatment 
Period (Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.5.2
Poisson Regression of Investigator-confirmed High-Morbidity HAE Attacks  during the Treatment 
Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.2.5.3
Poisson Regression of Investigator-confirmed High-Morbidity HAE Attacks  during Day 14 to Day 
182 by Treatment Group – ITT Population 
14.2.5.4
Poisson Regression of Investigator-confirmed High-Morbidity HAE Attacks  during Day 7 to Day 
182 by Treatment Group – ITT Population 
14.2.5.5
Poisson Regression of High-Morbidity HAE Attacks  during the Treatment Period (Day 0 to Day 
182) by Treatment Group – ITT Population 
14.2.5.6
Summary of Investigator-confirmed High-Morbidity HAE Attacks by Treatment Group – ITT 
Population
14.2.6.1
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency Department 
Visit or Admission to the Hospital during the Treatment Period (Day 0 to Day 182) by Treatment 
Group – ITT Population 
14.2.6.2
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency Department 
Visit or Admission to the Hospital during the Treatment Period (Day 0 to Day 182) by Treatment 
Group – Safety Population 
14.2.6.3
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency Department 
Visit or Admission to the Hospital during Day 14 to Day 182 by Treatment Group – ITT Population 
14.2.6.4
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency Department 
Visit or Admission to the Hospital during Day 7 to Day 182 by Treatment Group – ITT Population 
14.2.6.5
Poisson Regression of HAE Attacks resulting in an Emergency Department Visit or Admission to the 
Hospital during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.6.6
Summary of Investigator-confirmed HAE Attacks resulting in an Emergency Department Visit or 
Admission to the Hospital by Treatment Group – ITT Population
14.2.7.1
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency Department 
Visit during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.7.2
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency Department 
Visit during the Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.2.7.3
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency Department 
Visit during Day 14 to Day 182 by Treatment Group – ITT Population 
14.2.7.4
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency Department 
Visit during Day 7 to Day 182 by Treatment Group – ITT Population 
14.2.7.5
Poisson Regression of HAE Attacks resulting in an Emergency Department Visit during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.7.6
Summary of Investigator-confirmed HAE Attacks resulting in an Emergency Department Visit by 
Treatment Group – ITT Population
14.2.8.1
Poisson Regression of Investigator-confirmed HAE Attacks resulting in Admission to the Hospital 
during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.8.2
Poisson Regression of Investigator-confirmed HAE Attacks resulting in Admission to the Hospital 
during the Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.2.8.3
Poisson Regression of Investigator-confirmed HAE Attacks resulting in Admission to the Hospital 
during Day 14 to Day 182 by Treatment Group – ITT Population 
14.2.8.4
Poisson Regression of Investigator-confirmed HAE Attacks resulting in Admission to the Hospital 
during Day 7 to Day 182 by Treatment Group – ITT Population 


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14.2.8.5
Poisson Regression of HAE Attacks resulting in an Emergency Department Visit during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.8.6
Summary of Investigator-confirmed HAE Attacks resulting in Admission to the Hospital by 
Treatment Group – ITT Population
14.2.9.1
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Responder Threshold and Treatment Group– ITT Population
14.2.9.2
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Responder Threshold and Treatment Group– Safety Population
14.2.9.3
Responder Analysis using Investigator-confirmed HAE Attacks during Day 14 to Day 182 by 
Responder Threshold and Treatment Group– ITT Population
14.2.9.4
Responder Analysis using Investigator-confirmed HAE Attacks during Day 7 to Day 182 by 
Responder Threshold and Treatment Group– ITT Population
14.2.9.5
Responder Analysis using All HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Responder Threshold and Treatment Group– ITT Population
14.2.10.1
Characteristics of Investigator-confirmed HAE attacks during the Treatment Period (Day 0 to Day 
182) – ITT Population
14.2.10.2
Characteristics of Investigator-confirmed HAE attacks during the Treatment Period (Day 0 to Day 
182) – Safety Population
14.2.10.3
Characteristics of Investigator-confirmed HAE attacks during Day 14 to Day 182 – ITT Population
14.2.10.4
Characteristics of Investigator-confirmed HAE attacks during Day 7 to Day 182 – ITT Population
14.2.10.5
Characteristics of All HAE attacks during the Treatment Period (Day 0 to Day 182) – ITT Population
14.2.11.1
Percentage of Investigator-confirmed HAE Attack-free Days during the Treatment Period (Day 0 to 
Day 182) – ITT Population
14.2.11.2
Percentage of Investigator-confirmed HAE Attack-free Days during the Treatment Period (Day 0 to 
Day 182) – Safety Population
14.2.11.3
Percentage of Investigator-confirmed HAE Attack-free Days during Day 14 to Day 182 – ITT 
Population
14.2.11.4
Percentage of Investigator-confirmed HAE Attack-free Days during Day 7 to Day 182 – ITT 
Population
14.2.11.5
Percentage of HAE Attack-free Days during the Treatment Period (Day 0 to Day 182) – ITT 
Population
14.2.12.1
Subject Listing of Efficacy Parameters – ITT Population
14.2.13.1
Plasma Concentrations of DX-2390 by Treatment Group and Study Visit – Safety Population
14.2.14.1
Plasma Kallikrein Activity by Treatment Group and Study Visit – Safety Population
14.2.15.1
Summary of EQ-5D-5L Dimensions and VAS Score by Treatment Group and Study Visit – Safety 
Population
14.2.15.2
Summary of Angioedema Quality of Life Items, Domains and Total Score by Treatment Group and 
Study Visit – Safety Population
14.3.1.1.1
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Treatment Group – Safety Population
14.3.1.1.2
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Age Group and Treatment Group – Safety Population
14.3.1.1.3
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Sex and Treatment Group – Safety Population
14.3.1.1.4
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 


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by Race Group and Treatment Group – Safety Population
14.3.1.1.5
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Weight Group and Treatment Group – Safety Population
14.3.1.1.6
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by BMI Group and Treatment Group – Safety Population
14.3.1.1.7
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Run-in Period HAE Attack Rate Group  and Treatment Group – Safety Population
14.3.1.1.8
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Pretreatment Period HAE Attack Rate Group  and Treatment Group – Safety Population
14.3.1.1.9
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by HAE Type and Treatment Group – Safety Population
14.3.1.1.10
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Geographic Region and Treatment Group – Safety Population
14.3.1.1.11
Summary of Treatment-Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Type of Long-term Prophylactic Therapy Prior to Study Randomization and Treatment Group –
Safety Population
14.3.1.2.1
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Treatment 
Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.2.2
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Treatment 
Group and Preferred Term – Safety Population
14.3.1.2.3
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Age Group, 
Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.2.4
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Sex, 
Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.2.5
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Race 
Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.2.6
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Weight 
Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.2.7
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by BMI 
Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.2.8
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Run-in 
Period HAE Attack Rate Group, Treatment Group, System Organ Class and Preferred Term – Safety 
Population
14.3.1.2.9
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Pretreatment Period HAE Attack Rate Group, Treatment Group, System Organ Class and Preferred 
Term – Safety Population
14.3.1.2.10
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by HAE Type, 
Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.2.11
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Geographic 
Region, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.2.12
Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by Type of 
Long-term Prophylactic Therapy Prior to Study Randomization, Treatment Group, System Organ 
Class and Preferred Term – Safety Population
14.3.1.3.1
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.3.2
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Preferred Term – Safety Population


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14.3.1.3.3
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Age Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.3.4
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Sex, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.3.5
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Race Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.3.6
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Weight Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.3.7
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
BMI Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.3.8
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Run-in Period HAE Attack Rate Group, Treatment Group, System Organ Class and Preferred Term –
Safety Population
14.3.1.3.9
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Pretreatment Period HAE Attack Rate Group, Treatment Group, System Organ Class and Preferred 
Term – Safety Population
14.3.1.3.10
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
HAE Type, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.3.11
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Geographic Region, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.3.12
Related Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Type of Long-term Prophylactic Therapy Prior to Study Randomization, Treatment Group, System 
Organ Class and Preferred Term – Safety Population
14.3.1.4.1
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.4.2
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Preferred Term – Safety Population
14.3.1.4.3
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Age Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.4.4
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Sex, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.4.5
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Race Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.4.6
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Weight Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.4.7
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
BMI Group, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.4.8
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Run-in Period HAE Attack Rate Group, Treatment Group, System Organ Class and Preferred Term –
Safety Population
14.3.1.4.9
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Pretreatment Period HAE Attack Rate Group, Treatment Group, System Organ Class and Preferred 
Term – Safety Population
14.3.1.4.10
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
HAE Type, Treatment Group, System Organ Class and Preferred Term – Safety Population
14.3.1.4.11
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Geographic Region, Treatment Group, System Organ Class and Preferred Term – Safety Population


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14.3.1.4.12
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Type of Long-term Prophylactic Therapy Prior to Study Randomization, Treatment Group, System 
Organ Class and Preferred Term – Safety Population
14.3.1.5.1
Related Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 
182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.6.1
Severe Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.7.1
Related Severe Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) 
by Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.8.1
Summary of Adverse Events during the Pretreatment Period (Prior to Day 0) by Treatment Group, 
System Organ Class, and Preferred Term – Safety Population
14.3.1.8.2
Adverse Events during the Pretreatment Period (Prior to Day 0) by Treatment Group, System Organ 
Class, and Preferred Term – Safety Population
14.3.1.8.3
Serious Adverse Events during the Pretreatment Period (Prior Day 0) by Treatment Group, System 
Organ Class, and Preferred Term – Safety Population
14.3.1.9.1
Summary of Treatment-Emergent Adverse Events during the Follow-up Period (>Day 182) by 
Treatment Group – Safety Population
14.3.1.9.2
Treatment Emergent Adverse Events during the Follow-up Period (>Day 182) by Treatment Group, 
System Organ Class, and Preferred Term – Safety Population
14.3.1.9.3
Related Treatment Emergent Adverse Events during the Follow-up Period (>Day 182) by Treatment 
Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.9.4
Serious Treatment Emergent Adverse Events during the Follow-up Period (>Day 182) by Treatment 
Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.9.5
Related Serious Treatment Emergent Adverse Events during the Follow-up Period (>Day 182) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.9.6
Severe Treatment Emergent Adverse Events during the Follow-up Period (>Day 182) by Treatment 
Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.9.7
Related Severe Treatment Emergent Adverse Events during the Follow-up Period (>Day 182) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.10.1
Treatment Emergent Adverse Events of Hypersensitivity during the Treatment Period (Day 0 to Day 
182) by Treatment Group, System Organ Class, and Preferred Term– Safety Population
14.3.1.10.2
Related Treatment Emergent Adverse Events of Hypersensitivity during the Treatment Period (Day 0 
to Day 182) by Treatment Group, System Organ Class, and Preferred Term– Safety Population 
14.3.1.10.3
Serious Treatment Emergent Adverse Events of Hypersensitivity during the Treatment Period (Day 0 
to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.10.4
Related Serious Treatment Emergent Adverse Events of Hypersensitivity during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.10.5
Severe Treatment Emergent Adverse Events of Hypersensitivity during the Treatment Period (Day 0 
to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.10.6
Related Severe Treatment Emergent Adverse Events of Hypersensitivity during the Treatment Period 
(Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.11.1
Treatment Emergent Adverse Events of Bleeding during the Treatment Period (Day 0 to Day 182) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.11.2
Related Treatment Emergent Adverse Events of Bleeding during the Treatment Period (Day 0 to Day 
182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 


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14.3.1.11.3
Serious Treatment Emergent Adverse Events of Bleeding during the Treatment Period (Day 0 to Day 
182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.11.4
Related Serious Treatment Emergent Adverse Events of Bleeding during the Treatment Period (Day 
0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.11.5
Severe Treatment Emergent Adverse Events of Bleeding during the Treatment Period (Day 0 to Day 
182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.11.6
Related Severe Treatment Emergent Adverse Events of Bleeding during the Treatment Period (Day 0 
to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.1
Treatment Emergent Adverse Events of Hypercoagulable during the Treatment Period (Day 0 to Day 
182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population
14.3.1.12.2
Related Treatment Emergent Adverse Events of Hypercoagulable during the Treatment Period (Day 
0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.3
Serious Treatment Emergent Adverse Events of Hypercoagulable during the Treatment Period (Day 
0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.4
Related Serious Treatment Emergent Adverse Events of Hypercoagulable during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.12.5
Severe Treatment Emergent Adverse Events of Hypercoagulable during the Treatment Period (Day 0 
to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.6
Related Severe Treatment Emergent Adverse Events of Hypercoagulable during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.2.1
Listing of Adverse Events Resulting in Death – All Subjects
14.3.2.2
Listing of Serious Adverse Events – All Subjects
14.3.2.3
Listing of Adverse Events Resulting in Study Drug Interrupted or Withdrawn – All Subjects
14.3.2.4
Listing of Related Adverse Events – All Subjects
14.3.2.5
Listing of Severe Adverse Events – All Subjects
14.3.2.6
Listing of Hypersensitivity Adverse Events – All Subjects
14.3.2.7
Listing of Bleeding Adverse Events – All Subjects
14.3.2.8
Listing of Hypercoagulable Adverse Events – All Subjects
14.3.3
No statistical table will be generated.  Numbering reserved for SAE narratives per ICH.
14.3.4.1.1
Actual Values and Change from Baseline in Hematology Results by Treatment Group and Study 
Visit – Safety Population
14.3.4.1.2
Categorical Hematology Results by Treatment Group and Study Visit – Safety Population
14.3.4.1.3
Listing of Clinically Significant Abnormal Hematology Results – Safety Population
14.3.4.2.1
Actual Values and Change from Baseline in Coagulation Results by Treatment Group and Study 
Visit – Safety Population
14.3.4.2.2
Categorical Coagulation Results by Treatment Group and Study Visit – Safety Population
14.3.4.2.3
Listing of Clinically Significant Abnormal Coagulation Results – Safety Population
14.3.4.3.1
Actual Values and Change from Baseline in Chemistry Results by Treatment Group and Study Visit 
– Safety Population
14.3.4.3.2
Categorical Chemistry Results by Treatment Group and Study Visit – Safety Population
14.3.4.3.3
Listing of Clinically Significant Abnormal Chemistry Results – Safety Population
14.3.4.4.1
Actual Values and Change from Baseline in Urinalysis Results by Treatment Group and Study Visit 


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– Safety Population
14.3.4.4.2
Categorical Urinalysis Results by Treatment Group and Study Visit – Safety Population
14.3.4.4.3
Listing of Clinically Significant Abnormal Urinalysis Results – Safety Population
14.3.4.5.1
Actual Values and Change from Baseline in Vital Signs by Treatment Group, Study Visit and Study 
Time Point – Safety Population
14.3.4.5.2
Categorical Vital Signs Results by Treatment Group, Study Visit and Study Time Point – Safety 
Population
14.3.4.5.3
Listing of Clinically Significant Vital Signs – Safety Population
14.3.4.6.1
Categorical Electrocardiogram Results by Treatment Group  and Study Visit – Safety Population
14.3.4.6.2
Listing of Clinically Significant Electrocardiogram Results – Safety Population
14.3.4.7.1
Categorical Physical Examination Findings by Treatment Group and Study Visit – Safety Population 
14.3.4.7.2
Listing of Clinically Significant Physical Examination Findings – Safety Population
14.3.4.8.1
Immunogenicity by Treatment Group and Study Visit – Safety Population


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10.1.2
List of Planned Figures
Figure No.
Title
14.2.1.1
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group – ITT Population
14.2.1.2
All HAE Attacks during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT 
Population
14.2.1.3
Investigator-confirmed HAE Attacks during Day 14 to Day 182 by Treatment Group – ITT 
Population
14.2.1.4
Investigator-confirmed HAE Attacks during Day 8 to Day 182 by Treatment Group – ITT 
Population
14.2.1.5
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Age Group – ITT Population
14.2.1.6
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Sex – ITT Population
14.2.1.7
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Race Group – ITT Population
14.2.1.8
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Weight Group – ITT Population
14.2.1.9
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and BMI Group – ITT Population
14.2.1.10
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182)  by 
Treatment Group and Run-in Period HAE Attack Rate Group – ITT Population
14.2.1.10
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182)  by 
Treatment Group and Pretreatment Period HAE Attack Rate Group – ITT Population
14.2.1.11
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and HAE Type – ITT Population
14.2.1.12
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182)  by 
Treatment Group and Geographic Region – ITT Population
14.2.1.12
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182)  by 
Treatment Group and Type of Long-term Prophylactic Therapy Prior to Study Randomization –
ITT Population
14.2.2.1
Investigator-confirmed HAE Attacks Requiring Acute Treatment during the Treatment Period 
(Day 0 to Day 182) by Treatment Group – ITT Population
14.2.3.1
Moderate and Severe Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Treatment Group – ITT Population
14.2.4.1
Time to First HAE Attack After Day 14 by Treatment Group – ITT Population
14.2.5.1
High-morbidity Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 
182) by Treatment Group – ITT Population
14.2.6.1
Investigator-confirmed HAE Attacks Requiring an Emergency Department Visit or Admission to 
the Hospital during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT 
Population
14.2.7.1
Investigator-confirmed HAE Attacks Requiring an Emergency Department Visit during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population
14.2.8.1
Investigator-confirmed HAE Attacks  Requiring Admission to the Hospital during the Treatment 
Period (Day 0 to Day 182) by Treatment Group – ITT Population


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14.2.9.1
Plot of Mean DX-2930 Concentration Over Time – PK Population


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10.1.3
List of Planned Listings
Listing No.
Title
16.2.1
Disposition
16.2.2
Protocol Deviations
16.2.3.1
Analysis Populations
16.2.3.2
Inclusion and Exclusion Criteria
16.2.4.1
Demographics 
16.2.4.2
Baseline Disease Characteristics
16.2.4.3
Medical History
16.2.4.4
Prior and Concomitant Medications
16.2.5.1
Study Drug Administration
16.2.5.2
Treatment Compliance and Exposure
16.2.6.1
HAE Attacks
16.2.6.2
Plasma Concentration of DX-2930
16.2.6.3
Kallikrein Activity
16.2.6.4
EQ5D
16.2.6.5
Angioedema Quality of Life
16.2.7
Adverse Events
16.2.8.1
Hematology Values
16.2.8.2
Coagulation Values
16.2.8.3
Chemistry Values
16.2.8.4
Urinalysis Values
16.2.8.5
Vital Signs
16.2.8.6
ECGs
16.2.8.7
Immunogenicity
16.2.8.8
Physical Examinations


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10.2
Definitions and Programming Conventions
10.2.1
Age
Age will be calculated as the date of birth minus the date of informed consent, truncated to years.
10.2.2
BMI
BMI will be calculated as:
10.2.3
Study Day
The study day is calculated as start or stop date – date of randomization + 1 for dates on or after 
randomization, or start or stop date – date of randomization for dates prior to randomization.
10.2.4
Durations of Events
The duration of an event is calculated as stop date/time – start date/time if time is not missing, 
and stop date – start date + 1 if either the start or stop time is missing.
10.2.5
Baseline
Baseline is defined as the last non-missing value prior to first exposure to study drug.
10.2.6
Analysis Periods
10.2.6.1
Pretreatment Period
The pretreatment period is defined as the interval of time that starts at the date/time informed 
consent is signed and ends prior to the date/time of first exposure to study drug (Day 0 visit).  
[date/time of informed consent, date/time of first exposure to study drug)
10.2.6.2
Run-in Period
The run-in period is defined as the interval of time that starts at the start date for the run-in 
period and ends on the end date for the run-in period.  
[start date of run-in period, end date of run-in period)
10.2.6.3
Treatment Period
The treatment period is defined as the interval of time that starts on the date/time of first 
exposure to study drug (Day 0 visit) and ends on the date of Day 182 visit.    
[date/time of first exposure to study drug, date of Day 182 visit]


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10.2.6.4
Follow-up Period
The follow-up period is defined as the interval of time that starts on the date of the Day 182 visit
+ 1 and ends on the date of the subject’s last date of contact for the study.    
[date of Day 182 visit + 1, date of last study contact]
10.2.7
HAE Attack Characteristics
10.2.7.1
HAE Attack Duration
The duration of an HAE attack is calculated as stop date/time – start date/time if time is not 
missing, and stop date – start date + 1 if both the start and stop time is missing. If the attack stop 
time is not missing but the start time is missing, start time will be imputed as 0:00. If start time is 
not missing but the end time is missing it will be imputed as 23:59.  
10.2.7.2
HAE Attack Severity
The overall severity of the subject’s attack will be determined by the site using the following 
definitions:
Mild: Transient or mild discomfort 
Moderate: Mild to moderate limitation in activity - some assistance needed
Severe: Marked limitation in activity, assistance required
To calculate the average attack severity per subject, a numeric value will be attributed to each 
severity as follows: 1=Mild, 2=Moderate, and 3=Severe. Higher values will indicate more severe 
attacks, while lower values will indicate less severe attacks.
10.2.8
Unique HAE Attacks
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.  
That is there must be at least 24 hours between the stop date/ time of the first event and the start 
date/time of the next event, for attacks to be considered distinct from the previous attack. If there 
is less than 24 hours between the stop date/time of the first event and the start date/time of the 
next event, the events will be counted as one attack.
10.2.9
HAE Attack Rate
10.2.9.1
Pretreatment HAE Attack Rate
The pretreatment HAE attack rate will be presented as the normalized number of attacks per 
month and calculated for each subject as the number of HAE attacks occurring during the 
pretreatment period divided by the number of days the subject contributed to the pretreatment
period multiplied by 28 days.


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May 24, 2016
Confidential
Page 53 of 59
10.2.9.2
Run-in Period HAE Attack Rate
The run-in period HAE attack rate will be presented as the normalized number of attacks per 
month and calculated for each subject as number of HAE attacks occurring during the run-in 
period divided by the number of days the subject contributed to the run-in period multiplied by 
28 days.
10.2.9.3
Treatment Period HAE Attack Rate
The treatment period HAE attack rate will be presented as the normalized number of attacks per 
month and calculated for each subject as the number of HAE attacks occurring during the 
treatment period divided by number of days the subject contributed to the treatment period 
multiplied by 28 days.  
10.2.10
Time to First HAE Attack
The time to first HAE attack (days) will be calculated as the earliest of the date of the HAE 
attack after the Day 14, date of study discontinuation or completion, or date of Day 182 visit for 
subjects who do not roll-over into the OLE visit minus the date of Day 14 visit plus 1.  
Subjects with attacks occurring first will be events. Subjects who discontinue/complete the study 
or roll-over into the OLE prior to having a post-Day 14 visit HAE attack will be censored.
10.2.11
Adverse Events 
10.2.11.1
Treatment-emergent Adverse Events
Treatment-emergent AEs (TEAEs) are defined as AEs with onset at the time of or following the 
start of treatment with study medication, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.  
10.2.11.2
Related Adverse Events
Related AEs are AEs classified as related to study drug by the investigator.  
10.2.11.3
Severe Adverse Events
Severe AEs are AEs classified as severe (grade 3) or life threatening (grade 4) by the 
investigator.
10.2.12
GLM Model Sample SAS Code
Sample code for the primary efficacy analysis of the primary endpoint.


DX-2930-03 Statistical Analysis Plan
May 24, 2016
Confidential
Page 54 of 59
PROC GENMOD DATA=eff_data;
CLASS trtgrp;
MODEL no_attks = trtgrp bl_rate / DIST=poisson LINK=log OFFSET=logdays PSCALE;
LSMEANS trt / DIFF CL EXP ILINK;
ESTIMATE ‘300mg every 2 wk vs pbo’ trtgrp 1 0 0 -1 / EXP;
ESTIMATE ‘300mg every 4 wk vs pbo’ trtgrp 0 1 0 -1 / EXP;
ESTIMATE ‘150mg every 4 wk vs pbo’ trtgrp 0 0 1 -1 / EXP;
RUN;
Where:
eff_data = efficacy analysis dataset
trtgrp = treatment group (categorical)
no_attks = number of HAE attacks during the analysis period
bl_rate = normalized pretreatment HAE attack rate (continuous)
logdays = logarithm of time in days each subject was observed during the analysis period
10.2.13
GEE Model Sample SAS Code
Sample code for a sensitivity analysis of the primary endpoint.
PROC GENMOD DATA=eff_data;
CLASS trtgrp subject;
   MODEL no_attks = trtgrp bl_rate / DIST=poisson LINK=log;
REPEATED SUBJECT=subject / CORR=IND;
LSMEANS trtgrp / DIFF CL EXP ILINK;
  ESTIMATE ‘300mg every 2 wk vs pbo’ trtgrp 1 0 0 -1 / EXP;
ESTIMATE ‘300mg every 4 wk vs pbo’ trtgrp 0 1 0 -1 / EXP;
ESTIMATE ‘150mg every 4 wk vs pbo’ trtgrp 0 0 1 -1 / EXP;
RUN;
Where:
eff_data = efficacy analysis dataset
trtgrp = treatment group (categorical)
no_attks = number of HAE attacks per week
bl_rate = normalized pretreatment HAE attack rate (continuous)
10.2.14
Angioedema Quality of Life
Below are instructions for how to calculate AE-QoL domain scores and total score.
AE-QoL is meant to be evaluated by determining its four individual domain scores (profile 
instrument), but it may also be used to determine a total score (index instrument).
Each item answered by the subject scores between 0 and 4 points depending on the answer 
option chosen by the subject. The first answer option gets 0 points, the second option 1 point, the 


DX-2930-03 Statistical Analysis Plan
May 24, 2016
Confidential
Page 55 of 59
third option 2 points, etc. The AE-QoL domain scores and total score are calculated by using the 
following formula:
(Sum of all completed items)  / (maximum sum of all possible items)*100 
Computation of AE-QoL Total Score
Example 1: All items were completed (maximum possible sum: 68 points) 
Sum of all 17 completed items: 41 points.
Total score = 100*(41/68) = 60 (out of a possible 100 points)
Example 2: 2 items were not completed (maximum possible sum: 60 points). 
Sum of all 15 completed items: 41 points.
Total score = 100*(41/60) = 68 (out of a possible 100 points)
Computation of Domain Scores (Example: Fears/Shame)
Example: Sum of all 6 completed items: 14 points 
Maximum possible sum: 24 points
Domain Score = 100*(14/24) = 58 (out of a possible 100 points)
Remarks
Since only answered items are included in the computation (and the calculated domain and total 
scores are not raw scores but linear transformations to a 0-to-100 scale), the calculated scores are 
not or only little influenced by missing items.
An AE-QoL domain score should not be calculated if more than one item is left unanswered in 
that domain. The AE-QoL total score should not be calculated if more than 25% of items (>4 
items) are left unanswered.
The minimal and highest possible domain and total scores are 0 and 100, respectively.
References
Weller K, Groffik A, Magerl M, Tohme N, Martus P, Krause K, Metz M, Staubach P, Maurer M. 
Development and construct validation of the angioedema quality of life questionnaire. Allergy. 
2012; 67(10): 1289-98.


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May 24, 2016
Confidential
Page 56 of 59
10.3
Treatment Period Dosing Schedule
Treatment Period
Treatment Arms: DX-2930 or Placebo
Dose 
Number
Dose Day/ Week
300 mg
every 2 weeks
300 mg
every 4 weeks
150 mg
every 4 weeks
Placebo
1
Day 0/ Week 0
DX-2930
DX-2930
DX-2930
Placebo
2
Day 14/ Week 2
DX-2930
Placebo
Placebo
Placebo
3
Day 28/ Week 4
DX-2930
DX-2930
DX-2930
Placebo
4
Day 42/ Week 6
DX-2930
Placebo
Placebo
Placebo
5
Day 56/ Week 8
DX-2930
DX-2930
DX-2930
Placebo
6
Day 70/ Week 10
DX-2930
Placebo
Placebo
Placebo
7
Day 84/ Week 12
DX-2930
DX-2930
DX-2930
Placebo
8
Day 98/ Week 14
DX-2930
Placebo
Placebo
Placebo
9
Day 112/ Week 16
DX-2930
DX-2930
DX-2930
Placebo
10
Day 126/ Week 18
DX-2930
Placebo
Placebo
Placebo
11
Day 140/ Week 20
DX-2930
DX-2930
DX-2930
Placebo
12
Day 154/ Week 22
DX-2930
Placebo
Placebo
Placebo
13
Day 168/ Week 24
DX-2930
DX-2930
DX-2930
Placebo
--
Day 182/ Week 26
No Dose
No Dose
No Dose
No Dose


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May 24, 2016
Confidential
Page 57 of 59
10.4
Study Activity Schedule
Study Activities Schedule
Screening 
Visit
Run-in 
Period 1
Treatment Period2
Follow-up 
Period3
Tests and 
Assessments
Visit 1
Dose 1
Day 0
Site 
Check-
in4
Visit 2 
Dose 2
Day 14
Visit 3 
Dose 3
Day 28
Visit 4 
Dose 4
Day 42
Visit 5 
Dose 5
Day 56
Visits 6 and 7 
Doses 6 and 7
Days 70 and 
84
Visit 8 
Dose 8
Day 98
Visits 9 and 10 
Doses 9 and 10
Days 112 and 
126
Visit 11 
Dose 11
Day 140
Day 
144±1
Visits 12 and 13 
Doses 12 and 13
Days 154 and 
168
Visit 
14
Day 
182
Visit 
15
Day 
210
Visit 
16
Day 
238
Informed Consent
X
Eligibility Review
X
X
Long-term 
prophylactic 
therapy washout5
X
Randomization 
X
Blinded IMP 
Treatment
X
X
X
X
X
X
X
X
X
X
Demographic and 
Medical History
X
C1-INH, C1q and
C4 Testing6
X
Pregnancy Test7 
(females)
X
X
X
X
X
X
X
X
X
Vital Signs8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examination9
X
X
X
X
X
X
X
X
12-Lead ECG10
X
X
X
X
X
Clinical 
Laboratory 
Testing11
X
X
X
X
X
X
X
X
Serologies: 
HBsAg, HCV, and 
HIV
X
Concomitant 
Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


DX-2930-03 Statistical Analysis Plan
May 24, 2016
Confidential
Page 58 of 59
Study Activities Schedule
Screening 
Visit
Run-in 
Period 1
Treatment Period2
Follow-up 
Period3
Tests and 
Assessments
Visit 1
Dose 1
Day 0
Site 
Check-
in4
Visit 2 
Dose 2
Day 14
Visit 3 
Dose 3
Day 28
Visit 4 
Dose 4
Day 42
Visit 5 
Dose 5
Day 56
Visits 6 and 7 
Doses 6 and 7
Days 70 and 
84
Visit 8 
Dose 8
Day 98
Visits 9 and 10 
Doses 9 and 10
Days 112 and 
126
Visit 11 
Dose 11
Day 140
Day 
144±1
Visits 12 and 13 
Doses 12 and 13
Days 154 and 
168
Visit 
14
Day 
182
Visit 
15
Day 
210
Visit 
16
Day 
238
HAE Attack 
Data12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life 
Assessments13
X
X
X
X
X
X
X
X
PK Blood 
Sampling
X
X
X
X
X
X
X
PD Sample 
Collection
X
X
X
X
X
X
X
Plasma Anti-Drug 
Antibody Testing
X
X
X
X
X
X
Discharge from 
Study14,15
X
X
ECG = Electrocardiogram; PK = Pharmacokinetic; PD = Pharmacodynamic; IMP = Investigational Medicinal Product
1.
Subjects will undergo a run-in period to determine their baseline HAE attack rate. Only subjects with a baseline rate of at least 1 Investigator-confirmed HAE attack per 
4 weeks will be eligible for enrollment and randomization. Subjects who experience 3 or more Investigator-confirmed attacks before the end of the 4 weeks can exit the 
run-in period early and proceed to enrollment and randomization. Subjects without at least 1 Investigator-confirmed attack after 4 weeks of run-in will have their run-in 
period extended for another 4 weeks, during which time they need to have at least 2 Investigator-confirmed attacks to proceed to enrollment and randomization. To be 
eligible for enrollment, subjects who have their run-in extended must complete the full 8-week run-in period prior to entering the treatment period. Subjects who do not 
meet the minimum attack rate during run-in or are otherwise determined to be ineligible due to screening assessments will be considered a screen fail.
2.
Treatment Period visits have a ±3 day window, with a maximum of 17 days or a minimum of 11 days between any two doses, starting with Dose 2, Day 14 through 
Day 182.
3.
For subjects who do not rollover into OLE (DX-2930-04).  Follow-up visits have a ±3 day window
4.
Site personnel contact the subject to solicit for any attacks not already reported by the subject once between scheduled site visits or approximately 7 days after last contact 
with subject.
5.
Subjects who are on long-term prophylactic (LTP) therapy for HAE are required to undergo a minimum 2 week washout period prior to the start of the run-in period.  This 
LTP washout is permitted as long as the Investigator determines that doing so would not place the subject at any undue safety risk and the subject is at least 18 years of age.  
The Investigator must confirm that the subject has successfully completed the 2 week washout period before they can enter the run-in period.
6.
Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment.  
7.
The pregnancy test will only be conducted in females of childbearing potential.  Tests performed on Day 0 and Day 182 must be urine-based.  Tests performed at screening, 
Days 28, 56, 98, 126, 154, and Day 238 can be serum or urine-based.
8.
There is a ± 15 minute window for all vital signs. At study visits in which IMP is administered, vital signs including sitting or supine BP, HR, body temperature, and RR, 
will be obtained prior to dosing, 1 hour after dosing, and 2 hours after dosing for the first 4 doses with the ability to eliminate the 2 hour vitals for the remaining doses 
based on the discretion of the Investigator and the absence of safety signals.


DX-2930-03 Statistical Analysis Plan
May 24, 2016
Confidential
Page 59 of 59
9.
Height and weight will be collected at the Screening visit only.
10.
ECGs (single recordings) are collected at screening, baseline prior to Dose 1, Day 56, Day 144±1 day to capture the estimated Cmax and Day 182. The ECG assessment at 
Cmax on Day 144±1 day may be performed via at-home nurse or technician in lieu of a subject visit to the study site.
11.
Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis. 
12.
Historical attack information will be collected at screening. During the study subjects (or caregivers, in the event the subject is < 18 years old or is incapacitated) are 
instructed to report details of the attack to the study site within 72 hours of the onset of the attack. Site personnel will also contact the subject once a week or at 
approximately 7 days after last contact with the subject during the run-in period and once between study visits or approximately 7 days after last contact with the subject 
during the treatment period in order to solicit for any attack that may have occurred. In addition, during study visits, site personnel will solicit for any new HAE attack 
information that was not given through prior subject contact with the site.
13.
Quality of life data will be obtained using the EuroQoL Group 5-Dimension (EQ5D) Questionnaire at pre-dose on Days 0, 98±3, and 182±3 and using the 
Angioedema-Quality of Life (AE-QoL) Questionnaire at pre-dose on Days 0, 28 ±3, 56 ±3, 98±3, 126 ±3, 154 ±3, and 182±3.  An additional quality of life assessment 
(EQ5D and AE-QoL) will be conducted on Day 238±3 for subjects not entering OLE.
14.
Subjects who rollover into the Open-Label Extension protocol (DX-2930-04) will provide consent by Day 182 and receive their first open-label dose following the 
completion of all DX-2930-03 assessments scheduled on Day 182. At the completion of these assessments, the subject will be discharged from DX-2930-03 and roll into 
the DX-2930-04 study. 
15.
Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures as Day 182 at their final study visit.

Prot_003.pdf: 
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Clinical Trial Protocol: DX-2930-03
Study Title:
ⱶⱬꜙ͟ͼᴀᴡᴢᴑᴦᴁꜚⱡͼⱨͼꜚᴢꞌᴡ꞉ᴐᴒꜜᴡᴒᴟԓͼϸԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼⱫꜝᴢԝꞌᴒ᷄Ⱪꞌ꞉ꜜᴑԓͼ͟ꞌԜᴐᴒԝꜝ᷄
ⱪꜝꜜᴡᴟꜝꞌꞌᴒᴑͼⱬⱱⱱ꞉ᴐԜᴐᴦͼԜꜜᴑͼᴀԜⱱᴒᴡᴦͼᴀᴡᴢᴑᴦͼᴡꜝͼⱬᴣԜꞌᴢԜᴡᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱴꜝᴟͼ
ꜙꜝꜜⱲ᷄ᴁᴒᴟꜛͼ͟ᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼⱨⱲԜ꞉ꜜᴠᴡͼⱨᴐᴢᴡᴒͼⱨᴡᴡԜᴐꞋᴠͼꜝⱱͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼ
ⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼӿⱶⱨⱬԐͼ
Study Number:
Ⱬᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
Study Phase:
͟ⱳԜᴠᴒͼ᷊
Product Name:
Ⱬᴅ᷄᷉Ⱡ᷊᷇
IND Number:
᷈᷈⅍⅍᷾ⅎ
EudraCT Number:
᷿᷊᷉᷇᷈᷄᷇᷇Ⱡ᷊᷾᷄᷉᷇
Indication:
͟ᴟᴒᴣᴒꜜᴡ꞉ꜝꜜͼꜝⱱͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼԜᴡᴡԜᴐꞋᴠͼ꞉ꜜꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼⱶⱨⱬ
Investigators:
ꜚᴢꞌᴡ꞉ᴐᴒꜜᴡᴒᴟ
Sponsor:
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅ԓͼԜꜜͼ꞉ꜜᴑ꞉ᴟᴒᴐᴡԓͼᴤⱳꜝꞌꞌᴦ᷄ꜝᴤꜜᴒᴑͼᴠᴢԝᴠ꞉ᴑ꞉Ԝᴟᴦͼꜝⱱͼᴀⱳ꞉ᴟᴒͼꜞꞌᴐ᷅
᷿᷿ͼ꜠ᴒᴡᴤꜝᴟꞋͼⱫᴟ꞉ᴣᴒԓͼⱩᴢᴟꞌ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷈˲᷊᷇ͼᴂᴀⱨ
Sponsor Contact:
ꜗᴒꜜꜜ꞉ⱱᴒᴟͼᴀᴐⱳᴟԜꜜᴧԓͼꜚⱫ
ԓͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼⱫᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡ
᷊᷇᷇ͼᴀⱳ꞉ᴟᴒͼᴄԜᴦԓͼꜙᴒᴥ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷉᷾᷉᷈ͼᴂᴀⱨ
͟ⱳꜝꜜᴒⱡͼ
Medical Monitor
US and Canada:
ԓͼꜚⱫ
ԓͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼⱫᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡ
᷊᷇᷇ͼᴀⱳ꞉ᴟᴒͼᴄԜᴦԓͼꜙᴒᴥ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷉᷾᷉᷈ͼᴂᴀⱨ
͟ⱳꜝꜜᴒⱡͼ
ͼ
Medical Monitor 
Europe and Jordan:
ԓͼꜚⱫ
ԓͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼⱫᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡ
᷊᷇᷇ͼᴀⱳ꞉ᴟᴒͼᴄԜᴦԓͼꜙᴒᴥ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷉᷾᷉᷈ͼᴂᴀⱨ
͟ⱳꜝꜜᴒⱡͼ
ͼ
Date:
Original Protocol
᷈᷾ͼᴀᴒꜞᴡᴒꜛԝᴒᴟͼ᷿᷉᷇᷈
Amendment 1.0
᷈᷾ͼⱫᴒᴐᴒꜛԝᴒᴟͼ᷿᷉᷇᷈
Amendment 2.0
᷉᷈ͼⱨꜞᴟ꞉ꞌͼ᷉᷇᷈⅍
Amendment 3.0
᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
Confidentiality Statement
ᴁⱳ꞉ᴠͼᴑꜝᴐᴢꜛᴒꜜᴡͼ꞉ᴠͼᴡⱳᴒͼꜞᴟꜝꜞᴒᴟᴡᴦͼꜝⱱͼⱫᴦԜᴥͼⱪꜝᴟꜞ᷅ͼᴁⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴑꜝᴐᴢꜛᴒꜜᴡͼᴐꜝꜜᴡԜ꞉ꜜᴠͼᴡᴟԜᴑᴒͼᴠᴒᴐᴟᴒᴡᴠͼԜꜜᴑͼ
ᴐꜝꜛꜛᴒᴟᴐ꞉Ԝꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜᴟᴒͼꜞᴟ꞉ᴣ꞉ꞌᴒⱲᴒᴑͼꜝᴟͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉ԜꞌͼԜꜜᴑͼꜛԜᴦͼꜜꜝᴡͼԝᴒͼᴑ꞉ᴠᴐꞌꜝᴠᴒᴑͼᴤ꞉ᴡⱳꜝᴢᴡͼᴡⱳᴒͼᴒᴥꜞᴟᴒᴠᴠͼᴤᴟ꞉ᴡᴡᴒꜜͼ
ꜞᴒᴟꜛ꞉ᴠᴠ꞉ꜝꜜͼꜝⱱͼⱫᴦԜᴥͼᴢꜜꞌᴒᴠᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼԝᴦͼⱱᴒᴑᴒᴟԜꞌͼꜝᴟͼᴠᴡԜᴡᴒͼꞌԜᴤͼꜝᴟͼᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠ᷅ͼⱨꜜᴦͼꜞᴒᴟᴠꜝꜜͼᴡꜝͼᴤⱳꜝꜛͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ
꞉ᴠͼᴑ꞉ᴠᴐꞌꜝᴠᴒᴑͼꜛᴢᴠᴡͼԝᴒͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴡⱳԜᴡͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ꞉ᴠͼꜞᴟ꞉ᴣ꞉ꞌᴒⱲᴒᴑͼꜝᴟͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉ԜꞌͼԜꜜᴑͼꜛԜᴦͼꜜꜝᴡͼԝᴒͼⱱᴢᴟᴡⱳᴒᴟͼᴑ꞉ᴠᴐꞌꜝᴠᴒᴑͼ
ԝᴦͼᴡⱳᴒꜛ᷅ͼᴁⱳᴒᴠᴒͼᴟᴒᴠᴡᴟ꞉ᴐᴡ꞉ꜝꜜᴠͼꜝꜜͼᴑ꞉ᴠᴐꞌꜝᴠᴢᴟᴒͼᴤ꞉ꞌꞌͼԜꜞꜞꞌᴦͼᴒꜟᴢԜꞌꞌᴦͼᴡꜝͼԜꞌꞌͼⱱᴢᴡᴢᴟᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴠᴢꜞꜞꞌ꞉ᴒᴑͼᴡꜝͼᴦꜝᴢͼᴡⱳԜᴡͼ꞉ᴠͼ
꞉ꜜᴑ꞉ᴐԜᴡᴒᴑͼԜᴠͼꜞᴟ꞉ᴣ꞉ꞌᴒⱲᴒᴑͼꜝᴟͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ᷅
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


PROTOCOL SIGNATURE PAGE 
Study Title: 
HELP Study™: A Multicenter, Randomized, Double-
Blind, Placebo-Controlled Efficacy and Safety Study to 
Evaluate DX-2930 For Long-Term Prophylaxis Against 
Acute Attacks of Hereditary Angioedema (HAE) 
Study Number: 
DX-2930-03 
Amendment 3.0 Final Date: 
09 January 2017 
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor. The signature ofthe Sponsor representative indicates that the Sponsor will comply 
with all Sponsor obligations detailed in applicable regulations and guidelines and will ensure 
the Investigator is informed of all relevant information that becomes available. 
 Clinical Develop
, Lexington, MA 02421 
Date: 
I have read the foregoing protocol and agree that it contains all necessary details for carrying 
out this study. I will conduct the study in compliance with the Declaration ofHelsinki, GCP, 
and all applicable regulatory requirements and guidelines as outlined herein and will 
complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure they are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by Dyax Corp. and my Institutional 
Review Board (IRB), Research Ethics Board (REB) or Ethics Committee (EC) and will 
fulfill all responsibilities for submitting pertinent information to the IRB/REB/EC 
responsible for this study. 
I further agree that Dyax Corp. or their designees shall have access to any source documents 
from which eCRF information may have been generated. 
By signing this protocol, I agree to adhere to the instructions and procedures described in it 
and thereby to adhere to the principles of GCP to which it conforms. 
Signed: _______________ _ 
Date: ________ _ 
Investigator 
Address: 
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
PPD
PPD
PPD
PPD


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
AMENDMENT SUMMARY AND RATIONALE
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊ͼᴡꜝͼ͟ᴟꜝᴡꜝᴐꜝꞌͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇ͼ꞉ꜜᴐꞌᴢᴑᴒᴠͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴟᴒᴣ꞉ᴠ꞉ꜝꜜᴠⱡ

ⱨᴑᴑᴒᴑͼᴒⱱⱱ꞉ᴐԜᴐᴦͼꜛᴒԜᴠᴢᴟᴒͼᴡꜝͼԜᴠᴠᴒᴠᴠͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼ
ꜝᴐᴐᴢᴟᴟ꞉ꜜⱲͼꜝꜜͼⱫԜᴦͼ᷈᷾ͼᴡⱳᴟꜝᴢⱲⱳⱫԜᴦ᷈˲᷉ᴡꜝͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼⱱꜝᴟͼ
꞉ꜜᴐꞌᴢᴠ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼᴡᴒᴠᴡ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒӿᴡⱳ꞉ᴟᴑͼ꞉ꜜͼᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟԐͼᴡꜝͼԝᴒᴡᴡᴒᴟͼᴢꜜᴑᴒᴟᴠᴡԜꜜᴑͼ
ᴡⱳᴒͼᴒᴥꜞꜝᴠᴢᴟᴒ᷄ᴟᴒᴠꜞꜝꜜᴠᴒͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴠ꞉ꜜᴐᴒͼᴑԜᴡԜͼⱱᴟꜝꜛͼ͟ⱳԜᴠᴒͼ᷈ԝͼᴠᴡᴢᴑᴦͼӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉Ԑͼ
ᴠᴢⱲⱲᴒᴠᴡᴒᴑͼᴡⱳԜᴡͼꞌԜꜜԜᴑᴒꞌᴢꜛԜԝͼӿⱫᴅ᷄᷉Ⱡ᷊᷇ԐͼⱳԜᴠͼԜͼꜛᴒԜꜜͼᴒꞌ꞉ꜛ꞉ꜜԜᴡ꞉ꜝꜜͼⱳԜꞌⱱ᷄ꞌ꞉ⱱᴒͼꜝⱱͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ
᷈᷾ͼᴑԜᴦᴠͼᴤⱳᴒᴟᴒͼ꞉ᴡͼ꞉ᴠͼԜꜜᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼᴡⱳԜᴡͼ᷿᷇ӼͼᴠᴡᴒԜᴑᴦͼᴠᴡԜᴡᴒͼ꞉ᴠͼԜᴐⱳ꞉ᴒᴣᴒᴑͼ꞉ꜜͼⱶⱨⱬͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜꜜᴑͼ
ꞌԜꜜԜᴑᴒꞌᴢꜛԜԝͼᴒᴥꜞꜝᴠᴢᴟᴒͼᴟᴒԜᴐⱳᴒᴠͼᴟᴒԜᴠꜝꜜԜԝꞌᴒͼꞌᴒᴣᴒꞌᴠͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒᴟԜꜞᴒᴢᴡ꞉ᴐͼᴒⱱⱱᴒᴐᴡ᷅ͼ

ᴂꜞᴑԜᴡᴒᴑͼᴡⱳᴒͼꜛᴢꞌᴡ꞉ꜞꞌ꞉ᴐ꞉ᴡᴦͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼԝᴦͼԜᴑᴑ꞉ꜜⱲͼᴡⱳᴒͼᶰⱴԜꜛ꞉ꞌᴦͼ᷾ͼӿⱴ᷾Ԑᶱͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡͼᴡꜝͼᴡⱳᴒͼ
᷊᷄ԝᴟԜꜜᴐⱳͼⱲᴒꜜᴒᴟԜꞌͼⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼӿꜞᴟᴒᴣ꞉ꜝᴢᴠꞌᴦͼᴤ꞉ᴡⱳͼ᷊ͼⱱԜꜛ꞉ꞌ꞉ᴒᴠͼꜝⱱͼⱳᴦꜞꜝᴡⱳᴒᴠᴒᴠԐͼⱱꜝᴟͼ
ᴡⱳᴒͼᴡⱳ꞉ᴟᴑͼᴟԜꜜꞋᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅ͼͼ
꜠ꜝᴡᴒᴤꜝᴟᴡⱳᴦͼᴐⱳԜꜜⱲᴒᴠͼᴡꜝͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼԜᴟᴒͼᴐԜꜞᴡᴢᴟᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴡԜԝꞌᴒͼԝᴒꞌꜝᴤ᷅ⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼꜛ꞉ꜜꜝᴟͼᴟᴒᴣ꞉ᴠ꞉ꜝꜜᴠͼ
꞉ꜜͼⱲᴟԜꜛꜛԜᴟԓͼᴠꜞᴒꞌꞌ꞉ꜜⱲԓͼꜞᴢꜜᴐᴡᴢԜᴡ꞉ꜝꜜԓͼԜꜜᴑͼⱱꜝᴟꜛԜᴡͼⱳԜᴣᴒͼԝᴒᴒꜜͼꜛԜᴑᴒͼⱱꜝᴟͼᴐꞌԜᴟ꞉ᴡᴦͼԜꜜᴑͼԜᴟᴒͼꜜꜝᴡͼᴟᴒⱱꞌᴒᴐᴡᴒᴑͼ꞉ꜜͼ
ᴡⱳᴒͼᴠᴢꜛꜛԜᴟᴦͼꜝⱱͼᴐⱳԜꜜⱲᴒᴠ᷅
Summary of Changes from Previous Version
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3.0
Amendment Date
09 Jan 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
ᴂꜞᴑԜᴡᴒᴑͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ᴣᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡꜝͼᴟᴒⱱꞌᴒᴐᴡͼᴐᴢᴟᴟᴒꜜᴡͼᴐꜝꜜᴡԜᴐᴡͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜⱱꜝᴟͼᴡⱳᴒ
ᴀꜞꜝꜜᴠꜝᴟᶳᴠͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼ ⱱꜝᴟͼⱬᴢᴟꜝꜞᴒͼԜꜜᴑͼꜗꜝᴟᴑԜꜜᴡꜝͼ
ԓͼꜚⱫ
ᴁ꞉ᴡꞌᴒͼ͟ԜⱲᴒԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇
ᴀᴡᴢᴑᴦͼⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ᴣᴒͼ
ᴀᴡᴟᴢᴐᴡᴢᴟᴒ
ᴀꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼⱫᴦԜᴥͼⱪꜝᴟꜞͼ꞉ᴠͼԜꜜͼ꞉ꜜᴑ꞉ᴟᴒᴐᴡԓͼᴤⱳꜝꞌꞌᴦ᷄ꜝᴤꜜᴒᴑͼᴠᴢԝᴠ꞉ᴑ꞉Ԝᴟᴦͼꜝⱱͼᴀⱳ꞉ᴟᴒͼꜞꞌᴐ᷅
ᴁ꞉ᴡꞌᴒͼ͟ԜⱲᴒԓ ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԝԜᴠᴒᴑͼꜝꜜͼԜꜜͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼᴠꜞԜꜜꜜ꞉ꜜⱲͼⱫԜᴦͼ᷇ͼ(after study drug administrationԐͼ
ᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉ԓ unless otherwise specified᷅ͼ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ
⅍᷅᷾᷅᷈
ᴀꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜᴑ᷈ᴠᴡԜꜜᴑͼ᷉ꜜᴑᴟԜꜜꞋͼꜝᴟᴑᴒᴟᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼ
ᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠᴒᴠᴠᴒᴑͼduring the efficacy evaluation period (Day 0 through Day 
182) ᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼꜝᴡⱳᴒᴟͼᴠᴒᴐᴡ꞉ꜝꜜᴠͼӿᴀᴒᴐᴡ꞉ꜝꜜᴠͼⱠ᷅˲᷅᷈ͼԜꜜᴑͼⱠ᷅˲᷅᷉᷄ⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼ
͟ᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴀᴒᴐꜝꜜᴑԜᴟᴦͼⱬⱱⱱ꞉ᴐԜᴐᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠԐ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ
⅍᷅᷾᷅᷈ԓ ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅˲᷅᷉
ⱨᴑᴑᴒᴑͼᴒⱱⱱ꞉ᴐԜᴐᴦͼꜛᴒԜᴠᴢᴟᴒͼᴡꜝͼԜᴠᴠᴒᴠᴠͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋᴠͼꜝᴐᴐᴢᴟᴟ꞉ꜜⱲͼꜝꜜͼⱫԜᴦͼ᷈᷾ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉ͼᴡꜝͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼⱱꜝᴟͼ꞉ꜜᴐꞌᴢᴠ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼᴡᴒᴠᴡ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒӿᴡⱳ꞉ᴟᴑ꞉ꜜͼᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟԐͼ
ᴡꜝͼԝᴒᴡᴡᴒᴟͼᴢꜜᴑᴒᴟᴠᴡԜꜜᴑͼᴡⱳᴒͼᴒᴥꜞꜝᴠᴢᴟᴒ᷄ᴟᴒᴠꜞꜝꜜᴠᴒͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴠ꞉ꜜᴐᴒͼᴑԜᴡԜͼⱱᴟꜝꜛͼ͟ⱳԜᴠᴒͼ᷈ԝͼ
ᴠᴡᴢᴑᴦͼӿⱫᴅ᷉Ⱡ᷊᷇᷄᷇᷉ԐͼᴠᴢⱲⱲᴒᴠᴡᴒᴑͼᴡⱳԜᴡͼꞌԜꜜԜᴑᴒꞌᴢꜛԜԝͼⱳԜᴠͼԜͼꜛᴒԜꜜͼᴒꞌ꞉ꜛ꞉ꜜԜᴡ꞉ꜝꜜͼⱳԜꞌⱱ᷄ꞌ꞉ⱱᴒͼ
ꜝⱱͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷈᷾ͼᴑԜᴦᴠͼᴤⱳᴒᴟᴒͼ꞉ᴡͼ꞉ᴠͼԜꜜᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼᴡⱳԜᴡͼ᷿᷇ӼͼᴠᴡᴒԜᴑᴦͼᴠᴡԜᴡᴒͼ꞉ᴠͼԜᴐⱳ꞉ᴒᴣᴒᴑͼ
꞉ꜜͼⱶⱨⱬͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜꜜᴑͼꞌԜꜜԜᴑᴒꞌᴢꜛԜԝͼᴒᴥꜞꜝᴠᴢᴟᴒͼᴟᴒԜᴐⱳᴒᴠͼᴟᴒԜᴠꜝꜜԜԝꞌᴒͼꞌᴒᴣᴒꞌᴠͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼ
ᴤ꞉ᴡⱳͼᴡⱳᴒᴟԜꜞᴒᴢᴡ꞉ᴐͼᴒⱱⱱᴒᴐᴡ᷅ͼ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ
⅍᷅᷾᷅᷈ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅˲᷅᷉
ϸᴒꜛꜝᴣᴒᴑͼ꞉ꜜᴐꜝᴟᴟᴒᴐᴡͼᴐꜝꜜᴡԜᴐᴡͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼⱱꜝᴟͼ᷉᷾᷄ⱳꜝᴢᴟͼꜛᴒᴑ꞉ᴐԜꞌͼᴠԜⱱᴒᴡᴦͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷿᷿᷅᷅
PPD


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3.0
Amendment Date
09 Jan 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
ᴐꜝꜜᴡԜᴐᴡͼⱱꜝᴟͼᴂᴀԓͼⱪԜꜜԜᴑԜԓͼⱬᴢᴟꜝꜞᴒԓͼԜꜜᴑͼꜚ꞉ᴑᴑꞌᴒͼⱬԜᴠᴡ᷅ͼ
ᴂꜞᴑԜᴡᴒᴑͼᴡⱳᴒͼꜛᴢꞌᴡ꞉ꜞꞌ꞉ᴐ꞉ᴡᴦͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼԝᴦͼԜᴑᴑ꞉ꜜⱲͼᴡⱳᴒͼᶰⱴԜꜛ꞉ꞌᴦͼ᷾ͼӿⱴ᷾Ԑᶱͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡͼ
ᴡꜝͼᴡⱳᴒͼ᷊᷄ԝᴟԜꜜᴐⱳͼⱲᴒꜜᴒᴟԜꞌͼⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼӿꜞᴟᴒᴣ꞉ꜝᴢᴠꞌᴦͼᴤ꞉ᴡⱳͼ᷊ͼⱱԜꜛ꞉ꞌ꞉ᴒᴠͼꜝⱱͼ
ⱳᴦꜞꜝᴡⱳᴒᴠᴒᴠԐͼⱱꜝᴟͼᴡⱳᴒͼᴡⱳ꞉ᴟᴑͼᴟԜꜜꞋᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅ͼͼ
ᴀᴒᴐᴡ꞉ꜝꜜⱠ᷿᷅᷈᷉᷅
ϸᴒꜞꞌԜᴐᴒᴑͼᴡⱳᴒͼᴡԜԝꞌᴒͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴠᴐⱳᴒᴑᴢꞌᴒͼӿԜͼᴟᴒꜞᴒᴡ꞉ᴡ꞉ꜝꜜԐͼ꞉ꜜͼⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷈ͼ
ᴤ꞉ᴡⱳͼᴡⱳᴒͼ͟ᴟꜝᴡꜝᴐꜝꞌͼⱶ꞉ᴠᴡꜝᴟᴦ᷅ͼ꜠ᴢꜛԝᴒᴟᴒᴑͼᴡⱳᴒͼᴡԜԝꞌᴒͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴠᴐⱳᴒᴑᴢꞌᴒͼ
ӿᴡⱳԜᴡͼⱱꜝꞌꞌꜝᴤᴠͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԐͼԜᴠͼᴁԜԝꞌᴒͼ᷈᷅ͼϸᴒꜛꜝᴣᴒᴑͼᴐᴟꜝᴠᴠ᷄ᴟᴒⱱᴒᴟᴒꜜᴐᴒͼᴡꜝͼᴡⱳᴒͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼᴑꜝᴠ꞉ꜜⱲͼᴠᴐⱳᴒᴑᴢꞌᴒͼ꞉ꜜͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷉ԓͼⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷈
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒԓͼ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
SYNOPSIS
Sponsor:
ⱫᴦԜᴥⱪꜝᴟꜞ᷅ԓͼԜꜜͼ꞉ꜜᴑ꞉ᴟᴒᴐᴡԓͼᴤⱳꜝꞌꞌᴦ᷄ꜝᴤꜜᴒᴑͼᴠᴢԝᴠ꞉ᴑ꞉Ԝᴟᴦͼꜝⱱͼᴀⱳ꞉ᴟᴒͼꜞꞌᴐ
᷿᷿ͼ꜠ᴒᴡᴤꜝᴟꞋͼⱫᴟ꞉ᴣᴒԓͼⱩᴢᴟꞌ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷈˲᷊᷇ͼᴂᴀⱨ
Name of Finished Product:
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼⱫᴟᴢⱲͼ͟ᴟꜝᴑᴢᴐᴡͼӿⱫ͟Ԑ
Name of Active Ingredient:
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ᴠͼԜͼᴟᴒᴐꜝꜛԝ꞉ꜜԜꜜᴡԓͼⱪⱳ꞉ꜜᴒᴠᴒͼⱳԜꜛᴠᴡᴒᴟͼꜝᴣԜᴟᴦͼӿⱪⱶ꜡Ԑͼᴐᴒꞌꞌ᷄ᴒᴥꜞᴟᴒᴠᴠᴒᴑԓͼⱱᴢꞌꞌᴦͼⱳᴢꜛԜꜜͼ
꞉ꜛꜛᴢꜜꜝⱲꞌꜝԝᴢꞌ꞉ꜜͼⱵͼᴠᴢԝᴐꞌԜᴠᴠͼ᷈ͼӿⱷⱲⱵ᷈ԐԓͼꞋԜꜞꜞԜͼꞌ꞉ⱲⱳᴡͼᴐⱳԜ꞉ꜜԓͼꜛꜝꜜꜝᴐꞌꜝꜜԜꞌͼԜꜜᴡ꞉ԝꜝᴑᴦ᷅
Names of Inactive Ingredients:
ᴀꜝᴑ꞉ᴢꜛͼꜞⱳꜝᴠꜞⱳԜᴡᴒͼᴑ꞉ԝԜᴠ꞉ᴐͼᴑ꞉ⱳᴦᴑᴟԜᴡᴒԓͼᴐ꞉ᴡᴟ꞉ᴐͼԜᴐ꞉ᴑͼꜛꜝꜜꜝⱳᴦᴑᴟԜᴡᴒԓͼꜙ᷄ⱳ꞉ᴠᴡ꞉ᴑ꞉ꜜᴒԓͼᴠꜝᴑ꞉ᴢꜛͼᴐⱳꞌꜝᴟ꞉ᴑᴒԓͼ
Ԝꜜᴑͼ͟ꜝꞌᴦᴠꜝᴟԝԜᴡᴒͼ˲᷇
Study Title:
ⱶⱬꜙ͟ͼᴀᴡᴢᴑᴦᴁꜚⱡͼⱨͼꜚᴢꞌᴡ꞉ᴐᴒꜜᴡᴒᴟԓͼϸԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼⱫꜝᴢԝꞌᴒ᷄Ⱪꞌ꞉ꜜᴑԓͼ͟ꞌԜᴐᴒԝꜝ᷄ⱪꜝꜜᴡᴟꜝꞌꞌᴒᴑͼⱬⱱⱱ꞉ᴐԜᴐᴦͼԜꜜᴑͼ
ᴀԜⱱᴒᴡᴦͼᴀᴡᴢᴑᴦͼᴡꜝͼⱬᴣԜꞌᴢԜᴡᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱴꜝᴟͼꜙꜝꜜⱲ᷄ᴁᴒᴟꜛͼ͟ᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼⱨⱲԜ꞉ꜜᴠᴡͼⱨᴐᴢᴡᴒͼⱨᴡᴡԜᴐꞋᴠͼꜝⱱͼ
ⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼӿⱶⱨⱬԐ
Study Number:
Ⱬᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
Study Phase: ͟ⱳԜᴠᴒͼ᷊
Study Location:
ⱨꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ⅍᷇ͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒᴠͼꜞꞌԜꜜꜜᴒᴑͼԜᴐᴟꜝᴠᴠͼᴡⱳᴒͼᴂꜜ꞉ᴡᴒᴑͼᴀᴡԜᴡᴒᴠԓͼⱷᴡԜꞌᴦԓͼᴂꜜ꞉ᴡᴒᴑͼꜘ꞉ꜜⱲᴑꜝꜛԓͼ
ⱵᴒᴟꜛԜꜜᴦԓͼⱪԜꜜԜᴑԜͼԜꜜᴑͼꜗꜝᴟᴑԜꜜ
Primary Objective:
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ꜜͼꜞᴟᴒᴣᴒꜜᴡ꞉ꜜⱲͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠ
Secondary Objective:
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼꜝⱱͼᴟᴒꜞᴒԜᴡᴒᴑͼᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇
Tertiary Objectives:
ᶄ
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼӿ͟ⱫԐͼᴒⱱⱱᴒᴐᴡᴠͼꜝⱱͼᴐⱳᴟꜝꜜ꞉ᴐԜꞌꞌᴦͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼⱫᴅ᷄᷉Ⱡ᷊᷇
ᶄ
ᴁꜝͼԜᴠᴠᴒᴠᴠͼᴡⱳᴒͼ꞉ꜛꜛᴢꜜꜝⱲᴒꜜ꞉ᴐ꞉ᴡᴦͼꜝⱱͼᴐⱳᴟꜝꜜ꞉ᴐԜꞌꞌᴦͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼⱫᴅ᷄᷉Ⱡ᷊᷇
ᶄ
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐᴠͼӿ͟ꜘԐͼꜝⱱͼᴐⱳᴟꜝꜜ꞉ᴐԜꞌꞌᴦͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼⱫᴅ᷄᷉Ⱡ᷊᷇
ᶄ
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱᴒᴐᴡͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝꜜͼⱳᴒԜꞌᴡⱳ᷄ᴟᴒꞌԜᴡᴒᴑͼꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼӿϷꜝꜙԐ
Study Design:
ᴁⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼ꞉ᴠͼԜͼꜞⱳԜᴠᴒͼ᷊ԓͼꜛᴢꞌᴡ꞉ᴐᴒꜜᴡᴒᴟԓͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑԓͼꜞꞌԜᴐᴒԝꜝ᷄ᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼᴡᴟ꞉Ԝꞌͼᴡꜝͼ
ᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ꜜͼꜞᴟᴒᴣᴒꜜᴡ꞉ꜜⱲͼԜᴐᴢᴡᴒͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼԜᴡᴡԜᴐꞋᴠͼ꞉ꜜͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼᴁᴦꜞᴒͼⱷͼԜꜜᴑͼᴁᴦꜞᴒͼⱷⱷͼⱶⱨⱬ᷅
ꜙꜝꜜⱲ᷄ᴁᴒᴟꜛͼ͟ᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼӿꜙᴁ͟ԐͼᴁⱳᴒᴟԜꜞᴦͼᴄԜᴠⱳꜝᴢᴡⱡ
ⱴꜝꞌꞌꜝᴤ꞉ꜜⱲͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷅ͼᴀᴐᴟᴒᴒꜜᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ
ᴤⱳꜝͼԜᴟᴒͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬͼԜᴟᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼᴢꜜᴑᴒᴟⱲꜝͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼ
᷉ᴤᴒᴒꞋͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴁⱳ꞉ᴠͼꜙᴁ͟ͼᴤԜᴠⱳꜝᴢᴡͼ꞉ᴠͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼ
ԜᴠͼꞌꜝꜜⱲͼԜᴠͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴑꜝ꞉ꜜⱲͼᴠꜝͼᴤꜝᴢꞌᴑͼꜜꜝᴡͼꜞꞌԜᴐᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜᴡͼԜꜜᴦͼᴢꜜᴑᴢᴒͼ
ᴠԜⱱᴒᴡᴦͼᴟ꞉ᴠꞋͼԜꜜᴑͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡͼꞌᴒԜᴠᴡͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼᴐꜝꜜⱱ꞉ᴟꜛͼᴡⱳᴒͼ
ᴠᴢԝ꞊ᴒᴐᴡͼⱳԜᴠͼᴠᴢᴐᴐᴒᴠᴠⱱᴢꞌꞌᴦͼᴐꜝꜛꜞꞌᴒᴡᴒᴑͼᴡⱳᴒͼ᷉ͼᴤᴒᴒꞋͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒᴦͼᴐԜꜜͼᴒꜜᴡᴒᴟͼᴡⱳᴒͼᴟᴢꜜ᷄
꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅
ϸᴢꜜ᷄ⱷꜜͼ͟ᴒᴟ꞉ꜝᴑⱡ
ᴀᴐᴟᴒᴒꜜᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴒ꞉ᴡⱳᴒᴟͼꜜꜝᴡͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬԓͼꜝᴟͼⱳԜᴣᴒͼ
ᴐꜝꜛꜞꞌᴒᴡᴒᴑͼᴡⱳᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑԓͼᴤ꞉ꞌꞌͼᴒꜜᴡᴒᴟͼԜͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜝⱱͼ᷾ͼᴤᴒᴒꞋᴠͼᴡꜝͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼᴡⱳᴒͼ
ԝԜᴠᴒꞌ꞉ꜜᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒ᷅ͼ꜡ꜜꞌᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜛᴒᴒᴡ꞉ꜜⱲͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼԝԜᴠᴒꞌ꞉ꜜᴒͼᴟԜᴡᴒͼꜝⱱͼԜᴡͼꞌᴒԜᴠᴡͼ
᷈ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼ
ᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼ᷊ͼꜝᴟͼꜛꜝᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋᴠͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒͼ
ᴒꜜᴑͼꜝⱱͼᴡⱳᴒͼ᷾ͼᴤᴒᴒꞋᴠͼᴐԜꜜͼᴒᴥ꞉ᴡͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒԜᴟꞌᴦͼԜꜜᴑͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼ
ᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳꜝᴢᴡͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋͼԜⱱᴡᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼꜝⱱͼᴟᴢꜜ᷄
꞉ꜜͼᴤ꞉ꞌꞌͼⱳԜᴣᴒͼᴡⱳᴒ꞉ᴟͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒᴥᴡᴒꜜᴑᴒᴑͼⱱꜝᴟͼԜꜜꜝᴡⱳᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼᴑᴢᴟ꞉ꜜⱲͼᴤⱳ꞉ᴐⱳͼᴡ꞉ꜛᴒͼᴡⱳᴒᴦͼꜜᴒᴒᴑͼᴡꜝͼ
ⱳԜᴣᴒͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋᴠͼᴡꜝͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼ
ᴁꜝͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝⱳԜᴣᴒͼᴡⱳᴒ꞉ᴟͼᴟᴢꜜ᷄꞉ꜜͼᴒᴥᴡᴒꜜᴑᴒᴑͼꜛᴢᴠᴡͼᴐꜝꜛꜞꞌᴒᴡᴒͼᴡⱳᴒͼⱱᴢꞌꞌͼ
˲᷄ᴤᴒᴒꞋͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼꜛᴒᴒᴡͼᴡⱳᴒͼ
ꜛ꞉ꜜ꞉ꜛᴢꜛͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴑᴢᴟ꞉ꜜⱲͼᴟᴢꜜ᷄꞉ꜜͼꜝᴟͼԜᴟᴒͼꜝᴡⱳᴒᴟᴤ꞉ᴠᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼᴡꜝͼԝᴒͼ꞉ꜜᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼᴑᴢᴒͼᴡꜝͼ
ᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼᴠᴐᴟᴒᴒꜜͼⱱԜ꞉ꞌᴢᴟᴒᴠ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴠᴐᴟᴒᴒꜜͼⱱԜ꞉ꞌͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼ
Ԝꞌꞌꜝᴤᴒᴑͼᴡꜝͼᴟᴒᴠᴐᴟᴒᴒꜜͼ꞉ꜜᴡꜝͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼ
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡ
ⱨⱱᴡᴒᴟͼᴣᴒᴟ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼꜝⱱͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼ᷉ⱡ᷈ͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼᴟᴒꜞᴒԜᴡᴒᴑͼ
ᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼӿᴀⱪԐͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝͼ꞉ꜜͼԜͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼⱱԜᴠⱳ꞉ꜝꜜ᷅ͼ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠ꞉Ⱳꜜᴒᴑͼ꞉ꜜͼԜͼ᷈ⱡ᷈ⱡ᷈ͼᴟԜᴡ꞉ꜝͼᴡꜝͼꜝꜜᴒͼꜝⱱͼᴡⱳᴟᴒᴒͼ
ᴑꜝᴠᴒͼᴟᴒⱲ꞉ꜛᴒꜜᴠⱡͼ᷊᷇᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠԓͼ᷊᷇᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠͼꜝᴟͼ᷿᷈᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠ᷅ͼ
ϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼ꞉ꜜᴡꜝͼԜꞌꞌͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴡᴟԜᴡ꞉ⱱ꞉ᴒᴑͼԝᴦͼᴡⱳᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝԝᴠᴒᴟᴣᴒᴑͼ
ᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼ꞉ꜜᴡꜝͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼⱲᴟꜝᴢꜞᴠⱡͼ᷈ᴡꜝⱣ᷉ԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼ᷉ͼᴡꜝͼⱣͼ᷊ͼ
ԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼԜꜜᴑͼᶒͼ᷊ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠ᷅
ⱬԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼԜͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼᴐꜝꜜᴠ꞉ᴠᴡ꞉ꜜⱲͼꜝⱱͼ᷊᷈ͼᴑꜝᴠᴒᴠͼꜝⱱͼԝꞌ꞉ꜜᴑᴒᴑͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜚᴒᴑ꞉ᴐ꞉ꜜԜꞌͼ͟ᴟꜝᴑᴢᴐᴡͼӿⱷꜚ͟ԐԓͼⱱꜝᴟͼԜͼꜞᴒᴟ꞉ꜝᴑͼꜝⱱͼ᷉⅍ͼᴤᴒᴒꞋᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴑԜᴡᴒͼꜝⱱͼⱱ꞉ᴟᴠᴡͼᴑꜝᴠᴒͼ
ꜝꜜͼⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼᴡᴤꜝͼᴤᴒᴒꞋᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼᴑꜝᴠᴒ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼ᷾ͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛᴠͼᴤ꞉ꞌꞌͼᴒ꞉ᴡⱳᴒᴟͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝͼᴑꜝᴠᴒͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴑꜝᴠ꞉ꜜⱲͼ
ᴠᴐⱳᴒᴑᴢꞌᴒͼ꞉ꜜͼᴡⱳᴒͼᴡԜԝꞌᴒͼԝᴒꞌꜝᴤ᷅ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Treatment Period Dosing Schedule
Treatment Period
Treatment Arms: DX-2930 or Placebo
Dose Number
Dose Day/Week
300 mg
every 2 
weeks
300 mg
every 4 
weeks
150 mg
every 4 
weeks
Placebo
᷈
ⱫԜᴦͼ᷇᷆ᴄᴒᴒꞋͼ᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷉
ⱫԜᴦͼ᷈᷾᷆ᴄᴒᴒꞋͼ᷉
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
᷊
ⱫԜᴦͼ᷉˲᷆ᴄᴒᴒꞋͼ᷾
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷾
ⱫԜᴦͼ᷾᷉᷆ᴄᴒᴒꞋͼ⅍
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
᷿
ⱫԜᴦͼ᷿⅍᷆ᴄᴒᴒꞋͼ˲
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
⅍
ⱫԜᴦͼⅎ᷇᷆ᴄᴒᴒꞋͼ᷈᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
ⅎ
ⱫԜᴦͼ˲᷾᷆ᴄᴒᴒꞋͼ᷈᷉
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
˲
ⱫԜᴦͼⱠ˲᷆ᴄᴒᴒꞋͼ᷈᷾
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
Ⱡ
ⱫԜᴦͼ᷈᷈᷉᷆ᴄᴒᴒꞋͼ᷈⅍
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷈᷇
ⱫԜᴦͼ᷈᷉⅍᷆ᴄᴒᴒꞋͼ᷈˲
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
᷈᷈
ⱫԜᴦͼ᷈᷾᷇᷆ᴄᴒᴒꞋͼ᷉᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷈᷉
ⱫԜᴦͼ᷿᷈᷾᷆ᴄᴒᴒꞋͼ᷉᷉
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
᷊᷈
ⱫԜᴦͼ᷈⅍˲᷆ᴄᴒᴒꞋͼ᷉᷾
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷄᷄
ⱫԜᴦͼ᷈˲᷉᷆ᴄᴒᴒꞋͼ᷉⅍
꜠ꜝͼⱫꜝᴠᴒ
꜠ꜝͼⱫꜝᴠᴒ
꜠ꜝͼⱫꜝᴠᴒ
꜠ꜝͼⱫꜝᴠᴒ
꜡ꜞᴒꜜ᷄ꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼӿ꜡ꜙⱬԐͼᴀᴡᴢᴑᴦⱡ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴐꜝꜛꜞꞌᴒᴡᴒͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼᴤ꞉ꞌꞌͼԝᴒͼꜝⱱⱱᴒᴟᴒᴑͼᴡⱳᴒͼꜝꜞᴡ꞉ꜝꜜͼꜝⱱͼᴒꜜᴟꜝꞌꞌ꞉ꜜⱲͼ꞉ꜜͼԜꜜͼ
ꜝꜞᴒꜜ᷄ꞌԜԝᴒꞌͼᴒᴥᴡᴒꜜᴠ꞉ꜝꜜͼӿ꜡ꜙⱬԐͼᴠᴡᴢᴑᴦͼᴡⱳԜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼԜͼᴠᴒꜞԜᴟԜᴡᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾Ԑ᷅ͼ
ⱴꜝꞌꞌꜝᴤ᷄ᴂꜞͼ͟ᴒᴟ꞉ꜝᴑⱡ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼ꜡ꜙⱬͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼᴠԜⱱᴒᴡᴦͼԜꜜᴑͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜᴠͼ
ӿ꞉᷅ᴒ᷅ԓͼ͟ꜘͼԜꜜᴑͼ͟ⱫԐͼᴑᴢᴟ꞉ꜜⱲͼԜꜜͼ˲ͼᴤᴒᴒꞋͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼӿꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠԐͼᴤ꞉ꞌꞌͼԝᴒͼ
꞉ꜜᴠᴡᴟᴢᴐᴡᴒᴑͼᴡꜝͼ꞉ꜜⱱꜝᴟꜛͼᴡⱳᴒͼᴠ꞉ᴡᴒͼꜝⱱͼԜꜜᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴡⱳᴒᴦͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼⱱꜝᴟͼᴢꜞͼᴡꜝͼ᷊᷇ͼᴑԜᴦᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼ
ⱱ꞉ꜜԜꞌͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴣ꞉ᴠ꞉ᴡ᷅
Study Population:
ᴁⱳᴒͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼᴒꜜᴟꜝꞌꞌͼᴢꜞͼᴡꜝͼ᷈᷉᷇ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼ᷈᷇˲ͼᴐꜝꜛꜞꞌᴒᴡᴒᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ᷈᷉ᴦᴒԜᴟᴠͼ
ꜝⱱͼԜⱲᴒͼԜꜜᴑͼꜝꞌᴑᴒᴟͼᴤ꞉ᴡⱳͼԜͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼꜝⱱͼⱶⱨⱬͼӿᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷԐͼᴤⱳꜝͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼⱶⱨⱬͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼᴡⱳᴟꜝᴢⱲⱳͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼⱶⱨⱬͼԜꜜᴑͼᴑ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼᴡᴒᴠᴡ꞉ꜜⱲͼ
ᴐꜝꜜᴑᴢᴐᴡᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡ᷅ͼᴁⱳᴒͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԜ꞉ꜛͼᴡꜝͼᴒꜜᴟꜝꞌꞌͼԜᴡͼꞌᴒԜᴠᴡͼ᷿ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼ
᷈᷉ͼᴡꜝͼ᷈ⅎͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒ᷅
Criteria for Inclusion:
ᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛᴢᴠᴡͼꜛᴒᴒᴡͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝͼᴡꜝͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦⱡ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
᷈᷅ꜚԜꞌᴒᴠͼԜꜜᴑͼⱱᴒꜛԜꞌᴒᴠͼ᷈᷉ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒͼꜝᴟͼꜝꞌᴑᴒᴟͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲ᷅
᷉᷅Ⱬꜝᴐᴢꜛᴒꜜᴡᴒᴑͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼꜝⱱͼⱶⱨⱬͼӿᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷԐͼԝԜᴠᴒᴑͼᴢꜞꜝꜜͼԜꞌꞌꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲⱡͼ
᷄
Ⱬꜝᴐᴢꜛᴒꜜᴡᴒᴑͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼⱶⱨⱬͼӿᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼꜝᴟͼꜛᴢᴐꜝᴠԜꞌԓͼ
ꜜꜝꜜꜞᴟᴢᴟ꞉ᴡ꞉ᴐͼᴠᴤᴒꞌꞌ꞉ꜜⱲͼᴒꜞ꞉ᴠꜝᴑᴒᴠͼᴤ꞉ᴡⱳꜝᴢᴡͼԜᴐᴐꜝꜛꜞԜꜜᴦ꞉ꜜⱲͼᴢᴟᴡ꞉ᴐԜᴟ꞉ԜԐ᷅
᷄
Ⱬ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼᴡᴒᴠᴡ꞉ꜜⱲͼᴟᴒᴠᴢꞌᴡᴠͼꜝԝᴡԜ꞉ꜜᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴡⱳԜᴡͼᴐꜝꜜⱱ꞉ᴟꜛͼⱶⱨⱬͼᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷⱡͼ
ⱪ᷈ͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼӿⱪ᷈᷄ⱷ꜠ⱶԐͼⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼꞌᴒᴣᴒꞌͼⱣͼ᷾᷇ӼͼꜝⱱͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌͼꞌᴒᴣᴒꞌ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼ
ⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼⱪ᷈᷄ⱷ꜠ⱶͼꞌᴒᴣᴒꞌͼ᷿᷾᷇᷄᷇ӼͼꜝⱱͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌͼꞌᴒᴣᴒꞌͼꜛԜᴦͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ⱱͼᴡⱳᴒᴦͼԜꞌᴠꜝͼ
ⱳԜᴣᴒͼԜͼⱪ᷾ͼꞌᴒᴣᴒꞌͼԝᴒꞌꜝᴤͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌͼᴟԜꜜⱲᴒ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼԝᴒⱲ꞉ꜜͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼ꞉ꜜͼᴡⱳᴒͼᴟᴢꜜ᷄
꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒᴠᴒͼᴑ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼᴟᴒᴠᴢꞌᴡᴠͼԜᴟᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼԝᴒͼᴟᴒᴡᴒᴠᴡᴒᴑͼ꞉ⱱͼ
ᴟᴒᴠᴢꞌᴡᴠͼԜᴟᴒͼ꞉ꜜᴐꜝꜜⱲᴟᴢᴒꜜᴡͼᴤ꞉ᴡⱳͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝᴟͼԝᴒꞌ꞉ᴒᴣᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡꜝͼԝᴒͼ
ᴐꜝꜜⱱꜝᴢꜜᴑᴒᴑͼԝᴦͼᴟᴒᴐᴒꜜᴡͼꜙᴁ͟ͼᴢᴠᴒ᷅
᷄
ⱨᴡͼꞌᴒԜᴠᴡͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲⱡͼⱨⱲᴒͼԜᴡͼᴟᴒꜞꜝᴟᴡᴒᴑͼꜝꜜᴠᴒᴡͼꜝⱱͼⱱ꞉ᴟᴠᴡͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴠᴦꜛꜞᴡꜝꜛᴠͼ
ᶑ᷊᷇ͼᴦᴒԜᴟᴠԓͼԜͼⱱԜꜛ꞉ꞌᴦͼⱳ꞉ᴠᴡꜝᴟᴦͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼⱶⱨⱬͼᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷԓͼꜝᴟͼⱪ᷈ꜟͼᴤ꞉ᴡⱳ꞉ꜜͼꜜꜝᴟꜛԜꞌͼ
ᴟԜꜜⱲᴒ᷅
᷊᷅ⱬᴥꜞᴒᴟ꞉ᴒꜜᴐ꞉ꜜⱲͼԜͼԝԜᴠᴒꞌ꞉ꜜᴒͼᴟԜᴡᴒͼꜝⱱͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼꜞᴒᴟͼ᷾ᴤᴒᴒꞋᴠͼ
Ԝᴠͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼ
᷾᷅ⱨᴑᴢꞌᴡͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜꜜᴑͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴢꜜᴑᴒᴟͼᴡⱳᴒͼԜⱲᴒͼꜝⱱͼ᷈˲ͼԜᴟᴒͼᴤ꞉ꞌꞌ꞉ꜜⱲͼԜꜜᴑͼԜԝꞌᴒͼᴡꜝͼᴟᴒԜᴑԓͼ
ᴢꜜᴑᴒᴟᴠᴡԜꜜᴑԓͼԜꜜᴑͼᴠ꞉ⱲꜜͼԜꜜͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼⱱꜝᴟꜛ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼԜⱲᴒͼ᷈᷉ͼᴡꜝͼ᷈ⅎԓͼᴤⱳꜝᴠᴒͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟͼ
ꜞᴟꜝᴣ꞉ᴑᴒᴠͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡԓͼԜꜜᴑͼԜᴟᴒͼᴤ꞉ꞌꞌ꞉ꜜⱲͼԜꜜᴑͼԜԝꞌᴒͼᴡꜝͼᴟᴒԜᴑԓͼᴢꜜᴑᴒᴟᴠᴡԜꜜᴑԓͼԜꜜᴑͼᴠ꞉ⱲꜜͼԜꜜͼ
Ԝᴠᴠᴒꜜᴡͼⱱꜝᴟꜛ᷅
᷿᷅ꜚԜꞌᴒᴠͼԜꜜᴑͼⱱᴒꜛԜꞌᴒᴠͼᴤⱳꜝͼԜᴟᴒͼⱱᴒᴟᴡ꞉ꞌᴒͼԜꜜᴑͼᴠᴒᴥᴢԜꞌꞌᴦͼԜᴐᴡ꞉ᴣᴒͼꜛᴢᴠᴡͼԜᴑⱳᴒᴟᴒͼᴡꜝͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼ
ᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜᴠͼⱱꜝꞌꞌꜝᴤᴠⱡ
᷄
ⱴᴒꜛԜꞌᴒᴠͼꜝⱱͼᴐⱳ꞉ꞌᴑԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉ԜꞌͼꜛᴢᴠᴡͼԜⱲᴟᴒᴒͼᴡꜝͼԝᴒͼԜԝᴠᴡ꞉ꜜᴒꜜᴡͼꜝᴟͼ꞉ᴡͼ꞉ᴠͼᴟᴒᴐꜝꜛꜛᴒꜜᴑᴒᴑͼᴡꜝͼ
ᴢᴠᴒͼⱳ꞉Ⱳⱳꞌᴦͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒͼⱱꜝᴟꜛᴠͼꜝⱱͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴡⱳᴟꜝᴢⱲⱳͼ᷊᷇ᴑԜᴦᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼ
ⱱ꞉ꜜԜꞌͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡ᷅ͼᴁⱳ꞉ᴠͼ꞉ꜜᴐꞌᴢᴑᴒᴠͼꜞᴟꜝⱲᴒᴠᴡ꞉ꜜ᷄ꜝꜜꞌᴦͼꜝᴟԜꞌͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ᴣᴒͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼ
꞉ꜜⱳ꞉ԝ꞉ᴡ꞉ꜝꜜͼꜝⱱͼꜝᴣᴢꞌԜᴡ꞉ꜝꜜͼӿꜝᴟԜꞌԓͼ꞉ꜜ꞊ᴒᴐᴡԜԝꞌᴒԓͼꜝᴟͼ꞉ꜛꜞꞌԜꜜᴡԜԝꞌᴒԐԓͼ꞉ꜜᴡᴟԜ᷄ᴢᴡᴒᴟ꞉ꜜᴒͼᴑᴒᴣ꞉ᴐᴒͼӿⱷᴂⱫԓͼԜꞌꞌͼ
ᴡᴦꜞᴒᴠԐԓͼꜝᴟͼ꞉ꜜᴡᴟԜᴢᴡᴒᴟ꞉ꜜᴒͼⱳꜝᴟꜛꜝꜜᴒͼᴟᴒꞌᴒԜᴠ꞉ꜜⱲͼᴠᴦᴠᴡᴒꜛᴠͼӿⱷᴂᴀԐ᷅ͼ꜠ꜝᴡᴒᴠⱡͼ᷈ԐͼⱨͼⱱᴒꜛԜꞌᴒͼᴤⱳꜝᴠᴒͼ
ꜛԜꞌᴒͼꜞԜᴟᴡꜜᴒᴟͼⱳԜᴠͼⱳԜᴑͼԜͼᴣԜᴠᴒᴐᴡꜝꜛᴦͼꜛᴢᴠᴡͼԜⱲᴟᴒᴒͼᴡꜝͼᴢᴠᴒͼꜝꜜᴒͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼⱱꜝᴟꜛͼꜝⱱͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼ
ԜᴐᴐᴒꜞᴡԜԝꞌᴒͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜ᷅ͼ᷉ԐͼᴂᴠᴒͼꜝⱱͼԜͼꜛԜꞌᴒͼᴐꜝꜜᴑꜝꜛͼᴤ꞉ᴡⱳͼꜝᴟͼᴤ꞉ᴡⱳꜝᴢᴡͼᴠꜞᴒᴟꜛ꞉ᴐ꞉ᴑᴒͼꜝᴟͼ
ᴐᴒᴟᴣ꞉ᴐԜꞌͼᴐԜꜞԓͼᴑ꞉ԜꜞⱳᴟԜⱲꜛͼꜝᴟͼᴠꜞꜝꜜⱲᴒͼᴤ꞉ᴡⱳͼᴠꜞᴒᴟꜛ꞉ᴐ꞉ᴑᴒͼꜝᴟͼԜͼᴐꜝꜛԝ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴑꜝᴢԝꞌᴒ᷄ԝԜᴟᴟ꞉ᴒᴟͼ
ꜛᴒᴡⱳꜝᴑᴠԐͼ꞉ᴠͼꜜꜝᴡͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼⱳ꞉Ⱳⱳꞌᴦͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒ᷅ͼ
᷄
ⱴᴒꜛԜꞌᴒᴠͼꜝⱱͼꜜꜝꜜ᷄ᴐⱳ꞉ꞌᴑԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌԓͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼᴠᴢᴟⱲ꞉ᴐԜꞌꞌᴦͼᴠᴡᴒᴟ꞉ꞌᴒͼӿᴠᴡԜᴡᴢᴠͼꜞꜝᴠᴡͼ
ⱳᴦᴠᴡᴒᴟᴒᴐᴡꜝꜛᴦԓͼԝ꞉ꞌԜᴡᴒᴟԜꞌͼꜝꜝꜞⱳꜝᴟᴒᴐᴡꜝꜛᴦԓͼꜝᴟͼԝ꞉ꞌԜᴡᴒᴟԜꞌͼᴡᴢԝԜꞌͼꞌ꞉ⱲԜᴡ꞉ꜝꜜԐͼꜝᴟͼꜞꜝᴠᴡ᷄ꜛᴒꜜꜝꜞԜᴢᴠԜꞌͼ
ⱱꜝᴟͼԜᴡͼꞌᴒԜᴠᴡͼ᷈᷉ͼꜛꜝꜜᴡⱳᴠԓͼᴑꜝͼꜜꜝᴡͼᴟᴒꜟᴢ꞉ᴟᴒͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
᷄
ꜚԜꞌᴒᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼꜛԜꞌᴒᴠͼᴤⱳꜝͼԜᴟᴒͼᴠᴢᴟⱲ꞉ᴐԜꞌꞌᴦͼᴠᴡᴒᴟ꞉ꞌᴒͼӿꜞꜝᴠᴡͼᴣԜᴠᴒᴐᴡꜝꜛᴦԐԓͼᴤ꞉ᴡⱳͼⱱᴒꜛԜꞌᴒͼ
ꜞԜᴟᴡꜜᴒᴟᴠͼꜝⱱͼᴐⱳ꞉ꞌᴑԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉ԜꞌͼꜛᴢᴠᴡͼԜⱲᴟᴒᴒͼᴡꜝͼԝᴒͼԜԝᴠᴡ꞉ꜜᴒꜜᴡͼꜝᴟͼᴒꞌᴠᴒͼᴢᴠᴒͼԜͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼ
ԜᴐᴐᴒꜞᴡԜԝꞌᴒͼⱱꜝᴟꜛͼꜝⱱͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴡⱳᴟꜝᴢⱲⱳͼ⅍᷇ᴑԜᴦᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼᴠᴡᴢᴑᴦͼ
ᴣ꞉ᴠ꞉ᴡ᷅ͼ
Criteria for Exclusion:
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼꜛᴒᴒᴡͼԜꜜᴦͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴥᴐꞌᴢᴑᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦⱡ
᷈᷅ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼꜝⱱͼԜꜜꜝᴡⱳᴒᴟͼⱱꜝᴟꜛͼꜝⱱͼᴐⱳᴟꜝꜜ꞉ᴐԓͼᴟᴒᴐᴢᴟᴟᴒꜜᴡͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜԓͼᴠᴢᴐⱳͼԜᴠͼ
Ԝᴐꜟᴢ꞉ᴟᴒᴑͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼӿⱨⱨⱬԐԓͼⱶⱨⱬͼᴤ꞉ᴡⱳͼꜜꜝᴟꜛԜꞌͼⱪ᷈᷄ⱷ꜠ⱶͼӿԜꞌᴠꜝͼꞋꜜꜝᴤꜜͼԜᴠͼⱶⱨⱬͼᴁᴦꜞᴒͼⱷⱷⱷԐԓͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
꞉ᴑ꞉ꜝꜞԜᴡⱳ꞉ᴐͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜԓͼꜝᴟͼᴟᴒᴐᴢᴟᴟᴒꜜᴡͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼᴢᴟᴡ꞉ᴐԜᴟ꞉Ԝ᷅
᷉᷅͟Ԝᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜝꜜͼ꞉ꜜͼԜͼꜞᴟ꞉ꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴡᴢᴑᴦ᷅
᷊᷅Ⱬꜝᴠ꞉ꜜⱲͼᴤ꞉ᴡⱳͼԜꜜͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼᴑᴟᴢⱲͼꜝᴟͼᴒᴥꜞꜝᴠᴢᴟᴒͼᴡꜝͼԜꜜͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼᴑᴒᴣ꞉ᴐᴒͼᴤ꞉ᴡⱳ꞉ꜜͼ
᷾ᴤᴒᴒꞋᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲ᷅
᷾᷅ⱬᴥꜞꜝᴠᴢᴟᴒͼᴡꜝͼԜꜜⱲ꞉ꜝᴡᴒꜜᴠ꞉ꜜ᷄ᴐꜝꜜᴣᴒᴟᴡ꞉ꜜⱲͼᴒꜜᴧᴦꜛᴒͼӿⱨⱪⱬԐͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟᴠͼꜝᴟͼԜꜜᴦͼᴒᴠᴡᴟꜝⱲᴒꜜ᷄ᴐꜝꜜᴡԜ꞉ꜜ꞉ꜜⱲͼ
ꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼᴤ꞉ᴡⱳͼᴠᴦᴠᴡᴒꜛ꞉ᴐͼԜԝᴠꜝᴟꜞᴡ꞉ꜝꜜͼӿᴠᴢᴐⱳͼԜᴠͼꜝᴟԜꞌͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ᴣᴒᴠͼꜝᴟͼⱳꜝᴟꜛꜝꜜԜꞌͼ
ᴟᴒꜞꞌԜᴐᴒꜛᴒꜜᴡͼᴡⱳᴒᴟԜꜞᴦԐͼᴤ꞉ᴡⱳ꞉ꜜͼ᷾ͼᴤᴒᴒꞋᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲ᷅
᷿᷅ⱬᴥꜞꜝᴠᴢᴟᴒͼᴡꜝͼԜꜜᴑᴟꜝⱲᴒꜜᴠͼӿᴒ᷅Ⱳ᷅ͼᴠᴡԜꜜꜝᴧꜝꞌꜝꞌԓͼᴑԜꜜԜᴧꜝꞌԓͼꜝᴥԜꜜᴑᴟꜝꞌꜝꜜᴒԓͼꜛᴒᴡⱳᴦꞌᴡᴒᴠᴡꜝᴠᴡᴒᴟꜝꜜᴒԓͼ
ᴡᴒᴠᴡꜝᴠᴡᴒᴟꜝꜜᴒԐͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉ͼᴤᴒᴒꞋᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼ
⅍᷅ᴂᴠᴒͼꜝⱱͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬͼӿⱪ᷈᷄ⱷ꜠ⱶԓͼԜᴡᴡᴒꜜᴢԜᴡᴒᴑͼԜꜜᴑᴟꜝⱲᴒꜜᴠԓͼꜝᴟͼ
Ԝꜜᴡ꞉᷄ⱱ꞉ԝᴟ꞉ꜜꜝꞌᴦᴡ꞉ᴐᴠԐͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉ͼᴤᴒᴒꞋᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅
ⅎ᷅ᴂᴠᴒͼꜝⱱͼᴠⱳꜝᴟᴡ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼⱱꜝᴟͼⱶⱨⱬͼᴤ꞉ᴡⱳ꞉ꜜͼⅎͼᴑԜᴦᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼ
ᴀⱳꜝᴟᴡ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼ꞉ᴠͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼⱪ᷈᷄ⱷ꜠ⱶԓͼԜᴡᴡᴒꜜᴢԜᴡᴒᴑͼԜꜜᴑᴟꜝⱲᴒꜜᴠԓͼꜝᴟͼԜꜜᴡ꞉᷄ⱱ꞉ԝᴟ꞉ꜜꜝꞌᴦᴡ꞉ᴐᴠͼ
ᴢᴠᴒᴑͼᴡꜝͼԜᴣꜝ꞉ᴑͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴐꜝꜛꜞꞌ꞉ᴐԜᴡ꞉ꜝꜜᴠͼⱱᴟꜝꜛͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼ꞉ꜜᴑ꞉ᴐԜᴡᴒᴑͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠ᷅
˲᷅ⱨꜜᴦͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꞌ꞉ᴣᴒᴟͼⱱᴢꜜᴐᴡ꞉ꜝꜜͼᴡᴒᴠᴡͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠⱡͼԜꞌԜꜜ꞉ꜜᴒͼԜꜛ꞉ꜜꜝᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒͼӿⱨꜙᴁԐͼ
ⱥ᷊ᴥͼᴢꜞꜞᴒᴟͼꞌ꞉ꜛ꞉ᴡͼꜝⱱͼꜜꜝᴟꜛԜꞌԓͼꜝᴟͼԜᴠꜞԜᴟᴡԜᴡᴒͼԜꜛ꞉ꜜꜝᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒͼӿⱨᴀᴁԐͼⱥͼ᷊ᴥͼᴢꜞꜞᴒᴟͼꞌ꞉ꜛ꞉ᴡͼꜝⱱͼ
ꜜꜝᴟꜛԜꞌԓͼꜝᴟͼᴡꜝᴡԜꞌͼԝ꞉ꞌ꞉ᴟᴢԝ꞉ꜜͼⱥͼ᷉ᴥͼᴢꜞꜞᴒᴟͼꞌ꞉ꜛ꞉ᴡͼꜝⱱͼꜜꜝᴟꜛԜꞌͼӿᴢꜜꞌᴒᴠᴠͼᴡⱳᴒͼԝ꞉ꞌ꞉ᴟᴢԝ꞉ꜜͼᴒꞌᴒᴣԜᴡ꞉ꜝꜜͼ꞉ᴠͼԜͼ
ᴟᴒᴠᴢꞌᴡͼꜝⱱͼⱵ꞉ꞌԝᴒᴟᴡᶳᴠͼᴠᴦꜜᴑᴟꜝꜛᴒԐ᷅
Ⱡ᷅͟ᴟᴒⱲꜜԜꜜᴐᴦͼꜝᴟͼԝᴟᴒԜᴠᴡⱱᴒᴒᴑ꞉ꜜⱲ᷅
᷈᷇᷅ᴀᴢԝ꞊ᴒᴐᴡͼⱳԜᴠͼԜꜜᴦͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜͼᴡⱳԜᴡԓͼ꞉ꜜͼᴡⱳᴒͼꜝꜞ꞉ꜜ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼᴀꜞꜝꜜᴠꜝᴟԓͼꜛԜᴦͼ
ᴐꜝꜛꜞᴟꜝꜛ꞉ᴠᴒͼᴡⱳᴒ꞉ᴟͼᴠԜⱱᴒᴡᴦͼꜝᴟͼᴐꜝꜛꜞꞌ꞉Ԝꜜᴐᴒԓͼꜞᴟᴒᴐꞌᴢᴑᴒͼᴠᴢᴐᴐᴒᴠᴠⱱᴢꞌͼᴐꜝꜜᴑᴢᴐᴡͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼꜝᴟͼ
꞉ꜜᴡᴒᴟⱱᴒᴟᴒͼᴤ꞉ᴡⱳͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴟᴒᴠᴢꞌᴡᴠͼӿᴒ᷅Ⱳ᷅ԓͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝⱱͼᴠᴢԝᴠᴡԜꜜᴐᴒͼԜԝᴢᴠᴒͼꜝᴟͼᴑᴒꜞᴒꜜᴑᴒꜜᴐᴒԓͼ
ᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼꜞᴟᴒ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼ꞉ꞌꞌꜜᴒᴠᴠͼꜝᴟͼꜝᴡⱳᴒᴟͼꜛԜ꞊ꜝᴟͼᴐꜝꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼᴡⱳԜᴡͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴠͼ
ꜛԜᴦͼᴐꜝꜜⱱꜝᴢꜜᴑͼᴡⱳᴒͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜͼꜝⱱͼᴠᴡᴢᴑᴦͼᴟᴒᴠᴢꞌᴡᴠԐ᷅
Test Product; Dose; and Mode of Administration:
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ᴠͼԜͼᴠᴡᴒᴟ꞉ꞌᴒԓͼꜞᴟᴒᴠᴒᴟᴣԜᴡ꞉ᴣᴒ᷄ⱱᴟᴒᴒͼᴠꜝꞌᴢᴡ꞉ꜝꜜͼⱱꜝᴟͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜԓͼꜞⱶͼ⅍᷅᷇᷅ͼᴁⱳᴒͼԜᴐᴡ꞉ᴣᴒͼ꞉ꜜⱲᴟᴒᴑ꞉ᴒꜜᴡԓͼ
Ⱬᴅ᷄᷉Ⱡ᷊᷇ԓͼ꞉ᴠͼⱱꜝᴟꜛᴢꞌԜᴡᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐꜝꜛꜞᴒꜜᴑ꞉Ԝꞌͼᴐꜝꜛꜞꜝꜜᴒꜜᴡᴠⱡͼ᷊᷇ͼꜛꜚͼᴠꜝᴑ꞉ᴢꜛͼ
ꜞⱳꜝᴠꜞⱳԜᴡᴒͼᴑ꞉ԝԜᴠ꞉ᴐͼᴑ꞉ⱳᴦᴑᴟԜᴡᴒԓͼ᷈Ⱡ᷅⅍ͼꜛꜚͼᴐ꞉ᴡᴟ꞉ᴐͼԜᴐ꞉ᴑԓͼ᷿᷇ͼꜛꜚͼⱳ꞉ᴠᴡ꞉ᴑ꞉ꜜᴒԓͼⱠ᷇ꜛꜚͼᴠꜝᴑ꞉ᴢꜛͼᴐⱳꞌꜝᴟ꞉ᴑᴒԓͼ
᷇᷅᷇᷈Ӽͼ͟ꜝꞌᴦᴠꜝᴟԝԜᴡᴒͼ˲᷇᷅ͼⱬԜᴐⱳͼᴣ꞉ԜꞌͼᴐꜝꜜᴡԜ꞉ꜜᴠͼԜͼꜜꜝꜛ꞉ꜜԜꞌͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼ᷿᷈᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ
Ԝᴐᴡ꞉ᴣᴒͼ꞉ꜜⱲᴟᴒᴑ꞉ᴒꜜᴡͼ꞉ꜜͼ᷈ꜛꜙͼᴠꜝꞌᴢᴡ꞉ꜝꜜ᷅ͼᴁⱳᴒͼᴡᴒᴠᴡͼꜞᴟꜝᴑᴢᴐᴡͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠꞌᴦͼ꞉ꜜᴡꜝͼ
ᴡⱳᴒͼᴢꜞꜞᴒᴟͼԜᴟꜛͼ꞉ꜜͼԜͼԝꞌ꞉ꜜᴑᴒᴑͼꜛԜꜜꜜᴒᴟ᷅
ⱴꜝᴟͼᴒԜᴐⱳͼ᷊᷇᷇ꜛⱲͼᴑꜝᴠᴒͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼᴡꜝᴡԜꞌͼꜝⱱͼ᷉ͼꜛꜙԓͼᴑ꞉ᴣ꞉ᴑᴒᴑͼ꞉ꜜᴡꜝͼ
᷉ᴠᴒꜞԜᴟԜᴡᴒͼ᷈᷅᷇ͼꜛꜙͼᴀⱪͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇᷅ͼᴁⱳᴒͼ᷉ͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼⱲ꞉ᴣᴒꜜͼ꞉ꜜͼᴡⱳᴒͼᴠԜꜛᴒͼ
ᴢꜞꜞᴒᴟͼԜᴟꜛԓͼᴤ꞉ᴡⱳͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼᴐꜛͼᴠᴒꜞԜᴟԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴒԜᴐⱳͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼᴠ꞉ᴡᴒ᷅
ⱴꜝᴟͼᴒԜᴐⱳͼ᷿᷈᷇ͼꜛⱲͼᴑꜝᴠᴒͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼᴡꜝᴡԜꞌͼꜝⱱͼ᷉ͼꜛꜙԓͼᴑ꞉ᴣ꞉ᴑᴒᴑͼ꞉ꜜᴡꜝͼ
᷉ᴠᴒꜞԜᴟԜᴡᴒͼ᷈᷅᷇ͼꜛꜙͼᴀⱪͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠԓͼᴤⱳᴒᴟᴒͼꜝꜜᴒͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼ꞉ᴠͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑͼᴡⱳᴒͼꜝᴡⱳᴒᴟͼ꞉ᴠͼꜞꞌԜᴐᴒԝꜝ᷅ͼ
ᴁⱳᴒͼ᷉ͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼⱲ꞉ᴣᴒꜜͼ꞉ꜜͼᴡⱳᴒͼᴠԜꜛᴒͼᴢꜞꜞᴒᴟͼԜᴟꜛԓͼᴤ꞉ᴡⱳͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼᴐꜛͼᴠᴒꜞԜᴟԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼ
ᴒԜᴐⱳͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼᴠ꞉ᴡᴒ᷅
Placebo; Dose; and Mode of Administration:
͟ꞌԜᴐᴒԝꜝͼᴐꜝꜜᴠ꞉ᴠᴡᴠͼꜝⱱͼᴡⱳᴒͼ꞉ꜜԜᴐᴡ꞉ᴣᴒͼⱱꜝᴟꜛᴢꞌԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴡᴒᴠᴡͼꜞᴟꜝᴑᴢᴐᴡⱡͼ᷊᷇ͼꜛꜚͼᴠꜝᴑ꞉ᴢꜛͼꜞⱳꜝᴠꜞⱳԜᴡᴒͼ
ᴑ꞉ԝԜᴠ꞉ᴐͼᴑ꞉ⱳᴦᴑᴟԜᴡᴒԓͼ᷈Ⱡ᷅⅍ꜛꜚͼᴐ꞉ᴡᴟ꞉ᴐͼԜᴐ꞉ᴑԓͼ᷿᷇ͼꜛꜚͼⱳ꞉ᴠᴡ꞉ᴑ꞉ꜜᴒԓͼⱠ᷇ͼꜛꜚͼᴠꜝᴑ꞉ᴢꜛͼᴐⱳꞌꜝᴟ꞉ᴑᴒԓͼꜞⱶͼ⅍᷅᷇ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴤ꞉ᴡⱳͼ᷇᷅᷇᷈Ӽͼ͟ꜝꞌᴦᴠꜝᴟԝԜᴡᴒ˲᷇᷅ͼ
͟ꞌԜᴐᴒԝꜝͼᴑꜝᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴡꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛͼԜꜜᴑͼ
꞉ꜜͼԝᴒᴡᴤᴒᴒꜜͼᴑꜝᴠᴒᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱱꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼᴡⱳᴒͼ᷊᷇᷇ͼꜛⱲͼꜝᴟͼ᷿᷈᷇ͼꜛⱲͼⱫᴅ᷄᷄᷉Ⱡ᷊᷇ͼ
ᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛᴠԓͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴡԜԝꞌᴒͼⱱꜝᴟͼᴑꜝᴠ꞉ꜜⱲͼᴠᴐⱳᴒᴑᴢꞌᴒ᷅
ⱴꜝᴟͼᴒԜᴐⱳͼꜞꞌԜᴐᴒԝꜝͼᴑꜝᴠᴒԓͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼᴡꜝᴡԜꞌͼꜝⱱͼ᷉ͼꜛꜙԓͼᴑ꞉ᴣ꞉ᴑᴒᴑͼ꞉ꜜᴡꜝͼ᷉ᴠᴒꜞԜᴟԜᴡᴒͼ
᷈᷅᷇ꜛꜙͼᴀⱪͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼꜞꞌԜᴐᴒԝꜝ᷅ͼᴁⱳᴒͼ᷉ͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼⱲ꞉ᴣᴒꜜͼ꞉ꜜͼᴡⱳᴒͼᴠԜꜛᴒͼᴢꜞꜞᴒᴟͼԜᴟꜛԓͼᴤ꞉ᴡⱳͼ
ԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼᴐꜛͼᴠᴒꜞԜᴟԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴒԜᴐⱳͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼᴠ꞉ᴡᴒ᷅ͼ
Duration of Treatment:
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼᴑꜝᴠᴒͼꜝⱱͼԝꞌ꞉ꜜᴑᴒᴑͼⱷꜚ͟ͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼ᷉⅍᷄ᴤᴒᴒꞋͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
ꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜͼᴡꜝᴡԜꞌͼꜝⱱͼ᷊᷈ͼᴑꜝᴠᴒᴠ᷅ͼᴁⱳᴒͼⱱ꞉ᴟᴠᴡͼᴑꜝᴠᴒͼꜝⱱͼⱷꜚ͟ͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼᴡⱳᴒͼ
ꞌԜᴠᴡͼᴑꜝᴠᴒͼꜝⱱͼⱷꜚ͟ͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼꜝꜜͼⱫԜᴦͼ᷈⅍˲᷅ͼᴁⱳᴒᴟᴒͼᴤ꞉ꞌꞌͼԝᴒͼԜͼᶐ᷊᷄ᴑԜᴦͼᴤ꞉ꜜᴑꜝᴤͼԜᴟꜝᴢꜜᴑͼ
ᴒԜᴐⱳͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡԓͼᴤ꞉ᴡⱳͼԜͼꜛԜᴥ꞉ꜛᴢꜛͼꜝⱱͼ᷈ⅎͼᴑԜᴦᴠͼꜝᴟͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼꜝⱱͼ᷈᷈ͼᴑԜᴦᴠͼԝᴒᴡᴤᴒᴒꜜͼԜꜜᴦͼ᷉ͼᴑꜝᴠᴒᴠ᷅ͼ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼԜᴡͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒͼᴡⱳᴟꜝᴢⱲⱳͼ᷉ͼⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼⱱꜝᴟͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼ᷾ᴑꜝᴠᴒᴠͼ
ᴤ꞉ᴡⱳͼᴡⱳᴒͼԜԝ꞉ꞌ꞉ᴡᴦͼᴡꜝͼᴟᴒᴑᴢᴐᴒͼᴡⱳ꞉ᴠͼᴡ꞉ꜛᴒͼᴡꜝͼ᷈ͼⱳꜝᴢᴟͼⱱꜝᴟͼᴡⱳᴒͼᴟᴒꜛԜ꞉ꜜ꞉ꜜⱲͼᴑꜝᴠᴒᴠͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼ
ꜝⱱͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠ᷅ͼⱨͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴣ꞉ᴠ꞉ᴡͼᴤ꞉ꞌꞌͼꜝᴐᴐᴢᴟͼꜝꜜͼⱫԜᴦͼ᷈˲᷉᷅
Duration of Study for Individual Subjects:
ⱴꜝꞌꞌꜝᴤ꞉ꜜⱲͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷅ͼᴀᴐᴟᴒᴒꜜᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ
ᴤⱳꜝͼԜᴟᴒͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟⱶⱨⱬͼԜᴟᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼᴢꜜᴑᴒᴟⱲꜝͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼ
᷉ᴤᴒᴒꞋͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴟᴢꜜ᷄꞉ꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴒ꞉ᴡⱳᴒᴟͼꜜꜝᴡͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼ
ꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬԓͼꜝᴟͼⱳԜᴣᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑͼᴡⱳᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑԓͼᴤ꞉ꞌꞌͼᴒꜜᴡᴒᴟͼԜͼ
ᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜝⱱͼ᷾ͼᴤᴒᴒꞋᴠͼᴡꜝͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼᴡⱳᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒ᷅ᴁⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼ
ꞌԜᴠᴡͼԜᴠͼꞌꜝꜜⱲͼԜᴠͼ˲ͼᴤᴒᴒꞋᴠͼ꞉ꜜͼꜝᴟᴑᴒᴟͼᴡꜝͼꜛᴒᴒᴡͼᴡⱳᴒͼꜛ꞉ꜜ꞉ꜛᴢꜛͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡ᷅ͼ
ⱬꜜᴟꜝꞌꞌᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴡⱳᴒꜜͼᴢꜜᴑᴒᴟⱲꜝͼԜͼ᷉⅍᷄ᴤᴒᴒꞋͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼ
ꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼ꜡ꜙⱬͼᴤ꞉ꞌꞌͼԝᴒͼⱱꜝꞌꞌꜝᴤᴒᴑͼⱱꜝᴟͼԜꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ˲ͼᴤᴒᴒꞋᴠͼ꞉ꜜͼᴡⱳᴒͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼᴠᴡᴢᴑᴦ᷅
Prohibited Concomitant Treatments:
ᴂᴠᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡᴟᴒԜᴡꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦⱡ
ᶄ
ꜙꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼⱱꜝᴟͼⱶⱨⱬͼӿᴒ᷅Ⱳ᷅ԓͼᴢᴠᴒͼꜝⱱͼⱪ᷈᷄ⱷ꜠ⱶͼⱱꜝᴟͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠԓͼ
ԜᴡᴡᴒꜜᴢԜᴡᴒᴑͼԜꜜᴑᴟꜝⱲᴒꜜᴠԓͼꜝᴟͼԜꜜᴡ꞉᷄ⱱ꞉ԝᴟ꞉ꜜꜝꞌᴦᴡ꞉ᴐᴠԐ᷅ͼ
ᶄ
ⱨꜜⱲ꞉ꜝᴡᴒꜜᴠ꞉ꜜ᷄ᴐꜝꜜᴣᴒᴟᴡ꞉ꜜⱲͼᴒꜜᴧᴦꜛᴒͼӿⱨⱪⱬԐͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟᴠ᷅
ᶄ
ⱬᴠᴡᴟꜝⱲᴒꜜ᷄ᴐꜝꜜᴡԜ꞉ꜜ꞉ꜜⱲͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼᴤ꞉ᴡⱳͼᴠᴦᴠᴡᴒꜛ꞉ᴐͼԜԝᴠꜝᴟꜞᴡ꞉ꜝꜜͼӿᴠᴢᴐⱳͼԜᴠͼꜝᴟԜꞌͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ᴣᴒᴠͼꜝᴟͼ
ⱳꜝᴟꜛꜝꜜԜꞌͼᴟᴒꜞꞌԜᴐᴒꜛᴒꜜᴡͼᴡⱳᴒᴟԜꜞᴦԐ᷅
ᶄ
ⱨꜜᴑᴟꜝⱲᴒꜜᴠͼӿᴒ᷅Ⱳ᷅ԓͼᴠᴡԜꜜꜝᴧꜝꞌꜝꞌԓͼᴑԜꜜԜᴧꜝꞌԓͼꜝᴥԜꜜᴑᴟꜝꞌꜝꜜᴒԓͼꜛᴒᴡⱳᴦꞌᴡᴒᴠᴡꜝᴠᴡᴒᴟꜝꜜᴒԓͼᴡᴒᴠᴡꜝᴠᴡᴒᴟꜝꜜᴒԐ᷅
ᶄ
ⱨꜜᴦͼꜝᴡⱳᴒᴟͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼᴑᴟᴢⱲͼꜝᴟͼᴑᴒᴣ꞉ᴐᴒ᷅
ᴁⱳᴒͼᴢᴠᴒͼꜝⱱͼᴠⱳꜝᴟᴡ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱱꜝᴟͼⱶⱨⱬͼ꞉ᴠͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼ꞉ⱱͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼ꞉ꜜᴑ꞉ᴐԜᴡᴒᴑ᷅
Management of Acute Attacks:
ⱨᴐᴢᴡᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜᴟᴒͼᴡꜝͼԝᴒͼꜛԜꜜԜⱲᴒᴑͼ꞉ꜜͼԜᴐᴐꜝᴟᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼ
ᴢᴠᴢԜꞌͼᴐԜᴟᴒͼꜝⱱͼᴡⱳᴒ꞉ᴟͼꜞԜᴡ꞉ᴒꜜᴡᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴢᴠᴒͼꜝⱱͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋͼᴡⱳᴒᴟԜꜞ꞉ᴒᴠͼᴡⱳԜᴡͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ
ᴑᴒᴒꜛᴠͼԜᴠͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼԜꜞꜞᴟꜝꜞᴟ꞉Ԝᴡᴒ᷅ͼᴂᴠᴒͼꜝⱱͼⱪ᷈᷄ⱷ꜠ⱶͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼԜᴠͼԜꜜͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋͼᴡⱳᴒᴟԜꜞᴦͼ
ԝᴢᴡͼꜜꜝᴡͼԜᴠͼԜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠ᷅ͼⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼԜꜜᴑͼᴠᴡᴢᴑᴦͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴤ꞉ᴡⱳꜝᴢᴡͼԜꞌᴡᴒᴟԜᴡ꞉ꜝꜜͼᴡꜝͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌ᷄ᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴠᴡᴢᴑᴦͼᴠᴐⱳᴒᴑᴢꞌᴒԓͼᴒᴣᴒꜜͼ꞉ⱱͼ
ᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡͼᴟᴒᴐᴒ꞉ᴣᴒᴠͼԜꜜᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱱꜝᴟͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋ᷅
Safety Assessments:
ᴁⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒⱡ
ᶄ
ⱨᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼӿⱨⱬᴠԐԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴠᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼӿᴀⱨⱬᴠԐͼԜꜜᴑͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼꜝⱱͼ
ᴠꜞᴒᴐ꞉Ԝꞌͼ꞉ꜜᴡᴒᴟᴒᴠᴡͼӿⱨⱬᴀⱷԐ᷅
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴠ꞉ᴡᴡ꞉ꜜⱲͼꜝᴟͼᴠᴢꜞ꞉ꜜᴒͼԝꞌꜝꜝᴑͼꜞᴟᴒᴠᴠᴢᴟᴒͼӿⱩ͟ԐԓͼⱳᴒԜᴟᴡͼᴟԜᴡᴒͼӿⱶϸԐԓͼԝꜝᴑᴦͼ
ᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼԜꜜᴑͼᴟᴒᴠꜞ꞉ᴟԜᴡꜝᴟᴦͼᴟԜᴡᴒͼӿϸϸԐ᷅
ᶄ
͟ⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜ᷅
ᶄ
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼӿⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠԐ᷅
ᶄ
᷈᷉᷄ꜙᴒԜᴑͼᴒꞌᴒᴐᴡᴟꜝᴐԜᴟᴑ꞉ꜝⱲᴟԜꜛͼӿⱬⱪⱵԐ᷅
Pharmacokinetic (PK) Assessments:
ⱩꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼꜛᴒԜᴠᴢᴟᴒꜛᴒꜜᴡͼꜝⱱͼꜞꞌԜᴠꜛԜͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜᴠͼ
ꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼꜝꜜͼⱫԜᴦᴠͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷾᷇ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼ
ⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦᴠ᷉᷈᷇ᶐ᷊ͼԜꜜᴑͼ᷊᷉˲ᶐ᷊ͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑͼ
ⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅
Pharmacodynamic (PD) Assessments:
ⱩꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼᴡꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼᴒⱱⱱᴒᴐᴡᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ
ᴡⱳᴟꜝᴢⱲⱳͼԝ꞉ꜝꜛԜᴟꞋᴒᴟͼԜᴠᴠԜᴦᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼꜝꜜͼⱫԜᴦᴠͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ
᷈᷾᷇ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦᴠͼ᷉᷈᷇ᶐ᷊ͼԜꜜᴑͼ᷊᷉˲ᶐ᷊ͼᴑᴢᴟ꞉ꜜⱲͼ
ᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅
Immunogenicity Assessments:
ⱩꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼᴡꜝͼԜᴠᴠԜᴦͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟᴒᴠᴒꜜᴐᴒͼꜝⱱͼԜꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜝⱱͼꜜᴒᴢᴡᴟԜꞌ꞉ᴧ꞉ꜜⱲͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠͼӿ꞉ⱱͼԜꜜᴦͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼꜞꜝᴠ꞉ᴡ꞉ᴣᴒͼԜꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠͼԜᴟᴒͼ
ᴑᴒᴡᴒᴐᴡᴒᴑԐͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼꜝꜜͼⱫԜᴦᴠͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷾᷇ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼ
ⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜⱫԜᴦͼ᷊᷉˲ᶐ᷊ͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜᴦͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅
C1-INH, C4, and C1q Assessments:
ᴀԜꜛꜞꞌᴒᴠͼⱱꜝᴟͼⱪ᷈᷄ⱷ꜠ⱶԓͼⱪ᷾ԓͼԜꜜᴑͼⱪ᷈ꜟͼԜᴠᴠԜᴦᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼԜᴡͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼⱱꜝᴟͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼ
Ԝᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅ͼ
Quality of Life Assessments:
ϷᴢԜꞌ꞉ᴡᴦ᷄ꜝⱱ᷄ꞌ꞉ⱱᴒͼӿϷꜝꜙԐͼᴑԜᴡԜͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱬᴢᴟꜝϷꜝꜙͼⱵᴟꜝᴢꜞͼ᷿᷄Ⱬ꞉ꜛᴒꜜᴠ꞉ꜝꜜͼӿⱬϷ᷿ⱫԐͼ
Ϸᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼⱠ˲ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊ͼԜꜜᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷄ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼ
ꜙ꞉ⱱᴒͼӿⱨⱬ᷄ϷꜝꜙԐͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼ᷉˲ͼᶐ᷊ԓͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓ ᷈᷉⅍ͼᶐ᷊ԓͼ᷿᷈᷾ͼᶐ᷊ԓͼ
Ԝꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨꜜԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼϷꜝꜙͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦ᷊᷉˲ᶐ᷊ͼⱱꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼ
ᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅ͼ
Collection of HAE Attack Data:
ᴁⱳᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜԓͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼԜᴡᴡԜᴐꞋᴠͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴑꜝꜜᴒͼ꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴤ꞉ᴡⱳͼᴡⱳᴒͼⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼԜꜜᴑͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼ͟ᴟꜝᴐᴒᴑᴢᴟᴒᴠͼӿⱶⱨⱨϸ͟Ԑ᷅ͼᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼ
ԝᴒͼᴡᴟԜ꞉ꜜᴒᴑͼꜝꜜͼⱶⱨⱨϸ͟ͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜᴡͼᴡⱳᴒ꞉ᴟͼᴠ꞉ᴡᴒ᷅
Ⱬᴢᴟ꞉ꜜⱲͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲԓͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴡᴟԜ꞉ꜜͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜꜜᴑͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠͼꜝꜜͼ꞉ᴑᴒꜜᴡ꞉ⱱᴦ꞉ꜜⱲͼᴠᴦꜛꜞᴡꜝꜛᴠͼ
ꜝⱱͼԜꜜͼԜᴡᴡԜᴐꞋԓͼᴡⱳᴒͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼⱱꜝᴟͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼԜᴡᴡԜᴐꞋᴠͼԜꜜᴑͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡⱳᴒᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴥꜞᴒᴐᴡᴒᴑͼ
ᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒ᷅ͼᴁⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼӿԜꜜᴑͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟԐͼᴤ꞉ꞌꞌͼᴐꜝꜜⱱ꞉ᴟꜛͼᴡⱳᴒ꞉ᴟͼᴢꜜᴑᴒᴟᴠᴡԜꜜᴑ꞉ꜜⱲͼꜝⱱͼᴤⱳԜᴡͼ꞉ᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼ
ꜝⱱͼᴡⱳᴒꜛͼⱱꜝᴟͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼԜᴡᴡԜᴐꞋᴠͼᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒ᷅
ⱨᴡͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲԓͼᴠᴢԝ꞊ᴒᴐᴡͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼⱳ꞉ᴠᴡꜝᴟᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑ᷅ͼⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼ
Ԝꜜᴦͼꜞᴟ꞉ꜝᴟͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝⱱͼꞌԜᴟᴦꜜⱲᴒԜꞌͼԜᴡᴡԜᴐꞋᴠԓͼԜᴡᴡԜᴐꞋͼⱱᴟᴒꜟᴢᴒꜜᴐᴦԓͼԜᴣᴒᴟԜⱲᴒͼᴠᴒᴣᴒᴟ꞉ᴡᴦԓͼꜞᴟᴒᴑꜝꜛ꞉ꜜԜꜜᴡͼԜᴡᴡԜᴐꞋͼ
ꞌꜝᴐԜᴡ꞉ꜝꜜӿᴠԐԓͼԜᴣᴒᴟԜⱲᴒͼᴑᴢᴟԜᴡ꞉ꜝꜜԓͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋͼᴡⱳᴒᴟԜꜞᴦͼᴢᴠᴒԓͼԜꜜᴑͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝⱱͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠ᷅
Ⱬᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼӿꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠԐͼᴤ꞉ꞌꞌͼԝᴒͼ꞉ꜜᴠᴡᴟᴢᴐᴡᴒᴑͼᴡꜝͼꜜꜝᴡ꞉ⱱᴦͼԜꜜᴑͼᴟᴒꜞꜝᴟᴡͼᴑᴒᴡԜ꞉ꞌᴠͼᴡꜝͼᴡⱳᴒͼ
ᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒͼᴤ꞉ᴡⱳ꞉ꜜͼⅎ᷉ͼⱳꜝᴢᴟᴠͼꜝⱱͼᴡⱳᴒͼꜝꜜᴠᴒᴡͼꜝⱱͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋ᷅ͼⱷꜜͼᴡⱳᴒͼᴠ꞉ᴡᴢԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼ
꞉ꜜᴐԜꜞԜᴐ꞉ᴡԜᴡᴒᴑͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼԜꜜͼԜᴡᴡԜᴐꞋԓͼᴡⱳ꞉ᴠͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴐԜꜜͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒͼԝᴦͼԜͼⱱԜꜛ꞉ꞌᴦͼ
ꜛᴒꜛԝᴒᴟͼꜝᴟͼꜝᴡⱳᴒᴟͼ꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌᴤ꞉ᴡⱳͼᴑᴒᴡԜ꞉ꞌᴒᴑͼꞋꜜꜝᴤꞌᴒᴑⱲᴒͼꜝⱱͼᴡⱳᴒͼᴒᴣᴒꜜᴡ᷅ͼⱷⱱͼᴑᴒᴠ꞉ᴟᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡԓͼ
ꜛᴒꜛꜝᴟᴦͼԜ꞉ᴑᴠͼꜛԜᴦͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴡꜝͼԜᴠᴠ꞉ᴠᴡͼ꞉ꜜͼᴡᴟԜᴐꞋ꞉ꜜⱲͼԜꜜᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒ᷅ͼ
ᴄᴒᴒꞋꞌᴦͼᴐꜝꜛꜛᴢꜜ꞉ᴐԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡᴠͼԜꜜᴑͼᴡⱳᴒͼᴠ꞉ᴡᴒԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴟᴒꜞꜝᴟᴡᴠͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼ
ꜛᴢᴠᴡͼԝᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅
ᴀᴢԝ꞊ᴒᴐᴡᴠͼӿꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠԐͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠꞋᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴤⱳᴒꜜͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼԜꜜͼ
ԜᴡᴡԜᴐꞋⱡ
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ⱫԜᴡᴒͼԜꜜᴑͼᴡ꞉ꜛᴒͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜝⱱͼԜꜜͼԜᴡᴡԜᴐꞋͼᴤᴒᴟᴒͼⱱ꞉ᴟᴠᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴑ
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Ⱬᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴠᴦꜛꜞᴡꜝꜛᴠͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴑԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼꞌꜝᴐԜᴡ꞉ꜝꜜӿᴠԐ
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ⱷꜛꜞԜᴐᴡͼꜝꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼԜꜜᴑͼᴤⱳᴒᴡⱳᴒᴟͼԜꜜᴦͼԜᴠᴠ꞉ᴠᴡԜꜜᴐᴒͼꜝᴟͼꜛᴒᴑ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜͼᴤԜᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑԓͼ
꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜᴠͼꜝᴟͼᴒꜛᴒᴟⱲᴒꜜᴐᴦͼᴑᴒꜞԜᴟᴡꜛᴒꜜᴡͼᴣ꞉ᴠ꞉ᴡᴠ
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ⱨꜜᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼᴢᴠᴒᴑͼᴡꜝͼᴡᴟᴒԜᴡͼᴡⱳᴒͼԜᴡᴡԜᴐꞋ
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ⱷⱱͼᴡⱳᴒͼԜᴡᴡԜᴐꞋͼᴟᴒᴠꜝꞌᴣᴒᴑԓͼᴑԜᴡᴒͼԜꜜᴑͼᴡ꞉ꜛᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴤԜᴠͼꜜꜝͼꞌꜝꜜⱲᴒᴟͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐ꞉ꜜⱲͼᴠᴦꜛꜞᴡꜝꜛᴠ
ᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼԜꜜᴑͼᴠꜝꞌ꞉ᴐ꞉ᴡͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼԜᴠͼ
ꜜᴒᴐᴒᴠᴠԜᴟᴦͼᴡꜝͼᴑꜝᴐᴢꜛᴒꜜᴡͼᴡⱳᴒͼԜᴡᴡԜᴐꞋԓͼԜᴠͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼᴡⱳᴒͼⱶⱨⱨϸ᷅͟ͼ
ᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟͼꜝꜜͼԜͼᴤᴒᴒꞋꞌᴦͼԝԜᴠ꞉ᴠͼꜝᴟͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⅎᴑԜᴦᴠͼ
ԜⱱᴡᴒᴟͼꞌԜᴠᴡͼᴐꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴡⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼⱷⱱͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴠͼ᷈ͼꜝᴟͼ
ꜛꜝᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԝᴦͼᴒꜜᴑͼꜝⱱͼᴤᴒᴒꞋ᷾ԓͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼⱳԜᴣᴒͼⱱᴢꞌⱱ꞉ꞌꞌᴒᴑͼ
ᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡͼԜꜜᴑͼꜛԜᴦͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼ
ᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼ᷊ͼꜝᴟͼꜛꜝᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋᴠͼᴐԜꜜͼᴒᴥ꞉ᴡͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒԜᴟꞌᴦͼԜꜜᴑͼ
ꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼⱷⱱͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴠͼꜜꜝͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄
ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԝᴦͼᴡⱳᴒͼᴒꜜᴑͼꜝⱱͼᴤᴒᴒꞋͼ᷾ԓͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴟᴒꜛԜ꞉ꜜͼ꞉ꜜͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼ
ԜꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ᷾ᴤᴒᴒꞋᴠ᷅ͼᴁⱳᴒͼꜛԜᴥ꞉ꜛᴢꜛͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼ꞉ᴠͼ˲ͼᴤᴒᴒꞋᴠ᷅ⱷⱱͼᴟᴢꜜ᷄꞉ꜜͼⱳԜᴠͼ
ԝᴒᴒꜜͼᴒᴥᴡᴒꜜᴑᴒᴑͼԜꜜᴑͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱳԜᴠͼ᷉ͼꜝᴟͼꜛꜝᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԝᴦͼᴡⱳᴒͼᴒꜜᴑͼ
ꜝⱱͼᴤᴒᴒꞋͼ˲ԓͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼⱳԜᴣᴒͼⱱᴢꞌⱱ꞉ꞌꞌᴒᴑͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡͼԜꜜᴑͼꜛԜᴦͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴡⱳᴒͼ
ᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴁꜝͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼⱳԜᴣᴒͼᴡⱳᴒ꞉ᴟͼᴟᴢꜜ᷄꞉ꜜͼ
ᴒᴥᴡᴒꜜᴑᴒᴑͼꜛᴢᴠᴡͼᴐꜝꜛꜞꞌᴒᴡᴒͼᴡⱳᴒͼⱱᴢꞌꞌͼ˲᷄ᴤᴒᴒꞋͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼꜛᴒᴒᴡͼᴡⱳᴒͼꜛ꞉ꜜ꞉ꜛᴢꜛͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴑᴢᴟ꞉ꜜⱲͼᴟᴢꜜ᷄꞉ꜜͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜͼᴠᴐᴟᴒᴒꜜͼ
ⱱԜ꞉ꞌ᷅ͼ
Ⱬᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟͼꜝꜜᴐᴒͼԝᴒᴡᴤᴒᴒꜜͼ
ᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡᴠͼꜝᴟͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⅎͼᴑԜᴦᴠͼԜⱱᴡᴒᴟͼꞌԜᴠᴡͼᴐꜝꜜᴡԜᴐᴡͼᴡꜝͼᴠꜝꞌ꞉ᴐ꞉ᴡͼⱱꜝᴟͼԜꜜᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜜꜝᴡͼԜꞌᴟᴒԜᴑᴦͼᴟᴒꜞꜝᴟᴡᴒᴑ᷅
ᴁⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼᴠᴡᴢᴑᴦԓͼᴑᴢᴟ꞉ꜜⱲͼᴒԜᴐⱳͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡͼԜᴡͼᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ᴣᴒͼ
ᴠ꞉ᴡᴒԓͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴠꜝꞌ꞉ᴐ꞉ᴡͼⱱꜝᴟͼԜꜜᴦͼꜜᴒᴤͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼᴤԜᴠͼꜜꜝᴡͼԜꞌᴟᴒԜᴑᴦͼ
ꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒ᷅
ⱷꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜꜞᴡᴢᴟᴒᴑͼԜᴠͼⱨⱬᴠ᷅ͼⱨꞌꞌͼⱨⱬᴠԓͼᴟᴒⱲԜᴟᴑꞌᴒᴠᴠͼꜝⱱͼᴠᴒᴟ꞉ꜝᴢᴠꜜᴒᴠᴠԓͼ
ᴠᴒᴣᴒᴟ꞉ᴡᴦԓͼꜝᴟͼᴐԜᴢᴠԜꞌͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴡꜝͼⱷꜚ͟ԓͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼꜝꜜͼᴡⱳᴒͼⱨⱬͼꜞԜⱲᴒͼꜝⱱͼᴡⱳᴒͼᴒⱪϸⱴ᷅ͼⱨꜜᴦͼ
ⱨⱬͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒͼꜛᴒᴒᴡ꞉ꜜⱲͼᴐᴟ꞉ᴡᴒᴟ꞉ԜͼⱱꜝᴟͼԜͼᴠᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡͼꜛᴢᴠᴡͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴡꜝͼᴡⱳᴒͼ
ᴀꜞꜝꜜᴠꜝᴟͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼᴀⱨⱬͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼⱴꜝᴟꜛͼ꞉ꜜͼᴡⱳᴒͼⱬⱫⱪͼᴠᴦᴠᴡᴒꜛᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ͼⱳꜝᴢᴟᴠꜝⱱͼԝᴒᴐꜝꜛ꞉ꜜⱲͼ
ԜᴤԜᴟᴒͼꜝⱱͼᴡⱳᴒͼᴒᴣᴒꜜᴡ᷅ͼⱴꜝᴟͼԜꞌꞌͼᴠᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼᴡⱳԜᴡͼԜᴟᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴠͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼᴡⱳᴒͼ
͟ᴟ꞉ꜜᴐ꞉ꜞԜꞌͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼꜞⱳᴦᴠ꞉ᴐ꞉Ԝꜜͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼᴤ꞉ꞌꞌͼᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ⱳꜝᴢᴟᴠͼꜝⱱͼ꞉ꜜ꞉ᴡ꞉Ԝꞌͼ
ꜜꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼԜꜜᴑԓͼ꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼⱶⱨⱨϸ͟ԓͼᴒᴣԜꞌᴢԜᴡᴒͼ꞉ⱱͼ꞉ᴡͼᴟᴒꜞᴟᴒᴠᴒꜜᴡᴒᴑͼԜͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋ᷅ͼⱴꜝᴟͼԜꞌꞌͼꜜꜝꜜ᷄ᴠᴒᴟ꞉ꜝᴢᴠͼⱨⱬᴠͼᴡⱳԜᴡͼԜᴟᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴠͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼᴡⱳᴒͼ͟ᴟ꞉ꜜᴐ꞉ꜞԜꞌͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼ
ꜞⱳᴦᴠ꞉ᴐ꞉Ԝꜜͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼᴤ꞉ꞌꞌͼᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴤ꞉ᴡⱳ꞉ꜜͼ᷊ͼᴑԜᴦᴠͼꜝⱱͼ꞉ꜜ꞉ᴡ꞉Ԝꞌꜜꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼԜꜜᴑԓͼ꞉ꜜͼ
ԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼⱶⱨⱨϸ͟ԓͼᴒᴣԜꞌᴢԜᴡᴒͼ꞉ⱱͼ꞉ᴡͼᴟᴒꜞᴟᴒᴠᴒꜜᴡᴒᴑͼԜͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋ᷅ͼⱷⱱͼꜜᴒᴐᴒᴠᴠԜᴟᴦͼⱱꜝᴟͼ
ᴡⱳᴒͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼᴑᴒᴠ꞉ⱲꜜᴒᴒͼꜛԜᴦͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱱꜝᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ
꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜ᷅ͼⱨꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡ᷄ᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴡᴡԜᴐꞋͼꜜꜝᴡͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼⱳԜᴣᴒͼԜꜜͼ
ԜꞌᴡᴒᴟꜜԜᴡᴒͼⱨⱬͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼᴟᴒᴐꜝᴟᴑᴒᴑ᷅ͼⱨꞌꞌͼᴠᴢԝ꞊ᴒᴐᴡ᷄ᴟᴒꜞꜝᴟᴡᴒᴑͼԜꜜᴑͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅
ⱬꜛᴒᴟⱲᴒꜜᴐᴦͼᴑᴒꜞԜᴟᴡꜛᴒꜜᴡͼᴣ꞉ᴠ꞉ᴡᴠͼⱱꜝᴟͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԜꜜᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴟᴒᴠᴢꞌᴡ꞉ꜜⱲͼ꞉ꜜͼⱳꜝᴠꜞ꞉ᴡԜꞌͼ
Ԝᴑꜛ꞉ᴠᴠ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜꜞᴡᴢᴟᴒᴑ᷅
ᴁꜝͼԝᴒͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴠͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋԓͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼꜛᴢᴠᴡͼⱳԜᴣᴒͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜝᴟͼᴠ꞉Ⱳꜜᴠͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼ
ԜꜜͼԜᴡᴡԜᴐꞋͼ꞉ꜜͼԜᴡͼꞌᴒԜᴠᴡͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꞌꜝᴐԜᴡ꞉ꜝꜜᴠⱡͼ
ᶄ
͟ᴒᴟ꞉ꜞⱳᴒᴟԜꞌͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜⱡͼᴐᴢᴡԜꜜᴒꜝᴢᴠͼᴠᴤᴒꞌꞌ꞉ꜜⱲͼ꞉ꜜᴣꜝꞌᴣ꞉ꜜⱲͼԜꜜͼᴒᴥᴡᴟᴒꜛ꞉ᴡᴦԓͼᴡⱳᴒͼⱱԜᴐᴒԓͼꜜᴒᴐꞋԓͼᴡꜝᴟᴠꜝԓͼ
Ԝꜜᴑ᷆ꜝᴟͼⱲᴒꜜ꞉ᴡꜝᴢᴟ꞉ꜜԜᴟᴦͼᴟᴒⱲ꞉ꜝꜜ
ᶄ
ⱨԝᴑꜝꜛ꞉ꜜԜꞌͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜⱡͼԜԝᴑꜝꜛ꞉ꜜԜꞌͼꜞԜ꞉ꜜԓͼᴤ꞉ᴡⱳͼꜝᴟͼᴤ꞉ᴡⱳꜝᴢᴡͼԜԝᴑꜝꜛ꞉ꜜԜꞌͼᴑ꞉ᴠᴡᴒꜜᴡ꞉ꜝꜜԓͼꜜԜᴢᴠᴒԜԓͼ
ᴣꜝꜛ꞉ᴡ꞉ꜜⱲԓͼꜝᴟͼᴑ꞉ԜᴟᴟⱳᴒԜ
ᶄ
ꜙԜᴟᴦꜜⱲᴒԜꞌͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜⱡͼᴠᴡᴟ꞉ᴑꜝᴟԓͼᴑᴦᴠꜞꜜᴒԜԓͼᴑ꞉ⱱⱱ꞉ᴐᴢꞌᴡᴦͼᴠꜞᴒԜꞋ꞉ꜜⱲԓͼᴑ꞉ⱱⱱ꞉ᴐᴢꞌᴡᴦͼᴠᴤԜꞌꞌꜝᴤ꞉ꜜⱲԓͼᴡⱳᴟꜝԜᴡͼ
ᴡ꞉Ⱳⱳᴡᴒꜜ꞉ꜜⱲԓͼꜝᴟͼᴠᴤᴒꞌꞌ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼᴡꜝꜜⱲᴢᴒԓͼꜞԜꞌԜᴡᴒԓͼᴢᴣᴢꞌԜԓͼꜝᴟͼꞌԜᴟᴦꜜᴥ
Ⱬᴒᴠꜞ꞉ᴡᴒͼᴡⱳᴒͼꜞᴟᴒᴠᴒꜜᴐᴒͼꜝⱱͼᴡⱳᴒᴠᴒͼᴠᴦꜛꜞᴡꜝꜛᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛԜᴦͼᴠᴡ꞉ꞌꞌͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼᴡⱳԜᴡͼ
ᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴑ꞉ᴑͼꜜꜝᴡͼᴟᴒꜞᴟᴒᴠᴒꜜᴡͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ⱱͼᴡⱳᴒᴟᴒͼԜᴟᴒͼⱱᴒԜᴡᴢᴟᴒᴠͼᴡⱳԜᴡͼᴠᴡᴟꜝꜜⱲꞌᴦͼᴟᴒⱱᴢᴡᴒͼᴠᴢᴐⱳͼԜͼ
ᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠ᷅ͼⱴꜝᴟͼᴒᴥԜꜛꜞꞌᴒԓͼᴡⱳᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴒᴣᴒꜜᴡͼ꞉ᴠͼԜᴐᴐꜝꜛꜞԜꜜ꞉ᴒᴑͼԝᴦͼᴠᴦꜛꜞᴡꜝꜛᴠͼᴡⱳԜᴡͼԜᴟᴒͼꜜꜝᴡͼ
ᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼӿᴒ᷅Ⱳ᷅ԓͼᴢᴟᴡ꞉ᴐԜᴟ꞉ԜԐԓͼᴡⱳᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴒᴣᴒꜜᴡͼꜞᴒᴟᴠ꞉ᴠᴡᴠͼᴤᴒꞌꞌͼԝᴒᴦꜝꜜᴑͼᴡⱳᴒͼ
ᴡᴦꜞ꞉ᴐԜꞌͼᴡ꞉ꜛᴒͼᴐꜝᴢᴟᴠᴒͼꜝⱱͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋԓͼꜝᴟᴡⱳᴒᴟᴒͼ꞉ᴠͼԜͼꞌ꞉ꞋᴒꞌᴦͼԜꞌᴡᴒᴟꜜԜᴡᴒͼᴒᴡ꞉ꜝꞌꜝⱲᴦͼⱱꜝᴟͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼӿᴒ᷅Ⱳ᷅ԓͼ
ᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼԜԝᴑꜝꜛ꞉ꜜԜꞌͼᴠᴦꜛꜞᴡꜝꜛᴠͼԜᴟᴒԜᴡᴡᴟ꞉ԝᴢᴡԜԝꞌᴒͼᴡꜝͼԜͼᴣ꞉ᴟԜꞌͼⱲԜᴠᴡᴟꜝᴒꜜᴡᴒᴟ꞉ᴡ꞉ᴠͼꜝᴢᴡԝᴟᴒԜꞋͼ꞉ꜜͼᴡⱳᴒͼ
ⱳꜝᴢᴠᴒⱳꜝꞌᴑԐ᷅ͼ
ᴁꜝͼԝᴒͼᴐꜝᴢꜜᴡᴒᴑͼԜᴠͼԜͼᴢꜜ꞉ꜟᴢᴒͼԜᴡᴡԜᴐꞋͼᴑ꞉ᴠᴡ꞉ꜜᴐᴡͼⱱᴟꜝꜛͼᴡⱳᴒͼꜞᴟᴒᴣ꞉ꜝᴢᴠͼԜᴡᴡԜᴐꞋԓͼᴡⱳᴒͼꜜᴒᴤͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜛᴢᴠᴡͼ
ꜝᴐᴐᴢᴟͼԜᴡͼꞌᴒԜᴠᴡͼ᷉᷾ͼⱳꜝᴢᴟᴠͼԜⱱᴡᴒᴟͼᴟᴒᴠꜝꞌᴢᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼꜞᴟ꞉ꜝᴟͼԜᴡᴡԜᴐꞋᶳᴠͼᴠᴦꜛꜞᴡꜝꜛᴠ᷅
Interim Analysis and Data Safety Monitoring Board:
꜠ꜝͼ꞉ꜜᴡᴒᴟ꞉ꜛͼԜꜜԜꞌᴦᴠ꞉ᴠͼ꞉ᴠͼꜞꞌԜꜜꜜᴒᴑͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅ͼⱫᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼꜞԜᴡ꞉ᴒꜜᴡͼᴠԜⱱᴒᴡᴦͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼꜝꜜͼԜͼᴐꜝꜜᴡ꞉ꜜᴢꜝᴢᴠͼԝԜᴠ꞉ᴠͼԝᴦͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼᴢꜜᴡ꞉ꞌͼᴡⱳᴒͼꞌԜᴠᴡͼꜞԜᴡ꞉ᴒꜜᴡͼᴐꜝꜛꜞꞌᴒᴡᴒᴠͼⱳ꞉ᴠͼ
ꜝᴟͼⱳᴒᴟͼꞌԜᴠᴡͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴠᴡᴢᴑᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱨꜜͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼⱫԜᴡԜͼᴀԜⱱᴒᴡᴦͼꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼⱩꜝԜᴟᴑͼӿⱫᴀꜚⱩԐͼᴤ꞉ꞌꞌͼԜꞌᴠꜝͼԝᴒͼᴒᴠᴡԜԝꞌ꞉ᴠⱳᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼ
ԜꜜͼꜝꜜⱲꜝ꞉ꜜⱲԓͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼᴟᴒᴣ꞉ᴒᴤͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼᴑԜᴡԜԓͼԜꜜᴑͼᴡꜝͼᴠԜⱱᴒⱲᴢԜᴟᴑͼᴡⱳᴒͼ
꞉ꜜᴡᴒᴟᴒᴠᴡᴠͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜝⱱͼᴡⱳᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼꜞԜᴡ꞉ᴒꜜᴡᴠͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼᴁⱳᴒͼꜝꜜⱲꜝ꞉ꜜⱲͼᴟᴒᴣ꞉ᴒᴤͼꜝⱱͼᴀⱨⱬᴠͼ
Ԝꜜᴑͼꜝᴡⱳᴒᴟͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝ꞉ꞌ꞉ᴡ꞉ᴒᴠͼꜝⱱͼᴡⱳᴒͼⱫᴀꜚⱩͼԜᴟᴒͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼᴡⱳᴒͼⱫᴀꜚⱩͼⱪⱳԜᴟᴡᴒᴟ᷅
Individual Stopping Rules:
Ⱬꜝᴠ꞉ꜜⱲͼⱱꜝᴟͼԜꜜᴦͼ꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼ꞉ⱱͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴠͼԜͼ
Ⱬᴅ᷄᷉Ⱡ᷊᷇᷄ᴟᴒꞌԜᴡᴒᴑͼᴀⱨⱬͼӿꜝᴟͼԜͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄ᴟᴒꞌԜᴡᴒᴑԓͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡꜜꜝꜜ᷄ᴠᴒᴟ꞉ꜝᴢᴠͼⱨⱬԐͼᴡⱳԜᴡԓͼ꞉ꜜͼ
ᴡⱳᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤԜᴟᴟԜꜜᴡᴠͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼⱱᴢᴟᴡⱳᴒᴟͼᴑꜝᴠ꞉ꜜⱲͼⱱꜝᴟͼᴡⱳԜᴡͼ
ᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼᴤᴒꞌꞌ᷄ԝᴒ꞉ꜜⱲ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼⱳԜᴠͼᴡⱳᴒͼԜԝ꞉ꞌ꞉ᴡᴦͼᴡꜝͼᴐꜝꜜᴡԜᴐᴡͼԜꜜᴑͼᴐꜝꜜᴠᴢꞌᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼ
ꜚꜝꜜ꞉ᴡꜝᴟͼꜝꜜͼᴠᴢᴐⱳͼꜛԜᴡᴡᴒᴟᴠ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴡꜝͼԝᴒͼⱱꜝꞌꞌꜝᴤᴒᴑͼᴡⱳᴟꜝᴢⱲⱳͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝⱱͼԜꞌꞌͼ
ᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴣ꞉ᴠ꞉ᴡᴠԓͼᴢꜜꞌᴒᴠᴠͼᴡⱳᴒᴦͼᴟᴒꜟᴢᴒᴠᴡͼᴡꜝͼԝᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼ
ᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼⱱᴟꜝꜛͼⱱᴢᴟᴡⱳᴒᴟͼᴑꜝᴠ꞉ꜜⱲͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼᴡꜝͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼ꜡ꜙⱬ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Criteria for Evaluation:
͟ᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԝԜᴠᴒᴑͼꜝꜜͼԜꜜͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼ
ᴠꜞԜꜜꜜ꞉ꜜⱲͼⱫԜᴦͼ᷇ͼӿԜⱱᴡᴒᴟͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜԐͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉ԓ ᴢꜜꞌᴒᴠᴠͼꜝᴡⱳᴒᴟᴤ꞉ᴠᴒͼ
ᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑ᷅
Primary Efficacy Endpoint

꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼ
ӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ
Secondary Efficacy Endpoints (rank ordered)
᷈᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴟᴒꜟᴢ꞉ᴟ꞉ꜜⱲͼԜᴐᴢᴡᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ
᷉᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼꜛꜝᴑᴒᴟԜᴡᴒͼꜝᴟͼᴠᴒᴣᴒᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ
᷊᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼꜝᴐᴐᴢᴟᴟ꞉ꜜⱲͼꜝꜜͼⱫԜᴦͼ᷈᷾ͼԜⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼ
ꜝⱱͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉ͼӿⱫԜᴦͼ᷈᷾ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ
Exploratory Efficacy Endpoints

ᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ԓͼ꞉᷅ᴒ᷅ԓͼᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡᴡԜᴐꞋ᷄ⱱᴟᴒᴒͼԜⱱᴡᴒᴟͼⱫԜᴦͼ
᷈᷾ͼ

꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑⱢͼԜͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ᴠͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼԜꜜᴦͼԜᴡᴡԜᴐꞋͼᴡⱳԜᴡͼⱳԜᴠͼԜᴡͼꞌᴒԜᴠᴡͼ
ꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐⱳԜᴟԜᴐᴡᴒᴟ꞉ᴠᴡ꞉ᴐᴠⱡͼᴠᴒᴣᴒᴟᴒԓͼᴟᴒᴠᴢꞌᴡᴠͼ꞉ꜜͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼӿᴒᴥᴐᴒꜞᴡͼ
ⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼⱱꜝᴟͼꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜͼⱣͼ᷉᷾ͼⱳꜝᴢᴟᴠԐԓͼⱳᴒꜛꜝᴑᴦꜜԜꜛ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼӿᴠᴦᴠᴡꜝꞌ꞉ᴐͼԝꞌꜝꜝᴑͼ
ꜞᴟᴒᴠᴠᴢᴟᴒͼⱣͼⱠ᷇ԓͼᴟᴒꜟᴢ꞉ᴟᴒᴠͼⱷᴃͼⱳᴦᴑᴟԜᴡ꞉ꜝꜜԓͼꜝᴟͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼᴠᴦꜜᴐꜝꜞᴒͼꜝᴟͼꜜᴒԜᴟ᷄ᴠᴦꜜᴐꜝꜞᴒԐͼꜝᴟͼ
ꞌԜᴟᴦꜜⱲᴒԜꞌ᷅
Safety Measures:

ⱨᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼӿⱨⱬᴠԐͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴠᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼӿᴀⱨⱬᴠԐͼԜꜜᴑͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼꜝⱱͼ
ᴠꜞᴒᴐ꞉Ԝꞌͼ꞉ꜜᴡᴒᴟᴒᴠᴡͼӿⱨⱬᴀⱷԐ

ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼӿⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠԐ

ᴃ꞉ᴡԜꞌᴠͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꞌꜝꜝᴑͼꜞᴟᴒᴠᴠᴢᴟᴒԓͼⱳᴒԜᴟᴡͼᴟԜᴡᴒԓͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒͼԜꜜᴑͼᴟᴒᴠꜞ꞉ᴟԜᴡꜝᴟᴦͼᴟԜᴡᴒ

͟ⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜ

᷈᷉᷄ꞌᴒԜᴑͼᴒꞌᴒᴐᴡᴟꜝᴐԜᴟᴑ꞉ꜝⱲᴟԜꜛͼӿⱬⱪⱵԐ
Additional Measures:

͟ⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼӿ͟ⱫԐͼᴒⱱⱱᴒᴐᴡᴠ

ⱨꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴑᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡ

͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐᴠͼӿ͟ꜘԐͼ

ⱶᴒԜꞌᴡⱳ᷄ᴟᴒꞌԜᴡᴒᴑͼꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ
Analysis Populations:
Intent-to-treat (ITT) Population: ᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼԜꞌꞌͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼᴑꜝᴠᴒͼꜝⱱͼԜᴐᴡ꞉ᴣᴒͼⱷꜚ͟ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝ᷅ͼᴁⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜꜜԜꞌᴦᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐԜᴟᴟ꞉ᴒᴑͼꜝᴢᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼⱷᴁᴁͼ͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ᷅
Safety Population: ᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼԜꞌꞌͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼᴑꜝᴠᴒͼꜝⱱͼԜᴐᴡ꞉ᴣᴒͼ
ⱷꜚ͟ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝ᷅ⱨꞌꞌᴠԜⱱᴒᴡᴦԜꜜԜꞌᴦᴠᴒᴠᴤ꞉ꞌꞌᴢᴠᴒᴡⱳᴒᴀԜⱱᴒᴡᴦ͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ᷅
Sample Size Determination:
͟ꜝᴤᴒᴟͼԜꜜԜꞌᴦᴠ꞉ᴠͼԜꜜᴑͼᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒͼᴒᴠᴡ꞉ꜛԜᴡ꞉ꜝꜜͼᴤԜᴠͼԝԜᴠᴒᴑͼꜝꜜͼ᷈᷇᷇᷇ͼᴐꜝꜛꜞᴢᴡᴒᴟͼᴠ꞉ꜛᴢꞌԜᴡ꞉ꜝꜜᴠͼᴢᴠ꞉ꜜⱲͼԜͼ
ⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼⱱꜝᴟᴐꜝᴢꜜᴡͼᴑԜᴡԜͼԜᴠᴠᴢꜛ꞉ꜜⱲͼԜͼ͟ꜝ꞉ᴠᴠꜝꜜͼᴑ꞉ᴠᴡᴟ꞉ԝᴢᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼ͟ᴒԜᴟᴠꜝꜜͼᴐⱳ꞉᷄
ᴠꜟᴢԜᴟᴒͼᴠᴐԜꞌ꞉ꜜⱲͼꜝⱱͼᴠᴡԜꜜᴑԜᴟᴑͼᴒᴟᴟꜝᴟᴠͼᴡꜝͼԜᴐᴐꜝᴢꜜᴡͼⱱꜝᴟͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼꜝᴣᴒᴟᴑ꞉ᴠꜞᴒᴟᴠ꞉ꜝꜜ᷅ͼᴁⱳᴒͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
ᴑꜝᴠᴒͼ꞉ꜜͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼᴟԜᴡ꞉ꜝͼᴤԜᴠͼᴠᴒᴡͼԜᴡͼ᷈ⱡ᷿᷈᷅᷅ͼⱨͼ᷈᷇Ӽͼꜛ꞉ᴠᴠ꞉ꜜⱲͼ
ᴑԜᴡԜ᷆ᴑᴟꜝꜞꜝᴢᴡͼᴟԜᴡᴒͼⱱꜝᴟͼԝꜝᴡⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜꜜᴑͼꜞꞌԜᴐᴒԝꜝͼᴤԜᴠͼԜꞌᴠꜝͼԝᴢ꞉ꞌᴡͼ꞉ꜜᴡꜝͼᴡⱳᴒͼᴒꜛꜞ꞉ᴟ꞉ᴐԜꞌͼ
ᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒͼᴠ꞉ꜛᴢꞌԜᴡ꞉ꜝꜜᴠ᷅
ⱴꜝᴟͼԜͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴒⱱⱱᴒᴐᴡͼꜝⱱͼ⅍᷇Ӽͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ꜜͼԜᴡᴡԜᴐꞋᴠͼԜᴠͼᴐꜝꜛꜞԜᴟᴒᴑͼᴡꜝͼꜞꞌԜᴐᴒԝꜝԓͼԜᴠᴠᴢꜛ꞉ꜜⱲͼԜͼ
ꜞꞌԜᴐᴒԝꜝͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝⱱͼ᷊᷇᷅ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴤᴒᴒꞋͼꜝᴣᴒᴟͼԜͼ᷉⅍ͼᴤᴒᴒꞋͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜͼԜᴣᴒᴟԜⱲᴒͼᴡꜝᴡԜꞌͼꜝⱱͼⅎ᷅˲ͼ
ԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑԓͼԜͼᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒͼꜝⱱͼ᷉᷾ͼԜᴐᴡ꞉ᴣᴒꞌᴦͼᴡᴟᴒԜᴡᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼ
ꜞᴟ꞉ꜛԜᴟᴦͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛͼԜꜜᴑͼ᷊⅍ͼꜞꞌԜᴐᴒԝꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤꜝᴢꞌᴑͼꜞᴟꜝᴣ꞉ᴑᴒͼԜᴡͼꞌᴒԜᴠᴡͼⱠ᷿ӼͼꜞꜝᴤᴒᴟͼӿԜᴡͼ
ԜꞌꜞⱳԜⱤ᷿᷇᷅᷇᷉ԓͼꜝꜜᴒ᷄ᴠ꞉ᴑᴒᴑԐ᷅ͼⱨͼ⅍᷇Ӽͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ᴠͼᴤᴒꞌꞌͼԝᴒꞌꜝᴤͼᴡⱳᴒͼᴠꜛԜꞌꞌᴒᴠᴡͼᴒᴥꜞᴒᴐᴡᴒᴑͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ꜜͼ
ԜᴡᴡԜᴐꞋᴠԓͼⱱꜝᴟͼ꞉ꜜͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉ͼᴠᴡᴢᴑᴦԓͼᴤᴒͼꜝԝᴠᴒᴟᴣᴒᴑͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼԜᴡᴡԜᴐꞋᴠͼꜝⱱͼꜜᴒԜᴟͼ᷈᷇᷇Ӽ᷅ͼᴁⱳᴒᴠᴒͼ
ᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒᴠͼᴤ꞉ꞌꞌͼԜꞌᴠꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼԜᴑᴒꜟᴢԜᴡᴒꞌᴦͼᴠ꞉ᴧᴒᴑͼᴠԜⱱᴒᴡᴦͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜͼⱱꜝᴟͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜ᷅ͼᴂꜞͼᴡꜝͼ᷈᷉᷇ͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼӿԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ˲᷇ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴡⱳᴒͼ᷊ͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼԜꜜᴑͼ᷾᷇ͼ꞉ꜜͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼ
ⱲᴟꜝᴢꜞԐͼꜛԜᴦͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼᴡꜝͼԜᴐᴐꜝᴢꜜᴡͼⱱꜝᴟͼꜞꜝᴡᴒꜜᴡ꞉ԜꞌͼᴒԜᴟꞌᴦͼᴑᴟꜝꜞꜝᴢᴡᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼ
Statistical Methods: 
ᴁⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜԜꞌᴦᴠ꞉ᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴡꜝͼᴐꜝꜛꜞԜᴟᴒͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡԓͼᴤⱳ꞉ᴐⱳͼ꞉ᴠͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼꜝԝᴠᴒᴟᴣᴒᴑͼ꞉ꜜͼᴒԜᴐⱳͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛͼᴡꜝͼᴡⱳԜᴡͼ꞉ꜜͼᴡⱳᴒͼ
ꜞꞌԜᴐᴒԝꜝͼԜᴟꜛͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ᷅ͼⱴꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼ
ᴒꜜᴑꜞꜝ꞉ꜜᴡԓͼԜꜜͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼԜꞌꞌͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼⱳԜᴣᴒͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ᴑꜝᴠᴒͼꜝⱱͼⱷꜚ͟ͼꜝᴟͼ
ꜞꞌԜᴐᴒԝꜝͼӿⱷᴁᴁͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜԐͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑ᷅ͼ
ᴁⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡԓͼꜜᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑԓͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜛꜞԜᴟᴒᴑͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼӿⱫᴅ᷄᷉Ⱡ᷊᷇ԐͼᴡꜝͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼᴢᴠ꞉ꜜⱲͼԜͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼⱱꜝᴟͼᴐꜝᴢꜜᴡͼ
ᴑԜᴡԜͼԜᴠᴠᴢꜛ꞉ꜜⱲͼԜͼ͟ꜝ꞉ᴠᴠꜝꜜͼᴑ꞉ᴠᴡᴟ꞉ԝᴢᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼԜͼꞌꜝⱲͼꞌ꞉ꜜꞋͼⱱᴢꜜᴐᴡ꞉ꜝꜜͼԜꜜᴑͼ͟ᴒԜᴟᴠꜝꜜͼᴐⱳ꞉᷄ᴠꜟᴢԜᴟᴒͼᴠᴐԜꞌ꞉ꜜⱲͼ
ꜝⱱͼᴠᴡԜꜜᴑԜᴟᴑͼᴒᴟᴟꜝᴟᴠͼᴡꜝͼԜᴐᴐꜝᴢꜜᴡͼⱱꜝᴟͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼꜝᴣᴒᴟᴑ꞉ᴠꜞᴒᴟᴠ꞉ꜝꜜ᷅ͼᴁⱳᴒͼꜛꜝᴑᴒꞌͼᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼⱱ꞉ᴥᴒᴑͼ
ᴒⱱⱱᴒᴐᴡᴠͼⱱꜝᴟͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼӿᴐԜᴡᴒⱲꜝᴟ꞉ᴐԜꞌԐͼԜꜜᴑͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌ꞉ᴧᴒᴑͼԝԜᴠᴒꞌ꞉ꜜᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼӿᴐꜝꜜᴡ꞉ꜜᴢꜝᴢᴠԐԓͼ
ԜꜜᴑͼᴡⱳᴒͼꞌꜝⱲԜᴟ꞉ᴡⱳꜛͼꜝⱱͼᴡ꞉ꜛᴒͼ꞉ꜜͼᴑԜᴦᴠͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤԜᴠͼꜝԝᴠᴒᴟᴣᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼ
ꜞᴒᴟ꞉ꜝᴑͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼԜᴠͼԜꜜͼꜝⱱⱱᴠᴒᴡͼᴣԜᴟ꞉Ԝԝꞌᴒͼ꞉ꜜͼᴡⱳᴒͼꜛꜝᴑᴒꞌ᷅ͼ
ⱴᴟꜝꜛͼᴡⱳ꞉ᴠͼꜛꜝᴑᴒꞌԓͼᴡⱳᴒͼꞌᴒԜᴠᴡͼᴠꜟᴢԜᴟᴒᴠͼꜛᴒԜꜜͼᴟԜᴡᴒͼԜꜜᴑͼᴠᴡԜꜜᴑԜᴟᴑͼᴒᴟᴟꜝᴟͼⱱꜝᴟͼᴒԜᴐⱳͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼԜᴠͼ
ᴤᴒꞌꞌͼԜᴠͼᴡⱳᴒͼꜛᴒԜꜜͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝᴠͼᴟᴒꞌԜᴡ꞉ᴣᴒͼᴡꜝͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼԜꜜᴑͼᴐꜝᴟᴟᴒᴠꜞꜝꜜᴑ꞉ꜜⱲͼⱠ᷿Ӽͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼ
꞉ꜜᴡᴒᴟᴣԜꞌᴠͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴤ꞉ꞌꞌͼԝᴒᴒᴠᴡ꞉ꜛԜᴡᴒᴑ᷅ͼᴁⱳᴒᴠᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼ
ԜᴠͼꜛᴒԜꜜͼᴒᴣᴒꜜᴡͼᴟԜᴡᴒᴠͼꜞᴒᴟͼᴢꜜ꞉ᴡͼꜝⱱͼᴡ꞉ꜛᴒͼӿᴤᴒᴒꞋͼԜꜜᴑͼꜛꜝꜜᴡⱳꞌᴦԐͼԝᴦͼᴡᴟԜꜜᴠⱱꜝᴟꜛ꞉ꜜⱲͼᴡⱳᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴠͼᴢᴠ꞉ꜜⱲͼ
ᴡⱳᴒͼᴒᴥꜞꜝꜜᴒꜜᴡ꞉Ԝꞌͼⱱᴢꜜᴐᴡ꞉ꜝꜜͼԜꜜᴑͼᴠᴐԜꞌ꞉ꜜⱲͼԝᴦͼᴡⱳᴒͼᴢꜜ꞉ᴡͼꜝⱱͼᴡ꞉ꜛᴒ᷅ͼ
ᴁⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴡᴒᴠᴡᴒᴑͼԝᴦͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠⱡ
ⱶ᷇ⱡͼȜⱫᴅ᷄᷉Ⱡ᷊᷇᷆ͼȜꜞꞌԜᴐᴒԝꜝⱤͼ᷈ͼᴣᴒᴟᴠᴢᴠͼⱶ᷈ⱡͼȜⱫᴅ᷄᷉Ⱡ᷊᷇᷆ͼȜꜞꞌԜᴐᴒԝꜝᶌͼ᷈
ᴄⱳᴒᴟᴒͼȜⱫᴅ᷄᷉Ⱡ᷊᷇ᴟᴒⱱᴒᴟᴠͼᴡꜝͼᴡⱳᴒͼꜛᴒԜꜜͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈ⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱲᴟꜝᴢꜞͼԜꜜᴑͼȜꜞꞌԜᴐᴒԝꜝͼᴟᴒⱱᴒᴟᴠͼᴡꜝͼᴡⱳᴒͼꜛᴒԜꜜͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼ
Ⱳᴟꜝᴢꜞ᷅ͼᴁⱳᴒͼꜜᴢꞌꞌͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼ꞉ᴠͼᴡⱳԜᴡͼᴡⱳᴒͼꜛᴒԜꜜͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝͼ꞉ᴠͼ᷈ͼ
ӿꜜꜝͼᴑ꞉ⱱⱱᴒᴟᴒꜜᴐᴒͼԝᴒᴡᴤᴒᴒꜜͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠԐԓͼᴣᴒᴟᴠᴢᴠͼᴡⱳᴒͼԜꞌᴡᴒᴟꜜԜᴡ꞉ᴣᴒͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡⱳԜᴡͼᴡⱳᴒͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝͼ꞉ᴠͼꜜꜝᴡͼ᷈᷅ͼⱬᴠᴡ꞉ꜛԜᴡᴒᴑͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝᴠͼꞌᴒᴠᴠͼᴡⱳԜꜜͼꜝꜜᴒͼᴤꜝᴢꞌᴑͼ꞉ꜜᴑ꞉ᴐԜᴡᴒͼᴡⱳԜᴡͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡᴟᴒԜᴡᴒᴑͼᴤ꞉ᴡⱳͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼꜝꜜͼԜᴣᴒᴟԜⱲᴒԓͼⱳԜᴣᴒͼԜͼꞌꜝᴤᴒᴟͼ꞉ꜜᴐ꞉ᴑᴒꜜᴐᴒͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴁⱳᴒͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴡᴒᴠᴡᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼ
ꜛꜝᴑᴒꞌ᷄ԝԜᴠᴒᴑͼꞌᴒԜᴠᴡͼᴠꜟᴢԜᴟᴒᴠͼꜛᴒԜꜜᴠͼᴒᴠᴡ꞉ꜛԜᴡᴒͼꜝⱱͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴑ꞉ⱱⱱᴒᴟᴒꜜᴐᴒͼᴢᴠ꞉ꜜⱲͼԜͼᴄԜꞌᴑ᷄ԝԜᴠᴒᴑͼ
ᴐⱳ꞉᷄ᴠꜟᴢԜᴟᴒͼᴡᴒᴠᴡ᷅
ᴁⱳᴒͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼᴐⱳԜꜜⱲᴒͼ꞉ꜜͼꜛᴒԜꜜͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝⱱͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼⱱᴟꜝꜛͼᴡⱳᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝⱱͼꜞꞌԜᴐᴒԝꜝͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜꞌᴐᴢꞌԜᴡᴒᴑͼԜᴠͼ᷈᷇᷇ӼͼԑͼӿꜛᴒԜꜜͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝͼ
ᶮ᷈Ԑ᷅ͼᴀ꞉ꜛ꞉ꞌԜᴟꞌᴦԓͼᴡⱳᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴑͼᴢꜞꜞᴒᴟͼԜꜜᴑͼꞌꜝᴤᴒᴟͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼꞌ꞉ꜛ꞉ᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼꜛᴒԜꜜͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝͼᴐԜꜜͼԝᴒͼ
ᴡᴟԜꜜᴠⱱꜝᴟꜛᴒᴑͼԝᴦͼᴠᴢԝᴡᴟԜᴐᴡ꞉ꜜⱲͼ᷈ͼԜꜜᴑͼꜛᴢꞌᴡ꞉ꜞꞌᴦ꞉ꜜⱲͼԝᴦͼ᷈᷇᷇ӼͼᴡꜝͼᴐԜꞌᴐᴢꞌԜᴡᴒͼⱠ᷿Ӽͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼ꞉ꜜᴡᴒᴟᴣԜꞌᴠͼ
ⱱꜝᴟͼᴡⱳᴒͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼᴐⱳԜꜜⱲᴒ᷅ͼᴁⱳᴒͼꜛᴒԜꜜͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝᴠͼԜꜜᴑͼᴐꜝᴟᴟᴒᴠꜞꜝꜜᴑ꞉ꜜⱲͼⱠ᷿Ӽͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼ꞉ꜜᴡᴒᴟᴣԜꞌᴠͼ
ᴤ꞉ꞌꞌͼԝᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼԜᴠͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼꜞᴟᴒᴣ꞉ꜝᴢᴠꞌᴦ᷅ͼ
ⱷꜜͼꜝᴟᴑᴒᴟͼᴡꜝͼꜛԜ꞉ꜜᴡԜ꞉ꜜͼᴡⱳᴒͼꜝᴣᴒᴟԜꞌꞌͼᴁᴦꜞᴒͼⱷͼᴒᴟᴟꜝᴟͼԜᴡͼ᷿᷇᷅᷇ԓͼԜͼᴐꜝꜜᴠᴒᴟᴣԜᴡ꞉ᴣᴒͼⱩꜝꜜⱱᴒᴟᴟꜝꜜ꞉᷄ԝԜᴠᴒᴑͼ
ꜞᴟꜝᴐᴒᴑᴢᴟᴒͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜᴠͼꜝⱱͼᴒԜᴐⱳͼꜝⱱͼᴡⱳᴒͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼᴤ꞉ᴡⱳͼᴡⱳᴒͼ
ꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞᴤ꞉ᴡⱳͼᴒꜟᴢԜꞌͼᴤᴒ꞉ⱲⱳᴡᴠͼⱱꜝᴟͼᴒԜᴐⱳͼᴡᴒᴠᴡͼᴠᴒᴡͼԜᴡͼ᷈᷅⅍ⅎӼͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌͼӿĮ᷊᷆Ԑ᷅
ᴁⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜꜜԜꞌᴦᴧᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼᴠԜꜛᴒͼꜛᴒᴡⱳꜝᴑͼԜᴠͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ
ⱱꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅ͼᴁꜝͼԜᴑ꞊ᴢᴠᴡͼⱱꜝᴟͼᴡⱳᴒꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼꜝⱱͼ꞉ꜜⱱꞌԜᴡᴒᴑͼꜝᴣᴒᴟԜꞌꞌͼᴁᴦꜞᴒͼⱷͼᴒᴟᴟꜝᴟͼ
ᴟԜᴡᴒԓͼᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴡᴒᴠᴡᴒᴑͼ꞉ꜜͼԜͼⱱ꞉ᴥᴒᴑͼᴠᴒꜟᴢᴒꜜᴐᴒͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼᴢᴠ꞉ꜜⱲͼԜͼⱲᴒꜜᴒᴟԜꞌͼⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼԜꜞꜞᴟꜝԜᴐⱳͼ
ᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꞌꜝⱲ꞉ᴐԜꞌͼᴟᴒᴠᴡᴟ꞉ᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅ᴀᴒᴐꜝꜜᴑԜᴟᴦͼ
ᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼᴑᴒᴐꞌԜᴟᴒᴑͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼᴢꜜꞌᴒᴠᴠͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼⱱꜝᴟͼᴡⱳԜᴡͼ
Ԝᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼ꞉ᴠͼⱱꜝᴢꜜᴑͼᴡꜝͼԝᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡ᷅
Safety Analysis:
ᴁᴟᴒԜᴡꜛᴒꜜᴡ᷄ᴒꜛᴒᴟⱲᴒꜜᴡͼⱨⱬᴠͼԜᴟᴒͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼⱨⱬᴠͼᴤ꞉ᴡⱳͼꜝꜜᴠᴒᴡͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼꜝᴟͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡԜᴟᴡͼ
ꜝⱱͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴤ꞉ᴡⱳͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜԓͼꜝᴟͼꜛᴒᴑ꞉ᴐԜꞌͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠͼꜞᴟᴒᴠᴒꜜᴡͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼԝᴢᴡͼ꞉ꜜᴐᴟᴒԜᴠ꞉ꜜⱲͼ꞉ꜜͼᴠᴒᴣᴒᴟ꞉ᴡᴦͼꜝᴟͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼꜝᴟͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡ᷅ͼᴁⱳᴒͼꜜᴢꜛԝᴒᴟͼԜꜜᴑͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼᴁⱬⱨⱬᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑ꞉ᴠꜞꞌԜᴦᴒᴑͼⱱꜝᴟͼᴒԜᴐⱳͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼԝᴦͼԝꜝᴑᴦͼᴠᴦᴠᴡᴒꜛͼԜꜜᴑͼꜞᴟᴒⱱᴒᴟᴟᴒᴑͼᴡᴒᴟꜛͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼⱫ꞉ᴐᴡ꞉ꜝꜜԜᴟᴦͼⱱꜝᴟͼ
ϸᴒⱲᴢꞌԜᴡꜝᴟᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼӿꜚᴒᴑⱫϸⱨᶇԐ᷅ͼᴀᴢꜛꜛԜᴟ꞉ᴒᴠͼ꞉ꜜͼᴡᴒᴟꜛᴠͼꜝⱱͼᴠᴒᴣᴒᴟ꞉ᴡᴦͼԜꜜᴑͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴡꜝͼᴠᴡᴢᴑᴦͼ
ꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԜꞌᴠꜝͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑ᷅ͼᴀᴒᴟ꞉ꜝᴢᴠͼⱨⱬᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼᴠᴒꜞԜᴟԜᴡᴒꞌᴦͼ꞉ꜜͼԜͼᴠ꞉ꜛ꞉ꞌԜᴟͼ
ⱱԜᴠⱳ꞉ꜝꜜ᷅ͼ͟Ԝᴡ꞉ᴒꜜᴡͼꞌ꞉ᴠᴡ꞉ꜜⱲᴠͼꜝⱱͼⱨⱬᴠͼᴐԜᴢᴠ꞉ꜜⱲͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜԓͼⱨⱬᴠͼꞌᴒԜᴑ꞉ꜜⱲͼᴡꜝͼ
ᴑᴒԜᴡⱳԓͼᴀⱨⱬᴠͼԜꜜᴑͼⱨⱬᴀⱷͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴑᴢᴐᴒᴑ᷅ͼ
ⱨⱬᴀⱷͼᴤ꞉ꞌꞌͼԝᴒͼԜꜜԜꞌᴦᴧᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼꜞᴟ꞉ꜛԜᴟᴦͼᴀᴦᴠᴡᴒꜛͼ꜡ᴟⱲԜꜜͼⱪꞌԜᴠᴠᴒᴠͼӿᴀ꜡ⱪᴠԐͼԜꜜᴑͼ͟ᴟᴒⱱᴒᴟᴟᴒᴑͼ
ᴁᴒᴟꜛᴠͼӿ͟ᴁᴠԐͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴒԜᴟᴐⱳꜝⱱᴟᴒꞌᴒᴣԜꜜᴡᴀᴡԜꜜᴑԜᴟᴑ꞉ᴧᴒᴑͼꜚᴒᴑⱫϸⱨϷᴢᴒᴟ꞉ᴒᴠӿᴀꜚϷᴠԐ᷅ͼ
ᴀᴢꜛꜛԜᴟᴦͼᴡԜԝꞌᴒᴠͼᴤ꞉ᴡⱳͼᴀ꜡ⱪᴠͼԜꜜᴑ͟ᴁᴠԓͼⱱᴟꜝꜛͼᴡⱳᴒͼᴀꜚϷ ᴠᴒԜᴟᴐⱳᴒᴠԓ ᴤ꞉ꞌꞌͼԝᴒͼⱲᴒꜜᴒᴟԜᴡᴒᴑͼ
ꜞᴟᴒᴠᴒꜜᴡ꞉ꜜⱲᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼԜꜜᴑͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԝᴦͼⱨⱬԓͼᴠᴒᴣᴒᴟ꞉ᴡᴦԓͼᴠᴒᴟ꞉ꜝᴢᴠꜜᴒᴠᴠԓͼԜꜜᴑͼ
ᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴡꜝͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜ᷅
ᴂᴠԜⱲᴒͼꜝⱱͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼӿꜝᴡⱳᴒᴟͼᴡⱳԜꜜͼᴟᴒᴠᴐᴢᴒͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠԐͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼ
ᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ᴣᴒꞌᴦͼⱱꜝᴟͼᴒԜᴐⱳͼꜝⱱͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼԜꜜᴑͼᴡⱳᴒͼᴐꜝꜛԝ꞉ꜜᴒᴑͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞ᷅
ⱨᴐᴡᴢԜꞌͼᴣԜꞌᴢᴒᴠͼԜꜜᴑͼᴐⱳԜꜜⱲᴒͼⱱᴟꜝꜛͼԝԜᴠᴒꞌ꞉ꜜᴒͼ꞉ꜜͼᴣ꞉ᴡԜꞌͼᴠ꞉ⱲꜜᴠͼԜꜜᴑͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼⱱꜝᴟͼᴒԜᴐⱳͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴤ꞉ᴡⱳͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ᴣᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐᴠͼԜᴡͼᴒԜᴐⱳͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝԝᴡԜ꞉ꜜᴒᴑ᷅ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱴꜝᴟͼԜꞌꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠԓͼԜͼᴠⱳ꞉ⱱᴡͼᴡԜԝꞌᴒͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴑᴢᴐᴒᴑͼᴠᴢꜛꜛԜᴟ꞉ᴧ꞉ꜜⱲͼᴐⱳԜꜜⱲᴒᴠͼⱱᴟꜝꜛͼꜜꜝᴟꜛԜꞌͼᴡꜝͼ
ԜԝꜜꜝᴟꜛԜꞌͼԜꜜᴑͼᴣ꞉ᴐᴒͼᴣᴒᴟᴠԜ᷅
ⱨԝꜜꜝᴟꜛԜꞌͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼᴤ꞉ꞌꞌͼԝᴒͼꞌ꞉ᴠᴡᴒᴑ᷅
ᴁⱳᴒͼꜜᴢꜛԝᴒᴟͼԜꜜᴑͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼꜜꜝᴟꜛԜꞌԓͼԜԝꜜꜝᴟꜛԜꞌ᷄ꜜꜝᴡͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡԓͼԜꜜᴑͼ
ԜԝꜜꜝᴟꜛԜꞌ᷄ᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼⱬⱪⱵͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑ꞉ᴠꜞꞌԜᴦᴒᴑͼⱱꜝᴟͼᴒԜᴐⱳͼꜝⱱͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
Ⱳᴟꜝᴢꜞᴠ᷅
ⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼԜꜜԜꞌᴦᴠᴒᴠͼꜝⱱͼⱨⱬᴠԓͼᴀⱨⱬᴠԓͼᴠᴒᴣᴒᴟᴒͼⱨⱬᴠԓͼⱨⱬᴀⱷԓͼԜꜜᴑͼԜԝꜜꜝᴟꜛԜꞌͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼᴤ꞉ꞌꞌͼԝᴒͼԝԜᴠᴒᴑͼ
ꜝꜜͼᴡⱳᴒͼᴡ꞉ꜛ꞉ꜜⱲͼӿᴀᴡᴢᴑᴦͼⱫԜᴦԐͼԜꜜᴑͼꜜᴢꜛԝᴒᴟͼꜝⱱͼꜞᴟ꞉ꜝᴟͼᴑꜝᴠᴒᴠͼꜝⱱͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜ᷅ͼᴁⱳᴒͼ꞉ꜜᴐ꞉ᴑᴒꜜᴐᴒͼꜝⱱͼ
ⱨⱬᴠͼԝᴦͼꜛꜝꜜᴡⱳͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴥԜꜛ꞉ꜜᴒᴑͼԜꜜᴑͼᴡⱳᴒͼ꞉ꜜᴐ꞉ᴑᴒꜜᴐᴒͼԜꜛꜝꜜⱲͼ
ᴡⱳᴒͼⱱꜝᴢᴟͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜛꜞԜᴟᴒᴑ᷅ͼᴁⱳᴒͼᴟԜᴡᴒͼꜝⱱͼᴠᴡᴢᴑᴦͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼԜꜛꜝꜜⱲͼᴡⱳᴒͼⱱꜝᴢᴟͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛᴠͼᴤ꞉ꞌꞌͼԜꞌᴠꜝͼԝᴒͼᴐꜝꜛꜞԜᴟᴒᴑ᷅
Date of Amendment 3.0: ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈Ⱡ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Table 1.
Study Activities Schedule
Study Activities Schedule
Screening 
Visit
Run-in 
Period 1
Treatment Period2
Follow-up 
Period3
Tests and 
Assessments
Visit 1
Dose 1
Day 0
Site 
Check-
in4
Visit 2 
Dose 2
Day 14
Visit 3 
Dose 3
Day 28
Visit 4 
Dose 4
Day 42
Visit 5 
Dose 5
Day 56
Visits 6 and 7 
Doses 6 and 7
Days 70 and 
84
Visit 8 
Dose 8
Day 98
Visits 9 and 10 
Doses 9 and 10
Days 112 and 
126
Visit 11 
Dose 11
Day 140
Day 
144±1
Visits 12 and 13 
Doses 12 and 13
Days 154 and 
168
Visit 
14
Day 
182
Visit 
15
Day 
210
Visit 
16
Day 
238
Informed Consent
ᴅ
Eligibility Review
ᴅ
ᴅ
Long-term 
Prophylactic 
Therapy 
Washout5
ᴅ
Randomization 
ᴅ
Blinded IMP 
Treatment
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
Demographic and 
Medical History
ᴅ
C1-INH, C1q and 
C4 Testing6
ᴅ
Pregnancy Test7 
(females)
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
Vital Signs8
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
Physical 
Examination9
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
12-Lead ECG10
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
Clinical 
Laboratory 
Testing11
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
Serologies: 
HBsAg, HCV, and 
HIV
ᴅ
Concomitant 
Therapy
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
Adverse Events
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴁԜԝꞌᴒͼ᷈᷅
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒ
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒ
ᴀᴐᴟᴒᴒꜜ꞉ꜜⱲͼ
ᴃ꞉ᴠ꞉ᴡ
ϸᴢꜜ᷄꞉ꜜͼ
͟ᴒᴟ꞉ꜝᴑͼ᷈
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑ᷉
ⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼ
͟ᴒᴟ꞉ꜝᴑ᷊
ᴁᴒᴠᴡᴠͼԜꜜᴑͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ
ᴃ꞉ᴠ꞉ᴡͼ᷈
Ⱬꜝᴠᴒͼ᷈
ⱫԜᴦͼ᷇
ᴀ꞉ᴡᴒͼ
ⱪⱳᴒᴐꞋ᷄
꞉ꜜ᷾
ᴃ꞉ᴠ꞉ᴡͼ᷉ͼ
Ⱬꜝᴠᴒͼ᷉
ⱫԜᴦͼ᷈᷾
ᴃ꞉ᴠ꞉ᴡͼ᷊ͼ
Ⱬꜝᴠᴒͼ᷊
ⱫԜᴦͼ᷉˲
ᴃ꞉ᴠ꞉ᴡͼ᷾ͼ
Ⱬꜝᴠᴒͼ᷾
ⱫԜᴦͼ᷾᷉
ᴃ꞉ᴠ꞉ᴡͼ᷿ͼ
Ⱬꜝᴠᴒͼ᷿
ⱫԜᴦͼ᷿⅍
ᴃ꞉ᴠ꞉ᴡᴠͼ⅍ͼԜꜜᴑͼⅎͼ
Ⱬꜝᴠᴒᴠͼ⅍ͼԜꜜᴑͼⅎ
ⱫԜᴦᴠͼⅎ᷇ͼԜꜜᴑͼ
˲᷾
ᴃ꞉ᴠ꞉ᴡͼ˲ͼ
Ⱬꜝᴠᴒͼ˲
ⱫԜᴦͼⱠ˲
ᴃ꞉ᴠ꞉ᴡᴠͼⱠͼԜꜜᴑͼ᷈᷇ͼ
ⱫꜝᴠᴒᴠͼⱠͼԜꜜᴑͼ᷈᷇
ⱫԜᴦᴠͼ᷈᷈᷉ͼԜꜜᴑͼ
᷈᷉⅍
ᴃ꞉ᴠ꞉ᴡͼ᷈᷈ͼ
Ⱬꜝᴠᴒͼ᷈᷈
ⱫԜᴦͼ᷈᷾᷇
ⱫԜᴦͼ
᷈᷾᷾ᶐ᷈
ᴃ꞉ᴠ꞉ᴡᴠͼ᷈᷉ͼԜꜜᴑͼ᷊᷈ͼ
Ⱬꜝᴠᴒᴠͼ᷈᷉ͼԜꜜᴑͼ᷊᷈
ⱫԜᴦᴠͼ᷿᷈᷾ͼԜꜜᴑͼ
᷈⅍˲
ᴃ꞉ᴠ꞉ᴡͼ
᷈᷾
ⱫԜᴦͼ
᷈˲᷉
ᴃ꞉ᴠ꞉ᴡͼ
᷿᷈
ⱫԜᴦͼ
᷉᷈᷇
ᴃ꞉ᴠ꞉ᴡͼ
᷈⅍
ⱫԜᴦͼ
᷊᷉˲
ⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼ
ⱫԜᴡԜ᷈᷉
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷊᷈
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
͟ꜘͼⱩꞌꜝꜝᴑͼ
ᴀԜꜛꜞꞌ꞉ꜜⱲ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
͟ⱫͼᴀԜꜛꜞꞌᴒͼ
ⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
͟ꞌԜᴠꜛԜͼⱨꜜᴡ꞉᷄ⱫᴟᴢⱲͼ
ⱨꜜᴡ꞉ԝꜝᴑᴦͼᴁᴒᴠᴡ꞉ꜜⱲ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
ᴅ
Ⱬ꞉ᴠᴐⱳԜᴟⱲᴒͼⱱᴟꜝꜛͼ
ᴀᴡᴢᴑᴦ᷈᷾ԓ᷿᷈
ᴅ
ᴅ
Ⱪ͟ͼⱤͼԝꞌꜝꜝᴑͼ͟ᴟᴒᴠᴠᴢᴟᴒⱢͼⱪ᷈᷄ⱷ꜠ⱶͼⱤͼⱪ᷈ͼⱷꜜⱳ꞉ԝ꞉ᴡꜝᴟⱢͼⱪꜛԜᴥⱤͼꜚԜᴥ꞉ꜛᴢꜛͼꜞꞌԜᴠꜛԜͼᴑᴟᴢⱲͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜⱢͼⱬⱪⱵͼⱤͼⱬꞌᴒᴐᴡᴟꜝᴐԜᴟᴑ꞉ꜝⱲᴟԜꜛⱢͼⱶⱨⱬͼⱤͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜⱢͼⱶԝᴠⱨⱲͼⱤͼ
ⱶᴒꜞԜᴡ꞉ᴡ꞉ᴠͼⱩͼᴀᴢᴟⱱԜᴐᴒͼⱨꜜᴡ꞉ⱲᴒꜜⱢͼⱶⱪᴃͼⱤͼⱶᴒꜞԜᴡ꞉ᴡ꞉ᴠͼⱪͼᴃ꞉ᴟᴢᴠⱢͼⱶⱷᴃͼⱤͼⱶᴢꜛԜꜜͼⱷꜛꜛᴢꜜꜝᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦͼᴣ꞉ᴟᴢᴠⱢͼⱶϸͼⱤͼⱶᴒԜᴟᴡͼϸԜᴡᴒⱢͼⱷꜚ͟ͼⱤͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜚᴒᴑ꞉ᴐ꞉ꜜԜꞌͼ͟ᴟꜝᴑᴢᴐᴡⱢͼ
ꜙᴁ͟ͼⱤͼꜙꜝꜜⱲ᷄ᴡᴒᴟꜛͼ͟ᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐⱢͼ꜡ꜙᴒͼⱤͼ꜡ꜞᴒꜜ᷄ꞌԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜⱢͼ͟ⱫͼⱤͼ͟ⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐⱢͼ͟ꜘͼⱤͼ͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐⱢͼϸϸͼⱤͼϸᴒᴠᴡ꞉ꜜⱲͼϸԜᴡᴒ
᷈᷅
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼԜͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴡꜝͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼᴡⱳᴒ꞉ᴟͼԝԜᴠᴒꞌ꞉ꜜᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒ᷅ͼ꜡ꜜꞌᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼԜͼԝԜᴠᴒꞌ꞉ꜜᴒͼᴟԜᴡᴒͼꜝⱱͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼ᷊ͼꜝᴟͼꜛꜝᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋᴠͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒͼ
ᴒꜜᴑͼꜝⱱͼᴡⱳᴒͼ᷾ͼᴤᴒᴒꞋᴠͼᴐԜꜜͼᴒᴥ꞉ᴡͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒԜᴟꞌᴦͼԜꜜᴑͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳꜝᴢᴡͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋͼ
Ԝⱱᴡᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼꜝⱱͼᴟᴢꜜ᷄꞉ꜜͼᴤ꞉ꞌꞌͼⱳԜᴣᴒͼᴡⱳᴒ꞉ᴟͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒᴥᴡᴒꜜᴑᴒᴑͼⱱꜝᴟͼԜꜜꜝᴡⱳᴒᴟͼ᷾ᴤᴒᴒꞋᴠԓͼᴑᴢᴟ꞉ꜜⱲͼᴤⱳ꞉ᴐⱳͼᴡ꞉ꜛᴒͼᴡⱳᴒᴦͼꜜᴒᴒᴑͼᴡꜝͼⱳԜᴣᴒͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼ
ԜᴡᴡԜᴐꞋᴠͼᴡꜝͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴁꜝͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼⱳԜᴣᴒͼᴡⱳᴒ꞉ᴟͼᴟᴢꜜ᷄꞉ꜜͼᴒᴥᴡᴒꜜᴑᴒᴑͼꜛᴢᴠᴡͼᴐꜝꜛꜞꞌᴒᴡᴒͼᴡⱳᴒͼⱱᴢꞌꞌͼ˲᷄ᴤᴒᴒꞋͼ
ᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼꜛᴒᴒᴡͼᴡⱳᴒͼꜛ꞉ꜜ꞉ꜛᴢꜛͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴑᴢᴟ꞉ꜜⱲͼᴟᴢꜜ᷄꞉ꜜͼꜝᴟͼԜᴟᴒͼꜝᴡⱳᴒᴟᴤ꞉ᴠᴒᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼᴡꜝͼԝᴒͼ
꞉ꜜᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼᴑᴢᴒͼᴡꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜͼᴠᴐᴟᴒᴒꜜͼⱱԜ꞉ꞌ᷅
᷉᷅
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑͼᴣ꞉ᴠ꞉ᴡᴠͼⱳԜᴣᴒͼԜͼᶐ᷊ͼᴑԜᴦͼᴤ꞉ꜜᴑꜝᴤԓͼᴤ꞉ᴡⱳͼԜͼꜛԜᴥ꞉ꜛᴢꜛͼꜝⱱͼ᷈ⅎͼᴑԜᴦᴠͼꜝᴟͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼꜝⱱͼ᷈᷈ͼᴑԜᴦᴠͼԝᴒᴡᴤᴒᴒꜜͼԜꜜᴦͼᴡᴤꜝͼᴑꜝᴠᴒᴠԓͼᴠᴡԜᴟᴡ꞉ꜜⱲͼᴤ꞉ᴡⱳͼⱫꜝᴠᴒͼ᷉ԓͼⱫԜᴦͼ᷈᷾ͼ
ᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉᷅
᷊᷅
ⱴꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼᴟꜝꞌꞌꜝᴣᴒᴟͼ꞉ꜜᴡꜝͼ꜡ꜙⱬͼӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾Ԑ᷅ͼⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴣ꞉ᴠ꞉ᴡᴠͼⱳԜᴣᴒͼԜͼᶐ᷊ͼᴑԜᴦͼᴤ꞉ꜜᴑꜝᴤ᷅
᷾᷅
ᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴡꜝͼᴠꜝꞌ꞉ᴐ꞉ᴡͼⱱꜝᴟͼԜꜜᴦͼԜᴡᴡԜᴐꞋᴠͼꜜꜝᴡͼԜꞌᴟᴒԜᴑᴦͼᴟᴒꜞꜝᴟᴡᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜝꜜᴐᴒͼԝᴒᴡᴤᴒᴒꜜͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴠ꞉ᴡᴒᴣ꞉ᴠ꞉ᴡᴠͼꜝᴟͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⅎͼᴑԜᴦᴠͼ
ԜⱱᴡᴒᴟͼꞌԜᴠᴡͼᴐꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼᴠᴢԝ꞊ᴒᴐᴡ᷅
᷿᷅
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼӿꜙᴁ͟ԐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬͼԜᴟᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼᴢꜜᴑᴒᴟⱲꜝͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼ᷉ͼᴤᴒᴒꞋͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴡⱳᴒͼᴟᴢꜜ᷄
꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴁⱳ꞉ᴠͼꜙᴁ͟ͼᴤԜᴠⱳꜝᴢᴡͼ꞉ᴠͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼԜᴠͼꞌꜝꜜⱲͼԜᴠͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴑꜝ꞉ꜜⱲͼᴠꜝͼᴤꜝᴢꞌᴑͼꜜꜝᴡͼꜞꞌԜᴐᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜᴡͼԜꜜᴦͼᴢꜜᴑᴢᴒͼᴠԜⱱᴒᴡᴦͼᴟ꞉ᴠꞋͼԜꜜᴑͼᴡⱳᴒͼ
ᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡͼꞌᴒԜᴠᴡͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼᴐꜝꜜⱱ꞉ᴟꜛͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱳԜᴠͼᴠᴢᴐᴐᴒᴠᴠⱱᴢꞌꞌᴦͼᴐꜝꜛꜞꞌᴒᴡᴒᴑͼᴡⱳᴒͼ᷉ͼᴤᴒᴒꞋͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒᴦͼᴐԜꜜͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴁԜԝꞌᴒͼ᷈᷅
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒ
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒ
ᴀᴐᴟᴒᴒꜜ꞉ꜜⱲͼ
ᴃ꞉ᴠ꞉ᴡ
ϸᴢꜜ᷄꞉ꜜͼ
͟ᴒᴟ꞉ꜝᴑͼ᷈
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑ᷉
ⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼ
͟ᴒᴟ꞉ꜝᴑ᷊
ᴁᴒᴠᴡᴠͼԜꜜᴑͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ
ᴃ꞉ᴠ꞉ᴡͼ᷈
Ⱬꜝᴠᴒͼ᷈
ⱫԜᴦͼ᷇
ᴀ꞉ᴡᴒͼ
ⱪⱳᴒᴐꞋ᷄
꞉ꜜ᷾
ᴃ꞉ᴠ꞉ᴡͼ᷉ͼ
Ⱬꜝᴠᴒͼ᷉
ⱫԜᴦͼ᷈᷾
ᴃ꞉ᴠ꞉ᴡͼ᷊ͼ
Ⱬꜝᴠᴒͼ᷊
ⱫԜᴦͼ᷉˲
ᴃ꞉ᴠ꞉ᴡͼ᷾ͼ
Ⱬꜝᴠᴒͼ᷾
ⱫԜᴦͼ᷾᷉
ᴃ꞉ᴠ꞉ᴡͼ᷿ͼ
Ⱬꜝᴠᴒͼ᷿
ⱫԜᴦͼ᷿⅍
ᴃ꞉ᴠ꞉ᴡᴠͼ⅍ͼԜꜜᴑͼⅎͼ
Ⱬꜝᴠᴒᴠͼ⅍ͼԜꜜᴑͼⅎ
ⱫԜᴦᴠͼⅎ᷇ͼԜꜜᴑͼ
˲᷾
ᴃ꞉ᴠ꞉ᴡͼ˲ͼ
Ⱬꜝᴠᴒͼ˲
ⱫԜᴦͼⱠ˲
ᴃ꞉ᴠ꞉ᴡᴠͼⱠͼԜꜜᴑͼ᷈᷇ͼ
ⱫꜝᴠᴒᴠͼⱠͼԜꜜᴑͼ᷈᷇
ⱫԜᴦᴠͼ᷈᷈᷉ͼԜꜜᴑͼ
᷈᷉⅍
ᴃ꞉ᴠ꞉ᴡͼ᷈᷈ͼ
Ⱬꜝᴠᴒͼ᷈᷈
ⱫԜᴦͼ᷈᷾᷇
ⱫԜᴦͼ
᷈᷾᷾ᶐ᷈
ᴃ꞉ᴠ꞉ᴡᴠͼ᷈᷉ͼԜꜜᴑͼ᷊᷈ͼ
Ⱬꜝᴠᴒᴠͼ᷈᷉ͼԜꜜᴑͼ᷊᷈
ⱫԜᴦᴠͼ᷿᷈᷾ͼԜꜜᴑͼ
᷈⅍˲
ᴃ꞉ᴠ꞉ᴡͼ
᷈᷾
ⱫԜᴦͼ
᷈˲᷉
ᴃ꞉ᴠ꞉ᴡͼ
᷿᷈
ⱫԜᴦͼ
᷉᷈᷇
ᴃ꞉ᴠ꞉ᴡͼ
᷈⅍
ⱫԜᴦͼ
᷊᷉˲
ᴒꜜᴡᴒᴟͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅
⅍᷅
ᴀԜꜛꜞꞌᴒᴠͼⱱꜝᴟͼⱪ᷈᷄ⱷ꜠ⱶԓͼⱪ᷾ԓͼԜꜜᴑͼⱪ᷈ꜟͼԜᴠᴠԜᴦᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼԜᴡͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼⱱꜝᴟͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅ͼ
ⅎ᷅
ᴁⱳᴒͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡͼᴤ꞉ꞌꞌͼꜝꜜꞌᴦͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼ꞉ꜜͼⱱᴒꜛԜꞌᴒᴠͼꜝⱱͼᴐⱳ꞉ꞌᴑԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌ᷅ͼᴁᴒᴠᴡᴠͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼⱫԜᴦͼ᷈˲᷉ͼꜛᴢᴠᴡͼԝᴒͼᴢᴟ꞉ꜜᴒ᷄ԝԜᴠᴒᴑ᷅ͼᴁᴒᴠᴡᴠͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑͼԜᴡᴠᴐᴟᴒᴒꜜ꞉ꜜⱲԓͼⱫԜᴦᴠ᷉˲ԓͼ᷿⅍ԓͼⱠ˲ԓͼ᷈᷉⅍ԓͼ᷿᷈᷾ԓͼԜꜜᴑͼⱫԜᴦ᷊᷉˲ͼᴐԜꜜͼԝᴒͼᴠᴒᴟᴢꜛ᷄ꜝᴟͼᴢᴟ꞉ꜜᴒ᷄ԝԜᴠᴒᴑ᷅
˲᷅
ᴁⱳᴒᴟᴒͼ꞉ᴠͼԜͼᶐ᷿᷈ͼꜛ꞉ꜜᴢᴡᴒͼᴤ꞉ꜜᴑꜝᴤͼⱱꜝᴟͼԜꞌꞌͼᴣ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠ᷅ͼⱨᴡͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡᴠͼ꞉ꜜͼᴤⱳ꞉ᴐⱳͼⱷꜚ͟ͼ꞉ᴠͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑԓͼᴣ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴠ꞉ᴡᴡ꞉ꜜⱲꜝᴟͼᴠᴢꜞ꞉ꜜᴒͼⱩ͟ԓͼⱶϸԓͼԝꜝᴑᴦͼ
ᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼԜꜜᴑͼϸϸԓͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴑꜝᴠ꞉ꜜⱲԓͼ᷈ͼⱳꜝᴢᴟͼԜⱱᴡᴒᴟͼᴑꜝᴠ꞉ꜜⱲԓͼԜꜜᴑͼ᷉ͼⱳꜝᴢᴟᴠͼԜⱱᴡᴒᴟͼᴑꜝᴠ꞉ꜜⱲͼⱱꜝᴟͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼ᷾ͼᴑꜝᴠᴒᴠͼᴤ꞉ᴡⱳͼᴡⱳᴒͼԜԝ꞉ꞌ꞉ᴡᴦͼᴡꜝͼᴒꞌ꞉ꜛ꞉ꜜԜᴡᴒͼᴡⱳᴒͼ᷉ͼ
ⱳꜝᴢᴟͼᴣ꞉ᴡԜꞌᴠͼⱱꜝᴟͼᴡⱳᴒͼᴟᴒꜛԜ꞉ꜜ꞉ꜜⱲͼᴑꜝᴠᴒᴠͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠ᷅
Ⱡ᷅
ⱶᴒ꞉ⱲⱳᴡͼԜꜜᴑͼᴤᴒ꞉Ⱳⱳᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼԜᴡͼᴡⱳᴒͼᴀᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡͼꜝꜜꞌᴦ᷅
᷈᷇᷅
ⱬⱪⱵᴠͼӿᴠ꞉ꜜⱲꞌᴒͼᴟᴒᴐꜝᴟᴑ꞉ꜜⱲᴠԐͼԜᴟᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼԜᴡͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲԓͼԝԜᴠᴒꞌ꞉ꜜᴒͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱫꜝᴠᴒͼ᷈ԓͼⱫԜᴦͼ᷿⅍ԓͼⱫԜᴦͼ᷈᷾᷾ᶐ᷈ͼᴑԜᴦͼᴡꜝͼᴐԜꜞᴡᴢᴟᴒͼᴡⱳᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴑⱪꜛԜᴥԜꜜᴑͼⱫԜᴦͼ᷈˲᷉᷅ͼᴁⱳᴒͼⱬⱪⱵͼ
ԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼԜᴡͼⱪꜛԜᴥꜝꜜͼⱫԜᴦͼ᷈᷾᷾ᶐ᷈ᴑԜᴦͼꜛԜᴦͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼᴣ꞉ԜͼԜᴡ᷄ⱳꜝꜛᴒͼꜜᴢᴟᴠᴒͼꜝᴟͼᴡᴒᴐⱳꜜ꞉ᴐ꞉Ԝꜜͼ꞉ꜜͼꞌ꞉ᴒᴢͼꜝⱱͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼᴣ꞉ᴠ꞉ᴡͼᴡꜝͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒ᷅
᷈᷈᷅
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼⱶᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼⱪꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴀᴒᴟᴢꜛͼⱪⱳᴒꜛ꞉ᴠᴡᴟᴦԓͼԜꜜᴑͼᴂᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠ᷅ͼ
᷈᷉᷅
ⱶ꞉ᴠᴡꜝᴟ꞉ᴐԜꞌͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼԜᴡͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲ᷅ͼⱫᴢᴟ꞉ꜜⱲͼᴡⱳᴒᴠᴡᴢᴑᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼӿꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠԓͼ꞉ꜜͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼⱣͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝꞌᴑͼꜝᴟͼ꞉ᴠͼ
꞉ꜜᴐԜꜞԜᴐ꞉ᴡԜᴡᴒᴑԐͼԜᴟᴒͼ꞉ꜜᴠᴡᴟᴢᴐᴡᴒᴑͼᴡꜝͼᴟᴒꜞꜝᴟᴡͼᴑᴒᴡԜ꞉ꞌᴠͼꜝⱱͼᴡⱳᴒͼԜᴡᴡԜᴐꞋͼᴡꜝͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒͼᴤ꞉ᴡⱳ꞉ꜜͼⅎ᷉ͼⱳꜝᴢᴟᴠͼꜝⱱͼᴡⱳᴒͼꜝꜜᴠᴒᴡͼꜝⱱͼᴡⱳᴒͼԜᴡᴡԜᴐꞋ᷅ͼᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼԜꞌᴠꜝͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼ
ᴠᴢԝ꞊ᴒᴐᴡͼꜝꜜᴐᴒͼԜ ᴤᴒᴒꞋͼꜝᴟͼԜᴡͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⅎͼᴑԜᴦᴠͼԜⱱᴡᴒᴟͼꞌԜᴠᴡͼᴐꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼԜꜜᴑͼꜝꜜᴐᴒͼԝᴒᴡᴤᴒᴒꜜͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡᴠͼꜝᴟͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⅎͼ
ᴑԜᴦᴠͼԜⱱᴡᴒᴟͼꞌԜᴠᴡͼᴐꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼ꞉ꜜͼꜝᴟᴑᴒᴟͼᴡꜝͼᴠꜝꞌ꞉ᴐ꞉ᴡͼⱱꜝᴟͼԜꜜᴦͼԜᴡᴡԜᴐꞋͼᴡⱳԜᴡͼꜛԜᴦͼⱳԜᴣᴒͼꜝᴐᴐᴢᴟᴟᴒᴑ᷅ͼⱷꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԓͼᴑᴢᴟ꞉ꜜⱲͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡᴠԓͼ
ᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴠꜝꞌ꞉ᴐ꞉ᴡͼⱱꜝᴟͼԜꜜᴦͼꜜᴒᴤͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼᴤԜᴠͼꜜꜝᴡͼⱲ꞉ᴣᴒꜜͼᴡⱳᴟꜝᴢⱲⱳͼꜞᴟ꞉ꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡͼᴐꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠ꞉ᴡᴒ᷅
᷊᷈᷅
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼᴑԜᴡԜͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱬᴢᴟꜝϷꜝꜙͼⱵᴟꜝᴢꜞͼ᷿᷄Ⱬ꞉ꜛᴒꜜᴠ꞉ꜝꜜͼӿⱬϷ᷿ⱫԐͼᴀᴒꞌⱱ᷄ϸᴒꜞꜝᴟᴡͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼⱠ˲ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊ͼ
Ԝꜜᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼӿⱨⱬ᷄ϷꜝꜙԐͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼ᷉˲ᶐ᷊ԓͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷉⅍ᶐ᷊ԓͼ᷿᷈᷾ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ
ꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼӿⱬϷ᷿ⱫͼԜꜜᴑͼⱨⱬ᷄ϷꜝꜙԐͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦͼ᷊᷉˲ᶐ᷊ͼⱱꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅ͼ
᷈᷾᷅
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴟꜝꞌꞌꜝᴣᴒᴟͼ꞉ꜜᴡꜝͼᴡⱳᴒͼ꜡ꜞᴒꜜ᷄ꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼꜞᴟꜝᴡꜝᴐꜝꞌͼӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾Ԑͼᴤ꞉ꞌꞌͼꜞᴟꜝᴣ꞉ᴑᴒͼᴐꜝꜜᴠᴒꜜᴡͼԝᴦͼⱫԜᴦͼ᷈˲᷉ͼԜꜜᴑͼᴟᴒᴐᴒ꞉ᴣᴒͼᴡⱳᴒ꞉ᴟͼⱱ꞉ᴟᴠᴡͼꜝꜞᴒꜜ᷄ꞌԜԝᴒꞌͼᴑꜝᴠᴒͼ
ⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡⱳᴒͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝⱱͼԜꞌꞌͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇ͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼꜝꜜͼⱫԜᴦͼ᷈˲᷉᷅ͼⱨᴡͼᴡⱳᴒͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒᴠᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠԓͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴑ꞉ᴠᴐⱳԜᴟⱲᴒᴑͼ
ⱱᴟꜝꜛͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇ͼԜꜜᴑͼᴟꜝꞌꞌͼ꞉ꜜᴡꜝͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾ͼᴠᴡᴢᴑᴦ᷅ͼ
᷿᷈᷅
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴡᴒᴟꜛ꞉ꜜԜᴡᴒͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴒԜᴟꞌᴦͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼӿ꞉ⱱͼꜞꜝᴠᴠ꞉ԝꞌᴒԐͼԜꞌꞌͼꜝⱱͼᴡⱳᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜꜜᴑͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜᴠͼⱫԜᴦͼ᷈˲᷉ͼԜᴡͼᴡⱳᴒ꞉ᴟͼⱱ꞉ꜜԜꞌͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
TABLE OF CONTENTS
͟ϸ꜡ᴁ꜡ⱪ꜡ꜙͼᴀⱷⱵ꜠ⱨᴁᴂϸⱬͼ͟ⱨⱵⱬ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷉
ⱨꜚⱬ꜠Ⱬꜚⱬ꜠ᴁͼᴀᴂꜚꜚⱨϸᴆͼⱨ꜠Ⱬͼϸⱨᴁⱷ꜡꜠ⱨꜙⱬ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
ᴀᴆ꜠꜡͟ᴀⱷᴀ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
ꜙⱷᴀᴁͼ꜡ⱴͼⱨⱩⱩϸⱬᴃⱷⱨᴁⱷ꜡꜠ᴀͼⱨ꜠ⱫͼⱫⱬⱴⱷ꜠ⱷᴁⱷ꜡꜠ᴀͼ꜡ⱴͼᴁⱬϸꜚᴀ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷉˲
᷈
ⱷ꜠ᴁϸ꜡Ⱬᴂⱪᴁⱷ꜡꜠᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷉
᷈᷅᷈
Ⱬᴅ᷄᷉Ⱡ᷊᷊᷇᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷉
᷈᷅᷉
ⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷉
᷊᷈᷅
ᴁⱳᴒᴟԜꜞᴒᴢᴡ꞉ᴐͼϸԜᴡ꞉ꜝꜜԜꞌᴒͼⱱꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷉
᷈᷅᷾
ᴀԜⱱᴒᴡᴦͼϸԜᴡ꞉ꜝꜜԜꞌᴒͼⱱꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷊᷊᷇᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
᷿᷈᷅
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼ꜠ꜝꜜ᷄ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼ͟ⱳԜᴟꜛԜᴐꜝꞌꜝⱲᴦͼԜꜜᴑͼᴁꜝᴥ꞉ᴐꜝꞌꜝⱲᴦ᷊᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
᷈᷅⅍
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼⱫԜᴡԜ ᷊᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
᷈᷅⅍᷅᷈
ᴀ꞉ꜜⱲꞌᴒ᷄ⱨᴠᴐᴒꜜᴑ꞉ꜜⱲͼⱫꜝᴠᴒͼᴀᴡᴢᴑᴦͼ꞉ꜜͼⱶᴒԜꞌᴡⱳᴦͼᴀᴢԝ꞊ᴒᴐᴡᴠͼӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷈Ԑ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷈᷅⅍᷅᷉
ꜚᴢꞌᴡ꞉ꜞꞌᴒ᷄ⱨᴠᴐᴒꜜᴑ꞉ꜜⱲͼⱫꜝᴠᴒͼᴀᴡᴢᴑᴦͼ꞉ꜜͼⱶⱨⱬͼ͟Ԝᴡ꞉ᴒꜜᴡᴠͼӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉Ԑ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷉
ᴀᴁᴂⱫᴆͼ꜡Ⱪꜗⱬⱪᴁⱷᴃⱬᴀ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
᷉᷅᷈
͟ᴟ꞉ꜛԜᴟᴦͼ꜡ԝ꞊ᴒᴐᴡ꞉ᴣᴒ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
᷉᷅᷉
ᴀᴒᴐꜝꜜᴑԜᴟᴦͼ꜡ԝ꞊ᴒᴐᴡ꞉ᴣᴒ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
᷊᷉᷅
ᴁᴒᴟᴡ꞉Ԝᴟᴦͼ꜡ԝ꞊ᴒᴐᴡ꞉ᴣᴒᴠ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
᷊
ⱷ꜠ᴃⱬᴀᴁⱷⱵⱨᴁⱷ꜡꜠ⱨꜙͼ͟ꜙⱨ꜠᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲
᷊᷅᷈
꜡ᴣᴒᴟԜꞌꞌͼᴀᴡᴢᴑᴦͼⱫᴒᴠ꞉ⱲꜜͼԜꜜᴑͼ͟ꞌԜꜜ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲
᷊᷅᷈᷅᷈
꜡ᴣᴒᴟᴣ꞉ᴒᴤ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲
᷊᷅᷈᷅᷈᷅᷈
ꜙꜝꜜⱲ᷄ᴁᴒᴟꜛͼ͟ᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼӿꜙᴁ͟ԐͼᴁⱳᴒᴟԜꜞᴦͼᴄԜᴠⱳꜝᴢᴡ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲
᷊᷅᷈᷅᷈᷅᷉
ϸᴢꜜ᷄ⱷꜜͼ͟ᴒᴟ꞉ꜝᴑ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲
᷊᷊᷅᷈᷅᷈᷅
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ
᷊᷅᷈᷅᷈᷅᷾
꜡ꜞᴒꜜ᷄ꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼӿ꜡ꜙⱬԐ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ
᷊᷿᷅᷈᷅᷈᷅
ⱴꜝꞌꞌꜝᴤ᷄ᴂꜞͼ͟ᴒᴟ꞉ꜝᴑ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷇
᷊᷅᷈᷅᷉
ᴀԜⱱᴒᴡᴦͼ꜡ᴣᴒᴟᴠ꞉ⱲⱳᴡͼԜꜜᴑͼᴀᴡꜝꜞꜞ꞉ꜜⱲͼϸᴢꞌᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷇
᷊᷅᷈᷅᷉᷅᷈
ⱷꜜᴡᴒᴟ꞉ꜛͼⱨꜜԜꞌᴦᴠ꞉ᴠͼԜꜜᴑͼⱫԜᴡԜͼᴀԜⱱᴒᴡᴦͼꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼⱩꜝԜᴟᴑͼӿⱫᴀꜚⱩԐ ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷇
᷊᷅᷈᷅᷉᷅᷉
ⱷꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴀᴡꜝꜞꜞ꞉ꜜⱲͼϸᴢꞌᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷇
᷊᷊᷅᷈᷅
ⱴꜝꞌꞌꜝᴤ᷄ᴂꜞͼⱱꜝᴟͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜚᴒᴒᴡ꞉ꜜⱲͼᴀᴡꜝꜞꜞ꞉ꜜⱲͼⱪᴟ꞉ᴡᴒᴟ꞉Ԝ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷈
᷊᷅᷉
ϸԜᴡ꞉ꜝꜜԜꞌᴒͼⱱꜝᴟͼ͟꞉ᴣꜝᴡԜꞌͼⱫꜝᴠᴒͼᴀᴒꞌᴒᴐᴡ꞉ꜝꜜ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷈
᷊᷊᷅
ⱷꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴀᴢԝ꞊ᴒᴐᴡͼⱫꜝᴠ꞉ꜜⱲͼԜꜜᴑͼⱴꜝꞌꞌꜝᴤ᷄ᴂꜞ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷉
᷊᷅᷾
ᴀᴡᴢᴑᴦͼⱫᴢᴟԜᴡ꞉ꜝꜜͼⱱꜝᴟͼⱷꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴀᴢԝ꞊ᴒᴐᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷉
᷾
ᴀᴁᴂⱫᴆͼ͟꜡͟ᴂꜙⱨᴁⱷ꜡꜠ͼᴀⱬꜙⱬⱪᴁⱷ꜡꜠᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷾᷅᷈
ᴀᴡᴢᴑᴦͼ͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷾᷅᷉
ⱷꜜᴐꞌᴢᴠ꞉ꜝꜜͼⱪᴟ꞉ᴡᴒᴟ꞉Ԝ ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷊᷾᷅
ⱬᴥᴐꞌᴢᴠ꞉ꜝꜜͼⱪᴟ꞉ᴡᴒᴟ꞉Ԝ ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷾
᷿
ᴀᴁᴂⱫᴆͼᴁϸⱬⱨᴁꜚⱬ꜠ᴁӿᴀԐ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
᷿᷅᷈
Ⱬᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡӿᴠԐ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷿᷅᷈᷅᷈
Ⱬᴅ᷄᷉Ⱡ᷊᷿᷇᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷿᷅᷈᷅᷉
͟ꞌԜᴐᴒԝꜝ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷿᷅᷉
Ⱬꜝᴠ꞉ꜜⱲͼԜꜜᴑͼⱴꜝꞌꞌꜝᴤ᷄ᴂꜞͼᴀᴐⱳᴒᴑᴢꞌᴒ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷿᷊᷅
ꜚᴒᴡⱳꜝᴑͼꜝⱱͼⱨᴠᴠ꞉Ⱳꜜ꞉ꜜⱲͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴡꜝͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼⱵᴟꜝᴢꜞᴠ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
᷿᷅᷾
Ⱪꞌ꞉ꜜᴑ꞉ꜜⱲͼԜꜜᴑͼᴂꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾⅍
᷿᷿᷅
͟ᴟ꞉ꜝᴟͼԜꜜᴑͼⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴁⱳᴒᴟԜꜞᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾⅍
᷿᷿᷅᷅᷈
ⱨꞌꞌꜝᴤᴒᴑͼᴁⱳᴒᴟԜꜞ꞉ᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾⅍
᷿᷿᷅᷅᷉
ⱬᴥᴐꞌᴢᴑᴒᴑͼⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴁⱳᴒᴟԜꜞ꞉ᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾ⅎ
᷿᷅⅍
ϸᴒᴠᴡᴟ꞉ᴐᴡ꞉ꜝꜜᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾ⅎ
᷿᷅⅍᷅᷈
ꜚᴒᴑ꞉ᴐԜꞌͼⱷꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾ⅎ
᷿᷅⅍᷅᷉
ⱴꞌᴢ꞉ᴑͼԜꜜᴑͼⱴꜝꜝᴑͼⱷꜜᴡԜꞋᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾ⅎ
᷿᷅⅍᷊᷅
ⱨᴐᴡ꞉ᴣ꞉ᴡᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾ⅎ
᷿᷅ⅎ
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼⱪꜝꜛꜞꞌ꞉Ԝꜜᴐᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾ⅎ
᷿᷅˲
͟ԜᴐꞋԜⱲ꞉ꜜⱲͼԜꜜᴑͼꜙԜԝᴒꞌ꞉ꜜⱲ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾ⅎ
᷿᷅Ⱡ
ᴀᴡꜝᴟԜⱲᴒͼԜꜜᴑͼⱨᴐᴐꜝᴢꜜᴡԜԝ꞉ꞌ꞉ᴡᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾˲
᷿᷅᷈᷇
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜚᴒᴑ꞉ᴐ꞉ꜜԜꞌͼ͟ᴟꜝᴑᴢᴐᴡͼϸᴒᴡᴒꜜᴡ꞉ꜝꜜͼԜᴡͼᴀᴡᴢᴑᴦͼᴀ꞉ᴡᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾˲
⅍
ᴀᴁᴂⱫᴆͼ͟ϸ꜡ⱪⱬⱫᴂϸⱬᴀ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾Ⱡ
⅍᷅᷈
ⱷꜜⱱꜝᴟꜛᴒᴑͼⱪꜝꜜᴠᴒꜜᴡ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾Ⱡ
⅍᷅᷉
ⱬꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼϸᴒᴣ꞉ᴒᴤ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾Ⱡ
⅍᷊᷅
ⱫᴒꜛꜝⱲᴟԜꜞⱳ꞉ᴐᴠͼԜꜜᴑͼꜚᴒᴑ꞉ᴐԜꞌͼⱶ꞉ᴠᴡꜝᴟᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾Ⱡ
⅍᷅᷾
ⱬⱱⱱ꞉ᴐԜᴐᴦͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾Ⱡ
⅍᷅᷾᷅᷈
͟ᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴀᴒᴐꜝꜜᴑԜᴟᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾Ⱡ
⅍᷅᷾᷅᷉
ⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷇
⅍᷿᷅
ᴃ꞉ᴡԜꞌͼᴀ꞉Ⱳꜜᴠ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷉
⅍᷅⅍
͟ⱳᴦᴠ꞉ᴐԜꞌͼⱬᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷉
⅍᷅ⅎ
ⱬꞌᴒᴐᴡᴟꜝᴐԜᴟᴑ꞉ꜝⱲᴟԜꜞⱳᴦͼӿⱬⱪⱵԐ ᷿᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴁᴒᴠᴡᴠ᷿᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲᷅᷈
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼ͟ԜᴟԜꜛᴒᴡᴒᴟᴠ᷿᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲᷅᷈᷅᷈
ⱶᴒꜛԜᴡꜝꞌꜝⱲᴦ᷿᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲᷅᷈᷅᷉
ⱪꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
⅍᷅˲᷊᷅᷈᷅
ⱪⱳᴒꜛ꞉ᴠᴡᴟᴦ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾
⅍᷅˲᷅᷈᷅᷾
ᴂᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠ᷿᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲᷿᷅᷈᷅
ᴀᴒᴟꜝꞌꜝⱲᴦ᷿᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲᷅᷈᷅⅍
͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴁᴒᴠᴡ᷿᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲᷅᷈᷅ⅎ
ⱪ᷈᷄ⱷ꜠ⱶͼⱴᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼⱨᴠᴠԜᴦ᷿᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲᷅᷈᷅˲
ⱪ᷾ͼⱨᴠᴠԜᴦ᷿᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅
⅍᷅˲᷅᷈᷅Ⱡ
ⱪ᷈ꜟͼⱨᴠᴠԜᴦ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
⅍᷅˲᷅᷈᷅᷈᷇
͟ꜘͼᴀԜꜛꜞꞌᴒͼⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍
⅍᷅˲᷅᷈᷅᷈᷈
͟ⱫͼᴀԜꜛꜞꞌᴒͼⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍
⅍᷅˲᷅᷈᷅᷈᷉
͟ꞌԜᴠꜛԜͼⱨꜜᴡ꞉᷄ⱫᴟᴢⱲͼⱨꜜᴡ꞉ԝꜝᴑᴦͼᴁᴒᴠᴡ꞉ꜜⱲ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍
⅍᷅˲᷅᷉
ᴀԜꜛꜞꞌᴒͼⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜԓͼᴀᴡꜝᴟԜⱲᴒԓͼԜꜜᴑͼᴀⱳ꞉ꜞꜞ꞉ꜜⱲ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍
⅍᷅Ⱡ
͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍
⅍᷅᷈᷇
͟ⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍
⅍᷅᷈᷈
͟ꞌԜᴠꜛԜͼⱨꜜᴡ꞉᷄ⱫᴟᴢⱲͼⱨꜜᴡ꞉ԝꜝᴑᴦͼᴁᴒᴠᴡ꞉ꜜⱲ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍
⅍᷅᷈᷉
͟ᴟ꞉ꜝᴟͼԜꜜᴑͼⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴁⱳᴒᴟԜꜞᴦ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
⅍᷊᷅᷈
ϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
⅍᷅᷈᷾
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜚᴒᴑ꞉ᴐ꞉ꜜԜꞌͼ͟ᴟꜝᴑᴢᴐᴡͼᴁᴟᴒԜᴡꜛᴒꜜᴡ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
⅍᷿᷅᷈
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
⅍᷅᷈⅍
ⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
⅍᷅᷈⅍᷅᷈
Ⱬᴒⱱ꞉ꜜ꞉ᴡ꞉ꜝꜜᴠ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
⅍᷅᷈⅍᷅᷈᷅᷈
ⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ
⅍᷅᷈⅍᷅᷈᷅᷉
ᴀᴒᴟ꞉ꜝᴢᴠͼⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲
⅍᷅᷈⅍᷊᷅᷈᷅
꜡ᴣᴒᴟᴑꜝᴠᴒ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ
⅍᷅᷈⅍᷅᷈᷅᷾
͟ꞌԜꜜꜜᴒᴑͼⱶꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ
⅍᷅᷈⅍᷿᷅᷈᷅
ᴁᴟᴒԜᴡꜛᴒꜜᴡ᷄ⱬꜛᴒᴟⱲᴒꜜᴡͼⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡᴠͼӿᴁⱬⱨⱬԐ ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ
⅍᷅᷈⅍᷅᷈᷅⅍
ⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡᴠͼꜝⱱͼᴀꜞᴒᴐ꞉ԜꞌͼⱷꜜᴡᴒᴟᴒᴠᴡͼӿⱨⱬᴀⱷԐ᷿᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ
⅍᷅᷈⅍᷅᷉
ꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷇
⅍᷅᷈⅍᷅᷉᷅᷈
ꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜝⱱͼⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷇
⅍᷅᷈⅍᷅᷉᷅᷉
ꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜝⱱͼᴀԜⱱᴒᴡᴦͼꜙԜԝꜝᴟԜᴡꜝᴟᴦͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷇
⅍᷅᷈⅍᷊᷅
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷇
⅍᷅᷈⅍᷊᷅᷅᷈
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴀᴒᴣᴒᴟ꞉ᴡᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷇
⅍᷅᷈⅍᷊᷅᷅᷉
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼⱪԜᴢᴠԜꞌ꞉ᴡᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷈
⅍᷅᷈⅍᷊᷊᷅᷅
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴀ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷉
⅍᷅᷈⅍᷅᷾
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼꜙԜԝꜝᴟԜᴡꜝᴟᴦͼⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷉
⅍᷅᷈⅍᷿᷅
ϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴀԜⱱᴒᴡᴦͼ꜡ԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜᴠͼᴡꜝͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷊
⅍᷅᷈⅍᷿᷅᷅᷈
ϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼ꜠ꜝꜜ᷄ᴀᴒᴟ꞉ꜝᴢᴠͼⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷊
⅍᷅᷈⅍᷿᷅᷅᷉
ϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼ͟ᴟᴒⱲꜜԜꜜᴐ꞉ᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷊
⅍᷅᷈⅍᷿᷊᷅᷅
ᴀԜⱱᴒᴡᴦͼ꜡ԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜᴠͼϸᴒꜟᴢ꞉ᴟ꞉ꜜⱲͼⱬᴥꜞᴒᴑ꞉ᴡᴒᴑͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼԝᴦͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡꜝᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷊
⅍᷅᷈⅍᷿᷅᷅᷾
ⱬᴥꜞᴒᴑ꞉ᴡᴒᴑͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴡꜝͼԜͼϸᴒⱲᴢꞌԜᴡꜝᴟᴦͼⱶᴒԜꞌᴡⱳͼ
ⱨᴢᴡⱳꜝᴟ꞉ᴡᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷾
⅍᷅᷈⅍᷿᷿᷅᷅
ᴀԜⱱᴒᴡᴦͼⱪꜝꜜᴡԜᴐᴡͼⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷾
⅍᷅᷈⅍᷿᷅᷅⅍
ᴀԜⱱᴒᴡᴦͼ꜠ꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜᴠͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴡꜝͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷾
⅍᷅᷈⅍᷿᷅᷅ⅎ
ᴂꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲͼԜͼᴀᴢԝ꞊ᴒᴐᴡᶳᴠͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴁᴟ꞉Ԝꞌ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷾
⅍᷅᷈ⅎ
ᴀᴢԝ꞊ᴒᴐᴡͼᴄ꞉ᴡⱳᴑᴟԜᴤԜꞌ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷾


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
⅍᷅᷈˲
ⱨꜞꜞᴟꜝꜞᴟ꞉ԜᴡᴒꜜᴒᴠᴠͼꜝⱱͼꜚᴒԜᴠᴢᴟᴒꜛᴒꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍᷿
ⅎ
ᴀᴁᴂⱫᴆͼⱨⱪᴁⱷᴃⱷᴁⱷⱬᴀ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍⅍
ⅎ᷅᷈
ᴀᴐᴟᴒᴒꜜ꞉ꜜⱲ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍⅍
ⅎ᷅᷉
ϸᴢꜜ᷄꞉ꜜͼ͟ᴒᴟ꞉ꜝᴑ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍⅍
ⅎ᷊᷅
ᴀᴡԜᴟᴡͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡͼ᷈ԓͼⱫꜝᴠᴒͼ᷈ͼӿⱫԜᴦͼ᷇Ԑ ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍ⅎ
ⅎ᷅᷾
ᴀ꞉ᴡᴒͼⱪꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴀᴢԝ꞊ᴒᴐᴡ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍˲
ⅎ᷿᷅
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡͼ᷉ԓͼⱫꜝᴠᴒͼ᷉ͼӿⱫԜᴦͼ᷈᷾ᶐ᷊ⱫԜᴦᴠԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍˲
ⅎ᷅⅍
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡͼ᷊ԓͼⱫꜝᴠᴒͼ᷊ͼӿⱫԜᴦͼ᷉˲ᶐ᷊ⱫԜᴦᴠԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍Ⱡ
ⅎ᷅ⅎ
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡͼ᷾ԓͼⱫꜝᴠᴒͼ᷾ͼӿⱫԜᴦͼ᷾᷉ͼᶐ᷊ⱫԜᴦᴠԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅⅍Ⱡ
ⅎ᷅˲
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡͼ᷿ԓͼⱫꜝᴠᴒͼ᷿ͼӿⱫԜᴦͼ᷿⅍ᶐ᷊ⱫԜᴦᴠԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ᷇
ⅎ᷅Ⱡ
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡᴠͼ⅍ͼԜꜜᴑͼⅎԓͼⱫꜝᴠᴒᴠͼ⅍ͼԜꜜᴑͼⅎͼͼ
ӿⱫԜᴦᴠⅎ᷇Ԝꜜᴑ˲᷾ԓͼⱨꞌꞌͼᶐ᷊ⱫԜᴦᴠԐ ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ᷈
ⅎ᷅᷈᷇
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡͼ˲ԓͼⱫꜝᴠᴒͼ˲ͼӿⱫԜᴦͼⱠ˲ᶐ᷊ⱫԜᴦᴠԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ᷉
ⅎ᷅᷈᷈
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡᴠͼⱠͼԜꜜᴑͼ᷈᷇ԓͼⱫꜝᴠᴒᴠͼⱠͼԜꜜᴑͼ᷈᷇ͼ ӿⱫԜᴦᴠͼ᷈᷈᷉ͼ
Ԝꜜᴑͼ᷈᷉⅍ԓͼⱨꞌꞌͼᶐ᷊ⱫԜᴦᴠԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ᷊
ⅎ᷅᷈᷉
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡͼ᷈᷈ԓͼⱫꜝᴠᴒͼ᷈᷈ͼӿⱫԜᴦͼ᷈᷾᷇ᶐ᷊ⱫԜᴦᴠԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ᷊
ⅎ᷊᷅᷈
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷈᷾᷾ᶐ᷈ⱫԜᴦԐ ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ᷾
ⅎ᷅᷈᷾
ⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡᴠͼ᷈᷉ͼԜꜜᴑͼ᷊᷈ԓͼⱫꜝᴠᴒᴠͼ᷈᷉ͼԜꜜᴑͼ᷊᷈ͼӿⱫԜᴦᴠͼ᷿᷈᷾ͼ
Ԝꜜᴑͼ᷈⅍˲ԓͼⱨꞌꞌͼᶐ᷊ⱫԜᴦᴠԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ᷾
ⅎ᷿᷅᷈
ⱪꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱡͼᴃ꞉ᴠ꞉ᴡͼ᷈᷾ԓͼⱫԜᴦͼ᷈˲᷉ᶐ᷊ⱫԜᴦᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ᷿
ⅎ᷅᷈⅍
ⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼ͟ᴒᴟ꞉ꜝᴑͼӿᴀᴢԝ꞊ᴒᴐᴡᴠͼ꜠ꜝᴡͼⱪꜝꜜᴡ꞉ꜜᴢ꞉ꜜⱲͼ꞉ꜜͼ꜡ꜞᴒꜜ᷄ꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼᴀᴡᴢᴑᴦԐⱡͼ
ᴃ꞉ᴠ꞉ᴡͼ᷿᷈ԓͼⱫԜᴦͼ᷉᷈᷇ͼᶐ᷊ⱫԜᴦᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ⅍
ⅎ᷅᷈ⅎ
ⱴ꞉ꜜԜꞌͼⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴃ꞉ᴠ꞉ᴡͼӿᴀᴢԝ꞊ᴒᴐᴡᴠͼ꜠ꜝᴡͼⱪꜝꜜᴡ꞉ꜜᴢ꞉ꜜⱲͼ꞉ꜜͼ꜡ꜞᴒꜜ᷄ꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼᴀᴡᴢᴑᴦԐⱡͼ
ᴃ꞉ᴠ꞉ᴡͼ᷈⅍ԓͼⱫԜᴦͼ᷊᷉˲ᶐ᷊ⱫԜᴦᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ⅍
ⅎ᷅᷈˲
ⱬԜᴟꞌᴦͼᴁᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿⱬᴁԐ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ⅍
˲
Ϸᴂⱨꜙⱷᴁᴆͼⱪ꜡꜠ᴁϸ꜡ꜙͼⱨ꜠Ⱬͼⱨᴀᴀᴂϸⱨ꜠ⱪⱬ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎⅎ
Ⱡ
Ⱬⱨᴁⱨͼⱨ꜠ⱨꜙᴆᴀⱷᴀͼ᷆ͼᴀᴁⱨᴁⱷᴀᴁⱷⱪⱨꜙͼꜚⱬᴁⱶ꜡Ⱬᴀ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ˲
Ⱡ᷅᷈
ⱵᴒꜜᴒᴟԜꞌͼⱪꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ˲
Ⱡ᷅᷉
ᴀԜꜛꜞꞌᴒͼᴀ꞉ᴧᴒͼⱫᴒᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ˲
Ⱡ᷊᷅
ꜚᴒᴡⱳꜝᴑͼꜝⱱͼⱨᴠᴠ꞉Ⱳꜜ꞉ꜜⱲͼᴀᴡᴢᴑᴦͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴡꜝͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼⱵᴟꜝᴢꜞᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎ˲
Ⱡ᷅᷾
ⱨꜜԜꞌᴦᴠ꞉ᴠͼ͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎⱠ
Ⱡ᷿᷅
ⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼⱫ꞉ᴠꜞꜝᴠ꞉ᴡ꞉ꜝꜜ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎⱠ
Ⱡ᷅⅍
ⱫᴒꜛꜝⱲᴟԜꜞⱳ꞉ᴐᴠͼԜꜜᴑͼⱩԜᴠᴒꞌ꞉ꜜᴒͼⱪⱳԜᴟԜᴐᴡᴒᴟ꞉ᴠᴡ꞉ᴐᴠͼⱨꜜԜꞌᴦᴠᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎⱠ
Ⱡ᷅ⅎ
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼⱪꜝꜛꜞꞌ꞉ԜꜜᴐᴒͼԜꜜᴑͼⱬᴥᴡᴒꜜᴡͼꜝⱱͼⱬᴥꜞꜝᴠᴢᴟᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎⱠ
Ⱡ᷅˲
ⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼ͟ᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴀᴒᴐꜝꜜᴑԜᴟᴦͼⱬⱱⱱ꞉ᴐԜᴐᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎⱠ
Ⱡ᷅˲᷅᷈
͟ᴟ꞉ꜛԜᴟᴦͼⱬⱱⱱ꞉ᴐԜᴐᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅ⅎⱠ
Ⱡ᷅˲᷅᷉
ᴀᴒᴐꜝꜜᴑԜᴟᴦͼⱬⱱⱱ꞉ᴐԜᴐᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷇
Ⱡ᷅˲᷊᷅
ⱬᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼⱬⱱⱱ꞉ᴐԜᴐᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷈
Ⱡ᷅Ⱡ
ⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼ͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐͼԜꜜᴑͼ͟ⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷈


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Ⱡ᷅Ⱡ᷅᷈
͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷈
Ⱡ᷅Ⱡ᷅᷉
͟ⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷈
Ⱡ᷅Ⱡ᷊᷅
ⱷꜛꜛᴢꜜꜝⱲᴒꜜ꞉ᴐ꞉ᴡᴦͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷉
Ⱡ᷅Ⱡ᷅᷾
ⱪ᷈᷄ⱷ꜠ⱶͼԜꜜᴑͼⱪ᷾ͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷉
Ⱡ᷅᷈᷇
ᴀԜⱱᴒᴡᴦͼⱨꜜԜꞌᴦᴠ꞉ᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷉
Ⱡ᷅᷈᷈
ⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷊
Ⱡ᷅᷈᷉
ᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌ᷆ⱨꜜԜꞌᴦᴡ꞉ᴐͼⱷᴠᴠᴢᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷊
Ⱡ᷅᷈᷉᷅᷈
ⱨᴑ꞊ᴢᴠᴡꜛᴒꜜᴡͼⱱꜝᴟͼⱪꜝᴣԜᴟ꞉Ԝᴡᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷊
Ⱡ᷅᷈᷉᷅᷉
ⱶԜꜜᴑꞌ꞉ꜜⱲͼꜝⱱͼⱫᴟꜝꜞꜝᴢᴡᴠͼꜝᴟͼꜚ꞉ᴠᴠ꞉ꜜⱲͼⱫԜᴡԜ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷊
Ⱡ᷊᷅᷈᷉᷅
ⱷꜜᴡᴒᴟ꞉ꜛͼⱨꜜԜꞌᴦᴠ꞉ᴠͼԜꜜᴑͼⱫԜᴡԜͼꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷊
Ⱡ᷅᷈᷉᷅᷾
ꜚᴢꞌᴡ꞉ᴐᴒꜜᴡᴒᴟͼᴀᴡᴢᴑ꞉ᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷊
Ⱡ᷿᷅᷈᷉᷅
ꜚᴢꞌᴡ꞉ꜞꞌᴒͼⱪꜝꜛꜞԜᴟ꞉ᴠꜝꜜᴠ᷆ꜚᴢꞌᴡ꞉ꜞꞌ꞉ᴐ꞉ᴡᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷊
Ⱡ᷅᷈᷉᷅⅍
ᴀᴒꜜᴠ꞉ᴡ꞉ᴣ꞉ᴡᴦͼⱨꜜԜꞌᴦᴠᴒᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷾
᷈᷇
ᴀᴁᴂⱫᴆͼⱨⱫꜚⱷ꜠ⱷᴀᴁϸⱨᴁⱷᴃⱬᴀᴁϸᴂⱪᴁᴂϸⱬ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷿
᷈᷇᷅᷈
ⱷꜜᴠᴡ꞉ᴡᴢᴡ꞉ꜝꜜԜꞌͼϸᴒᴣ꞉ᴒᴤͼⱩꜝԜᴟᴑ᷆ϸᴒᴠᴒԜᴟᴐⱳͼⱬᴡⱳ꞉ᴐᴠͼⱩꜝԜᴟᴑ᷆ⱷꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼⱬᴡⱳ꞉ᴐᴠͼ
ⱪꜝꜛꜛ꞉ᴡᴡᴒᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷿
᷈᷇᷅᷉
ⱬᴡⱳ꞉ᴐԜꞌͼⱪꜝꜜᴑᴢᴐᴡͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲⅍
᷊᷈᷇᷅
ᴀᴢԝ꞊ᴒᴐᴡͼⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼԜꜜᴑͼⱪꜝꜜᴠᴒꜜᴡ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲⅍
᷈᷇᷅᷾
ᴀᴢԝ꞊ᴒᴐᴡͼⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ꞉ᴡᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲⅍
᷿᷈᷇᷅
ᴀᴡᴢᴑᴦͼꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲⅍
᷈᷇᷅⅍
ⱪԜᴠᴒͼϸᴒꜞꜝᴟᴡͼⱴꜝᴟꜛᴠͼԜꜜᴑͼᴀᴡᴢᴑᴦͼϸᴒᴐꜝᴟᴑᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲ⅎ
᷈᷇᷅ⅎ
ⱫԜᴡԜͼᴀԜⱱᴒᴡᴦͼꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼⱩꜝԜᴟᴑ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲ⅎ
᷈᷇᷅˲
͟ᴟꜝᴡꜝᴐꜝꞌͼᴃ꞉ꜝꞌԜᴡ꞉ꜝꜜᴠ᷆Ⱬᴒᴣ꞉Ԝᴡ꞉ꜝꜜᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲˲
᷈᷇᷅Ⱡ
͟ᴟᴒꜛԜᴡᴢᴟᴒͼⱪꞌꜝᴠᴢᴟᴒͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲˲
᷈᷇᷅᷈᷇ⱨᴐᴐᴒᴠᴠͼᴡꜝͼᴀꜝᴢᴟᴐᴒͼⱫꜝᴐᴢꜛᴒꜜᴡԜᴡ꞉ꜝꜜͼԜꜜᴑͼ꜡ꜜ᷄ᴀ꞉ᴡᴒͼⱨᴢᴑ꞉ᴡᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲˲
᷈᷇᷅᷈᷈ⱫԜᴡԜͼⱵᴒꜜᴒᴟԜᴡ꞉ꜝꜜͼԜꜜᴑͼⱨꜜԜꞌᴦᴠ꞉ᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲Ⱡ
᷈᷇᷅᷈᷉ⱫԜᴡԜͼⱶԜꜜᴑꞌ꞉ꜜⱲͼⱪꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲Ⱡ
᷊᷈᷇᷅᷈ϸᴒᴡᴒꜜᴡ꞉ꜝꜜͼꜝⱱͼⱫԜᴡԜ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲Ⱡ
᷈᷇᷅᷈᷾ⱴ꞉ꜜԜꜜᴐ꞉ԜꞌͼⱫ꞉ᴠᴐꞌꜝᴠᴢᴟᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ᷇
᷿᷈᷇᷅᷈͟ᴢԝꞌ꞉ᴐԜᴡ꞉ꜝꜜͼԜꜜᴑͼⱫ꞉ᴠᴐꞌꜝᴠᴢᴟᴒͼ͟ꜝꞌ꞉ᴐᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ᷇
᷈᷈
ϸⱬⱴⱬϸⱬ꜠ⱪⱬͼꜙⱷᴀᴁ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ᷈
᷈᷉
ⱨ͟͟ⱬ꜠Ⱬⱷⱪⱬᴀ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ᷊
LIST OF IN-TEXT TABLES
ᴁԜԝꞌᴒͼ᷈᷅
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷈Ⱡ
ᴁԜԝꞌᴒ᷉᷅
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑͼⱫꜝᴠ꞉ꜜⱲͼᴀᴐⱳᴒᴑᴢꞌᴒ᷊᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ
ᴁԜԝꞌᴒ᷊᷅
ᴀᴡᴢᴑᴦͼⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ᴣᴒͼᴀᴡᴟᴢᴐᴡᴢᴟᴒ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅˲᷿


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉ⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
LIST OF IN-TEXT FIGURES
ⱴ꞉Ⱳᴢᴟᴒ᷈᷅
꜡ᴣᴒᴟᴣ꞉ᴒᴤͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱫᴒᴠ꞉Ⱳꜜ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷾᷇
LIST OF APPENDICES
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷈
͟ᴟꜝᴡꜝᴐꜝꞌͼⱶ꞉ᴠᴡꜝᴟᴦ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅Ⱡ᷾
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷉
꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠԓͼⱫ꞉ᴣ꞉ᴠ꞉ꜝꜜͼꜝⱱͼ
ꜚ꞉ᴐᴟꜝԝ꞉ꜝꞌꜝⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠͼӿⱫꜚⱷⱫԐͼⱨᴑᴢꞌᴡͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒͼӿꜚꜝᴑ꞉ⱱ꞉ᴒᴑԐͼͼͼͼ
ӿᴂᴀ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒᴠͼꜝⱱͼⱶᴒԜꞌᴡⱳⱢͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼ
Ⱬ꞉ᴠᴒԜᴠᴒᴠԐᶨᶨᶨ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷈᷇᷾
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷊
꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠԓͼⱫ꞉ᴣ꞉ᴠ꞉ꜝꜜͼꜝⱱͼ
ꜚ꞉ᴐᴟꜝԝ꞉ꜝꞌꜝⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠͼӿⱫꜚⱷⱫԐͼ͟ᴒᴑ꞉Ԝᴡᴟ꞉ᴐͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒᴠͼӿꜚꜝᴑ꞉ⱱ꞉ᴒᴑԐ
ӿᴂᴀͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒᴠͼꜝⱱͼⱶᴒԜꞌᴡⱳⱢͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠ
Ⱬ꞉ᴠᴒԜᴠᴒᴠᶨᶨᶨ᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷅᷈᷈ⅎ
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷾
ⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼԜꜜᴑͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼ͟ᴟꜝᴐᴒᴑᴢᴟᴒᴠͼӿⱶⱨⱨϸ͟Ԑ᷊᷅᷅᷅᷅᷅᷅᷈᷈


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ⱨⱨⱬ
ⱨᴐꜟᴢ꞉ᴟᴒᴑͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜ
ⱨⱪⱬ
ⱨꜜⱲ꞉ꜝᴡᴒꜜᴠ꞉ꜜͼᴐꜝꜜᴣᴒᴟᴡ꞉ꜜⱲͼᴒꜜᴧᴦꜛᴒ
ⱨⱬ
ⱨᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡ
ⱨⱬᴀⱷ
ⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡͼꜝⱱͼᴀꜞᴒᴐ꞉Ԝꞌͼⱷꜜᴡᴒᴟᴒᴠᴡ
ⱨⱬ᷄Ϸꜝꜙ
ⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷄ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒ
ⱨꜙᴁ
ⱨꞌԜꜜ꞉ꜜᴒͼԜꜛ꞉ꜜꜝᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒ
ⱨ꜠꜡ᴃⱨ
ⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼᴣԜᴟ꞉Ԝꜜᴐᴒ
Ԝ͟ᴁᴁ
ⱨᴐᴡ꞉ᴣԜᴡᴒᴑͼꜞԜᴟᴡ꞉ԜꞌͼᴡⱳᴟꜝꜛԝꜝꜞꞌԜᴠᴡ꞉ꜜͼᴡ꞉ꜛᴒ
ⱨᴀᴁ
ⱨᴠꜞԜᴟᴡԜᴡᴒͼԜꜛ꞉ꜜꜝᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒ
ⱨᴂⱪ
ⱨᴟᴒԜͼᴢꜜᴑᴒᴟͼᴡⱳᴒͼꜞꞌԜᴠꜛԜ ᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜ᷄ᴡ꞉ꜛᴒͼᴐᴢᴟᴣᴒ
ⱨᴂⱪ᷇᷄ᴡ
ⱨᴂⱪͼⱱᴟꜝꜛͼᴡ꞉ꜛᴒͼᴧᴒᴟꜝͼᴡꜝͼᴡⱳᴒͼꞌԜᴠᴡͼꜟᴢԜꜜᴡ꞉ⱱ꞉ԜԝꞌᴒͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼ꞉ꜜͼꜞꞌԜᴠꜛԜͼԜᴡͼ
ᴡ꞉ꜛᴒͼᴡ
ⱨᴂⱪ᷇᷄ᶏ
ⱨᴂⱪͼⱱᴟꜝꜛͼᴡ꞉ꜛᴒͼ᷇ͼᴡꜝͼ꞉ꜜⱱ꞉ꜜ꞉ᴡᴦ
ⱨᴂⱪꞌԜᴠᴡ
ⱨᴂⱪͼⱱᴟꜝꜛͼᴡ꞉ꜛᴒͼ᷇ͼᴡꜝͼᴡⱳᴒͼꞌԜᴠᴡͼꜛᴒԜᴠᴢᴟԜԝꞌᴒͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜ
Ⱪꜙⱨ
Ⱪ꞉ꜝꞌꜝⱲ꞉ᴐᴠͼꜙ꞉ᴐᴒꜜᴠᴒͼⱨꜞꜞꞌ꞉ᴐԜᴡ꞉ꜝꜜ
Ⱪꜚⱷ
ⱩꜝᴑᴦͼꜛԜᴠᴠͼ꞉ꜜᴑᴒᴥ
Ⱪ͟
Ⱪꞌꜝꜝᴑͼꜞᴟᴒᴠᴠᴢᴟᴒ
Ⱪᴂ꜠
ⱩꞌꜝꜝᴑͼᴢᴟᴒԜͼꜜ꞉ᴡᴟꜝⱲᴒꜜ
ⱪ᷈᷄ⱷ꜠ⱶ
ⱪ᷈ͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟ
ⱪⱴϸ
ⱪꜝᴑᴒͼꜝⱱͼⱴᴒᴑᴒᴟԜꞌͼϸᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠ
ⱪⱶ꜡
ⱪⱳ꞉ꜜᴒᴠᴒͼⱳԜꜛᴠᴡᴒᴟͼꜝᴣԜᴟᴦ
ⱪꜙ᷆ⱴ
ԜꜞꜞԜᴟᴒꜜᴡͼᴡꜝᴡԜꞌͼꜞꞌԜᴠꜛԜͼᴐꞌᴒԜᴟԜꜜᴐᴒͼԜⱱᴡᴒᴟͼᴒᴥᴡᴟԜᴣԜᴠᴐᴢꞌԜᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜ
ⱪꜛԜᴥ
ꜚԜᴥ꞉ꜛᴢꜛͼꜞꞌԜᴠꜛԜͼᴑᴟᴢⱲͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜ
ⱪ꜡᷉
ⱪԜᴟԝꜝꜜͼᴑ꞉ꜝᴥ꞉ᴑᴒ
ⱪ͟ꜘ
ⱪᴟᴒԜᴡ꞉ꜜᴒͼꜞⱳꜝᴠꜞⱳꜝꞋ꞉ꜜԜᴠᴒ
ⱪϸⱴ
ⱪԜᴠᴒͼᴟᴒꜞꜝᴟᴡͼⱱꜝᴟꜛ
ⱪϸ꜡
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼϸᴒᴠᴒԜᴟᴐⱳͼ꜡ᴟⱲԜꜜ꞉ᴧԜᴡ꞉ꜝꜜ
ⱪᴀϸ
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴀᴡᴢᴑᴦͼϸᴒꜞꜝᴟᴡ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷉Ⱡ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Ⱬꜙᴁ
Ⱬꜝᴠᴒͼꜙ꞉ꜛ꞉ᴡ꞉ꜜⱲͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦ
ⱫꜚⱷⱫ
Ⱬ꞉ᴣ꞉ᴠ꞉ꜝꜜͼꜝⱱͼꜚ꞉ᴐᴟꜝԝ꞉ꜝꞌꜝⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠ
Ⱬ͟
ⱫᴟᴢⱲͼꜞᴟꜝᴑᴢᴐᴡ
ⱫᴀꜚⱩ
ⱫԜᴡԜͼᴀԜⱱᴒᴡᴦͼꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲⱩꜝԜᴟᴑ
ⱬⱪⱵ
ⱬꞌᴒᴐᴡᴟꜝᴐԜᴟᴑ꞉ꜝⱲᴟԜꜛ
ᴒⱪϸⱴ
ⱬꞌᴒᴐᴡᴟꜝꜜ꞉ᴐͼᴐԜᴠᴒͼᴟᴒꜞꜝᴟᴡͼⱱꜝᴟꜛ
ⱬⱫⱪ
ⱬꞌᴒᴐᴡᴟꜝꜜ꞉ᴐͼᴑԜᴡԜͼᴐԜꜞᴡᴢᴟᴒ
ⱬᴁ
ⱬԜᴟꞌᴦͼᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜ
ⱬϷ᷿Ⱬ
ⱬᴢᴟꜝϷꜝꜙͼⱵᴟꜝᴢꜞͼ᷿᷄Ⱬ꞉ꜛᴒꜜᴠ꞉ꜝꜜͼϸᴒꜞꜝᴟᴡͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒ
ⱴᴄⱬϸ
ⱱԜꜛ꞉ꞌᴦ᷄ᴤ꞉ᴠᴒͼᴡᴦꜞᴒⱷᴒᴟᴟꜝᴟͼᴟԜᴡᴒ
ⱴⱫⱨ
ⱴꜝꜝᴑͼԜꜜᴑͼⱫᴟᴢⱲͼⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜ
ⱴᴅⱷӿԜԐ
ⱴԜᴐᴡꜝᴟͼᴅⱷͼӿԜᴐᴡ꞉ᴣԜᴡᴒᴑԐ
ⱴᴅⱷⱷӿԜԐ
ⱴԜᴐᴡꜝᴟͼᴅⱷⱷͼӿԜᴐᴡ꞉ᴣԜᴡᴒᴑԐ
Ⱶⱪ͟
Ⱶꜝꜝᴑͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼ͟ᴟԜᴐᴡ꞉ᴐᴒ
Ⱶⱬⱬ
ⱵᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼᴒᴠᴡ꞉ꜛԜᴡ꞉ꜜⱲͼᴒꜟᴢԜᴡ꞉ꜝꜜ
ⱵⱵᴁ
ⱵԜꜛꜛԜ᷄ⱲꞌᴢᴡԜꜛᴦꞌͼᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒ
ⱶⱨⱬ
ⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜ
ⱶⱩᴠⱨⱲ
ⱶᴒꜞԜᴡ꞉ᴡ꞉ᴠͼⱩͼᴠᴢᴟⱱԜᴐᴒͼԜꜜᴡ꞉Ⱳᴒꜜ
ⱶⱪᴃ
ⱶᴒꜞԜᴡ꞉ᴡ꞉ᴠͼⱪͼᴣ꞉ᴟᴢᴠ
ⱶⱷ͟ⱨⱨ
ⱶᴒԜꞌᴡⱳͼⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ͟ꜝᴟᴡԜԝ꞉ꞌ꞉ᴡᴦͼԜꜜᴑͼⱨᴐᴐꜝᴢꜜᴡԜԝ꞉ꞌ꞉ᴡᴦͼⱨᴐᴡ
ⱶⱷᴃ
ⱶᴢꜛԜꜜͼ꞉ꜛꜛᴢꜜꜝᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦͼᴣ꞉ᴟᴢᴠ
ⱶꜚᴄꜘ
ⱶ꞉ⱲⱳͼꜛꜝꞌᴒᴐᴢꞌԜᴟͼᴤᴒ꞉ⱲⱳᴡͼꞋ꞉ꜜ꞉ꜜꜝⱲᴒꜜ
ⱶϸ
ⱶᴒԜᴟᴡͼᴟԜᴡᴒ
ⱷⱪⱶ
ⱷꜜᴡᴒᴟꜜԜᴡ꞉ꜝꜜԜꞌͼⱪꜝꜜⱱᴒᴟᴒꜜᴐᴒͼꜝꜜͼⱶԜᴟꜛꜝꜜ꞉ᴠԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴒᴐⱳꜜ꞉ᴐԜꞌͼϸᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼ
ⱱꜝᴟͼϸᴒⱲ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼ͟ⱳԜᴟꜛԜᴐᴒᴢᴡ꞉ᴐԜꞌᴠͼⱱꜝᴟͼⱶᴢꜛԜꜜͼᴂᴠᴒ
ⱷⱬⱪ
ⱷꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼⱬᴡⱳ꞉ᴐᴠͼⱪꜝꜛꜛ꞉ᴡᴡᴒᴒ
ⱷⱲⱵ
ⱷꜛꜛᴢꜜꜝⱲꞌꜝԝᴢꞌ꞉ꜜͼⱵ
ⱷⱲⱵ᷈
ⱷꜛꜛᴢꜜꜝⱲꞌꜝԝᴢꞌ꞉ꜜͼⱵͼᴠᴢԝᴐꞌԜᴠᴠͼ᷈
ⱷꜚ͟
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜛᴒᴑ꞉ᴐ꞉ꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡ
ⱷ꜠Ⱬ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼ꜠ᴒᴤͼⱫᴟᴢⱲ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱷ꜠ϸ
ⱷꜜᴡᴒᴟꜜԜᴡ꞉ꜝꜜԜꞌͼꜜꜝᴟꜛԜꞌ꞉ᴧᴒᴑͼᴟԜᴡ꞉ꜝ
ⱷϸⱩ
ⱷꜜᴠᴡ꞉ᴡᴢᴡ꞉ꜝꜜԜꞌͼϸᴒᴣ꞉ᴒᴤͼⱩꜝԜᴟᴑ
ⱷᴂⱫ
ⱷꜜᴡᴟԜᴢᴡᴒᴟ꞉ꜜᴒͼᴑᴒᴣ꞉ᴐᴒ
ⱷᴂᴀ
ⱷꜜᴡᴟԜᴢᴡᴒᴟ꞉ꜜᴒͼⱳꜝᴟꜛꜝꜜᴒͼᴟᴒꞌᴒԜᴠ꞉ꜜⱲͼᴠᴦᴠᴡᴒꜛᴠ
ⱷᴃ
ⱷꜜᴡᴟԜᴣᴒꜜꜝᴢᴠ
ⱷᴄϸᴀ
ⱷꜜᴡᴒᴟԜᴐᴡ꞉ᴣᴒͼᴄᴒԝ᷄ԝԜᴠᴒᴑͼϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼᴀᴦᴠᴡᴒꜛ
ꜘ꞉
꞉ꜜⱳ꞉ԝ꞉ᴡ꞉ꜝꜜͼᴐꜝꜜᴠᴡԜꜜᴡ
ꜙⱫⱶ
ꜙԜᴐᴡԜᴡᴒͼᴑᴒⱳᴦᴑᴟꜝⱲᴒꜜԜᴠᴒ
ꜙ꜡ⱪⱴ
ꜙԜᴠᴡͼꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜͼᴐԜᴟᴟ꞉ᴒᴑͼⱱꜝᴟᴤԜᴟᴑ
ꜙᴁ͟
ꜙꜝꜜⱲ᷄ᴁᴒᴟꜛͼ͟ᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐ
ꜚⱪⱶ
ꜚᴒԜꜜͼᴐꜝᴟꜞᴢᴠᴐᴢꞌԜᴟͼⱳᴒꜛꜝⱲꞌꜝԝ꞉ꜜ
ꜚⱪⱶⱪ
ꜚᴒԜꜜͼᴐꜝᴟꜞᴢᴠᴐᴢꞌԜᴟͼⱳᴒꜛꜝⱲꞌꜝԝ꞉ꜜͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜ
ꜚⱪᴃ
ꜚᴒԜꜜͼᴐꜝᴟꜞᴢᴠᴐᴢꞌԜᴟͼᴣꜝꞌᴢꜛᴒ
ꜚᴒᴑⱫϸⱨ
ꜚᴒᴑ꞉ᴐԜꞌͼⱫ꞉ᴐᴡ꞉ꜝꜜԜᴟᴦͼⱱꜝᴟͼϸᴒⱲᴢꞌԜᴡꜝᴟᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠ
ꜚꜚϸꜚ
ꜚ꞉ᴥᴒᴑͼꜛꜝᴑᴒꞌͼᴟᴒꜞᴒԜᴡᴒᴑͼꜛᴒԜᴠᴢᴟᴒᴠ
꜡ꜙⱬ
꜡ꜞᴒꜜ᷄ꞌԜԝᴒꞌͼᴒᴥᴡᴒꜜᴠ꞉ꜝꜜ
͟Ⱬ
͟ⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐӿᴠԐ
͟ꜘ
͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐӿᴠԐ
ꜞꜘԜꞌ
͟ꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜ
͟ᴁ
͟ᴟꜝᴡⱳᴟꜝꜛԝ꞉ꜜͼᴡ꞉ꜛᴒ
Ϸꜝꜙ
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒ
ϸⱬⱩ
ϸᴒᴠᴒԜᴟᴐⱳͼⱬᴡⱳ꞉ᴐᴠͼⱩꜝԜᴟᴑ
ϸⱩⱪ
ϸᴒᴑͼԝꞌꜝꜝᴑͼᴐᴒꞌꞌͼӿᴐꜝᴢꜜᴡԐ
ϸϸ
ϸᴒᴠꜞ꞉ᴟԜᴡꜝᴟᴦͼᴟԜᴡᴒ
ᴀⱨⱬ
ᴀᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡ
ᴀⱨ͟
ᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼⱨꜜԜꞌᴦᴠ꞉ᴠͼ͟ꞌԜꜜ
ᴀⱪ
ᴀᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠ
ᴀⱫ
ᴀᴡԜꜜᴑԜᴟᴑͼᴑᴒᴣ꞉Ԝᴡ꞉ꜝꜜ
ᴀⱵ꜡ᴁ
ᴀᴒᴟᴢꜛͼⱲꞌᴢᴡԜꜛ꞉ᴐͼꜝᴥԜꞌꜝԜᴐᴒᴡ꞉ᴐͼᴡᴟԜꜜᴠԜꜛ꞉ꜜԜᴠᴒͼӿⱨᴀᴁԐ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴀⱵ͟ᴁ
ᴀᴒᴟᴢꜛͼⱲꞌᴢᴡԜꜛ꞉ᴐͼꜞᴦᴟᴢᴣ꞉ᴐͼᴡᴟԜꜜᴠԜꜛ꞉ꜜԜᴠᴒͼӿⱨꜙᴁԐ
ᴀꜚ
ᴀԜⱱᴒᴡᴦͼꜚԜꜜԜⱲᴒꜛᴒꜜᴡ
ᴀꜚϷ
ᴀᴡԜꜜᴑԜᴟᴑͼꜚᴒᴑⱫϸⱨͼꜟᴢᴒᴟᴦ
ᴀ꜡ⱪ
ᴀᴦᴠᴡᴒꜛͼ꜡ᴟⱲԜꜜͼⱪꞌԜᴠᴠ
ᴀ꜡͟
ᴀᴡԜꜜᴑԜᴟᴑͼꜝꜞᴒᴟԜᴡ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒ
ᴡӷ
ᴁᴒᴟꜛ꞉ꜜԜꞌͼᴒꞌ꞉ꜛ꞉ꜜԜᴡ꞉ꜝꜜͼⱳԜꞌⱱ᷄ꞌ꞉ⱱᴒ
ᴡꜛԜᴥ
ᴁ꞉ꜛᴒͼᴡꜝͼꜛԜᴥ꞉ꜛᴢꜛͼꜞꞌԜᴠꜛԜͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜ
ᴁⱬⱨⱬ
ᴁᴟᴒԜᴡꜛᴒꜜᴡ᷄ⱬꜛᴒᴟⱲᴒꜜᴡͼⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡ
ᴁᴁ
ᴁⱳᴟꜝꜛԝ꞉ꜜͼᴡ꞉ꜛᴒ
ᴂᴀ
ᴂꜜ꞉ᴡᴒᴑͼᴀᴡԜᴡᴒᴠ
ᴃᴑ᷆ⱴ
ⱨꜞꜞԜᴟᴒꜜᴡͼᴣꜝꞌᴢꜛᴒͼꜝⱱͼᴑ꞉ᴠᴡᴟ꞉ԝᴢᴡ꞉ꜝꜜᴑᴢᴟ꞉ꜜⱲͼᴡᴒᴟꜛ꞉ꜜԜꞌͼꜞⱳԜᴠᴒͼԜⱱᴡᴒᴟͼᴒᴥᴡᴟԜᴣԜᴠᴐᴢꞌԜᴟͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜ
ᴄⱩⱪ
ᴄⱳ꞉ᴡᴒͼԝꞌꜝꜝᴑͼᴐᴒꞌꞌͼӿᴐꜝᴢꜜᴡԐ
ᴄⱶ꜡
ᴄꜝᴟꞌᴑͼⱶᴒԜꞌᴡⱳͼ꜡ᴟⱲԜꜜ꞉ᴧԜᴡ꞉ꜝꜜ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
1
INTRODUCTION
1.1
DX-2930
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ᴠͼԜͼⱱᴢꞌꞌᴦͼⱳᴢꜛԜꜜͼⱷⱲⱵ᷈ͼᴟᴒᴐꜝꜛԝ꞉ꜜԜꜜᴡͼꜛꜝꜜꜝᴐꞌꜝꜜԜꞌͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴡⱳԜᴡͼԝ꞉ꜜᴑᴠͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐԜꞌꞌᴦͼᴡꜝͼ
Ԝᴐᴡ꞉ᴣᴒͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜ᷅ͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ᴠͼԝᴒ꞉ꜜⱲͼᴑᴒᴣᴒꞌꜝꜞᴒᴑͼⱱꜝᴟͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜝⱱͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼ
ԜᴡᴡԜᴐꞋᴠͼ꞉ꜜͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼӿⱶⱨⱬԐԓͼԜͼᴠᴒᴟ꞉ꜝᴢᴠͼԜꜜᴑͼꞌ꞉ⱱᴒ᷄ᴡⱳᴟᴒԜᴡᴒꜜ꞉ꜜⱲͼᴑ꞉ᴠᴒԜᴠᴒ᷅
1.2
Hereditary Angioedema
ⱶⱨⱬͼ꞉ᴠͼԜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛԓͼᴑᴒԝ꞉ꞌ꞉ᴡԜᴡ꞉ꜜⱲԓͼԜꜜᴑͼꞌ꞉ⱱᴒ᷄ᴡⱳᴟᴒԜᴡᴒꜜ꞉ꜜⱲͼᴑ꞉ᴠᴒԜᴠᴒͼᴐԜᴢᴠᴒᴑͼԝᴦͼꜛᴢᴡԜᴡ꞉ꜝꜜᴠͼ꞉ꜜͼᴡⱳᴒͼ
ⱪ᷈᷄꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼӿⱪ᷈᷄ⱷ꜠ⱶԐͼⱲᴒꜜᴒԓͼᴟᴒᴠᴢꞌᴡ꞉ꜜⱲͼ꞉ꜜͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦͼꜝᴟͼᴑᴦᴠⱱᴢꜜᴐᴡ꞉ꜝꜜͼꜝⱱͼⱪ᷈᷄ⱷ꜠ⱶͼꜞᴟꜝᴡᴒ꞉ꜜ᷅ͼⱶⱨⱬͼ
ꜛԜꜜ꞉ⱱᴒᴠᴡᴠͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼԜᴠͼᴢꜜꜞᴟᴒᴑ꞉ᴐᴡԜԝꞌᴒԓͼ꞉ꜜᴡᴒᴟꜛ꞉ᴡᴡᴒꜜᴡͼԜᴡᴡԜᴐꞋᴠͼꜝⱱͼᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼꜝᴟͼᴠᴢԝꜛᴢᴐꜝᴠԜꞌͼᴒᴑᴒꜛԜͼ
ꜝⱱͼᴡⱳᴒͼⱱԜᴐᴒԓͼꞌԜᴟᴦꜜᴥԓͼⱲԜᴠᴡᴟꜝ꞉ꜜᴡᴒᴠᴡ꞉ꜜԜꞌͼᴡᴟԜᴐᴡԓͼꞌ꞉ꜛԝᴠͼԜꜜᴑ᷆ꜝᴟͼⱲᴒꜜ꞉ᴡԜꞌ꞉ԜͼӿᴇᴢᴟԜᴤԓͼ᷉᷇᷇˲Ԑ᷅ͼᴀᴤᴒꞌꞌ꞉ꜜⱲͼꜛԜᴦͼꞌԜᴠᴡͼ
ᴢꜞͼᴡꜝͼⱱ꞉ᴣᴒͼꜝᴟͼꜛꜝᴟᴒͼᴑԜᴦᴠⱢͼꜛꜝᴠᴡͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴠᴢⱱⱱᴒᴟͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴦᴒԜᴟ᷅ͼⱶⱨⱬͼ꞉ᴠͼԜꜜͼꜝᴟꜞⱳԜꜜͼ
ᴑ꞉ᴠꜝᴟᴑᴒᴟ᷅ͼᴁⱳᴒͼᴒᴥԜᴐᴡͼꜞᴟᴒᴣԜꞌᴒꜜᴐᴒͼꜝⱱͼⱶⱨⱬͼ꞉ᴠͼᴢꜜꞋꜜꜝᴤꜜԓͼԝᴢᴡͼᴐᴢᴟᴟᴒꜜᴡͼᴒᴠᴡ꞉ꜛԜᴡᴒᴠͼᴟԜꜜⱲᴒͼⱱᴟꜝꜛͼ᷈ͼꜞᴒᴟͼ
᷈᷇ԓ᷇᷇᷇ͼᴡꜝͼ᷈ͼꜞᴒᴟͼ᷿᷈᷇ԓ᷇᷇᷇ͼꜞᴒᴟᴠꜝꜜᴠԓͼᴤ꞉ᴡⱳͼꜛԜꜜᴦͼԜᴢᴡⱳꜝᴟᴠͼԜⱲᴟᴒᴒ꞉ꜜⱲͼᴡⱳԜᴡͼ᷈ꜞᴒᴟ᷿᷇ԓ᷇᷇᷇ͼ꞉ᴠͼꞌ꞉Ꞌᴒꞌᴦͼᴡⱳᴒͼ
ᴐꞌꜝᴠᴒᴠᴡͼᴒᴠᴡ꞉ꜛԜᴡᴒͼӿⱩᴦⱲᴢꜛԓͼ᷉᷇᷇ⱠⱢͼⱵꜝᴟ꞉ꜜⱲͼᴒᴡͼԜꞌ᷅ԓͼ᷈ⱠⱠ˲Ɫͼꜙᴒ꞉ͼᴒᴡͼԜꞌ᷅ԓͼ᷉᷇᷈᷈Ɫͼ꜠ꜝᴟᴑᴒꜜⱱᴒꞌᴡͼᴒᴡͼԜꞌ᷅ԓͼ᷉᷇᷈᷾Ɫͼ
ϸꜝᴐⱳᴒͼᴒᴡͼԜꞌ᷅ԓͼ᷿᷉᷇᷇Ԑ᷅ͼ
ᴀᴤᴒꞌꞌ꞉ꜜⱲͼ꞉ꜜͼᴡⱳᴒͼꞌԜᴟᴦꜜᴥͼᴐԜꜜͼꜝԝᴠᴡᴟᴢᴐᴡͼᴡⱳᴒͼԜ꞉ᴟᴤԜᴦᴠͼԜꜜᴑͼᴐԜᴢᴠᴒͼᴑᴒԜᴡⱳͼⱱᴟꜝꜛͼԜᴠꜞⱳᴦᴥ꞉Ԝᴡ꞉ꜝꜜͼӿⱩꜝᴟꞋͼᴒᴡͼԜꞌ᷅ԓͼ
᷉᷇᷈᷉ⱢͼⱩꜝᴟꞋͼᴒᴡͼԜꞌ᷅ԓͼ᷉᷇᷇᷇Ԑ᷅ͼⱨꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷿᷇ӼͼꜝⱱͼԜꞌꞌͼⱶⱨⱬͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼԜͼꞌԜᴟᴦꜜⱲᴒԜꞌͼ
ԜᴡᴡԜᴐꞋͼ꞉ꜜͼᴡⱳᴒ꞉ᴟͼꞌ꞉ⱱᴒᴡ꞉ꜛᴒԓͼԜꜜᴑͼᴡⱳᴒᴟᴒͼ꞉ᴠͼꜜꜝͼᴤԜᴦͼᴡꜝͼꜞᴟᴒᴑ꞉ᴐᴡͼᴤⱳ꞉ᴐⱳͼꜞԜᴡ꞉ᴒꜜᴡᴠͼԜᴟᴒͼԜᴡͼᴟ꞉ᴠꞋͼꜝⱱͼԜͼꞌԜᴟᴦꜜⱲᴒԜꞌͼ
ԜᴡᴡԜᴐꞋͼӿⱩꜝᴟꞋͼᴒᴡͼԜꞌ᷅ԓͼ᷊᷉᷇᷇ⱢͼⱩꜝᴟꞋͼᴒᴡͼԜꞌ᷅ԓͼ᷉᷇᷇⅍Ԑ᷅ͼ
ⱨԝᴑꜝꜛ꞉ꜜԜꞌͼԜᴡᴡԜᴐꞋᴠͼԜᴟᴒͼꜝⱱᴡᴒꜜͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼꜜԜᴢᴠᴒԜԓͼᴣꜝꜛ꞉ᴡ꞉ꜜⱲԓͼԜꜜᴑͼᴠᴒᴣᴒᴟᴒͼꜞԜ꞉ꜜⱢͼ꞉ꜜᴡᴒᴠᴡ꞉ꜜԜꞌͼ
ᴠᴦꜛꜞᴡꜝꜛᴠͼᴟᴒᴠᴒꜛԝꞌ꞉ꜜⱲͼԜԝᴑꜝꜛ꞉ꜜԜꞌͼᴒꜛᴒᴟⱲᴒꜜᴐ꞉ᴒᴠͼꜛԜᴦͼꞌᴒԜᴑͼᴡꜝͼᴢꜜꜜᴒᴐᴒᴠᴠԜᴟᴦͼᴠᴢᴟⱲᴒᴟᴦͼӿᴇᴢᴟԜᴤԓͼ᷉᷇᷇˲Ԑ᷅ͼ
ⱨꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ˲᷿ӼͼꜝⱱͼꜞԜᴡ꞉ᴒꜜᴡᴠͼⱳԜᴣᴒͼᴁᴦꜞᴒͼⱷͼⱶⱨⱬԓͼᴐⱳԜᴟԜᴐᴡᴒᴟ꞉ᴧᴒᴑͼԝᴦͼᴣᴒᴟᴦͼꞌꜝᴤͼꜞᴟꜝᴑᴢᴐᴡ꞉ꜝꜜͼꜝⱱͼ
ⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌꞌᴦͼꜜꜝᴟꜛԜꞌͼⱪ᷈᷄ⱷ꜠ⱶͼꜞᴟꜝᴡᴒ꞉ꜜԓͼᴤⱳ꞉ꞌᴒͼᴡⱳᴒͼᴟᴒꜛԜ꞉ꜜ꞉ꜜⱲͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷿᷈ӼͼꜝⱱͼꜞԜᴡ꞉ᴒꜜᴡᴠͼⱳԜᴣᴒͼ
ᴁᴦꜞᴒͼⱷⱷͼⱶⱨⱬͼԜꜜᴑͼꜞᴟꜝᴑᴢᴐᴒͼꜜꜝᴟꜛԜꞌͼꜝᴟͼᴒꞌᴒᴣԜᴡᴒᴑͼꞌᴒᴣᴒꞌᴠͼꜝⱱͼԜͼⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌꞌᴦͼ꞉ꜛꜞԜ꞉ᴟᴒᴑͼⱪ᷈᷄ⱷ꜠ⱶͼӿᴇᴢᴟԜᴤԓͼ
᷉᷇᷇˲Ԑ᷅ͼⱷꜜͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼᴁᴦꜞᴒᴠͼⱷͼԜꜜᴑͼⱷⱷͼⱶⱨⱬԓͼᴢꜜᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼⱲᴒꜜᴒᴟԜᴡ꞉ꜝꜜͼᴟᴒᴠᴢꞌᴡᴠͼ꞉ꜜͼ
ᴒᴥᴐᴒᴠᴠͼԝᴟԜᴑᴦꞋ꞉ꜜ꞉ꜜͼᴟᴒꞌᴒԜᴠᴒͼⱱᴟꜝꜛͼⱳ꞉Ⱳⱳ᷄ꜛꜝꞌᴒᴐᴢꞌԜᴟͼᴤᴒ꞉ⱲⱳᴡͼꞋ꞉ꜜ꞉ꜜꜝⱲᴒꜜͼӿⱶꜚᴄꜘԐͼԜꜜᴑͼᴣԜᴠᴐᴢꞌԜᴟͼꞌᴒԜꞋͼ
ꜛᴒᴑ꞉ԜᴡᴒᴑͼԝᴦͼԝᴟԜᴑᴦꞋ꞉ꜜ꞉ꜜͼԝ꞉ꜜᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼⱩ᷉ͼᴟᴒᴐᴒꜞᴡꜝᴟͼӿⱩ᷉᷄ϸԐͼꜝꜜͼᴡⱳᴒͼᴠᴢᴟⱱԜᴐᴒͼꜝⱱͼᴒꜜᴑꜝᴡⱳᴒꞌ꞉Ԝꞌͼᴐᴒꞌꞌᴠͼ
ӿᴇᴢᴟԜᴤԓͼ᷉᷇᷇˲Ԑ᷅ͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴢᴠꜞ꞉ᴐ꞉ꜝꜜͼꜝⱱͼᴁᴦꜞᴒᴠͼⱷͼԜꜜᴑͼⱷⱷͼⱶⱨⱬͼᴐԜꜜͼԝᴒͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԝᴦͼԜᴣԜ꞉ꞌԜԝꞌᴒͼԝꞌꜝꜝᴑͼ
ᴡᴒᴠᴡᴠ᷅ͼⱷꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜͼᴡꜝͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠͼ꞉ꜜͼⱪ᷈᷄ⱷ꜠ⱶͼꞌᴒᴣᴒꞌͼԜꜜᴑͼⱱᴢꜜᴐᴡ꞉ꜝꜜԓͼꜞꞌԜᴠꜛԜͼⱪ᷾ͼꞌᴒᴣᴒꞌᴠͼԜᴟᴒͼꜛԜᴟꞋᴒᴑꞌᴦͼ
ᴟᴒᴑᴢᴐᴒᴑͼԜᴡͼԜꞌꞌͼᴡ꞉ꜛᴒᴠͼ꞉ꜜͼԝꞌꜝꜝᴑͼⱱᴟꜝꜛͼꜛꜝᴠᴡͼꜞԜᴡ꞉ᴒꜜᴡᴠ᷅
1.3
Therapeutic Rationale for DX-2930
͟ꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼꜞꞌԜᴦᴠͼԜͼᴐᴟ꞉ᴡ꞉ᴐԜꞌͼᴟꜝꞌᴒͼ꞉ꜜͼᴡⱳᴒͼꜞԜᴡⱳꜝⱲᴒꜜᴒᴠ꞉ᴠͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼӿⱫԜᴣ꞉ᴠԓͼ᷉᷇᷇⅍ⱢͼꜘԜꜞꞌԜꜜͼ
Ԝꜜᴑͼꜗꜝᴠᴒꜞⱳԓͼ᷉᷇᷈᷇Ԑ᷅ͼⱷꜜͼꜜꜝᴟꜛԜꞌͼꜞⱳᴦᴠ꞉ꜝꞌꜝⱲᴦԓͼⱪ᷈᷄ⱷ꜠ⱶͼᴟᴒⱲᴢꞌԜᴡᴒᴠͼᴡⱳᴒͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼꜝⱱͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼԜᴠͼ
ᴤᴒꞌꞌͼԜᴠͼԜͼᴣԜᴟ꞉ᴒᴡᴦͼꜝⱱͼꜝᴡⱳᴒᴟͼꜞᴟꜝᴡᴒԜᴠᴒᴠԓͼᴠᴢᴐⱳͼԜᴠͼⱪ᷈ᴟԓͼⱪ᷈ᴠԓͼⱱԜᴐᴡꜝᴟᴅⱷԜԓͼԜꜜᴑͼⱱԜᴐᴡꜝᴟͼᴅⱷⱷԜ᷅ͼ͟ꞌԜᴠꜛԜͼ
ꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼᴟᴒⱲᴢꞌԜᴡᴒᴠͼᴡⱳᴒͼᴟᴒꞌᴒԜᴠᴒͼꜝⱱͼԝᴟԜᴑᴦꞋ꞉ꜜ꞉ꜜͼⱱᴟꜝꜛͼⱳ꞉ⱲⱳͼꜛꜝꞌᴒᴐᴢꞌԜᴟͼᴤᴒ꞉ⱲⱳᴡͼꞋ꞉ꜜ꞉ꜜꜝⱲᴒꜜͼӿⱶꜚᴄꜘԐ᷅ͼ
ⱫᴢᴒͼᴡꜝͼԜͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦͼꜝⱱͼⱪ᷈᷄ⱷ꜠ⱶͼ꞉ꜜͼⱶⱨⱬԓͼᴢꜜᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼꜝᴐᴐᴢᴟᴠͼԜꜜᴑͼꞌᴒԜᴑᴠͼ
ᴡꜝͼᴡⱳᴒͼᴒᴥᴐᴒᴠᴠ꞉ᴣᴒͼⱲᴒꜜᴒᴟԜᴡ꞉ꜝꜜͼꜝⱱͼԝᴟԜᴑᴦꞋ꞉ꜜ꞉ꜜ᷅ͼⱩᴟԜᴑᴦꞋ꞉ꜜ꞉ꜜͼ꞉ᴠͼԜͼᴣԜᴠꜝᴑ꞉ꞌԜᴡꜝᴟͼᴤⱳ꞉ᴐⱳͼ꞉ᴠͼᴡⱳꜝᴢⱲⱳᴡͼᴡꜝͼԝᴒͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷊
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴟᴒᴠꜞꜝꜜᴠ꞉ԝꞌᴒͼⱱꜝᴟͼᴡⱳᴒͼᴐⱳԜᴟԜᴐᴡᴒᴟ꞉ᴠᴡ꞉ᴐͼⱶⱨⱬͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜝⱱͼꞌꜝᴐԜꞌ꞉ᴧᴒᴑͼᴠᴤᴒꞌꞌ꞉ꜜⱲԓͼ꞉ꜜⱱꞌԜꜛꜛԜᴡ꞉ꜝꜜԓͼԜꜜᴑͼꜞԜ꞉ꜜͼ
ӿⱪᴟԜ꞉ⱲͼᴒᴡͼԜꞌ᷅ԓͼ᷉᷇᷈᷉ⱢͼᴇᴢᴟԜᴤͼᴒᴡͼԜꞌ᷅ԓͼ᷊᷉᷇᷈Ԑ᷅ͼⱷꜜᴡᴒᴟᴣᴒꜜ꞉ꜜⱲͼԜᴡͼᴡⱳᴒͼꞌᴒᴣᴒꞌͼꜝⱱͼԝᴟԜᴑᴦꞋ꞉ꜜ꞉ꜜͼꜞᴟꜝᴑᴢᴐᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼԜͼ
ꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼᴡⱳᴒᴟᴒⱱꜝᴟᴒͼᴟᴒꜞᴟᴒᴠᴒꜜᴡᴠͼԜꜜͼԜᴡᴡᴟԜᴐᴡ꞉ᴣᴒͼԜꜜᴑͼᴟԜᴡ꞉ꜝꜜԜꞌͼᴡⱳᴒᴟԜꜞᴒᴢᴡ꞉ᴐͼᴠᴡᴟԜᴡᴒⱲᴦͼⱱꜝᴟͼ
ⱶⱨⱬ᷅ͼⱷꜜᴑᴒᴒᴑԓͼᴡⱳᴒͼ꞉ꜛꜞꜝᴟᴡԜꜜᴐᴒͼꜝⱱͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼԜᴠͼԜͼᴑᴟᴢⱲͼᴡԜᴟⱲᴒᴡͼ꞉ꜜͼⱶⱨⱬͼⱳԜᴠԝᴒᴒꜜͼᴣԜꞌ꞉ᴑԜᴡᴒᴑͼ
ᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼꜝԝᴠᴒᴟᴣᴒᴑͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒꜜᴒᴠᴠͼꜝⱱͼꜘԜꞌԝ꞉ᴡꜝᴟᶇӿᴒᴐԜꞌꞌԜꜜᴡ꞉ᴑᴒԐԓͼԜͼꜞᴒꜞᴡ꞉ᴑᴒͼᴡⱳԜᴡͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐԜꞌꞌᴦͼᴡԜᴟⱲᴒᴡᴠͼ
ꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜԓͼᴤⱳ꞉ᴐⱳͼᴤԜᴠͼԜꜞꜞᴟꜝᴣᴒᴑͼԝᴦͼᴡⱳᴒͼⱴⱫⱨͼⱱꜝᴟͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜝⱱͼԜᴐᴢᴡᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼ
ӿꜘԜꞌԝ꞉ᴡꜝᴟᶇ͟ԜᴐꞋԜⱲᴒͼⱷꜜᴠᴒᴟᴡԓͼ᷿᷉᷇᷈Ԑ᷅ͼ
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ᴠͼԜͼⱳ꞉ⱲⱳꞌᴦͼꜞꜝᴡᴒꜜᴡͼԜꜜᴑͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼꜝⱱͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼӿꜘ꞉ͼⱤͼ᷿᷈᷉ͼꜞꜚԐ᷅ͼᴅ᷄ᴟԜᴦͼ
ᴐᴟᴦᴠᴡԜꞌꞌꜝⱲᴟԜꜞⱳᴦͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴐꜝꜛԝ꞉ꜜᴒᴑͼᴤ꞉ᴡⱳͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼᴑᴒꜛꜝꜜᴠᴡᴟԜᴡᴒᴠͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԝ꞉ꜜᴑ꞉ꜜⱲͼᴡꜝͼ
ᴡⱳᴒͼԜᴐᴡ꞉ᴣᴒͼᴠ꞉ᴡᴒͼꜝⱱͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼӿꜘᴒꜜꜜ꞉ᴠᴡꜝꜜͼᴒᴡͼԜꞌ᷅ԓͼ᷉᷇᷈᷾Ԑ᷅
1.4
Safety Rationale for DX-2930
ᴀԜⱱᴒᴡᴦͼᴑԜᴡԜͼⱱᴟꜝꜛͼᴡⱳᴒͼ͟ⱳԜᴠᴒͼ᷈Ԝͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦԓͼԜͼⱱ꞉ᴟᴠᴡ᷄꞉ꜜ᷄ⱳᴢꜛԜꜜͼᴠᴡᴢᴑᴦͼᴤ꞉ᴡⱳͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ꜜͼⱳᴒԜꞌᴡⱳᴦͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴑ꞉ᴑͼꜜꜝᴡͼ꞉ᴑᴒꜜᴡ꞉ⱱᴦͼԜꜜᴦͼᴠԜⱱᴒᴡᴦͼᴐꜝꜜᴐᴒᴟꜜᴠ᷅ͼᴀ꞉ꜜⱲꞌᴒͼᴑꜝᴠᴒᴠͼᴢꜞͼᴡꜝͼ᷊ͼꜛⱲ᷆ꞋⱲͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤᴒᴟᴒͼᴤᴒꞌꞌ᷄
ᴡꜝꞌᴒᴟԜᴡᴒᴑ᷅ͼᴁⱳᴒᴟᴒͼᴤᴒᴟᴒͼꜜꜝͼᴑꜝᴠᴒ᷄ꞌ꞉ꜛ꞉ᴡ꞉ꜜⱲᴡꜝᴥ꞉ᴐ꞉ᴡ꞉ᴒᴠԓͼᴠᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠԓͼꜝᴟͼԜꜜᴦͼꜝᴡⱳᴒᴟͼᴠԜⱱᴒᴡᴦͼ
ᴐꜝꜜᴐᴒᴟꜜᴠͼ꞉ᴑᴒꜜᴡ꞉ⱱ꞉ᴒᴑ᷅
͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐͼӿ͟ꜘԐͼᴑԜᴡԜͼⱱᴟꜝꜛͼᴡⱳᴒͼ͟ⱳԜᴠᴒͼ᷈ԜͼԜꜜᴑͼ᷈ԝͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑ꞉ᴒᴠͼ꞉ꜜͼᴐꜝꜜ꞊ᴢꜜᴐᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼᴑԜᴡԜͼ
ⱱᴟꜝꜛͼᴡⱳᴒͼꜜꜝꜜᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦͼᴠᴡᴢᴑ꞉ᴒᴠͼᴠᴢꜞꜞꜝᴟᴡͼԜͼᴤ꞉ᴑᴒͼᴠԜⱱᴒᴡᴦͼꜛԜᴟⱲ꞉ꜜ᷅ͼᴁⱳᴒͼꜛᴒԜꜜͼⱪꜛԜᴥⱱꜝᴟⱳᴢꜛԜꜜͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡᴟᴒԜᴡᴒᴑͼԜᴡͼԜͼᴑꜝᴠᴒͼꜝⱱͼ᷊᷇᷇ͼꜛⱲͼꜝꜜͼⱫԜᴦᴠͼ᷈ͼԜꜜᴑͼ᷿᷈ͼᴤԜᴠͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷉ⅎͼⱲ᷆ꜛꜙ᷅ͼⱨᴠͼ
ᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜԓͼԜͼꜛᴒԜꜜͼⱪꜛԜᴥꜝⱱͼⅎ᷾᷾ͼⱲͼ᷆ꜛꜙͼᴤԜᴠͼꜝԝᴠᴒᴟᴣᴒᴑͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴑꜝᴠ꞉ꜜⱲͼꜝⱱͼꜛꜝꜜꞋᴒᴦᴠͼᴤ꞉ᴡⱳͼ
᷿᷇ꜛⱲ᷆ꞋⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴀⱪͼᴤᴒᴒꞋꞌᴦͼⱱꜝᴟͼ⅍ͼꜛꜝꜜᴡⱳᴠͼᴟᴒᴠᴢꞌᴡ꞉ꜜⱲͼ꞉ꜜͼԜͼᴠԜⱱᴒᴡᴦͼꜛԜᴟⱲ꞉ꜜͼꜝⱱͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷉˲᷄
ⱱꜝꞌᴑ᷅ͼ꜠ꜝͼᴡꜝᴥ꞉ᴐꜝꞌꜝⱲ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼᴤᴒᴟᴒͼꜝԝᴠᴒᴟᴣᴒᴑͼ꞉ꜜͼᴡⱳᴒᴠᴒͼᴡᴟᴒԜᴡᴒᴑͼԜꜜ꞉ꜛԜꞌᴠͼꜝᴟͼ꞉ꜜͼԜꜜᴦͼ
ꜝᴡⱳᴒᴟͼꜜꜝꜜᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦͼᴠᴡᴢᴑᴦͼᴡꜝͼᴑԜᴡᴒͼⱱꜝᴟͼᴠᴦᴠᴡᴒꜛ꞉ᴐԜꞌꞌᴦͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼⱫᴅ᷄᷉Ⱡ᷊᷇᷅
ᴀԜⱱᴒᴡᴦͼᴑԜᴡԜͼ꞉ᴠͼԜꞌᴠꜝͼԜᴣԜ꞉ꞌԜԝꞌᴒͼⱱᴟꜝꜛͼᴡⱳᴒͼ͟ⱳԜᴠᴒͼ᷈ԝͼᴠᴡᴢᴑᴦԓͼԜͼꜛᴢꞌᴡ꞉ꜞꞌᴒ᷄Ԝᴠᴐᴒꜜᴑ꞉ꜜⱲͼᴑꜝᴠᴒͼᴠᴡᴢᴑᴦͼ꞉ꜜͼⱶⱨⱬͼ
ꜞԜᴡ꞉ᴒꜜᴡᴠ᷅ͼⱷꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦԓͼᴡᴤꜝͼᴑꜝᴠᴒᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴢꜞͼᴡꜝͼ᷾᷇᷇ͼꜛⱲͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼ᷈᷾ͼᴑԜᴦᴠͼԜꜞԜᴟᴡͼᴤᴒᴟᴒͼ
ᴤᴒꞌꞌ᷄ᴡꜝꞌᴒᴟԜᴡᴒᴑ᷅ͼᴁⱳᴒᴟᴒͼᴤᴒᴟᴒͼꜜꜝͼᴑꜝᴠᴒ᷄ꞌ꞉ꜛ꞉ᴡ꞉ꜜⱲͼᴡꜝᴥ꞉ᴐ꞉ᴡ꞉ᴒᴠԓͼᴠᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼ꞉ꜜͼԜꜜᴦͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ
ᴡᴟᴒԜᴡᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠԓͼꜝᴟͼԜꜜᴦͼꜝᴡⱳᴒᴟͼᴠԜⱱᴒᴡᴦͼᴐꜝꜜᴐᴒᴟꜜᴠͼ꞉ᴑᴒꜜᴡ꞉ⱱ꞉ᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼꜝⱱͼⱶⱨⱬͼꜞԜᴡ꞉ᴒꜜᴡᴠ᷅ͼ
͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐͼᴑԜᴡԜͼⱱᴟꜝꜛͼᴡⱳᴒͼ᷈ԝͼᴠᴡᴢᴑᴦͼⱱꜝᴢꜜᴑͼᴡⱳԜᴡͼᴡⱳᴒͼᴑᴟᴢⱲͼᴒᴥꜞꜝᴠᴢᴟᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡᴤꜝͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼӿᴢꜞͼᴡꜝͼԜͼꜛԜᴥ꞉ꜛᴢꜛͼꜝⱱͼ᷾᷇᷇ͼꜛⱲԐͼᴤԜᴠͼᴠᴢԝᴠᴡԜꜜᴡ꞉ԜꞌꞌᴦͼꞌᴒᴠᴠͼᴡⱳԜꜜͼᴡⱳԜᴡͼ
ԜᴡᴡԜ꞉ꜜᴒᴑͼԜꜜᴑͼᴒᴣԜꞌᴢԜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼꜜꜝꜜᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦͼᴠᴡᴢᴑ꞉ᴒᴠ᷅
ⱴꜝᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴑᴒᴡԜ꞉ꞌͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼᴟԜᴡ꞉ꜝꜜԜꞌᴒͼⱱꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼꜞꞌᴒԜᴠᴒͼᴟᴒⱱᴒᴟͼᴡꜝͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼⱩᴟꜝᴐⱳᴢᴟᴒ᷅
1.5
DX-2930 Non-Clinical Pharmacology and Toxicology
ⱴꜝᴟͼᴑᴒᴡԜ꞉ꞌͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴡⱳᴒͼꜜꜝꜜᴐꞌ꞉ꜜ꞉ᴐԜꞌͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠԓ ꜞꞌᴒԜᴠᴒͼᴟᴒⱱᴒᴟͼᴡꜝͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼ
Ⱪᴟꜝᴐⱳᴢᴟᴒ᷅
1.6
DX-2930 Clinical Data
ᴁⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴑᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡͼꜞᴟꜝⱲᴟԜꜛͼᴡꜝͼᴑԜᴡᴒͼⱱꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴐꜝꜜᴠ꞉ᴠᴡᴠͼꜝⱱͼ᷉ͼᴠᴡᴢᴑ꞉ᴒᴠͼᴡꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼ
ᴠԜⱱᴒᴡᴦԓͼᴡꜝꞌᴒᴟԜԝ꞉ꞌ꞉ᴡᴦԓͼԜꜜᴑͼ͟ꜘͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԜͼ͟ⱳԜᴠᴒͼ᷈Ԝ ᴠ꞉ꜜⱲꞌᴒ᷄Ԝᴠᴐᴒꜜᴑ꞉ꜜⱲͼᴑꜝᴠᴒͼᴠᴡᴢᴑᴦͼ꞉ꜜͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱳᴒԜꞌᴡⱳᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜꜜᴑͼԜͼ͟ⱳԜᴠᴒͼ᷈ԝͼꜛᴢꞌᴡ꞉ꜞꞌᴒ᷄Ԝᴠᴐᴒꜜᴑ꞉ꜜⱲͼᴑꜝᴠᴒͼᴠᴡᴢᴑᴦͼ꞉ꜜͼⱶⱨⱬͼꜞԜᴡ꞉ᴒꜜᴡᴠ᷅ͼᴁⱳᴒᴠᴒͼᴠᴡᴢᴑ꞉ᴒᴠͼ
ԜᴟᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼ꞉ꜜͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴠᴒᴐᴡ꞉ꜝꜜᴠ᷅
1.6.1
Single-Ascending Dose Study in Healthy Subjects (DX-2930-01)
Ⱬᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷈ͼᴤԜᴠͼԜͼ͟ⱳԜᴠᴒͼ᷈ԜͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑԓͼꜞꞌԜᴐᴒԝꜝ᷄ᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼᴠᴡᴢᴑᴦͼ꞉ꜜͼⱳᴒԜꞌᴡⱳᴦͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦԓͼᴡꜝꞌᴒᴟԜԝ꞉ꞌ꞉ᴡᴦԓͼԜꜜᴑͼ͟ꜘͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼԜͼᴠ꞉ꜜⱲꞌᴒԓͼᴀⱪͼᴑꜝᴠᴒͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇᷅ͼ
͟Ԝᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤᴒᴟᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼꜞꞌԜᴐᴒԝꜝͼꜝᴟͼԜᴐᴡ꞉ᴣᴒͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼᴤ꞉ᴡⱳ꞉ꜜͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼ
ⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴠᴒꜟᴢᴒꜜᴡ꞉ԜꞌԓͼԜᴠᴐᴒꜜᴑ꞉ꜜⱲͼᴑꜝᴠᴒͼᴐꜝⱳꜝᴟᴡᴠⱡͼ᷇᷅᷈ԓͼ᷊᷇᷅ԓͼ᷈᷅᷇ԓͼꜝᴟͼ᷊᷅᷇ͼꜛⱲ᷆ꞋⱲ᷅ͼⱴꜝᴟͼᴒԜᴐⱳͼᴑꜝᴠ꞉ꜜⱲͼᴐꜝⱳꜝᴟᴡԓͼ
⅍ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤᴒᴟᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼԜᴐᴡ꞉ᴣᴒͼᴑᴟᴢⱲͼԜꜜᴑͼ᷉ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼꜞꞌԜᴐᴒԝꜝ᷅ͼ
ⱨͼᴡꜝᴡԜꞌͼꜝⱱͼ᷊᷉ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜꜜᴑͼᴤᴒᴟᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑ᷅ͼᴁⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼᴤᴒᴟᴒͼ
ᴤᴒꞌꞌͼԝԜꞌԜꜜᴐᴒᴑͼⱱꜝᴟͼᴑᴒꜛꜝⱲᴟԜꜞⱳ꞉ᴐͼᴐⱳԜᴟԜᴐᴡᴒᴟ꞉ᴠᴡ꞉ᴐᴠ᷅ͼᴁⱳᴒͼԜᴐᴡᴢԜꞌͼᴑꜝᴠᴒͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴡꜝͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴟԜꜜⱲᴒᴑͼⱱᴟꜝꜛͼ⅍᷅᷉ꜛⱲͼӿ꞉ꜜͼᴡⱳᴒͼ᷇᷅᷈ͼꜛⱲ᷆ꞋⱲͼⱲᴟꜝᴢꜞԐͼᴡꜝͼ᷊᷇᷇ͼꜛⱲͼӿ꞉ꜜͼᴡⱳᴒͼ᷊᷅᷇ͼꜛⱲ᷆ꞋⱲͼⱲᴟꜝᴢꜞԐͼԜᴐᴟꜝᴠᴠͼ
Ԝꞌꞌͼᴐꜝⱳꜝᴟᴡᴠ᷅
ⱩԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼԜꜜԜꞌᴦᴠ꞉ᴠԓͼԜͼᴠ꞉ꜜⱲꞌᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤԜᴠͼᴤᴒꞌꞌͼᴡꜝꞌᴒᴟԜᴡᴒᴑͼᴢꜞͼᴡꜝͼᴑꜝᴠᴒᴠͼ
ꜝⱱͼ᷊᷅᷇ͼꜛⱲ᷆ꞋⱲͼᴤ꞉ᴡⱳꜝᴢᴡͼᴒᴣ꞉ᴑᴒꜜᴐᴒͼꜝⱱͼᴑꜝᴠᴒ᷄ꞌ꞉ꜛ꞉ᴡ꞉ꜜⱲͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦ᷅ͼᴁⱳᴒᴟᴒͼᴤᴒᴟᴒͼꜜꜝͼᴑᴒԜᴡⱳᴠԓͼᴀⱨⱬᴠԓͼꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡͼ
ᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜᴠͼᴑᴢᴒͼᴡꜝͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼӿⱨⱬᴠԐͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼⱴᴢᴟᴡⱳᴒᴟꜛꜝᴟᴒԓͼᴡⱳᴒᴟᴒͼᴤԜᴠͼꜜꜝͼ
ᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼ꞉ꜛԝԜꞌԜꜜᴐᴒͼԝᴒᴡᴤᴒᴒꜜͼꜞꞌԜᴐᴒԝꜝͼԜꜜᴑͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱱꜝᴟͼԜꜜᴦͼꜞԜᴟᴡ꞉ᴐᴢꞌԜᴟͼᴡᴟᴒԜᴡꜛᴒꜜᴡ᷄ᴒꜛᴒᴟⱲᴒꜜᴡͼ
ԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡͼӿᴁⱬⱨⱬԐ᷅ͼᴁⱳᴒͼꜛꜝᴠᴡͼᴐꜝꜛꜛꜝꜜꞌᴦͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴁⱬⱨⱬͼᴤԜᴠͼⱳᴒԜᴑԜᴐⱳᴒԓͼᴤⱳ꞉ᴐⱳͼꜝᴐᴐᴢᴟᴟᴒᴑͼԜᴡͼԜͼ
ᴟԜᴡᴒͼꜝⱱͼ᷿᷉ӼͼⱱꜝᴟͼԝꜝᴡⱳͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑͼꜞꞌԜᴐᴒԝꜝ᷅
ᴁⱳᴒͼ͟ꜘͼꜞᴟꜝⱱ꞉ꞌᴒͼᴑᴒꜛꜝꜜᴠᴡᴟԜᴡᴒᴑͼꞌ꞉ꜜᴒԜᴟԓͼᴑꜝᴠᴒ᷄ᴑᴒꜞᴒꜜᴑᴒꜜᴡͼᴑᴟᴢⱲͼᴒᴥꜞꜝᴠᴢᴟᴒͼᴤ꞉ᴡⱳͼԜͼꜛᴒԜꜜͼⱳԜꞌⱱ᷄ꞌ꞉ⱱᴒͼꜝⱱͼ
Ԝꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷈ⅎͼᴡꜝͼ᷉᷈ͼᴑԜᴦᴠͼԜᴐᴟꜝᴠᴠͼᴑꜝᴠᴒͼⱲᴟꜝᴢꜞᴠ᷅ͼϸᴒᴠᴢꞌᴡᴠͼⱱᴟꜝꜛͼᴡᴤꜝͼᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼԝ꞉ꜝꜛԜᴟꞋᴒᴟͼԜᴠᴠԜᴦᴠͼ
ꜞᴟꜝᴣ꞉ᴑᴒͼᴒᴣ꞉ᴑᴒꜜᴐᴒͼⱱꜝᴟͼԜꜜͼ꞉ꜛꜞꜝᴟᴡԜꜜᴡͼꜞⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼᴒⱱⱱᴒᴐᴡͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ꜜͼⱳᴢꜛԜꜜᴠ᷅ͼ
ⱴꜝᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴑᴒᴡԜ꞉ꞌͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴡⱳᴒͼᴠ꞉ꜜⱲꞌᴒͼᴑꜝᴠᴒԓͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦͼ꞉ꜜͼⱳᴒԜꞌᴡⱳᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠԓͼꜞꞌᴒԜᴠᴒͼᴟᴒⱱᴒᴟͼᴡꜝͼ
ᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼⱩᴟꜝᴐⱳᴢᴟᴒ᷅
1.6.2
Multiple-Ascending Dose Study in HAE Patients (DX-2930-02)
Ⱬᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉ͼᴤԜᴠͼԜͼ͟ⱳԜᴠᴒͼ᷈ԝͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑԓͼꜞꞌԜᴐᴒԝꜝ᷄ᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑԓͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼԜᴠᴐᴒꜜᴑ꞉ꜜⱲ᷄
ᴑꜝᴠᴒͼᴠᴡᴢᴑᴦͼ꞉ꜜͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼⱶⱨⱬͼᴡꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴠԜⱱᴒᴡᴦԓͼᴡꜝꞌᴒᴟԜԝ꞉ꞌ꞉ᴡᴦԓͼԜꜜᴑͼ͟ꜘͼꜝⱱͼᴀⱪͼⱫᴅ᷄᷉Ⱡ᷊᷇᷅ͼ
͟Ԝᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤᴒᴟᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼ᷉ⱡ᷈ͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼᴒ꞉ᴡⱳᴒᴟͼԜᴐᴡ꞉ᴣᴒͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼꜝᴟͼꜞꞌԜᴐᴒԝꜝͼᴤ꞉ᴡⱳ꞉ꜜͼ
ꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴠᴒꜟᴢᴒꜜᴡ꞉ԜꞌԓͼԜᴠᴐᴒꜜᴑ꞉ꜜⱲͼᴑꜝᴠᴒͼᴐꜝⱳꜝᴟᴡᴠⱡͼ᷊᷇ԓͼ᷈᷇᷇ԓͼ᷊᷇᷇ԓͼꜝᴟͼ᷾᷇᷇ꜛⱲͼӿꜜꜝꜛ꞉ꜜԜꞌͼ⅍ͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼꜞᴒᴟͼᴐꜝⱳꜝᴟᴡԐ᷅ͼⱬԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼ᷉ͼᴑꜝᴠᴒᴠͼꜝⱱͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼᴠᴒꜞԜᴟԜᴡᴒᴑͼԝᴦͼ᷈᷾ͼᴑԜᴦᴠͼԜꜜᴑͼᴤᴒᴟᴒͼ
ⱱꜝꞌꞌꜝᴤᴒᴑͼⱱꜝᴟͼ᷿᷈ͼᴤᴒᴒꞋᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼᴠᴒᴐꜝꜜᴑͼᴑꜝᴠᴒ᷅ͼ
ⱨͼᴡꜝᴡԜꞌͼꜝⱱͼ᷊ⅎͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤᴒᴟᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼԜꜜᴑͼᴡᴟᴒԜᴡᴒᴑͼᴤ꞉ᴡⱳͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝ᷅ͼ꜡ꜜᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ꜜͼᴡⱳᴒͼ
᷾᷇᷇ͼꜛⱲͼᴑꜝᴠᴒͼⱲᴟꜝᴢꜞͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼԜͼᴠ꞉ꜜⱲꞌᴒͼᴑꜝᴠᴒͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑԓͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴠᴒᴣᴒᴟԜꞌͼᴢꜜᴠᴢᴐᴐᴒᴠᴠⱱᴢꞌͼ
Ԝᴡᴡᴒꜛꜞᴡᴠͼᴡꜝͼᴠᴐⱳᴒᴑᴢꞌᴒͼᴡⱳᴒ꞉ᴟͼᴠᴒᴐꜝꜜᴑͼᴑꜝᴠᴒԓͼᴤԜᴠͼᴟᴒꜞꞌԜᴐᴒᴑ᷅ͼᴁⱳ꞉ᴠͼᴠᴢԝ꞊ᴒᴐᴡͼᴟᴒᴡᴢᴟꜜᴒᴑͼⱱꜝᴟͼԜͼᴠ꞉ꜜⱲꞌᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼ
ᴣ꞉ᴠ꞉ᴡͼԝᴒⱱꜝᴟᴒͼԝᴒ꞉ꜜⱲͼꞌꜝᴠᴡͼᴡꜝͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼⱱꜝᴟͼᴟᴒԜᴠꜝꜜᴠͼꜜꜝᴡͼᴟᴒꞌԜᴡᴒᴑͼᴡꜝͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼϸꜝᴢᴡ꞉ꜜᴒͼⱪ᷈᷄ⱷ꜠ⱶͼᴡᴒᴠᴡ꞉ꜜⱲͼ
ᴟᴒᴣᴒԜꞌᴒᴑͼᴡⱳԜᴡͼꜝꜜᴒͼꜝᴡⱳᴒᴟͼᴠᴢԝ꞊ᴒᴐᴡͼᴑ꞉ᴑͼꜜꜝᴡͼⱳԜᴣᴒͼⱶⱨⱬͼᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷԓͼᴑᴒᴠꜞ꞉ᴡᴒͼԜͼⱳ꞉ᴠᴡꜝᴟ꞉ᴐԜꞌͼꞌԜԝͼᴡᴒᴠᴡͼ
꞉ꜜᴑ꞉ᴐԜᴡ꞉ꜜⱲͼꜝᴡⱳᴒᴟᴤ꞉ᴠᴒ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷿
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴀᴢԝ꞊ᴒᴐᴡͼᴑᴒꜛꜝⱲᴟԜꜞⱳ꞉ᴐᴠͼᴤᴒᴟᴒͼԝԜꞌԜꜜᴐᴒᴑͼ꞉ꜜͼᴡᴒᴟꜛᴠͼꜝⱱͼԜⱲᴒԓͼᴟԜᴐᴒԓͼᴒᴡⱳꜜ꞉ᴐ꞉ᴡᴦͼԜꜜᴑͼⱩꜚⱷ᷅ͼᴁⱳᴒᴟᴒͼᴤᴒᴟᴒͼ
ᴠꞌ꞉ⱲⱳᴡꞌᴦͼꜛꜝᴟᴒͼⱱᴒꜛԜꞌᴒᴠͼ꞉ꜜͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱲᴟꜝᴢꜞͼᴡⱳԜꜜͼ꞉ꜜͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼӿ⅍⅍᷅ⅎӼͼᴣᴒᴟᴠᴢᴠͼ᷿᷊᷅˲ӼԐ᷅ͼ
ᴁⱳᴒͼꜛꜝᴠᴡͼᴐꜝꜛꜛꜝꜜͼⱨⱬᴠͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴤᴒᴟᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼᴠ꞉ᴡᴒͼꜞԜ꞉ꜜԓͼԜꜜᴑͼⱳᴒԜᴑԜᴐⱳᴒ᷅ͼᴁⱳᴒͼᴟԜᴡᴒᴠ
ᴤᴒᴟᴒͼꜜꜝᴡͼԜꜞꜞᴟᴒᴐ꞉Ԝԝꞌᴦͼⱳ꞉Ⱳⱳᴒᴟͼ꞉ꜜͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴐꜝꜛꜞԜᴟᴒᴑͼᴡꜝͼꜞꞌԜᴐᴒԝꜝ᷅ͼᴁᴤꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤᴒᴟᴒͼ
ᴟᴒꜞꜝᴟᴡᴒᴑͼᴡꜝͼⱳԜᴣᴒͼ᷊ͼᴟᴒꞌԜᴡᴒᴑͼᴠᴒᴣᴒᴟᴒͼᴁⱬⱨⱬᴠ᷅ͼ꜡ꜜᴒͼꜝⱱͼᴡⱳᴒᴠᴒͼᴤԜᴠͼԜͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴢԝ꞊ᴒᴐᴡͼӿ᷊᷇ͼꜛⱲԐͼᴤ꞉ᴡⱳͼ
꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼᴠ꞉ᴡᴒͼꜞԜ꞉ꜜͼꞌԜᴠᴡ꞉ꜜⱲͼ᷈ͼꜛ꞉ꜜᴢᴡᴒͼԜꜜᴑͼꜝꜜᴒͼᴤԜᴠͼԜͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴢԝ꞊ᴒᴐᴡͼӿ᷾᷇᷇ͼꜛⱲԐ ᴤ꞉ᴡⱳͼᴤꜝᴟᴠᴒꜜ꞉ꜜⱲͼ
ⱳᴒԜᴑԜᴐⱳᴒͼꞌԜᴠᴡ꞉ꜜⱲͼ᷈ͼꜛ꞉ꜜᴢᴡᴒͼԜꜜᴑͼꜜ꞉ⱲⱳᴡͼᴠᴤᴒԜᴡᴠ᷅
꜠ꜝͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠͼᴤᴒᴟᴒͼ꞉ᴑᴒꜜᴡ꞉ⱱ꞉ᴒᴑͼⱱꜝᴟͼᴣ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠԓͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜᴠԓͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠԓͼ
ꜝᴟͼᴒꞌᴒᴐᴡᴟꜝᴐԜᴟᴑ꞉ꜝⱲᴟԜꜛᴠͼӿⱬⱪⱵԐ᷅ͼϸᴒᴠᴢꞌᴡᴠͼᴠᴢⱲⱲᴒᴠᴡͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤԜᴠͼᴤᴒꞌꞌͼᴡꜝꞌᴒᴟԜᴡᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼᴤ꞉ᴡⱳͼꜜꜝͼ
ᴒᴣ꞉ᴑᴒꜜᴐᴒͼꜝⱱͼᴑꜝᴠᴒ᷄ꞌ꞉ꜛ꞉ᴡ꞉ꜜⱲͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦͼԜᴡͼᴑꜝᴠᴒᴠͼᴢꜞͼᴡꜝͼ᷾᷇᷇ͼꜛⱲ᷅ͼ
ⱨͼᴡꜝᴡԜꞌͼꜝⱱͼ᷊ͼꜝᴢᴡͼꜝⱱͼⱠ᷉ͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼᴠԜꜛꜞꞌᴒᴠͼӿ᷊᷊᷅ӼԐԓͼꜝԝᴡԜ꞉ꜜᴒᴑͼⱱᴟꜝꜛͼ᷉ͼꜝᴢᴡͼꜝⱱͼ᷊᷉ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼӿ˲᷅ⅎӼԐԓͼᴤᴒᴟᴒͼ
ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼᴡꜝͼԝᴒͼԜꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦ᷄ꜞꜝᴠ꞉ᴡ꞉ᴣᴒ᷅ͼ꜠ꜝͼᴠԜꜛꜞꞌᴒᴠͼᴤᴒᴟᴒͼꜞꜝᴠ꞉ᴡ꞉ᴣᴒͼⱱꜝᴟͼꜜᴒᴢᴡᴟԜꞌ꞉ᴧ꞉ꜜⱲͼԜᴐᴡ꞉ᴣ꞉ᴡᴦ᷅
ᴁⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐͼԜꜜԜꞌᴦᴠ꞉ᴠͼⱱꜝᴟͼԜꞌꞌͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴡⱳᴒͼ᷊᷇ԓͼ᷈᷇᷇ԓͼ᷊᷇᷇ԓͼԜꜜᴑͼ᷾᷇᷇ͼꜛⱲͼᴑꜝᴠᴒᴠͼᴠⱳꜝᴤᴒᴑͼᴑᴟᴢⱲͼ
ꞌᴒᴣᴒꞌᴠͼ꞉ꜜͼⱶⱨⱬͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤᴒᴟᴒͼᴑꜝᴠᴒ᷄ᴑᴒꜞᴒꜜᴑᴒꜜᴡͼԜꜜᴑͼᴒᴥⱳ꞉ԝ꞉ᴡᴒᴑͼԜͼꜞᴟꜝꞌꜝꜜⱲᴒᴑͼⱳԜꞌⱱ᷄ꞌ꞉ⱱᴒͼꜝⱱͼ
Ԝꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷉ͼᴤᴒᴒꞋᴠԓͼᴡᴦꜞ꞉ᴐԜꞌͼꜝⱱͼԜͼⱳᴢꜛԜꜜͼꜛꜝꜜꜝᴐꞌꜝꜜԜꞌͼԜꜜᴡ꞉ԝꜝᴑᴦ᷅ͼⱪꜛԜᴥᴑᴟᴢⱲͼꞌᴒᴣᴒꞌᴠͼ꞉ꜜᴐᴟᴒԜᴠᴒᴑͼᴤ꞉ᴡⱳͼ
꞉ꜜᴐᴟᴒԜᴠ꞉ꜜⱲͼᴑꜝᴠᴒԓͼԜᴠͼᴒᴥꜞᴒᴐᴡᴒᴑ᷅ͼᴁⱳᴒᴠᴒͼꜞԜᴟԜꜛᴒᴡᴒᴟᴠͼԜᴟᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒᴑͼᴤ꞉ᴡⱳͼᴣԜꞌᴢᴒᴠͼꜝԝᴡԜ꞉ꜜᴒᴑͼ꞉ꜜͼⱳᴒԜꞌᴡⱳᴦͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴠᴡᴢᴑᴦͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷈᷅
ⱨͼᴄᴒᴠᴡᴒᴟꜜͼԝꞌꜝᴡͼԜᴠᴠԜᴦͼᴠⱳꜝᴤᴒᴑͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼꞌᴒᴣᴒꞌᴠͼꜝⱱͼꜛᴒԜꜜͼ᷉᷄ᴐⱳԜ꞉ꜜͼⱳ꞉Ⱳⱳ᷄ꜛꜝꞌᴒᴐᴢꞌԜᴟ᷄ᴤᴒ꞉Ⱳⱳᴡͼ
Ꞌ꞉ꜜ꞉ꜜꜝⱲᴒꜜͼӿⱶꜚᴄꜘԐͼ꞉ꜜͼᴢꜜԜᴐᴡ꞉ᴣԜᴡᴒᴑͼꜞꞌԜᴠꜛԜͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼⱱᴟꜝꜛͼⱶⱨⱬͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤԜᴠͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ
᷿᷇Ӽ᷅ͼⱨͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ꜜͼ᷉᷄ᴐⱳԜ꞉ꜜͼⱶꜚᴄꜘͼꞌᴒᴣᴒꞌᴠͼᴤԜᴠͼꜝԝᴠᴒᴟᴣᴒᴑͼꜝꜜͼᴠᴡᴢᴑᴦͼᴑԜᴦᴠͼ˲ͼ
Ԝꜜᴑͼ᷉᷉ͼ꞉ꜜͼᴡⱳᴒͼ᷊᷇᷇ͼԜꜜᴑͼ᷾᷇᷇ͼꜛⱲͼᴑꜝᴠᴒͼⱲᴟꜝᴢꜞᴠͼᴐꜝꜛꜞԜᴟᴒᴑͼᴡꜝͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꞌᴒᴣᴒꞌᴠԓͼꞌᴒᴣᴒꞌᴠͼᴠ꞉ꜛ꞉ꞌԜᴟͼᴡꜝͼᴡⱳԜᴡͼ
ꜝԝᴠᴒᴟᴣᴒᴑͼ꞉ꜜͼⱳᴒԜꞌᴡⱳᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠ᷅ͼᴁⱳ꞉ᴠͼꜝᴢᴡᴐꜝꜛᴒͼᴑᴒꜛꜝꜜᴠᴡᴟԜᴡᴒᴠͼᴡⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼꜝⱱͼⱫᴅ᷄
᷉Ⱡ᷊᷇ͼԜꜜᴑͼ꞉ᴡᴠͼԜԝ꞉ꞌ꞉ᴡᴦͼᴡꜝͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒꞌᴦͼꜜꜝᴟꜛԜꞌ꞉ᴧᴒͼᴡⱳᴒͼ꞉ꜜᴠᴡԜԝ꞉ꞌ꞉ᴡᴦͼꜝⱱͼⱶⱨⱬͼꜞꞌԜᴠꜛԜͼ꞉ꜜͼᴡⱳ꞉ᴠͼԜᴠᴠԜᴦ᷅ͼ
͟ᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜꜜԜꞌᴦᴠᴒᴠͼᴤᴒᴟᴒͼԝԜᴠᴒᴑͼꜝꜜͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴡⱳᴒͼ᷊᷇᷇ͼꜛⱲԓͼ᷾᷇᷇ͼꜛⱲԓͼԜꜜᴑͼꜞꞌԜᴐᴒԝꜝͼᴑꜝᴠᴒͼ
ⱲᴟꜝᴢꜞᴠͼᴤⱳꜝͼᴟᴒꜞꜝᴟᴡᴒᴑͼⱳԜᴣ꞉ꜜⱲͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼԜᴡᴡԜᴐꞋᴠͼ꞉ꜜͼᴡⱳᴒͼ᷊ͼꜛꜝꜜᴡⱳᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴠᴡᴢᴑᴦͼᴒꜜᴡᴟᴦͼ
ӿ᷿᷇᷅᷈ԜᴡᴡԜᴐꞋᴠ᷆ᴤᴒᴒꞋԐ᷅ͼ꜡ⱱͼᴡⱳꜝᴠᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡᴟᴒԜᴡᴒᴑͼᴤ꞉ᴡⱳͼ᷊᷇᷇ͼꜝᴟͼ᷾᷇᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼ᷿᷈ͼꜝⱱͼ᷈⅍ᴠᴢԝ꞊ᴒᴐᴡᴠͼ
ꜛᴒᴡͼᴡⱳᴒᴠᴒͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝ᷅ͼ꜡ⱱͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼᴡᴟᴒԜᴡᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠԓͼ᷈᷈ͼꜝⱱͼ᷊᷈ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜛᴒᴡͼᴡⱳᴒᴠᴒͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝ᷅ͼ
ᴁⱳᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒᴠͼӿԜᴡᴡԜᴐꞋᴠ᷆ᴤᴒᴒꞋԐͼᴤᴒᴟᴒͼ᷊᷇᷅ⱠͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴤᴒᴒꞋͼ꞉ꜜͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞԓͼ
᷊᷊᷇᷅ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴤᴒᴒꞋͼ꞉ꜜͼᴡⱳᴒͼ᷊᷇᷇ͼꜛⱲͼⱲᴟꜝᴢꜞԓͼ᷿᷿᷇᷅ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴤᴒᴒꞋͼ꞉ꜜͼᴡⱳᴒͼ᷾᷇᷇ͼꜛⱲͼⱲᴟꜝᴢꜞͼԜꜜᴑͼ᷇᷅᷾Ⱡͼ
ԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴤᴒᴒꞋͼ꞉ꜜͼᴡⱳᴒͼ᷊᷇᷇ͼԜꜜᴑͼ᷾᷇᷇ͼꜛⱲͼᴐꜝꜛԝ꞉ꜜᴒᴑͼⱲᴟꜝᴢꜞ᷅ͼⱫᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼꜞᴟᴒ᷄ᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑԓͼꜞᴟ꞉ꜛԜᴟᴦͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼ꞉ꜜᴡᴒᴟᴣԜꞌͼꜝⱱͼ⅍ͼᴤᴒᴒꞋᴠͼӿⱱᴟꜝꜛͼᴑԜᴦᴠͼ˲ͼᴡꜝͼ᷿᷇Ɫͼᴐꜝᴟᴟᴒᴠꜞꜝꜜᴑ꞉ꜜⱲͼᴡꜝͼԜͼꜞᴒᴟ꞉ꜝᴑͼꜝⱱͼꜜꜝᴡԜԝꞌᴒͼᴑᴟᴢⱲͼ
ᴒᴥꜞꜝᴠᴢᴟᴒԐԓͼᴡⱳᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒԓͼԜᴑ꞊ᴢᴠᴡᴒᴑͼⱱꜝᴟͼԝԜᴠᴒꞌ꞉ꜜᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒԓͼᴤԜᴠͼ᷇ͼ꞉ꜜͼᴡⱳᴒͼ᷊᷇᷇ꜛⱲͼⱲᴟꜝᴢꜞͼԜꜜᴑͼ
᷿᷇᷅᷇᷾ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴤᴒᴒꞋͼ꞉ꜜͼᴡⱳᴒͼ᷾᷇᷇ͼꜛⱲͼⱲᴟꜝᴢꜞԓͼᴐꜝꜛꜞԜᴟᴒᴑͼᴡꜝͼ᷊᷇᷅ⅎͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴤᴒᴒꞋͼ꞉ꜜͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼ
Ⱳᴟꜝᴢꜞ᷅ͼᴁⱳ꞉ᴠͼᴟᴒᴠᴢꞌᴡᴒᴑͼ꞉ꜜͼԜͼ᷈᷇᷇Ӽͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼᴣᴠͼꜞꞌԜᴐᴒԝꜝͼⱱꜝᴟͼᴡⱳᴒͼ᷊᷇᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱲᴟꜝᴢꜞͼӿP Ᵽͼ᷇᷅᷇᷇᷇᷈Ԑͼ
ԜꜜᴑͼԜꜜͼ˲˲Ӽͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼᴣᴠͼꜞꞌԜᴐᴒԝꜝͼⱱꜝᴟͼ᷾᷇᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼӿP Ɽͼ᷿᷇᷅᷇᷇Ԑ᷅ͼⱫᴢᴟ꞉ꜜⱲͼᴡⱳ꞉ᴠͼꜞᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
꞉ꜜᴡᴒᴟᴣԜꞌԓͼ᷈᷇᷇Ӽͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴡⱳᴒͼ᷊᷇᷇ͼꜛⱲͼⱲᴟꜝᴢꜞͼӿP Ɽͼ᷇᷅᷇᷉⅍ԐͼԜꜜᴑͼ˲᷉Ӽͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴡⱳᴒͼ᷾᷇᷇ͼꜛⱲͼ
ⱲᴟꜝᴢꜞͼӿP Ɽͼ᷊᷇᷅᷇ԐͼᴤᴒᴟᴒͼԜᴡᴡԜᴐꞋ᷄ⱱᴟᴒᴒͼᴐꜝꜛꜞԜᴟᴒᴑͼᴤ꞉ᴡⱳͼ᷉ⅎӼͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞ᷅
ᴁⱳᴒͼᴑԜᴡԜͼⱱᴟꜝꜛͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼᴑᴒꜛꜝꜜᴠᴡᴟԜᴡᴒͼꜞᴟꜝꜝⱱͼꜝⱱͼᴐꜝꜜᴐᴒꜞᴡͼꜝⱱͼᴡⱳᴒͼԜԝ꞉ꞌ꞉ᴡᴦͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴡꜝͼꜞᴟᴒᴣᴒꜜᴡͼԜᴐᴢᴡᴒͼ
ԜᴡᴡԜᴐꞋᴠͼꜝⱱͼⱶⱨⱬ᷅ͼⱨͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼⱱ꞉ꜜᴑ꞉ꜜⱲͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼꜞᴟᴒᴣᴒꜜᴡ꞉ꜝꜜͼԝᴦͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤԜᴠͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜝԝᴠᴒᴟᴣᴒᴑ᷅ͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤԜᴠͼᴤᴒꞌꞌͼᴡꜝꞌᴒᴟԜᴡᴒᴑͼ꞉ꜜͼⱶⱨⱬͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴢꜞͼᴡꜝͼ᷾᷇᷇ͼꜛⱲ᷅ͼⱫᴟᴢⱲͼᴒᴥꜞꜝᴠᴢᴟᴒͼԜꜞꜞᴒԜᴟᴠͼᴡꜝͼ
ԝᴒͼᴑꜝᴠᴒ᷄ꜞᴟꜝꜞꜝᴟᴡ꞉ꜝꜜԜꞌͼԜꜜᴑͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴟᴒᴠᴢꞌᴡᴠͼꜝԝᴡԜ꞉ꜜᴒᴑͼ꞉ꜜͼⱳᴒԜꞌᴡⱳᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴠᴡᴢᴑᴦͼⱫᴅ᷄
᷉Ⱡ᷊᷇᷄᷇᷈᷅ͼ͟ⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼᴒⱱⱱᴒᴐᴡͼԜᴠᴠԜᴦᴠͼꜞᴟꜝᴣ꞉ᴑᴒͼᴒᴣ꞉ᴑᴒꜜᴐᴒͼᴡⱳԜᴡͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱳԜᴠͼԜͼᴑ꞉ᴟᴒᴐᴡͼᴒⱱⱱᴒᴐᴡͼꜝꜜͼ
ꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼ꞉ꜜͼꜞԜᴡ꞉ᴒꜜᴡͼꜞꞌԜᴠꜛԜ᷅
ⱴꜝᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴑᴒᴡԜ꞉ꞌͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴡⱳᴒͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼᴑꜝᴠᴒԓͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦͼ꞉ꜜͼⱶⱨⱬͼᴠᴢԝ꞊ᴒᴐᴡᴠԓͼꜞꞌᴒԜᴠᴒͼᴟᴒⱱᴒᴟͼᴡꜝͼ
ᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼⱩᴟꜝᴐⱳᴢᴟᴒ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊ⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
2
STUDY OBJECTIVES
2.1
Primary Objective
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ꜜͼꜞᴟᴒᴣᴒꜜᴡ꞉ꜜⱲͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠ᷅
2.2
Secondary Objective
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼꜝⱱͼᴟᴒꜞᴒԜᴡᴒᴑͼᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇᷅
2.3
Tertiary Objectives
ᶄ
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼӿ͟ⱫԐͼᴒⱱⱱᴒᴐᴡᴠͼꜝⱱͼᴐⱳᴟꜝꜜ꞉ᴐԜꞌꞌᴦͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼⱫᴅ᷄᷉Ⱡ᷊᷇
ᶄ
ᴁꜝͼԜᴠᴠᴒᴠᴠͼᴡⱳᴒͼ꞉ꜛꜛᴢꜜꜝⱲᴒꜜ꞉ᴐ꞉ᴡᴦͼꜝⱱͼᴐⱳᴟꜝꜜ꞉ᴐԜꞌꞌᴦͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼⱫᴅ᷄᷉Ⱡ᷊᷇
ᶄ
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐᴠͼӿ͟ꜘԐͼꜝⱱͼᴐⱳᴟꜝꜜ꞉ᴐԜꞌꞌᴦͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼⱫᴅ᷄᷉Ⱡ᷊᷇
ᶄ
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱᴒᴐᴡͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝꜜͼⱳᴒԜꞌᴡⱳ᷄ᴟᴒꞌԜᴡᴒᴑͼꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼӿϷꜝꜙԐͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
3.1.1
Overview
ᴁⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼ꞉ᴠͼԜͼꜞⱳԜᴠᴒͼ᷊ԓͼꜛᴢꞌᴡ꞉ᴐᴒꜜᴡᴒᴟԓͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑԓͼꜞꞌԜᴐᴒԝꜝ᷄ᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼᴡᴟ꞉Ԝꞌͼᴡꜝͼ
ᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ꜜͼꜞᴟᴒᴣᴒꜜᴡ꞉ꜜⱲͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋᴠͼ꞉ꜜͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼᴁᴦꜞᴒⱷͼ
Ԝꜜᴑͼᴁᴦꜞᴒͼⱷⱷͼⱶⱨⱬ᷅ͼᴁⱳ꞉ᴠͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼᴠᴡᴢᴑᴦͼ꞉ᴠͼꜞꞌԜꜜꜜᴒᴑͼᴡꜝͼԝᴒͼⱱꜝꞌꞌꜝᴤᴒᴑͼԝᴦͼԜꜜͼꜝꜞᴒꜜ᷄ꞌԜԝᴒꞌͼᴒᴥᴡᴒꜜᴠ꞉ꜝꜜͼ
ӿ꜡ꜙⱬԐͼᴡⱳԜᴡͼ꞉ᴠͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼԜͼᴠᴒꜞԜᴟԜᴡᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾Ԑ᷅
ᴀᴢԝ꞊ᴒᴐᴡᴠͼԜⱲᴒᴑͼ᷈᷉ͼԜꜜᴑͼꜝᴣᴒᴟͼᴤ꞉ᴡⱳͼԜͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼꜝⱱͼᴁᴦꜞᴒͼⱷͼꜝᴟͼᴁᴦꜞᴒͼⱷⱷͼⱶⱨⱬͼᴤⱳꜝͼ
ᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ԜᴡᴡԜᴐꞋͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴤ꞉ꞌꞌͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒ᷅ͼᴂꜞͼᴡꜝͼ᷈᷉᷇ͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼ᷈᷇˲ͼᴡⱳԜᴡͼᴐꜝꜛꜞꞌᴒᴡᴒ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼⱱᴟꜝꜛͼᴠ꞉ᴡᴒᴠͼ꞉ꜜͼᴡⱳᴒͼ
ᴂꜜ꞉ᴡᴒᴑᴀᴡԜᴡᴒᴠԓͼⱪԜꜜԜᴑԜԓͼⱷᴡԜꞌᴦԓͼⱵᴒᴟꜛԜꜜᴦԓͼᴂꜜ꞉ᴡᴒᴑͼꜘ꞉ꜜⱲᴑꜝꜛͼԜꜜᴑͼꜗꜝᴟᴑԜꜜ᷅
3.1.1.1
Long-Term Prophylactic (LTP) Therapy Washout
ⱴꜝꞌꞌꜝᴤ꞉ꜜⱲͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷅ͼᴀᴐᴟᴒᴒꜜᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ
ᴤⱳꜝͼԜᴟᴒͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬͼԜᴟᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼᴢꜜᴑᴒᴟⱲꜝͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼ᷉ᴤᴒᴒꞋͼ
ᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴁⱳ꞉ᴠͼꜙᴁ͟ͼᴤԜᴠⱳꜝᴢᴡͼ꞉ᴠͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼԜᴠͼꞌꜝꜜⱲͼԜᴠͼ
ᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴑꜝ꞉ꜜⱲͼᴠꜝͼᴤꜝᴢꞌᴑͼꜜꜝᴡͼꜞꞌԜᴐᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜᴡͼԜꜜᴦͼᴢꜜᴑᴢᴒͼᴠԜⱱᴒᴡᴦͼᴟ꞉ᴠꞋͼԜꜜᴑͼ
ᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡͼꞌᴒԜᴠᴡͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒ᷅ͼᴁⱳᴒᴠᴒͼᴐᴟ꞉ᴡᴒᴟ꞉ԜͼᴒꜜᴠᴢᴟᴒͼᴡⱳԜᴡͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤⱳꜝͼᴠⱳꜝᴢꞌᴑͼᴟᴒꜛԜ꞉ꜜͼꜝꜜͼ
ꜙᴁ͟ͼᴑꜝͼꜜꜝᴡͼᴤԜᴠⱳꜝᴢᴡͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦԓͼԝᴢᴡͼᴑꜝͼԜꞌꞌꜝᴤͼᴡⱳᴒͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼꜝⱱͼԜꜞꜞᴟꜝꜞᴟ꞉ԜᴡᴒͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼ
ᴠᴒᴣᴒᴟᴒͼᴑ꞉ᴠᴒԜᴠᴒͼᴤⱳ꞉ꞌᴒͼꜛ꞉ꜜ꞉ꜛ꞉ᴧ꞉ꜜⱲͼᴡⱳᴒ꞉ᴟͼᴡ꞉ꜛᴒͼꜝⱱⱱͼꜙᴁ᷅͟ͼⱪᴢᴟᴟᴒꜜᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴢ꞉ᴑᴒꞌ꞉ꜜᴒᴠͼᴟᴒᴐꜝⱲꜜ꞉ᴧᴒͼᴡᴤꜝͼ
ᴑ꞉ⱱⱱᴒᴟᴒꜜᴡͼᴠᴡԜꜜᴑԜᴟᴑͼꜝⱱͼᴐԜᴟᴒͼԜꜞꜞᴟꜝԜᴐⱳᴒᴠͼᴡꜝͼᴡᴟᴒԜᴡ꞉ꜜⱲͼⱶⱨⱬԓͼᴤⱳ꞉ᴐⱳͼ꞉ꜜᴐꞌᴢᴑᴒͼꜙᴁ͟ͼԜꜜᴑͼꜝꜜ᷄ᴑᴒꜛԜꜜᴑͼ
ᴡⱳᴒᴟԜꜞᴦͼӿⱪ꞉ᴐԜᴟᴑ꞉ͼᴒᴡͼԜꞌ᷅ԓͼ᷉᷇᷈᷉ⱢͼⱪᴟԜ꞉ⱲͼᴒᴡͼԜꞌ᷅ԓͼ᷉᷇᷈᷉ⱢͼᴇᴢᴟԜᴤͼᴒᴡͼԜꞌ᷅ԓͼ᷊᷉᷇᷈Ԑ᷅ͼᴁⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼᴡꜝͼᴡᴟᴒԜᴡͼԜᴐᴢᴡᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼ꞉ꜜͼԜᴐᴐꜝᴟᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼᴢᴠᴢԜꞌͼᴐԜᴟᴒͼ
ꜝⱱͼᴡⱳᴒ꞉ᴟͼꜞԜᴡ꞉ᴒꜜᴡᴠ᷅ͼᴁⱳᴢᴠԓͼᴡⱳꜝᴠᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴠᴡꜝꜞͼᴡⱳᴒ꞉ᴟͼꜙᴁ͟ͼᴡꜝͼᴒꜜᴡᴒᴟͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜꜜᴑͼԜᴟᴒͼᴠᴢԝᴠᴒꜟᴢᴒꜜᴡꞌᴦͼ
ᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼᴤ꞉ꞌꞌͼᴠᴡ꞉ꞌꞌͼԝᴒͼꜛԜꜜԜⱲᴒᴑͼᴤ꞉ᴡⱳͼꜜꜝͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒ꞉ᴟͼᴠᴡԜꜜᴑԜᴟᴑͼꜝⱱͼ
ᴐԜᴟᴒ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼᴐꜝꜜⱱ꞉ᴟꜛͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱳԜᴠͼᴠᴢᴐᴐᴒᴠᴠⱱᴢꞌꞌᴦͼᴐꜝꜛꜞꞌᴒᴡᴒᴑͼᴡⱳᴒͼ᷉ͼᴤᴒᴒꞋͼ
ᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒᴦͼᴐԜꜜͼᴒꜜᴡᴒᴟͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅
3.1.1.2
Run-In Period
ᴀᴐᴟᴒᴒꜜᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴒ꞉ᴡⱳᴒᴟͼꜜꜝᴡͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬԓͼꜝᴟͼⱳԜᴣᴒͼ
ᴐꜝꜛꜞꞌᴒᴡᴒᴑͼᴡⱳᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼᴤ꞉ꞌꞌͼᴒꜜᴡᴒᴟͼԜͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜝⱱͼ᷾ͼᴤᴒᴒꞋᴠͼᴡꜝͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼᴡⱳᴒͼ
ԝԜᴠᴒꞌ꞉ꜜᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒ᷅ͼ꜡ꜜꞌᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜛᴒᴒᴡ꞉ꜜⱲͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼԝԜᴠᴒꞌ꞉ꜜᴒͼᴟԜᴡᴒͼꜝⱱͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼ
ᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼ᷊ͼꜝᴟͼꜛꜝᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋᴠͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒͼᴒꜜᴑͼ
ꜝⱱͼᴡⱳᴒͼ᷾ͼᴤᴒᴒꞋᴠͼᴐԜꜜͼᴒᴥ꞉ᴡͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒԜᴟꞌᴦͼԜꜜᴑͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳꜝᴢᴡͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋͼԜⱱᴡᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼꜝⱱͼᴟᴢꜜ᷄꞉ꜜͼᴤ꞉ꞌꞌͼⱳԜᴣᴒͼᴡⱳᴒ꞉ᴟͼ
ᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒᴥᴡᴒꜜᴑᴒᴑͼⱱꜝᴟͼԜꜜꜝᴡⱳᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼᴑᴢᴟ꞉ꜜⱲͼᴤⱳ꞉ᴐⱳͼᴡ꞉ꜛᴒͼᴡⱳᴒᴦͼꜜᴒᴒᴑͼᴡꜝͼⱳԜᴣᴒͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋᴠͼᴡꜝͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴁꜝͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼ
ᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼⱳԜᴣᴒͼᴡⱳᴒ꞉ᴟͼᴟᴢꜜ᷄꞉ꜜͼᴒᴥᴡᴒꜜᴑᴒᴑͼꜛᴢᴠᴡͼᴐꜝꜛꜞꞌᴒᴡᴒͼᴡⱳᴒͼⱱᴢꞌꞌͼ˲᷄ᴤᴒᴒꞋͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼ
ꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼꜛᴒᴒᴡͼᴡⱳᴒͼꜛ꞉ꜜ꞉ꜛᴢꜛͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴑᴢᴟ꞉ꜜⱲͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊Ⱡ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴟᴢꜜ᷄꞉ꜜͼꜝᴟͼԜᴟᴒͼꜝᴡⱳᴒᴟᴤ꞉ᴠᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼᴡꜝͼԝᴒͼ꞉ꜜᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼᴑᴢᴒͼᴡꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜͼᴠᴐᴟᴒᴒꜜͼⱱԜ꞉ꞌ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴠᴐᴟᴒᴒꜜͼⱱԜ꞉ꞌͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼԜꞌꞌꜝᴤᴒᴑͼᴡꜝͼᴟᴒᴠᴐᴟᴒᴒꜜͼ꞉ꜜᴡꜝͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼ
3.1.1.3
Treatment Period
ⱨⱱᴡᴒᴟͼᴣᴒᴟ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼꜝⱱͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼ᷉ⱡ᷈ͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼᴟᴒꜞᴒԜᴡᴒᴑͼᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼ
ӿᴀⱪԐͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝͼ꞉ꜜͼԜͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼⱱԜᴠⱳ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼ
ᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠ꞉Ⱳꜜᴒᴑͼ꞉ꜜͼԜͼ᷈ⱡ᷈ⱡ᷈ͼᴟԜᴡ꞉ꜝͼᴡꜝͼꜝꜜᴒͼꜝⱱͼᴡⱳᴟᴒᴒͼᴑꜝᴠᴒͼᴟᴒⱲ꞉ꜛᴒꜜᴠⱡͼ᷊᷇᷇ͼꜛⱲͼ
ᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠԓͼ᷊᷇᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠͼꜝᴟͼ᷿᷈᷇ꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠ᷅ͼϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼ꞉ꜜᴡꜝͼԜꞌꞌͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴡᴟԜᴡ꞉ⱱ꞉ᴒᴑͼԝᴦͼᴡⱳᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝԝᴠᴒᴟᴣᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼ
꞉ꜜᴡꜝͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼⱲᴟꜝᴢꜞᴠⱡͼ᷈ᴡꜝⱣ᷉ԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼ᷉ͼᴡꜝͼⱣͼ᷊ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼԜꜜᴑͼᶒͼ᷊ͼ
ԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠ᷅
ⱬԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼԜͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼᴐꜝꜜᴠ꞉ᴠᴡ꞉ꜜⱲͼꜝⱱͼ᷊᷈ͼᴑꜝᴠᴒᴠͼꜝⱱͼԝꞌ꞉ꜜᴑᴒᴑͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼ
ꜚᴒᴑ꞉ᴐ꞉ꜜԜꞌͼ͟ᴟꜝᴑᴢᴐᴡͼӿⱷꜚ͟ԐԓͼⱱꜝᴟͼԜͼꜞᴒᴟ꞉ꜝᴑͼꜝⱱͼ᷉⅍ͼᴤᴒᴒꞋᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴑԜᴡᴒͼꜝⱱͼⱱ꞉ᴟᴠᴡͼᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼ
ᴡᴤꜝͼᴤᴒᴒꞋᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼᴑꜝᴠᴒ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼ᷾ͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛᴠͼᴤ꞉ꞌꞌͼᴒ꞉ᴡⱳᴒᴟͼ
ᴟᴒᴐᴒ꞉ᴣᴒͼԜͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝͼᴑꜝᴠᴒͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴑꜝᴠ꞉ꜜⱲͼᴠᴐⱳᴒᴑᴢꞌᴒͼ꞉ꜜͼᴁԜԝꞌᴒ᷉᷅ͼ
Table 2.
Treatment Period Dosing Schedule
Treatment Period
Treatment Arms: DX-2930 or Placebo
Dose 
Number
Dose Day/Week
300 mg
every 2 
weeks
300 mg
every 4 
weeks
150 mg
every 4 
weeks
Placebo
᷈
ⱫԜᴦͼ᷇᷆ᴄᴒᴒꞋͼ᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷉
ⱫԜᴦͼ᷈᷾᷆ᴄᴒᴒꞋͼ᷉
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
᷊
ⱫԜᴦͼ᷉˲᷆ᴄᴒᴒꞋͼ᷾
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷾
ⱫԜᴦͼ᷾᷉᷆ᴄᴒᴒꞋͼ⅍
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
᷿
ⱫԜᴦͼ᷿⅍᷆ᴄᴒᴒꞋͼ˲
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
⅍
ⱫԜᴦͼⅎ᷇᷆ᴄᴒᴒꞋͼ᷈᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
ⅎ
ⱫԜᴦͼ˲᷾᷆ᴄᴒᴒꞋͼ᷈᷉
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
˲
ⱫԜᴦͼⱠ˲᷆ᴄᴒᴒꞋͼ᷈᷾
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
Ⱡ
ⱫԜᴦͼ᷈᷈᷉᷆ᴄᴒᴒꞋͼ᷈⅍
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷈᷇
ⱫԜᴦͼ᷈᷉⅍᷆ᴄᴒᴒꞋͼ᷈˲
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
᷈᷈
ⱫԜᴦͼ᷈᷾᷇᷆ᴄᴒᴒꞋͼ᷉᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷈᷉
ⱫԜᴦͼ᷿᷈᷾᷆ᴄᴒᴒꞋͼ᷉᷉
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
͟ꞌԜᴐᴒԝꜝ
᷊᷈
ⱫԜᴦͼ᷈⅍˲᷆ᴄᴒᴒꞋͼ᷉᷾
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
Ⱬᴅ᷄᷉Ⱡ᷊᷇
͟ꞌԜᴐᴒԝꜝ
᷄᷄
ⱫԜᴦͼ᷈˲᷉᷆ᴄᴒᴒꞋͼ᷉⅍
꜠ꜝͼⱫꜝᴠᴒ
꜠ꜝͼⱫꜝᴠᴒ
꜠ꜝͼⱫꜝᴠᴒ
꜠ꜝͼⱫꜝᴠᴒ
3.1.1.4
Open-Label Extension (OLE)
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴐꜝꜛꜞꞌᴒᴡᴒͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼᴤ꞉ꞌꞌͼԝᴒͼꜝⱱⱱᴒᴟᴒᴑͼᴡⱳᴒͼꜝꜞᴡ꞉ꜝꜜͼꜝⱱͼᴒꜜᴟꜝꞌꞌ꞉ꜜⱲͼ꞉ꜜͼԜꜜͼꜝꜞᴒꜜ᷄
ꞌԜԝᴒꞌͼᴒᴥᴡᴒꜜᴠ꞉ꜝꜜͼӿ꜡ꜙⱬԐͼᴠᴡᴢᴑᴦͼᴡⱳԜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼԜͼᴠᴒꜞԜᴟԜᴡᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾Ԑ᷅ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱴ꞉Ⱳᴢᴟᴒ᷈ᴠⱳꜝᴤᴠͼԜͼᴠᴐⱳᴒꜛԜᴡ꞉ᴐͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴑᴒᴠ꞉Ⱳꜜ᷅
Figure 1.
Overview of the Study Design
3.1.1.5
Follow-Up Period
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼ꜡ꜙⱬͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼᴠԜⱱᴒᴡᴦͼԜꜜᴑͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜᴠͼӿ꞉᷅ᴒ᷅ԓͼ
͟ꜘͼԜꜜᴑͼ͟ⱫԐͼᴑᴢᴟ꞉ꜜⱲͼԜꜜͼ˲ͼᴤᴒᴒꞋͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑ᷅ᴀᴢԝ꞊ᴒᴐᴡᴠͼӿꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠԐͼᴤ꞉ꞌꞌͼԝᴒͼ꞉ꜜᴠᴡᴟᴢᴐᴡᴒᴑͼᴡꜝͼ
꞉ꜜⱱꜝᴟꜛͼᴡⱳᴒͼᴠ꞉ᴡᴒͼꜝⱱͼԜꜜᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴡⱳᴒᴦͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼⱱꜝᴟͼᴢꜞͼᴡꜝͼ᷊᷇ͼᴑԜᴦᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼ
ᴣ꞉ᴠ꞉ᴡ᷅
3.1.2
Safety Oversight and Stopping Rules
3.1.2.1
Interim Analysis and Data Safety Monitoring Board (DSMB)
꜠ꜝͼ꞉ꜜᴡᴒᴟ꞉ꜛͼԜꜜԜꞌᴦᴠ꞉ᴠͼ꞉ᴠͼꜞꞌԜꜜꜜᴒᴑͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅ͼⱫᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼꜞԜᴡ꞉ᴒꜜᴡͼᴠԜⱱᴒᴡᴦͼᴤ꞉ꞌꞌͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼ
ꜝꜜͼԜͼᴐꜝꜜᴡ꞉ꜜᴢꜝᴢᴠͼԝԜᴠ꞉ᴠͼԝᴦͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼᴢꜜᴡ꞉ꞌͼᴡⱳᴒͼꞌԜᴠᴡͼꜞԜᴡ꞉ᴒꜜᴡͼᴐꜝꜛꜞꞌᴒᴡᴒᴠͼⱳ꞉ᴠͼꜝᴟͼⱳᴒᴟͼꞌԜᴠᴡͼ
ᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴠᴡᴢᴑᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅ͼ
ⱨꜜͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼᴑԜᴡԜͼᴠԜⱱᴒᴡᴦͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼԝꜝԜᴟᴑͼӿⱫᴀꜚⱩԐͼᴤ꞉ꞌꞌͼԜꞌᴠꜝͼԝᴒͼᴒᴠᴡԜԝꞌ꞉ᴠⱳᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼԜꜜͼ
ꜝꜜⱲꜝ꞉ꜜⱲԓͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼᴟᴒᴣ꞉ᴒᴤͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼᴑԜᴡԜԓͼԜꜜᴑͼᴡꜝͼᴠԜⱱᴒⱲᴢԜᴟᴑͼᴡⱳᴒͼ꞉ꜜᴡᴒᴟᴒᴠᴡᴠͼԜꜜᴑͼ
ᴠԜⱱᴒᴡᴦͼꜝⱱͼᴡⱳᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼꜞԜᴡ꞉ᴒꜜᴡᴠͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼӿᴠᴒᴒͼᴀᴒᴐᴡ꞉ꜝꜜ᷈᷇᷅ⅎⱱꜝᴟͼԜͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼⱫᴀꜚⱩͼ
Ԝꜜᴑͼ꞉ᴡᴠͼᴟꜝꞌᴒԐ᷅ͼᴁⱳᴒͼꜝꜜⱲꜝ꞉ꜜⱲͼᴟᴒᴣ꞉ᴒᴤͼꜝⱱͼᴀⱨⱬᴠͼԜꜜᴑͼꜝᴡⱳᴒᴟͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝ꞉ꞌ꞉ᴡ꞉ᴒᴠͼꜝⱱͼᴡⱳᴒͼⱫᴀꜚⱩͼԜᴟᴒͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ
꞉ꜜͼᴡⱳᴒͼⱫᴀꜚⱩͼⱪⱳԜᴟᴡᴒᴟ᷅ͼ
3.1.2.2
Individual Stopping Rules
Ⱬꜝᴠ꞉ꜜⱲͼⱱꜝᴟͼԜꜜᴦͼ꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼ꞉ⱱͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴠͼԜͼ
Ⱬᴅ᷄᷉Ⱡ᷊᷇᷄ᴟᴒꞌԜᴡᴒᴑͼᴀⱨⱬͼӿꜝᴟͼԜͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄ᴟᴒꞌԜᴡᴒᴑԓͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼꜜꜝꜜ᷄ᴠᴒᴟ꞉ꜝᴢᴠͼⱨⱬԐͼᴡⱳԜᴡԓͼ꞉ꜜͼᴡⱳᴒͼ
Ԝᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟԓͼᴤԜᴟᴟԜꜜᴡᴠͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼⱱᴢᴟᴡⱳᴒᴟͼᴑꜝᴠ꞉ꜜⱲͼⱱꜝᴟͼᴡⱳԜᴡͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼ
ᴤᴒꞌꞌ᷄ԝᴒ꞉ꜜⱲ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼⱳԜᴠͼᴡⱳᴒͼԜԝ꞉ꞌ꞉ᴡᴦͼᴡꜝͼᴐꜝꜜᴡԜᴐᴡͼԜꜜᴑͼᴐꜝꜜᴠᴢꞌᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼꜝꜜͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴠᴢᴐⱳͼꜛԜᴡᴡᴒᴟᴠ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴡꜝͼԝᴒͼⱱꜝꞌꞌꜝᴤᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ᷉⅍ͼᴤᴒᴒꞋͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
ꜞᴒᴟ꞉ꜝᴑԓͼᴢꜜꞌᴒᴠᴠͼᴡⱳᴒᴦͼᴟᴒꜟᴢᴒᴠᴡͼᴡꜝͼԝᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼ
ⱱᴟꜝꜛͼⱱᴢᴟᴡⱳᴒᴟͼᴑꜝᴠ꞉ꜜⱲͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼᴡꜝͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼ꜡ꜙⱬ᷅
3.1.3
Follow-Up for Subjects Meeting Stopping Criteria
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴡⱳԜᴡͼᴑᴒᴣᴒꞌꜝꜞͼᴒ꞉ᴡⱳᴒᴟͼԜꜜͼᴀⱨⱬͼꜝᴟͼꜝᴡⱳᴒᴟͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴟᴒꞌᴒᴣԜꜜᴡͼ
ӿⱨⱬԓ ꞌԜԝꜝᴟԜᴡꜝᴟᴦԓͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜԓͼᴣ꞉ᴡԜꞌͼᴠ꞉ⱲꜜԓͼꜝᴟͼⱬⱪⱵͼⱱ꞉ꜜᴑ꞉ꜜⱲԐͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜᴟᴒⱱᴢꞌꞌᴦͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼ
ᴢꜜᴡ꞉ꞌͼᴟᴒᴠꜝꞌᴢᴡ꞉ꜝꜜԓͼᴤⱳ꞉ᴐⱳͼꜛԜᴦͼ꞉ꜜᴐꞌᴢᴑᴒͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲⱡ
ᶄ
ⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠͼԜꜜᴑ᷆ꜝᴟͼꜝᴡⱳᴒᴟͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜᴠ
ᶄ
ⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴣ꞉ᴠ꞉ᴡᴠͼꜝᴟͼᴒᴥᴡᴒꜜᴑᴒᴑͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞ
ᶄ
꜡ԝᴡԜ꞉ꜜ꞉ꜜⱲͼԜͼᴠꜞᴒᴐ꞉Ԝꞌ꞉ᴠᴡͼᴐꜝꜜᴠᴢꞌᴡԜᴡ꞉ꜝꜜ
3.2
Rationale for Pivotal Dose Selection
ᴁⱳᴒͼᴑꜝᴠᴒͼᴟԜᴡ꞉ꜝꜜԜꞌᴒͼ꞉ᴠͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼԝ꞉ꜝԜᴐᴡ꞉ᴣ꞉ᴡᴦԓͼ͟ꜘԓͼᴠԜⱱᴒᴡᴦԓͼԜꜜᴑͼᴒⱱⱱ꞉ᴐԜᴐᴦͼꜝⱱͼⱫᴅ᷄
᷉Ⱡ᷊᷇ͼⱱᴟꜝꜛͼᴡⱳᴒͼ͟ⱳԜᴠᴒͼ᷈ͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑ꞉ᴒᴠͼԜꜜᴑͼꜜꜝꜜᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑ꞉ᴒᴠ᷅ͼᴁꜝⱲᴒᴡⱳᴒᴟԓͼᴡⱳᴒᴠᴒͼԜᴡᴡᴟ꞉ԝᴢᴡᴒᴠͼꜞᴟꜝᴣ꞉ᴑᴒͼ
ᴡⱳᴒͼᴟԜᴡ꞉ꜝꜜԜꞌᴒͼⱱꜝᴟͼᴡⱳᴒͼᴠᴒꞌᴒᴐᴡᴒᴑͼᴑꜝᴠᴒᴠͼԜꜜᴑͼᴟᴒⱲ꞉ꜛᴒꜜᴠͼᴡꜝͼԜᴐⱳ꞉ᴒᴣᴒͼᴑᴟᴢⱲͼꞌᴒᴣᴒꞌᴠͼꞌ꞉ꞋᴒꞌᴦͼᴡꜝͼꜞᴟᴒᴣᴒꜜᴡͼԜͼ
ꜛԜ꞊ꜝᴟ꞉ᴡᴦͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠ᷅ͼⱩԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒᴠᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠԓͼ᷊᷇᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠԓͼ᷊᷇᷇ꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼ
ᴤᴒᴒꞋᴠԓͼԜꜜᴑͼ᷿᷈᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠͼᴤᴒᴟᴒͼ꞉ᴑᴒꜜᴡ꞉ⱱ꞉ᴒᴑͼԜᴠͼᴡⱳᴒͼᴑꜝᴠ꞉ꜜⱲͼᴟᴒⱲ꞉ꜛᴒꜜᴠͼⱱꜝᴟͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜ᷅
ⱷꜜͼᴠᴡᴢᴑᴦͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉ԓͼᴡᴤꜝͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴑꜝᴠᴒᴠͼꜝⱱͼ᷊᷇᷇ͼꜛⱲͼꜝᴟͼⱲᴟᴒԜᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼ᷉ͼᴤᴒᴒꞋᴠͼԜꜞԜᴟᴡͼ
ᴟᴒᴠᴢꞌᴡᴒᴑͼ꞉ꜜͼԜͼꜜꜝᴟꜛԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼꜝⱱͼꜞꞌԜᴠꜛԜͼ᷉᷄ᴐⱳԜ꞉ꜜͼⱶꜚᴄꜘͼꞌᴒᴣᴒꞌᴠͼԜꜜᴑͼԜͼꜛԜᴥ꞉ꜛԜꞌͼⱠ᷈Ӽͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ꜜͼ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼӿⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼⱩᴟꜝᴐⱳᴢᴟᴒԐ᷅ͼᴀᴡᴒԜᴑᴦ᷄ᴠᴡԜᴡᴒͼᴡᴟꜝᴢⱲⱳͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜᴠͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼ
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠͼᴤꜝᴢꞌᴑͼԝᴒͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷉ⅎԓ᷇᷇᷇ͼꜜⱲ᷆ꜛꜙ᷅ͼᴁⱳᴒͼꜛԜᴥ꞉ꜛᴢꜛͼ
ꜞꞌԜᴠꜛԜͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼӿⱪꜛԜᴥԐͼꜝԝᴡԜ꞉ꜜᴒᴑͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴒᴐԜꞌꞌԜꜜᴡ꞉ᴑᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼᴡꜝͼᴡᴟᴒԜᴡͼԜꜜͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋͼ
꞉ᴠͼᴠ꞉ꜛ꞉ꞌԜᴟͼᴡꜝͼᴡⱳ꞉ᴠͼᴡᴟꜝᴢⱲⱳͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇᷅ͼ
ⱷᴡͼ꞉ᴠͼꜞꜝᴠᴠ꞉ԝꞌᴒͼᴡⱳԜᴡͼꞌꜝᴤᴒᴟͼᴑᴟᴢⱲͼꞌᴒᴣᴒꞌᴠͼᴤꜝᴢꞌᴑͼꜞᴟᴒᴣᴒꜜᴡͼԜᴡᴡԜᴐꞋᴠͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴡⱳԜꜜͼ
ᴡⱳꜝᴠᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼⱱꜝᴟͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋͼᴡᴟᴒԜᴡꜛᴒꜜᴡԓͼᴠ꞉ꜜᴐᴒͼᴠᴦᴠᴡᴒꜛ꞉ᴐͼᴑᴟᴢⱲͼᴒᴥꜞꜝᴠᴢᴟᴒͼᴐꜝᴢꞌᴑͼԜᴡᴡᴒꜜᴢԜᴡᴒͼᴐꜝꜜᴡԜᴐᴡͼ
ᴠᴦᴠᴡᴒꜛͼԜᴐᴡ꞉ᴣԜᴡ꞉ꜝꜜͼᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼ꞉ꜜⱳ꞉ԝ꞉ᴡ꞉ꜝꜜͼꜝⱱͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜ᷄ꜛᴒᴑ꞉ԜᴡᴒᴑͼⱴᴅⱷⱷͼԜᴐᴡ꞉ᴣԜᴡ꞉ꜝꜜ᷅ͼⱨᴠͼᴠᴢᴐⱳԓͼ
᷉ͼᴑꜝᴠ꞉ꜜⱲͼᴟᴒⱲ꞉ꜛᴒꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼꜛꜝꜜᴡⱳꞌᴦͼԜᴟᴒԝᴒ꞉ꜜⱲͼᴒᴣԜꞌᴢԜᴡᴒᴑ᷅ͼⱫꜝᴠᴒᴠͼꜝⱱͼ᷊᷇᷇ͼꜛⱲͼꜝᴟͼ
᷿᷈᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠͼᴤꜝᴢꞌᴑͼᴟᴒᴠᴢꞌᴡͼ꞉ꜜͼԜͼᴠᴡᴒԜᴑᴦ᷄ᴠᴡԜᴡᴒͼᴡᴟꜝᴢⱲⱳͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼ
ꜝⱱͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⱠԓ᷿᷇᷇ͼԜꜜᴑͼ᷾ԓⅎ᷿᷇ͼꜜⱲ᷆ꜛꜙԓͼᴟᴒᴠꜞᴒᴐᴡ꞉ᴣᴒꞌᴦ᷅ͼᴁⱳᴒᴠᴒͼᴡᴟꜝᴢⱲⱳͼꞌᴒᴣᴒꞌᴠͼԝᴟԜᴐꞋᴒᴡͼᴡⱳᴒͼⱪꜛԜᴥ
ꜝԝᴠᴒᴟᴣᴒᴑͼ꞉ꜜͼᴡⱳᴒͼ᷈᷇᷇ͼꜛⱲͼᴑꜝᴠᴒͼⱲᴟꜝᴢꜞͼ꞉ꜜͼᴠᴡᴢᴑᴦͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉ԓͼᴤⱳ꞉ᴐⱳͼᴑᴒꜛꜝꜜᴠᴡᴟԜᴡᴒᴑͼԜͼᴠꞌ꞉Ⱳⱳᴡԓͼԝᴢᴡͼꜜꜝᴡͼ
ᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡԓͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ꜜͼ᷉᷄ᴐⱳԜ꞉ꜜͼⱶꜚᴄꜘͼꞌᴒᴣᴒꞌᴠ᷅
ᴁⱳᴒͼ᷊ͼꜞᴟꜝꜞꜝᴠᴒᴑͼᴑꜝᴠᴒ᷄ᴟᴒⱲ꞉ꜛᴒꜜͼᴐꜝꜛԝ꞉ꜜԜᴡ꞉ꜝꜜᴠͼꜞᴟꜝᴣ꞉ᴑᴒͼԜͼ⅍᷄ⱱꜝꞌᴑͼᴟԜꜜⱲᴒͼꜝⱱͼᴠᴡᴒԜᴑᴦ᷄ᴠᴡԜᴡᴒͼᴡᴟꜝᴢⱲⱳͼ
ᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜᴠͼԜꜜᴑͼꞌᴒᴣᴒᴟԜⱲᴒͼԝꜝᴡⱳͼᴡⱳᴒͼԝ꞉ꜝꜛԜᴟꞋᴒᴟͼԜꜜᴑᴒⱱⱱ꞉ᴐԜᴐᴦͼᴑԜᴡԜͼⱲᴒꜜᴒᴟԜᴡᴒᴑͼ꞉ꜜͼᴠᴡᴢᴑᴦͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄
᷇᷉᷅ͼⱬᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜞꞌԜᴠꜛԜͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜᴠͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼԜᴡᴡԜᴐꞋᴠͼᴟᴒꜞꜝᴟᴡᴒᴑͼԝᴦͼⱫᴅ᷄
᷉Ⱡ᷊᷇ͼᴡᴟᴒԜᴡᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉ͼᴠᴢⱲⱲᴒᴠᴡᴠͼᴡⱳԜᴡͼᴡⱳᴒͼ᷊ͼꜞꞌԜꜜꜜᴒᴑͼᴑꜝᴠ꞉ꜜⱲͼᴟᴒⱲ꞉ꜛᴒꜜᴠͼᴤ꞉ꞌꞌͼꜞᴟꜝᴣ꞉ᴑᴒͼԜͼ
ꜛᴒԜꜜ꞉ꜜⱲⱱᴢꞌͼᴟԜꜜⱲᴒͼꜝⱱͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴟᴒᴠꜞꜝꜜᴠᴒ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
3.3
Individual Subject Dosing and Follow-Up
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼᴑꜝᴠᴒͼꜝⱱͼԝꞌ꞉ꜜᴑᴒᴑͼⱷꜚ͟ͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼ᷉⅍ͼᴤᴒᴒꞋͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑͼ
ⱱꜝᴟͼԜͼᴡꜝᴡԜꞌͼꜝⱱͼ᷊᷈ͼᴑꜝᴠᴒᴠ᷅ͼᴁⱳᴒͼⱱ꞉ᴟᴠᴡͼᴑꜝᴠᴒͼꜝⱱͼⱷꜚ͟ͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼᴡⱳᴒͼꞌԜᴠᴡͼᴑꜝᴠᴒͼꜝⱱͼ
ⱷꜚ͟ͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼꜝꜜͼⱫԜᴦͼ᷈⅍˲᷅ͼᴁⱳᴒᴟᴒͼᴤ꞉ꞌꞌͼԝᴒͼԜͼᶐ᷊ᴑԜᴦͼᴤ꞉ꜜᴑꜝᴤͼԜᴟꜝᴢꜜᴑͼᴒԜᴐⱳͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡԓͼ
ᴤ꞉ᴡⱳͼԜͼꜛԜᴥ꞉ꜛᴢꜛͼꜝⱱͼ᷈ⅎͼᴑԜᴦᴠͼꜝᴟͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼꜝⱱͼ᷈᷈ͼᴑԜᴦᴠͼԝᴒᴡᴤᴒᴒꜜͼԜꜜᴦͼᴡᴤꜝͼᴑꜝᴠᴒᴠ᷅ͼⱨⱱᴡᴒᴟͼᴒԜᴐⱳͼᴑꜝᴠᴒԓͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼԜᴡͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒͼᴡⱳᴟꜝᴢⱲⱳͼ᷉ͼⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼⱱꜝᴟͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼ᷾ͼᴑꜝᴠᴒᴠͼᴤ꞉ᴡⱳͼ
ᴡⱳᴒͼԜԝ꞉ꞌ꞉ᴡᴦͼᴡꜝͼᴟᴒᴑᴢᴐᴒͼᴡⱳ꞉ᴠͼᴡ꞉ꜛᴒͼᴡꜝͼ᷈ͼⱳꜝᴢᴟͼⱱꜝᴟͼᴡⱳᴒͼᴟᴒꜛԜ꞉ꜜ꞉ꜜⱲͼᴑꜝᴠᴒᴠͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠ᷅ͼⱨͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴣ꞉ᴠ꞉ᴡͼᴤ꞉ꞌꞌͼꜝᴐᴐᴢᴟͼꜝꜜͼⱫԜᴦͼ᷈˲᷉᷅ͼ
3.4
Study Duration for Individual Subjects
ⱴꜝꞌꞌꜝᴤ꞉ꜜⱲͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷅ͼᴀᴐᴟᴒᴒꜜᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ
ᴤⱳꜝͼԜᴟᴒͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬͼԜᴟᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼᴢꜜᴑᴒᴟⱲꜝͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼ᷉ᴤᴒᴒꞋͼ
ᴤԜᴠⱳ᷄ꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴟᴢꜜ᷄꞉ꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴒ꞉ᴡⱳᴒᴟͼꜜꜝᴡͼꜝꜜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼ
ᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬԓͼꜝᴟͼⱳԜᴣᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑͼᴡⱳᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼᴤ꞉ꞌꞌͼᴒꜜᴡᴒᴟͼԜͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜝⱱͼ᷾ͼ
ᴤᴒᴒꞋᴠͼᴡꜝͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼᴡⱳᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒ᷅ͼᴁⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼꞌԜᴠᴡͼԜᴠͼꞌꜝꜜⱲͼԜᴠͼ˲ͼᴤᴒᴒꞋᴠͼ
꞉ꜜͼꜝᴟᴑᴒᴟͼᴡꜝͼꜛᴒᴒᴡͼᴡⱳᴒͼꜛ꞉ꜜ꞉ꜛᴢꜛͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡ᷅ͼⱬꜜᴟꜝꞌꞌᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴡⱳᴒꜜͼ
ᴢꜜᴑᴒᴟⱲꜝͼԜͼ᷉⅍᷄ᴤᴒᴒꞋͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼ꜡ꜙⱬͼᴤ꞉ꞌꞌͼԝᴒͼ
ⱱꜝꞌꞌꜝᴤᴒᴑͼⱱꜝᴟͼԜꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ˲ͼᴤᴒᴒꞋᴠ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
4
STUDY POPULATION SELECTION
4.1
Study Population
ᴁⱳᴒͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼᴒꜜᴟꜝꞌꞌͼᴢꜞͼᴡꜝͼ᷈᷉᷇ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼ᷈᷇˲ͼᴐꜝꜛꜞꞌᴒᴡᴒᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ᷈᷉ᴦᴒԜᴟᴠͼꜝⱱͼ
ԜⱲᴒͼԜꜜᴑͼꜝꞌᴑᴒᴟͼᴤ꞉ᴡⱳͼԜͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼꜝⱱͼⱶⱨⱬͼӿᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷԐͼᴤⱳꜝͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼԜᴡͼꞌᴒԜᴠᴡͼ
᷈ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼⱶⱨⱬͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼᴡⱳᴟꜝᴢⱲⱳͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼⱶⱨⱬͼԜꜜᴑͼᴑ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼᴡᴒᴠᴡ꞉ꜜⱲͼ
ᴐꜝꜜᴑᴢᴐᴡᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡ᷅ͼ
ᴁⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜͼ꞉ꜜᴐꞌᴢᴑᴒᴠͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼ᷈᷉ͼᴡꜝͼ᷈ⅎͼᴦᴒԜᴟᴠͼꜝꞌᴑ᷅ͼꜙ꞉ꞋᴒͼԜᴑᴢꞌᴡᴠԓͼᴐⱳ꞉ꞌᴑᴟᴒꜜͼᴤ꞉ᴡⱳͼ
ⱶⱨⱬͼᴐԜꜜͼᴠᴢⱱⱱᴒᴟͼⱱᴟꜝꜛͼᴟᴒᴐᴢᴟᴟᴒꜜᴡͼԜꜜᴑͼᴑᴒԝ꞉ꞌ꞉ᴡԜᴡ꞉ꜜⱲͼԜᴡᴡԜᴐꞋᴠ᷅ͼᴀᴦꜛꜞᴡꜝꜛᴠͼꜛԜᴦͼꜞᴟᴒᴠᴒꜜᴡͼᴣᴒᴟᴦͼᴒԜᴟꞌᴦͼ꞉ꜜͼ
ᴐⱳ꞉ꞌᴑⱳꜝꜝᴑԓͼԜꜜᴑͼᴢꜞꜞᴒᴟͼԜ꞉ᴟᴤԜᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼⱳԜᴠͼԝᴒᴒꜜͼᴟᴒꜞꜝᴟᴡᴒᴑͼ꞉ꜜͼⱶⱨⱬͼꜞԜᴡ꞉ᴒꜜᴡᴠͼԜᴠͼᴦꜝᴢꜜⱲͼԜᴠͼᴡⱳᴒͼԜⱲᴒͼ
ꜝⱱͼ᷊ͼӿⱩꜝᴟꞋͼᴒᴡͼԜꞌ᷅ԓͼ᷊᷉᷇᷇Ԑ᷅ͼⱷꜜͼꜝꜜᴒͼᴐԜᴠᴒͼᴠᴒᴟ꞉ᴒᴠͼꜝⱱͼ᷾Ⱡͼꜞᴒᴑ꞉Ԝᴡᴟ꞉ᴐͼⱶⱨⱬͼꜞԜᴡ꞉ᴒꜜᴡᴠԓͼ᷊᷉ⱳԜᴑͼᴠᴢⱱⱱᴒᴟᴒᴑͼԜᴡͼꞌᴒԜᴠᴡͼ
ꜝꜜᴒͼᴒꜞ꞉ᴠꜝᴑᴒͼꜝⱱͼԜ꞉ᴟᴤԜᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼԝᴦͼᴡⱳᴒͼԜⱲᴒͼꜝⱱͼ᷈˲ͼӿⱴԜᴟꞋԜᴠԓͼ᷉᷇᷈᷇Ԑ᷅ͼⱨꜜͼ꞉ꜛꜞꜝᴟᴡԜꜜᴡͼᴢꜜꜛᴒᴡͼꜛᴒᴑ꞉ᴐԜꞌͼ
ꜜᴒᴒᴑͼᴒᴥ꞉ᴠᴡᴠͼԜꜛꜝꜜⱲͼᴐⱳ꞉ꞌᴑᴟᴒꜜͼᴤ꞉ᴡⱳͼⱶⱨⱬԓͼᴒᴠꜞᴒᴐ꞉ԜꞌꞌᴦͼԜᴑꜝꞌᴒᴠᴐᴒꜜᴡᴠԓͼᴠ꞉ꜜᴐᴒͼᴡⱳᴒͼᴑ꞉ᴠᴒԜᴠᴒͼᴐꜝꜛꜛꜝꜜꞌᴦͼ
ᴤꜝᴟᴠᴒꜜᴠͼԜⱱᴡᴒᴟͼꜞᴢԝᴒᴟᴡᴦͼӿⱩᴒꜜꜜᴒᴡᴡͼԜꜜᴑͼⱪᴟԜ꞉Ⱳԓͼ᷿᷉᷇᷈ⱢͼᴇᴢᴟԜᴤԓͼ᷉᷇᷇˲Ԑ᷅ͼᴁⱳᴒͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԜ꞉ꜛͼᴡꜝͼᴒꜜᴟꜝꞌꞌͼԜᴡͼ
ꞌᴒԜᴠᴡͼ᷿ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼ᷈᷉ͼᴡꜝͼ᷈ⅎͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒ᷅
4.2
Inclusion Criteria
ⱬԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼꜛᴢᴠᴡͼꜛᴒᴒᴡͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝͼᴡꜝͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦⱡ
᷈᷅ꜚԜꞌᴒᴠͼԜꜜᴑͼⱱᴒꜛԜꞌᴒᴠͼ᷈᷉ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒͼꜝᴟͼꜝꞌᴑᴒᴟͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲ᷅
᷉᷅Ⱬꜝᴐᴢꜛᴒꜜᴡᴒᴑͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼꜝⱱͼⱶⱨⱬͼӿᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷԐͼԝԜᴠᴒᴑͼᴢꜞꜝꜜͼԜꞌꞌꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲⱡͼ
᷄
Ⱬꜝᴐᴢꜛᴒꜜᴡᴒᴑͼᴐꞌ꞉ꜜ꞉ᴐԜꞌⱳ꞉ᴠᴡꜝᴟᴦͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼⱶⱨⱬͼӿᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼꜝᴟͼꜛᴢᴐꜝᴠԜꞌԓͼꜜꜝꜜꜞᴟᴢᴟ꞉ᴡ꞉ᴐͼ
ᴠᴤᴒꞌꞌ꞉ꜜⱲͼᴒꜞ꞉ᴠꜝᴑᴒᴠͼᴤ꞉ᴡⱳꜝᴢᴡͼԜᴐᴐꜝꜛꜞԜꜜᴦ꞉ꜜⱲͼᴢᴟᴡ꞉ᴐԜᴟ꞉ԜԐ᷅
᷄
Ⱬ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼᴡᴒᴠᴡ꞉ꜜⱲͼᴟᴒᴠᴢꞌᴡᴠͼꜝԝᴡԜ꞉ꜜᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴡⱳԜᴡͼᴐꜝꜜⱱ꞉ᴟꜛͼⱶⱨⱬͼᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷⱡͼⱪ᷈ͼ
꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼӿⱪ᷈᷄ⱷ꜠ⱶԐͼⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼꞌᴒᴣᴒꞌͼⱣͼ᷾᷇ӼͼꜝⱱͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌͼꞌᴒᴣᴒꞌ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼ
ⱪ᷈᷄ⱷ꜠ⱶͼꞌᴒᴣᴒꞌͼ᷿᷾᷇᷄᷇ӼͼꜝⱱͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌͼꞌᴒᴣᴒꞌͼꜛԜᴦͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ⱱͼᴡⱳᴒᴦͼԜꞌᴠꜝͼⱳԜᴣᴒͼԜͼⱪ᷾ͼꞌᴒᴣᴒꞌͼ
ԝᴒꞌꜝᴤͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌͼᴟԜꜜⱲᴒ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼԝᴒⱲ꞉ꜜͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼ꞉ꜜͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼԝᴒⱱꜝᴟᴒͼ
ᴡⱳᴒᴠᴒͼᴑ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼᴟᴒᴠᴢꞌᴡᴠͼԜᴟᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼԝᴒͼᴟᴒᴡᴒᴠᴡᴒᴑͼ꞉ⱱͼᴟᴒᴠᴢꞌᴡᴠͼԜᴟᴒͼ꞉ꜜᴐꜝꜜⱲᴟᴢᴒꜜᴡͼ
ᴤ꞉ᴡⱳͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝᴟͼԝᴒꞌ꞉ᴒᴣᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡꜝͼԝᴒͼᴐꜝꜜⱱꜝᴢꜜᴑᴒᴑͼԝᴦͼᴟᴒᴐᴒꜜᴡͼꜙᴁ͟ͼᴢᴠᴒ᷅
᷄
ⱨᴡͼꞌᴒԜᴠᴡͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲⱡͼԜⱲᴒͼԜᴡͼᴟᴒꜞꜝᴟᴡᴒᴑͼꜝꜜᴠᴒᴡͼꜝⱱͼⱱ꞉ᴟᴠᴡͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴠᴦꜛꜞᴡꜝꜛᴠͼᶑ᷊᷇ͼ
ᴦᴒԜᴟᴠԓͼԜͼⱱԜꜛ꞉ꞌᴦͼⱳ꞉ᴠᴡꜝᴟᴦͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼⱶⱨⱬͼᴁᴦꜞᴒͼⱷͼꜝᴟͼⱷⱷԓͼꜝᴟͼⱪ᷈ꜟͼᴤ꞉ᴡⱳ꞉ꜜͼꜜꜝᴟꜛԜꞌͼᴟԜꜜⱲᴒ᷅
᷊᷅ⱬᴥꜞᴒᴟ꞉ᴒꜜᴐ꞉ꜜⱲͼԜͼԝԜᴠᴒꞌ꞉ꜜᴒͼᴟԜᴡᴒͼꜝⱱͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼꜞᴒᴟͼ᷾ᴤᴒᴒꞋᴠͼԜᴠͼ
ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼ
᷾᷅ⱨᴑᴢꞌᴡͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜꜜᴑͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴢꜜᴑᴒᴟͼᴡⱳᴒͼԜⱲᴒͼꜝⱱͼ᷈˲ͼԜᴟᴒͼᴤ꞉ꞌꞌ꞉ꜜⱲͼԜꜜᴑԜԝꞌᴒͼᴡꜝͼᴟᴒԜᴑԓͼ
ᴢꜜᴑᴒᴟᴠᴡԜꜜᴑԓͼԜꜜᴑͼᴠ꞉ⱲꜜͼԜꜜͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼⱱꜝᴟꜛ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼԜⱲᴒͼ᷈᷉ͼᴡꜝͼ᷈ⅎԓͼᴤⱳꜝᴠᴒͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟͼ
ꜞᴟꜝᴣ꞉ᴑᴒᴠͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡԓͼԜᴟᴒͼᴤ꞉ꞌꞌ꞉ꜜⱲͼԜꜜᴑͼԜԝꞌᴒͼᴡꜝͼᴟᴒԜᴑԓͼᴢꜜᴑᴒᴟᴠᴡԜꜜᴑͼԜꜜᴑͼᴠ꞉ⱲꜜͼԜꜜͼԜᴠᴠᴒꜜᴡͼⱱꜝᴟꜛ᷅
᷿᷅ꜚԜꞌᴒᴠͼԜꜜᴑͼⱱᴒꜛԜꞌᴒᴠͼᴤⱳꜝͼԜᴟᴒͼⱱᴒᴟᴡ꞉ꞌᴒͼԜꜜᴑͼᴠᴒᴥᴢԜꞌꞌᴦͼԜᴐᴡ꞉ᴣᴒͼꜛᴢᴠᴡͼԜᴑⱳᴒᴟᴒͼᴡꜝͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼ
ᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜᴠͼⱱꜝꞌꞌꜝᴤᴠⱡ
᷄
ⱴᴒꜛԜꞌᴒᴠͼꜝⱱͼᴐⱳ꞉ꞌᴑԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉ԜꞌͼꜛᴢᴠᴡͼԜⱲᴟᴒᴒͼᴡꜝͼԝᴒͼԜԝᴠᴡ꞉ꜜᴒꜜᴡͼꜝᴟͼ꞉ᴡͼ꞉ᴠͼᴟᴒᴐꜝꜛꜛᴒꜜᴑᴒᴑͼᴡꜝͼᴢᴠᴒͼ
ⱳ꞉Ⱳⱳꞌᴦͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒͼⱱꜝᴟꜛᴠͼꜝⱱͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴡⱳᴟꜝᴢⱲⱳͼ᷊᷇ᴑԜᴦᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼ
ᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡ᷅ͼᴁⱳ꞉ᴠͼ꞉ꜜᴐꞌᴢᴑᴒᴠͼꜞᴟꜝⱲᴒᴠᴡ꞉ꜜ᷄ꜝꜜꞌᴦͼꜝᴟԜꞌͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ᴣᴒͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼ꞉ꜜⱳ꞉ԝ꞉ᴡ꞉ꜝꜜͼꜝⱱͼ
ꜝᴣᴢꞌԜᴡ꞉ꜝꜜͼӿꜝᴟԜꞌԓͼ꞉ꜜ꞊ᴒᴐᴡԜԝꞌᴒͼꜝᴟͼ꞉ꜛꜞꞌԜꜜᴡԜԝꞌᴒԐԓͼ꞉ꜜᴡᴟԜᴢᴡᴒᴟ꞉ꜜᴒͼᴑᴒᴣ꞉ᴐᴒͼӿⱷᴂⱫԓͼԜꞌꞌͼᴡᴦꜞᴒᴠԐͼꜝᴟͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
꞉ꜜᴡᴟԜᴢᴡᴒᴟ꞉ꜜᴒͼⱳꜝᴟꜛꜝꜜᴒͼᴟᴒꞌᴒԜᴠ꞉ꜜⱲͼᴠᴦᴠᴡᴒꜛᴠͼӿⱷᴂᴀԐ᷅ͼ꜠ꜝᴡᴒᴠⱡͼ᷈ԐͼⱨͼⱱᴒꜛԜꞌᴒͼᴤⱳꜝᴠᴒͼꜛԜꞌᴒͼꜞԜᴟᴡꜜᴒᴟͼ
ⱳԜᴠͼⱳԜᴑͼԜͼᴣԜᴠᴒᴐᴡꜝꜛᴦͼꜛᴢᴠᴡͼԜⱲᴟᴒᴒͼᴡꜝͼᴢᴠᴒͼꜝꜜᴒͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼⱱꜝᴟꜛͼꜝⱱͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼԜᴐᴐᴒꜞᴡԜԝꞌᴒͼ
ᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜ᷅ͼ᷉ԐͼᴂᴠᴒͼꜝⱱͼԜͼꜛԜꞌᴒͼᴐꜝꜜᴑꜝꜛͼᴤ꞉ᴡⱳͼꜝᴟͼᴤ꞉ᴡⱳꜝᴢᴡͼᴠꜞᴒᴟꜛ꞉ᴐ꞉ᴑᴒͼꜝᴟͼᴐᴒᴟᴣ꞉ᴐԜꞌͼᴐԜꜞԓͼ
ᴑ꞉ԜꜞⱳᴟԜⱲꜛͼꜝᴟͼᴠꜞꜝꜜⱲᴒͼᴤ꞉ᴡⱳͼᴠꜞᴒᴟꜛ꞉ᴐ꞉ᴑᴒͼꜝᴟͼԜͼᴐꜝꜛԝ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴑꜝᴢԝꞌᴒ᷄ԝԜᴟᴟ꞉ᴒᴟͼꜛᴒᴡⱳꜝᴑᴠԐͼ꞉ᴠͼꜜꜝᴡͼ
ᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼⱳ꞉Ⱳⱳꞌᴦͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒ᷅ͼ
᷄
ⱴᴒꜛԜꞌᴒᴠͼꜝⱱͼꜜꜝꜜ᷄ᴐⱳ꞉ꞌᴑԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌԓͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼᴠᴢᴟⱲ꞉ᴐԜꞌꞌᴦͼᴠᴡᴒᴟ꞉ꞌᴒͼӿᴠᴡԜᴡᴢᴠͼꜞꜝᴠᴡͼ
ⱳᴦᴠᴡᴒᴟᴒᴐᴡꜝꜛᴦԓͼԝ꞉ꞌԜᴡᴒᴟԜꞌͼꜝꜝꜞⱳꜝᴟᴒᴐᴡꜝꜛᴦԓͼꜝᴟͼԝ꞉ꞌԜᴡᴒᴟԜꞌͼᴡᴢԝԜꞌͼꞌ꞉ⱲԜᴡ꞉ꜝꜜԐͼꜝᴟͼꜞꜝᴠᴡ᷄ꜛᴒꜜꜝꜞԜᴢᴠԜꞌͼⱱꜝᴟͼ
ԜᴡͼꞌᴒԜᴠᴡͼ᷈᷉ͼꜛꜝꜜᴡⱳᴠͼᴑꜝͼꜜꜝᴡͼᴟᴒꜟᴢ꞉ᴟᴒͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
᷄
ꜚԜꞌᴒᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼꜛԜꞌᴒᴠͼᴤⱳꜝͼԜᴟᴒͼᴠᴢᴟⱲ꞉ᴐԜꞌꞌᴦͼᴠᴡᴒᴟ꞉ꞌᴒͼӿꜞꜝᴠᴡͼᴣԜᴠᴒᴐᴡꜝꜛᴦԐԓͼᴤ꞉ᴡⱳͼⱱᴒꜛԜꞌᴒͼꜞԜᴟᴡꜜᴒᴟᴠͼ
ꜝⱱͼᴐⱳ꞉ꞌᴑԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉ԜꞌͼꜛᴢᴠᴡͼԜⱲᴟᴒᴒͼᴡꜝͼԝᴒͼԜԝᴠᴡ꞉ꜜᴒꜜᴡͼꜝᴟͼᴒꞌᴠᴒͼᴢᴠᴒͼԜͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼԜᴐᴐᴒꜞᴡԜԝꞌᴒͼ
ⱱꜝᴟꜛͼꜝⱱͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴡⱳᴟꜝᴢⱲⱳͼ⅍᷇ᴑԜᴦᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡ᷅ͼ
4.3
Exclusion Criteria
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼꜛᴒᴒᴡͼԜꜜᴦͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴥᴐꞌᴢᴑᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦⱡ
᷈᷅ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼꜝⱱͼԜꜜꜝᴡⱳᴒᴟͼⱱꜝᴟꜛͼꜝⱱͼᴐⱳᴟꜝꜜ꞉ᴐԓͼᴟᴒᴐᴢᴟᴟᴒꜜᴡͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜԓͼᴠᴢᴐⱳͼԜᴠͼԜᴐꜟᴢ꞉ᴟᴒᴑͼ
ԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼӿⱨⱨⱬԐԓͼⱶⱨⱬͼᴤ꞉ᴡⱳͼꜜꜝᴟꜛԜꞌͼⱪ᷈᷄ⱷ꜠ⱶͼӿԜꞌᴠꜝͼꞋꜜꜝᴤꜜͼԜᴠͼⱶⱨⱬͼᴁᴦꜞᴒͼⱷⱷⱷԐԓͼ꞉ᴑ꞉ꜝꜞԜᴡⱳ꞉ᴐͼ
ԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜԓͼꜝᴟͼᴟᴒᴐᴢᴟᴟᴒꜜᴡͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼᴢᴟᴡ꞉ᴐԜᴟ꞉Ԝ᷅
᷉᷅͟Ԝᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜝꜜͼ꞉ꜜͼԜͼꜞᴟ꞉ꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴡᴢᴑᴦ᷅
᷊᷅Ⱬꜝᴠ꞉ꜜⱲͼᴤ꞉ᴡⱳͼԜꜜͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼᴑᴟᴢⱲͼꜝᴟͼᴒᴥꜞꜝᴠᴢᴟᴒͼᴡꜝͼԜꜜͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼᴑᴒᴣ꞉ᴐᴒͼᴤ꞉ᴡⱳ꞉ꜜͼ᷾ᴤᴒᴒꞋᴠͼ
ꜞᴟ꞉ꜝᴟͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲ᷅
᷾᷅ⱬᴥꜞꜝᴠᴢᴟᴒͼᴡꜝͼԜꜜⱲ꞉ꜝᴡᴒꜜᴠ꞉ꜜ᷄ᴐꜝꜜᴣᴒᴟᴡ꞉ꜜⱲͼᴒꜜᴧᴦꜛᴒͼӿⱨⱪⱬԐͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟᴠͼꜝᴟͼԜꜜᴦͼᴒᴠᴡᴟꜝⱲᴒꜜ᷄ᴐꜝꜜᴡԜ꞉ꜜ꞉ꜜⱲͼ
ꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼᴤ꞉ᴡⱳͼᴠᴦᴠᴡᴒꜛ꞉ᴐͼԜԝᴠꜝᴟꜞᴡ꞉ꜝꜜͼӿᴠᴢᴐⱳͼԜᴠͼꜝᴟԜꞌͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ᴣᴒᴠͼꜝᴟͼⱳꜝᴟꜛꜝꜜԜꞌͼᴟᴒꜞꞌԜᴐᴒꜛᴒꜜᴡͼ
ᴡⱳᴒᴟԜꜞᴦԐͼᴤ꞉ᴡⱳ꞉ꜜͼ᷾ͼᴤᴒᴒꞋᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲ᷅
᷿᷅ⱬᴥꜞꜝᴠᴢᴟᴒͼᴡꜝͼԜꜜᴑᴟꜝⱲᴒꜜᴠͼӿᴒ᷅Ⱳ᷅ͼᴠᴡԜꜜꜝᴧꜝꞌꜝꞌԓͼᴑԜꜜԜᴧꜝꞌԓͼꜝᴥԜꜜᴑᴟꜝꞌꜝꜜᴒԓͼꜛᴒᴡⱳᴦꞌᴡᴒᴠᴡꜝᴠᴡᴒᴟꜝꜜᴒԓͼ
ᴡᴒᴠᴡꜝᴠᴡᴒᴟꜝꜜᴒԐͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉ͼᴤᴒᴒꞋᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅
⅍᷅ᴂᴠᴒͼꜝⱱͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡⱳᴒᴟԜꜞᴦͼⱱꜝᴟͼⱶⱨⱬͼӿⱪ᷈᷄ⱷ꜠ⱶԓͼԜᴡᴡᴒꜜᴢԜᴡᴒᴑͼԜꜜᴑᴟꜝⱲᴒꜜᴠԓͼꜝᴟͼԜꜜᴡ꞉᷄
ⱱ꞉ԝᴟ꞉ꜜꜝꞌᴦᴡ꞉ᴐᴠԐͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉ͼᴤᴒᴒꞋᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅
ⅎ᷅ᴂᴠᴒͼꜝⱱͼᴠⱳꜝᴟᴡ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼⱱꜝᴟͼⱶⱨⱬͼᴤ꞉ᴡⱳ꞉ꜜͼⅎͼᴑԜᴦᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼ
ᴀⱳꜝᴟᴡ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼ꞉ᴠͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼⱪ᷈᷄ⱷ꜠ⱶԓͼԜᴡᴡᴒꜜᴢԜᴡᴒᴑͼԜꜜᴑᴟꜝⱲᴒꜜᴠԓͼꜝᴟͼԜꜜᴡ꞉᷄ⱱ꞉ԝᴟ꞉ꜜꜝꞌᴦᴡ꞉ᴐᴠͼᴢᴠᴒᴑͼ
ᴡꜝͼԜᴣꜝ꞉ᴑͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴐꜝꜛꜞꞌ꞉ᴐԜᴡ꞉ꜝꜜᴠͼⱱᴟꜝꜛͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼ꞉ꜜᴑ꞉ᴐԜᴡᴒᴑͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠ᷅
˲᷅ⱨꜜᴦͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꞌ꞉ᴣᴒᴟͼⱱᴢꜜᴐᴡ꞉ꜝꜜͼᴡᴒᴠᴡͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠⱡͼԜꞌԜꜜ꞉ꜜᴒͼԜꜛ꞉ꜜꜝᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒͼӿⱨꜙᴁԐ ⱥ᷊ᴥͼ
ᴢꜞꜞᴒᴟͼꞌ꞉ꜛ꞉ᴡͼꜝⱱͼꜜꜝᴟꜛԜꞌԓͼꜝᴟͼԜᴠꜞԜᴟᴡԜᴡᴒͼԜꜛ꞉ꜜꜝᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒͼӿⱨᴀᴁԐͼⱥͼ᷊ᴥͼᴢꜞꜞᴒᴟͼꞌ꞉ꜛ꞉ᴡͼꜝⱱͼꜜꜝᴟꜛԜꞌԓͼꜝᴟͼ
ᴡꜝᴡԜꞌͼԝ꞉ꞌ꞉ᴟᴢԝ꞉ꜜͼⱥͼ᷉ᴥͼᴢꜞꜞᴒᴟͼꞌ꞉ꜛ꞉ᴡͼꜝⱱͼꜜꜝᴟꜛԜꞌͼӿᴢꜜꞌᴒᴠᴠͼᴡⱳᴒͼԝ꞉ꞌ꞉ᴟᴢԝ꞉ꜜͼᴒꞌᴒᴣԜᴡ꞉ꜝꜜͼ꞉ᴠͼԜͼᴟᴒᴠᴢꞌᴡͼꜝⱱͼ
Ⱶ꞉ꞌԝᴒᴟᴡᶳᴠͼᴠᴦꜜᴑᴟꜝꜛᴒԐ᷅
Ⱡ᷅͟ᴟᴒⱲꜜԜꜜᴐᴦͼꜝᴟͼԝᴟᴒԜᴠᴡⱱᴒᴒᴑ꞉ꜜⱲ᷅
᷈᷇᷅ᴀᴢԝ꞊ᴒᴐᴡͼⱳԜᴠͼԜꜜᴦͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜͼᴡⱳԜᴡԓͼ꞉ꜜͼᴡⱳᴒͼꜝꜞ꞉ꜜ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼᴀꜞꜝꜜᴠꜝᴟԓͼꜛԜᴦͼ
ᴐꜝꜛꜞᴟꜝꜛ꞉ᴠᴒͼᴡⱳᴒ꞉ᴟͼᴠԜⱱᴒᴡᴦͼꜝᴟͼᴐꜝꜛꜞꞌ꞉Ԝꜜᴐᴒԓͼꜞᴟᴒᴐꞌᴢᴑᴒͼᴠᴢᴐᴐᴒᴠᴠⱱᴢꞌͼᴐꜝꜜᴑᴢᴐᴡͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼꜝᴟͼ꞉ꜜᴡᴒᴟⱱᴒᴟᴒͼ
ᴤ꞉ᴡⱳͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴟᴒᴠᴢꞌᴡᴠͼӿᴒ᷅Ⱳ᷅ԓͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝⱱͼᴠᴢԝᴠᴡԜꜜᴐᴒͼԜԝᴢᴠᴒͼꜝᴟͼᴑᴒꜞᴒꜜᴑᴒꜜᴐᴒԓͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼ
ꜞᴟᴒ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼ꞉ꞌꞌꜜᴒᴠᴠͼꜝᴟͼꜝᴡⱳᴒᴟͼꜛԜ꞊ꜝᴟͼᴐꜝꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼᴡⱳԜᴡͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴠͼꜛԜᴦͼᴐꜝꜜⱱꜝᴢꜜᴑͼ
ᴡⱳᴒͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜͼꜝⱱͼᴠᴡᴢᴑᴦͼᴟᴒᴠᴢꞌᴡᴠԐ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
5
STUDY TREATMENT(S)
5.1
Description of Treatment(s)
ⱴꜝᴟͼᴑᴒᴡԜ꞉ꞌᴒᴑͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜԓͼᴟᴒⱱᴒᴟͼᴡꜝͼᴡⱳᴒͼ͟ⱳԜᴟꜛԜᴐᴦͼꜚԜꜜᴢԜꞌ᷅
5.1.1
DX-2930
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ᴠͼԜͼᴠᴡᴒᴟ꞉ꞌᴒԓͼꜞᴟᴒᴠᴒᴟᴣԜᴡ꞉ᴣᴒ᷄ⱱᴟᴒᴒͼᴠꜝꞌᴢᴡ꞉ꜝꜜͼⱱꜝᴟͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜԓͼꜞⱶͼ⅍᷅᷇᷅ͼᴁⱳᴒͼԜᴐᴡ꞉ᴣᴒͼ꞉ꜜⱲᴟᴒᴑ꞉ᴒꜜᴡԓͼ
Ⱬᴅ᷄᷉Ⱡ᷊᷇ԓͼ꞉ᴠͼⱱꜝᴟꜛᴢꞌԜᴡᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐꜝꜛꜞᴒꜜᴑ꞉Ԝꞌͼᴐꜝꜛꜞꜝꜜᴒꜜᴡᴠⱡͼ᷊᷇ͼꜛꜚͼᴠꜝᴑ꞉ᴢꜛͼꜞⱳꜝᴠꜞⱳԜᴡᴒͼ
ᴑ꞉ԝԜᴠ꞉ᴐͼᴑ꞉ⱳᴦᴑᴟԜᴡᴒԓͼ᷈Ⱡ᷅⅍ͼꜛꜚͼᴐ꞉ᴡᴟ꞉ᴐͼԜᴐ꞉ᴑԓͼ᷿᷇ͼꜛꜚͼⱳ꞉ᴠᴡ꞉ᴑ꞉ꜜᴒԓͼⱠ᷇ͼꜛꜚͼᴠꜝᴑ꞉ᴢꜛͼᴐⱳꞌꜝᴟ꞉ᴑᴒԓͼ᷇᷅᷇᷈Ӽͼ
͟ꜝꞌᴦᴠꜝᴟԝԜᴡᴒ˲᷇᷅ͼⱬԜᴐⱳͼᴣ꞉ԜꞌͼᴐꜝꜜᴡԜ꞉ꜜᴠͼԜͼꜜꜝꜛ꞉ꜜԜꞌͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼ᷿᷈᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜᴐᴡ꞉ᴣᴒͼ
꞉ꜜⱲᴟᴒᴑ꞉ᴒꜜᴡͼ꞉ꜜͼ᷈ꜛꜙͼᴠꜝꞌᴢᴡ꞉ꜝꜜ᷅ͼᴁⱳᴒͼᴡᴒᴠᴡͼꜞᴟꜝᴑᴢᴐᴡͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼԝᴦͼᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼ꞉ꜜᴡꜝͼ
ᴡⱳᴒͼᴢꜞꜞᴒᴟͼԜᴟꜛͼ꞉ꜜͼԜͼԝꞌ꞉ꜜᴑᴒᴑͼꜛԜꜜꜜᴒᴟ᷅
ⱴꜝᴟͼᴒԜᴐⱳͼ᷊᷇᷇ꜛⱲͼᴑꜝᴠᴒͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼᴡꜝᴡԜꞌͼꜝⱱͼ᷉ͼꜛꜙԓͼᴑ꞉ᴣ꞉ᴑᴒᴑͼ꞉ꜜᴡꜝͼ
᷉ᴠᴒꜞԜᴟԜᴡᴒͼ᷈᷅᷇ͼꜛꜙͼᴀⱪͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇᷅ͼᴁⱳᴒͼ᷉ͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼⱲ꞉ᴣᴒꜜͼ꞉ꜜͼᴡⱳᴒͼᴠԜꜛᴒͼᴢꜞꜞᴒᴟͼ
Ԝᴟꜛԓͼᴤ꞉ᴡⱳͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼᴐꜛͼᴠᴒꜞԜᴟԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴒԜᴐⱳͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼᴠ꞉ᴡᴒ᷅
ⱴꜝᴟͼᴒԜᴐⱳͼ᷿᷈᷇ͼꜛⱲͼᴑꜝᴠᴒͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼᴡꜝᴡԜꞌͼꜝⱱͼ᷉ͼꜛꜙԓͼᴑ꞉ᴣ꞉ᴑᴒᴑͼ꞉ꜜᴡꜝͼ
᷉ᴠᴒꜞԜᴟԜᴡᴒͼ᷈᷅᷇ͼꜛꜙͼᴀⱪͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠԓͼᴤⱳᴒᴟᴒͼꜝꜜᴒͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼ꞉ᴠͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑͼᴡⱳᴒͼꜝᴡⱳᴒᴟͼ꞉ᴠͼꜞꞌԜᴐᴒԝꜝ᷅ͼᴁⱳᴒͼ᷉ͼ
꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼⱲ꞉ᴣᴒꜜͼ꞉ꜜͼᴡⱳᴒͼᴠԜꜛᴒͼᴢꜞꜞᴒᴟͼԜᴟꜛԓͼᴤ꞉ᴡⱳͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼᴐꜛͼᴠᴒꜞԜᴟԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴒԜᴐⱳͼ
꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼᴠ꞉ᴡᴒ᷅
5.1.2
Placebo
͟ꞌԜᴐᴒԝꜝͼᴐꜝꜜᴠ꞉ᴠᴡᴠͼꜝⱱͼᴡⱳᴒͼ꞉ꜜԜᴐᴡ꞉ᴣᴒͼⱱꜝᴟꜛᴢꞌԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴡᴒᴠᴡͼꜞᴟꜝᴑᴢᴐᴡⱡͼ᷊᷇ͼꜛꜚͼᴠꜝᴑ꞉ᴢꜛͼꜞⱳꜝᴠꜞⱳԜᴡᴒͼ
ᴑ꞉ԝԜᴠ꞉ᴐͼᴑ꞉ⱳᴦᴑᴟԜᴡᴒԓͼ᷈Ⱡ᷅⅍ꜛꜚͼᴐ꞉ᴡᴟ꞉ᴐͼԜᴐ꞉ᴑԓͼ᷿᷇ͼꜛꜚͼⱳ꞉ᴠᴡ꞉ᴑ꞉ꜜᴒԓͼⱠ᷇ͼꜛꜚͼᴠꜝᴑ꞉ᴢꜛͼᴐⱳꞌꜝᴟ꞉ᴑᴒԓͼꜞⱶͼ⅍᷅᷇ͼᴤ꞉ᴡⱳͼ
᷇᷅᷇᷈Ӽͼ͟ꜝꞌᴦᴠꜝᴟԝԜᴡᴒ˲᷇᷅ͼ
͟ꞌԜᴐᴒԝꜝͼᴑꜝᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴡꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛͼԜꜜᴑͼ꞉ꜜͼ
ԝᴒᴡᴤᴒᴒꜜͼᴑꜝᴠᴒᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱱꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼᴡⱳᴒͼ᷊᷇᷇ͼꜛⱲͼꜝᴟͼ᷿᷈᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴒᴣᴒᴟᴦͼ᷾ͼ
ᴤᴒᴒꞋᴠͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛᴠԓͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴑꜝᴠ꞉ꜜⱲͼᴠᴐⱳᴒᴑᴢꞌᴒͼ꞉ꜜͼᴁԜԝꞌᴒ᷉᷅ͼ
ⱴꜝᴟͼᴒԜᴐⱳͼꜞꞌԜᴐᴒԝꜝͼᴑꜝᴠᴒԓͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜͼᴡꜝᴡԜꞌͼꜝⱱͼ᷉ͼꜛꜙԓͼᴑ꞉ᴣ꞉ᴑᴒᴑͼ꞉ꜜᴡꜝͼ᷉ᴠᴒꜞԜᴟԜᴡᴒͼ᷈᷅᷇ꜛꜙͼ
ᴀⱪͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼꜞꞌԜᴐᴒԝꜝ᷅ͼᴁⱳᴒͼ᷉ͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼⱲ꞉ᴣᴒꜜͼ꞉ꜜͼᴡⱳᴒͼᴠԜꜛᴒͼᴢꜞꜞᴒᴟͼԜᴟꜛԓͼᴤ꞉ᴡⱳͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ͼᴐꜛͼ
ᴠᴒꜞԜᴟԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴒԜᴐⱳͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼᴠ꞉ᴡᴒ᷅
5.2
Dosing and Follow-Up Schedule
ⱫᴒᴡԜ꞉ꞌᴠͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡͼᴑꜝᴠ꞉ꜜⱲͼԜꜜᴑͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼԜᴟᴒͼ꞉ꜜᴐꞌᴢᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒԓͼᴁԜԝꞌᴒͼ᷈.
5.3
Method of Assigning Subjects to Treatment Groups
ᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛᴒᴒᴡ꞉ꜜⱲͼԜꞌꞌͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝͼᴤ꞉ꞌꞌͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜꜜᴑͼᴠᴒꜟᴢᴒꜜᴡ꞉ԜꞌꞌᴦͼԜᴠᴠ꞉ⱲꜜᴒᴑͼԜꜜͼ
꞉ᴑᴒꜜᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼꜜᴢꜛԝᴒᴟ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠ꞉ⱲꜜᴒᴑͼᴡꜝͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
Ⱳᴟꜝᴢꜞᴠͼᴣ꞉ԜͼԜꜜͼⱷꜜᴡᴒᴟԜᴐᴡ꞉ᴣᴒͼᴄᴒԝ᷄ԝԜᴠᴒᴑͼϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼᴀᴦᴠᴡᴒꜛͼӿⱷᴄϸᴀԐ᷅ͼᴂᴠᴒͼꜝⱱͼᴡⱳᴒͼⱷᴄϸᴀͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜝᴢᴡꞌ꞉ꜜᴒᴑͼ꞉ꜜͼᴡⱳᴒͼ꜡ꜞᴒᴟԜᴡ꞉ꜝꜜᴠͼꜚԜꜜᴢԜꞌ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
5.4
Blinding and Unblinding
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼ᷊᷇᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠԓͼ᷊᷇᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴒᴣᴒᴟᴦͼ
᷾ͼᴤᴒᴒꞋᴠԓͼ᷿᷈᷇ͼꜛⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠͼꜝᴟͼꜞꞌԜᴐᴒԝꜝͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠͼ꞉ꜜͼԜͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼⱱԜᴠⱳ꞉ꜝꜜ᷅ͼ
ᴀᴢԝ꞊ᴒᴐᴡᴠԓͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠͼⱱꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴢꜜᴑᴒᴟͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒԓͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼԜꜜᴑͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼԝᴒͼ
ԝꞌ꞉ꜜᴑᴒᴑͼᴡꜝͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴢꜜᴡ꞉ꞌͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼ꞉ᴠͼᴐꜝꜛꜞꞌᴒᴡᴒ᷅ͼᴁⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴤ꞉ꞌꞌͼԝᴒͼԝꞌ꞉ꜜᴑᴒᴑͼᴡꜝͼ
ᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴢꜜᴡ꞉ꞌͼԜꞌꞌͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ꜜᴣꜝꞌᴣᴒꜛᴒꜜᴡͼ꞉ꜜͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼ꞉ᴠͼᴐꜝꜛꜞꞌᴒᴡᴒͼԜꜜᴑͼ
ꜞᴟ꞉ꜛԜᴟᴦͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼԜꜜԜꞌᴦᴠᴒᴠͼⱳԜᴣᴒͼԝᴒᴒꜜͼᴐꜝꜜᴑᴢᴐᴡᴒᴑ᷅
ᴁⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴐꜝᴑᴒͼⱱꜝᴟͼԜꜜͼ꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼꜞԜᴡ꞉ᴒꜜᴡͼꜛԜᴦͼꜝꜜꞌᴦͼԝᴒͼԝᴟꜝꞋᴒꜜͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼᴀꜞꜝꜜᴠꜝᴟͼ
ꜝᴟͼᴡⱳᴒͼⱫᴀꜚⱩͼⱱꜝᴟͼᴟᴒԜᴠꜝꜜᴠͼꜝⱱͼꜞԜᴡ꞉ᴒꜜᴡͼᴠԜⱱᴒᴡᴦͼꜝᴟͼ꞉ꜜͼԜꜜͼᴒꜛᴒᴟⱲᴒꜜᴐᴦͼᴤⱳᴒꜜͼꞋꜜꜝᴤꞌᴒᴑⱲᴒͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴤꜝᴢꞌᴑͼԝᴒͼ꞉ꜛꜞꜝᴟᴡԜꜜᴡͼⱱꜝᴟͼᴡⱳᴒᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡ᷅ͼ
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼᴑꜝᴐᴢꜛᴒꜜᴡͼᴡⱳᴒͼᴑԜᴡᴒԓͼᴡ꞉ꜛᴒͼԜꜜᴑͼᴟᴒԜᴠꜝꜜͼⱱꜝᴟͼᴡⱳᴒͼᴐꜝᴑᴒͼԝᴟᴒԜꞋ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ
ᴠⱳꜝᴢꞌᴑͼⱱꜝꞌꞌꜝᴤͼᴡⱳᴒͼ꞉ꜜᴠᴡᴟᴢᴐᴡ꞉ꜝꜜᴠͼᴤ꞉ᴡⱳ꞉ꜜͼᴡⱳᴒͼⱷᴄϸᴀͼᴀᴦᴠᴡᴒꜛͼᴠⱳꜝᴢꞌᴑͼԜͼᴐꜝᴑᴒͼԝᴟᴒԜꞋͼԝᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑ᷅ͼⱷꜜͼᴡⱳᴒͼ
ᴐԜᴠᴒͼꜝⱱͼԜͼᴐꜝꜜᴐᴒᴟꜜ꞉ꜜⱲͼᴑᴟᴢⱲ᷄ᴟᴒꞌԜᴡᴒᴑͼᴠԜⱱᴒᴡᴦᴒᴣᴒꜜᴡԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼⱳԜᴠͼᴡⱳᴒͼԜԝ꞉ꞌ꞉ᴡᴦͼᴡꜝͼᴐꜝꜜᴡԜᴐᴡͼԜꜜᴑͼ
ᴐꜝꜜᴠᴢꞌᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟ᷅ͼⱷꜜͼᴒꜛᴒᴟⱲᴒꜜᴐᴦͼᴠ꞉ᴡᴢԜᴡ꞉ꜝꜜᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛԜᴦͼԝᴟᴒԜꞋͼᴡⱳᴒͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴐꜝᴑᴒͼ꞉ꜛꜛᴒᴑ꞉ԜᴡᴒꞌᴦͼꜝᴟͼԜᴠͼꜟᴢ꞉ᴐꞋꞌᴦͼԜᴠͼꜞꜝᴠᴠ꞉ԝꞌᴒͼ꞉ⱱͼⱳᴒ᷆ᴠⱳᴒͼⱱ꞉ꜜᴑᴠͼ꞉ᴡͼ꞉ᴠͼ꞉ꜜͼᴡⱳᴒͼԝᴒᴠᴡͼ꞉ꜜᴡᴒᴟᴒᴠᴡͼꜝⱱͼᴡⱳᴒͼ
ᴡᴟ꞉Ԝꞌͼᴠᴢԝ꞊ᴒᴐᴡ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼⱳԜᴠͼᴢꜜᴟᴒᴠᴡᴟ꞉ᴐᴡᴒᴑͼԜꜜᴑͼ꞉ꜛꜛᴒᴑ꞉ԜᴡᴒͼԜᴐᴐᴒᴠᴠͼᴡꜝͼԝᴟᴒԜꞋͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴐꜝᴑᴒͼ
ᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼⱷᴄϸᴀͼᴀᴦᴠᴡᴒꜛ᷅
ᴁⱳᴒͼⱫԜᴡԜͼԜꜜᴑͼᴀԜⱱᴒᴡᴦͼꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼⱩꜝԜᴟᴑͼӿⱫᴀꜚⱩԐԓͼ꞉ꜜͼᴐꜝꜜᴠᴢꞌᴡԜᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟԓͼꜛԜᴦͼ
Ԝꞌᴠꜝͼᴟᴒꜟᴢᴒᴠᴡͼᴢꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲͼꜝⱱͼԜꜜͼ꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼꜞԜᴡ꞉ᴒꜜᴡᶳᴠͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴠᴠ꞉ⱲꜜꜛᴒꜜᴡͼⱱꜝᴟͼᴟᴒԜᴠꜝꜜᴠͼꜝⱱͼᴠԜⱱᴒᴡᴦ᷅ͼ
ⱷꜜͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼꜝⱱͼԜͼᴑᴟᴢⱲ᷄ᴟᴒꞌԜᴡᴒᴑԓͼᴠᴒᴟ꞉ꜝᴢᴠԓͼᴢꜜᴒᴥꜞᴒᴐᴡᴒᴑͼⱨⱬԓͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟᶳᴠͼ͟ⱳԜᴟꜛԜᴐꜝᴣ꞉Ⱳ꞉ꞌԜꜜᴐᴒͼ
ⱫᴒꜞԜᴟᴡꜛᴒꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴠᴠ꞉Ⱳꜜꜛᴒꜜᴡͼⱱꜝᴟͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱱꜝᴟͼᴡⱳᴒͼꜞᴢᴟꜞꜝᴠᴒͼꜝⱱͼ
ᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲ᷅
5.5
Prior and Concomitant Therapy
ϸᴒԜᴠꜝꜜԜԝꞌᴒͼᴒⱱⱱꜝᴟᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜛԜᴑᴒͼᴡꜝͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼԜꞌꞌͼᴟᴒꞌᴒᴣԜꜜᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡᴠͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱱᴟꜝꜛͼ
ᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴢꜞͼᴡꜝͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼᴑꜝᴠᴒͼꜝⱱͼⱷꜚ᷅͟ͼ
ⱨꞌꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜝꜜͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼⱱᴟꜝꜛͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼⱱ꞉ᴟᴠᴡͼᴑꜝᴠᴒͼꜝⱱͼⱷꜚ͟ͼᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼ
ᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡͼӿ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԜꞌꞌͼꜞᴟᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜ᷆ꜜꜝꜜ᷄ꜞᴟᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠԓͼⱳᴒᴟԝԜꞌͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼԜꜜᴑͼ
ᴣ꞉ᴡԜꜛ꞉ꜜͼᴠᴢꜞꜞꞌᴒꜛᴒꜜᴡᴠԐͼꜛᴢᴠᴡͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼꜝꜜͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼᴒꞌᴒᴐᴡᴟꜝꜜ꞉ᴐͼⱪԜᴠᴒͼϸᴒꜞꜝᴟᴡͼⱴꜝᴟꜛͼӿᴒⱪϸⱴԐͼ
Ԝꜜᴑͼᴠⱳꜝᴢꞌᴑͼ꞉ꜜᴐꞌᴢᴑᴒͼᴡⱳᴒͼꜜԜꜛᴒͼꜝⱱͼᴡⱳᴒͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼꜝᴟͼᴑᴟᴢⱲͼԜꜜᴑͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼӿᴠᴡԜᴟᴡͼԜꜜᴑͼ
ᴠᴡꜝꜞͼᴑԜᴡᴒᴠԐ᷅ͼⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡᴠͼӿꜜꜝꜜ᷄ꜞⱳԜᴟꜛԜᴐꜝꞌꜝⱲ꞉ᴐԜꞌͼᴡᴟᴒԜᴡꜛᴒꜜᴡᴠԐͼ꞉ꜜᴐꞌᴢᴑᴒͼԜꜜᴦͼᴠᴢᴟⱲ꞉ᴐԜꞌͼꜝᴟͼ
ᴑ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠ᷅
5.5.1
Allowed Therapies
ᴁⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡⱳᴒᴟԜꜞ꞉ᴒᴠͼԜᴟᴒͼԜꞌꞌꜝᴤᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦⱡ
ᶄ
ᴁⱳᴒᴟԜꜞ꞉ᴒᴠͼⱱꜝᴟͼᴐꜝ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴡⱳꜝᴠᴒͼⱱꜝᴟͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋᴠͼꜝⱱͼⱶⱨⱬԓͼԜᴟᴒͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼ
꞉ⱱͼꜜꜝᴡͼᴒᴥᴐꞌᴢᴑᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷿᷅᷅᷉᷅ͼⱨᴐᴢᴡᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜᴟᴒͼᴡꜝͼԝᴒͼꜛԜꜜԜⱲᴒᴑͼ꞉ꜜͼ
Ԝᴐᴐꜝᴟᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼᴢᴠᴢԜꞌͼᴐԜᴟᴒͼꜝⱱͼᴡⱳᴒ꞉ᴟͼꜞԜᴡ꞉ᴒꜜᴡᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴢᴠᴒͼꜝⱱͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾ⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴡⱳᴒᴟԜꜞ꞉ᴒᴠͼᴡⱳԜᴡͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴒꜛᴠͼԜᴠͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼԜꜞꜞᴟꜝꜞᴟ꞉Ԝᴡᴒ᷅ͼᴂᴠᴒͼꜝⱱͼⱪ᷈᷄ⱷ꜠ⱶͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼԜᴠͼԜꜜͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋͼᴡⱳᴒᴟԜꜞᴦͼԝᴢᴡͼꜜꜝᴡͼԜᴠͼԜͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠ᷅ͼⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼԜꜜᴑͼᴠᴡᴢᴑᴦͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴤ꞉ᴡⱳꜝᴢᴡͼԜꞌᴡᴒᴟԜᴡ꞉ꜝꜜͼᴡꜝͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼ
ᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴠᴡᴢᴑᴦͼᴠᴐⱳᴒᴑᴢꞌᴒԓͼᴒᴣᴒꜜͼ꞉ⱱͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡͼᴟᴒᴐᴒ꞉ᴣᴒᴠͼԜꜜᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱱꜝᴟͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋ᷅
ᶄ
ᴁⱳᴒͼᴢᴠᴒͼꜝⱱͼᴠⱳꜝᴟᴡ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱱꜝᴟͼⱶⱨⱬͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼ꞉ⱱͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼ
꞉ꜜᴑ꞉ᴐԜᴡᴒᴑ᷅
ᶄ
ᴁⱳᴒᴟԜꜞ꞉ᴒᴠͼᴡꜝͼᴡᴟᴒԜᴡͼԜꜜᴦͼⱨⱬᴠͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜᴟᴒͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑ᷅
5.5.2
Excluded Concomitant Therapies
ᴂᴠᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡᴟᴒԜᴡꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦⱡ
ᶄ
ꜙꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼⱱꜝᴟͼⱶⱨⱬͼӿᴒ᷅Ⱳ᷅ԓͼᴢᴠᴒͼꜝⱱͼⱪ᷈᷄ⱷ꜠ⱶͼⱱꜝᴟͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠԓͼԜᴡᴡᴒꜜᴢԜᴡᴒᴑͼ
ԜꜜᴑᴟꜝⱲᴒꜜᴠԓͼꜝᴟͼԜꜜᴡ꞉᷄ⱱ꞉ԝᴟ꞉ꜜꜝꞌᴦᴡ꞉ᴐᴠԐ᷅
ᶄ
ⱨꜜⱲ꞉ꜝᴡᴒꜜᴠ꞉ꜜ᷄ᴐꜝꜜᴣᴒᴟᴡ꞉ꜜⱲͼᴒꜜᴧᴦꜛᴒͼӿⱨⱪⱬԐͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟᴠ᷅
ᶄ
ⱬᴠᴡᴟꜝⱲᴒꜜ᷄ᴐꜝꜜᴡԜ꞉ꜜ꞉ꜜⱲͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼᴤ꞉ᴡⱳͼᴠᴦᴠᴡᴒꜛ꞉ᴐͼԜԝᴠꜝᴟꜞᴡ꞉ꜝꜜͼӿᴠᴢᴐⱳͼԜᴠͼꜝᴟԜꞌͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ᴣᴒᴠͼꜝᴟͼ
ⱳꜝᴟꜛꜝꜜԜꞌͼᴟᴒꜞꞌԜᴐᴒꜛᴒꜜᴡͼᴡⱳᴒᴟԜꜞᴦԐ᷅
ᶄ
ⱨꜜᴑᴟꜝⱲᴒꜜᴠͼӿᴒ᷅Ⱳ᷅ԓͼᴠᴡԜꜜꜝᴧꜝꞌꜝꞌԓͼᴑԜꜜԜᴧꜝꞌԓͼꜝᴥԜꜜᴑᴟꜝꞌꜝꜜᴒԓͼꜛᴒᴡⱳᴦꞌᴡᴒᴠᴡꜝᴠᴡᴒᴟꜝꜜᴒԓͼᴡᴒᴠᴡꜝᴠᴡᴒᴟꜝꜜᴒԐ᷅
ᶄ
ⱨꜜᴦͼꜝᴡⱳᴒᴟͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼᴑᴟᴢⱲͼꜝᴟͼᴑᴒᴣ꞉ᴐᴒ᷅
5.6
Restrictions
5.6.1
Medical Interventions
ꜚᴒᴑ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜᴠͼᴑᴒᴒꜛᴒᴑͼꜜᴒᴐᴒᴠᴠԜᴟᴦͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼⱱꜝᴟͼᴡⱳᴒͼⱳᴒԜꞌᴡⱳͼԜꜜᴑͼᴤᴒꞌꞌ᷄ԝᴒ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼ
ᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼᴒᴥᴐꞌᴢᴑᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅ͼ
5.6.2
Fluid and Food Intake 
ᴁⱳᴒᴟᴒͼԜᴟᴒͼꜜꜝͼᴟᴒᴠᴡᴟ꞉ᴐᴡ꞉ꜝꜜᴠͼꜝꜜͼⱱꞌᴢ꞉ᴑͼԜꜜᴑͼⱱꜝꜝᴑͼ꞉ꜜᴡԜꞋᴒ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴡⱳᴒ꞉ᴟͼᴢᴠᴢԜꞌͼᴑ꞉ᴒᴡԜᴟᴦͼ
ᴟᴒⱲ꞉ꜛᴒꜜᴠ᷅
5.6.3
Activity
ᴁⱳᴒᴟᴒͼԜᴟᴒͼꜜꜝͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼᴟᴒᴠᴡᴟ꞉ᴐᴡ꞉ꜝꜜᴠ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴡⱳᴒ꞉ᴟͼᴢᴠᴢԜꞌͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼᴟᴒⱲ꞉ꜛᴒꜜᴠ᷅
5.7
Treatment Compliance
ⱨꞌꞌͼᴑꜝᴠᴒᴠͼꜝⱱͼᴡⱳᴒͼⱷꜚ͟ͼᴤ꞉ꞌꞌͼԝᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴐꞌ꞉ꜜ꞉ᴐͼᴣ꞉ᴠ꞉ᴡᴠͼᴢꜜᴑᴒᴟͼᴡⱳᴒͼᴑ꞉ᴟᴒᴐᴡͼᴠᴢꜞᴒᴟᴣ꞉ᴠ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴑᴒᴠ꞉ⱲꜜԜᴡᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅ͼ
5.8
Packaging and Labeling
ᴁⱳᴒͼᴡᴒᴠᴡͼꜞᴟꜝᴑᴢᴐᴡᴠͼӿⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑͼꜞꞌԜᴐᴒԝꜝԐͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴢꜞꜞꞌ꞉ᴒᴑͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԜꜜᴑͼꜞԜᴐꞋԜⱲᴒᴑͼԜꜜᴑͼ
ꞌԜԝᴒꞌᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒͼꞌꜝᴐԜꞌͼԜꜜᴑͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼⱱꜝᴟͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼᴠᴡᴢᴑ꞉ᴒᴠ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
5.9
Storage and Accountability
ⱨꞌꞌͼᴠᴢꜞꜞꞌ꞉ᴒᴠͼꜝⱱͼᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡᴠͼӿⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑͼꜞꞌԜᴐᴒԝꜝԐͼꜛᴢᴠᴡͼԝᴒͼᴠᴡꜝᴟᴒᴑͼᴟᴒⱱᴟ꞉ⱲᴒᴟԜᴡᴒᴑͼ
ӿ᷉ᶛⱪͼᴡꜝͼ˲ᶛⱪ᷊᷆⅍ᶛⱴͼᴡꜝͼ᷾⅍ᶛⱴԐͼ꞉ꜜͼᴡⱳᴒͼꜝᴟ꞉Ⱳ꞉ꜜԜꞌͼᴐԜᴟᴡꜝꜜͼԜꜜᴑͼꜞᴟꜝᴡᴒᴐᴡᴒᴑͼⱱᴟꜝꜛͼꞌ꞉Ⱳⱳᴡԓͼ꞉ꜜͼԜͼᴠᴒᴐᴢᴟᴒꞌᴦͼꞌꜝᴐꞋᴒᴑͼ
ԜᴟᴒԜԓͼԜᴐᴐᴒᴠᴠ꞉ԝꞌᴒͼᴡꜝͼԜᴢᴡⱳꜝᴟ꞉ᴧᴒᴑͼꜞᴒᴟᴠꜝꜜᴠͼꜝꜜꞌᴦԓͼᴢꜜᴡ꞉ꞌͼꜜᴒᴒᴑᴒᴑͼⱱꜝᴟͼᴑꜝᴠᴒͼꜞᴟᴒꜞԜᴟԜᴡ꞉ꜝꜜ᷅ͼϷᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴠ꞉ᴡᴒͼ
ꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼ꞉ꜜᴣᴒꜜᴡꜝᴟᴦͼᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼԜꜜᴑͼᴤ꞉ꞌꞌͼꜛԜ꞉ꜜᴡԜ꞉ꜜͼᴟᴒᴐꜝᴟᴑᴠͼꜝⱱͼ
ᴑ꞉ᴠꜞꜝᴠ꞉ᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴑᴟᴢⱲԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴑԜᴡᴒᴠԓͼꜟᴢԜꜜᴡ꞉ᴡᴦͼԜꜜᴑͼᴢᴠᴒ᷅
5.10
Investigational Medicinal Product Retention at Study Site
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼӿꜝᴟͼᴑᴒᴠ꞉ⱲꜜᴒᴒԐͼ꞉ᴠͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝꞌᴒͼⱱꜝᴟͼꜛԜ꞉ꜜᴡԜ꞉ꜜ꞉ꜜⱲͼԜᴐᴐᴢᴟԜᴡᴒͼԜᴐᴐꜝᴢꜜᴡԜԝ꞉ꞌ꞉ᴡᴦͼᴟᴒᴐꜝᴟᴑᴠͼꜝⱱͼ
ᴡⱳᴒͼⱷꜚ͟ͼᴡⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦ᷅ͼⱨꞌꞌͼⱷꜚ͟ͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼԜᴡͼᴡⱳᴒͼᴠ꞉ᴡᴒͼꜛᴢᴠᴡͼԝᴒͼ꞉ꜜᴣᴒꜜᴡꜝᴟ꞉ᴒᴑͼԜꜜᴑͼ
Ԝᴐᴐꜝᴢꜜᴡᴒᴑͼⱱꜝᴟͼ꞉ꜜͼԜꜜͼԜᴐᴐꜝᴢꜜᴡԜԝ꞉ꞌ꞉ᴡᴦͼꞌꜝⱲͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ᷅ͼⱨꞌꞌͼᴑ꞉ᴠꜞᴒꜜᴠ꞉ꜜⱲͼԜꜜᴑͼ
ԜᴐᴐꜝᴢꜜᴡԜԝ꞉ꞌ꞉ᴡᴦͼᴟᴒᴐꜝᴟᴑᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒͼⱱꜝᴟͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒᴣ꞉ᴒᴤ᷅ⱷꜚ͟ͼԜᴐᴐꜝᴢꜜᴡԜԝ꞉ꞌ꞉ᴡᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴣᴒᴟ꞉ⱱ꞉ᴒᴑͼ
ᴑᴢᴟ꞉ꜜⱲͼꜝꜜ᷄ᴠ꞉ᴡᴒͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡᴠ᷅
ᴂꜞꜝꜜͼᴡⱳᴒͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝᴟͼᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼԜꜜᴑͼᴢꜞꜝꜜͼᴤᴟ꞉ᴡᴡᴒꜜͼԜᴢᴡⱳꜝᴟ꞉ᴧԜᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴡⱳᴒͼ
ᴀꜞꜝꜜᴠꜝᴟԓͼꜝᴟͼ꞉ᴡᴠͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒԓͼԜꞌꞌͼᴢꜜᴢᴠᴒᴑͼԜꜜᴑ᷆ꜝᴟͼꜞԜᴟᴡ꞉Ԝꞌꞌᴦͼᴢᴠᴒᴑͼⱷꜚ͟ͼᴠⱳꜝᴢꞌᴑͼԝᴒͼᴟᴒᴡᴢᴟꜜᴒᴑͼꜝᴟͼ
ᴑᴒᴠᴡᴟꜝᴦᴒᴑͼԜᴡͼᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼᴠ꞉ᴡᴒԓͼԜᴠͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼԝᴦͼᴀꜞꜝꜜᴠꜝᴟ᷅ͼⱷᴡͼ꞉ᴠͼᴡⱳᴒⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼ
ᴟᴒᴠꜞꜝꜜᴠ꞉ԝ꞉ꞌ꞉ᴡᴦͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼᴡⱳԜᴡͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟԓͼꜝᴟͼ꞉ᴡᴠͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒԓͼⱳԜᴠͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴤᴟ꞉ᴡᴡᴒꜜͼԜᴢᴡⱳꜝᴟ꞉ᴧԜᴡ꞉ꜝꜜͼ
ᴡⱳԜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼⱱꜝᴟͼꜞᴟꜝꜞᴒᴟͼᴑ꞉ᴠꜞꜝᴠԜꞌͼꜝⱱͼᴡⱳᴒͼⱷꜚ͟ͼⱳԜᴣᴒͼԝᴒᴒꜜͼᴒᴠᴡԜԝꞌ꞉ᴠⱳᴒᴑԓͼԜꜜᴑͼᴡⱳԜᴡͼԜꜞꜞᴟꜝꜞᴟ꞉Ԝᴡᴒͼ
ᴟᴒᴐꜝᴟᴑᴠͼꜝⱱͼᴡⱳᴒͼᴑ꞉ᴠꜞꜝᴠԜꞌͼԜᴟᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼԜꜜᴑͼꜛԜ꞉ꜜᴡԜ꞉ꜜᴒᴑ᷅ͼ꜠ꜝͼᴢꜜᴢᴠᴒᴑͼⱷꜚ͟ͼꜛԜᴦͼԝᴒͼᴑ꞉ᴠꜞꜝᴠᴒᴑͼᴢꜜᴡ꞉ꞌͼ
ⱱᴢꞌꞌᴦͼԜᴐᴐꜝᴢꜜᴡᴒᴑͼⱱꜝᴟͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼꜛꜝꜜ꞉ᴡꜝᴟͼӿꜝᴟͼᴑᴒᴠ꞉ⱲꜜᴒᴒԐ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷾Ⱡ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
6
STUDY PROCEDURES
͟ꞌᴒԜᴠᴒͼᴟᴒⱱᴒᴟͼᴡꜝͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒԓͼᴁԜԝꞌᴒͼ᷈᷅
6.1
Informed Consent
ⱷꜜⱱꜝᴟꜛᴒᴑͼⱪꜝꜜᴠᴒꜜᴡͼԜꜜᴑͼⱨᴠᴠᴒꜜᴡͼⱱꜝᴟꜛᴠͼꜛᴢᴠᴡͼԝᴒͼԜꜞꜞᴟꜝᴣᴒᴑͼⱱꜝᴟͼᴢᴠᴒͼԝᴦͼᴡⱳᴒᴟᴒᴣ꞉ᴒᴤ꞉ꜜⱲͼ꞉ꜜᴠᴡ꞉ᴡᴢᴡ꞉ꜝꜜԜꞌͼ
ᴟᴒᴣ꞉ᴒᴤͼԝꜝԜᴟᴑͼӿⱷϸⱩԐԓͼᴟᴒᴠᴒԜᴟᴐⱳͼᴒᴡⱳ꞉ᴐᴠͼԝꜝԜᴟᴑͼӿϸⱬⱩԐͼꜝᴟͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼᴒᴡⱳ꞉ᴐᴠͼᴐꜝꜛꜛ꞉ᴡᴡᴒᴒͼӿⱷⱬⱪԐ᷅ͼ
ⱷꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡԓͼԜꜜᴑͼԜᴠᴠᴒꜜᴡͼᴤⱳᴒꜜͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒԓͼꜛᴢᴠᴡͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼⱱꜝᴟͼԜꞌꞌͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼ꞉ꜜͼ
ᴡⱳᴒͼᴠᴡᴢᴑᴦͼꜞᴟ꞉ꜝᴟͼᴡꜝͼꜞᴒᴟⱱꜝᴟꜛ꞉ꜜⱲͼԜꜜᴦͼᴠᴡᴢᴑᴦͼᴟᴒꞌԜᴡᴒᴑԜᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼᴤ꞉ᴡⱳᴑᴟԜᴤͼᴐꜝꜜᴠᴒꜜᴡͼԜᴡͼԜꜜᴦͼ
ᴡ꞉ꜛᴒ᷅ͼ͟Ԝᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼꜛԜᴦͼԝᴒͼᴡᴒᴟꜛ꞉ꜜԜᴡᴒᴑͼԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒͼᴤ꞉ᴡⱳꜝᴢᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼᴐꜝꜜᴠᴒꜜᴡͼԜᴠͼ
ᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅
6.2
Eligibility Review
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴐꜝꜜⱱ꞉ᴟꜛͼᴡⱳԜᴡͼԜꞌꞌͼⱷꜜᴐꞌᴢᴠ꞉ꜝꜜͼԜꜜᴑͼⱬᴥᴐꞌᴢᴠ꞉ꜝꜜͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝͼ
ⱳԜᴣᴒͼԝᴒᴒꜜͼꜛᴒᴡ᷅
6.3
Demographics and Medical History
ⱫᴒꜛꜝⱲᴟԜꜞⱳ꞉ᴐᴠⱡͼᴑԜᴡᴒͼꜝⱱͼԝ꞉ᴟᴡⱳͼӿԜꞌᴡᴒᴟꜜԜᴡ꞉ᴣᴒꞌᴦͼԜⱲᴒͼꜝᴟͼᴦᴒԜᴟͼꜝⱱͼԝ꞉ᴟᴡⱳԓͼ꞉ⱱͼⱱᴢꞌꞌͼᴑԜᴡᴒͼꜝⱱͼԝ꞉ᴟᴡⱳͼ꞉ᴠͼꜜꜝᴡͼԜꞌꞌꜝᴤᴒᴑͼ
ᴡꜝͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼⱱꜝᴟͼꞌᴒⱲԜꞌͼᴟᴒԜᴠꜝꜜᴠԐԓͼᴠᴒᴥԓͼᴟԜᴐᴒͼԜꜜᴑͼᴒᴡⱳꜜ꞉ᴐ꞉ᴡᴦͼӿᴤⱳᴒᴟᴒͼꞌꜝᴐԜꞌꞌᴦͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑԐͼԜꜜᴑͼꜛᴒᴑ꞉ᴐԜꞌͼ
ⱳ꞉ᴠᴡꜝᴟᴦͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜꜜᴑͼᴟᴒᴐꜝᴟᴑᴒᴑͼ꞉ꜜͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼԜꜜᴑͼᴡⱳᴒͼᴒⱪϸⱴ᷅ͼ
ꜚᴒᴑ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼᴤ꞉ꞌꞌͼᴐԜꜞᴡᴢᴟᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼᴐᴢᴟᴟᴒꜜᴡͼᴟᴒꞌᴒᴣԜꜜᴡͼꜛᴒᴑ꞉ᴐԜꞌͼᴠᴡԜᴡᴢᴠͼӿᴐᴢᴟᴟᴒꜜᴡͼᴑ꞉ᴠᴒԜᴠᴒͼ
ꜞᴟꜝᴐᴒᴠᴠᴒᴠԐԓͼꜞԜᴠᴡͼᴟᴒꞌᴒᴣԜꜜᴡͼꜛᴒᴑ꞉ᴐԜꞌͼᴠᴡԜᴡᴢᴠͼӿꜞԜᴠᴡͼᴑ꞉ᴠᴒԜᴠᴒͼꜞᴟꜝᴐᴒᴠᴠᴒᴠԐԓͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝⱱͼᴠᴢᴟⱲᴒᴟᴦԓͼԜꞌꞌᴒᴟⱲ꞉ᴒᴠͼԜꜜᴑͼ
ᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠ᷅
6.4
Efficacy Assessments
6.4.1
Primary and Secondary Endpoints
͟ᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԝԜᴠᴒᴑͼꜝꜜͼԜꜜͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼ
ᴠꜞԜꜜꜜ꞉ꜜⱲͼⱫԜᴦͼ᷇ͼӿԜⱱᴡᴒᴟͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜԐͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉ԓͼᴢꜜꞌᴒᴠᴠͼꜝᴡⱳᴒᴟᴤ꞉ᴠᴒͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼ
Primary Efficacy Endpoint

꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼ
ᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ
Secondary Efficacy Endpoints (rank ordered)
᷈᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴟᴒꜟᴢ꞉ᴟ꞉ꜜⱲͼԜᴐᴢᴡᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ
᷉᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼꜛꜝᴑᴒᴟԜᴡᴒͼꜝᴟͼᴠᴒᴣᴒᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ
᷊᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼꜝᴐᴐᴢᴟᴟ꞉ꜜⱲͼꜝꜜͼⱫԜᴦͼ᷈᷾ͼԜⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼ
ᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉ͼӿⱫԜᴦͼ᷈᷾ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Exploratory Efficacy Endpoints

ᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ԓͼ꞉᷅ᴒ᷅ԓͼᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡᴡԜᴐꞋ᷄ⱱᴟᴒᴒͼԜⱱᴡᴒᴟͼⱫԜᴦ᷈᷾
ᶄ
꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑⱢͼԜͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ᴠͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼԜꜜᴦͼԜᴡᴡԜᴐꞋͼᴡⱳԜᴡͼⱳԜᴠͼԜᴡͼꞌᴒԜᴠᴡͼꜝꜜᴒͼ
ꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐⱳԜᴟԜᴐᴡᴒᴟ꞉ᴠᴡ꞉ᴐᴠⱡͼᴠᴒᴣᴒᴟᴒԓͼᴟᴒᴠᴢꞌᴡᴠͼ꞉ꜜͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼӿᴒᴥᴐᴒꜞᴡͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼⱱꜝᴟͼ
ꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜͼⱣͼ᷉᷾ͼⱳꜝᴢᴟᴠԐԓͼⱳᴒꜛꜝᴑᴦꜜԜꜛ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼӿᴠᴦᴠᴡꜝꞌ꞉ᴐͼԝꞌꜝꜝᴑͼꜞᴟᴒᴠᴠᴢᴟᴒͼⱣͼⱠ᷇ԓͼᴟᴒꜟᴢ꞉ᴟᴒᴠͼ
ⱷᴃͼⱳᴦᴑᴟԜᴡ꞉ꜝꜜԓͼꜝᴟͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼᴠᴦꜜᴐꜝꜞᴒͼꜝᴟͼꜜᴒԜᴟ᷄ᴠᴦꜜᴐꜝꜞᴒԐͼꜝᴟͼꞌԜᴟᴦꜜⱲᴒԜꞌ᷅
6.4.2
HAE Attack Information Collection
ᴁⱳᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜԓͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼԜᴡᴡԜᴐꞋᴠͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴑꜝꜜᴒͼ꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼ
ᴡⱳᴒͼⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼԜꜜᴑͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼ͟ᴟꜝᴐᴒᴑᴢᴟᴒᴠͼӿⱶⱨⱨϸ͟Ԑͼӿⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷾Ԑ᷅ͼᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼ
ᴤ꞉ꞌꞌͼԝᴒͼᴡᴟԜ꞉ꜜᴒᴑͼꜝꜜͼⱶⱨⱨϸ͟ͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜᴡͼᴡⱳᴒ꞉ᴟͼᴠ꞉ᴡᴒ᷅
Ⱬᴢᴟ꞉ꜜⱲͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲԓͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴡᴟԜ꞉ꜜᴠᴢԝ꞊ᴒᴐᴡᴠͼԜꜜᴑͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠͼꜝꜜͼ꞉ᴑᴒꜜᴡ꞉ⱱᴦ꞉ꜜⱲͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜝⱱͼԜꜜͼ
ԜᴡᴡԜᴐꞋԓͼᴡⱳᴒͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼⱱꜝᴟͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼԜᴡᴡԜᴐꞋᴠͼԜꜜᴑͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡⱳᴒᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴥꜞᴒᴐᴡᴒᴑͼᴡꜝͼ
ꜞᴟꜝᴣ꞉ᴑᴒ᷅ͼᴁⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼӿԜꜜᴑͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟԐͼᴤ꞉ꞌꞌͼᴐꜝꜜⱱ꞉ᴟꜛͼᴡⱳᴒ꞉ᴟͼᴢꜜᴑᴒᴟᴠᴡԜꜜᴑ꞉ꜜⱲͼꜝⱱͼᴤⱳԜᴡͼ꞉ᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼꜝⱱͼᴡⱳᴒꜛͼ
ⱱꜝᴟͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼԜᴡᴡԜᴐꞋᴠͼᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒ᷅
ⱨᴡͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲԓͼᴠᴢԝ꞊ᴒᴐᴡͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼⱳ꞉ᴠᴡꜝᴟᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑ᷅ͼⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼ
Ԝꜜᴦͼꜞᴟ꞉ꜝᴟͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝⱱͼꞌԜᴟᴦꜜⱲᴒԜꞌͼԜᴡᴡԜᴐꞋᴠԓͼԜᴡᴡԜᴐꞋͼⱱᴟᴒꜟᴢᴒꜜᴐᴦԓͼԜᴣᴒᴟԜⱲᴒͼᴠᴒᴣᴒᴟ꞉ᴡᴦԓͼꜞᴟᴒᴑꜝꜛ꞉ꜜԜꜜᴡͼԜᴡᴡԜᴐꞋͼ
ꞌꜝᴐԜᴡ꞉ꜝꜜӿᴠԐԓͼԜᴣᴒᴟԜⱲᴒͼᴑᴢᴟԜᴡ꞉ꜝꜜԓͼԜᴐᴢᴡᴒͼԜᴡᴡԜᴐꞋͼᴡⱳᴒᴟԜꜞᴦͼᴢᴠᴒԓͼԜꜜᴑͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝⱱͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠ᷅
Ⱬᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼӿꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠԓͼ꞉ꜜͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼⱣͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝꞌᴑԐͼᴤ꞉ꞌꞌͼԝᴒͼ
꞉ꜜᴠᴡᴟᴢᴐᴡᴒᴑͼᴡꜝͼꜜꜝᴡ꞉ⱱᴦͼԜꜜᴑͼᴟᴒꜞꜝᴟᴡͼᴑᴒᴡԜ꞉ꞌᴠͼᴡꜝͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒͼᴤ꞉ᴡⱳ꞉ꜜͼⅎ᷉ͼⱳꜝᴢᴟᴠͼꜝⱱͼᴡⱳᴒͼꜝꜜᴠᴒᴡͼꜝⱱͼԜꜜͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋ᷅ͼⱷꜜͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼ꞉ꜜᴐԜꜞԜᴐ꞉ᴡԜᴡᴒᴑͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼԜꜜͼԜᴡᴡԜᴐꞋԓͼᴡⱳ꞉ᴠͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴐԜꜜͼԝᴒͼ
ꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒͼԝᴦͼԜͼⱱԜꜛ꞉ꞌᴦͼꜛᴒꜛԝᴒᴟͼꜝᴟͼꜝᴡⱳᴒᴟͼ꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴤ꞉ᴡⱳͼᴑᴒᴡԜ꞉ꞌᴒᴑͼꞋꜜꜝᴤꞌᴒᴑⱲᴒͼꜝⱱͼᴡⱳᴒͼ
ᴒᴣᴒꜜᴡ᷅ͼⱷⱱͼᴑᴒᴠ꞉ᴟᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡԓͼꜛᴒꜛꜝᴟᴦͼԜ꞉ᴑᴠͼꜛԜᴦͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴡꜝͼԜᴠᴠ꞉ᴠᴡͼ꞉ꜜͼᴡᴟԜᴐꞋ꞉ꜜⱲͼԜꜜᴦͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋᴠͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒ᷅ͼᴄᴒᴒꞋꞌᴦͼᴐꜝꜛꜛᴢꜜ꞉ᴐԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡᴠͼԜꜜᴑͼᴡⱳᴒͼᴠ꞉ᴡᴒԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼ
ᴟᴒꜞꜝᴟᴡᴠͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼꜛᴢᴠᴡͼԝᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅
ᴀᴢԝ꞊ᴒᴐᴡᴠͼӿꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠԐͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠꞋᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴤⱳᴒꜜͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼԜꜜͼ
ԜᴡᴡԜᴐꞋⱡ
ᶄ
ⱫԜᴡᴒͼԜꜜᴑͼᴡ꞉ꜛᴒͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜝⱱͼԜꜜͼԜᴡᴡԜᴐꞋͼᴤᴒᴟᴒͼⱱ꞉ᴟᴠᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴑ
ᶄ
Ⱬᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴠᴦꜛꜞᴡꜝꜛᴠͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴑԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼꞌꜝᴐԜᴡ꞉ꜝꜜӿᴠԐ
ᶄ
ⱷꜛꜞԜᴐᴡͼꜝꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼԜꜜᴑͼᴤⱳᴒᴡⱳᴒᴟͼԜꜜᴦͼԜᴠᴠ꞉ᴠᴡԜꜜᴐᴒͼꜝᴟͼꜛᴒᴑ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜͼᴤԜᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑԓͼ
꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜᴠͼꜝᴟͼᴒꜛᴒᴟⱲᴒꜜᴐᴦͼᴑᴒꜞԜᴟᴡꜛᴒꜜᴡͼᴣ꞉ᴠ꞉ᴡᴠ
ᶄ
ⱨꜜᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼᴢᴠᴒᴑͼᴡꜝͼᴡᴟᴒԜᴡͼᴡⱳᴒͼԜᴡᴡԜᴐꞋ
ᶄ
ⱷⱱͼᴡⱳᴒͼԜᴡᴡԜᴐꞋͼᴟᴒᴠꜝꞌᴣᴒᴑԓͼᴑԜᴡᴒͼԜꜜᴑͼᴡ꞉ꜛᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴤԜᴠͼꜜꜝͼꞌꜝꜜⱲᴒᴟͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐ꞉ꜜⱲͼᴠᴦꜛꜞᴡꜝꜛᴠ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼԜꜜᴑͼᴠꜝꞌ꞉ᴐ꞉ᴡͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼԜᴠͼ
ꜜᴒᴐᴒᴠᴠԜᴟᴦͼᴡꜝͼᴑꜝᴐᴢꜛᴒꜜᴡͼᴡⱳᴒͼԜᴡᴡԜᴐꞋԓͼԜᴠͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼⱶⱨⱨϸ᷅͟ͼ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤԜᴠⱳ꞉ꜜⱲͼꜝᴢᴡͼꜝⱱͼꜙᴁ͟ͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴡԜᴐᴡᴒᴑͼԝᴦͼᴡⱳᴒͼᴠ꞉ᴡᴒͼԜᴡͼᴡⱳᴒͼᴒꜜᴑͼꜝⱱͼᴡⱳᴒͼ᷉ͼᴤᴒᴒꞋͼᴤԜᴠⱳꜝᴢᴡͼ
ꜞᴒᴟ꞉ꜝᴑ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼᴐꜝꜜⱱ꞉ᴟꜛͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱳԜᴠͼᴠᴢᴐᴐᴒᴠᴠⱱᴢꞌꞌᴦͼᴐꜝꜛꜞꞌᴒᴡᴒᴑͼᴡⱳᴒͼ᷉ͼᴤᴒᴒꞋͼ
ᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒᴦͼᴐԜꜜͼᴒꜜᴡᴒᴟͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼⱪꜝꜜⱱ꞉ᴟꜛԜᴡ꞉ꜝꜜͼꜝⱱͼᴤԜᴠⱳꜝᴢᴡͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐԜꜞᴡᴢᴟᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅ͼ
ᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟͼᴤᴒᴒꞋꞌᴦԓͼꜝᴟͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⅎͼᴑԜᴦᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒ꞉ᴟͼ
ꞌԜᴠᴡͼᴐꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡԓͼᴡⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼⱷⱱͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴠͼ᷈ꜝᴟͼꜛꜝᴟᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԝᴦͼᴡⱳᴒͼᴒꜜᴑͼꜝⱱͼᴤᴒᴒꞋͼ᷾ԓͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼⱳԜᴣᴒͼⱱᴢꞌⱱ꞉ꞌꞌᴒᴑͼᴡⱳᴒͼᴟᴢꜜ᷄
꞉ꜜͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡͼԜꜜᴑͼꜛԜᴦͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼ᷊ͼꜝᴟͼ
ꜛꜝᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋᴠͼᴐԜꜜͼᴒᴥ꞉ᴡͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒԜᴟꞌᴦͼԜꜜᴑͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼ
ԜꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ᷅ͼⱷⱱͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴠͼꜜꜝͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴡⱳᴒͼᴒꜜᴑͼꜝⱱͼ
ᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᴤ꞉ꞌꞌͼᴟᴒꜛԜ꞉ꜜͼ꞉ꜜͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ᷾ᴤᴒᴒꞋᴠ᷅ͼᴁⱳᴒͼꜛԜᴥ꞉ꜛᴢꜛͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼ
ᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼ꞉ᴠͼ˲ͼᴤᴒᴒꞋᴠ᷅ⱷⱱͼᴟᴢꜜ᷄꞉ꜜͼⱳԜᴠͼԝᴒᴒꜜͼᴒᴥᴡᴒꜜᴑᴒᴑͼԜꜜᴑͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱳԜᴠͼ᷉ͼꜝᴟͼꜛꜝᴟᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԝᴦͼᴡⱳᴒͼᴒꜜᴑͼꜝⱱͼᴤᴒᴒꞋͼ˲ԓͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼⱳԜᴣᴒͼⱱᴢꞌⱱ꞉ꞌꞌᴒᴑͼᴡⱳᴒͼᴟᴢꜜ᷄
꞉ꜜͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡͼԜꜜᴑͼꜛԜᴦͼꜞᴟꜝᴐᴒᴒᴑͼᴡꜝͼᴡⱳᴒͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴁꜝͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼ
ᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡԓͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼⱳԜᴣᴒͼᴡⱳᴒ꞉ᴟͼᴟᴢꜜ᷄꞉ꜜͼᴒᴥᴡᴒꜜᴑᴒᴑͼꜛᴢᴠᴡͼᴐꜝꜛꜞꞌᴒᴡᴒͼᴡⱳᴒͼⱱᴢꞌꞌͼ˲᷄ᴤᴒᴒꞋͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼ
ꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴑꜝͼꜜꜝᴡͼꜛᴒᴒᴡͼᴡⱳᴒͼꜛ꞉ꜜ꞉ꜛᴢꜛͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴑᴢᴟ꞉ꜜⱲͼ
ᴟᴢꜜ᷄꞉ꜜͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜͼᴠᴐᴟᴒᴒꜜͼⱱԜ꞉ꞌ᷅
Ⱬᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟͼꜝꜜᴐᴒͼԝᴒᴡᴤᴒᴒꜜͼ
ᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡᴠͼꜝᴟͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⅎͼᴑԜᴦᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒ꞉ᴟͼꞌԜᴠᴡͼᴐꜝꜜᴡԜᴐᴡͼᴡꜝͼᴠꜝꞌ꞉ᴐ꞉ᴡͼⱱꜝᴟͼԜꜜᴦͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜜꜝᴡͼԜꞌᴟᴒԜᴑᴦͼᴟᴒꜞꜝᴟᴡᴒᴑ᷅
ᴁⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼᴠᴡᴢᴑᴦԓͼᴑᴢᴟ꞉ꜜⱲͼᴒԜᴐⱳͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡͼԜᴡͼᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ᴣᴒͼ
ᴠ꞉ᴡᴒԓͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼᴠꜝꞌ꞉ᴐ꞉ᴡͼⱱꜝᴟͼԜꜜᴦͼꜜᴒᴤͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼᴤԜᴠͼꜜꜝᴡͼԜꞌᴟᴒԜᴑᴦͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼ
ᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒ᷅
ⱷꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜꜞᴡᴢᴟᴒᴑͼԜᴠͼⱨⱬᴠ᷅ͼⱨꞌꞌͼⱨⱬᴠԓͼᴟᴒⱲԜᴟᴑꞌᴒᴠᴠͼꜝⱱͼᴠᴒᴟ꞉ꜝᴢᴠꜜᴒᴠᴠԓͼᴠᴒᴣᴒᴟ꞉ᴡᴦԓͼ
ꜝᴟͼᴐԜᴢᴠԜꞌͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴡꜝͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲԓͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼꜝꜜͼᴡⱳᴒͼⱨⱬͼꜞԜⱲᴒͼꜝⱱͼᴡⱳᴒͼᴒⱪϸⱴ᷅ͼⱨꜜᴦͼⱨⱬͼ
ᴟᴒꜞꜝᴟᴡᴒᴑͼᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒͼꜛᴒᴒᴡ꞉ꜜⱲͼᴐᴟ꞉ᴡᴒᴟ꞉ԜͼⱱꜝᴟͼԜͼᴠᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡͼꜛᴢᴠᴡͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴡꜝͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼ
ᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼᴀⱨⱬͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼⱴꜝᴟꜛͼ꞉ꜜͼᴡⱳᴒͼⱬⱫⱪͼᴠᴦᴠᴡᴒꜛᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ͼⱳꜝᴢᴟᴠꜝⱱͼԝᴒᴐꜝꜛ꞉ꜜⱲͼԜᴤԜᴟᴒͼꜝⱱͼᴡⱳᴒͼ
ᴒᴣᴒꜜᴡ᷅ͼⱴꜝᴟͼԜꞌꞌͼᴠᴒᴟ꞉ꜝᴢᴠͼԜᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼᴡⱳԜᴡͼԜᴟᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴠͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼᴡⱳᴒͼ͟ᴟ꞉ꜜᴐ꞉ꜞԜꞌͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ
ꜝᴟͼꜞⱳᴦᴠ꞉ᴐ꞉Ԝꜜͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼᴤ꞉ꞌꞌͼᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ͼⱳꜝᴢᴟᴠͼꜝⱱͼ꞉ꜜ꞉ᴡ꞉Ԝꞌͼꜜꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼԜꜜᴑԓͼ꞉ꜜͼ
ԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼⱶⱨⱨϸ͟ԓͼᴒᴣԜꞌᴢԜᴡᴒͼ꞉ⱱͼ꞉ᴡͼᴟᴒꜞᴟᴒᴠᴒꜜᴡᴒᴑͼԜͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋ᷅ͼⱴꜝᴟͼԜꞌꞌͼꜜꜝꜜ᷄ᴠᴒᴟ꞉ꜝᴢᴠͼ
ⱨⱬᴠͼᴡⱳԜᴡͼԜᴟᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴠͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼᴡⱳᴒͼ͟ᴟ꞉ꜜᴐ꞉ꜞԜꞌͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼꜞⱳᴦᴠ꞉ᴐ꞉Ԝꜜͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼᴤ꞉ꞌꞌͼ
ᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴤ꞉ᴡⱳ꞉ꜜͼ᷊ͼᴑԜᴦᴠͼꜝⱱͼ꞉ꜜ꞉ᴡ꞉Ԝꞌͼꜜꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼԜꜜᴑԓͼ꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼⱶⱨⱨϸ͟ԓͼᴒᴣԜꞌᴢԜᴡᴒͼ꞉ⱱͼ
꞉ᴡͼᴟᴒꜞᴟᴒᴠᴒꜜᴡᴒᴑͼԜͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋ᷅ͼⱷⱱͼꜜᴒᴐᴒᴠᴠԜᴟᴦͼⱱꜝᴟͼᴡⱳᴒͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼ
ᴑᴒᴠ꞉ⱲꜜᴒᴒͼꜛԜᴦͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼⱱꜝᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜ᷅ͼⱨꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡ᷄ᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴡᴡԜᴐꞋͼꜜꜝᴡͼ
ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼⱳԜᴣᴒͼԜꜜͼԜꞌᴡᴒᴟꜜԜᴡᴒͼⱨⱬͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼᴟᴒᴐꜝᴟᴑᴒᴑ᷅ͼⱨꞌꞌͼᴠᴢԝ꞊ᴒᴐᴡ᷄ᴟᴒꜞꜝᴟᴡᴒᴑͼ
Ԝꜜᴑͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅
ⱬꜛᴒᴟⱲᴒꜜᴐᴦͼᴑᴒꜞԜᴟᴡꜛᴒꜜᴡͼᴣ꞉ᴠ꞉ᴡᴠͼⱱꜝᴟͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԜꜜᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴟᴒᴠᴢꞌᴡ꞉ꜜⱲͼ꞉ꜜͼⱳꜝᴠꜞ꞉ᴡԜꞌͼԜᴑꜛ꞉ᴠᴠ꞉ꜝꜜᴠͼ
ᴤ꞉ꞌꞌͼԝᴒͼᴐԜꜞᴡᴢᴟᴒᴑ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴁꜝͼԝᴒͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴠͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋԓͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼꜛᴢᴠᴡͼⱳԜᴣᴒͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜝᴟͼᴠ꞉Ⱳꜜᴠͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼԜꜜͼ
ԜᴡᴡԜᴐꞋͼ꞉ꜜͼԜᴡͼꞌᴒԜᴠᴡͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꞌꜝᴐԜᴡ꞉ꜝꜜᴠⱡͼ
ᶄ
͟ᴒᴟ꞉ꜞⱳᴒᴟԜꞌͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜⱡͼᴐᴢᴡԜꜜᴒꜝᴢᴠͼᴠᴤᴒꞌꞌ꞉ꜜⱲͼ꞉ꜜᴣꜝꞌᴣ꞉ꜜⱲͼԜꜜͼᴒᴥᴡᴟᴒꜛ꞉ᴡᴦԓͼᴡⱳᴒͼⱱԜᴐᴒԓͼꜜᴒᴐꞋԓͼᴡꜝᴟᴠꜝԓͼ
Ԝꜜᴑ᷆ꜝᴟͼⱲᴒꜜ꞉ᴡꜝᴢᴟ꞉ꜜԜᴟᴦͼᴟᴒⱲ꞉ꜝꜜ᷅
ᶄ
ⱨԝᴑꜝꜛ꞉ꜜԜꞌͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜⱡͼԜԝᴑꜝꜛ꞉ꜜԜꞌͼꜞԜ꞉ꜜԓͼᴤ꞉ᴡⱳͼꜝᴟͼᴤ꞉ᴡⱳꜝᴢᴡͼԜԝᴑꜝꜛ꞉ꜜԜꞌͼᴑ꞉ᴠᴡᴒꜜᴡ꞉ꜝꜜԓͼꜜԜᴢᴠᴒԜԓͼ
ᴣꜝꜛ꞉ᴡ꞉ꜜⱲԓͼꜝᴟͼᴑ꞉ԜᴟᴟⱳᴒԜ᷅
ᶄ
ꜙԜᴟᴦꜜⱲᴒԜꞌͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜⱡͼᴠᴡᴟ꞉ᴑꜝᴟԓͼᴑᴦᴠꜞꜜᴒԜԓͼᴑ꞉ⱱⱱ꞉ᴐᴢꞌᴡᴦͼᴠꜞᴒԜꞋ꞉ꜜⱲԓͼᴑ꞉ⱱⱱ꞉ᴐᴢꞌᴡᴦͼᴠᴤԜꞌꞌꜝᴤ꞉ꜜⱲԓͼᴡⱳᴟꜝԜᴡͼ
ᴡ꞉Ⱳⱳᴡᴒꜜ꞉ꜜⱲԓͼꜝᴟͼᴠᴤᴒꞌꞌ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼᴡꜝꜜⱲᴢᴒԓͼꜞԜꞌԜᴡᴒԓͼᴢᴣᴢꞌԜԓͼꜝᴟͼꞌԜᴟᴦꜜᴥ᷅
Ⱬᴒᴠꜞ꞉ᴡᴒͼᴡⱳᴒͼꜞᴟᴒᴠᴒꜜᴐᴒͼꜝⱱͼᴡⱳᴒᴠᴒͼᴠᴦꜛꜞᴡꜝꜛᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛԜᴦͼᴠᴡ꞉ꞌꞌͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼᴡⱳԜᴡͼᴡⱳᴒͼ
ᴒᴣᴒꜜᴡͼᴑ꞉ᴑͼꜜꜝᴡͼᴟᴒꜞᴟᴒᴠᴒꜜᴡͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ⱱͼᴡⱳᴒᴟᴒͼԜᴟᴒͼⱱᴒԜᴡᴢᴟᴒᴠͼᴡⱳԜᴡͼᴠᴡᴟꜝꜜⱲꞌᴦͼᴟᴒⱱᴢᴡᴒͼᴠᴢᴐⱳͼԜͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠ᷅ͼ
ⱴꜝᴟͼᴒᴥԜꜛꜞꞌᴒԓͼᴡⱳᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴒᴣᴒꜜᴡͼ꞉ᴠͼԜᴐᴐꜝꜛꜞԜꜜ꞉ᴒᴑͼԝᴦͼᴠᴦꜛꜞᴡꜝꜛᴠͼᴡⱳԜᴡͼԜᴟᴒͼꜜꜝᴡͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼԜꜜͼ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼӿᴒ᷅Ⱳ᷅ԓͼᴢᴟᴡ꞉ᴐԜᴟ꞉ԜԐԓͼᴡⱳᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴒᴣᴒꜜᴡͼꜞᴒᴟᴠ꞉ᴠᴡᴠͼᴤᴒꞌꞌͼԝᴒᴦꜝꜜᴑͼᴡⱳᴒͼᴡᴦꜞ꞉ᴐԜꞌͼᴡ꞉ꜛᴒͼᴐꜝᴢᴟᴠᴒͼꜝⱱͼԜꜜͼ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋԓͼꜝᴟͼᴡⱳᴒᴟᴒͼ꞉ᴠͼԜͼꞌ꞉ꞋᴒꞌᴦͼԜꞌᴡᴒᴟꜜԜᴡᴒͼᴒᴡ꞉ꜝꞌꜝⱲᴦͼⱱꜝᴟͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼӿᴒ᷅Ⱳ᷅ԓ ᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼԜԝᴑꜝꜛ꞉ꜜԜꞌͼ
ᴠᴦꜛꜞᴡꜝꜛᴠͼԜᴟᴒͼԜᴡᴡᴟ꞉ԝᴢᴡԜԝꞌᴒͼᴡꜝԜͼᴣ꞉ᴟԜꞌͼⱲԜᴠᴡᴟꜝᴒꜜᴡᴒᴟ꞉ᴡ꞉ᴠͼꜝᴢᴡԝᴟᴒԜꞋͼ꞉ꜜͼᴡⱳᴒͼⱳꜝᴢᴠᴒⱳꜝꞌᴑԐ᷅ͼ
ᴁꜝͼԝᴒͼᴐꜝᴢꜜᴡᴒᴑͼԜᴠͼԜͼᴢꜜ꞉ꜟᴢᴒͼԜᴡᴡԜᴐꞋͼᴑ꞉ᴠᴡ꞉ꜜᴐᴡͼⱱᴟꜝꜛͼᴡⱳᴒͼꜞᴟᴒᴣ꞉ꜝᴢᴠͼԜᴡᴡԜᴐꞋԓͼᴡⱳᴒͼꜜᴒᴤͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜛᴢᴠᴡͼꜝᴐᴐᴢᴟͼ
ԜᴡͼꞌᴒԜᴠᴡͼ᷉᷾ͼⱳꜝᴢᴟᴠͼԜⱱᴡᴒᴟͼᴟᴒᴠꜝꞌᴢᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼꜞᴟ꞉ꜝᴟͼԜᴡᴡԜᴐꞋᶳᴠͼᴠᴦꜛꜞᴡꜝꜛᴠ᷅
6.5
Vital Signs
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠᴒᴠᴠᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼⱳ꞉ᴠ᷆ⱳᴒᴟͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴑᴒᴠ꞉ⱲꜜᴒᴒͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼ
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒͼӿᴁԜԝꞌᴒͼ᷈Ԑ᷅ͼϸꜝᴢᴡ꞉ꜜᴒͼᴣ꞉ᴡԜꞌͼᴠ꞉ⱲꜜͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴡԜꞋᴒꜜͼᴤ꞉ᴡⱳͼᴡⱳᴒͼ
ᴠᴢԝ꞊ᴒᴐᴡͼ꞉ꜜͼᴡⱳᴒͼᴠ꞉ᴡᴡ꞉ꜜⱲͼꜝᴟͼᴠᴢꜞ꞉ꜜᴒͼꜞꜝᴠ꞉ᴡ꞉ꜝꜜͼԜⱱᴡᴒᴟͼ᷿ͼꜛ꞉ꜜᴢᴡᴒᴠͼԜᴡͼᴟᴒᴠᴡͼԜꜜᴑͼᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼ
ⱳᴒԜᴟᴡͼᴟԜᴡᴒͼӿⱶϸԐԓͼԝꞌꜝꜝᴑͼꜞᴟᴒᴠᴠᴢᴟᴒͼӿⱩ͟ԐͼԜꜜᴑͼᴟᴒᴠꜞ꞉ᴟԜᴡꜝᴟᴦͼᴟԜᴡᴒͼӿϸϸԐ᷅ͼⱩ͟ͼᴠⱳꜝᴢꞌᴑͼԝᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼᴢᴠ꞉ꜜⱲͼ
ᴡⱳᴒͼᴠԜꜛᴒͼԜᴟꜛͼԜꜜᴑͼᴡⱳᴒͼᴠԜꜛᴒͼᴒꜟᴢ꞉ꜞꜛᴒꜜᴡͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅ͼᴁⱳᴒᴟᴒͼ꞉ᴠͼԜͼᶐ᷿᷈ͼꜛ꞉ꜜᴢᴡᴒͼᴤ꞉ꜜᴑꜝᴤͼⱱꜝᴟͼԜꞌꞌͼ
ᴣ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠ᷅
6.6
Physical Examination
ⱨͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳᴒ꞉Ⱳⱳᴡԓͼᴤᴒ꞉ⱲⱳᴡͼԜꜜᴑͼᴐԜꞌᴐᴢꞌԜᴡ꞉ꜝꜜͼꜝⱱͼⱩꜝᴑᴦͼꜚԜᴠᴠͼⱷꜜᴑᴒᴥͼӿⱩꜚⱷԐͼᴤ꞉ꞌꞌͼ
ԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼⱳ꞉ᴠ᷆ⱳᴒᴟͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴑᴒᴠ꞉ⱲꜜᴒᴒͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼ
ᴀᴐⱳᴒᴑᴢꞌᴒͼӿᴁԜԝꞌᴒͼ᷈Ԑ᷅ͼᴁⱳᴒͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼꜝⱱͼᴒԜᴐⱳͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼꜝꜜͼᴡⱳᴒͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼ
Ԝꜜᴑͼᴒⱪϸⱴ᷅ͼᴁⱳᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼᴡⱳᴒͼԝꜝᴑᴦͼᴠᴦᴠᴡᴒꜛᴠͼꞌ꞉ᴠᴡᴒᴑͼԝᴒꞌꜝᴤⱡ
ᶄ
ⱶᴒ꞉ⱲⱳᴡͼԜꜜᴑͼᴤᴒ꞉ⱲⱳᴡͼӿԜᴡͼᴀᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡͼꜝꜜꞌᴦԐ
ᶄ
ⱵᴒꜜᴒᴟԜꞌͼԜꜞꜞᴒԜᴟԜꜜᴐᴒ
ᶄ
ⱬԜᴟᴠԓͼꜜꜝᴠᴒԓͼԜꜜᴑͼᴡⱳᴟꜝԜᴡ
ᶄ
ⱶᴒԜᴑͼԜꜜᴑͼ꜠ᴒᴐꞋ
ᶄ
꜡ꜞⱳᴡⱳԜꞌꜛꜝꞌꜝⱲ꞉ᴐԜꞌ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷊
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᶄ
ϸᴒᴠꜞ꞉ᴟԜᴡꜝᴟᴦ
ᶄ
ⱪԜᴟᴑ꞉ꜝᴣԜᴠᴐᴢꞌԜᴟ
ᶄ
ⱨԝᴑꜝꜛᴒꜜ
ᶄ
꜠ᴒᴢᴟꜝꞌꜝⱲ꞉ᴐԜꞌ
ᶄ
ⱬᴥᴡᴟᴒꜛ꞉ᴡ꞉ᴒᴠ
ᶄ
ⱫᴒᴟꜛԜᴡꜝꞌꜝⱲ꞉ᴐԜꞌ
ᶄ
ꜙᴦꜛꜞⱳԜᴡ꞉ᴐ
6.7
Electrocardiography (ECG)
ⱨͼᴠᴡԜꜜᴑԜᴟᴑͼ᷈᷉᷄ꞌᴒԜᴑͼⱬⱪⱵͼӿᴠ꞉ꜜⱲꞌᴒͼᴟᴒᴐꜝᴟᴑ꞉ꜜⱲԐͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼ
ᴀᴐⱳᴒᴑᴢꞌᴒͼӿᴁԜԝꞌᴒͼ᷈Ԑ᷅ͼᴁⱳᴒͼᴑԜᴡᴒͼԜꜜᴑͼᴡ꞉ꜛᴒͼꜝⱱͼᴒԜᴐⱳͼⱬⱪⱵͼԜꜜᴑͼ꞉ᴡᴠͼᴟᴒᴠᴢꞌᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼ
ᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼԜꜜᴑͼᴒⱪϸⱴ᷅ͼⱬꞌᴒᴐᴡᴟꜝᴐԜᴟᴑ꞉ꜝⱲᴟԜꜛᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴒꜜᴡͼᴡꜝͼԜͼᴐᴒꜜᴡᴟԜꞌͼᴟᴒԜᴑ꞉ꜜⱲͼᴣᴒꜜᴑꜝᴟͼⱱꜝᴟͼ
Ԝᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅
6.8
Clinical Laboratory Tests
6.8.1
Laboratory Parameters
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒͼӿᴁԜԝꞌᴒͼ᷈Ԑ᷅
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑᴒᴠͼⱲᴒꜜᴒᴟԜꞌͼᴠԜⱱᴒᴡᴦͼꜞԜᴟԜꜛᴒᴡᴒᴟᴠͼӿⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠԓͼԜꜜᴑͼ
ᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦԐԓͼᴠᴒᴟꜝꞌꜝⱲᴦԓͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡᴠԓͼⱪ᷈᷄ⱷ꜠ⱶͼⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼԜᴠᴠԜᴦԓͼⱪ᷾ͼԜᴠᴠԜᴦԓͼⱪ᷈ꜟԜᴠᴠԜᴦԓͼ͟ꜘͼ
ᴠԜꜛꜞꞌᴒᴠԓͼ͟ⱫͼᴠԜꜛꜞꞌᴒᴠԓͼԜꜜᴑͼꜞꞌԜᴠꜛԜͼԜꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴡᴒᴠᴡ꞉ꜜⱲ᷅ͼⱨꞌꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑͼᴢᴠ꞉ꜜⱲͼᴒᴠᴡԜԝꞌ꞉ᴠⱳᴒᴑͼԜꜜᴑͼᴣԜꞌ꞉ᴑԜᴡᴒᴑͼꜛᴒᴡⱳꜝᴑᴠ᷅ͼ
ᴄⱳᴒꜜͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼᴡᴦꜞᴒᴠͼԜᴟᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼԜᴡͼᴡⱳᴒͼᴠԜꜛᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼᴡ꞉ꜛᴒͼꜞꜝ꞉ꜜᴡԓͼᴡⱳᴒͼ
ᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴟԜᴤꜜͼ꞉ꜜͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜝᴟᴑᴒᴟͼӿᴑᴒꜞᴒꜜᴑ꞉ꜜⱲͼꜝꜜͼᴤⱳԜᴡͼᴠԜꜛꜞꞌᴒͼᴡᴦꜞᴒᴠͼԜᴟᴒͼᴡꜝͼԝᴒͼ
ᴐꜝꞌꞌᴒᴐᴡᴒᴑͼԜᴡͼᴡⱳԜᴡͼᴡ꞉ꜛᴒͼꜞꜝ꞉ꜜᴡԐⱡͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴠԜⱱᴒᴡᴦͼᴠԜꜛꜞꞌᴒᴠͼӿⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼ
ᴐⱳᴒꜛ꞉ᴠᴡᴟᴦԐԓͼⱪ᷈᷄ⱷ꜠ⱶԓͼⱪ᷾ԓͼⱪ᷈ꜟԓͼ͟ꜘԓͼԜꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠԓͼ͟Ⱬ᷅ͼⱨꞌ꞉ꜟᴢꜝᴡᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼ͟ꜘԓͼ͟ⱫͼԜꜜᴑͼԜꜜᴡ꞉᷄
ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴠԜꜛꜞꞌᴒᴠͼꜛԜᴦͼԝᴒͼᴟᴒᴡԜ꞉ꜜᴒᴑͼԜᴠͼԝԜᴐꞋ᷄ᴢꜞͼⱱꜝᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼꜞԜᴟԜꜛᴒᴡᴒᴟͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ⱱͼꜜᴒᴐᴒᴠᴠԜᴟᴦ᷅ͼ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ꞉ꜜͼԜͼᴠᴒԜᴡᴒᴑͼꜝᴟͼᴠᴢꜞ꞉ꜜᴒͼꜞꜝᴠ꞉ᴡ꞉ꜝꜜͼᴑᴢᴟ꞉ꜜⱲͼԝꞌꜝꜝᴑͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜ᷅ͼᴁⱳᴒͼᴡꜝᴡԜꞌͼԝꞌꜝꜝᴑͼᴑᴟԜᴤͼⱱꜝᴟͼ
ᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤⱳꜝͼᴑꜝᴒᴠͼꜜꜝᴡͼᴟꜝꞌꞌꜝᴣᴒᴟͼ꞉ꜜᴡꜝͼᴡⱳᴒͼ꜡ꜙⱬͼᴤ꞉ꞌꞌͼԝᴒͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷉ⅎ᷈ꜛꜙ᷅ͼᴁⱳᴒͼᴡꜝᴡԜꞌͼԝꞌꜝꜝᴑͼ
ᴑᴟԜᴤͼⱱꜝᴟͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴡⱳԜᴡͼᴑꜝᴒᴠͼᴟꜝꞌꞌꜝᴣᴒᴟͼ꞉ꜜᴡꜝᴡⱳᴒͼ꜡ꜙⱬͼᴤ꞉ꞌꞌͼԝᴒͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ᷉᷇˲ͼꜛꜙ᷅ͼ͟ꞌᴒԜᴠᴒͼᴟᴒⱱᴒᴟͼ
ᴡꜝͼᴡⱳᴒͼꜙԜԝꜝᴟԜᴡꜝᴟᴦͼꜚԜꜜᴢԜꞌͼⱱꜝᴟͼꜛꜝᴟᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜ᷅
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼԜᴠͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒͼӿᴁԜԝꞌᴒͼ
᷈Ԑ᷅
6.8.1.1
Hematology
ᶄ
ⱶᴒꜛꜝⱲꞌꜝԝ꞉ꜜ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᶄ
ⱶᴒꜛԜᴡꜝᴐᴟ꞉ᴡ
ᶄ
ϸᴒᴑͼԝꞌꜝꜝᴑͼᴐᴒꞌꞌͼӿϸⱩⱪԐͼᴐꜝᴢꜜᴡ
ᶄ
ᴄⱳ꞉ᴡᴒͼԝꞌꜝꜝᴑͼᴐᴒꞌꞌͼӿᴄⱩⱪԐͼᴐꜝᴢꜜᴡͼᴤ꞉ᴡⱳͼᴑ꞉ⱱⱱᴒᴟᴒꜜᴡ꞉Ԝꞌ
ᶄ
ꜚᴒԜꜜͼᴐꜝᴟꜞᴢᴠᴐᴢꞌԜᴟͼᴣꜝꞌᴢꜛᴒͼӿꜚⱪᴃԐ
ᶄ
ꜚᴒԜꜜͼᴐꜝᴟꜞᴢᴠᴐᴢꞌԜᴟͼⱳᴒꜛꜝⱲꞌꜝԝ꞉ꜜͼӿꜚⱪⱶԐ
ᶄ
ꜚᴒԜꜜͼᴐꜝᴟꜞᴢᴠᴐᴢꞌԜᴟͼⱳᴒꜛꜝⱲꞌꜝԝ꞉ꜜͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼӿꜚⱪⱶⱪԐ
ᶄ
ⱨԝᴠꜝꞌᴢᴡᴒͼꜞꞌԜᴡᴒꞌᴒᴡͼᴐꜝᴢꜜᴡ
6.8.1.2
Coagulation
ᶄ
͟ᴟꜝᴡⱳᴟꜝꜛԝ꞉ꜜͼᴡ꞉ꜛᴒͼӿ͟ᴁԐ
ᶄ
ⱨᴐᴡ꞉ᴣԜᴡᴒᴑͼꜞԜᴟᴡ꞉ԜꞌͼᴡⱳᴟꜝꜛԝꜝꜞꞌԜᴠᴡ꞉ꜜͼᴡ꞉ꜛᴒͼӿԜ͟ᴁᴁԐ
ᶄ
ⱷꜜᴡᴒᴟꜜԜᴡ꞉ꜝꜜԜꞌͼ꜠ꜝᴟꜛԜꞌ꞉ᴧᴒᴑͼϸԜᴡ꞉ꜝͼӿⱷ꜠ϸԐ
6.8.1.3
Chemistry
ᶄ
ⱨꞌԝᴢꜛ꞉ꜜ
ᶄ
ⱨꞌꞋԜꞌ꞉ꜜᴒͼꜞⱳꜝᴠꜞⱳԜᴡԜᴠᴒ
ᶄ
ⱨꞌԜꜜ꞉ꜜᴒͼԜꜛ꞉ꜜꜝᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒͼӿⱨꜙᴁⱢͼᴀⱵ͟ᴁԐ
ᶄ
ⱨᴠꜞԜᴟᴡԜᴡᴒͼԜꜛ꞉ꜜꜝᴡᴟԜꜜᴠⱱᴒᴟԜᴠᴒͼӿⱨᴀᴁⱢͼᴀⱵ꜡ᴁԐ
ᶄ
Ⱪ꞉ꞌ꞉ᴟᴢԝ꞉ꜜͼӿᴡꜝᴡԜꞌͼԜꜜᴑͼᴑ꞉ᴟᴒᴐᴡԐ
ᶄ
ⱩꞌꜝꜝᴑͼᴢᴟᴒԜͼꜜ꞉ᴡᴟꜝⱲᴒꜜͼӿⱩᴂ꜠Ԑ
ᶄ
ⱪԜꞌᴐ꞉ᴢꜛ
ᶄ
ⱪԜᴟԝꜝꜜͼᴑ꞉ꜝᴥ꞉ᴑᴒͼӿⱪ꜡᷉Ԑ
ᶄ
ⱪⱳꞌꜝᴟ꞉ᴑᴒ
ᶄ
ⱪᴟᴒԜᴡ꞉ꜜ꞉ꜜᴒ
ᶄ
ⱪᴟᴒԜᴡ꞉ꜜᴒͼꜞⱳꜝᴠꜞⱳꜝꞋ꞉ꜜԜᴠᴒͼӿⱪ͟ꜘԐ
ᶄ
Ⱶꞌᴢᴐꜝᴠᴒ
ᶄ
͟ⱳꜝᴠꜞⱳԜᴡᴒ
ᶄ
ꜚԜⱲꜜᴒᴠ꞉ᴢꜛ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿᷿
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᶄ
͟ꜝᴡԜᴠᴠ꞉ᴢꜛ
ᶄ
ᴀꜝᴑ꞉ᴢꜛ
ᶄ
ᴁꜝᴡԜꞌͼꜞᴟꜝᴡᴒ꞉ꜜ
ᶄ
ᴂᴟ꞉ᴐͼԜᴐ꞉ᴑ
6.8.1.4
Urinalysis
ᶄ
Ⱪ꞉ꞌ꞉ᴟᴢԝ꞉ꜜ
ᶄ
Ⱶꞌᴢᴐꜝᴠᴒ
ᶄ
ꜘᴒᴡꜝꜜᴒᴠ
ᶄ
Ⱪꞌꜝꜝᴑͼ
ᶄ
꜠꞉ᴡᴟ꞉ᴡᴒ
ᶄ
ꜞⱶ
ᶄ
͟ᴟꜝᴡᴒ꞉ꜜ
ᶄ
ᴀꜞᴒᴐ꞉ⱱ꞉ᴐͼⱲᴟԜᴣ꞉ᴡᴦ
ᶄ
ꜚ꞉ᴐᴟꜝᴠᴐꜝꜞᴦͼӿ꞉ⱱͼ꞉ꜜᴑ꞉ᴐԜᴡᴒᴑͼԝᴦͼꜛԜᴐᴟꜝᴠᴐꜝꜞ꞉ᴐͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠԐ
6.8.1.5
Serology
ⱶⱩᴠⱨⱲԓͼⱶⱪᴃԓͼԜꜜᴑͼⱶⱷᴃͼᴡᴒᴠᴡᴠ
6.8.1.6
Pregnancy Test
ᴀᴒᴟᴢꜛͼꜝᴟͼᴢᴟ꞉ꜜᴒͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡ
6.8.1.7
C1-INH Functional Assay
ϸᴒᴠᴢꞌᴡᴠͼꜝⱱͼԜͼⱪ᷈᷄ⱷ꜠ⱶͼⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼԜᴠᴠԜᴦͼԜᴟᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼⱱꜝᴟͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅ͼᴀԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴑᴟԜᴤꜜͼԜᴡͼᴡⱳᴒͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼԝᴒͼᴟᴒᴡᴒᴠᴡᴒᴑͼ꞉ⱱͼᴟᴒᴠᴢꞌᴡᴠͼԜᴟᴒͼ꞉ꜜᴐꜝꜜⱲᴟᴢᴒꜜᴡͼᴤ꞉ᴡⱳͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ
ⱳ꞉ᴠᴡꜝᴟᴦͼꜝᴟͼԝᴒꞌ꞉ᴒᴣᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡꜝͼԝᴒͼᴐꜝꜜⱱꜝᴢꜜᴑᴒᴑͼԝᴦͼᴟᴒᴐᴒꜜᴡͼꜙᴁ͟ͼᴢᴠᴒ᷅
6.8.1.8
C4 Assay
ϸᴒᴠᴢꞌᴡᴠͼꜝⱱͼԜͼⱪ᷾ͼԜᴠᴠԜᴦͼꜛԜᴦͼԝᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼⱱꜝᴟͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅ͼᴀԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴟԜᴤꜜͼԜᴡͼᴡⱳᴒͼ
ᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼԝᴒͼᴟᴒᴡᴒᴠᴡᴒᴑͼ꞉ⱱͼᴟᴒᴠᴢꞌᴡᴠͼԜᴟᴒͼ꞉ꜜᴐꜝꜜⱲᴟᴢᴒꜜᴡͼᴤ꞉ᴡⱳͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝᴟͼ
ԝᴒꞌ꞉ᴒᴣᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡꜝͼԝᴒͼᴐꜝꜜⱱꜝᴢꜜᴑᴒᴑͼԝᴦͼᴟᴒᴐᴒꜜᴡͼꜙᴁ͟ͼᴢᴠᴒ᷅ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
6.8.1.9
C1q Assay
ϸᴒᴠᴢꞌᴡᴠͼꜝⱱͼԜͼⱪ᷈ꜟͼԜᴠᴠԜᴦͼꜛԜᴦͼԝᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼⱱꜝᴟͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅ͼᴀԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴟԜᴤꜜͼԜᴡͼᴡⱳᴒͼ
ᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼꜛԜᴦͼԝᴒͼᴟᴒᴡᴒᴠᴡᴒᴑͼ꞉ⱱͼᴟᴒᴠᴢꞌᴡᴠͼԜᴟᴒͼ꞉ꜜᴐꜝꜜⱲᴟᴢᴒꜜᴡͼᴤ꞉ᴡⱳͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼꜝᴟͼ
ԝᴒꞌ꞉ᴒᴣᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡꜝͼԝᴒͼᴐꜝꜜⱱꜝᴢꜜᴑᴒᴑͼԝᴦͼᴟᴒᴐᴒꜜᴡͼꜙᴁ͟ͼᴢᴠᴒ᷅ͼ
6.8.1.10
PK Sample Collection
ⱨᴠͼꜝᴢᴡꞌ꞉ꜜᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅Ⱡ᷅
6.8.1.11
PD Sample Collection
ⱨᴠͼꜝᴢᴡꞌ꞉ꜜᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷇᷅
6.8.1.12
Plasma Anti-Drug Antibody Testing
ⱨᴠͼꜝᴢᴡꞌ꞉ꜜᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷈᷅
6.8.2
Sample Collection, Storage, and Shipping
ⱩꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼⱱꜝᴟͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼԜᴡͼᴡⱳᴒͼᴠ꞉ᴡᴒͼԝᴦͼԜͼᴡᴟԜ꞉ꜜᴒᴑͼꜞⱳꞌᴒԝꜝᴡꜝꜛ꞉ᴠᴡͼ
ᴑᴒᴠ꞉ⱲꜜԜᴡᴒᴑͼԜꜜᴑ᷆ꜝᴟͼԜꜞꜞᴟꜝᴣᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅ͼⱫᴒᴡԜ꞉ꞌᴠͼⱱꜝᴟͼᴡⱳᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜԓͼꜞᴟꜝᴐᴒᴠᴠ꞉ꜜⱲԓͼ
ᴠᴡꜝᴟԜⱲᴒͼԜꜜᴑͼᴠⱳ꞉ꜞꜛᴒꜜᴡͼꜝⱱͼᴠԜꜛꜞꞌᴒᴠͼⱱꜝᴟͼԜꞌꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴑᴒᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼ
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼꜚԜꜜᴢԜꞌ᷅
Ⱪ꞉ꜝꞌꜝⱲ꞉ᴐԜꞌͼꜛԜᴡᴒᴟ꞉Ԝꞌͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴡꜝᴟᴒᴑͼԜꜜᴑͼᴠᴒᴐᴢᴟᴒᴑͼ꞉ꜜͼԜͼꜛԜꜜꜜᴒᴟͼᴡⱳԜᴡͼԜᴠᴠᴢᴟᴒᴠͼᴡⱳԜᴡͼᴢꜜԜᴢᴡⱳꜝᴟ꞉ᴧᴒᴑͼԜᴐᴐᴒᴠᴠͼ
꞉ᴠͼꜞᴟꜝⱳ꞉ԝ꞉ᴡᴒᴑͼԜꜜᴑͼᴡⱳᴒͼᴠԜꜛꜞꞌᴒᴠͼԜᴟᴒͼꜜꜝᴡͼꞌꜝᴠᴡԓͼԜꞌꞌꜝᴤᴒᴑͼᴡꜝͼᴑᴒᴡᴒᴟ꞉ꜝᴟԜᴡᴒԓͼꜝᴟͼԜᴐᴐ꞉ᴑᴒꜜᴡԜꞌꞌᴦͼꜝᴟͼ꞉ꞌꞌᴒⱲԜꞌꞌᴦͼ
ᴑᴒᴠᴡᴟꜝᴦᴒᴑ᷅ͼ
6.9
Pharmacokinetic Assessments
ⱩꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼⱱꜝᴟͼᴡⱳᴒͼꜛᴒԜᴠᴢᴟᴒꜛᴒꜜᴡͼꜝⱱͼꜞꞌԜᴠꜛԜͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼԜᴡͼ
ꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷾᷇ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼ
ⱫԜᴦᴠͼ᷉᷈᷇ᶐ᷊ͼԜꜜᴑͼ᷊᷉˲ᶐ᷊ͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅
6.10
Pharmacodynamic Assessments
ᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼ͟ⱫͼᴒⱱⱱᴒᴐᴡᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴢꜞꜝꜜͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦԓͼԝꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜝԝᴡԜ꞉ꜜᴒᴑͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷾᷇ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦᴠͼ᷉᷈᷇ᶐ᷊ͼԜꜜᴑͼ᷊᷉˲ᶐ᷊ͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ
꜡ꜙⱬ᷅
6.11
Plasma Anti-Drug Antibody Testing 
͟ꞌԜᴠꜛԜͼᴠԜꜛꜞꞌᴒᴠͼⱱꜝᴟͼᴡᴒᴠᴡ꞉ꜜⱲͼⱱꜝᴟͼⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜝⱱͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠͼᴡꜝͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼ
ꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷾᷇ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦᴠͼ᷊᷉˲ᶐ᷊ͼ
ᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿ⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
6.12
Prior and Concomitant Therapy
ᴁⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒᴠͼԜꜜᴑͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜᴡͼᴡⱳᴒͼᴠ꞉ᴡᴒͼᴐꜝꜜᴑᴢᴐᴡ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟ꞉Ԝꞌͼᴤ꞉ꞌꞌͼᴟᴒᴣ꞉ᴒᴤͼԜꜜᴑͼ
ᴒᴣԜꞌᴢԜᴡᴒͼꜞᴟ꞉ꜝᴟͼԜꜜᴑͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜͼᴢᴠԜⱲᴒͼꜝꜜͼԜꜜͼꜝꜜⱲꜝ꞉ꜜⱲͼԝԜᴠ꞉ᴠ᷅ͼⱨꞌꞌͼꜞᴟᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜԓͼꜝᴣᴒᴟ᷄ᴡⱳᴒ᷄
ᴐꜝᴢꜜᴡᴒᴟͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠԓͼⱳᴒᴟԝԜꞌᴠԓͼԜꜜᴑͼᴠᴢꜞꜞꞌᴒꜛᴒꜜᴡᴠͼᴡⱳԜᴡͼԜᴟᴒͼԝᴒ꞉ꜜⱲͼᴡԜꞋᴒꜜͼꜝᴟͼⱳԜᴣᴒͼԝᴒᴒꜜͼᴡԜꞋᴒꜜͼԝᴦͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼᴑᴢᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒⱲԜᴟᴑᴒᴑͼԜᴠͼ
ᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼԜꜜᴑͼꜛᴢᴠᴡͼԝᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼԜꜜᴑͼᴒⱪϸⱴ᷅ͼ
6.13
Randomization
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼ᷉ⱡ᷈ͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼᴟᴒꜞᴒԜᴡᴒᴑͼᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼӿᴀⱪԐͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄
᷉Ⱡ᷊᷇ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝͼ꞉ꜜͼԜͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼⱱԜᴠⱳ꞉ꜝꜜ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤ꞉ꞌꞌͼԝᴒͼ
Ԝᴠᴠ꞉Ⱳꜜᴒᴑͼ꞉ꜜͼԜͼ᷈ⱡ᷈ⱡ᷈ͼᴟԜᴡ꞉ꜝͼᴡꜝꜝꜜᴒͼꜝⱱͼᴡⱳᴟᴒᴒͼᴑꜝᴠᴒͼᴟᴒⱲ꞉ꜛᴒꜜᴠⱡͼ᷊᷇᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠԓͼ᷊᷇᷇ꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼ
ᴤᴒᴒꞋᴠͼꜝᴟͼ᷿᷈᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠ᷅ͼϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼ꞉ꜜᴡꜝͼԜꞌꞌͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴡᴟԜᴡ꞉ⱱ꞉ᴒᴑͼԝᴦͼ
ᴡⱳᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼ꞉ꜜᴡꜝͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼⱲᴟꜝᴢꜞᴠⱡͼ᷈ᴡꜝⱣ᷉ԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ᴤᴒᴒꞋᴠԓͼ᷉ͼᴡꜝͼⱣͼ᷊ͼԜᴡᴡԜᴐꞋᴠͼ
ꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼԜꜜᴑͼᶒͼ᷊ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠ᷅ͼ
6.14
Investigational Medicinal Product Treatment
ⱷꜜᴠᴡᴟᴢᴐᴡ꞉ꜝꜜᴠͼⱱꜝᴟͼᴠԜⱱᴒͼⱳԜꜜᴑꞌ꞉ꜜⱲͼꜝⱱͼⱷꜚ͟ԓͼꜞᴟᴒꜞԜᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴒԜᴐⱳͼᴠᴢԝᴐᴢᴡԜꜜᴒꜝᴢᴠͼᴑꜝᴠᴒԓͼԜꜜᴑͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼ
ꜝⱱͼⱷꜚ͟ͼԜᴟᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼ͟ⱳԜᴟꜛԜᴐᴦͼꜚԜꜜᴢԜꞌ᷅ͼ͟ᴟᴒꜞԜᴟԜᴡ꞉ꜝꜜͼԜꜜᴑͼᴑ꞉ᴠꜞᴒꜜᴠ꞉ꜜⱲꜝⱱͼᴡⱳᴒͼⱷꜚ͟ͼᴤ꞉ꞌꞌͼԝᴒͼ
ⱳԜꜜᴑꞌᴒᴑͼԝᴦͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼԜᴠͼᴑ꞉ᴟᴒᴐᴡᴒᴑͼԝᴦͼᴡⱳᴒͼ͟ᴟ꞉ꜜᴐ꞉ꜞԜꞌͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜᴡͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒ᷅ͼᴁⱳᴒͼ
͟ᴟ꞉ꜜᴐ꞉ꜞԜꞌͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴠ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴤ꞉ꞌꞌͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼᴡⱳᴒͼԜᴠᴠ꞉Ⱳꜜᴒᴑͼⱷꜚ᷅͟ͼᴁⱳᴒͼ
ᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼⱱꜝᴟͼꜛԜ꞉ꜜᴡԜ꞉ꜜ꞉ꜜⱲͼⱷꜚ͟ͼԜᴐᴐꜝᴢꜜᴡԜԝ꞉ꞌ꞉ᴡᴦͼԜᴟᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜ᷿᷅Ⱡꜝⱱͼᴡⱳ꞉ᴠͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅
6.15
Quality of Life Assessments
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼᴑԜᴡԜͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱬᴢᴟꜝϷꜝꜙͼⱵᴟꜝᴢꜞͼ᷿᷄Ⱬ꞉ꜛᴒꜜᴠ꞉ꜝꜜͼӿⱬϷ᷿ⱫԐͼ
Ϸᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼⱠ˲ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊ͼԜꜜᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼ
ꜙ꞉ⱱᴒͼӿⱨⱬ᷄ϷꜝꜙԐͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼ᷉˲ᶐ᷊ԓͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷉⅍ᶐ᷊ԓͼ᷿᷈᷾ᶐ᷊ԓͼԜꜜᴑͼ
᷈˲᷉ᶐ᷊᷅ͼⱨꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦͼ᷊᷉˲ᶐ᷊ͼⱱꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼ
ᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅
6.16
Adverse Event Reporting
ⱨᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼⱱᴟꜝꜛͼᴠ꞉Ⱳꜜ꞉ꜜⱲꜝⱱͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼꞌԜᴠᴡͼᴠᴡᴢᴑᴦͼ
ᴣ꞉ᴠ꞉ᴡ᷅
6.16.1
Definitions
6.16.1.1
Adverse Event
ⱨꜜͼⱨⱬͼ꞉ᴠͼԜꜜᴦͼᴢꜜᴡꜝᴤԜᴟᴑͼꜛᴒᴑ꞉ᴐԜꞌͼꜝᴐᴐᴢᴟᴟᴒꜜᴐᴒͼ꞉ꜜͼԜͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴡᴟ꞉Ԝꞌͼᴠᴢԝ꞊ᴒᴐᴡͼᴤⱳᴒᴡⱳᴒᴟͼꜝᴟͼꜜꜝᴡͼ꞉ᴡͼԜꜞꜞᴒԜᴟᴠͼᴡꜝͼ
ⱳԜᴣᴒͼԜͼᴐԜᴢᴠԜꞌͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑ᷅ͼ
ⱨꜜͼⱨⱬͼᴐԜꜜͼᴡⱳᴒᴟᴒⱱꜝᴟᴒͼԝᴒͼԜꜜᴦͼᴢꜜⱱԜᴣꜝᴟԜԝꞌᴒͼԜꜜᴑͼᴢꜜ꞉ꜜᴡᴒꜜᴑᴒᴑͼᴠ꞉Ⱳꜜͼӿ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԜꜜͼԜԝꜜꜝᴟꜛԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼ
ⱱ꞉ꜜᴑ꞉ꜜⱲԐԓͼᴠᴦꜛꜞᴡꜝꜛԓͼꜝᴟͼᴑ꞉ᴠᴒԜᴠᴒͼᴡᴒꜛꜞꜝᴟԜꞌꞌᴦͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴢᴠᴒͼꜝⱱͼԜͼꜛᴒᴑ꞉ᴐ꞉ꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼꜝᴟͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜝꜜͼ꞉ꜜͼԜͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦԓͼᴤⱳᴒᴡⱳᴒᴟͼꜝᴟͼꜜꜝᴡͼᴑ꞉ᴟᴒᴐᴡꞌᴦͼᴟᴒꞌԜᴡᴒᴑͼᴡꜝͼᴡⱳᴒͼꜛᴒᴑ꞉ᴐ꞉ꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼꜝᴟͼᴠᴡᴢᴑᴦͼ
ꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜝꜜ᷅
ᶄ
ⱨⱬᴠͼꜛԜᴦͼԝᴒͼꜜᴒᴤͼᴒᴣᴒꜜᴡᴠͼꜝᴟͼꜛԜᴦͼԝᴒͼꜞᴟᴒ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠͼᴡⱳԜᴡͼⱳԜᴣᴒͼԝᴒᴐꜝꜛᴒͼԜⱲⱲᴟԜᴣԜᴡᴒᴑͼꜝᴟͼ
ⱳԜᴣᴒͼᴤꜝᴟᴠᴒꜜᴒᴑͼ꞉ꜜͼᴠᴒᴣᴒᴟ꞉ᴡᴦͼꜝᴟͼⱱᴟᴒꜟᴢᴒꜜᴐᴦͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴐꜝᴢᴟᴠᴒͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
ᶄ
ⱨⱬᴠͼꜛԜᴦͼԝᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼᴐⱳԜꜜⱲᴒᴠͼⱱᴟꜝꜛͼԝԜᴠᴒꞌ꞉ꜜᴒͼ꞉ꜜͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜԓͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼ
ᴡᴒᴠᴡᴠԓͼꜝᴟͼꜝᴡⱳᴒᴟͼᴑ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜͼӿᴒ᷅Ⱳ᷅ԓͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴟᴒᴠᴢꞌᴡᴠԓͼᴥ᷄ᴟԜᴦͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠԐ᷅
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠͼⱲᴒꜜᴒᴟԜꞌꞌᴦͼԜᴟᴒͼꜜꜝᴡͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼⱨⱬᴠͼᴢꜜꞌᴒᴠᴠͼᴡⱳᴒᴦͼԜᴟᴒͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼ
ᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠ꞉Ⱳꜜᴠͼꜝᴟͼᴠᴦꜛꜞᴡꜝꜛᴠԓͼꜝᴟͼᴟᴒꜟᴢ꞉ᴟᴒͼꜛᴒᴑ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜ᷅ͼⱨͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼ
ԜԝꜜꜝᴟꜛԜꞌ꞉ᴡᴦͼᴡⱳԜᴡͼ꞉ᴠͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼⱱᴟꜝꜛͼԜͼꞋꜜꜝᴤꜜͼᴢꜜᴑᴒᴟꞌᴦ꞉ꜜⱲͼꜛᴒᴑ꞉ᴐԜꞌͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜͼԜꜜᴑͼᴡⱳԜᴡͼᴟᴒꜟᴢ꞉ᴟᴒᴠͼ
ꜛᴒᴑ꞉ᴐԜꞌͼꜝᴟͼᴠᴢᴟⱲ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜԓͼꜝᴟͼꞌᴒԜᴑᴠͼᴡꜝͼⱷꜚ͟ͼ꞉ꜜᴡᴒᴟᴟᴢꜞᴡ꞉ꜝꜜͼꜝᴟͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜԓͼᴤ꞉ꞌꞌԓͼ꞉ꜜͼ꞉ᴡᴠᴒꞌⱱԓͼԝᴒͼ
ᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜꜜͼⱨⱬ᷅ͼꜙԜԝꜝᴟԜᴡꜝᴟᴦͼꜝᴟͼᴑ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼᴡᴒᴠᴡ꞉ꜜⱲͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠͼᴡⱳԜᴡͼᴟᴒⱱꞌᴒᴐᴡͼꜝᴟͼԜᴟᴒͼꜞԜᴟᴡͼꜝⱱͼԜͼ
Ꞌꜜꜝᴤꜜͼᴢꜜᴑᴒᴟꞌᴦ꞉ꜜⱲͼꜛᴒᴑ꞉ᴐԜꞌͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜͼԜᴟᴒͼꜜꜝᴡԓͼ꞉ꜜͼᴡⱳᴒꜛᴠᴒꞌᴣᴒᴠԓͼⱨⱬᴠⱢͼᴟԜᴡⱳᴒᴟԓͼᴡⱳᴒͼᴢꜜᴑᴒᴟꞌᴦ꞉ꜜⱲͼꜛᴒᴑ꞉ᴐԜꞌͼ
ᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜͼꞌᴒԜᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠͼᴤꜝᴢꞌᴑͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴠͼᴡⱳᴒͼⱨⱬ᷅
͟ᴟᴒⱲꜜԜꜜᴐᴦͼ꞉ᴠͼꜜꜝᴡͼԜꜜͼⱨⱬⱢͼⱳꜝᴤᴒᴣᴒᴟԓͼ꞉ⱱͼԜͼⱱᴒꜛԜꞌᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԝᴒᴐꜝꜛᴒᴠͼꜞᴟᴒⱲꜜԜꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴐꜝꜜᴑᴢᴐᴡͼꜝⱱͼ
ᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼꜜꜝᴡ꞉ⱱᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼ꞉ꜜͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷿᷅᷅᷉᷅
6.16.1.2
Serious Adverse Event
ⱨͼᴀⱨⱬͼ꞉ᴠͼԜꜜᴦͼԜᴑᴣᴒᴟᴠᴒͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼꜝᴐᴐᴢᴟᴟ꞉ꜜⱲͼԜᴡͼԜꜜᴦͼᴑꜝᴠᴒͼᴡⱳԜᴡͼᴟᴒᴠᴢꞌᴡᴠͼ꞉ꜜͼԜꜜᴦͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼ
ꜝᴢᴡᴐꜝꜛᴒᴠⱡ
ᶄ
ⱫᴒԜᴡⱳ
ᶄ
ꜙ꞉ⱱᴒ᷄ᴡⱳᴟᴒԜᴡᴒꜜ꞉ꜜⱲͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒⱢͼ꜠ꜝᴡᴒⱡͼᶰꜙ꞉ⱱᴒ᷄ᴡⱳᴟᴒԜᴡᴒꜜ꞉ꜜⱲᶱͼᴟᴒⱱᴒᴟᴠͼᴡꜝͼԜͼᴠ꞉ᴡᴢԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴤⱳ꞉ᴐⱳͼᴡⱳᴒͼ
ᴠᴢԝ꞊ᴒᴐᴡͼᴤԜᴠͼԜᴡͼᴠᴢԝᴠᴡԜꜜᴡ꞉Ԝꞌͼᴟ꞉ᴠꞋͼꜝⱱͼᴑᴒԜᴡⱳͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼᴡⱳᴒͼᴒᴣᴒꜜᴡⱢͼ꞉ᴡͼᴑꜝᴒᴠͼꜜꜝᴡͼᴟᴒⱱᴒᴟͼᴡꜝͼԜꜜͼᴒᴣᴒꜜᴡͼ
ᴡⱳԜᴡͼꜛ꞉ⱲⱳᴡͼⱳԜᴣᴒᴐԜᴢᴠᴒᴑͼᴑᴒԜᴡⱳͼ꞉ⱱͼ꞉ᴡͼᴤᴒᴟᴒͼꜛꜝᴟᴒͼᴠᴒᴣᴒᴟᴒ᷅
ᶄ
ϸᴒꜟᴢ꞉ᴟᴒᴠͼ꞉ꜜꜞԜᴡ꞉ᴒꜜᴡͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼꜝᴟͼꜞᴟꜝꞌꜝꜜⱲԜᴡ꞉ꜝꜜͼꜝⱱͼᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜⱢͼ꜠ꜝᴡᴒⱡͼⱫꜝᴒᴠͼꜜꜝᴡͼ
꞉ꜜᴐꞌᴢᴑᴒͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼⱱꜝᴟͼꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼᴟᴒꞌᴒԜᴠᴒͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ͼⱳꜝᴢᴟᴠ᷅ͼⱨͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼ
ⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼⱱꜝᴟͼԜͼꜞᴟᴒ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜͼᴡⱳԜᴡͼⱳԜᴠͼꜜꜝᴡͼᴤꜝᴟᴠᴒꜜᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼ
ᴠᴡᴢᴑᴦͼᴑꜝᴒᴠͼꜜꜝᴡͼꜛᴒᴒᴡͼᴡⱳ꞉ᴠͼᴐᴟ꞉ᴡᴒᴟ꞉ꜝꜜ᷅ͼ͟ᴟᴒ᷄ꜞꞌԜꜜꜜᴒᴑͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜᴠͼⱱꜝᴟͼԜꜜͼᴒꞌᴒᴐᴡ꞉ᴣᴒͼ
ꜛᴒᴑ꞉ᴐԜꞌ᷆ᴠᴢᴟⱲ꞉ᴐԜꞌͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼꜝᴟͼᴟꜝᴢᴡ꞉ꜜᴒͼᴐⱳᴒᴐꞋ᷄ᴢꜞᴠͼᴑꜝͼꜜꜝᴡͼꜛᴒᴒᴡͼᴡⱳ꞉ᴠͼᴐᴟ꞉ᴡᴒᴟ꞉ꜝꜜ᷅
ᶄ
ϸᴒᴠᴢꞌᴡᴠͼ꞉ꜜͼꜞᴒᴟᴠ꞉ᴠᴡᴒꜜᴡͼꜝᴟͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼᴑ꞉ᴠԜԝ꞉ꞌ꞉ᴡᴦͼꜝᴟͼ꞉ꜜᴐԜꜞԜᴐ꞉ᴡᴦ᷅
ᶄ
ⱷᴠͼԜͼᴐꜝꜜⱲᴒꜜ꞉ᴡԜꞌͼԜꜜꜝꜛԜꞌᴦͼꜝᴟͼԝ꞉ᴟᴡⱳͼᴑᴒⱱᴒᴐᴡ᷅
ᶄ
ⱷᴠͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼᴡꜝͼԝᴒͼԜꜜͼ꞉ꜛꜞꜝᴟᴡԜꜜᴡͼꜛᴒᴑ꞉ᴐԜꞌͼᴒᴣᴒꜜᴡͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼᴡⱳꜝᴠᴒͼᴡⱳԜᴡͼꜛԜᴦͼꜜꜝᴡͼԝᴒͼ꞉ꜛꜛᴒᴑ꞉Ԝᴡᴒꞌᴦͼ
ꞌ꞉ⱱᴒ᷄ᴡⱳᴟᴒԜᴡᴒꜜ꞉ꜜⱲͼꜝᴟͼᴟᴒᴠᴢꞌᴡͼ꞉ꜜͼᴑᴒԜᴡⱳͼꜝᴟͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜԓͼԝᴢᴡͼꜛԜᴦͼ꞊ᴒꜝꜞԜᴟᴑ꞉ᴧᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜝᴟͼꜛԜᴦͼ
ᴟᴒꜟᴢ꞉ᴟᴒͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜͼᴡꜝͼꜞᴟᴒᴣᴒꜜᴡͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼꜝᴢᴡᴐꜝꜛᴒᴠͼꞌ꞉ᴠᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴑᴒⱱ꞉ꜜ꞉ᴡ꞉ꜝꜜͼԜԝꜝᴣᴒ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷿Ⱡ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
6.16.1.3
Overdose
ⱨꜜͼꜝᴣᴒᴟᴑꜝᴠᴒͼ꞉ᴠͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼԜͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼᴣԜᴟ꞉Ԝᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴡⱳᴒͼᴟᴒᴐꜝꜛꜛᴒꜜᴑᴒᴑ᷆ᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴑꜝᴠԜⱲᴒͼⱱꜝᴟͼԜͼ
ꜞᴟꜝᴑᴢᴐᴡ᷅ͼᴁⱳᴒͼᴑꜝᴠ꞉ꜜⱲͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼ꞉ꜜͼԜͼᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴒᴡᴡ꞉ꜜⱲͼԜꜜᴑͼԜꜜͼ
ꜝᴣᴒᴟᴑꜝᴠᴒͼ꞉ᴠͼꜜꜝᴡͼԜꜜᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑ᷅ͼⱶꜝᴤᴒᴣᴒᴟԓͼ꞉ꜜͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼꜝⱱͼԜꜜͼԜᴐᴐ꞉ᴑᴒꜜᴡԓͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦԓͼԜꜜͼꜝᴣᴒᴟᴑꜝᴠᴒͼꜝⱱͼ
Ⱬᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ᴠͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜͼᴑꜝᴠᴒͼᴡⱳԜᴡͼ꞉ᴠͼᴡᴤꜝ᷄ⱱꜝꞌᴑͼⱳ꞉ⱲⱳᴒᴟͼᴡⱳԜꜜͼᴡⱳᴒͼ꞉ꜜᴡᴒꜜᴑᴒᴑͼᴑꜝᴠᴒͼⱱꜝᴟͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡ᷅
6.16.1.4
Planned Hospitalization
ⱨͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼꜞꞌԜꜜꜜᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼᴑꜝᴠᴒͼꜝⱱͼⱷꜚ͟ͼ꞉ᴠͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜͼᴡⱳᴒᴟԜꜞᴒᴢᴡ꞉ᴐͼ
꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜͼԜꜜᴑͼꜜꜝᴡͼᴡⱳᴒͼᴟᴒᴠᴢꞌᴡͼꜝⱱͼԜͼꜜᴒᴤͼᴀⱨⱬͼԜꜜᴑͼᴠⱳꜝᴢꞌᴑͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼԜᴠͼꜛᴒᴑ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦ᷅ͼⱷⱱͼᴡⱳᴒͼ
ꜞꞌԜꜜꜜᴒᴑͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼꜝᴟͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼ꞉ᴠͼᴒᴥᴒᴐᴢᴡᴒᴑͼԜᴠͼꜞꞌԜꜜꜜᴒᴑԓͼᴡⱳᴒͼᴟᴒᴐꜝᴟᴑͼ꞉ꜜͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠꜛᴒᴑ꞉ᴐԜꞌͼ
ⱳ꞉ᴠᴡꜝᴟᴦͼ꞉ᴠͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼᴐꜝꜛꜞꞌᴒᴡᴒ᷅ͼⱶꜝᴤᴒᴣᴒᴟԓͼ꞉ⱱͼᴡⱳᴒͼᴒᴣᴒꜜᴡ᷆ᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜͼᴤꜝᴟᴠᴒꜜᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟ꞉Ԝꞌԓͼ꞉ᴡͼꜛᴢᴠᴡͼ
ԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴠͼԜꜜͼⱨⱬ᷅
6.16.1.5
Treatment-Emergent Adverse Events (TEAE)
ⱨꜜͼⱨⱬͼ꞉ᴠͼᴡᴟᴒԜᴡꜛᴒꜜᴡ᷄ᴒꜛᴒᴟⱲᴒꜜᴡͼ꞉ⱱͼᴡⱳᴒͼꜝꜜᴠᴒᴡͼᴡ꞉ꜛᴒͼ꞉ᴠͼԜⱱᴡᴒᴟͼⱱ꞉ᴟᴠᴡͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ͼᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼ
ⱱ꞉ꜜԜꞌͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴣ꞉ᴠ꞉ᴡͼꜝᴟԓͼ꞉ꜜͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴡⱳԜᴡͼꜝꜜᴠᴒᴡͼᴡ꞉ꜛᴒͼꜞᴟᴒᴐᴒᴑᴒᴠͼⱱ꞉ᴟᴠᴡͼⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜԓͼᴡⱳᴒͼⱨⱬͼ
꞉ꜜᴐᴟᴒԜᴠᴒᴠͼ꞉ꜜͼᴠᴒᴣᴒᴟ꞉ᴡᴦͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑ᷅
6.16.1.6
Adverse Events of Special Interest (AESI)
ⱨᴑᴣᴒᴟᴠᴒͼᴒᴣᴒꜜᴡᴠͼꜝⱱͼᴠꜞᴒᴐ꞉Ԝꞌͼ꞉ꜜᴡᴒᴟᴒᴠᴡͼӿⱨⱬᴀⱷԐͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜꜞᴡᴢᴟᴒᴑͼԜꜜᴑͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅ͼ
Investigators will report all AESI to the Sponsor, regardless of causality, using the same 
timelines as described for SAE reporting. ᴁⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴑᴒᴠᴐᴟ꞉ԝᴒͼᴡⱳᴒͼⱨⱬᴀⱷͼԜꜜᴑͼᴡⱳᴒͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝͼⱱꜝᴟͼ
ᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼⱨⱬᴀⱷ᷅ͼ
HYPERSENSITIVITY REACTIONS
ⱨᴠͼⱳᴦꜞᴒᴟᴠᴒꜜᴠ꞉ᴡ꞉ᴣ꞉ᴡᴦͼᴟᴒԜᴐᴡ꞉ꜝꜜᴠͼⱳԜᴣᴒͼԝᴒᴒꜜͼꜝԝᴠᴒᴟᴣᴒᴑͼⱱꜝᴟͼꜛꜝꜜꜝᴐꞌꜝꜜԜꞌͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠͼԜᴠͼԜͼᴐꞌԜᴠᴠԓͼᴡⱳᴒᴠᴒͼ
ᴒᴣᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼⱨⱬᴀⱷͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼᴤ꞉ꞌꞌͼᴟᴒꜞꜝᴟᴡͼԜꞌꞌͼᴑ꞉ԜⱲꜜꜝᴠᴒᴠԓͼꜝᴟͼᴠ꞉ⱲꜜᴠͼԜꜜᴑͼ
ᴠᴦꜛꜞᴡꜝꜛᴠͼᴤⱳᴒꜜͼᴑ꞉ԜⱲꜜꜝᴠᴒᴠͼᴐԜꜜꜜꜝᴡͼԝᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑԓͼᴡⱳԜᴡͼԜᴟᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼⱳᴦꜞᴒᴟᴠᴒꜜᴠ꞉ᴡ꞉ᴣ꞉ᴡᴦͼ
ᴟᴒԜᴐᴡ꞉ꜝꜜᴠԓͼᴟᴒⱲԜᴟᴑꞌᴒᴠᴠͼꜝⱱͼᴐԜᴢᴠԜꞌ꞉ᴡᴦԓͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ͼⱳꜝᴢᴟᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜ᷅ͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼᴤ꞉ꞌꞌͼᴟᴒꜞꜝᴟᴡͼⱳᴦꜞᴒᴟᴠᴒꜜᴠ꞉ᴡ꞉ᴣ꞉ᴡᴦͼᴟᴒԜᴐᴡ꞉ꜝꜜᴠͼᴡⱳԜᴡͼꜝᴐᴐᴢᴟͼԜⱱᴡᴒᴟͼ᷉᷾ͼⱳꜝᴢᴟᴠԓ ꜝꜜꞌᴦͼ꞉ⱱᴡⱳᴒͼᴟᴒԜᴐᴡ꞉ꜝꜜᴠͼ
ԜᴟᴒͼᴠᴢᴠꜞᴒᴐᴡᴒᴑͼᴡꜝͼԝᴒͼᴟᴒꞌԜᴡᴒᴑͼᴡꜝͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲ᷅ͼ
EVENTS OF DISORDERED COAGULATION
Bleeding AESI
ⱨꞌᴡⱳꜝᴢⱲⱳͼԜ͟ᴁᴁͼꜞᴟꜝꞌꜝꜜⱲԜᴡ꞉ꜝꜜͼᴑᴢᴒͼᴡꜝͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼ꞉ꜜⱳ꞉ԝ꞉ᴡ꞉ꜝꜜͼ꞉ᴠͼԜꜜͼԜᴟᴡ꞉ⱱԜᴐᴡᴢԜꞌͼin vitro
ꜞⱳᴒꜜꜝꜛᴒꜜꜝꜜԓͼԜᴠͼԜͼꜞᴟᴒᴐԜᴢᴡ꞉ꜝꜜԜᴟᴦͼꜛᴒԜᴠᴢᴟᴒͼ꞉ꜜͼᴒᴣԜꞌᴢԜᴡ꞉ꜜⱲͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼԝꞌᴒᴒᴑ꞉ꜜⱲͼᴒᴣᴒꜜᴡᴠͼ
ᴤ꞉ꞌꞌͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴠͼⱨⱬᴀⱷͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼᴤ꞉ꞌꞌͼᴟᴒꜞꜝᴟᴡͼԜꞌꞌͼᴑ꞉ԜⱲꜜꜝᴠᴒᴠԓͼꜝᴟͼᴠ꞉ⱲꜜᴠͼԜꜜᴑͼ
ᴠᴦꜛꜞᴡꜝꜛᴠͼᴤⱳᴒꜜͼᴑ꞉ԜⱲꜜꜝᴠᴒᴠͼᴐԜꜜꜜꜝᴡͼԝᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑԓͼᴡⱳԜᴡͼԜᴟᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼԜͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴒᴣᴒꜜᴡͼꜝⱱͼ
ԝꞌᴒᴒᴑ꞉ꜜⱲ᷅ͼⱪꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜͼᴡᴒᴠᴡ꞉ꜜⱲͼӿԜ͟ᴁᴁԓͼ͟ᴁԓͼⱷ꜠ϸԐͼᴠⱳꜝᴢꞌᴑͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼᴤⱳᴒꜜͼꜞꜝᴠᴠ꞉ԝꞌᴒԓͼԜꜜᴑͼᴤⱳᴒꜜͼ
ᴡᴒꜛꜞꜝᴟԜꞌꞌᴦͼᴟᴒԜᴠꜝꜜԜԝꞌᴒԓͼᴤ꞉ᴡⱳͼԜꜜᴦͼᴟᴒꜞꜝᴟᴡᴠͼꜝⱱͼԝꞌᴒᴒᴑ꞉ꜜⱲͼꜝᴟͼⱱꜝᴟͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠͼꜞꜝᴠᴠ꞉ԝꞌᴦͼ꞉ꜜᴑ꞉ᴐԜᴡ꞉ᴣᴒͼ
ꜝⱱͼԝꞌᴒᴒᴑ꞉ꜜⱲ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Hypercoagulable AESI
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼᴤ꞉ꞌꞌͼᴟᴒꜞꜝᴟᴡͼԜꞌꞌͼᴑ꞉ԜⱲꜜꜝᴠᴒᴠԓͼꜝᴟͼᴠ꞉ⱲꜜᴠͼԜꜜᴑͼᴠᴦꜛꜞᴡꜝꜛᴠͼᴤⱳᴒꜜͼᴑ꞉ԜⱲꜜꜝᴠᴒᴠͼᴐԜꜜꜜꜝᴡͼԝᴒͼ
ᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑԓͼᴡⱳԜᴡͼԜᴟᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼԜͼᴡⱳᴟꜝꜛԝꜝᴡ꞉ᴐͼꜝᴟͼᴒꜛԝꜝꞌ꞉ᴐͼᴒᴡ꞉ꜝꞌꜝⱲᴦ᷅ͼ
6.16.2
Monitoring
6.16.2.1
Monitoring of Adverse Events
ⱬԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤ꞉ꞌꞌͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼꜝᴐᴐᴢᴟᴟᴒꜜᴐᴒͼꜝⱱͼⱨⱬᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴀⱨⱬᴠԓͼⱱᴟꜝꜛͼᴠ꞉Ⱳꜜ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼ
ⱷⱪⱴͼᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴣ꞉ᴠ꞉ᴡ᷅
ᶄ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜟᴢᴒᴠᴡ꞉ꜝꜜᴒᴑͼԜꜜᴑ᷆ꜝᴟͼᴒᴥԜꜛ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼԜͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼⱱꜝᴟͼ
ᴒᴣ꞉ᴑᴒꜜᴐᴒͼꜝⱱͼⱨⱬᴠ᷅ͼᴁⱳᴒͼꜟᴢᴒᴠᴡ꞉ꜝꜜ꞉ꜜⱲͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼᴟᴒⱲԜᴟᴑͼᴡꜝͼᴡⱳᴒͼꜞꜝᴠᴠ꞉ԝꞌᴒͼꜝᴐᴐᴢᴟᴟᴒꜜᴐᴒͼꜝⱱͼⱨⱬᴠͼ
ᴤ꞉ꞌꞌͼԝᴒͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼᴠᴢᴐⱳͼԜᴠԓͼ₭ⱶꜝᴤͼⱳԜᴣᴒͼᴦꜝᴢͼԝᴒᴒꜜͼⱱᴒᴒꞌ꞉ꜜⱲͼᴠ꞉ꜜᴐᴒͼᴦꜝᴢᴟͼꞌԜᴠᴡͼᴣ꞉ᴠ꞉ᴡⱦᶱͼͼᴁⱳᴒͼꜞᴟᴒᴠᴒꜜᴐᴒͼ
ꜝᴟͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐͼⱨⱬᴠͼᴠⱳꜝᴢꞌᴑͼꜜꜝᴡͼԝᴒͼᴒꞌ꞉ᴐ꞉ᴡᴒᴑͼⱱᴟꜝꜛͼᴠᴢԝ꞊ᴒᴐᴡᴠ᷅
ᶄ
ᴀᴢԝ꞊ᴒᴐᴡᴠͼⱳԜᴣ꞉ꜜⱲͼᴁⱬⱨⱬᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼᴢꜜᴡ꞉ꞌͼᴟᴒᴠꜝꞌᴢᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼᴟᴒꞌᴒᴣԜꜜᴡͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼ
ԜꜜᴑͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠԓͼԜᴠͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅
ᶄ
ⱨⱬᴠԓͼԜᴐᴡ꞉ꜝꜜᴠͼᴡԜꞋᴒꜜͼԜᴠͼԜͼᴟᴒᴠᴢꞌᴡͼꜝⱱͼⱨⱬᴠԓͼԜꜜᴑͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴟᴒᴠᴢꞌᴡᴠͼꜛᴢᴠᴡͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴͼԜᴠͼ
ᴤᴒꞌꞌͼԜᴠͼ꞉ꜜͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡӾᴠͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡԜᴡ꞉ꜝꜜ᷅ͼⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴟᴒᴠᴢꞌᴡᴠͼᴠⱳꜝᴢꞌᴑͼԝᴒͼⱱ꞉ꞌᴒᴑͼ
ᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡӾᴠͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡԜᴡ꞉ꜝꜜ᷅
ⱴꜝᴟͼԜꜜᴦͼᴀⱨⱬᴠͼꜝᴟͼⱨⱬᴠͼᴡⱳԜᴡͼᴟᴒꜟᴢ꞉ᴟᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴡꜝͼԝᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼⱱᴟꜝꜛͼᴑꜝᴠ꞉ꜜⱲԓͼᴟᴒꞌᴒᴣԜꜜᴡͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ
ԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜꜜᴑͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒꜞᴒԜᴡᴒᴑͼԜᴠͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼԜꜞꜞᴟꜝꜞᴟ꞉Ԝᴡᴒԓͼᴢꜜᴡ꞉ꞌͼⱱ꞉ꜜԜꞌͼᴟᴒᴠꜝꞌᴢᴡ꞉ꜝꜜͼ
ꜝᴟͼᴠᴡԜԝ꞉ꞌ꞉ᴧԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴒᴣᴒꜜᴡӿᴠԐ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴡꜝͼԝᴒͼⱱꜝꞌꞌꜝᴤᴒᴑͼᴡⱳᴟꜝᴢⱲⱳͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝⱱͼԜꞌꞌͼ
ᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴣ꞉ᴠ꞉ᴡᴠ᷅
6.16.2.2
Monitoring of Safety Laboratory Assessments
ⱨꞌꞌͼᴠԜⱱᴒᴡᴦͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼԜᴡͼԜͼᴐᴒꜜᴡᴟԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦ᷅ͼᴁⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ
ꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴣԜꞌᴢᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴡꜝͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤⱳꜝͼᴤ꞉ꞌꞌͼᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒꜛͼⱱꜝᴟͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ
ᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼԜꜜᴑͼᴐꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜͼꜝⱱͼԜԝꜜꜝᴟꜛԜꞌͼᴣԜꞌᴢᴒᴠͼԜᴠͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼⱨⱬᴠ᷅
6.16.3
Assessment of Adverse Events
6.16.3.1
Assessment of Severity
ᴁⱳᴒͼᴡᴒᴟꜛͼᶰᴠᴒᴣᴒᴟᴒᶱͼ꞉ᴠͼꜝⱱᴡᴒꜜͼᴢᴠᴒᴑͼᴡꜝͼᴑᴒᴠᴐᴟ꞉ԝᴒͼᴡⱳᴒͼ꞉ꜜᴡᴒꜜᴠ꞉ᴡᴦͼӿᴠᴒᴣᴒᴟ꞉ᴡᴦԐͼꜝⱱͼԜͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐͼᴒᴣᴒꜜᴡͼӿԜᴠͼ꞉ꜜͼꜛ꞉ꞌᴑԓͼ
ꜛꜝᴑᴒᴟԜᴡᴒԓ ꜝᴟͼᴠᴒᴣᴒᴟᴒͼꜛᴦꜝᴐԜᴟᴑ꞉Ԝꞌͼ꞉ꜜⱱԜᴟᴐᴡ꞉ꜝꜜԐⱢͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼ꞉ᴡᴠᴒꞌⱱԓͼⱳꜝᴤᴒᴣᴒᴟԓͼꜛԜᴦͼԝᴒͼꜝⱱͼᴟᴒꞌԜᴡ꞉ᴣᴒꞌᴦͼꜛ꞉ꜜꜝᴟͼ
ꜛᴒᴑ꞉ᴐԜꞌͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼӿᴠᴢᴐⱳͼԜᴠͼᴠᴒᴣᴒᴟᴒͼꜜԜᴢᴠᴒԜԐ᷅ͼᴁⱳ꞉ᴠͼ꞉ᴠͼꜜꜝᴡͼᴡⱳᴒͼᴠԜꜛᴒͼԜᴠͼᶰᴠᴒᴟ꞉ꜝᴢᴠԓᶱͼᴤⱳ꞉ᴐⱳͼ꞉ᴠͼԝԜᴠᴒᴑͼ
ꜝꜜͼᴠᴢԝ꞊ᴒᴐᴡ᷆ᴒᴣᴒꜜᴡͼꜝᴢᴡᴐꜝꜛᴒͼꜝᴟͼԜᴐᴡ꞉ꜝꜜͼᴐᴟ꞉ᴡᴒᴟ꞉ԜͼᴢᴠᴢԜꞌꞌᴦͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼᴒᴣᴒꜜᴡᴠͼᴡⱳԜᴡͼꜞꜝᴠᴒͼԜͼᴡⱳᴟᴒԜᴡͼᴡꜝͼԜͼ
ᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼꞌ꞉ⱱᴒͼꜝᴟͼⱱᴢꜜᴐᴡ꞉ꜝꜜ꞉ꜜⱲ᷅
ⱷꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦԓͼᴡⱳᴒͼᴠᴒᴣᴒᴟ꞉ᴡᴦͼꜝⱱͼⱨⱬᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠᴒᴠᴠᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼⱫ꞉ᴣ꞉ᴠ꞉ꜝꜜͼꜝⱱͼꜚ꞉ᴐᴟꜝԝ꞉ꜝꞌꜝⱲᴦͼԜꜜᴑͼ
ⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠͼӿⱫꜚⱷⱫԐͼⱨᴑᴢꞌᴡͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒԓͼⱫᴟԜⱱᴡԓͼ꜠ꜝᴣᴒꜛԝᴒᴟͼ᷉᷇᷇ⅎͼӿᴂᴀͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼ
ⱷꜜᴠᴡ꞉ᴡᴢᴡᴒᴠͼꜝⱱͼⱶᴒԜꞌᴡⱳⱡͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠԐͼӿⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷉ԐͼԜꜜᴑͼᴡⱳᴒͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Ⱬ꞉ᴣ꞉ᴠ꞉ꜝꜜͼꜝⱱͼꜚ꞉ᴐᴟꜝԝ꞉ꜝꞌꜝⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠͼӿⱫꜚⱷⱫԐͼ͟ᴒᴑ꞉Ԝᴡᴟ꞉ᴐͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒԓͼⱫᴟԜⱱᴡԓͼ
꜠ꜝᴣᴒꜛԝᴒᴟͼ᷉᷇᷇ⅎͼӿᴂᴀͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒᴠͼꜝⱱͼⱶᴒԜꞌᴡⱳⱡͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼ
Ⱬ꞉ᴠᴒԜᴠᴒᴠԐͼӿⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷊Ԑ᷅ͼⱴꜝᴟͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠͼꜜꜝᴡͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐԜꞌꞌᴦͼⱱꜝᴢꜜᴑͼ꞉ꜜͼᴡⱳᴒͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒᴠԓͼᴡⱳᴒͼ
ⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼⱲᴒꜜᴒᴟԜꞌͼᴠᴐԜꞌᴒͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼᴡꜝͼᴒᴠᴡ꞉ꜛԜᴡᴒͼⱲᴟԜᴑᴒͼꜝⱱͼᴠᴒᴣᴒᴟ꞉ᴡᴦⱡ
ᶄ
ⱵϸⱨⱫⱬͼ᷈ͼӿꜚ꞉ꞌᴑԐⱡͼᴁᴟԜꜜᴠ꞉ᴒꜜᴡͼꜝᴟͼꜛ꞉ꞌᴑͼᴑ꞉ᴠᴐꜝꜛⱱꜝᴟᴡⱢͼꜜꜝͼꜛᴒᴑ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜ᷆ᴡⱳᴒᴟԜꜞᴦͼᴟᴒꜟᴢ꞉ᴟᴒᴑ
ᶄ
ⱵϸⱨⱫⱬͼ᷉ͼӿꜚꜝᴑᴒᴟԜᴡᴒԐⱡͼꜚ꞉ꞌᴑͼᴡꜝͼꜛꜝᴑᴒᴟԜᴡᴒͼꞌ꞉ꜛ꞉ᴡԜᴡ꞉ꜝꜜͼ꞉ꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼ᷄ᴠꜝꜛᴒͼԜᴠᴠ꞉ᴠᴡԜꜜᴐᴒͼꜛԜᴦͼԝᴒͼ
ꜜᴒᴒᴑᴒᴑⱢͼꜜꜝͼꜝᴟͼꜛ꞉ꜜ꞉ꜛԜꞌͼꜛᴒᴑ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜ᷆ᴡⱳᴒᴟԜꜞᴦͼᴟᴒꜟᴢ꞉ᴟᴒᴑ
ᶄ
ⱵϸⱨⱫⱬͼ᷊ͼӿᴀᴒᴣᴒᴟᴒԐⱡͼꜚԜᴟꞋᴒᴑͼꞌ꞉ꜛ꞉ᴡԜᴡ꞉ꜝꜜͼ꞉ꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦԓͼᴠꜝꜛᴒͼԜᴠᴠ꞉ᴠᴡԜꜜᴐᴒͼᴢᴠᴢԜꞌꞌᴦͼᴟᴒꜟᴢ꞉ᴟᴒᴑⱢͼꜛᴒᴑ꞉ᴐԜꞌͼ
꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜ᷆ᴡⱳᴒᴟԜꜞᴦͼᴟᴒꜟᴢ꞉ᴟᴒᴑԓͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜᴠͼꜞꜝᴠᴠ꞉ԝꞌᴒͼ
ᶄ
ⱵϸⱨⱫⱬͼ᷾ͼӿꜙ꞉ⱱᴒ᷄ᴡⱳᴟᴒԜᴡᴒꜜ꞉ꜜⱲԐⱡͼⱬᴥᴡᴟᴒꜛᴒͼꞌ꞉ꜛ꞉ᴡԜᴡ꞉ꜝꜜͼ꞉ꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦԓͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼԜᴠᴠ꞉ᴠᴡԜꜜᴐᴒͼᴟᴒꜟᴢ꞉ᴟᴒᴑⱢͼ
ᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼꜛᴒᴑ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜ᷆ᴡⱳᴒᴟԜꜞᴦͼᴟᴒꜟᴢ꞉ᴟᴒᴑԓͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼꜝᴟͼⱳꜝᴠꜞ꞉ᴐᴒͼᴐԜᴟᴒͼꜞᴟꜝԝԜԝꞌᴒ
ⱨꜜᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡ᷄ᴒꜛᴒᴟⱲᴒꜜᴡͼⱬⱪⱵͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡᴦͼᴡⱳԜᴡͼ꞉ᴠͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜᴠͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼ
ᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼԜꜜᴑͼᴟᴒꜟᴢ꞉ᴟ꞉ꜜⱲͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜ᷆ᴡⱳᴒᴟԜꜞᴦͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠᴒᴠᴠᴒᴑͼԜᴠͼԜͼᴠᴒᴣᴒᴟᴒͼⱨⱬ᷅
6.16.3.2
Assessment of Causality
ⱨͼꜛᴒᴑ꞉ᴐԜꞌꞌᴦͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼԜᴠᴠᴒᴠᴠͼᴡⱳᴒͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼꜝⱱͼԜꜜᴦͼⱨⱬͼӿ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴀⱨⱬᴠԐͼᴡꜝͼ
ᴡⱳᴒͼᴢᴠᴒͼꜝⱱͼᴡⱳᴒͼⱷꜚ͟ԓͼԜᴠͼᴟᴒꞌԜᴡᴒᴑͼꜝᴟͼꜜꜝᴡͼᴟᴒꞌԜᴡᴒᴑԓͼԝԜᴠᴒᴑͼꜝꜜͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ꞊ᴢᴑⱲꜛᴒꜜᴡͼԜꜜᴑͼᴢᴠ꞉ꜜⱲͼԜꞌꞌͼԜᴣԜ꞉ꞌԜԝꞌᴒͼ
꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜԓͼԜꜜᴑͼꜛԜᴦͼ꞉ꜜᴐꞌᴢᴑᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜͼꜝⱱᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼⱱԜᴐᴡꜝᴟᴠⱡ
ᶄ
͟ꜝᴠᴠ꞉ԝꞌᴒͼԜꞌᴡᴒᴟꜜԜᴡ꞉ᴣᴒͼᴐԜᴢᴠᴒᴠͼꜝⱱͼᴡⱳᴒͼⱨⱬԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴡⱳᴒͼᴑ꞉ᴠᴒԜᴠᴒͼᴢꜜᴑᴒᴟͼᴡᴟᴒԜᴡꜛᴒꜜᴡԓͼꜞᴟᴒ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼ
ᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠԓͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴢᴠᴒͼꜝⱱͼꜝᴡⱳᴒᴟͼᴑᴟᴢⱲᴠԓͼԜꜜᴑͼꜞᴟᴒᴠᴒꜜᴐᴒͼꜝⱱͼᴒꜜᴣ꞉ᴟꜝꜜꜛᴒꜜᴡԜꞌͼꜝᴟͼⱲᴒꜜᴒᴡ꞉ᴐͼⱱԜᴐᴡꜝᴟᴠ᷅
ᶄ
ᴁⱳᴒͼᴡᴒꜛꜞꜝᴟԜꞌͼԜᴠᴠꜝᴐ꞉Ԝᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼⱷꜚ͟ͼᴒᴥꜞꜝᴠᴢᴟᴒͼԜꜜᴑͼꜝꜜᴠᴒᴡͼꜝⱱͼᴡⱳᴒͼⱨⱬ᷅
ᶄ
ᴄⱳᴒᴡⱳᴒᴟͼᴡⱳᴒͼꜛԜꜜ꞉ⱱᴒᴠᴡԜᴡ꞉ꜝꜜᴠͼꜝⱱͼᴡⱳᴒͼⱨⱬͼԜᴟᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼꞋꜜꜝᴤꜜͼԜᴐᴡ꞉ꜝꜜᴠͼꜝᴟͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦͼꜝⱱͼᴡⱳᴒͼ
ⱷꜚ᷅͟
ᶄ
ᴁⱳᴒͼⱨⱬͼᴟᴒᴠꜝꞌᴣᴒᴑͼꜝᴟͼ꞉ꜛꜞᴟꜝᴣᴒᴑͼᴤ꞉ᴡⱳͼᴑᴒᴐᴟᴒԜᴠ꞉ꜜⱲͼᴡⱳᴒͼᴑꜝᴠᴒͼꜝᴟͼᴠᴡꜝꜞꜞ꞉ꜜⱲͼᴢᴠᴒͼꜝⱱͼᴡⱳᴒͼⱷꜚ͟ͼ
ӿᴑᴒᴐⱳԜꞌꞌᴒꜜⱲᴒԐ᷅ͼꜗᴢᴑⱲꜛᴒꜜᴡͼᴠⱳꜝᴢꞌᴑͼԝᴒͼᴢᴠᴒᴑͼ꞉ⱱͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼꜞᴟꜝᴑᴢᴐᴡᴠͼԜᴟᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼԜᴡͼᴡⱳᴒͼᴠԜꜛᴒͼ
ᴡ꞉ꜛᴒ᷅
ᴁⱳᴒͼᴐԜᴢᴠԜꞌͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼԝᴒᴡᴤᴒᴒꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼⱷꜚ͟ͼԜꜜᴑͼᴡⱳᴒͼⱨⱬͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠᴒᴠᴠᴒᴑͼᴢᴠ꞉ꜜⱲͼꜝꜜᴒͼꜝⱱͼᴡⱳᴒͼ
ⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐԜᴡᴒⱲꜝᴟ꞉ᴒᴠⱡ
Not Related:ͼͼⱴԜᴐᴡꜝᴟᴠͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼԜꜜͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼ꜠ꜝᴡͼϸᴒꞌԜᴡᴒᴑͼ꞉ꜜᴐꞌᴢᴑᴒⱡ
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ᴁᴒꜛꜞꜝᴟԜꞌͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼ꞉ᴠͼꞌԜᴐꞋ꞉ꜜⱲͼӿᴒ᷅Ⱳ᷅ԓͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼᴑ꞉ᴑͼꜜꜝᴡͼꜝᴐᴐᴢᴟͼᴤ꞉ᴡⱳ꞉ꜜͼԜͼᴟᴒԜᴠꜝꜜԜԝꞌᴒͼ
ᴡ꞉ꜛᴒͼⱱᴟԜꜛᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼⱷꜚ͟ԐⱢͼꜝᴟ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
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꜡ᴡⱳᴒᴟͼᴐԜᴢᴠԜᴡ꞉ᴣᴒͼⱱԜᴐᴡꜝᴟᴠͼꜛꜝᴟᴒͼꞌ꞉ꞋᴒꞌᴦͼᴒᴥꜞꞌԜ꞉ꜜͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼӿᴒ᷅Ⱳ᷅ԓͼԜͼꜞᴟᴒ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼ
ᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜԓͼꜝᴡⱳᴒᴟͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡᴠԐ᷅
Related:ͼͼⱴԜᴐᴡꜝᴟᴠͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼԜꜜͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼϸᴒꞌԜᴡᴒᴑͼ꞉ꜜᴐꞌᴢᴑᴒⱡ

ᴁⱳᴒᴟᴒͼ꞉ᴠͼԜͼꜞꜝᴠ꞉ᴡ꞉ᴣᴒͼᴡᴒꜛꜞꜝᴟԜꞌͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼӿᴒ᷅Ⱳ᷅ԓͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼꜝᴐᴐᴢᴟᴟᴒᴑͼᴤ꞉ᴡⱳ꞉ꜜͼԜͼ
ᴟᴒԜᴠꜝꜜԜԝꞌᴒͼᴡ꞉ꜛᴒͼⱱᴟԜꜛᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԐⱢͼꜝᴟ

ᴁⱳᴒͼⱨⱬͼ꞉ᴠͼꜛꜝᴟᴒͼꞌ꞉ꞋᴒꞌᴦͼᴒᴥꜞꞌԜ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼᴡⱳԜꜜͼԝᴦͼԜꜜꜝᴡⱳᴒᴟͼ
ᴐԜᴢᴠᴒͼӿ꞉᷅ᴒ᷅ԓͼᴡⱳᴒͼⱨⱬͼᴠⱳꜝᴤᴠͼԜͼꜞԜᴡᴡᴒᴟꜜͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼꜞᴟᴒᴣ꞉ꜝᴢᴠͼꞋꜜꜝᴤꞌᴒᴑⱲᴒͼꜝⱱͼᴡⱳᴒͼ
꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼꜝᴟͼᴡⱳᴒͼᴐꞌԜᴠᴠͼꜝⱱͼᴡⱳᴒͼⱷꜚ͟Ԑ᷅
6.16.3.3
Assessment of Clinical Significance
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꜝⱱͼ꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼⱨⱬᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟԓͼᴤ꞉ᴡⱳͼᴑ꞉ᴠᴐᴢᴠᴠ꞉ꜝꜜͼ
ᴤ꞉ᴡⱳͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼԜᴠͼԜꜞꜞᴟꜝꜞᴟ꞉ԜᴡᴒԓͼꜝᴟͼԝᴦͼᴡⱳᴒͼⱫᴀꜚⱩͼⱱꜝᴟͼꜝᴣᴒᴟԜꞌꞌͼᴠᴡᴢᴑᴦͼⱨⱬͼᴟᴒᴣ꞉ᴒᴤ᷅
6.16.4
Clinical Laboratory Adverse Events
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠͼⱲᴒꜜᴒᴟԜꞌꞌᴦͼԜᴟᴒͼꜜꜝᴡͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼⱨⱬᴠͼᴢꜜꞌᴒᴠᴠͼᴡⱳᴒᴦͼԜᴟᴒͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼ
ᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠ꞉Ⱳꜜᴠͼꜝᴟͼᴠᴦꜛꜞᴡꜝꜛᴠԓͼꜝᴟͼᴟᴒꜟᴢ꞉ᴟᴒͼꜛᴒᴑ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜ᷅ͼⱨͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼ
ԜԝꜜꜝᴟꜛԜꞌ꞉ᴡᴦͼᴡⱳԜᴡͼ꞉ᴠͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼⱱᴟꜝꜛͼԜͼꞋꜜꜝᴤꜜͼᴢꜜᴑᴒᴟꞌᴦ꞉ꜜⱲͼꜛᴒᴑ꞉ᴐԜꞌͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜͼԜꜜᴑͼᴡⱳԜᴡͼᴟᴒꜟᴢ꞉ᴟᴒᴠͼ
ꜛᴒᴑ꞉ᴐԜꞌͼꜝᴟͼᴠᴢᴟⱲ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟᴣᴒꜜᴡ꞉ꜝꜜԓͼꜝᴟͼꞌᴒԜᴑᴠͼᴡꜝͼⱷꜚ͟ͼ꞉ꜜᴡᴒᴟᴟᴢꜞᴡ꞉ꜝꜜͼꜝᴟͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜԓͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜꜜͼⱨⱬ᷅
ᴄⱳᴒꜜͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡ꞉ᴒᴠͼԜᴟᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼᴡꜝͼԝᴒͼⱨⱬᴠԓͼᴡⱳᴒͼⱫꜚⱷⱫͼⱨᴑᴢꞌᴡͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒͼ
ӿⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷉ԐͼꜝᴟͼⱫꜚⱷⱫͼ͟ᴒᴑ꞉Ԝᴡᴟ꞉ᴐͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒᴠͼӿⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷊Ԑͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼᴡꜝͼԜᴠᴠᴒᴠᴠͼᴠᴒᴣᴒᴟ꞉ᴡᴦ᷅ͼ
ᴄⱳᴒᴟᴒͼᴑ꞉ᴠᴐᴟᴒꜞԜꜜᴐ꞉ᴒᴠͼ꞉ꜜͼᴡⱳᴒͼᴢꜞꜞᴒᴟͼꞌ꞉ꜛ꞉ᴡͼꜝⱱͼꜜꜝᴟꜛԜꞌͼӿᴂꜙ꜠ԐͼԜꜜᴑͼꞌꜝᴤᴒᴟͼꞌ꞉ꜛ꞉ᴡͼꜝⱱͼꜜꜝᴟꜛԜꞌͼӿꜙꜙ꜠Ԑͼꜝⱱͼ
ꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴟԜꜜⱲᴒᴠͼꜝᴐᴐᴢᴟͼԝᴒᴡᴤᴒᴒꜜͼᴡⱳꜝᴠᴒͼ꞉ꜜᴐꞌᴢᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼⱫꜚⱷⱫͼᴡԜԝꞌᴒᴠͼԜꜜᴑͼᴡⱳꜝᴠᴒͼꜝⱱͼᴡⱳᴒͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼ
ᴡⱳԜᴡͼꜞᴒᴟⱱꜝᴟꜛᴠͼᴡⱳᴒͼԜᴠᴠԜᴦᴠԓͼᴡⱳᴒͼᴣԜꞌᴢᴒᴠͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼԝᴦͼᴡⱳᴒͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼⱱꜝᴟͼԜᴠᴠ꞉Ⱳꜜꜛᴒꜜᴡͼꜝⱱͼ
ᴠᴒᴣᴒᴟ꞉ᴡᴦͼⱲᴟԜᴑᴒ᷅ͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꜝⱱͼ꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼⱨⱬᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ᴡⱳͼ꞉ꜜꜞᴢᴡͼⱱᴟꜝꜛͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼԜᴠͼꜜᴒᴒᴑᴒᴑ᷅ͼ
ⱴꜝꞌꞌꜝᴤ꞉ꜜⱲͼ꞉ᴠͼԜꜜͼᴒᴥᴐᴒꜞᴡ꞉ꜝꜜͼᴡꜝͼᴑᴒⱱ꞉ꜜ꞉ꜜⱲͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡԓͼԜԝꜜꜝᴟꜛԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴣԜꞌᴢᴒᴠͼԜᴠͼⱨⱬᴠⱡ
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ⱨ͟ᴁᴁͼꜞᴟꜝꞌꜝꜜⱲԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼԜꜜᴦͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼԝꞌᴒᴒᴑ꞉ꜜⱲͼꜝᴟͼꜝᴡⱳᴒᴟͼᴒᴣ꞉ᴑᴒꜜᴐᴒͼꜝⱱͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ
ᴟᴒꞌᴒᴣԜꜜᴐᴒͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼԜԝꜜꜝᴟꜛԜꞌ꞉ᴡᴦͼꜝᴟͼⱨⱬ᷅ͼⱷꜜͼᴡⱳᴒͼ
Ԝꜞꜞᴟꜝꜞᴟ꞉Ԝᴡᴒͼꜞⱳᴦᴠ꞉ꜝꞌꜝⱲ꞉ᴐͼᴠᴒᴡᴡ꞉ꜜⱲԓͼᴠᴢᴐⱳͼԜᴠͼⱷᴃͼⱳᴒꜞԜᴟ꞉ꜜͼᴡⱳᴒᴟԜꜞᴦԓͼԜ͟ᴁᴁͼᴐԜꜜͼԝᴒͼᴢᴠᴒᴑͼᴡꜝͼꜛꜝꜜ꞉ᴡꜝᴟͼ
ԝꞌᴒᴒᴑ꞉ꜜⱲͼᴟ꞉ᴠꞋ᷅ͼⱶꜝᴤᴒᴣᴒᴟԓͼԜᴠͼꜜꜝᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼⱩᴟꜝᴐⱳᴢᴟᴒԓͼԜ͟ᴁᴁͼꜞᴟꜝꞌꜝꜜⱲԜᴡ꞉ꜝꜜͼᴑᴢᴒͼᴡꜝͼ
ꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼ꞉ꜜⱳ꞉ԝ꞉ᴡ꞉ꜝꜜͼ꞉ᴠͼԜꜜͼԜᴟᴡ꞉ⱱԜᴐᴡᴢԜꞌͼin vitro ꜞⱳᴒꜜꜝꜛᴒꜜꜝꜜ᷅ͼⱨꞌᴡⱳꜝᴢⱲⱳͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼ
ᴑᴟ꞉ᴣᴒᴠͼⱱ꞉ԝᴟ꞉ꜜͼⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼԜ͟ᴁᴁͼԜᴠᴠԜᴦԓͼꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜ᷄ᴑᴟ꞉ᴣᴒꜜͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜͼᴑꜝᴒᴠͼꜜꜝᴡͼ
ԜꜞꜞᴒԜᴟͼᴡꜝͼⱳԜᴣᴒͼⱳᴒꜛꜝᴠᴡԜᴡ꞉ᴐͼꜝᴟͼꜝᴡⱳᴒᴟͼꜞⱳᴦᴠ꞉ꜝꞌꜝⱲ꞉ᴐԜꞌꞌᴦͼ꞉ꜛꜞꜝᴟᴡԜꜜᴡͼⱱᴢꜜᴐᴡ꞉ꜝꜜᴠͼin vivo᷅ͼⱷᴡͼ꞉ᴠͼᴤᴒꞌꞌͼ
ᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼᴡⱳԜᴡԓͼ꞉ꜜͼⱳᴢꜛԜꜜᴠԓͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦͼꜝⱱͼⱱԜᴐᴡꜝᴟͼᴅⱷⱷͼꜝᴟͼꜞᴟᴒꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼӿԜꜜᴑͼᴡⱳᴢᴠͼꜞꞌԜᴠꜛԜͼ
ꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜԐͼ꞉ᴠͼꜜꜝᴡͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼԜԝꜜꜝᴟꜛԜꞌԝꞌᴒᴒᴑ꞉ꜜⱲԓͼᴒ꞉ᴡⱳᴒᴟͼᴠꜞꜝꜜᴡԜꜜᴒꜝᴢᴠͼꜝᴟͼᴑᴢᴟ꞉ꜜⱲͼᴠᴢᴟⱲ꞉ᴐԜꞌͼ
ꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼӿϸᴒꜜꜜᴒͼԜꜜᴑͼⱵᴟᴢԝᴒᴟԓͼ᷉᷇᷈᷉Ԑ᷅ͼⱫᴒᴠꜞ꞉ᴡᴒͼᴡⱳᴒͼꞌԜᴐꞋͼꜝⱱͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴒⱱⱱᴒᴐᴡԓ ᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦͼꜝⱱͼᴒ꞉ᴡⱳᴒᴟͼ
ꜞᴟꜝᴡᴒ꞉ꜜͼ꞉ᴠͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼꜛԜᴟꞋᴒᴑͼꜞᴟꜝꞌꜝꜜⱲԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼԜ͟ᴁᴁ᷅ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍᷊
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
6.16.5
Reporting Investigator Safety Observations to the Sponsor
6.16.5.1
Reporting Non-Serious Adverse Events
ⱨꞌꞌͼⱨⱬᴠԓͼᴟᴒⱲԜᴟᴑꞌᴒᴠᴠͼꜝⱱͼᴠᴒᴟ꞉ꜝᴢᴠꜜᴒᴠᴠԓͼᴠᴒᴣᴒᴟ꞉ᴡᴦԓͼꜝᴟͼᴐԜᴢᴠԜꞌͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴡꜝͼⱷꜚ͟ԓͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼꜝꜜͼ
ᴡⱳᴒͼⱨⱬͼꜞԜⱲᴒͼꜝⱱͼᴡⱳᴒͼᴒⱪϸⱴ᷅ͼⱷꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼԜꞌꞌͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴟᴒꜞꜝᴟᴡᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡԓͼᴟᴒⱲԜᴟᴑꞌᴒᴠᴠͼꜝⱱͼ
ᴤⱳᴒᴡⱳᴒᴟͼꜝᴟͼꜜꜝᴡͼᴡⱳᴒᴦͼԜᴟᴒͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟԓͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜꜞᴡᴢᴟᴒᴑͼԜᴠͼⱨⱬᴠ᷅
6.16.5.2
Reporting Pregnancies
ⱷⱱͼԜͼⱱᴒꜛԜꞌᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜝᴟͼᴡⱳᴒͼⱱᴒꜛԜꞌᴒͼꜞԜᴟᴡꜜᴒᴟͼꜝⱱͼԜͼꜛԜꞌᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԝᴒᴐꜝꜛᴒᴠͼꜞᴟᴒⱲꜜԜꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴐꜝᴢᴟᴠᴒͼꜝⱱͼ
ᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼᴟᴒꜞꜝᴟᴡͼᴡⱳᴒͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡꜝͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟӾᴠͼ͟ⱳԜᴟꜛԜᴐꜝᴣ꞉Ⱳ꞉ꞌԜꜜᴐᴒͼ
ⱫᴒꜞԜᴟᴡꜛᴒꜜᴡͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼPregnancy Reporting Form ᴤ꞉ᴡⱳ꞉ꜜͼ24 hours ꜝⱱͼԝᴒᴐꜝꜛ꞉ꜜⱲͼԜᴤԜᴟᴒͼꜝⱱͼᴡⱳᴒͼ
ᴒᴣᴒꜜᴡ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼꜝԝᴡԜ꞉ꜜͼᴐꜝꜜᴠᴒꜜᴡͼᴡꜝͼᴐꜝꞌꞌᴒᴐᴡͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴡⱳᴒͼ
ᴠᴡԜᴡᴢᴠͼꜝⱱͼᴡⱳᴒͼꜜᴒᴤԝꜝᴟꜜԓͼ꞉ⱱͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒԐ᷅
ⱷⱱͼᴠꜝꜛᴒͼꜝⱱͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼⱱꜝᴟͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ͟ᴟᴒⱲꜜԜꜜᴐᴦͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼⱴꜝᴟꜛͼ꞉ᴠͼ
ᴢꜜԜᴣԜ꞉ꞌԜԝꞌᴒͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼᴡⱳᴒͼ꞉ꜜ꞉ᴡ꞉Ԝꞌͼᴟᴒꜞꜝᴟᴡԓͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴟᴒꜞꜝᴟᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑͼԜꜜᴑͼᴠᴢԝꜛ꞉ᴡᴡᴒᴑͼ
ᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ͼⱳꜝᴢᴟᴠͼꜝⱱͼԝᴒᴐꜝꜛ꞉ꜜⱲͼԜᴤԜᴟᴒͼꜝⱱͼᴡⱳᴒͼꜜᴒᴤͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ꞉ᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼ
ⱱꜝꞌꞌꜝᴤͼᴡⱳᴒͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡⱳᴟꜝᴢⱲⱳͼᴑᴒꞌ꞉ᴣᴒᴟᴦ᷅ͼᴁⱳᴒͼꜝᴢᴡᴐꜝꜛᴒͼꜝⱱͼᴡⱳᴒͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼԜꜜᴑͼᴡⱳᴒͼᴠᴡԜᴡᴢᴠͼꜝⱱͼᴡⱳᴒͼ
ꜜᴒᴤԝꜝᴟꜜͼӿ꞉ⱱͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒԐͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑꜝꜜͼᴡⱳᴒͼ͟ᴟᴒⱲꜜԜꜜᴐᴦͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼⱴꜝᴟꜛͼᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ⱳꜝᴢᴟᴠͼꜝⱱͼ
ԝᴒᴐꜝꜛ꞉ꜜⱲͼԜᴤԜᴟᴒ᷅
6.16.5.3
Safety Observations Requiring Expedited Reporting by the Investigator to the 
Sponsor
ⱨꜜᴦͼꜝᴐᴐᴢᴟᴟᴒꜜᴐᴒͼꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴒᴣᴒꜜᴡᴠͼꜝᴟͼꜝᴢᴡᴐꜝꜛᴒᴠͼ꞉ꜜͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ꜜͼᴡⱳᴒͼᴡᴟ꞉Ԝꞌͼꜛᴢᴠᴡͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼ
ᴒᴥꜞᴒᴑ꞉ᴡ꞉ꜝᴢᴠꞌᴦͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼꜟᴢԜꞌ꞉ⱱ꞉ᴒᴑͼᴑᴒᴠ꞉ⱲꜜᴒᴒͼᴡꜝͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟӾᴠͼ͟ⱳԜᴟꜛԜᴐꜝᴣ꞉Ⱳ꞉ꞌԜꜜᴐᴒͼ
ⱫᴒꜞԜᴟᴡꜛᴒꜜᴡⱡ
ᶄ
ᴀⱨⱬ
ᶄ
ⱨⱬᴀⱷ
ᶄ
꜡ᴣᴒᴟᴑꜝᴠᴒ
ᶄ
ⱪԜꜜᴐᴒᴟ
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ꞉ᴠͼᴡꜝͼᴟᴒꜞꜝᴟᴡͼԜꜜᴦͼᴒᴥꜞᴒᴑ꞉ᴡᴒᴑͼᴠԜⱱᴒᴡᴦͼꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼꞌ꞉ᴠᴡͼԜԝꜝᴣᴒͼᴡꜝͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼ
ᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼSAE Reporting Form in the EDC system ᴤ꞉ᴡⱳ꞉ꜜͼ᷉᷾ͼⱳꜝᴢᴟᴠꜝⱱͼԝᴒᴐꜝꜛ꞉ꜜⱲͼԜᴤԜᴟᴒͼꜝⱱͼᴡⱳᴒͼ
ᴒᴣᴒꜜᴡ᷅
ⱨꜜᴦͼᴀⱨⱬͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴡꜝͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼ͟ⱳԜᴟꜛԜᴐꜝᴣ꞉Ⱳ꞉ꞌԜꜜᴐᴒͼⱫᴒꜞԜᴟᴡꜛᴒꜜᴡͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼᴀⱨⱬͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼ
ⱴꜝᴟꜛͼ꞉ꜜͼᴡⱳᴒͼⱬⱫⱪͼᴠᴦᴠᴡᴒꜛͼ꞉ᴠͼᴡꜝͼԝᴒͼᴟᴒᴐꜝᴟᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴԓͼԜᴠͼᴤᴒꞌꞌͼԜᴠͼ꞉ꜜͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡӾᴠͼᴠꜝᴢᴟᴐᴒͼ
ᴑꜝᴐᴢꜛᴒꜜᴡԜᴡ꞉ꜝꜜͼԜꞌꜝꜜⱲͼᴤ꞉ᴡⱳͼԜꜜᴦͼԜᴐᴡ꞉ꜝꜜᴠͼᴡԜꞋᴒꜜ᷅ͼⱷⱱͼԜꞌꞌͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜝꜜͼᴡⱳᴒͼⱱꜝᴟꜛͼ꞉ᴠͼꜜꜝᴡͼ
ԜᴣԜ꞉ꞌԜԝꞌᴒͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼᴡⱳᴒͼ꞉ꜜ꞉ᴡ꞉Ԝꞌͼᴟᴒꜞꜝᴟᴡԓͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼⱬⱫⱪͼ
ᴠᴦᴠᴡᴒꜛ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ꞉ᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼⱱꜝꞌꞌꜝᴤͼᴀⱨⱬᴠͼᴢꜜᴡ꞉ꞌͼᴟᴒᴠꜝꞌᴢᴡ꞉ꜝꜜͼᴟᴒⱲԜᴟᴑꞌᴒᴠᴠͼꜝⱱͼᴤⱳᴒᴡⱳᴒᴟͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ
Ԝᴟᴒͼᴠᴡ꞉ꞌꞌͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼᴀⱨⱬͼᴟᴒᴠꜝꞌᴢᴡ꞉ꜝꜜͼ꞉ᴠͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠⱡ
ᶄ
ϸᴒᴠꜝꞌᴣᴒᴑͼᴤ꞉ᴡⱳͼꜝᴟͼᴤ꞉ᴡⱳꜝᴢᴡͼᴟᴒᴠ꞉ᴑᴢԜꞌͼᴒⱱⱱᴒᴐᴡᴠ᷅
ᶄ
ⱨͼᴟᴒᴡᴢᴟꜜͼᴡꜝͼԝԜᴠᴒꞌ꞉ꜜᴒͼⱱꜝᴟͼԜͼꜞᴟᴒ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜ᷅
ᶄ
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴣԜꞌᴢᴒᴠͼⱳԜᴣᴒͼᴟᴒᴡᴢᴟꜜᴒᴑͼᴡꜝͼԝԜᴠᴒꞌ꞉ꜜᴒͼꜝᴟͼᴠᴡԜԝ꞉ꞌ꞉ᴧᴒᴑ᷅
ᶄ
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑꜝᴒᴠͼꜜꜝᴡͼᴒᴥꜞᴒᴐᴡͼԜꜜᴦͼⱱᴢᴟᴡⱳᴒᴟͼ꞉ꜛꜞᴟꜝᴣᴒꜛᴒꜜᴡͼꜝᴟͼᴤꜝᴟᴠᴒꜜ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼᴒᴣᴒꜜᴡ᷅
ᶄ
ⱴԜᴡԜꞌͼꜝᴢᴡᴐꜝꜛᴒᶯ꞉ⱱͼԜꜜͼԜᴢᴡꜝꜞᴠᴦͼ꞉ᴠͼꜞᴒᴟⱱꜝᴟꜛᴒᴑԓͼᴡⱳᴒͼԜᴢᴡꜝꜞᴠᴦͼᴟᴒꜞꜝᴟᴡͼ꞉ᴠͼᴟᴒꜟᴢᴒᴠᴡᴒᴑͼᴡꜝͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴡꜝͼ
ᴡⱳᴒͼᴠꜞꜝꜜᴠꜝᴟͼԜᴠͼᴠꜝꜝꜜͼԜᴠͼ꞉ᴡͼ꞉ᴠͼԜᴣԜ꞉ꞌԜԝꞌᴒ᷅
6.16.5.4
Expedited Reporting by the Sponsor to a Regulatory Health Authority
ᴁⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼꜝᴟͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼᴤ꞉ꞌꞌͼᴟᴒꜞꜝᴟᴡͼᴟᴒꞌᴒᴣԜꜜᴡͼᴠԜⱱᴒᴡᴦͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡꜝͼᴐꜝꜜᴐᴒᴟꜜᴒᴑͼⱳᴒԜꞌᴡⱳͼԜᴢᴡⱳꜝᴟ꞉ᴡ꞉ᴒᴠͼ
꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼꞌꜝᴐԜꞌͼꞌԜᴤᴠͼԜꜜᴑͼᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠ᷅
6.16.5.5
Safety Contact Information 
24-Hour Medical Safety Contact for US, Canada, Europe, and Middle East
Sponsor Pharmacovigilance Department
ⱬꜛԜ꞉ꞌⱡͼ
͟ⱳꜝꜜᴒͼӿᴂᴀԐⱡͼ
6.16.5.6
Safety Notifications by the Sponsor to the Investigator
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼꜞᴟꜝꜛꜞᴡͼꜜꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼꜝⱱͼԜꜜᴦͼԜᴑᴣᴒᴟᴠᴒͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼᴟᴒꞌԜᴡᴒᴑͼᴡꜝͼⱷꜚ͟ͼᴡⱳԜᴡͼ꞉ᴠͼ
ԝꜝᴡⱳͼᴠᴒᴟ꞉ꜝᴢᴠͼԜꜜᴑͼᴢꜜᴒᴥꜞᴒᴐᴡᴒᴑԓͼꜝᴟͼԜꜜᴦͼⱱ꞉ꜜᴑ꞉ꜜⱲͼᴡⱳԜᴡͼᴠᴢⱲⱲᴒᴠᴡᴠͼԜͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼᴟ꞉ᴠꞋͼⱱꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠ᷅ͼᴁⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ꞌꞌͼꜞᴟꜝꜛꜞᴡꞌᴦͼ꞉ꜜⱱꜝᴟꜛͼⱳ꞉ᴠ᷆ⱳᴒᴟͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪͼꜝⱱͼᴡⱳᴒͼꜜꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼԜꜜᴑͼ꞉ꜜᴠᴒᴟᴡͼᴡⱳᴒͼ
ꜜꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼϸᴒⱲᴢꞌԜᴡꜝᴟᴦͼⱩ꞉ꜜᴑᴒᴟͼ꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼꞌꜝᴐԜꞌͼᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠ᷅ͼ
6.16.5.7
Unblinding a Subject’s Treatment during the Trial
ϸᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼⱱꜝᴟͼᴒꜛᴒᴟⱲᴒꜜᴐᴦͼᴢꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜᴟᴒͼᴑᴒᴡԜ꞉ꞌᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷅᷾᷅ͼᴁꜝͼԜᴠᴠᴒᴠᴠͼ
ԜꜜͼꜝᴐᴐᴢᴟᴟᴒꜜᴐᴒͼꜝⱱͼԜͼᴠԜⱱᴒᴡᴦͼꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜԓͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ͟ⱳԜᴟꜛԜᴐꜝᴣ꞉Ⱳ꞉ꞌԜꜜᴐᴒͼⱫᴒꜞԜᴟᴡꜛᴒꜜᴡͼꜛԜᴦͼᴢꜜԝꞌ꞉ꜜᴑͼ
ᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜝⱱͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡ᷅
6.17
Subject Withdrawal
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛԜᴦͼᴤ꞉ᴡⱳᴑᴟԜᴤͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼⱱᴟꜝꜛͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴤ꞉ᴡⱳͼᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼⱱꜝᴟͼԜꜜᴦͼꜝⱱͼᴡⱳᴒͼᴟᴒԜᴠꜝꜜᴠͼ
ꞌ꞉ᴠᴡᴒᴑͼԝᴒꞌꜝᴤ᷅ͼ
ᶄ
ⱷꜜͼᴡⱳᴒͼꜝꜞ꞉ꜜ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟԓͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼᴢꜜԜԝꞌᴒͼᴡꜝͼᴐꜝꜛꜞꞌᴦͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼꜝⱱͼ
ᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼⱱꜝᴟͼᴠԜᴡ꞉ᴠⱱԜᴐᴡꜝᴟᴦͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝᴟͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜͼꜝⱱͼᴠᴡᴢᴑᴦͼᴟᴒᴠᴢꞌᴡᴠͼӿ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴢᴠᴒͼꜝⱱͼ
ꜞᴟꜝⱳ꞉ԝ꞉ᴡ꞉ᴣᴒͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠԐԓ
PPD
PPD


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍᷿
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᶄ
ⱨͼᴠᴒᴟ꞉ꜝᴢᴠͼꜝᴟͼ꞉ꜜᴡꜝꞌᴒᴟԜԝꞌᴒͼⱨⱬͼꜝᴐᴐᴢᴟᴠԓ
ᶄ
ⱨͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼᴐⱳԜꜜⱲᴒͼ꞉ꜜͼԜͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼꜞԜᴟԜꜛᴒᴡᴒᴟͼꜝᴐᴐᴢᴟᴠԓ
ᶄ
ᴁⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼꜝᴟͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡᴒᴟꜛ꞉ꜜԜᴡᴒᴠͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼꜝᴟ
ᶄ
ᴁⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴟᴒꜟᴢᴒᴠᴡᴠͼᴡꜝͼԝᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴡꜝͼԝᴒͼⱱꜝꞌꞌꜝᴤᴒᴑͼᴡⱳᴟꜝᴢⱲⱳͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝⱱͼԜꞌꞌͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴣ꞉ᴠ꞉ᴡᴠԓͼᴢꜜꞌᴒᴠᴠͼᴡⱳᴒͼ
ᴠᴢԝ꞊ᴒᴐᴡͼᴟᴒꜟᴢᴒᴠᴡᴠͼᴡꜝͼԝᴒͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼᴁⱳᴒͼᴐᴟ꞉ᴡᴒᴟ꞉ԜͼᴢᴠᴒᴑͼԝᴦͼᴡⱳᴒͼⱫᴀꜚⱩͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼ
ᴑꜝᴠᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼᴠᴢᴠꜞᴒꜜᴠ꞉ꜝꜜͼԜꜜᴑ᷆ꜝᴟͼᴠᴡᴢᴑᴦͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼԜᴟᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷊᷅᷈᷅᷉᷅
6.18
Appropriateness of Measurements
ᴁⱳ꞉ᴠͼ꞉ᴠͼԜͼ͟ⱳԜᴠᴒͼ᷊ͼꜛᴢꞌᴡ꞉᷄ᴐᴒꜜᴡᴒᴟԓͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑԓͼꜞꞌԜᴐᴒԝꜝ᷄ᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼᴠᴡᴢᴑᴦͼᴡⱳԜᴡͼ꞉ᴠͼ
ᴑᴒᴠ꞉ⱲꜜᴒᴑͼᴡꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ꜜͼꜞᴟᴒᴣᴒꜜᴡ꞉ꜝꜜͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼ꞉ꜜͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼⱶⱨⱬ᷅ͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ꞉ᴠͼԜͼᴟᴒᴐꜝꜛԝ꞉ꜜԜꜜᴡԓͼⱱᴢꞌꞌᴦͼⱳᴢꜛԜꜜͼⱷⱲⱵ᷈ԓͼꞋԜꜞꜞԜͼꞌ꞉ⱲⱳᴡͼᴐⱳԜ꞉ꜜԓͼꜛꜝꜜꜝᴐꞌꜝꜜԜꞌͼ
Ԝꜜᴡ꞉ԝꜝᴑᴦ᷅ͼᴁⱳᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼꜞꞌԜᴐᴒԝꜝͼᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼᴠᴡᴢᴑᴦͼᴑᴒᴠ꞉Ⱳꜜͼ꞉ᴠͼԜͼᴠᴡԜꜜᴑԜᴟᴑͼԜꜞꜞᴟꜝԜᴐⱳͼⱱꜝᴟͼ
ᴑ꞉ⱱⱱᴒᴟᴒꜜᴡ꞉Ԝᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜞᴟꜝⱱ꞉ꞌᴒᴠͼꜝⱱͼԜꜜͼԜᴐᴡ꞉ᴣᴒͼԜꜜᴑͼꜞꞌԜᴐᴒԝꜝͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴤⱳᴒꜜͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼᴡꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠ᷅ͼⱨꞌꞌͼꜝⱱͼᴡⱳᴒͼꜛᴒԜᴠᴢᴟᴒᴠͼᴒꜛꜞꞌꜝᴦᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼꜞᴟꜝᴡꜝᴐꜝꞌͼԜᴟᴒͼᴠᴡԜꜜᴑԜᴟᴑͼꜛᴒԜᴠᴢᴟᴒᴠͼ
ᴟꜝᴢᴡ꞉ꜜᴒꞌᴦͼᴢᴠᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦԓͼᴠԜⱱᴒᴡᴦͼԜꜜᴑͼᴡꜝꞌᴒᴟԜԝ꞉ꞌ꞉ᴡᴦͼꜝⱱͼԜꜜͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼ
ꜞᴟꜝᴑᴢᴐᴡ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
7
STUDY ACTIVITIES
ᴀᴡᴢᴑᴦͼԜᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼԜᴟᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼԝᴦͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡͼ꞉ꜜͼᴁԜԝꞌᴒͼ᷈ӿᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒԐ᷅
7.1
Screening 
The following procedures and assessments are to be performed during Screening:
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ⱷꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈Ԑ
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ⱬꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼᴟᴒᴣ꞉ᴒᴤͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷉Ԑ
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ⱫᴒꜛꜝⱲᴟԜꜞⱳ꞉ᴐᴠͼԜꜜᴑͼꜛᴒᴑ꞉ᴐԜꞌͼⱳ꞉ᴠᴡꜝᴟᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷊᷅Ԑ
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ⱪ᷈᷄ⱷ꜠ⱶͼⱱᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼԜᴠᴠԜᴦԓͼⱪ᷾ͼԜꜜᴑͼⱪ᷈ꜟͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
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͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡԓͼᴠᴒᴟᴢꜛͼꜝᴟͼᴢᴟ꞉ꜜᴒͼӿⱱᴒꜛԜꞌᴒᴠԐͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
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ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅Ԑ
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ⱪꜝꜛꜞꞌᴒᴡᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅⅍ԐⱢͼᴑꜝᴐᴢꜛᴒꜜᴡԜᴡ꞉ꜝꜜͼꜝⱱͼⱳᴒ꞉ⱲⱳᴡͼԜꜜᴑͼᴤᴒ꞉Ⱳⱳᴡ
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᷈᷉᷄ꜙᴒԜᴑͼⱬⱪⱵͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⅎԐ
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ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲԓͼᴠᴒᴟꜝꞌꜝⱲᴦԓͼⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦͼԜꜜᴑͼ
ᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
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͟ᴟ꞉ꜝᴟͼԜꜜᴑͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
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ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
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ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍ԐⱢͼꜞᴟᴒ᷄ᴒᴥ꞉ᴠᴡ꞉ꜜⱲͼᴠ꞉ⱲꜜᴠͼԜꜜᴑͼᴠᴦꜛꜞᴡꜝꜛᴠ
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ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼꜝꜜͼꜙᴁ͟ͼⱱꜝᴟͼⱶⱨⱬͼꜛᴢᴠᴡͼᴐꜝꜛꜞꞌᴒᴡᴒͼԜͼ᷉ͼᴤᴒᴒꞋͼᴤԜᴠⱳꜝᴢᴡͼꜞᴒᴟ꞉ꜝᴑԓͼԜᴠͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԝᴦͼ
ᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟԓͼԝᴒⱱꜝᴟᴒͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑ᷅
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ꜙᴁ͟ͼᴤԜᴠⱳꜝᴢᴡͼ꞉ᴠͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼԜᴠͼꞌꜝꜜⱲͼԜᴠͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴑꜝ꞉ꜜⱲͼᴠꜝͼᴤꜝᴢꞌᴑͼꜜꜝᴡͼ
ꜞꞌԜᴐᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜᴡͼԜꜜᴦͼᴢꜜᴑᴢᴒͼᴠԜⱱᴒᴡᴦͼᴟ꞉ᴠꞋͼԜꜜᴑͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡͼꞌᴒԜᴠᴡͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒ᷅
7.2
Run-in Period 
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴤᴒᴟᴒͼꜝꜜͼꜙᴁ͟ͼꜛԜᴦͼᴒꜜᴡᴒᴟͼᴟᴢꜜ᷄꞉ꜜͼԜⱱᴡᴒᴟͼᴠᴢᴐᴐᴒᴠᴠⱱᴢꞌꞌᴦͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜜⱲͼԜͼ᷉ͼᴤᴒᴒꞋͼᴤԜᴠⱳꜝᴢᴡͼꜝⱱͼ
ᴡⱳᴒ꞉ᴟͼꜙᴁ᷅͟ͼⱨꞌꞌͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼԜͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜝⱱͼ᷾ͼᴤᴒᴒꞋᴠͼᴡꜝͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒͼᴡⱳᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ᷅ͼᴁⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼԝᴒͼᴠⱳꜝᴟᴡᴒꜜᴒᴑͼᴡꜝͼꞌᴒᴠᴠͼᴡⱳԜꜜͼ᷾ͼᴤᴒᴒꞋᴠͼⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡͼ
ᴤⱳꜝͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒᴠͼ᷊ͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼԜᴡᴡԜᴐꞋᴠͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒͼ᷾ͼᴤᴒᴒꞋᴠͼⱳԜᴣᴒͼᴒꜜᴑᴒᴑ᷅ͼᴁⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼ
ꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼԝᴒͼᴒᴥꜞԜꜜᴑᴒᴑͼԝᴦͼԜꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ᷾ͼᴤᴒᴒꞋᴠͼ꞉ⱱͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴑꜝᴒᴠͼꜜꜝᴡͼꜛᴒᴒᴡͼᴡⱳᴒͼꜛ꞉ꜜ꞉ꜛᴢꜛͼ
ԜᴡᴡԜᴐꞋͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼ᷾ͼᴤᴒᴒꞋᴠ᷅
ᴁⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼԜꜜͼꜝꜜⱲꜝ꞉ꜜⱲͼԝԜᴠ꞉ᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼԝᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼӿꜝᴟͼ
ᴐԜᴟᴒⱲ꞉ᴣᴒᴟᴠԐͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼᴠᴦꜛꜞᴡꜝꜛᴠͼꜝⱱͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴡꜝͼᴡⱳᴒͼᴠ꞉ᴡᴒͼꜝᴟͼᴡⱳᴟꜝᴢⱲⱳͼᴟᴒⱲᴢꞌԜᴟͼᴠ꞉ᴡᴒͼᴐꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼ
ᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼӿꜝᴟͼᴐԜᴟᴒⱲ꞉ᴣᴒᴟԐⱡ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍ⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
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͟ᴟ꞉ꜝᴟͼԜꜜᴑͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
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ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
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ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.3
Start of Treatment Period: Visit 1, Dose 1 (Day 0)
ᴁⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴡꜝͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜝꜜͼⱫԜᴦ᷇ͼꜞᴟ꞉ꜝᴟᴡꜝͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼᴑꜝᴠᴒͼꜝⱱͼ
ⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ
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ⱬꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼᴟᴒᴣ꞉ᴒᴤͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷉Ԑ
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ϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼᴡꜝͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷊᷅᷈Ԑ
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ᴂᴟ꞉ꜜᴒͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡͼӿⱱᴒꜛԜꞌᴒᴠԐͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
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ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅Ԑ
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ⱪꜝꜛꜞꞌᴒᴡᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅⅍Ԑ
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᷈᷉᷄ꜙᴒԜᴑͼⱬⱪⱵͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⅎԐ
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ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠͼ
ӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
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͟ꜘͼԝԜᴠᴒꞌ꞉ꜜᴒͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⱠԐ
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͟ⱫͼԝԜᴠᴒꞌ꞉ꜜᴒͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷇Ԑ
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ⱩԜᴠᴒꞌ꞉ꜜᴒͼԜꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷈Ԑ
ᶄ
͟ᴟ꞉ꜝᴟͼԜꜜᴑͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ᶄ
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡͼⱬϷ᷿ⱫͼԜꜜᴑͼⱨⱬ᷄Ϸꜝꜙͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅᷈Ԑ
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ
ᶄ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.4
Site Contact with the Subject
ᴀ꞉ᴡᴒͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼꜝꜜᴐᴒͼԝᴒᴡᴤᴒᴒꜜͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼᴠᴡᴢᴑᴦͼᴣ꞉ᴠ꞉ᴡᴠͼꜝᴟͼԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼⅎͼᴑԜᴦᴠͼ
Ԝⱱᴡᴒᴟͼᴡⱳᴒ꞉ᴟͼꞌԜᴠᴡͼᴐꜝꜜᴡԜᴐᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴡꜝͼᴠꜝꞌ꞉ᴐ꞉ᴡͼⱱꜝᴟͼԜꜜᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜜꜝᴡͼԜꞌᴟᴒԜᴑᴦͼ
ᴟᴒꜞꜝᴟᴡᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡ᷅
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.5
Continuation of Treatment Period: Visit 2, Dose 2 (Day 14±3 Days)
꜡ꜜͼⱫԜᴦͼ᷈᷾ͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅Ԑ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ
ᶄ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ⅍Ⱡ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
7.6
Continuation of Treatment Period: Visit 3, Dose 3 (Day 28±3 Days)
꜡ꜜͼⱫԜᴦͼ᷉˲ԓ ᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅Ԑ
ᶄ
ⱪꜝꜛꜞꞌᴒᴡᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅⅍Ԑ
ᶄ
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠͼ
ӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
ᶄ
͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡԓͼᴠᴒᴟᴢꜛͼꜝᴟͼᴢᴟ꞉ꜜᴒͼӿⱱᴒꜛԜꞌᴒᴠԐͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ᶄ
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡͼⱨⱬ᷄Ϸꜝꜙͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅᷈Ԑ
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ
ᶄ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.7
Continuation of Treatment Period: Visit 4, Dose 4 (Day 42 ±3 Days)
꜡ꜜͼⱫԜᴦͼ᷾᷉ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅Ԑ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ
ᶄ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.8
Continuation of Treatment Period: Visit 5, Dose 5 (Day 56±3 Days)
꜡ꜜͼⱫԜᴦͼ᷿⅍ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅Ԑ
ᶄ
ⱪꜝꜛꜞꞌᴒᴡᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅⅍Ԑ
ᶄ
᷈᷉᷄ꜙᴒԜᴑͼⱬⱪⱵͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⅎԐ
ᶄ
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠͼ
ӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
ᶄ
͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡԓͼᴠᴒᴟᴢꜛͼꜝᴟͼᴢᴟ꞉ꜜᴒͼӿⱱᴒꜛԜꞌᴒᴠԐͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
ᶄ
͟ꜘͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⱠԐ
ᶄ
͟ⱫͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷇Ԑ
ᶄ
ⱨꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷈Ԑ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ᶄ
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡͼⱨⱬ᷄Ϸꜝꜙͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅᷈Ԑ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ
ᶄ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ᷅ͼᴁⱳ꞉ᴠͼ᷉ͼⱳꜝᴢᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴣ꞉ᴡԜꞌᴠͼꜛԜᴦͼԝᴒͼᴑ꞉ᴠꜛ꞉ᴠᴠᴒᴑͼ꞉ⱱԓͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ
ꜝꜜꞌᴦͼꜜᴒᴒᴑᴠͼᴡꜝͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼⱱꜝᴟͼ᷈ͼⱳꜝᴢᴟͼꜞꜝᴠᴡͼᴑꜝᴠᴒ᷅ͼᴁⱳᴒͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼԝᴒͼ
ꞌᴒꜜⱲᴡⱳᴒꜜᴒᴑͼԝԜᴐꞋͼᴡꜝͼ᷉ͼⱳꜝᴢᴟᴠͼԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԝԜᴠᴒᴑͼꜝꜜͼⱫᴀꜚⱩͼᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜ᷅
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.9
Continuation of Treatment Period: Visits 6 and 7, Doses 6 and 7 
(Days 70 and 84, All ±3 Days)
꜡ꜜͼⱫԜᴦᴠͼⅎ᷇ͼԜꜜᴑͼ˲᷾ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅Ԑ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ
ᶄ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ᷅ͼᴁⱳ꞉ᴠͼ᷉ͼⱳꜝᴢᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴣ꞉ᴡԜꞌᴠͼꜛԜᴦͼԝᴒͼᴑ꞉ᴠꜛ꞉ᴠᴠᴒᴑͼ꞉ⱱԓͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ
ꜝꜜꞌᴦͼꜜᴒᴒᴑᴠͼᴡꜝͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼⱱꜝᴟͼ᷈ͼⱳꜝᴢᴟͼꜞꜝᴠᴡͼᴑꜝᴠᴒ᷅ͼᴁⱳᴒͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼԝᴒͼ
ꞌᴒꜜⱲᴡⱳᴒꜜᴒᴑͼԝԜᴐꞋͼᴡꜝͼ᷉ͼⱳꜝᴢᴟᴠͼԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԝԜᴠᴒᴑͼꜝꜜͼⱫᴀꜚⱩͼᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜ᷅
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.10
Continuation of Treatment Period: Visit 8, Dose 8 (Day 98±3 Days)
꜡ꜜͼⱫԜᴦͼⱠ˲ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅Ԑ
ᶄ
ⱪꜝꜛꜞꞌᴒᴡᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅⅍Ԑ
ᶄ
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠͼ
ӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
ᶄ
͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡԓͼᴠᴒᴟᴢꜛͼꜝᴟͼᴢᴟ꞉ꜜᴒͼӿⱱᴒꜛԜꞌᴒᴠԐͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
ᶄ
͟ꜘͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⱠԐ
ᶄ
͟ⱫͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷇Ԑ
ᶄ
ⱨꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷈Ԑ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ᶄ
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡͼⱬϷ᷿ⱫͼԜꜜᴑͼⱨⱬ᷄Ϸꜝꜙͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅᷈Ԑ
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ
ᶄ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ᷅ͼᴁⱳ꞉ᴠͼ᷉ͼⱳꜝᴢᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴣ꞉ᴡԜꞌᴠͼꜛԜᴦͼԝᴒͼᴑ꞉ᴠꜛ꞉ᴠᴠᴒᴑͼ꞉ⱱԓͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ
ꜝꜜꞌᴦͼꜜᴒᴒᴑᴠͼᴡꜝͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼⱱꜝᴟͼ᷈ͼⱳꜝᴢᴟͼꜞꜝᴠᴡͼᴑꜝᴠᴒ᷅ͼᴁⱳᴒͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼԝᴒͼ
ꞌᴒꜜⱲᴡⱳᴒꜜᴒᴑͼԝԜᴐꞋͼᴡꜝͼ᷉ͼⱳꜝᴢᴟᴠͼԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԝԜᴠᴒᴑͼꜝꜜͼⱫᴀꜚⱩͼᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜ᷅
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ᷊
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
7.11
Continuation of Treatment Period: Visits 9 and 10, Doses 9 and 10 
(Days 112 and 126, All ±3 Days)
꜡ꜜͼⱫԜᴦᴠͼ᷈᷈᷉ͼԜꜜᴑͼ᷈᷉⅍ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅Ԑ
ᶄ
͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡԓͼᴠᴒᴟᴢꜛͼꜝᴟͼᴢᴟ꞉ꜜᴒͼӿⱱᴒꜛԜꞌᴒᴠԐͼꜝꜜͼⱫԜᴦ᷈᷉⅍ᶐ᷊ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ᶄ
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡͼⱨⱬ᷄ϷꜝꜙͼꜝꜜͼⱫԜᴦͼ᷈᷉⅍ᶐ᷊ͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅᷈Ԑ
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ
ᶄ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ
ᶄ
ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ᷅ͼᴁⱳ꞉ᴠͼ᷉ͼⱳꜝᴢᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴣ꞉ᴡԜꞌᴠͼꜛԜᴦͼԝᴒͼᴑ꞉ᴠꜛ꞉ᴠᴠᴒᴑͼ꞉ⱱԓͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ
ꜝꜜꞌᴦͼꜜᴒᴒᴑᴠͼᴡꜝͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼⱱꜝᴟͼ᷈ͼⱳꜝᴢᴟͼꜞꜝᴠᴡͼᴑꜝᴠᴒ᷅ͼᴁⱳᴒͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼԝᴒͼ
ꞌᴒꜜⱲᴡⱳᴒꜜᴒᴑͼԝԜᴐꞋͼᴡꜝͼ᷉ͼⱳꜝᴢᴟᴠͼԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԝԜᴠᴒᴑͼꜝꜜⱫᴀꜚⱩͼᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜ᷅
ᶄ
ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ
ᶄ
ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.12
Continuation of Treatment Period: Visit 11, Dose 11 (Day 140±3 Days)
꜡ꜜͼⱫԜᴦͼ᷈᷾᷇ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ

ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅Ԑ

ⱪꜝꜛꜞꞌᴒᴡᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅⅍Ԑ

ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠͼ
ӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ

͟ꜘͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⱠԐ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅

͟ⱫͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷇Ԑ

ⱨꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷈Ԑ

ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ

ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ

ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ

ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ ӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ

ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ᷅ͼᴁⱳ꞉ᴠͼ᷉ͼⱳꜝᴢᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴣ꞉ᴡԜꞌᴠͼꜛԜᴦͼԝᴒͼᴑ꞉ᴠꜛ꞉ᴠᴠᴒᴑͼ꞉ⱱԓͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ
ꜝꜜꞌᴦͼꜜᴒᴒᴑᴠͼᴡꜝͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼⱱꜝᴟͼ᷈ͼⱳꜝᴢᴟͼꜞꜝᴠᴡͼᴑꜝᴠᴒ᷅ͼᴁⱳᴒͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼԝᴒͼ
ꞌᴒꜜⱲᴡⱳᴒꜜᴒᴑͼԝԜᴐꞋͼᴡꜝͼ᷉ͼⱳꜝᴢᴟᴠͼԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԝԜᴠᴒᴑͼꜝꜜͼⱫᴀꜚⱩͼᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜ᷅

ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ

ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.13
Continuation of Treatment Period (Day 144±1 Day)
ᴁⱳ꞉ᴠͼⱬⱪⱵͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜛԜᴦͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼᴡⱳᴟꜝᴢⱲⱳͼԜꜜͼԜᴡ᷄ⱳꜝꜛᴒͼᴣ꞉ᴠ꞉ᴡͼԝᴦͼԜͼꜜᴢᴟᴠᴒͼꜝᴟͼᴡᴒᴐⱳꜜ꞉ᴐ꞉ԜꜜͼꜝᴟԜᴡͼ
ᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒ᷅ͼᴁⱳᴒͼᴑԜᴡᴒԓͼᴡ꞉ꜛᴒͼԜꜜᴑͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼꞌꜝᴐԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳ꞉ᴠͼⱬⱪⱵͼԜꜜᴑͼ꞉ᴡᴠͼᴟᴒᴠᴢꞌᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼԜꜜᴑͼᴒⱪϸⱴ᷅ͼ

᷈᷉᷄ꜙᴒԜᴑͼⱬⱪⱵͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⅎԐ
7.14
Continuation of Treatment Period: Visits 12 and 13, Doses 12 and 13 
(Days 154 and 168, All ±3 Days)
꜡ꜜͼⱫԜᴦᴠͼ᷿᷈᷾ͼԜꜜᴑͼ᷈⅍˲ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼ
Ԝᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜⱡ

ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅Ԑ

͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡԓͼᴠᴒᴟᴢꜛͼꜝᴟͼᴢᴟ꞉ꜜᴒͼӿⱱᴒꜛԜꞌᴒᴠԐͼꜝꜜͼⱫԜᴦ᷿᷈᷾ᶐ᷊ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ

ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ

ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ

ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ

ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡͼⱨⱬ᷄ϷꜝꜙͼꜝꜜͼⱫԜᴦͼ᷿᷈᷾ᶐ᷊ͼӿᴀᴒᴐᴡ꞉ꜝꜜ⅍᷿᷅᷈Ԑ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ᷿
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱨⱱᴡᴒᴟͼᴡⱳᴒͼꜞᴟᴒᴐᴒᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜᴟᴒͼᴐꜝꜛꜞꞌᴒᴡᴒᴑⱡ

ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟͼⱷꜚ͟ͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷾Ԑ
ⱨⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱷꜚ͟ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞꜝᴠᴡͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ

ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅ԐͼԜᴡͼ᷈ͼԜꜜᴑͼ᷉ⱳꜝᴢᴟᴠͼꜞꜝᴠᴡ᷄
ᴑꜝᴠᴒ᷅ͼᴁⱳ꞉ᴠͼ᷉ͼⱳꜝᴢᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴣ꞉ᴡԜꞌᴠͼꜛԜᴦͼԝᴒͼᴑ꞉ᴠꜛ꞉ᴠᴠᴒᴑͼ꞉ⱱԓ ԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼᴡⱳᴒͼԜԝᴠᴒꜜᴐᴒͼꜝⱱͼᴠԜⱱᴒᴡᴦͼᴠ꞉ⱲꜜԜꞌᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴠͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼ
ꜝꜜꞌᴦͼꜜᴒᴒᴑᴠͼᴡꜝͼԝᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼⱱꜝᴟͼ᷈ͼⱳꜝᴢᴟͼꜞꜝᴠᴡͼᴑꜝᴠᴒ᷅ͼᴁⱳᴒͼꜞꜝᴠᴡ᷄ᴑꜝᴠᴒͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜞᴒᴟ꞉ꜝᴑͼꜛԜᴦͼԝᴒͼ
ꞌᴒꜜⱲᴡⱳᴒꜜᴒᴑͼԝԜᴐꞋͼᴡꜝͼ᷉ͼⱳꜝᴢᴟᴠͼԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԝԜᴠᴒᴑͼꜝꜜͼⱫᴀꜚⱩͼᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜ᷅

ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ

ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.15
Completion of Treatment Period: Visit 14, Day 182±3 Days
꜡ꜜͼⱫԜᴦͼ᷈˲᷉ԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑⱡ

ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅Ԑ

ⱪꜝꜛꜞꞌᴒᴡᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅⅍Ԑ

᷈᷉᷄ꜙᴒԜᴑͼⱬⱪⱵͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⅎԐ

ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠͼ
ӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ

ᴂᴟ꞉ꜜᴒͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡͼӿⱱᴒꜛԜꞌᴒᴠԐͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ

͟ꜘͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⱠԐ

͟ⱫͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷇Ԑ

ⱨꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷈Ԑ

ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ

ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ

ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ

ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡͼⱬϷ᷿ⱫͼԜꜜᴑͼⱨⱬ᷄Ϸꜝꜙͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅᷈Ԑ

Ⱬ꞉ᴠᴐⱳԜᴟⱲᴒͼⱱᴟꜝꜛͼᴠᴡᴢᴑᴦⱡͼͼ

ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜝⱱⱱᴒᴟᴒᴑͼᴡⱳᴒͼꜝꜞᴡ꞉ꜝꜜͼꜝⱱͼᴒꜜᴟꜝꞌꞌ꞉ꜜⱲͼ꞉ꜜͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾ͼ꜡ꜞᴒꜜͼꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼ
ӿ꜡ꜙⱬԐͼᴠᴡᴢᴑᴦͼⱱꜝᴟͼᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞ᷅ͼ

ⱷꜜⱱꜝᴟꜛᴒᴑͼⱪꜝꜜᴠᴒꜜᴡͼꜝԝᴡԜ꞉ꜜᴒᴑͼⱱꜝᴟͼᴠᴡᴢᴑᴦͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅

ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴐꜝꜜᴠᴒꜜᴡͼᴡꜝͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒͼ꞉ꜜͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷾ͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼᴡⱳᴒ꞉ᴟͼⱱ꞉ᴟᴠᴡͼ꜡ꜙⱬͼᴑꜝᴠᴒͼ
ⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡⱳᴒͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜͼꜝⱱͼԜꞌꞌͼᴑꜝᴢԝꞌᴒ᷄ԝꞌ꞉ꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼꜝꜜͼⱫԜᴦͼ᷈˲᷉᷅ͼ
7.16
Follow-up Period (Subjects Not Continuing in Open-Label Extension 
Study): Visit 15, Day 210 ±3 Days

ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅Ԑ

͟ꜘͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⱠԐ

͟ⱫͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷇Ԑ

ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ

ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ

ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ
7.17
Final Follow-up Visit (Subjects Not Continuing in Open-Label 
Extension Study): Visit 16, Day 238±3 Days

ᴃ꞉ᴡԜꞌͼᴠ꞉Ⱳꜜᴠͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼԝꜝᴑᴦͼᴡᴒꜛꜞᴒᴟԜᴡᴢᴟᴒԓͼⱶϸԓͼⱩ͟ͼԜꜜᴑͼϸϸͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅Ԑ

ⱪꜝꜛꜞꞌᴒᴡᴒͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅⅍Ԑ

᷈᷉᷄ꜙᴒԜᴑͼⱬⱪⱵͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⅎԐ

ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼⱳᴒꜛԜᴡꜝꞌꜝⱲᴦԓͼᴐꜝԜⱲᴢꞌԜᴡ꞉ꜝꜜԓͼᴠᴒᴟᴢꜛͼᴐⱳᴒꜛ꞉ᴠᴡᴟᴦͼԜꜜᴑͼᴢᴟ꞉ꜜԜꞌᴦᴠ꞉ᴠͼ
ӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ

͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡԓͼᴠᴒᴟᴢꜛͼꜝᴟͼᴢᴟ꞉ꜜᴒͼӿⱱᴒꜛԜꞌᴒᴠԐͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲Ԑ

͟ꜘͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅ⱠԐ

͟ⱫͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷇Ԑ

ⱨꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷈Ԑ

ⱪꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼᴡⱳᴒᴟԜꜞᴦͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈᷉Ԑ

ⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾Ԑ

ⱨⱬͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍Ԑ

ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱡͼⱬϷ᷿ⱫͼԜꜜᴑͼⱨⱬ᷄Ϸꜝꜙͼӿᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅᷈Ԑ
7.18
Early Termination (ET)
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴡⱳԜᴡͼᴡᴒᴟꜛ꞉ꜜԜᴡᴒͼᴒԜᴟꞌᴦͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼᴢꜜᴑᴒᴟⱲꜝͼӿ꞉ⱱͼꜞꜝᴠᴠ꞉ԝꞌᴒԐͼԜꞌꞌͼꜝⱱͼᴡⱳᴒͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼԜꜜᴑͼ
ꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼⱱꜝᴟͼⱫԜᴦͼ᷈˲᷉᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
8
QUALITY CONTROL AND ASSURANCE
ᴁⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԜꜜᴑͼᴡⱳᴒͼⱪꜝꜜᴡᴟԜᴐᴡͼϸᴒᴠᴒԜᴟᴐⱳͼ꜡ᴟⱲԜꜜ꞉ᴧԜᴡ꞉ꜝꜜͼӿⱪϸ꜡Ԑͼᴐꜝꜜᴑᴢᴐᴡ꞉ꜜⱲͼᴡᴟ꞉ԜꞌͼꜛԜꜜԜⱲᴒꜛᴒꜜᴡͼ
ᴠᴒᴟᴣ꞉ᴐᴒᴠԓͼϸⱳꜝԓͼⱷꜜᴐ᷅ͼᴤ꞉ꞌꞌͼ꞉ꜛꜞꞌᴒꜛᴒꜜᴡͼԜͼᴠᴦᴠᴡᴒꜛͼꜝⱱͼꜟᴢԜꞌ꞉ᴡᴦͼԜᴠᴠᴢᴟԜꜜᴐᴒͼᴡⱳԜᴡͼ꞉ꜜᴐꞌᴢᴑᴒᴠͼԜꞌꞌͼᴒꞌᴒꜛᴒꜜᴡᴠͼ
ᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅ͼᴄ꞉ᴡⱳ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴦᴠᴡᴒꜛԓͼᴀ꜡͟ᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԜꜜᴑͼⱪϸ꜡ͼᴤ꞉ꞌꞌͼԝᴒͼ
꞉ꜛꜞꞌᴒꜛᴒꜜᴡᴒᴑͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼᴡⱳԜᴡͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴡᴟ꞉Ԝꞌͼ꞉ᴠͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼ꞉ꜜͼᴐꜝꜛꜞꞌ꞉Ԝꜜᴐᴒͼᴤ꞉ᴡⱳͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼ
ᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼԜꜜᴑͼⱵꜝꜝᴑͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼ͟ᴟԜᴐᴡ꞉ᴐᴒᴠͼӿⱵⱪ͟Ԑ᷅ͼϷᴢԜꞌ꞉ᴡᴦͼᴐꜝꜜᴡᴟꜝꞌͼᴤ꞉ꞌꞌͼԝᴒͼԜꜞꜞꞌ꞉ᴒᴑͼᴡꜝͼᴒԜᴐⱳͼᴠᴡԜⱲᴒͼꜝⱱͼ
ᴑԜᴡԜͼⱳԜꜜᴑꞌ꞉ꜜⱲͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼᴡⱳԜᴡͼᴑԜᴡԜͼԜᴟᴒͼԜᴐᴐᴢᴟԜᴡᴒԓͼᴟᴒꞌ꞉ԜԝꞌᴒͼԜꜜᴑͼꜞᴟꜝᴐᴒᴠᴠᴒᴑͼᴐꜝᴟᴟᴒᴐᴡꞌᴦ᷅ͼ
ᴁⱳᴒͼᴠ꞉ᴡᴒͼᴠᴡԜⱱⱱͼᴠⱳꜝᴢꞌᴑͼԜᴠᴠ꞉ᴠᴡͼ꞉ꜜͼԜꞌꞌͼԜᴠꜞᴒᴐᴡᴠͼꜝⱱͼԜᴢᴑ꞉ᴡ᷆꞉ꜜᴠꜞᴒᴐᴡ꞉ꜝꜜ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎ˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
9
DATA ANALYSIS / STATISTICAL METHODS
9.1
General Considerations
ⱨꞌꞌͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼԜꜜԜꞌᴦᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼᴢᴠ꞉ꜜⱲͼᴀⱨᴀᶇᴃᴒᴟᴠ꞉ꜝꜜͼⱠ᷊᷅ͼꜝᴟͼⱳ꞉Ⱳⱳᴒᴟͼӿᴀⱨᴀͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒԓͼ
ԓͼ
ԓͼᴂᴀⱨԐ᷅
ᴂꜜꞌᴒᴠᴠͼꜝᴡⱳᴒᴟᴤ꞉ᴠᴒͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑԓͼᴠᴢꜛꜛԜᴟᴦͼᴡԜԝᴢꞌԜᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟᴒᴠᴒꜜᴡᴒᴑͼԝᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞ᷅ͼⱴꜝᴟͼ
ᴐԜᴡᴒⱲꜝᴟ꞉ᴐԜꞌͼᴣԜᴟ꞉ԜԝꞌᴒᴠԓͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼԜꜜᴑͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳ꞉ꜜͼᴒԜᴐⱳͼᴐԜᴡᴒⱲꜝᴟᴦͼӿᴤ꞉ᴡⱳͼԜͼ
ᴐԜᴡᴒⱲꜝᴟᴦͼⱱꜝᴟͼꜛ꞉ᴠᴠ꞉ꜜⱲͼᴑԜᴡԜͼԜᴠͼꜜᴒᴒᴑᴒᴑԐͼꜝⱱͼᴡⱳᴒͼꜞԜᴟԜꜛᴒᴡᴒᴟͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟᴒᴠᴒꜜᴡᴒᴑ᷅ͼⱴꜝᴟͼᴐꜝꜜᴡ꞉ꜜᴢꜝᴢᴠͼ
ᴣԜᴟ꞉Ԝԝꞌᴒᴠԓͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠԓͼꜛᴒԜꜜԓͼꜛᴒᴑ꞉ԜꜜԓͼᴠᴡԜꜜᴑԜᴟᴑͼᴑᴒᴣ꞉Ԝᴡ꞉ꜝꜜͼӿᴀⱫԐԓͼꜛ꞉ꜜ꞉ꜛᴢꜛԓͼԜꜜᴑͼ
ꜛԜᴥ꞉ꜛᴢꜛͼᴣԜꞌᴢᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟᴒᴠᴒꜜᴡᴒᴑ᷅ͼᴄⱳᴒᴟᴒͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒԓͼᴒᴠᴡ꞉ꜛԜᴡᴒᴠͼⱱᴟꜝꜛͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌͼꜝⱱͼꞌᴒԜᴠᴡͼ
ᴠꜟᴢԜᴟᴒᴠͼꜛᴒԜꜜᴠԓͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴑ꞉ⱱⱱᴒᴟᴒꜜᴐᴒᴠԓͼꜞ᷄ᴣԜꞌᴢᴒᴠԓͼԜꜜᴑͼⱠ᷿Ӽͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼ꞉ꜜᴡᴒᴟᴣԜꞌᴠͼⱱꜝᴟͼꞌᴒԜᴠᴡͼᴠꜟᴢԜᴟᴒᴠͼ
ꜛᴒԜꜜͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴑ꞉ⱱⱱᴒᴟᴒꜜᴐᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑ᷅ͼᴁ꞉ꜛᴒ᷄ᴡꜝ᷄ᴒᴣᴒꜜᴡͼᴑԜᴡԜͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼᴢᴠ꞉ꜜⱲͼ
ꜘԜꜞꞌԜꜜ᷄ꜚᴒ꞉ᴒᴟͼᴒᴠᴡ꞉ꜛԜᴡᴒᴠͼꜝⱱͼᴡⱳᴒͼ᷿᷉ᴡⱳԓͼ᷿᷇ᴡⱳͼӿꜛᴒᴑ꞉ԜꜜԐԓͼԜꜜᴑͼⅎ᷿ᴡⱳͼꜞᴒᴟᴐᴒꜜᴡ꞉ꞌᴒᴠͼᴤ꞉ᴡⱳͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴡᴤꜝ᷄
ᴠ꞉ᴑᴒᴑͼⱠ᷿Ӽͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼ꞉ꜜᴡᴒᴟᴣԜꞌᴠԓͼԜᴠͼᴤᴒꞌꞌͼԜᴠͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼᴐᴒꜜᴠꜝᴟᴒᴑͼꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜᴠ᷅ͼ͟ꞌꜝᴡᴠͼꜝⱱͼᴡⱳᴒͼ
ꜘԜꜞꞌԜꜜ᷄ꜚᴒ꞉ᴒᴟͼᴐᴢᴟᴣᴒᴠͼԜꜜᴑͼᴠᴢꜞꜞꜝᴟᴡ꞉ꜜⱲͼᴑԜᴡԜͼꞌ꞉ᴠᴡ꞉ꜜⱲᴠͼᴑᴒᴡԜ꞉ꞌ꞉ꜜⱲͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼᴐꜝꜜᴡᴟ꞉ԝᴢᴡ꞉ꜝꜜͼᴡꜝͼᴡⱳᴒͼ
ԜꜜԜꞌᴦᴠ꞉ᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑ᷅ͼ
ⱴꜝᴟꜛԜꞌͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡ꞉ꜜⱲͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜝꜜͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟᴒᴑͼ
ᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ᴡⱳͼᴡⱳᴒͼⱲꞌꜝԝԜꞌͼⱱԜꜛ꞉ꞌᴦ᷄ᴤ꞉ᴠᴒͼᴡᴦꜞᴒͼⱷͼᴒᴟᴟꜝᴟͼᴟԜᴡᴒͼӿⱴᴄⱬϸԐͼᴠᴡᴟꜝꜜⱲꞌᴦͼ
ᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼԜᴡͼᴡᴤꜝ᷄ᴠ꞉ᴑᴒᴑͼ᷿᷇᷅᷇ͼᴢᴠ꞉ꜜⱲͼԜͼⱩꜝꜜⱱᴒᴟᴟꜝꜜ꞉᷄ԝԜᴠᴒᴑͼⱲᴒꜜᴒᴟԜꞌͼⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼԜᴠͼ
ᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷿᷅᷈᷉᷅᷅ͼ
9.2
Sample Size Determination
͟ꜝᴤᴒᴟͼԜꜜԜꞌᴦᴠ꞉ᴠͼԜꜜᴑͼᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒͼᴒᴠᴡ꞉ꜛԜᴡ꞉ꜝꜜͼᴤԜᴠͼԝԜᴠᴒᴑͼꜝꜜͼ᷈᷇᷇᷇ͼᴐꜝꜛꜞᴢᴡᴒᴟͼᴠ꞉ꜛᴢꞌԜᴡ꞉ꜝꜜᴠͼᴢᴠ꞉ꜜⱲͼԜͼ
ⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼⱱꜝᴟͼᴐꜝᴢꜜᴡͼᴑԜᴡԜͼԜᴠᴠᴢꜛ꞉ꜜⱲͼԜͼ͟ꜝ꞉ᴠᴠꜝꜜͼᴑ꞉ᴠᴡᴟ꞉ԝᴢᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼ͟ᴒԜᴟᴠꜝꜜͼᴐⱳ꞉᷄ᴠꜟᴢԜᴟᴒͼ
ᴠᴐԜꞌ꞉ꜜⱲͼꜝⱱͼᴠᴡԜꜜᴑԜᴟᴑͼᴒᴟᴟꜝᴟᴠͼᴡꜝͼԜᴐᴐꜝᴢꜜᴡͼⱱꜝᴟͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼꜝᴣᴒᴟᴑ꞉ᴠꜞᴒᴟᴠ꞉ꜝꜜ᷅ͼᴁⱳᴒͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴑꜝᴠᴒͼ꞉ꜜͼ
ᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼᴟԜᴡ꞉ꜝͼᴤԜᴠͼᴠᴒᴡͼԜᴡͼ᷈ⱡ᷿᷈᷅᷅ͼⱨͼ᷈᷇Ӽͼꜛ꞉ᴠᴠ꞉ꜜⱲͼᴑԜᴡԜ᷆ᴑᴟꜝꜞꜝᴢᴡͼᴟԜᴡᴒͼⱱꜝᴟͼ
ԝꜝᴡⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜꜜᴑͼꜞꞌԜᴐᴒԝꜝͼᴤԜᴠͼԜꞌᴠꜝͼԝᴢ꞉ꞌᴡͼ꞉ꜜᴡꜝͼᴡⱳᴒͼᴒꜛꜞ꞉ᴟ꞉ᴐԜꞌͼᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒͼᴠ꞉ꜛᴢꞌԜᴡ꞉ꜝꜜᴠ᷅
ⱴꜝᴟͼԜͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴒⱱⱱᴒᴐᴡͼꜝⱱͼ⅍᷇Ӽͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ꜜͼԜᴡᴡԜᴐꞋᴠͼԜᴠͼᴐꜝꜛꜞԜᴟᴒᴑͼᴡꜝͼꜞꞌԜᴐᴒԝꜝԓͼԜᴠᴠᴢꜛ꞉ꜜⱲͼԜͼꜞꞌԜᴐᴒԝꜝͼ
ԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝⱱͼ᷊᷇᷅ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼᴤᴒᴒꞋͼꜝᴣᴒᴟͼԜͼ᷉⅍ͼᴤᴒᴒꞋͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜͼԜᴣᴒᴟԜⱲᴒͼᴡꜝᴡԜꞌͼꜝⱱͼⅎ᷅˲ͼԜᴡᴡԜᴐꞋᴠͼ
ᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑԓͼԜͼᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒͼꜝⱱͼ᷉᷾ͼԜᴐᴡ꞉ᴣᴒꞌᴦͼᴡᴟᴒԜᴡᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜᴐᴡ꞉ᴣᴒͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛͼԜꜜᴑͼ᷊⅍ͼꜞꞌԜᴐᴒԝꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤꜝᴢꞌᴑͼꜞᴟꜝᴣ꞉ᴑᴒͼԜᴡͼꞌᴒԜᴠᴡͼⱠ᷿ӼͼꜞꜝᴤᴒᴟͼӿԜᴡͼԜꞌꜞⱳԜⱤ᷿᷇᷅᷇᷉ԓͼ
ꜝꜜᴒ᷄ᴠ꞉ᴑᴒᴑԐ᷅ͼⱨͼ⅍᷇Ӽͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ᴠͼᴤᴒꞌꞌͼԝᴒꞌꜝᴤͼᴡⱳᴒͼᴠꜛԜꞌꞌᴒᴠᴡͼᴒᴥꜞᴒᴐᴡᴒᴑͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜͼ꞉ꜜͼԜᴡᴡԜᴐꞋᴠԓͼⱱꜝᴟͼ꞉ꜜͼᴡⱳᴒͼ
Ⱬᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉ͼᴠᴡᴢᴑᴦԓͼᴤᴒͼꜝԝᴠᴒᴟᴣᴒᴑͼᴟᴒᴑᴢᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼԜᴡᴡԜᴐꞋᴠͼꜝⱱͼꜜᴒԜᴟͼ᷈᷇᷇Ӽ᷅ͼᴁⱳᴒᴠᴒͼᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒᴠͼᴤ꞉ꞌꞌͼ
Ԝꞌᴠꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼԜᴑᴒꜟᴢԜᴡᴒꞌᴦͼᴠ꞉ᴧᴒᴑͼᴠԜⱱᴒᴡᴦͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜͼⱱꜝᴟͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜ᷅ͼᴂꜞͼᴡꜝͼ᷈᷉᷇ᴠᴢԝ꞊ᴒᴐᴡᴠͼ
ӿԜꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼ˲᷇ͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴡⱳᴒͼ᷊ͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼԜꜜᴑͼ᷾᷇꞉ꜜͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞԐͼꜛԜᴦͼԝᴒͼ
ᴒꜜᴟꜝꞌꞌᴒᴑͼᴡꜝͼԜᴐᴐꜝᴢꜜᴡͼⱱꜝᴟͼꜞꜝᴡᴒꜜᴡ꞉ԜꞌͼᴒԜᴟꞌᴦͼᴑᴟꜝꜞꜝᴢᴡᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
9.3
Method of Assigning Study Subjects to Treatment Groups
ᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼԜⱱᴡᴒᴟͼᴐꜝꜜⱱ꞉ᴟꜛԜᴡ꞉ꜝꜜͼꜝⱱͼᴠᴡᴢᴑᴦͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼ꞉ꜜͼԜͼᴟԜᴡ꞉ꜝͼꜝⱱͼ᷉ⱡ᷈ͼᴣ꞉ԜͼԜͼ
ᴐꜝꜛꜞᴢᴡᴒᴟ᷄ⱲᴒꜜᴒᴟԜᴡᴒᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼᴠᴐⱳᴒᴑᴢꞌᴒͼᴡꜝͼᴟᴒᴐᴒ꞉ᴣᴒͼᴟᴒꜞᴒԜᴡᴒᴑͼᴀⱪͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ
PPD
PPD


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⅎⱠ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜝᴟͼꜞꞌԜᴐᴒԝꜝ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡꜝͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤ꞉ꞌꞌͼԝᴒͼԜᴠᴠ꞉Ⱳꜜᴒᴑͼ꞉ꜜͼԜͼ᷈ⱡ᷈ⱡ᷈ᴟԜᴡ꞉ꜝͼᴡꜝͼ᷈ͼꜝⱱͼ᷊ͼ
ᴑꜝᴠ꞉ꜜⱲͼᴟᴒⱲ꞉ꜛᴒꜜᴠⱡͼ᷊᷇᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷉ͼᴤᴒᴒꞋᴠԓͼ᷊᷇᷇ͼꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠԓͼꜝᴟͼ᷿᷈᷇ꜛⱲͼᴒᴣᴒᴟᴦͼ᷾ͼᴤᴒᴒꞋᴠ᷅ͼ
ϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼᴐᴒꜜᴡᴟԜꞌꞌᴦͼԜꜜᴑͼᴠᴡᴟԜᴡ꞉ⱱ꞉ᴒᴑͼԝᴦͼᴡⱳᴒͼԝԜᴠᴒꞌ꞉ꜜᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝԝᴠᴒᴟᴣᴒᴑͼ
ᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼ꞉ꜜᴡꜝͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼⱲᴟꜝᴢꜞᴠⱡͼ᷈ͼᴡꜝͼⱣͼ᷉ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼ᷉ͼᴡꜝͼⱣͼ᷊ͼԜᴡᴡԜᴐꞋᴠͼ
ꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠԓͼԜꜜᴑͼᶒͼ᷊ͼԜᴡᴡԜᴐꞋᴠͼꜞᴒᴟͼ᷾ͼᴤᴒᴒꞋᴠ᷅ͼ͟ᴒᴟꜛᴢᴡᴒᴑͼԝꞌꜝᴐꞋᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼᴡⱳԜᴡͼ
Ԝꜞꜞᴟꜝᴥ꞉ꜛԜᴡᴒꞌᴦͼᴒꜟᴢԜꞌͼꜜᴢꜛԝᴒᴟᴠͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜᴟᴒͼԜᴠᴠ꞉ⱲꜜᴒᴑͼᴒԜᴐⱳͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴤ꞉ᴡⱳ꞉ꜜͼᴠᴡᴟԜᴡԜ᷅
9.4
Analysis Populations
ᴁⱳᴒͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼⱱꜝꞌꞌꜝᴤᴠⱡͼ
Intent-to-treat (ITT) Population: ᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼԜꞌꞌͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴠᴢԝ꞊ᴒᴐᴡᴠᴤⱳꜝͼԜᴟᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼԜᴡͼ
ꞌᴒԜᴠᴡͼ᷈ͼᴑꜝᴠᴒͼꜝⱱͼԜᴐᴡ꞉ᴣᴒͼⱷꜚ͟ͼꜝᴟͼꜞꞌԜᴐᴒԝꜝ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜꜜԜꞌᴦᴧᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒ꞉ᴟͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴠᴠ꞉ⱲꜜꜛᴒꜜᴡͼᴟᴒⱲԜᴟᴑꞌᴒᴠᴠͼꜝⱱͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴐᴡᴢԜꞌꞌᴦͼᴟᴒᴐᴒ꞉ᴣᴒᴑ᷅ͼᴁⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ԜꜜԜꞌᴦᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜᴟᴟ꞉ᴒᴑͼꜝᴢᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼⱷᴁᴁͼ͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ᷅
Safety Population: ᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼԜꞌꞌͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴒᴟᴒᴑͼԜᴡͼꞌᴒԜᴠᴡͼ᷈ͼᴑꜝᴠᴒͼꜝⱱͼԜᴐᴡ꞉ᴣᴒͼⱷꜚ͟ͼ
ꜝᴟͼꜞꞌԜᴐᴒԝꜝ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜꜜԜꞌᴦᴧᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴡⱳᴒᴦͼԜᴐᴡᴢԜꞌꞌᴦͼᴟᴒᴐᴒ꞉ᴣᴒᴑ᷅ͼⱨꞌꞌ
ᴠԜⱱᴒᴡᴦԜꜜԜꞌᴦᴠᴒᴠᴤ꞉ꞌꞌᴢᴠᴒᴡⱳᴒᴀԜⱱᴒᴡᴦ͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ᷅
9.5
Analysis of Disposition
ᴁⱳᴒͼꜜᴢꜛԝᴒᴟᴠͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑԓͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜜⱲԓͼꜝᴟͼᴤ꞉ᴡⱳᴑᴟԜᴤ꞉ꜜⱲԓͼԜꞌꜝꜜⱲͼᴤ꞉ᴡⱳͼᴟᴒԜᴠꜝꜜᴠͼⱱꜝᴟͼ
ᴤ꞉ᴡⱳᴑᴟԜᴤԜꞌԓͼᴤ꞉ꞌꞌͼԝᴒͼᴡԜԝᴢꞌԜᴡᴒᴑͼԝᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼԜꜜᴑͼꜝᴣᴒᴟԜꞌꞌͼⱱꜝᴟͼᴡⱳᴒͼⱷᴁᴁͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜᴠ᷅
9.6
Demographics and Baseline Characteristics Analyses
ⱩԜᴠᴒꞌ꞉ꜜᴒͼԜꜜᴑͼᴑᴒꜛꜝⱲᴟԜꜞⱳ꞉ᴐͼᴣԜᴟ꞉Ԝԝꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ᴣᴒꞌᴦͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼԝᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼԜꜜᴑͼ
ꜝᴣᴒᴟԜꞌꞌͼⱱꜝᴟͼᴡⱳᴒͼⱷᴁᴁͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜᴠ᷅
9.7
Treatment Compliance and Extent of Exposure
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼᴐꜝꜛꜞꞌ꞉ԜꜜᴐᴒͼԜꜜᴑͼᴒᴥᴡᴒꜜᴡͼꜝⱱͼᴒᴥꜞꜝᴠᴢᴟᴒͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼԝᴦͼᴐԜꞌᴐᴢꞌԜᴡ꞉ꜜⱲͼᴡⱳᴒͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼ
ꜞꞌԜꜜꜜᴒᴑͼᴑꜝᴠᴒᴠͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜꜜᴑͼᴡⱳᴒͼᴡꜝᴡԜꞌͼꜜᴢꜛԝᴒᴟͼꜝⱱͼᴑꜝᴠᴒᴠͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜꜜᴑͼ
ᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼԝᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼⱱꜝᴟͼᴡⱳᴒͼⱷᴁᴁͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜᴠ᷅
9.8
Analysis of Primary and Secondary Efficacy Endpoints
9.8.1 Primary Efficacy Endpoint
ᴁⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡԓͼꜜᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑԓͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜛꜞԜᴟᴒᴑͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
ⱲᴟꜝᴢꜞͼӿⱫᴅ᷄᷉Ⱡ᷊᷇ԐͼᴡꜝͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼᴢᴠ꞉ꜜⱲͼԜͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼⱱꜝᴟͼᴐꜝᴢꜜᴡͼᴑԜᴡԜͼԜᴠᴠᴢꜛ꞉ꜜⱲͼ
Ԝͼ͟ꜝ꞉ᴠᴠꜝꜜͼᴑ꞉ᴠᴡᴟ꞉ԝᴢᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼԜͼꞌꜝⱲͼꞌ꞉ꜜꞋͼⱱᴢꜜᴐᴡ꞉ꜝꜜͼԜꜜᴑͼ͟ᴒԜᴟᴠꜝꜜͼᴐⱳ꞉᷄ᴠꜟᴢԜᴟᴒͼᴠᴐԜꞌ꞉ꜜⱲͼꜝⱱͼᴠᴡԜꜜᴑԜᴟᴑͼᴒᴟᴟꜝᴟᴠͼ
ᴡꜝͼԜᴐᴐꜝᴢꜜᴡͼⱱꜝᴟͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼꜝᴣᴒᴟᴑ꞉ᴠꜞᴒᴟᴠ꞉ꜝꜜ᷅ͼᴁⱳᴒͼꜛꜝᴑᴒꞌͼᴤ꞉ꞌꞌͼ꞉ꜜᴐꞌᴢᴑᴒͼⱱ꞉ᴥᴒᴑͼᴒⱱⱱᴒᴐᴡᴠͼⱱꜝᴟͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼ
ӿᴐԜᴡᴒⱲꜝᴟ꞉ᴐԜꞌԐͼԜꜜᴑͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌ꞉ᴧᴒᴑͼԝԜᴠᴒꞌ꞉ꜜᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼӿᴐꜝꜜᴡ꞉ꜜᴢꜝᴢᴠԐԓͼԜꜜᴑͼᴡⱳᴒͼꞌꜝⱲԜᴟ꞉ᴡⱳꜛͼꜝⱱͼᴡ꞉ꜛᴒͼ꞉ꜜͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴑԜᴦᴠͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴤԜᴠͼꜝԝᴠᴒᴟᴣᴒᴑͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼԜᴠͼԜꜜͼꜝⱱⱱᴠᴒᴡͼ
ᴣԜᴟ꞉Ԝԝꞌᴒͼ꞉ꜜͼᴡⱳᴒͼꜛꜝᴑᴒꞌ᷅ͼ
ⱴᴟꜝꜛͼᴡⱳ꞉ᴠͼꜛꜝᴑᴒꞌԓͼᴡⱳᴒͼꞌᴒԜᴠᴡͼᴠꜟᴢԜᴟᴒᴠͼꜛᴒԜꜜͼᴟԜᴡᴒͼԜꜜᴑͼᴠᴡԜꜜᴑԜᴟᴑͼᴒᴟᴟꜝᴟͼⱱꜝᴟͼᴒԜᴐⱳͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼԜᴠͼᴤᴒꞌꞌͼ
ԜᴠԓͼᴡⱳᴒͼꜛᴒԜꜜͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝᴠͼᴟᴒꞌԜᴡ꞉ᴣᴒͼᴡꜝͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼԜꜜᴑͼᴐꜝᴟᴟᴒᴠꜞꜝꜜᴑ꞉ꜜⱲͼⱠ᷿Ӽͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼ꞉ꜜᴡᴒᴟᴣԜꞌᴠͼ
ⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴑ᷅ͼᴁⱳᴒᴠᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼԜᴠͼꜛᴒԜꜜͼᴒᴣᴒꜜᴡͼ
ᴟԜᴡᴒᴠͼꜞᴒᴟͼᴢꜜ꞉ᴡͼꜝⱱͼᴡ꞉ꜛᴒͼӿᴤᴒᴒꞋͼԜꜜᴑͼꜛꜝꜜᴡⱳꞌᴦԐͼԝᴦͼᴡᴟԜꜜᴠⱱꜝᴟꜛ꞉ꜜⱲͼᴡⱳᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴠͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼᴒᴥꜞꜝꜜᴒꜜᴡ꞉Ԝꞌͼ
ⱱᴢꜜᴐᴡ꞉ꜝꜜͼԜꜜᴑͼᴠᴐԜꞌ꞉ꜜⱲͼԝᴦͼᴡⱳᴒͼᴢꜜ꞉ᴡͼꜝⱱͼᴡ꞉ꜛᴒ᷅ͼ
ᴁⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴡᴒᴠᴡᴒᴑͼԝᴦͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠⱡ
ⱶ᷇ⱡͼȜⱫᴅ᷄᷉Ⱡ᷊᷇᷆ͼȜꜞꞌԜᴐᴒԝꜝⱤͼ᷈ͼᴣᴒᴟᴠᴢᴠͼⱶ᷈ⱡͼȜⱫᴅ᷄᷉Ⱡ᷊᷇᷆ͼȜꜞꞌԜᴐᴒԝꜝᶌͼ᷈
ȜⱫᴅ᷄᷉Ⱡ᷊᷇ᴟᴒⱱᴒᴟᴠͼᴡꜝͼᴡⱳᴒͼꜛᴒԜꜜͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱲᴟꜝᴢꜞͼԜꜜᴑͼ
ȜꜞꞌԜᴐᴒԝꜝͼᴟᴒⱱᴒᴟᴠͼᴡꜝͼᴡⱳᴒͼꜛᴒԜꜜͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼ꞉ꜜͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞ᷅ͼᴁⱳᴒͼꜜᴢꞌꞌͼ
ⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼ꞉ᴠͼᴡⱳԜᴡͼᴡⱳᴒͼꜛᴒԜꜜͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝͼ꞉ᴠͼ᷈ͼӿꜜꜝᴑ꞉ⱱⱱᴒᴟᴒꜜᴐᴒͼ
ԝᴒᴡᴤᴒᴒꜜᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠԐԓͼᴣᴒᴟᴠᴢᴠͼᴡⱳᴒͼԜꞌᴡᴒᴟꜜԜᴡ꞉ᴣᴒͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡⱳԜᴡͼᴡⱳᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝͼ꞉ᴠͼꜜꜝᴡͼ
᷈᷅ͼⱬᴠᴡ꞉ꜛԜᴡᴒᴑͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝᴠͼꞌᴒᴠᴠͼᴡⱳԜꜜͼꜝꜜᴒͼᴤꜝᴢꞌᴑͼ꞉ꜜᴑ꞉ᴐԜᴡᴒͼᴡⱳԜᴡͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡᴟᴒԜᴡᴒᴑͼᴤ꞉ᴡⱳͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼ
ꜝꜜͼԜᴣᴒᴟԜⱲᴒԓͼⱳԜᴣᴒͼԜͼꞌꜝᴤᴒᴟͼ꞉ꜜᴐ꞉ᴑᴒꜜᴐᴒͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑ᷅ͼᴁⱳᴒͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴡᴒᴠᴡᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼꜛꜝᴑᴒꞌ᷄ԝԜᴠᴒᴑͼꞌᴒԜᴠᴡͼᴠꜟᴢԜᴟᴒᴠͼꜛᴒԜꜜᴠͼ
ᴒᴠᴡ꞉ꜛԜᴡᴒͼꜝⱱͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴑ꞉ⱱⱱᴒᴟᴒꜜᴐᴒͼᴢᴠ꞉ꜜⱲͼԜͼᴄԜꞌᴑ᷄ԝԜᴠᴒᴑͼᴐⱳ꞉᷄ᴠꜟᴢԜᴟᴒͼᴡᴒᴠᴡ᷅
ᴁⱳᴒͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼᴐⱳԜꜜⱲᴒͼ꞉ꜜͼꜛᴒԜꜜͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝⱱͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
ⱲᴟꜝᴢꜞͼⱱᴟꜝꜛͼᴡⱳᴒͼԜᴡᴡԜᴐꞋͼᴟԜᴡᴒͼꜝⱱͼꜞꞌԜᴐᴒԝꜝͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜꞌᴐᴢꞌԜᴡᴒᴑͼԜᴠͼ᷈᷇᷇ӼͼԑͼӿꜛᴒԜꜜͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝͼᶮ᷈Ԑ᷅ͼ
ᴀ꞉ꜛ꞉ꞌԜᴟꞌᴦԓͼᴡⱳᴒͼᴒᴠᴡ꞉ꜛԜᴡᴒᴑͼᴢꜞꜞᴒᴟͼԜꜜᴑͼꞌꜝᴤᴒᴟͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼꞌ꞉ꜛ꞉ᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼꜛᴒԜꜜͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝͼᴐԜꜜͼԝᴒͼ
ᴡᴟԜꜜᴠⱱꜝᴟꜛᴒᴑͼԝᴦͼᴠᴢԝᴡᴟԜᴐᴡ꞉ꜜⱲͼ᷈ͼԜꜜᴑͼꜛᴢꞌᴡ꞉ꜞꞌᴦ꞉ꜜⱲͼԝᴦͼ᷈᷇᷇ӼͼᴡꜝͼᴐԜꞌᴐᴢꞌԜᴡᴒͼⱠ᷿Ӽͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼ꞉ꜜᴡᴒᴟᴣԜꞌᴠͼⱱꜝᴟͼ
ᴡⱳᴒͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼᴐⱳԜꜜⱲᴒ᷅ͼᴁⱳᴒͼꜛᴒԜꜜͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝᴠͼԜꜜᴑͼᴐꜝᴟᴟᴒᴠꜞꜝꜜᴑ꞉ꜜⱲͼⱠ᷿Ӽͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼ꞉ꜜᴡᴒᴟᴣԜꞌᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴒᴠᴡ꞉ꜛԜᴡᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼԜᴠͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼꜞᴟᴒᴣ꞉ꜝᴢᴠꞌᴦ᷅ͼ
ⱨꞌꞌͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜꜜԜꞌᴦᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱷᴁᴁͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜ᷅
ⱷꜜͼꜝᴟᴑᴒᴟͼᴡꜝͼꜛԜ꞉ꜜᴡԜ꞉ꜜͼᴡⱳᴒͼꜝᴣᴒᴟԜꞌꞌͼᴁᴦꜞᴒͼⱷͼᴒᴟᴟꜝᴟͼԜᴡͼ᷿᷇᷅᷇ԓͼԜͼᴐꜝꜜᴠᴒᴟᴣԜᴡ꞉ᴣᴒͼⱩꜝꜜⱱᴒᴟᴟꜝꜜ꞉᷄ԝԜᴠᴒᴑͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼ
ᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜᴠͼꜝⱱͼᴒԜᴐⱳͼꜝⱱͼᴡⱳᴒͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼ
ᴤ꞉ᴡⱳͼᴒꜟᴢԜꞌͼᴤᴒ꞉ⱲⱳᴡᴠͼⱱꜝᴟͼᴒԜᴐⱳͼᴡᴒᴠᴡͼᴠᴒᴡͼԜᴡͼ᷈᷅⅍ⅎӼ ᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌͼӿĮ᷊᷆Ԑ᷅
9.8.2 Secondary Efficacy Endpoints
ᴁⱳᴒͼᴟԜꜜꞋ᷄ꜝᴟᴑᴒᴟᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼԜᴟᴒͼԜᴠͼⱱꜝꞌꞌꜝᴤᴠⱡ
᷈᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴟᴒꜟᴢ꞉ᴟ꞉ꜜⱲͼԜᴐᴢᴡᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ᷅
᷉᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼꜛꜝᴑᴒᴟԜᴡᴒͼꜝᴟͼᴠᴒᴣᴒᴟᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼӿⱫԜᴦͼ᷇ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ᷅ͼ
᷊᷅꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼꜝᴐᴐᴢᴟᴟ꞉ꜜⱲͼꜝꜜͼⱫԜᴦͼ᷈᷾ͼԜⱱᴡᴒᴟͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼ
ᴠᴡᴢᴑᴦͼᴑᴟᴢⱲͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉ͼӿⱫԜᴦͼ᷈᷾ͼᴡⱳᴟꜝᴢⱲⱳͼⱫԜᴦͼ᷈˲᷉Ԑ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴁⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜꜜԜꞌᴦᴧᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼᴠԜꜛᴒͼꜛᴒᴡⱳꜝᴑͼԜᴠͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅ͼ
ᴁꜝͼԜᴑ꞊ᴢᴠᴡͼⱱꜝᴟͼᴡⱳᴒͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼꜝⱱͼ꞉ꜜⱱꞌԜᴡᴒᴑͼꜝᴣᴒᴟԜꞌꞌͼᴁᴦꜞᴒͼⱷͼᴒᴟᴟꜝᴟͼᴟԜᴡᴒԓͼᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼ
ᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴡᴒᴠᴡᴒᴑͼ꞉ꜜͼԜͼⱱ꞉ᴥᴒᴑͼᴠᴒꜟᴢᴒꜜᴐᴒͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼ
ᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼᴢᴠ꞉ꜜⱲͼԜͼⱲᴒꜜᴒᴟԜꞌͼⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼԜꜞꜞᴟꜝԜᴐⱳͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꞌꜝⱲ꞉ᴐԜꞌͼᴟᴒᴠᴡᴟ꞉ᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼᴡⱳᴒͼ
ᴟԜꜜꞋͼꜝᴟᴑᴒᴟ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅ͼᴀᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼᴑᴒᴐꞌԜᴟᴒᴑͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼ
ᴢꜜꞌᴒᴠᴠͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼⱱꜝᴟͼᴡⱳԜᴡͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼ꞉ᴠͼⱱꜝᴢꜜᴑͼ
ᴡꜝͼԝᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡ᷅ͼᴁⱳᴒͼᴡᴒᴠᴡ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼ꞉ᴠͼᴑᴒᴡԜ꞉ꞌᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜⱠ᷿᷅᷈᷉᷅᷅
9.8.3 Exploratory Efficacy Endpoints
ᴁⱳᴒͼᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼ꞉ꜜᴐꞌᴢᴑᴒⱡ

ᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ԓͼ꞉᷅ᴒ᷅ԓͼᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡᴡԜᴐꞋ᷄ⱱᴟᴒᴒͼԜⱱᴡᴒᴟͼⱫԜᴦ᷈᷾

꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷄ᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑⱢͼԜͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ꞉ᴠͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼԜꜜᴦͼԜᴡᴡԜᴐꞋͼᴡⱳԜᴡͼⱳԜᴠͼԜᴡͼꞌᴒԜᴠᴡͼꜝꜜᴒͼ
ꜝⱱͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴐⱳԜᴟԜᴐᴡᴒᴟ꞉ᴠᴡ꞉ᴐᴠⱡͼᴠᴒᴣᴒᴟᴒԓͼᴟᴒᴠᴢꞌᴡᴠͼ꞉ꜜͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼӿᴒᴥᴐᴒꜞᴡͼⱳꜝᴠꜞ꞉ᴡԜꞌ꞉ᴧԜᴡ꞉ꜝꜜͼⱱꜝᴟͼ
ꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜͼⱣͼ᷉᷾ͼⱳꜝᴢᴟᴠԐԓͼⱳᴒꜛꜝᴑᴦꜜԜꜛ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼӿᴠᴦᴠᴡꜝꞌ꞉ᴐͼԝꞌꜝꜝᴑͼꜞᴟᴒᴠᴠᴢᴟᴒͼⱣͼⱠ᷇ԓͼᴟᴒꜟᴢ꞉ᴟᴒᴠͼ
ⱷᴃͼⱳᴦᴑᴟԜᴡ꞉ꜝꜜԓͼꜝᴟͼԜᴠᴠꜝᴐ꞉Ԝᴡᴒᴑͼᴤ꞉ᴡⱳͼᴠᴦꜜᴐꜝꜞᴒͼꜝᴟͼꜜᴒԜᴟ᷄ᴠᴦꜜᴐꜝꜞᴒԐͼꜝᴟͼꞌԜᴟᴦꜜⱲᴒԜꞌ᷅
ᴁⱳᴒͼᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼԜᴟᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼᴠᴢꜞꜞꜝᴟᴡ꞉ᴣᴒͼԜꜜᴑͼԜꜜᴦͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼᴡᴒᴠᴡᴠͼᴐꜝꜛꜞԜᴟ꞉ꜜⱲͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜛԜᴑᴒͼᴤ꞉ᴡⱳꜝᴢᴡͼԜᴑ꞊ᴢᴠᴡꜛᴒꜜᴡͼⱱꜝᴟͼꜛᴢꞌᴡ꞉ꜞꞌ꞉ᴐ꞉ᴡᴦ᷅ͼᴁⱳᴒͼᴟᴒᴠᴢꞌᴡ꞉ꜜⱲͼꜞ᷄ᴣԜꞌᴢᴒᴠͼⱱᴟꜝꜛͼᴡⱳᴒᴠᴒͼ
ᴠᴢꜞꜞꜝᴟᴡ꞉ᴣᴒͼԜꜜԜꞌᴦᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡᴒᴑͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ᴣᴒꞌᴦͼԜᴠͼᴠᴢꜛꜛԜᴟ꞉ᴧ꞉ꜜⱲͼᴡⱳᴒͼᴤᴒ꞉Ⱳⱳᴡͼꜝⱱͼᴒᴣ꞉ᴑᴒꜜᴐᴒͼⱱꜝᴟͼԜͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴒⱱⱱᴒᴐᴡ᷅
9.9
Analysis of Pharmacokinetic and Pharmacodynamic Endpoints
9.9.1
Pharmacokinetic Assessments:
ⱩꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼꜛᴒԜᴠᴢᴟᴒꜛᴒꜜᴡͼꜝⱱͼꜞꞌԜᴠꜛԜͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼ
ⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼꜝꜜͼⱫԜᴦᴠͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷾᷇ᶐ᷊ͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴠԜꜛꜞꞌᴒᴠͼ
ᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦᴠͼ᷉᷈᷇ᶐ᷊ԓͼԜꜜᴑͼ᷊᷉˲ᶐ᷊ͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼ
ᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅
͟ꞌԜᴠꜛԜͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼᴤ꞉ᴡⱳͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ᴣᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐᴠͼԝᴦͼꜜꜝꜛ꞉ꜜԜꞌͼ͟ꜘͼ
ᴠԜꜛꜞꞌ꞉ꜜⱲͼᴡ꞉ꜛᴒ᷅
9.9.2
Pharmacodynamic Assessments:
ⱩꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼᴡꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼꜞⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼᴒⱱⱱᴒᴐᴡᴠͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴡⱳᴟꜝᴢⱲⱳͼ
ԝ꞉ꜝꜛԜᴟꞋᴒᴟͼԜᴠᴠԜᴦᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼꜝꜜͼⱫԜᴦᴠͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷾᷇ᶐ᷊ԓͼԜꜜᴑͼ
᷈˲᷉ᶐ᷊᷅ͼⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦᴠͼ᷉᷈᷇ᶐ᷊ԓͼԜꜜᴑͼ᷊᷉˲ᶐ᷊ͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼ
ꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
͟ꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼᴤ꞉ᴡⱳͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ᴣᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐᴠͼԝᴦͼꜜꜝꜛ꞉ꜜԜꞌͼ͟ⱫͼᴠԜꜛꜞꞌ꞉ꜜⱲͼ
ᴡ꞉ꜛᴒ᷅
9.9.3
Immunogenicity Assessments:
ⱩꞌꜝꜝᴑͼᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼᴡꜝͼԜᴠᴠԜᴦͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟᴒᴠᴒꜜᴐᴒͼꜝⱱͼԜꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼ
ᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜝⱱͼꜜᴒᴢᴡᴟԜꞌ꞉ᴧ꞉ꜜⱲͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠͼӿ꞉ⱱͼԜꜜᴦͼᴐꜝꜜⱱ꞉ᴟꜛᴒᴑͼꜞꜝᴠ꞉ᴡ꞉ᴣᴒͼԜꜜᴡ꞉᷄ᴑᴟᴢⱲͼԜꜜᴡ꞉ԝꜝᴑ꞉ᴒᴠͼԜᴟᴒͼᴑᴒᴡᴒᴐᴡᴒᴑԐͼ
ꜞᴟ꞉ꜝᴟͼᴡꜝͼⱷꜚ͟ͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝꜜͼⱫԜᴦͼ᷇ͼԜꜜᴑͼꜝꜜͼⱫԜᴦᴠͼ᷿⅍ᶐ᷊ԓͼⱠ˲ᶐ᷊ԓͼ᷈᷾᷇ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ
ᴠԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦͼ᷊᷉˲ᶐ᷊ͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼԜꜜᴦͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼ
ᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ
9.9.4
C1-INH and C4 Assessments:
ᴀԜꜛꜞꞌᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼⱱꜝᴟͼⱪ᷈᷄ⱷ꜠ⱶԓͼⱪ᷾ͼԜꜜᴑͼⱪ᷈ꜟͼԜᴠᴠԜᴦᴠͼԜᴡͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼⱱꜝᴟͼᴒꞌ꞉Ⱳ꞉ԝ꞉ꞌ꞉ᴡᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅
9.10
Safety Analysis
ᴁᴟᴒԜᴡꜛᴒꜜᴡ᷄ᴒꜛᴒᴟⱲᴒꜜᴡͼⱨⱬᴠͼԜᴟᴒͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼⱨⱬᴠͼᴤ꞉ᴡⱳͼꜝꜜᴠᴒᴡͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼꜝᴟͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴤ꞉ᴡⱳͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜԓͼꜝᴟͼꜛᴒᴑ꞉ᴐԜꞌͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠͼꜞᴟᴒᴠᴒꜜᴡͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԝᴢᴡͼ
꞉ꜜᴐᴟᴒԜᴠ꞉ꜜⱲͼ꞉ꜜͼᴠᴒᴣᴒᴟ꞉ᴡᴦͼꜝᴟͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼԜᴡͼᴡⱳᴒͼᴡ꞉ꜛᴒͼꜝⱱͼꜝᴟͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴡᴟᴒԜᴡꜛᴒꜜᴡ᷅ͼᴁⱳᴒͼ
ꜜᴢꜛԝᴒᴟͼԜꜜᴑͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼᴁⱬⱨⱬᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑ꞉ᴠꜞꞌԜᴦᴒᴑͼⱱꜝᴟͼᴒԜᴐⱳͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼԝᴦͼ
ԝꜝᴑᴦͼᴠᴦᴠᴡᴒꜛͼԜꜜᴑͼꜞᴟᴒⱱᴒᴟᴟᴒᴑͼᴡᴒᴟꜛͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼⱫ꞉ᴐᴡ꞉ꜝꜜԜᴟᴦͼⱱꜝᴟͼϸᴒⱲᴢꞌԜᴡꜝᴟᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼ
ӿꜚᴒᴑⱫϸⱨᶇԐ᷅ͼᴀᴢꜛꜛԜᴟ꞉ᴒᴠͼ꞉ꜜͼᴡᴒᴟꜛᴠͼꜝⱱͼᴠᴒᴣᴒᴟ꞉ᴡᴦͼԜꜜᴑͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴡꜝͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԜꞌᴠꜝͼԝᴒͼ
ꜞᴟꜝᴣ꞉ᴑᴒᴑ᷅ͼᴀᴒᴟ꞉ꜝᴢᴠͼⱨⱬᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼᴠᴒꜞԜᴟԜᴡᴒꞌᴦͼ꞉ꜜͼԜͼᴠ꞉ꜛ꞉ꞌԜᴟͼⱱԜᴠⱳ꞉ꜝꜜ᷅ͼ͟Ԝᴡ꞉ᴒꜜᴡͼꞌ꞉ᴠᴡ꞉ꜜⱲᴠͼꜝⱱͼⱨⱬᴠͼ
ᴐԜᴢᴠ꞉ꜜⱲͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜԓͼⱨⱬᴠͼꞌᴒԜᴑ꞉ꜜⱲͼᴡꜝͼᴑᴒԜᴡⱳԓͼᴀⱨⱬᴠͼԜꜜᴑͼⱨⱬᴀⱷͼᴤ꞉ꞌꞌͼԝᴒͼ
ꜞᴟꜝᴑᴢᴐᴒᴑ᷅
ⱨⱬᴀⱷͼᴤ꞉ꞌꞌͼԝᴒͼԜꜜԜꞌᴦᴧᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼꜞᴟ꞉ꜛԜᴟᴦͼᴠᴦᴠᴡᴒꜛͼ꜡ᴟⱲԜꜜͼⱪꞌԜᴠᴠᴒᴠͼӿᴀ꜡ⱪᴠԐͼԜꜜᴑͼ͟ᴟᴒⱱᴒᴟᴟᴒᴑͼᴁᴒᴟꜛᴠͼ
ӿ͟ᴁᴠԐͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴒԜᴟᴐⱳꜝⱱᴟᴒꞌᴒᴣԜꜜᴡᴀᴡԜꜜᴑԜᴟᴑ꞉ᴧᴒᴑͼꜚᴒᴑⱫϸⱨϷᴢᴒᴟ꞉ᴒᴠӿᴀꜚϷᴠԐ᷅ͼᴀᴢꜛꜛԜᴟᴦͼ
ᴡԜԝꞌᴒᴠͼᴤ꞉ᴡⱳͼᴀ꜡ⱪᴠͼԜꜜᴑ͟ᴁᴠԓͼⱱᴟꜝꜛͼᴡⱳᴒͼᴀꜚϷ ᴠᴒԜᴟᴐⱳᴒᴠԓ ᴤ꞉ꞌꞌͼԝᴒͼⱲᴒꜜᴒᴟԜᴡᴒᴑͼꜞᴟᴒᴠᴒꜜᴡ꞉ꜜⱲᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼԜꜜᴑͼ
ꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԝᴦͼⱨⱬԓͼᴠᴒᴣᴒᴟ꞉ᴡᴦԓͼᴠᴒᴟ꞉ꜝᴢᴠꜜᴒᴠᴠԓͼԜꜜᴑͼᴟᴒꞌԜᴡ꞉ꜝꜜᴠⱳ꞉ꜞͼᴡꜝͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜ᷅
ᴂᴠԜⱲᴒͼꜝⱱͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼӿꜝᴡⱳᴒᴟͼᴡⱳԜꜜͼᴟᴒᴠᴐᴢᴒͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠԐͼᴤ꞉ꞌꞌͼԝᴒͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼ
ᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ᴣᴒꞌᴦͼⱱꜝᴟͼᴒԜᴐⱳͼꜝⱱͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠͼԜꜜᴑͼᴡⱳᴒͼᴐꜝꜛԝ꞉ꜜᴒᴑԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞ᷅
ⱨᴐᴡᴢԜꞌͼᴣԜꞌᴢᴒᴠͼԜꜜᴑͼᴐⱳԜꜜⱲᴒͼⱱᴟꜝꜛͼᴠᴐᴟᴒᴒꜜ꞉ꜜⱲͼ꞉ꜜͼᴣ꞉ᴡԜꞌͼᴠ꞉ⱲꜜᴠͼԜꜜᴑͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼⱱꜝᴟͼᴒԜᴐⱳͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴤ꞉ᴡⱳͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ᴣᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐᴠͼԜᴡͼᴒԜᴐⱳͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝԝᴡԜ꞉ꜜᴒᴑ᷅ͼⱴꜝᴟͼ
ԜꞌꞌͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴡᴒᴠᴡᴠԓͼԜͼᴠⱳ꞉ⱱᴡͼᴡԜԝꞌᴒͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴑᴢᴐᴒᴑͼᴠᴢꜛꜛԜᴟ꞉ᴧ꞉ꜜⱲͼᴐⱳԜꜜⱲᴒᴠͼⱱᴟꜝꜛͼꜜꜝᴟꜛԜꞌͼᴡꜝͼԜԝꜜꜝᴟꜛԜꞌͼ
Ԝꜜᴑͼᴣ꞉ᴐᴒ᷄ᴣᴒᴟᴠԜ᷅
ⱨԝꜜꜝᴟꜛԜꞌͼꜞⱳᴦᴠ꞉ᴐԜꞌͼᴒᴥԜꜛ꞉ꜜԜᴡ꞉ꜝꜜͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼᴤ꞉ꞌꞌͼԝᴒͼꞌ꞉ᴠᴡᴒᴑ᷅
ᴁⱳᴒͼꜜᴢꜛԝᴒᴟͼԜꜜᴑͼꜞᴒᴟᴐᴒꜜᴡԜⱲᴒͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ᴡⱳͼꜜꜝᴟꜛԜꞌԓͼԜԝꜜꜝᴟꜛԜꞌ᷄ꜜꜝᴡͼᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡԓͼԜꜜᴑͼ
ԜԝꜜꜝᴟꜛԜꞌ᷄ᴐꞌ꞉ꜜ꞉ᴐԜꞌꞌᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼⱬⱪⱵͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑ꞉ᴠꜞꞌԜᴦᴒᴑͼⱱꜝᴟͼᴒԜᴐⱳͼꜝⱱͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞᴠ᷅
ⱨᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼԜꜜԜꞌᴦᴠᴒᴠͼꜝⱱͼⱨⱬᴠԓͼᴀⱨⱬᴠԓͼᴠᴒᴣᴒᴟᴒͼⱨⱬᴠԓͼⱨⱬᴀⱷԓͼԜꜜᴑͼԜԝꜜꜝᴟꜛԜꞌͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼᴤ꞉ꞌꞌͼԝᴒͼԝԜᴠᴒᴑͼꜝꜜͼ
ᴡⱳᴒͼᴡ꞉ꜛ꞉ꜜⱲͼӿᴀᴡᴢᴑᴦͼⱫԜᴦԐͼԜꜜᴑͼꜜᴢꜛԝᴒᴟͼꜝⱱͼꜞᴟ꞉ꜝᴟͼᴑꜝᴠᴒᴠͼꜝⱱͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜ᷅ͼᴁⱳᴒͼ꞉ꜜᴐ꞉ᴑᴒꜜᴐᴒͼꜝⱱͼⱨⱬᴠͼԝᴦͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲᷊
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜛꜝꜜᴡⱳͼⱱᴟꜝꜛᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴠᴡᴢᴑᴦͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴥԜꜛ꞉ꜜᴒᴑͼԜꜜᴑͼᴡⱳᴒͼ꞉ꜜᴐ꞉ᴑᴒꜜᴐᴒͼԜꜛꜝꜜⱲͼᴡⱳᴒͼⱱꜝᴢᴟͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴟꜛᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜛꜞԜᴟᴒᴑ᷅ͼᴁⱳᴒͼᴟԜᴡᴒͼꜝⱱͼᴠᴡᴢᴑᴦͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼԜꜛꜝꜜⱲͼᴡⱳᴒͼⱱꜝᴢᴟͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
Ԝᴟꜛᴠͼᴤ꞉ꞌꞌͼԜꞌᴠꜝͼԝᴒͼᴐꜝꜛꜞԜᴟᴒᴑ᷅ͼ
9.11
Analysis of Quality of Life Assessments
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼᴑԜᴡԜͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱬϷ᷿ⱫͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼⱠ˲ᶐ᷊ԓͼ
Ԝꜜᴑͼ᷈˲᷉ᶐ᷊ͼԜꜜᴑͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱨⱬ᷄ϷꜝꜙͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼԜᴡͼꜞᴟᴒ᷄ᴑꜝᴠᴒͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼ᷉˲ᶐ᷊ԓͼ᷿⅍ᶐ᷊ԓͼ
Ⱡ˲ᶐ᷊ԓ ᷈᷉⅍ᶐ᷊ԓͼ᷿᷈᷾ᶐ᷊ԓͼԜꜜᴑͼ᷈˲᷉ᶐ᷊᷅ͼⱨꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼϷꜝꜙͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼꜝꜜͼⱫԜᴦͼ᷊᷉˲ᶐ᷊ͼ
ⱱꜝᴟᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼ꜡ꜙⱬ᷅ͼ
9.12
Statistical/Analytic Issues
9.12.1 Adjustment for Covariates
ᴁⱳᴒͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼԜᴑ꞊ᴢᴠᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼꜜꜝᴟꜛԜꞌ꞉ᴧᴒᴑͼԝԜᴠᴒꞌ꞉ꜜᴒͼⱶⱨⱬͼ
ԜᴡᴡԜᴐꞋͼᴟԜᴡᴒ᷅ͼ꜠ꜝͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴐꜝᴣԜᴟ꞉ԜᴡᴒͼԜᴑ꞊ᴢᴠᴡꜛᴒꜜᴡͼ꞉ᴠͼꜞꞌԜꜜꜜᴒᴑ᷅
9.12.2 Handling of Dropouts or Missing Data
ⱨꞌꞌͼԜᴣԜ꞉ꞌԜԝꞌᴒͼᴑԜᴡԜͼᴤ꞉ꞌꞌͼԝᴒͼ꞉ꜜᴐꞌᴢᴑᴒᴑͼ꞉ꜜͼᴡⱳᴒͼԜꜜԜꞌᴦᴠ꞉ᴠ᷅ͼᴁⱳᴒͼꞌᴒꜜⱲᴡⱳͼꜝⱱͼᴡ꞉ꜛᴒͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼᴤԜᴠͼꜝԝᴠᴒᴟᴣᴒᴑͼ
ᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼᴤ꞉ꞌꞌͼԝᴒͼ꞉ꜜᴐꞌᴢᴑᴒᴑͼԜᴠͼԜͼᴣԜᴟ꞉Ԝԝꞌᴒͼ꞉ꜜͼᴡⱳᴒͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼ
ꜛꜝᴑᴒꞌͼᴡꜝͼԜᴑ꞊ᴢᴠᴡͼⱱꜝᴟͼᴑ꞉ⱱⱱᴒᴟᴒꜜᴐᴒᴠͼ꞉ꜜͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴡ꞉ꜛᴒ᷅
9.12.3 Interim Analysis and Data Monitoring
꜠ꜝͼ꞉ꜜᴡᴒᴟ꞉ꜛͼԜꜜԜꞌᴦᴠᴒᴠͼԜᴟᴒͼꜞꞌԜꜜꜜᴒᴑ᷅ͼⱶꜝᴤᴒᴣᴒᴟԓͼԜꜜͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼⱫᴀꜚⱩͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴠᴡԜԝꞌ꞉ᴠⱳᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼ
ꜝꜜⱲꜝ꞉ꜜⱲԓͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼᴟᴒᴣ꞉ᴒᴤͼԜꜜᴑͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼᴑԜᴡԜԓͼԜꜜᴑͼᴡꜝͼᴠԜⱱᴒⱲᴢԜᴟᴑͼᴡⱳᴒͼ꞉ꜜᴡᴒᴟᴒᴠᴡᴠͼԜꜜᴑͼ
ᴠԜⱱᴒᴡᴦͼꜝⱱͼᴡⱳᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼᴡⱳᴒͼᴑԜᴡԜͼⱱꜝᴟͼⱫᴀꜚⱩͼᴟᴒᴣ꞉ᴒᴤͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐꜝꜜᴑᴢᴐᴡᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼⱫᴀꜚⱩͼⱪⱳԜᴟᴡᴒᴟͼԜꜜᴑͼⱫᴀꜚⱩͼᴀⱨ᷅͟ͼⱩᴒᴐԜᴢᴠᴒͼꜜꜝͼⱱꜝᴟꜛԜꞌͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼ
ᴡᴒᴠᴡ꞉ꜜⱲͼⱱꜝᴟͼᴠԜⱱᴒᴡᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼ꞉ᴠͼꜞꞌԜꜜꜜᴒᴑԓͼꜛᴢꞌᴡ꞉ꜞꞌ꞉ᴐ꞉ᴡᴦͼᴐꜝꜜᴐᴒᴟꜜᴠͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴟᴒꜞᴒԜᴡᴒᴑͼԜꜜԜꞌᴦᴠᴒᴠͼԜᴟᴒͼ
ꜜꜝᴡͼԜꜜͼ꞉ᴠᴠᴢᴒ᷅
9.12.4 Multicenter Studies
ⱫԜᴡԜͼⱱᴟꜝꜛͼԜꞌꞌͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒᴠͼᴡⱳԜᴡͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒͼ꞉ꜜͼᴡⱳ꞉ᴠͼꜞᴟꜝᴡꜝᴐꜝꞌͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜛԝ꞉ꜜᴒᴑͼᴠꜝͼᴡⱳԜᴡͼԜꜜͼԜᴑᴒꜟᴢԜᴡᴒͼ
ꜜᴢꜛԝᴒᴟͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒͼⱱꜝᴟͼԜꜜԜꞌᴦᴠ꞉ᴠ᷅
9.12.5 Multiple Comparisons/Multiplicity
ᴁⱳᴒͼⱲꞌꜝԝԜꞌͼⱱԜꜛ꞉ꞌᴦ᷄ᴤ꞉ᴠᴒͼᴁᴦꜞᴒͼⱷͼᴒᴟᴟꜝᴟͼᴟԜᴡᴒͼӿⱴᴄⱬϸԐͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼᴡᴒᴠᴡᴠͼꜝⱱͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴟԜꜜꞋͼ
ꜝᴟᴑᴒᴟᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼӿᴟԜꜜꞋͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾᷅᷈Ԑͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴡᴟꜝꞌꞌᴒᴑͼԜᴡͼ᷿᷇᷅᷇᷅ͼ
ᴁꜝͼᴠᴡᴟꜝꜜⱲꞌᴦͼᴐꜝꜜᴡᴟꜝꞌͼᴡⱳᴒͼⱲꞌꜝԝԜꞌͼⱴᴄⱬϸͼԜᴡͼᴡⱳ꞉ᴠͼꞌᴒᴣᴒꞌԓͼԜͼⱲᴒꜜᴒᴟԜꞌͼⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼԜꜞꜞᴟꜝԜᴐⱳͼᴤ꞉ᴡⱳͼԝᴟԜꜜᴐⱳᴒᴠͼ
ⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴡ꞉ꞌ꞉ᴧᴒᴑͼ꞉ꜜͼᴤⱳ꞉ᴐⱳͼᴒԜᴐⱳͼ
ⱱԜꜛ꞉ꞌᴦͼꜝⱱͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼᴡᴒᴠᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼ꞉ꜜͼԜͼᴠᴒꜟᴢᴒꜜᴡ꞉ԜꞌͼꜛԜꜜꜜᴒᴟ᷅ͼᴀꜞᴒᴐ꞉ⱱ꞉ᴐԜꞌꞌᴦԓͼԜͼᴡⱳᴟᴒᴒ᷄ԝᴟԜꜜᴐⱳͼ
ⱲᴒꜜᴒᴟԜꞌͼⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴤ꞉ᴡⱳͼⱱꜝᴢᴟͼⱱԜꜛ꞉ꞌ꞉ᴒᴠͼꜝⱱͼⱳᴦꜞꜝᴡⱳᴒᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒⱱ꞉ꜜᴒᴑͼԜᴠͼⱱꜝꞌꞌꜝᴤᴠⱡ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅

ⱴԜꜛ꞉ꞌᴦͼ᷈ͼӿⱴ᷈Ԑⱡͼⱶᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡԓͼꜝꜜᴒͼᴡᴒᴠᴡͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼꜝᴟᴑᴒᴟᴒᴑͼԝᴦͼⱳ꞉ⱲⱳᴒᴠᴡͼᴡꜝᴡԜꞌͼꜛꜝꜜᴡⱳꞌᴦͼᴑꜝᴠᴒӿⱶ᷈᷈ԓͼⱶ᷈᷉ԓͼԜꜜᴑͼⱶ᷊᷈Ԑ᷅

ⱴԜꜛ꞉ꞌᴦͼ᷉ͼӿⱴ᷉Ԑⱡͼⱶᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼᴟԜꜜꞋᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡԓͼꜝꜜᴒͼᴡᴒᴠᴡͼⱱꜝᴟͼᴒԜᴐⱳͼ
Ԝᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼꜝᴟᴑᴒᴟᴒᴑͼԝᴦͼⱳ꞉ⱲⱳᴒᴠᴡͼᴡꜝᴡԜꞌͼꜛꜝꜜᴡⱳꞌᴦͼᴑꜝᴠᴒӿⱶ᷉᷈ԓͼⱶ᷉᷉ԓͼԜꜜᴑͼ
ⱶ᷊᷉Ԑ᷅

ⱴԜꜛ꞉ꞌᴦͼ᷊ͼӿⱴ᷊Ԑⱡͼⱶᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼᴠᴒᴐꜝꜜᴑͼᴟԜꜜꞋᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡԓͼꜝꜜᴒͼᴡᴒᴠᴡͼⱱꜝᴟͼᴒԜᴐⱳͼ
Ԝᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼꜝᴟᴑᴒᴟᴒᴑͼԝᴦͼⱳ꞉ⱲⱳᴒᴠᴡͼᴡꜝᴡԜꞌͼꜛꜝꜜᴡⱳꞌᴦͼᴑꜝᴠᴒӿⱶ᷊᷈ԓͼⱶ᷊᷉ԓͼԜꜜᴑͼ
ⱶ᷊᷊Ԑ᷅

ⱴԜꜛ꞉ꞌᴦͼ᷾ͼӿⱴ᷾Ԑⱡͼⱶᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼᴡⱳ꞉ᴟᴑͼᴟԜꜜꞋᴒᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡԓͼꜝꜜᴒͼᴡᴒᴠᴡͼⱱꜝᴟͼᴒԜᴐⱳͼ
Ԝᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼꜝᴟᴑᴒᴟᴒᴑͼԝᴦͼⱳ꞉ⱲⱳᴒᴠᴡͼᴡꜝᴡԜꞌͼꜛꜝꜜᴡⱳꞌᴦͼᴑꜝᴠᴒӿⱶ᷾᷈ԓͼⱶ᷾᷉ԓͼԜꜜᴑͼ
ⱶ᷊᷾Ԑ᷅
ᴁⱳᴒͼ᷾ͼᴠᴒᴡᴠͼꜝⱱͼⱳᴦꜞꜝᴡⱳᴒᴠᴒᴠͼ꞉ꜜͼⱴ᷈ԓͼⱴ᷉ԓͼⱴ᷊ԓͼԜꜜᴑͼⱴ᷾ͼᴤ꞉ꞌꞌͼԝᴒͼᴡᴒᴠᴡᴒᴑͼ꞉ꜜͼԜͼⱱ꞉ᴥᴒᴑͼᴠᴒꜟᴢᴒꜜᴐᴒͼᴤ꞉ᴡⱳ꞉ꜜͼᴒԜᴐⱳͼ
Ԝᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼꜝᴟͼԝᴟԜꜜᴐⱳ᷅ͼᴁᴒᴠᴡ꞉ꜜⱲͼᴤ꞉ᴡⱳ꞉ꜜͼԜͼԝᴟԜꜜᴐⱳͼᴤ꞉ꞌꞌͼ
ᴐꜝꜜᴡ꞉ꜜᴢᴒͼ꞉ꜜͼᴠᴒꜟᴢᴒꜜᴐᴒͼᴢꜜᴡ꞉ꞌᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼᴡᴒᴠᴡͼᴡⱳԜᴡͼᴡⱳᴒͼꜜᴢꞌꞌͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴐԜꜜꜜꜝᴡͼԝᴒͼᴟᴒ꞊ᴒᴐᴡᴒᴑⱢͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼ
ᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼᴐԜꜜꜜꜝᴡͼԝᴒͼᴑᴒᴐꞌԜᴟᴒᴑͼⱱꜝᴟͼᴡⱳԜᴡͼᴡᴒᴠᴡͼꜝᴟͼⱱꜝᴟͼԜꜜᴦͼꜝⱱͼᴡⱳᴒͼᴟᴒꜛԜ꞉ꜜ꞉ꜜⱲͼᴡᴒᴠᴡᴠͼᴤ꞉ᴡⱳ꞉ꜜͼᴡⱳᴒͼԝᴟԜꜜᴐⱳ᷅
ᴄ꞉ᴡⱳ꞉ꜜͼԜͼⱱԜꜛ꞉ꞌᴦԓͼⱳᴦꜞꜝᴡⱳᴒᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴡᴒᴠᴡᴒᴑͼᴢᴠ꞉ꜜⱲͼԜͼᴐꜝꜜᴠᴒᴟᴣԜᴡ꞉ᴣᴒͼⱩꜝꜜⱱᴒᴟᴟꜝꜜ꞉᷄ԝԜᴠᴒᴑͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼᴤ꞉ᴡⱳͼ
ᴒꜟᴢԜꞌͼᴤᴒ꞉ⱲⱳᴡᴠͼⱱꜝᴟͼᴒԜᴐⱳͼᴡᴒᴠᴡͼᴠᴒᴡͼԜᴡͼ᷈᷅⅍ⅎӼͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌͼӿĮ᷊᷆Ԑ᷅ͼⱷⱱͼᴡⱳᴒͼꜜᴢꞌꞌͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼⱱꜝᴟͼԜͼᴡᴒᴠᴡͼ꞉ᴠͼ
ᴟᴒ꞊ᴒᴐᴡᴒᴑԓͼĮͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝꜞԜⱲԜᴡᴒᴑͼᴒꜜᴡ꞉ᴟᴒꞌᴦͼᴡꜝͼᴡⱳᴒͼꜜᴒᴥᴡͼᴡᴒᴠᴡͼ꞉ꜜͼᴡⱳᴒͼᴠᴒꜟᴢᴒꜜᴐᴒԓͼᴤⱳ꞉ᴐⱳͼᴤ꞉ꞌꞌͼᴡⱳᴒꜜͼԝᴒͼᴡᴒᴠᴡᴒᴑͼ
Ԝᴡͼᴡⱳᴒͼ᷈᷅⅍ⅎӼͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌ᷅
ᴁꜝͼⱱᴢᴟᴡⱳᴒᴟͼ꞉ꞌꞌᴢᴠᴡᴟԜᴡᴒͼᴡⱳ꞉ᴠͼԜꜞꜞᴟꜝԜᴐⱳԓͼᴡⱳᴒͼᴡᴒᴠᴡͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼⱱ꞉ᴟᴠᴡͼԜᴡͼᴡⱳᴒͼ
᷈᷅⅍ⅎӼͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴐꜝꜛꜞԜᴟᴒᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞͼԜꜜᴑԓͼ
꞉ⱱͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡԓͼᴡⱳᴒͼⱱ꞉ᴟᴠᴡͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼᴠ꞉ꜛ꞉ꞌԜᴟꞌᴦͼᴡᴒᴠᴡᴒᴑͼԜᴡͼᴡⱳᴒͼ᷈᷅⅍ⅎӼͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌ᷅ͼ
ᴁⱳᴒͼᴡᴒᴠᴡ꞉ꜜⱲͼᴠᴒꜟᴢᴒꜜᴐᴒͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼ꞉ꜜͼꜝᴟᴑᴒᴟͼᴡⱳᴟꜝᴢⱲⱳͼᴡⱳᴒͼᴟᴒꜛԜ꞉ꜜ꞉ꜜⱲͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼⱱꜝᴟͼᴒԜᴐⱳͼ
Ԝᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴡꜝͼꜞꞌԜᴐᴒԝꜝͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼꜝᴟͼԝᴟԜꜜᴐⱳͼԜᴠͼꞌꜝꜜⱲͼԜᴠͼᴡⱳᴒͼꜜᴢꞌꞌͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼ꞉ᴠͼᴟᴒ꞊ᴒᴐᴡᴒᴑͼ
Ԝᴡͼᴡⱳᴒͼ᷈᷅⅍ⅎӼͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌ᷅ͼ
ᴁᴒᴠᴡ꞉ꜜⱲͼᴤ꞉ᴡⱳ꞉ꜜͼᴡⱳᴒͼꞌԜᴠᴡͼⱱԜꜛ꞉ꞌᴦͼӿⱴ᷾Ԑͼᴤ꞉ꞌꞌͼᴢᴡ꞉ꞌ꞉ᴧᴒͼᴡⱳᴒͼᴟᴒꜛԜ꞉ꜜ꞉ꜜⱲͼĮͼԝᴦͼԜꜞꜞꞌᴦ꞉ꜜⱲͼᴡⱳᴒⱶꜝꞌꜛ᷄Ⱪꜝꜜⱱᴒᴟᴟꜝꜜ꞉ͼ
ꜞᴟꜝᴐᴒᴑᴢᴟᴒ᷅ͼ
9.12.6 Sensitivity Analyses
ᴀᴒꜜᴠ꞉ᴡ꞉ᴣ꞉ᴡᴦͼԜꜜԜꞌᴦᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼꜝꜜͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᴡꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼ
ᴟꜝԝᴢᴠᴡꜜᴒᴠᴠͼꜝⱱͼᴡⱳᴒͼᴟᴒᴠᴢꞌᴡᴠͼⱱᴟꜝꜛᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜛᴒᴡⱳꜝᴑ᷅ͼᴁⱳᴒᴠᴒͼԜꜜԜꞌᴦᴠᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼ
ᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜞꞌԜꜜ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲᷿
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
10 STUDY ADMINISTRATIVE STRUCTURE
ᴁⱳᴒͼᴠᴡᴢᴑᴦͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼᴠᴡᴟᴢᴐᴡᴢᴟᴒͼ꞉ᴠͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼ꞉ꜜͼᴁԜԝꞌᴒ᷊᷅
Table 3.
Study Administrative Structure
Sponsor Contact/Sponsor Medical 
Director:
ꜗᴒꜜꜜ꞉ⱱᴒᴟͼᴀᴐⱳᴟԜꜜᴧԓͼꜚⱫ
ԓͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼⱫᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡ
᷊᷇᷇ͼᴀⱳ꞉ᴟᴒͼᴄԜᴦԓͼꜙᴒᴥ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷉᷾᷉᷈ͼᴂᴀⱨ
͟ⱳꜝꜜᴒⱡͼ
Medical Monitor (US, Canada):
ԓͼꜚⱫ
ԓͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼⱫᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡ
᷊᷇᷇ͼᴀⱳ꞉ᴟᴒͼᴄԜᴦԓͼꜙᴒᴥ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷉᷾᷉᷈ͼᴂᴀⱨ
͟ⱳꜝꜜᴒⱡͼ
ⱬꜛԜ꞉ꞌⱡͼ
Medical Monitor (Jordan, Europe):
ԓͼꜚⱫ
ԓͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼⱫᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡ
᷊᷇᷇ͼᴀⱳ꞉ᴟᴒͼᴄԜᴦԓͼꜙᴒᴥ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷉᷾᷉᷈ͼᴂᴀⱨ
͟ⱳꜝꜜᴒⱡͼ
ⱬꜛԜ꞉ꞌⱡͼ
Study Monitoring (US):
ϸⱳꜝԓͼⱷꜜᴐ᷅
ԓͼ
ԓͼ
͟ⱳꜝꜜᴒⱡͼ
Study Monitoring (Jordan)
ᴁᴟ꞉ᴢꜛꜞⱳԜᴟꜛԜ
ԓͼ
ԓͼ
ԓͼꜗꜝᴟᴑԜꜜ
͟ⱳꜝꜜᴒⱡͼ
Study Monitoring (Canada)
ϸᴒᴑͼꜚԜꜞꞌᴒͼᴁᴟ꞉ԜꞌᴠͼⱷꜜᴐꜝᴟꜞꜝᴟԜᴡᴒᴑ
ԓͼ
ԓͼ
ԓͼⱪԜꜜԜᴑԜԓͼ
͟ⱳꜝꜜᴒⱡͼ
Study Monitoring (Europe)
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅ԓͼԜꜜͼ꞉ꜜᴑ꞉ᴟᴒᴐᴡԓͼᴤⱳꜝꞌꞌᴦ᷄ꜝᴤꜜᴒᴑͼᴠᴢԝᴠ꞉ᴑ꞉Ԝᴟᴦͼꜝⱱͼ
ᴀⱳ꞉ᴟᴒͼꜞꞌᴐ᷅
᷿᷿ͼ꜠ᴒᴡᴤꜝᴟꞋͼⱫᴟ꞉ᴣᴒԓͼⱩᴢᴟꞌ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨͼ᷇᷈˲᷊᷇
͟ⱳꜝꜜᴒⱡͼ
10.1
Institutional Review Board/Research Ethics Board/Independent 
Ethics Committee
ᴁⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼԜꜜᴑͼԜꞌꞌͼꜞᴟꜝᴡꜝᴐꜝꞌͼԜꜛᴒꜜᴑꜛᴒꜜᴡᴠͼꜛᴢᴠᴡͼԝᴒͼᴠ꞉ⱲꜜᴒᴑͼԜꜜᴑͼᴑԜᴡᴒᴑͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜꜜᴑͼ
Ԝꜞꜞᴟꜝᴣᴒᴑͼ꞉ꜜͼᴤᴟ꞉ᴡ꞉ꜜⱲͼԝᴦͼᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪͼ꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼⱵⱪ͟ͼꜞᴟ꞉ꜝᴟͼᴡꜝͼ꞉ꜛꜞꞌᴒꜛᴒꜜᴡԜᴡ꞉ꜝꜜ᷅ͼⱷꜜͼ
Ԝᴑᴑ꞉ᴡ꞉ꜝꜜԓͼᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪͼꜛᴢᴠᴡͼԜꜞꜞᴟꜝᴣᴒͼᴡⱳᴒͼᴤᴟ꞉ᴡᴡᴒꜜͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼԜꜜᴑͼԜᴠᴠᴒꜜᴡͼⱱꜝᴟꜛᴠԓͼԜꜜᴦͼ
ᴐꜝꜜᴠᴒꜜᴡͼꜝᴟͼԜᴠᴠᴒꜜᴡͼⱱꜝᴟꜛͼᴢꜞᴑԜᴡᴒᴠԓͼᴠᴢԝ꞊ᴒᴐᴡͼᴟᴒᴐᴟᴢ꞉ᴡꜛᴒꜜᴡͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼӿᴒ᷅Ⱳ᷅ԓͼԜᴑᴣᴒᴟᴡ꞉ᴠᴒꜛᴒꜜᴡᴠԐԓͼԜꜜᴑͼԜꜜᴦͼ
ᴤᴟ꞉ᴡᴡᴒꜜͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴡꜝͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴡꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼ꞉ꜛꜞꞌᴒꜛᴒꜜᴡԜᴡ꞉ꜝꜜ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼ
ꜞᴟꜝᴣ꞉ᴑᴒͼԜꜜͼԜꜜꜜᴢԜꞌͼᴟᴒꜞꜝᴟᴡͼᴡꜝͼᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪͼꜝꜜͼᴡⱳᴒͼꜞᴟꜝⱲᴟᴒᴠᴠͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼꜜᴢꜛԝᴒᴟͼꜝⱱͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴒꜜᴟꜝꞌꞌᴒᴑԓͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒᴑԓͼԜꜜᴑͼᴀⱨⱬᴠ᷅ͼⱷᴡͼ꞉ᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡⱳԜᴡͼԜͼᴦᴒԜᴟꞌᴦͼᴟᴒᴣ꞉ᴒᴤͼꜝⱱͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼԝᴦͼ
ᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪͼԝᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼ꞉ꜜͼԜͼꞌᴒᴡᴡᴒᴟͼⱱᴟꜝꜛͼᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼ
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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PPD
PPD
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PPD
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Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜞᴟꜝᴣ꞉ᴑᴒͼꜜꜝᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼᴡꜝͼᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪͼꜝⱱͼᴡⱳᴒͼᴐꜝꜛꜞꞌᴒᴡ꞉ꜝꜜԓͼᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜͼꜝᴟͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
ᴠᴡᴢᴑᴦ᷅
10.2
Ethical Conduct of the Study
ᴁⱳᴒͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴠᴒᴡͼꜝᴢᴡͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦͼꜞᴟꜝᴡꜝᴐꜝꞌͼԜᴟᴒͼᴑᴒᴠ꞉ⱲꜜᴒᴑͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼᴡⱳԜᴡͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԜꜜᴑͼ
ᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜԝ꞉ᴑᴒͼԝᴦͼᴡⱳᴒͼꜞᴟ꞉ꜜᴐ꞉ꜞꞌᴒᴠͼꜝⱱͼᴡⱳᴒͼⱷꜜᴡᴒᴟꜜԜᴡ꞉ꜝꜜԜꞌͼⱪꜝꜜⱱᴒᴟᴒꜜᴐᴒͼꜝꜜͼⱶԜᴟꜛꜝꜜ꞉ᴠԜᴡ꞉ꜝꜜͼӿⱷⱪⱶԐͼ
Ⱳᴢ꞉ᴑᴒꞌ꞉ꜜᴒᴠͼꜝꜜͼⱵⱪ͟ԓͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒͼꞌꜝᴐԜꞌͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠԓͼԜꜜᴑͼᴡⱳᴒͼⱫᴒᴐꞌԜᴟԜᴡ꞉ꜝꜜͼꜝⱱͼⱶᴒꞌᴠ꞉ꜜꞋ꞉ͼ
ӿᴃᴒᴟᴠ꞉ꜝꜜͼ᷉᷇᷇˲Ԑ᷅ͼᴁⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦͼԜꞌᴠꜝͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜᴟᴟ꞉ᴒᴑͼꜝᴢᴡͼ꞉ꜜͼꞋᴒᴒꜞ꞉ꜜⱲͼᴤ꞉ᴡⱳͼꜜԜᴡ꞉ꜝꜜԜꞌͼԜꜜᴑͼꞌꜝᴐԜꞌͼ
ꞌᴒⱲԜꞌͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼᴈ꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳͼᴂꜜ꞉ᴡᴒᴑͼᴀᴡԜᴡᴒᴠͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼ꜠ᴒᴤͼⱫᴟᴢⱲͼӿⱷ꜠ⱫԐͼ
ᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠͼӿ᷉᷈ͼⱪⱴϸͼ᷿⅍Ԑᴊ᷅
10.3
Subject Information and Consent
ⱩᴒⱱꜝᴟᴒͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦԓͼᴤᴟ꞉ᴡᴡᴒꜜͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼꜝԝᴡԜ꞉ꜜᴒᴑͼ
Ԝᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼԜꜜᴑͼꞌᴒⱲԜꞌͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼꜝⱱͼᴡⱳᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼᴐꜝᴢꜜᴡᴟᴦ᷅ͼⱨᴠͼꜞԜᴟᴡͼꜝⱱͼᴡⱳ꞉ᴠͼ
ꜞᴟꜝᴐᴒᴑᴢᴟᴒԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼᴒᴥꜞꞌԜ꞉ꜜͼꜝᴟԜꞌꞌᴦͼԜꜜᴑͼ꞉ꜜͼᴤᴟ꞉ᴡ꞉ꜜⱲͼᴡⱳᴒͼꜜԜᴡᴢᴟᴒԓͼᴑᴢᴟԜᴡ꞉ꜝꜜԓͼԜꜜᴑͼꜞᴢᴟꜞꜝᴠᴒͼ
ꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼԜꜜᴑͼᴡⱳᴒͼԜᴐᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴑᴟᴢⱲͼ꞉ꜜͼᴠᴢᴐⱳͼԜͼꜛԜꜜꜜᴒᴟͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴤԜᴟᴒͼꜝⱱͼᴡⱳᴒͼ
ꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼᴟ꞉ᴠꞋᴠԓͼ꞉ꜜᴐꜝꜜᴣᴒꜜ꞉ᴒꜜᴐᴒᴠԓͼꜝᴟͼⱨⱬᴠͼᴡⱳԜᴡͼꜛԜᴦͼꜝᴐᴐᴢᴟ᷅ͼᴁⱳᴒͼᴠᴡᴢᴑᴦͼᴠᴢԝ꞊ᴒᴐᴡͼᴠⱳꜝᴢꞌᴑͼԝᴒͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼ
ᴡⱳԜᴡͼⱳᴒ᷆ᴠⱳᴒͼ꞉ᴠͼⱱᴟᴒᴒͼᴡꜝͼᴤ꞉ᴡⱳᴑᴟԜᴤͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒ᷅ͼⱶᴒ᷆ᴠⱳᴒͼᴤ꞉ꞌꞌͼᴟᴒᴐᴒ꞉ᴣᴒͼԜꞌꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ
ᴡⱳԜᴡͼ꞉ᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼԝᴦͼⱱᴒᴑᴒᴟԜꞌͼᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠͼԜꜜᴑͼⱷⱪⱶͼⱲᴢ꞉ᴑᴒꞌ꞉ꜜᴒᴠ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼᴢꜜᴑᴒᴟͼᴡⱳᴒͼԜⱲᴒͼꜝⱱͼ᷈˲ͼ
ӿꜝᴟͼꞌꜝᴤᴒᴟͼ꞉ⱱͼԜⱲᴒͼꜝⱱͼᴐꜝꜜᴠᴒꜜᴡͼ꞉ᴠͼꞌᴒᴠᴠͼᴡⱳԜꜜͼ᷈˲ͼ꞉ꜜͼԜͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐͼᴐꜝᴢꜜᴡᴟᴦԐͼԜꜜᴑͼᴤⱳꜝᴠᴒͼꞌᴒⱲԜꞌͼⱲᴢԜᴟᴑ꞉Ԝꜜͼꜝᴟͼ
ᴐԜᴟᴒᴡԜꞋᴒᴟͼⱳԜᴠͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴤᴟ꞉ᴡᴡᴒꜜͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼᴤ꞉ꞌꞌͼꜞᴟꜝᴣ꞉ᴑᴒͼᴡⱳᴒ꞉ᴟͼԜᴠᴠᴒꜜᴡͼᴡꜝͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒ᷅ͼᴁⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼᴤ꞉ꞌꞌͼꜞᴟꜝᴣ꞉ᴑᴒͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴤ꞉ᴡⱳͼԜͼᴐꜝꜞᴦͼꜝⱱͼᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪ᷄Ԝꜞꜞᴟꜝᴣᴒᴑͼ
꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼԜꜜᴑͼԜᴠᴠᴒꜜᴡͼⱱꜝᴟꜛᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
10.4
Subject Confidentiality
ᴁⱳᴒͼԜꜜꜝꜜᴦꜛ꞉ᴡᴦͼꜝⱱͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼᴠᴢԝ꞊ᴒᴐᴡᴠͼꜛᴢᴠᴡͼԝᴒͼꜛԜ꞉ꜜᴡԜ꞉ꜜᴒᴑ᷅ͼᴀᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼꜝꜜͼᴠᴡᴢᴑᴦͼ
ᴑꜝᴐᴢꜛᴒꜜᴡᴠͼԝᴦͼᴡⱳᴒ꞉ᴟͼᴠᴢԝ꞊ᴒᴐᴡꜜᴢꜛԝᴒᴟͼԜꜜᴑͼԝ꞉ᴟᴡⱳͼᴑԜᴡᴒͼӿ꞉ⱱͼԜꞌꞌꜝᴤᴒᴑͼԝԜᴠᴒᴑͼꜝꜜͼꞌꜝᴐԜꞌͼᴑԜᴡԜͼꜞᴟꜝᴡᴒᴐᴡ꞉ꜝꜜͼ
ᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠԐԓͼꜜꜝᴡͼԝᴦͼꜜԜꜛᴒ᷅ͼⱫꜝᴐᴢꜛᴒꜜᴡᴠͼᴡⱳԜᴡͼ꞉ᴑᴒꜜᴡ꞉ⱱᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼӿᴒ᷅Ⱳ᷅ԓͼᴡⱳᴒͼᴠ꞉Ⱳꜜᴒᴑͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼ
ᴑꜝᴐᴢꜛᴒꜜᴡԐͼꜛᴢᴠᴡͼԝᴒͼꜛԜ꞉ꜜᴡԜ꞉ꜜᴒᴑͼ꞉ꜜͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴐᴒͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԜⱲᴟᴒᴒᴠͼꜜꜝᴡͼᴡꜝͼᴢᴠᴒͼꜝᴟͼᴑ꞉ᴠᴐꞌꜝᴠᴒͼꜞᴟꜝᴡᴒᴐᴡᴒᴑͼⱳᴒԜꞌᴡⱳͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜝᴡⱳᴒᴟͼᴡⱳԜꜜͼԜᴠͼ
ꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼꜝᴟͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼԝᴦͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜᴢᴡⱳꜝᴟ꞉ᴧԜᴡ꞉ꜝꜜͼꜝᴟͼԜᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼԝᴦͼꞌԜᴤ᷅
10.5
Study Monitoring
ᴁⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼӿꜝᴟͼᴑᴒᴠ꞉ⱲꜜᴒᴒԐͼᴤ꞉ꞌꞌͼᴐꜝꜜᴑᴢᴐᴡͼԜͼᴠᴡᴢᴑᴦͼ꞉ꜜ꞉ᴡ꞉Ԝᴡ꞉ꜝꜜͼᴣ꞉ᴠ꞉ᴡͼᴡꜝͼᴣᴒᴟ꞉ⱱᴦͼᴡⱳᴒͼꜟᴢԜꞌ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜᴠͼꜝⱱͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟԓͼ꞉ꜜᴠꜞᴒᴐᴡͼᴡⱳᴒͼⱱԜᴐ꞉ꞌ꞉ᴡ꞉ᴒᴠԓͼԜꜜᴑͼ꞉ꜜⱱꜝᴟꜛͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝⱱͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝ꞉ꞌ꞉ᴡ꞉ᴒᴠͼԜꜜᴑͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼ
ⱱꜝᴟͼᴒꜜᴠᴢᴟ꞉ꜜⱲͼԜᴑᴒꜟᴢԜᴡᴒͼԜꜜᴑͼᴐꜝᴟᴟᴒᴐᴡͼᴑꜝᴐᴢꜛᴒꜜᴡԜᴡ꞉ꜝꜜ᷅
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼꜞᴟᴒꜞԜᴟᴒͼԜꜜᴑͼꜛԜ꞉ꜜᴡԜ꞉ꜜͼԜᴑᴒꜟᴢԜᴡᴒͼԜꜜᴑͼԜᴐᴐᴢᴟԜᴡᴒͼᴟᴒᴐꜝᴟᴑᴠͼꜝⱱͼԜꞌꞌͼꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜᴠͼ
ԜꜜᴑͼꜝᴡⱳᴒᴟͼᴑԜᴡԜͼꜞᴒᴟᴡ꞉ꜜᴒꜜᴡͼᴡꜝͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦͼⱱꜝᴟͼᴒԜᴐⱳͼᴠᴡᴢᴑᴦͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜꜜᴡ᷅ͼⱴᴟᴒꜟᴢᴒꜜᴡͼᴐꜝꜛꜛᴢꜜ꞉ᴐԜᴡ꞉ꜝꜜͼ
ԝᴒᴡᴤᴒᴒꜜͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠ꞉ᴡᴒͼԜꜜᴑͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼ꞉ᴠͼᴒᴠᴠᴒꜜᴡ꞉ԜꞌͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼᴡⱳԜᴡͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼ꞉ᴠͼ
ꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼԜᴑᴒꜟᴢԜᴡᴒꞌᴦ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ꞌꞌͼꜛԜꞋᴒͼԜꞌꞌͼԜꜞꜞᴟꜝꜞᴟ꞉ԜᴡᴒͼᴠԜⱱᴒᴡᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼꜝꜜͼԜꜜͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲ⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜝꜜⱲꜝ꞉ꜜⱲͼԝԜᴠ꞉ᴠ᷅ͼᴁⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼꜛԜᴦͼᴟᴒᴣ꞉ᴒᴤͼᴠԜⱱᴒᴡᴦͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼԜᴠͼ꞉ᴡͼԝᴒᴐꜝꜛᴒᴠͼԜᴣԜ꞉ꞌԜԝꞌᴒͼ
ᴡⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
ⱨꞌꞌͼԜᴠꜞᴒᴐᴡᴠͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴐԜᴟᴒⱱᴢꞌꞌᴦͼꜛꜝꜜ꞉ᴡꜝᴟᴒᴑͼᴤ꞉ᴡⱳͼᴟᴒᴠꜞᴒᴐᴡͼᴡꜝͼⱵⱪ͟ͼԜꜜᴑͼᴀ꜡͟ᴠͼⱱꜝᴟͼ
ᴐꜝꜛꜞꞌ꞉Ԝꜜᴐᴒͼᴤ꞉ᴡⱳͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒͼⱲꜝᴣᴒᴟꜜꜛᴒꜜᴡͼᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠ᷅ͼᴁⱳᴒͼᴀᴡᴢᴑᴦͼꜚꜝꜜ꞉ᴡꜝᴟͼᴤ꞉ꞌꞌͼԝᴒͼԜꜜͼԜᴢᴡⱳꜝᴟ꞉ᴧᴒᴑͼ
꞉ꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴑᴒᴠ꞉ⱲꜜԜᴡᴒᴑͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ᷅ͼᴁⱳᴒͼᴀᴡᴢᴑᴦͼꜚꜝꜜ꞉ᴡꜝᴟͼᴤ꞉ꞌꞌͼⱳԜᴣᴒͼԜᴐᴐᴒᴠᴠͼᴡꜝͼԜꞌꞌͼᴟᴒᴐꜝᴟᴑᴠͼ
ꜜᴒᴐᴒᴠᴠԜᴟᴦͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼ꞉ꜜᴡᴒⱲᴟ꞉ᴡᴦͼꜝⱱͼᴡⱳᴒͼᴑԜᴡԜͼԜꜜᴑͼᴤ꞉ꞌꞌͼꜞᴒᴟ꞉ꜝᴑ꞉ᴐԜꞌꞌᴦͼᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒͼꜞᴟꜝⱲᴟᴒᴠᴠͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼ
ᴤ꞉ᴡⱳͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅
10.6
Case Report Forms and Study Records
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ꞌꞌͼᴒꜜᴠᴢᴟᴒͼᴡⱳᴒͼԜᴐᴐᴢᴟԜᴐᴦԓͼᴐꜝꜛꜞꞌᴒᴡᴒꜜᴒᴠᴠԓͼԜꜜᴑͼᴡ꞉ꜛᴒꞌ꞉ꜜᴒᴠᴠͼꜝⱱͼᴡⱳᴒͼᴑԜᴡԜͼᴟᴒꜞꜝᴟᴡᴒᴑͼᴡꜝͼ
ᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ᷅ͼⱫԜᴡԜͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼꜞᴟꜝᴐᴒᴠᴠᴒᴠͼԜꜜᴑͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒᴣ꞉ᴒᴤᴒᴑͼԜꜜᴑͼᴣԜꞌ꞉ᴑԜᴡᴒᴑͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼ
ᴐꜝꜛꜞꞌᴒᴡᴒꜜᴒᴠᴠԓͼԜᴐᴐᴢᴟԜᴐᴦԓͼᴟᴒꞌ꞉Ԝԝ꞉ꞌ꞉ᴡᴦԓͼԜꜜᴑͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴐᴦ᷅ͼⱨͼᴐꜝꜛꜞꞌᴒᴡᴒͼԜᴢᴑ꞉ᴡͼᴡᴟԜ꞉ꞌͼᴤ꞉ꞌꞌͼԝᴒͼꜛԜ꞉ꜜᴡԜ꞉ꜜᴒᴑͼꜝⱱͼ
ԜꞌꞌͼᴑԜᴡԜͼᴐⱳԜꜜⱲᴒᴠ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼᴤ꞉ꞌꞌͼᴐꜝꜝꜞᴒᴟԜᴡᴒͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟᶳᴠͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒӿᴠԐͼ
ⱱꜝᴟͼᴡⱳᴒͼꜞᴒᴟ꞉ꜝᴑ꞉ᴐͼᴟᴒᴣ꞉ᴒᴤͼꜝⱱͼᴠᴡᴢᴑᴦͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼᴡꜝͼᴒꜜᴠᴢᴟᴒͼᴡⱳᴒͼԜᴐᴐᴢᴟԜᴐᴦͼԜꜜᴑͼᴐꜝꜛꜞꞌᴒᴡᴒꜜᴒᴠᴠͼꜝⱱͼᴡⱳᴒͼᴑԜᴡԜͼ
ᴐԜꜞᴡᴢᴟᴒͼᴠᴦᴠᴡᴒꜛͼԜᴡͼᴒԜᴐⱳͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼᴣ꞉ᴠ꞉ᴡ᷅
ⱬꞌᴒᴐᴡᴟꜝꜜ꞉ᴐͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴐᴦͼᴐⱳᴒᴐꞋᴠͼԜꜜᴑͼꜛԜꜜᴢԜꞌͼᴟᴒᴣ꞉ᴒᴤͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼᴡꜝͼ꞉ᴑᴒꜜᴡ꞉ⱱᴦͼԜꜜᴦͼᴒᴟᴟꜝᴟᴠͼꜝᴟͼ
꞉ꜜᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴐ꞉ᴒᴠͼ꞉ꜜͼᴡⱳᴒͼᴑԜᴡԜ᷅ͼᴁⱳ꞉ᴠͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴡꜝͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠ꞉ᴡᴒᴠͼԝᴦͼꜛᴒԜꜜᴠͼꜝⱱͼ
ᴒꞌᴒᴐᴡᴟꜝꜜ꞉ᴐͼꜝᴟͼꜛԜꜜᴢԜꞌͼꜟᴢᴒᴟ꞉ᴒᴠ᷅
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜝᴟͼᴑᴒᴠ꞉Ⱳꜜᴒᴒͼᴤ꞉ꞌꞌͼꜞᴟᴒꜞԜᴟᴒͼԜꜜᴑͼꜛԜ꞉ꜜᴡԜ꞉ꜜͼԜᴑᴒꜟᴢԜᴡᴒͼԜꜜᴑͼԜᴐᴐᴢᴟԜᴡᴒͼᴠᴡᴢᴑᴦͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼ
ӿꜛᴒᴑ꞉ᴐԜꞌͼᴟᴒᴐꜝᴟᴑᴠԓͼⱬⱪⱵᴠԓͼⱨⱬͼԜꜜᴑͼᴐꜝꜜᴐꜝꜛ꞉ᴡԜꜜᴡͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲԓͼᴠꜝᴢᴟᴐᴒͼᴑԜᴡԜͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼⱱꜝᴟꜛᴠԓͼ
ᴒᴡᴐ᷅Ԑͼᴑᴒᴠ꞉ⱲꜜᴒᴑͼᴡꜝͼᴟᴒᴐꜝᴟᴑͼԜꞌꞌͼꜝԝᴠᴒᴟᴣԜᴡ꞉ꜝꜜᴠͼԜꜜᴑͼꜝᴡⱳᴒᴟͼꜞᴒᴟᴡ꞉ꜜᴒꜜᴡͼᴑԜᴡԜͼⱱꜝᴟͼᴒԜᴐⱳͼᴠᴢԝ꞊ᴒᴐᴡͼᴟᴒᴐᴒ꞉ᴣ꞉ꜜⱲͼ
ᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴠᴡᴢᴑᴦͼᴑᴢⱲ᷅
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ꞌꞌͼԜꞌꞌꜝᴤͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒᴠԓͼᴐꜝꜜᴡᴟԜᴐᴡͼᴑᴒᴠ꞉ⱲꜜᴒᴒᴠԓͼԜᴢᴡⱳꜝᴟ꞉ᴧᴒᴑͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼ
Ԝᴢᴡⱳꜝᴟ꞉ᴡᴦͼ꞉ꜜᴠꜞᴒᴐᴡꜝᴟᴠԓͼԜꜜᴑͼᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪͼᴡꜝͼⱳԜᴣᴒͼᴑ꞉ᴟᴒᴐᴡͼԜᴐᴐᴒᴠᴠͼᴡꜝͼԜꞌꞌͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼꜞᴒᴟᴡԜ꞉ꜜ꞉ꜜⱲͼᴡꜝͼ
ᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
ⱨͼᴁᴟ꞉ԜꞌͼꜚԜᴠᴡᴒᴟͼⱴ꞉ꞌᴒͼᴤ꞉ꞌꞌͼԝᴒͼꜛԜ꞉ꜜᴡԜ꞉ꜜᴒᴑͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼӿꜝᴟͼᴑᴒᴠ꞉ⱲꜜᴒᴒԐ᷅ͼⱨꞌꞌͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼԜꜜᴑͼꜝᴡⱳᴒᴟͼ
ꜛԜᴡᴒᴟ꞉ԜꞌᴠͼᴡⱳԜᴡͼꜞᴒᴟᴡԜ꞉ꜜͼᴡꜝͼᴡⱳᴒͼᴐꜝꜜᴑᴢᴐᴡͼꜝⱱͼᴡⱳᴒͼᴡᴟ꞉ԜꞌԓͼꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼᴡⱳᴒͼᴑԜᴡԜԓͼԜꜜᴑͼᴐꜝꜛꜞꞌ꞉Ԝꜜᴐᴒͼᴤ꞉ᴡⱳͼⱵⱪ͟ᴠͼ
ᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴁᴟ꞉ԜꞌͼꜚԜᴠᴡᴒᴟͼⱴ꞉ꞌᴒ᷅
10.7
Data Safety Monitoring Board 
ⱨꜜͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼⱫᴀꜚⱩͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴠᴡԜԝꞌ꞉ᴠⱳᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼԜꜜͼꜝꜜⱲꜝ꞉ꜜⱲԓͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼᴟᴒᴣ꞉ᴒᴤͼԜꜜᴑͼ
ԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼᴠԜⱱᴒᴡᴦͼᴑԜᴡԜԓͼԜꜜᴑͼᴡꜝͼᴠԜⱱᴒⱲᴢԜᴟᴑͼᴡⱳᴒͼ꞉ꜜᴡᴒᴟᴒᴠᴡᴠͼԜꜜᴑͼᴠԜⱱᴒᴡᴦͼꜝⱱͼᴡⱳᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡ꞉ꜜⱲͼ
ꜞԜᴡ꞉ᴒꜜᴡᴠͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼ
ᴁⱳᴒͼⱫᴀꜚⱩͼᴤ꞉ꞌꞌͼԜᴑⱳᴒᴟᴒͼᴡꜝͼԜͼꜞᴟꜝᴠꜞᴒᴐᴡ꞉ᴣᴒꞌᴦͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼⱪⱳԜᴟᴡᴒᴟԓͼᴤⱳ꞉ᴐⱳͼᴤ꞉ꞌꞌͼԝᴒͼᴤᴟ꞉ᴡᴡᴒꜜͼԝᴦͼᴡⱳᴒͼ
ᴀꜞꜝꜜᴠꜝᴟͼԜꜜᴑͼԜꜞꜞᴟꜝᴣᴒᴑͼԝᴦͼᴡⱳᴒͼⱫᴀꜚⱩ᷅ͼᴁⱳᴒͼⱪⱳԜᴟᴡᴒᴟͼᴤ꞉ꞌꞌͼᴑᴒⱱ꞉ꜜᴒͼᴡⱳᴒͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝ꞉ꞌ꞉ᴡ꞉ᴒᴠͼꜝⱱͼᴡⱳᴒͼⱫᴀꜚⱩͼ
ԜꜜᴑͼᴀꜞꜝꜜᴠꜝᴟԓͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼԜꜜᴑͼᴡ꞉ꜛ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼⱫᴀꜚⱩͼꜛᴒᴒᴡ꞉ꜜⱲᴠԓͼᴡⱳᴒͼᴐꜝꜜᴑᴢᴐᴡͼꜝⱱͼᴡⱳᴒͼꜛᴒᴒᴡ꞉ꜜⱲᴠԓͼԜꜜᴑͼ
ᴡⱳᴒͼᴑԜᴡԜͼᴠᴒᴡᴠͼᴡꜝͼԝᴒͼᴟᴒᴣ꞉ᴒᴤᴒᴑͼԝᴦͼᴡⱳᴒͼⱫᴀꜚⱩ᷅ⱴᴢᴟᴡⱳᴒᴟͼᴑᴒᴡԜ꞉ꞌᴠͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴡⱳᴒͼⱫᴀꜚⱩͼᴐԜꜜͼԝᴒͼⱱꜝᴢꜜᴑͼ꞉ꜜͼ
ᴡⱳᴒͼⱫᴀꜚⱩͼᴐⱳԜᴟᴡᴒᴟ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
10.8
Protocol Violations/Deviations
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ꞌꞌͼԝᴒͼ꞉ꜜᴠᴡᴟᴢᴐᴡᴒᴑͼꜜꜝᴡͼᴡꜝͼᴑᴒᴣ꞉ԜᴡᴒͼⱱᴟꜝꜛͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌԓͼᴒᴥᴐᴒꜞᴡͼᴤⱳᴒᴟᴒͼꜜᴒᴐᴒᴠᴠԜᴟᴦͼᴡꜝͼ
ᴒꞌ꞉ꜛ꞉ꜜԜᴡᴒͼԜꜜͼ꞉ꜛꜛᴒᴑ꞉ԜᴡᴒͼⱳԜᴧԜᴟᴑᴡꜝͼᴠᴡᴢᴑᴦͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜꜜᴡᴠ᷅ͼᴀⱳꜝᴢꞌᴑͼꜝᴡⱳᴒᴟͼᴢꜜᴒᴥꜞᴒᴐᴡᴒᴑͼᴐ꞉ᴟᴐᴢꜛᴠᴡԜꜜᴐᴒᴠͼ
Ԝᴟ꞉ᴠᴒͼᴡⱳԜᴡͼᴤ꞉ꞌꞌͼᴟᴒꜟᴢ꞉ᴟᴒͼᴑᴒᴣ꞉Ԝᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼꜞᴟꜝᴡꜝᴐꜝꞌ᷄ᴠꜞᴒᴐ꞉ⱱ꞉ᴐͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴠⱳꜝᴢꞌᴑͼ
ᴐꜝꜜᴡԜᴐᴡͼᴡⱳᴒ꞉ᴟͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒͼᴡꜝͼᴑ꞉ᴠᴐᴢᴠᴠͼᴡⱳᴒͼԜꜞꜞᴟꜝꜞᴟ꞉ԜᴡᴒͼᴐꜝᴢᴟᴠᴒͼꜝⱱͼԜᴐᴡ꞉ꜝꜜ᷅ͼ
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴠⱳꜝᴢꞌᴑͼᴑꜝᴐᴢꜛᴒꜜᴡͼԜꞌꞌͼꜞᴟꜝᴡꜝᴐꜝꞌͼᴑᴒᴣ꞉Ԝᴡ꞉ꜝꜜᴠ᷆ᴣ꞉ꜝꞌԜᴡ꞉ꜝꜜᴠͼ꞉ꜜͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼᴒⱪϸⱴͼԜꜜᴑͼ
ᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼꜝᴟͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴀ꞉ᴡᴒͼⱴ꞉ꞌᴒͼ꞉ⱱͼԜꜞꜞᴟꜝꜞᴟ꞉Ԝᴡᴒ᷅ͼⱷꜜͼᴡⱳᴒͼᴒᴣᴒꜜᴡͼꜝⱱͼԜͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼ
ᴑᴒᴣ꞉Ԝᴡ꞉ꜝꜜ᷆ᴣ꞉ꜝꞌԜᴡ꞉ꜝꜜԓͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴠⱳꜝᴢꞌᴑͼꜜꜝᴡ꞉ⱱᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒ᷅ͼᴀ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼ
ᴑᴒᴣ꞉Ԝᴡ꞉ꜝꜜᴠ᷆ᴣ꞉ꜝꞌԜᴡ꞉ꜝꜜᴠͼ꞉ꜜᴐꞌᴢᴑᴒԓͼԝᴢᴡͼԜᴟᴒͼꜜꜝᴡͼꞌ꞉ꜛ꞉ᴡᴒᴑͼᴡꜝͼᴡⱳꜝᴠᴒͼᴡⱳԜᴡͼ꞉ꜜᴐᴟᴒԜᴠᴒͼᴡⱳᴒͼⱳᴒԜꞌᴡⱳͼᴟ꞉ᴠꞋͼᴡꜝͼᴡⱳᴒͼ
ᴠᴢԝ꞊ᴒᴐᴡԓͼꜝᴟͼᴐꜝꜜⱱꜝᴢꜜᴑͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜͼꜝⱱͼꜞᴟ꞉ꜛԜᴟᴦͼᴠᴡᴢᴑᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ꞌꞌͼꜞᴟꜝꜛꜞᴡꞌᴦͼ
ᴟᴒꜞꜝᴟᴡͼԜꞌꞌͼᴐⱳԜꜜⱲᴒᴠͼ꞉ꜜͼᴟᴒᴠᴒԜᴟᴐⱳͼԜᴐᴡ꞉ᴣ꞉ᴡᴦͼԜꜜᴑͼԜꞌꞌͼᴢꜜԜꜜᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼꜞᴟꜝԝꞌᴒꜛᴠͼ꞉ꜜᴣꜝꞌᴣ꞉ꜜⱲͼᴟ꞉ᴠꞋᴠͼᴡꜝͼⱳᴢꜛԜꜜͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼꜝᴟͼꜝᴡⱳᴒᴟᴠͼᴡꜝͼⱳ꞉ᴠͼꜝᴟͼⱳᴒᴟͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪ᷅
10.9
Premature Closure of the Study
ⱷⱱͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟԓͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟԓͼⱫᴀꜚⱩԓͼꜝᴟͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼԜᴢᴡⱳꜝᴟ꞉ᴡ꞉ᴒᴠͼᴑ꞉ᴠᴐꜝᴣᴒᴟͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠͼԜᴟ꞉ᴠ꞉ꜜⱲͼᴑᴢᴟ꞉ꜜⱲͼ
ᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴤⱳ꞉ᴐⱳͼ꞉ꜜᴑ꞉ᴐԜᴡᴒͼᴡⱳԜᴡͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜͼᴠⱳꜝᴢꞌᴑͼԝᴒͼⱳԜꞌᴡᴒᴑͼᴑᴢᴒͼᴡꜝͼԜꜜͼᴢꜜԜᴐᴐᴒꜞᴡԜԝꞌᴒͼ
ꜞԜᴡ꞉ᴒꜜᴡͼᴟ꞉ᴠꞋԓͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼꜛԜᴦͼԝᴒͼᴡᴒᴟꜛ꞉ꜜԜᴡᴒᴑͼꜝᴣᴒᴟԜꞌꞌͼꜝᴟͼԜᴡͼԜͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐͼᴠ꞉ᴡᴒͼԜⱱᴡᴒᴟͼԜꜞꜞᴟꜝꜞᴟ꞉Ԝᴡᴒͼ
ᴐꜝꜜᴠᴢꞌᴡԜᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԜꜜᴑͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟӿᴠԐ᷅ͼⱷꜜͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԓͼԜͼᴑᴒᴐ꞉ᴠ꞉ꜝꜜͼꜝꜜͼᴡⱳᴒͼꜞԜᴟᴡͼꜝⱱͼ
ᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴡꜝͼᴠᴢᴠꜞᴒꜜᴑͼꜝᴟͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴑᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼꜛԜᴦͼԝᴒͼꜛԜᴑᴒͼ
ԜᴡͼԜꜜᴦͼᴡ꞉ꜛᴒ᷅ͼⱪꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠͼᴡⱳԜᴡͼꜛԜᴦͼᴤԜᴟᴟԜꜜᴡͼᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼꜝᴟͼᴠ꞉ᴡᴒͼ꞉ꜜᴐꞌᴢᴑᴒԓͼԝᴢᴡͼԜᴟᴒͼꜜꜝᴡͼ
ꞌ꞉ꜛ꞉ᴡᴒᴑͼᴡꜝԓͼᴡⱳᴒͼⱱꜝꞌꞌꜝᴤ꞉ꜜⱲⱡ
ᶄ
ᴁⱳᴒͼᴑ꞉ᴠᴐꜝᴣᴒᴟᴦͼꜝⱱͼԜꜜͼᴢꜜᴒᴥꜞᴒᴐᴡᴒᴑԓͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡԓͼꜝᴟͼᴢꜜԜᴐᴐᴒꜞᴡԜԝꞌᴒͼᴟ꞉ᴠꞋͼᴡꜝͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ꜜͼ
ᴡⱳᴒͼᴠᴡᴢᴑᴦ
ᶄ
ⱴԜ꞉ꞌᴢᴟᴒͼꜝⱱͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡꜝͼᴐꜝꜛꜞꞌᴦͼᴤ꞉ᴡⱳͼꜞᴒᴟᴡ꞉ꜜᴒꜜᴡͼⱲꞌꜝԝԜꞌͼᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠ
ᶄ
ᴀᴢԝꜛ꞉ᴠᴠ꞉ꜝꜜͼꜝⱱͼꞋꜜꜝᴤ꞉ꜜⱲꞌᴦͼⱱԜꞌᴠᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴠ꞉ᴡᴒͼᴡꜝͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼꜝᴟͼꜝᴡⱳᴒᴟͼ
ꜞᴒᴟᴡ꞉ꜜᴒꜜᴡͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼԜᴢᴡⱳꜝᴟ꞉ᴡ꞉ᴒᴠ
ᶄ
ⱷꜜᴠᴢⱱⱱ꞉ᴐ꞉ᴒꜜᴡͼԜᴑⱳᴒᴟᴒꜜᴐᴒͼԝᴦͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴡꜝͼꜞᴟꜝᴡꜝᴐꜝꞌͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠ
10.10 Access to Source Documentation and On-Site Audits
ϸᴒⱲᴢꞌԜᴡꜝᴟᴦͼԜⱲᴒꜜᴐ꞉ᴒᴠͼꜛԜᴦͼᴟᴒꜟᴢᴒᴠᴡͼԜᴐᴐᴒᴠᴠͼᴡꜝͼԜꞌꞌͼᴠᴡᴢᴑᴦͼᴟᴒᴐꜝᴟᴑᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠԓͼⱱꜝᴟͼ
꞉ꜜᴠꜞᴒᴐᴡ꞉ꜝꜜͼԜꜜᴑͼᴐꜝꜞᴦ꞉ꜜⱲԓͼ꞉ꜜͼꞋᴒᴒꜞ꞉ꜜⱲͼᴤ꞉ᴡⱳͼᴐꜝᴢꜜᴡᴟᴦͼᴟᴒⱲᴢꞌԜᴡ꞉ꜝꜜᴠ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴠⱳꜝᴢꞌᴑͼ
꞉ꜛꜛᴒᴑ꞉Ԝᴡᴒꞌᴦͼꜜꜝᴡ꞉ⱱᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒͼꜝⱱͼԜꜜᴦͼԜꜜꜜꜝᴢꜜᴐᴒᴑͼꜝᴟͼᴢꜜԜꜜꜜꜝᴢꜜᴐᴒᴑͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼ
ԜⱲᴒꜜᴐᴦͼ꞉ꜜᴠꜞᴒᴐᴡ꞉ꜝꜜᴠ᷅ͼⱨꜜͼԜᴢᴑ꞉ᴡ꞉ꜜⱲͼ꞉ꜜᴠꜞᴒᴐᴡ꞉ꜝꜜͼꜛԜᴦͼԜꞌᴠꜝͼԝᴒͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒͼ
ꜝᴟͼᴑᴒᴠ꞉Ⱳꜜᴒᴒ᷅ͼⱨꜜᴦͼԜᴠꜞᴒᴐᴡͼꜝⱱͼᴡⱳᴒͼᴡᴟ꞉ԜꞌͼꜛԜᴦԝᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴡꜝͼԜᴢᴑ꞉ᴡͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼԜꜜᴑ᷆ꜝᴟͼ꞉ꜜᴠꜞᴒᴐᴡ꞉ꜝꜜͼԝᴦͼ
ᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼԜᴢᴡⱳꜝᴟ꞉ᴡ꞉ᴒᴠͼꜝᴟͼᴡⱳᴒͼⱷϸⱩ᷆ϸⱬⱩ᷆ⱷⱬⱪ᷅ͼᴀᴢᴐⱳͼԜᴢᴑ꞉ᴡᴠ᷆꞉ꜜᴠꜞᴒᴐᴡ꞉ꜝꜜᴠͼꜛԜᴦͼᴡԜꞋᴒͼꜞꞌԜᴐᴒͼԜᴡͼᴡⱳᴒͼ
ᴀꜞꜝꜜᴠꜝᴟᶳᴠͼᴠ꞉ᴡᴒӿᴠԐԓͼᴡⱳᴒͼⱪϸ꜡ԓͼꜝᴟͼԜᴡͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠ꞉ᴡᴒᴠԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼꞌԜԝꜝᴟԜᴡꜝᴟ꞉ᴒᴠԓͼꜞⱳԜᴟꜛԜᴐ꞉ᴒᴠͼԜꜜᴑͼԜꜜᴦͼ
ꜝᴡⱳᴒᴟͼⱱԜᴐ꞉ꞌ꞉ᴡ꞉ᴒᴠͼᴢᴠᴒᴑͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅ͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ˲Ⱡ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝꞌᴒͼⱱꜝᴟͼᴡⱳᴒͼԜᴐᴐᴢᴟԜᴐᴦͼꜝⱱͼᴡⱳᴒͼᴑԜᴡԜͼᴒꜜᴡᴒᴟᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅ͼᴁⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴤ꞉ꞌꞌͼꜞᴒᴟꜛ꞉ᴡͼᴡⱳᴒͼᴑᴒᴠ꞉ⱲꜜԜᴡᴒᴑͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒᴠͼԜꜜᴑͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼԝꜝᴑ꞉ᴒᴠͼᴡꜝͼⱳԜᴣᴒͼ
ᴑ꞉ᴟᴒᴐᴡͼԜᴐᴐᴒᴠᴠͼᴡꜝͼᴡⱳᴒͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼᴡꜝͼᴣᴒᴟ꞉ⱱᴦͼᴑԜᴡԜͼᴟᴒꜞᴟᴒᴠᴒꜜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅
10.11 Data Generation and Analysis
ᴁⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼ꞉ꜜͼԜᴐᴐꜝᴟᴑԜꜜᴐᴒͼᴤ꞉ᴡⱳᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼꜝᴢᴡꞌ꞉ꜜᴒᴑͼ꞉ꜜͼⱴꜝꜝᴑͼԜꜜᴑͼ
ⱫᴟᴢⱲͼⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼӿⱴⱫⱨԐ ᷉᷈ⱪⱴϸ ͟Ԝᴟᴡͼ᷿᷇ԓͼ᷉᷈ͼⱪⱴϸ ͟Ԝᴟᴡͼ᷿᷾ԓͼ᷉᷈ͼⱪⱴϸ ͟Ԝᴟᴡͼ᷿⅍ԓͼ᷉᷈ⱪⱴϸ ͟Ԝᴟᴡ᷊᷈᷉ͼ
Ԝꜜᴑͼ᷉᷈ͼⱪⱴϸ ͟Ԝᴟᴡͼ᷈᷈ͼԜᴠͼᴤᴒꞌꞌͼԜᴠͼᴡⱳᴒͼⱷⱪⱶͼⱵⱪ͟ͼⱬ⅍ͼⱵᴢ꞉ᴑᴒꞌ꞉ꜜᴒᴠ᷅ͼᴁⱳᴒͼᴠᴡᴢᴑᴦͼꜛꜝꜜ꞉ᴡꜝᴟᴠͼᴤ꞉ꞌꞌͼꜛᴒᴒᴡͼᴤ꞉ᴡⱳͼ
ᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼԜꜜᴑͼᴠᴡԜⱱⱱͼᴠⱳꜝᴟᴡꞌᴦͼԝᴒⱱꜝᴟᴒͼᴡⱳᴒͼᴠᴡԜᴟᴡͼꜝⱱͼᴡⱳᴒͼᴡᴟ꞉Ԝꞌͼᴡꜝͼᴟᴒᴣ꞉ᴒᴤͼᴡⱳᴒͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼⱱꜝᴟͼᴠᴡᴢᴑᴦͼ
ᴐꜝꜜᴑᴢᴐᴡͼԜꜜᴑͼᴑꜝᴐᴢꜛᴒꜜᴡԜᴡ꞉ꜝꜜ᷅ͼⱫᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼᴡⱳᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴠͼᴤ꞉ꞌꞌͼᴣ꞉ᴠ꞉ᴡͼᴡⱳᴒͼᴠ꞉ᴡᴒᴠͼᴡꜝͼᴣᴒᴟ꞉ⱱᴦͼᴟᴒᴐꜝᴟᴑͼ
Ꞌᴒᴒꜞ꞉ꜜⱲͼԜꜜᴑͼԜᴑⱳᴒᴟᴒꜜᴐᴒͼᴡꜝͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅ͼⱴꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦԓͼᴒⱪϸⱴᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑ᷅ͼᴁⱳᴒͼꜛꜝꜜ꞉ᴡꜝᴟᴠͼᴤ꞉ꞌꞌͼ
ᴐꜝꜜᴑᴢᴐᴡͼ᷈᷇᷇Ӽͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡͼᴣᴒᴟ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼԝᴦͼᴐꜝꜛꜞԜᴟ꞉ꜜⱲͼᴡⱳᴒͼᴒⱪϸⱴᴠͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼ
ᴡꜝͼᴒꜜᴠᴢᴟᴒͼԜᴐᴐᴢᴟԜᴐᴦͼԜꜜᴑͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴐᴦ᷅ͼⱬᴑ꞉ᴡͼᴐⱳᴒᴐꞋͼꜞᴟꜝⱲᴟԜꜛᴠԓͼꜝᴡⱳᴒᴟͼⱱꜝᴟꜛᴠͼꜝⱱͼᴒꞌᴒᴐᴡᴟꜝꜜ꞉ᴐͼᴣԜꞌ꞉ᴑԜᴡ꞉ꜝꜜԓͼ
ꜛԜꜜᴢԜꞌͼꞌ꞉ᴠᴡ꞉ꜜⱲᴠͼԜꜜᴑͼԜͼꜟᴢᴒᴟᴦͼꜞᴟꜝᴐᴒᴠᴠͼᴤ꞉ꞌꞌͼԝᴒͼᴒᴥᴒᴐᴢᴡᴒᴑͼᴡꜝͼᴣᴒᴟ꞉ⱱᴦͼᴡⱳᴒͼԜᴐᴐᴢᴟԜᴐᴦͼꜝⱱͼᴡⱳᴒͼᴑԜᴡԜԝԜᴠᴒ᷅ͼᴁⱳᴒͼ
ⱬⱫⱪͼᴠᴦᴠᴡᴒꜛͼᴤ꞉ꞌꞌͼꜛԜ꞉ꜜᴡԜ꞉ꜜͼԜͼⱱᴢꞌꞌͼԜᴢᴑ꞉ᴡͼᴡᴟԜ꞉ꞌͼꜝⱱͼᴒꞌᴒᴐᴡᴟꜝꜜ꞉ᴐͼᴑԜᴡԜͼᴐⱳԜꜜⱲᴒᴠ᷅ͼⱨᴐᴐᴒᴠᴠͼᴡꜝͼԜꞌꞌͼᴠꜝᴢᴟᴐᴒͼ
ᴑꜝᴐᴢꜛᴒꜜᴡԜᴡ꞉ꜝꜜͼᴤ꞉ꞌꞌͼԝᴒͼꜛԜᴑᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒͼⱱꜝᴟͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼԜꜜᴑͼԜᴢᴑ꞉ᴡͼꜞᴢᴟꜞꜝᴠᴒᴠ᷅
10.12 Data Handling Considerations
ⱫԜᴡԜͼᴡⱳԜᴡͼꜛԜᴦͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌꞌᴦͼᴢꜜԝꞌ꞉ꜜᴑͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴠᴠ꞉Ⱳꜜꜛᴒꜜᴡͼӿ꞉᷅ᴒ᷅ԓͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼᴠᴒᴟᴢꜛͼ
ᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜᴠԓͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜꞌꞌꜝᴐԜᴡ꞉ꜝꜜԓͼԜꜜᴑͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼꜞᴟᴒꜞԜᴟԜᴡ꞉ꜝꜜ᷆ԜᴐᴐꜝᴢꜜᴡԜԝ꞉ꞌ꞉ᴡᴦͼᴑԜᴡԜԐͼ
ᴤ꞉ꞌꞌͼԝᴒͼⱳԜꜜᴑꞌᴒᴑͼᴤ꞉ᴡⱳͼᴠꜞᴒᴐ꞉ԜꞌͼᴐԜᴟᴒͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴑԜᴡԜͼᴐꞌᴒԜꜜ꞉ꜜⱲͼԜꜜᴑͼᴟᴒᴣ꞉ᴒᴤͼꜞᴟꜝᴐᴒᴠᴠ᷅ͼᴁⱳᴒᴠᴒͼᴑԜᴡԜͼᴤ꞉ꞌꞌͼԝᴒͼ
ⱳԜꜜᴑꞌᴒᴑͼ꞉ꜜͼᴠᴢᴐⱳͼԜͼᴤԜᴦͼᴡⱳԜᴡԓͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴢꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲԓͼԜꜜᴦͼᴑԜᴡԜͼᴡⱳԜᴡͼꜛԜᴦͼᴢꜜԝꞌ꞉ꜜᴑͼᴠᴡᴢᴑᴦͼᴡᴒԜꜛͼꜞᴒᴟᴠꜝꜜꜜᴒꞌͼ
ᴤ꞉ꞌꞌͼԝᴒͼꜞᴟᴒᴠᴒꜜᴡᴒᴑͼԜᴠͼԝꞌ꞉ꜜᴑᴒᴑͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜝᴟͼꜝᴡⱳᴒᴟᴤ꞉ᴠᴒͼᴤ꞉ꞌꞌͼꜜꜝᴡͼԝᴒͼꜛԜᴑᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒ᷅ͼⱷⱱͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒԓͼ
ᴢꜜԝꞌ꞉ꜜᴑᴒᴑͼᴑԜᴡԜͼꜛԜᴦͼԝᴒͼꜛԜᴑᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒͼᴡꜝͼꜟᴢԜꞌ꞉ᴡᴦͼԜᴠᴠᴢᴟԜꜜᴐᴒͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒᴠͼⱱꜝᴟͼᴡⱳᴒͼꜞᴢᴟꜞꜝᴠᴒᴠͼꜝⱱͼ
ᴐꜝꜜᴑᴢᴐᴡ꞉ꜜⱲͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼᴑᴟᴢⱲͼԜᴢᴑ꞉ᴡᴠ᷅
10.13 Retention of Data
ⱨꞌꞌͼᴠꜝᴢᴟᴐᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼӿᴒ᷅Ⱳ᷅ԓͼ꞉ꜜⱱꜝᴟꜛᴒᴑͼᴐꜝꜜᴠᴒꜜᴡͼⱱꜝᴟꜛᴠԓͼꞌԜԝꜝᴟԜᴡꜝᴟᴦͼᴟᴒꜞꜝᴟᴡᴠԓͼꜞᴟꜝⱲᴟᴒᴠᴠͼꜜꜝᴡᴒᴠԓͼꜛᴒᴑ꞉ᴐԜꞌͼ
ⱳ꞉ᴠᴡꜝᴟ꞉ᴒᴠԓͼꜞⱳᴦᴠ꞉ᴐԜꞌͼԜꜜᴑͼᴑ꞉ԜⱲꜜꜝᴠᴡ꞉ᴐͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠԓͼᴑ꞉ԜⱲꜜꜝᴠ꞉ᴠͼԜꜜᴑͼꜞⱳԜᴟꜛԜᴐᴦͼᴟᴒᴐꜝᴟᴑᴠԓͼԜꜜᴑͼⱷꜚ͟ͼ
ᴑ꞉ᴠꜞᴒꜜᴠ꞉ꜜⱲ᷆ᴑ꞉ᴠꜞꜝᴠ꞉ᴡ꞉ꜝꜜͼᴟᴒᴐꜝᴟᴑᴠԐͼᴡⱳԜᴡͼᴠᴢꜞꜞꜝᴟᴡͼᴑԜᴡԜͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴᴠͼꜝⱱͼᴒԜᴐⱳͼᴠᴡᴢᴑᴦͼᴠᴢԝ꞊ᴒᴐᴡͼꜛᴢᴠᴡͼԝᴒͼ
ᴟᴒᴡԜ꞉ꜜᴒᴑͼ꞉ꜜͼᴡⱳᴒͼⱱ꞉ꞌᴒᴠͼꜝⱱͼᴡⱳᴒͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝꞌᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅
ⱨᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼⱷⱪⱶͼⱲᴢ꞉ᴑᴒꞌ꞉ꜜᴒᴠԓͼᴒᴠᴠᴒꜜᴡ꞉ԜꞌͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼᴠⱳꜝᴢꞌᴑͼԝᴒͼᴟᴒᴡԜ꞉ꜜᴒᴑͼⱱꜝᴟͼԜͼꜛ꞉ꜜ꞉ꜛᴢꜛͼꜝⱱͼ᷉ᴦᴒԜᴟᴠͼ
ԜⱱᴡᴒᴟͼᴡⱳᴒͼꞌԜᴠᴡͼԜꜞꜞᴟꜝᴣԜꞌͼꜝⱱͼԜͼꜛԜᴟꞋᴒᴡ꞉ꜜⱲͼԜꜞꜞꞌ꞉ᴐԜᴡ꞉ꜝꜜͼ꞉ꜜͼԜꜜͼⱷⱪⱶͼᴟᴒⱲ꞉ꜝꜜͼԜꜜᴑͼᴢꜜᴡ꞉ꞌͼᴡⱳᴒᴟᴒͼԜᴟᴒͼꜜꜝͼꜞᴒꜜᴑ꞉ꜜⱲͼ
ꜝᴟͼᴐꜝꜜᴡᴒꜛꜞꞌԜᴡᴒᴑͼꜛԜᴟꞋᴒᴡ꞉ꜜⱲͼԜꜞꜞꞌ꞉ᴐԜᴡ꞉ꜝꜜᴠͼ꞉ꜜͼԜꜜͼⱷⱪⱶͼᴟᴒⱲ꞉ꜝꜜͼꜝᴟͼԜᴡͼꞌᴒԜᴠᴡͼ᷉ᴦᴒԜᴟᴠͼⱳԜᴣᴒͼᴒꞌԜꜞᴠᴒᴑͼᴠ꞉ꜜᴐᴒͼ
ᴡⱳᴒͼⱱꜝᴟꜛԜꞌͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴑᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡͼꜝⱱͼᴡⱳᴒͼⱷꜚ᷅͟ͼⱶꜝᴤᴒᴣᴒᴟԓͼᴡⱳᴒᴠᴒͼᴑꜝᴐᴢꜛᴒꜜᴡᴠͼ
ᴠⱳꜝᴢꞌᴑͼԝᴒͼᴟᴒᴡԜ꞉ꜜᴒᴑͼⱱꜝᴟͼԜͼꞌꜝꜜⱲᴒᴟͼꜞᴒᴟ꞉ꜝᴑͼ꞉ⱱͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼԝᴦͼᴡⱳᴒͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒͼꞌᴒⱲԜꞌͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠ᷅
ⱷⱱͼᴡⱳᴒͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝꞌᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴟᴒᴡ꞉ᴟᴒᴠԓͼᴟᴒꞌꜝᴐԜᴡᴒᴠͼꜝᴟͼⱱꜝᴟͼԜꜜᴦͼꜝᴡⱳᴒᴟͼᴟᴒԜᴠꜝꜜͼᴤ꞉ᴡⱳᴑᴟԜᴤᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼ
ᴟᴒᴠꜞꜝꜜᴠ꞉ԝ꞉ꞌ꞉ᴡᴦͼꜝⱱͼꞋᴒᴒꜞ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴟᴒᴐꜝᴟᴑᴠԓͼᴐᴢᴠᴡꜝᴑᴦͼꜛᴢᴠᴡͼԝᴒͼᴡᴟԜꜜᴠⱱᴒᴟᴟᴒᴑͼᴡꜝͼԜͼꜞᴒᴟᴠꜝꜜͼᴤⱳꜝͼᴤ꞉ꞌꞌͼ
Ԝᴐᴐᴒꜞᴡͼᴡⱳᴒͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝ꞉ꞌ꞉ᴡᴦ᷅ͼᴁⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒͼꜛᴢᴠᴡͼԝᴒͼꜜꜝᴡ꞉ⱱ꞉ᴒᴑͼ꞉ꜜͼᴤᴟ꞉ᴡ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼꜜԜꜛᴒͼԜꜜᴑͼ
Ԝᴑᴑᴟᴒᴠᴠͼꜝⱱͼᴡⱳᴒͼꜜᴒᴤͼᴐᴢᴠᴡꜝᴑ꞉Ԝꜜԓͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴡⱳᴒͼᴡᴟԜꜜᴠⱱᴒᴟ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
10.14 Financial Disclosure
ᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ꞉ᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼᴑ꞉ᴠᴐꞌꜝᴠᴒͼԜꜜᴦͼⱱ꞉ꜜԜꜜᴐ꞉ԜꞌͼԜᴟᴟԜꜜⱲᴒꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜꜜᴑͼⱱꜝᴟͼ᷈ᴦᴒԜᴟͼ
Ԝⱱᴡᴒᴟԓͼᴤⱳᴒᴟᴒԝᴦͼᴡⱳᴒͼꜝᴢᴡᴐꜝꜛᴒͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴐꜝᴢꞌᴑͼԝᴒͼ꞉ꜜⱱꞌᴢᴒꜜᴐᴒᴑͼԝᴦͼᴡⱳᴒͼᴣԜꞌᴢᴒͼꜝⱱͼᴡⱳᴒͼᴐꜝꜛꜞᴒꜜᴠԜᴡ꞉ꜝꜜͼⱱꜝᴟͼ
ᴐꜝꜜᴑᴢᴐᴡ꞉ꜜⱲͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼꜝᴟͼꜝᴡⱳᴒᴟͼꜞԜᴦꜛᴒꜜᴡᴠͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴟᴒᴐᴒ꞉ᴣᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ᷅ͼᴁⱳᴒͼ
ⱱꜝꞌꞌꜝᴤ꞉ꜜⱲͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ꞉ᴠͼᴐꜝꞌꞌᴒᴐᴡᴒᴑⱡͼԜꜜᴦͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼꜞԜᴦꜛᴒꜜᴡᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼꜝᴟͼᴠᴢԝᴠ꞉ᴑ꞉Ԝᴟ꞉ᴒᴠͼ
ᴠᴢᴐⱳͼԜᴠͼԜͼⱲᴟԜꜜᴡͼᴡꜝͼⱱᴢꜜᴑͼꜝꜜⱲꜝ꞉ꜜⱲͼᴟᴒᴠᴒԜᴟᴐⱳԓͼᴐꜝꜛꜞᴒꜜᴠԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼⱱꜝᴟꜛͼꜝⱱͼᴒꜟᴢ꞉ꜞꜛᴒꜜᴡԓͼᴟᴒᴡԜ꞉ꜜᴒᴟͼⱱꜝᴟͼ
ꜝꜜⱲꜝ꞉ꜜⱲͼᴐꜝꜜᴠᴢꞌᴡԜᴡ꞉ꜝꜜͼꜝᴟͼⱳꜝꜜꜝᴟԜᴟ꞉ԜⱢͼԜꜜᴦͼꜞᴟꜝꜞᴟ꞉ᴒᴡԜᴟᴦͼ꞉ꜜᴡᴒᴟᴒᴠᴡͼ꞉ꜜͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡⱢԜꜜᴦͼ
ᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴡͼᴒꜟᴢ꞉ᴡᴦͼ꞉ꜜᴡᴒᴟᴒᴠᴡͼ꞉ꜜͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼꜝᴟͼᴠᴢԝᴠ꞉ᴑ꞉Ԝᴟ꞉ᴒᴠͼԜᴠͼᴑᴒⱱ꞉ꜜᴒᴑͼ꞉ꜜͼ᷉᷈ͼⱪⱴϸͼ᷿᷾ͼ᷉ӿԝԐͼӿ᷈ⱠⱠ˲Ԑ᷅
10.15 Publication and Disclosure Policy
ⱨꞌꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴐꜝꜜᴐᴒᴟꜜ꞉ꜜⱲͼⱫᴅ᷄᷉Ⱡ᷊᷇ԓͼᴀꜞꜝꜜᴠꜝᴟͼꜝꜞᴒᴟԜᴡ꞉ꜝꜜᴠԓͼꜞԜᴡᴒꜜᴡͼԜꜞꜞꞌ꞉ᴐԜᴡ꞉ꜝꜜᴠԓͼⱱꜝᴟꜛᴢꞌԜᴠԓͼ
ꜛԜꜜᴢⱱԜᴐᴡᴢᴟ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴠᴠᴒᴠԓͼԝԜᴠ꞉ᴐͼᴠᴐ꞉ᴒꜜᴡ꞉ⱱ꞉ᴐͼᴑԜᴡԜԓͼԜꜜᴑͼⱱꜝᴟꜛᴢꞌԜᴡ꞉ꜝꜜͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜԓͼᴠᴢꜞꜞꞌ꞉ᴒᴑͼᴡꜝͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼԝᴦͼԜͼᴀꜞꜝꜜᴠꜝᴟͼᴟᴒꜞᴟᴒᴠᴒꜜᴡԜᴡ꞉ᴣᴒͼԜꜜᴑͼꜜꜝᴡͼꜞᴟᴒᴣ꞉ꜝᴢᴠꞌᴦͼꜞᴢԝꞌ꞉ᴠⱳᴒᴑԓͼ꞉ᴠͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼᴐꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌͼ
ԜꜜᴑͼᴟᴒꜛԜ꞉ꜜᴠͼᴡⱳᴒͼᴠꜝꞌᴒͼꜞᴟꜝꜞᴒᴟᴡᴦͼꜝⱱͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ᷅ͼᴁⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼꜛᴢᴠᴡͼԜⱲᴟᴒᴒͼᴡꜝͼᴢᴠᴒͼᴡⱳ꞉ᴠͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ
ꜝꜜꞌᴦͼᴡꜝͼԜᴐᴐꜝꜛꜞꞌ꞉ᴠⱳͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦԓͼԜꜜᴑͼꜛᴢᴠᴡͼꜜꜝᴡͼᴢᴠᴒͼ꞉ᴡͼⱱꜝᴟͼꜝᴡⱳᴒᴟͼꜞᴢᴟꜞꜝᴠᴒᴠͼᴤ꞉ᴡⱳꜝᴢᴡͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟᶳᴠͼ
ԜᴑᴣԜꜜᴐᴒᴑͼᴤᴟ꞉ᴡᴡᴒꜜͼᴐꜝꜜᴠᴒꜜᴡ᷅ͼⱨͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳ꞉ᴠͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑᴦͼꜛԜᴦͼԜꞌᴠꜝͼԝᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒͼꜝꜜͼꜝᴡⱳᴒᴟͼ
ᴒᴥᴡᴒᴟꜜԜꞌꞌᴦͼⱱԜᴐ꞉ꜜⱲͼꜞᴢԝꞌ꞉ᴐͼᴤᴒԝᴠ꞉ᴡᴒᴠͼԜꜜᴑͼᴟᴒⱲ꞉ᴠᴡᴟ꞉ᴒᴠ᷅ͼⱨͼᴠᴢꜛꜛԜᴟᴦͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴟᴒᴠᴢꞌᴡᴠͼꜛԜᴦͼԝᴒͼ
ꜞꜝᴡᴒꜜᴡ꞉Ԝꞌꞌᴦͼᴑ꞉ᴠᴐꞌꜝᴠᴒᴑͼԜᴠͼꜞᴒᴟͼꞌꜝᴐԜꞌͼԜꜜᴑͼᴐꜝᴢꜜᴡᴟᴦͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠ᷅
ᴁⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴑᴒᴣᴒꞌꜝꜞᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼԝᴦͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼ꞉ꜜͼᴐꜝꜜꜜᴒᴐᴡ꞉ꜝꜜͼᴤ꞉ᴡⱳͼᴡⱳᴒͼ
ᴐꜝꜜᴡ꞉ꜜᴢᴒᴑͼᴑᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑͼᴡⱳᴢᴠͼꜛԜᴦͼԝᴒͼᴑ꞉ᴠᴐꞌꜝᴠᴒᴑͼԜᴠͼᴟᴒꜟᴢ꞉ᴟᴒᴑͼᴡꜝͼꜝᴡⱳᴒᴟͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᴠͼꜝᴟͼⱲꜝᴣᴒᴟꜜꜛᴒꜜᴡͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼԜⱲᴒꜜᴐ꞉ᴒᴠ᷅ͼᴁꜝͼꜞᴒᴟꜛ꞉ᴡͼᴡⱳᴒͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴑᴒᴟ꞉ᴣᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼ
ᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑ꞉ᴒᴠͼᴡꜝͼԝᴒͼᴢᴠᴒᴑԓͼᴡⱳᴒⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ꞉ᴠͼꜝԝꞌ꞉ⱲԜᴡᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟͼᴤ꞉ᴡⱳͼԜꞌꞌͼᴑԜᴡԜͼ
ꜝԝᴡԜ꞉ꜜᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
11 REFERENCE LIST
ⱩᴒꜜꜜᴒᴡᴡͼⱵԓͼⱪᴟԜ꞉Ⱳͼᴁ᷅ͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴤ꞉ᴡⱳͼԜͼⱱꜝᴐᴢᴠͼꜝꜜͼᴡⱳᴒͼᴐⱳ꞉ꞌᴑ᷅ͼⱨꞌꞌᴒᴟⱲᴦͼⱨᴠᴡⱳꜛԜͼ͟ᴟꜝᴐ᷅ͼ
᷿᷉᷇᷈Ɫ᷊⅍ӿ᷈Ԑⱡⅎ᷊᷇᷄᷅
ⱩꜝᴟꞋͼꜘԓͼⱶԜᴟᴑᴡͼꜗԓͼᴀᴐⱳ꞉ᴐꞋᴒᴡԜꜜᴧͼꜘ᷄ⱶԓͼϸᴒᴠᴠᴒꞌͼ꜠᷅ͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴠᴡᴢᴑ꞉ᴒᴠͼꜝⱱͼᴠᴢᴑᴑᴒꜜͼᴢꜞꜞᴒᴟͼԜ꞉ᴟᴤԜᴦͼꜝԝᴠᴡᴟᴢᴐᴡ꞉ꜝꜜͼ
꞉ꜜͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴑᴢᴒͼᴡꜝͼⱪ᷈ͼᴒᴠᴡᴒᴟԜᴠᴒͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦ᷅ͼⱨᴟᴐⱳͼⱷꜜᴡͼꜚᴒᴑ᷅ͼ
᷊᷉᷇᷇Ɫ᷈⅍᷊ⱡ᷈᷉᷉Ⱡ᷊᷿᷄᷈᷉᷅
ⱩꜝᴟꞋͼꜘԓͼⱶԜᴟᴑᴡͼꜗԓͼᴄ꞉ᴡᴧꞋᴒͼⱵ᷅ͼⱴԜᴡԜꞌͼꞌԜᴟᴦꜜⱲᴒԜꞌͼԜᴡᴡԜᴐꞋᴠͼԜꜜᴑͼꜛꜝᴟᴡԜꞌ꞉ᴡᴦͼ꞉ꜜͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴑᴢᴒͼᴡꜝͼ
ⱪ᷈᷄ⱷ꜠ⱶͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦ᷅ͼꜗͼⱨꞌꞌᴒᴟⱲᴦͼⱪꞌ꞉ꜜͼⱷꜛꜛᴢꜜꜝꞌ᷅ͼ᷉᷇᷈᷉Ɫ᷊᷈᷇ӿ᷊Ԑⱡ⅍Ⱡ᷉᷄ⅎ᷅
ⱩꜝᴟꞋͼꜘԓͼꜚᴒꜜⱲͼⱵԓͼᴀᴡԜᴢԝԜᴐⱳͼ͟ԓͼⱶԜᴟᴑᴡͼꜗ᷅ͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜⱡͼ꜠ᴒᴤͼⱱ꞉ꜜᴑ꞉ꜜⱲᴠͼᴐꜝꜜᴐᴒᴟꜜ꞉ꜜⱲͼ
ᴠᴦꜛꜞᴡꜝꜛᴠԓͼԜⱱⱱᴒᴐᴡᴒᴑͼꜝᴟⱲԜꜜᴠԓͼԜꜜᴑͼᴐꜝᴢᴟᴠᴒ᷅ͼⱨꜛͼꜗͼꜚᴒᴑ᷅ͼ᷉᷇᷇⅍Ɫ᷈᷈Ⱡӿ᷊Ԑⱡ᷉⅍ⅎ᷄᷉ⅎ᷾᷅
ⱩꜝᴟꞋͼꜘԓͼᴀ꞉ᴒᴑꞌᴒᴐꞋ꞉ͼꜘԓͼⱩꜝᴠᴐⱳͼᴀԓͼᴀᴐⱳꜝꜞⱱͼϸⱬԓͼꜘᴟᴒᴢᴧͼᴄ᷅ͼⱨᴠꜞⱳᴦᴥ꞉Ԝᴡ꞉ꜝꜜͼԝᴦͼꞌԜᴟᴦꜜⱲᴒԜꞌͼᴒᴑᴒꜛԜͼ꞉ꜜͼ
ꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷅ͼꜚԜᴦꜝͼⱪꞌ꞉ꜜͼ͟ᴟꜝᴐ᷅ͼ᷉᷇᷇᷇Ɫⅎ᷿ӿ᷾Ԑⱡ᷊᷾Ⱡ᷿᷄᷾᷅
ⱩᴦⱲᴢꜛͼⱨ᷅ͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝ᷄ꜝᴒᴑᴒꜛԜͼ꞉ꜜͼⱫᴒꜜꜛԜᴟꞋⱡͼԜͼꜜԜᴡ꞉ꜝꜜᴤ꞉ᴑᴒͼᴠᴢᴟᴣᴒᴦ᷅ͼⱩᴟͼꜗͼⱫᴒᴟꜛԜᴡꜝꞌ᷅ͼ
᷉᷇᷇ⱠⱢ᷈⅍᷈ӿ᷿Ԑⱡ᷿᷊᷈᷈᷄˲᷅
ⱪ꞉ᴐԜᴟᴑ꞉ͼꜚԓͼⱩꜝᴟꞋͼꜘԓͼⱪԜԝԜꞌꞌᴒᴟꜝͼᴁԓͼⱪᴟԜ꞉Ⱳͼᴁԓͼꜙ꞉ͼⱶⱶԓͼꜙꜝꜜⱲⱳᴢᴟᴠᴡͼⱶԓͼᴒᴡͼԜꞌ᷅ͼⱬᴣ꞉ᴑᴒꜜᴐᴒ᷄ԝԜᴠᴒᴑͼ
ᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜᴠͼⱱꜝᴟͼᴡⱳᴒͼᴡⱳᴒᴟԜꜞᴒᴢᴡ꞉ᴐͼꜛԜꜜԜⱲᴒꜛᴒꜜᴡͼꜝⱱͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼꜝᴤ꞉ꜜⱲͼᴡꜝͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼⱪ᷈ͼ
꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦⱡͼᴐꜝꜜᴠᴒꜜᴠᴢᴠͼᴟᴒꜞꜝᴟᴡͼꜝⱱͼԜꜜͼⱷꜜᴡᴒᴟꜜԜᴡ꞉ꜝꜜԜꞌͼᴄꜝᴟꞋ꞉ꜜⱲͼⱵᴟꜝᴢꜞ᷅ͼⱨꞌꞌᴒᴟⱲᴦ᷅ͼ
᷉᷇᷈᷉Ɫ⅍ⅎӿ᷉Ԑⱡ᷈᷾ⅎ᷿᷄ⅎ᷅
ⱪᴟԜ꞉Ⱳͼᴁԓͼ͟ᴢᴟᴠᴢꜜͼⱬⱨԓͼⱩꜝᴟꞋͼꜘԓͼⱩꜝᴤᴒꜜͼᴁԓͼⱩꜝᴦᴠᴒꜜͼⱶԓͼⱴԜᴟꞋԜᴠͼⱶԓͼᴒᴡͼԜꞌ᷅ͼᴄⱨ꜡ͼⱵᴢ꞉ᴑᴒꞌ꞉ꜜᴒͼⱱꜝᴟͼᴡⱳᴒͼ
ꜚԜꜜԜⱲᴒꜛᴒꜜᴡͼꜝⱱͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷅ͼᴄꜝᴟꞌᴑͼⱨꞌꞌᴒᴟⱲᴦͼ꜡ᴟⱲԜꜜͼꜗ᷅ͼ᷉᷇᷈᷉Ɫ᷿ӿ᷈᷉Ԑⱡ᷈˲᷉᷄᷈ⱠⱠ᷅
ⱫԜᴣ꞉ᴠͼⱨⱬԓͼ᷊ᴟᴑ᷅ͼꜚᴒᴐⱳԜꜜ꞉ᴠꜛͼꜝⱱͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼ꞉ꜜͼⱱ꞉ᴟᴠᴡͼᴐꜝꜛꜞꞌᴒꜛᴒꜜᴡͼᴐꜝꜛꜞꜝꜜᴒꜜᴡͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦ᷅ͼ
ⱷꜛꜛᴢꜜꜝꞌͼⱨꞌꞌᴒᴟⱲᴦͼⱪꞌ꞉ꜜͼ꜠ꜝᴟᴡⱳͼⱨꜛ᷅ͼ᷉᷇᷇⅍Ɫ᷉⅍ӿ᷾Ԑⱡ⅍᷊᷊᷿᷄᷈᷅
ⱴԜᴟꞋԜᴠͼⱶ᷅ͼ͟ᴒᴑ꞉Ԝᴡᴟ꞉ᴐͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴑᴢᴒͼᴡꜝͼⱪ᷈᷄꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦ᷅ͼⱨꞌꞌᴒᴟⱲᴦͼⱨᴠᴡⱳꜛԜͼⱪꞌ꞉ꜜͼ
ⱷꜛꜛᴢꜜꜝꞌ᷅ͼ᷉᷇᷈᷇Ɫ⅍ӿ᷈Ԑⱡ᷈˲᷅
Ⱶꜝᴟ꞉ꜜⱲͼⱶⱫԓͼⱩꜝᴟꞋͼꜘԓͼᴀꜞԜᴡⱳͼ͟ꜗԓͼⱩԜᴢᴒᴟͼϸԓͼᴇ꞉ᴒꜛᴒᴟͼⱨԓͼⱶ꞉ꜜᴡꜜᴒᴟͼⱶԓͼᴒᴡͼԜꞌ᷅ͼᴈⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼ꞉ꜜͼ
ᴡⱳᴒͼⱵᴒᴟꜛԜꜜ᷄ᴠꜞᴒԜꞋ꞉ꜜⱲͼᴟᴒⱲ꞉ꜝꜜᴊ᷅ͼⱶԜᴢᴡԜᴟᴧᴡ᷅ͼ᷈ⱠⱠ˲Ɫ᷾Ⱡӿ᷉Ԑⱡ᷈᷈᷾᷄᷉᷉᷅
ꜘⱨꜙⱩⱷᴁ꜡ϸᶇͼӿᴒᴐԜꞌꞌԜꜜᴡ꞉ᴑᴒԐͼᴈꜞԜᴐꞋԜⱲᴒͼ꞉ꜜᴠᴒᴟᴡᴊͼⱩᴢᴟꞌ꞉ꜜⱲᴡꜝꜜԓͼꜚⱨⱡͼⱫᴦԜᴥͼⱪꜝᴟꜞ᷅Ɫͼ᷿᷉᷇᷈᷅
ꜘԜꜞꞌԜꜜͼⱨ͟ԓͼꜗꜝᴠᴒꜞⱳͼꜘ᷅ͼᴁⱳᴒͼԝᴟԜᴑᴦꞋ꞉ꜜ꞉ꜜ᷄ⱱꜝᴟꜛ꞉ꜜⱲͼᴐԜᴠᴐԜᴑᴒͼԜꜜᴑͼ꞉ᴡᴠͼᴟꜝꞌᴒͼ꞉ꜜͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷅ͼ
ⱨꜜꜜͼⱨꞌꞌᴒᴟⱲᴦͼⱨᴠᴡⱳꜛԜͼⱷꜛꜛᴢꜜꜝꞌ᷅ͼ᷉᷇᷈᷇Ɫ᷈᷇᷾ӿ᷊Ԑⱡ᷈Ⱡ᷊᷄᷉᷇᷾᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ꜘᴒꜜꜜ꞉ᴠᴡꜝꜜͼꜗⱨԓͼⱴԜᴢᴐᴒᴡᴡᴒͼϸϸԓͼꜚԜᴟᴡ꞉ꞋͼⱫԓͼⱪꜝꜛᴒԜᴢͼᴀϸԓͼꜙ꞉ꜜᴑԝᴒᴟⱲͼⱨ͟ԓͼꜘꜝꜞԜᴐᴧͼꜘꜗԓͼᴒᴡͼԜꞌ᷅ͼⱷꜜⱳ꞉ԝ꞉ᴡ꞉ꜝꜜͼꜝⱱͼ
ꜞꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜͼԝᴦͼԜͼⱳ꞉Ⱳⱳꞌᴦͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐͼԜᴐᴡ꞉ᴣᴒͼᴠ꞉ᴡᴒͼԝꞌꜝᴐꞋ꞉ꜜⱲͼԜꜜᴡ꞉ԝꜝᴑᴦ᷅ͼꜗͼⱩ꞉ꜝꞌͼⱪⱳᴒꜛ᷅ͼ
᷉᷇᷈᷾Ɫ᷉˲Ⱡӿ᷊᷾Ԑⱡ᷊᷿᷉Ⱡ⅍᷄⅍᷇˲᷅
ꜙᴒ꞉ͼᴄᴁԓͼᴀⱳᴦᴢᴟͼᴀⱫԓͼⱶᴢԜꜜⱲͼꜙⱶԓͼꜘԜꜝͼᴆⱶԓͼꜙꜝͼⱪᴆ᷅ͼᴁᴦꜞᴒͼⱷͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼ꞉ꜜͼᴁԜ꞉ᴤԜꜜͼ᷄᷄
ᴐꞌ꞉ꜜ꞉ᴐԜꞌԓͼԝ꞉ꜝꞌꜝⱲ꞉ᴐԜꞌͼⱱᴒԜᴡᴢᴟᴒᴠͼԜꜜᴑͼⱲᴒꜜᴒᴡ꞉ᴐͼᴠᴡᴢᴑᴦ᷅ͼⱨᴠ꞉Ԝꜜͼ͟ԜᴐͼꜗͼⱨꞌꞌᴒᴟⱲᴦͼⱷꜛꜛᴢꜜꜝꞌ᷅ͼ᷉᷇᷈᷈Ɫ᷉Ⱡӿ᷾Ԑⱡ᷊᷉ⅎ᷊᷄᷈᷅
꜠ꜝᴟᴑᴒꜜⱱᴒꞌᴡͼ͟ԓͼⱫԜᴤᴠꜝꜜͼᴀԓͼᴄԜⱳꞌⱲᴟᴒꜜͼⱪⱴԓͼꜙ꞉ꜜᴑⱱꜝᴟᴠͼⱨԓͼꜚԜꞌꞌԝᴟ꞉ᴠͼꜙԓͼⱩ꞊ꜝᴟꞋԜꜜᴑᴒᴟͼꜗ᷅ͼϷᴢԜꜜᴡ꞉ⱱᴦ꞉ꜜⱲͼᴡⱳᴒͼ
ԝᴢᴟᴑᴒꜜͼꜝⱱͼᴑ꞉ᴠᴒԜᴠᴒͼԜꜜᴑͼꜞᴒᴟᴐᴒ꞉ᴣᴒᴑͼⱳᴒԜꞌᴡⱳͼᴠᴡԜᴡᴒͼ꞉ꜜͼꜞԜᴡ꞉ᴒꜜᴡᴠͼᴤ꞉ᴡⱳͼⱳᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼ꞉ꜜͼᴀᴤᴒᴑᴒꜜ᷅ͼ
ⱨꞌꞌᴒᴟⱲᴦͼⱨᴠᴡⱳꜛԜͼ͟ᴟꜝᴐ᷅ͼ᷉᷇᷈᷾Ɫ᷊᷿ӿ᷉Ԑⱡ᷈˲᷿᷄Ⱡ᷇᷅
ϸᴒꜜꜜᴒͼᴁԓͼⱵᴟᴢԝᴒᴟͼⱨ᷅ͼ͟ꞌԜᴠꜛԜͼꞋԜꞌꞌ꞉Ꞌᴟᴒ꞉ꜜⱡͼꜜꜝᴣᴒꞌͼⱱᴢꜜᴐᴡ꞉ꜝꜜᴠͼⱱꜝᴟͼԜꜜͼꜝꞌᴑͼꜞᴟꜝᴡᴒԜᴠᴒ᷅ͼᴁⱳᴟꜝꜛԝͼⱶԜᴒꜛꜝᴠᴡ᷅ͼ
᷉᷇᷈᷉Ɫ᷈᷇ⅎӿ⅍Ԑⱡ᷊᷈᷇᷈᷉᷄᷅
ϸꜝᴐⱳᴒͼ꜡ԓͼⱩꞌԜꜜᴐⱳͼⱨԓͼⱪԜԝԜꞌꞌᴒᴟꜝͼᴁԓͼᴀԜᴠᴡᴟᴒͼ꜠ԓͼⱪԜꞌꞌᴒ꞊ꜝͼⱫԓͼꜙꜝꜞᴒᴧ᷄ᴁᴟԜᴠᴐԜᴠԜͼꜚ᷅ͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼ
ԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼᴑᴢᴒͼᴡꜝͼⱪ᷈ͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦⱡͼꜞԜᴡ꞉ᴒꜜᴡͼᴟᴒⱲ꞉ᴠᴡᴟᴦͼԜꜜᴑͼԜꜞꜞᴟꜝԜᴐⱳͼᴡꜝͼᴡⱳᴒͼꜞᴟᴒᴣԜꞌᴒꜜᴐᴒͼ꞉ꜜͼ
ᴀꜞԜ꞉ꜜ᷅ͼⱨꜜꜜͼⱨꞌꞌᴒᴟⱲᴦͼⱨᴠᴡⱳꜛԜͼⱷꜛꜛᴢꜜꜝꞌ᷅ͼ᷿᷉᷇᷇ⱢⱠ᷾ӿ᷾Ԑⱡ᷾Ⱡ˲᷿᷊᷄᷇᷅
ᴇᴢᴟԜᴤͼⱩꜙ᷅ͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼꜞᴟԜᴐᴡ꞉ᴐᴒ᷅ͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷅ͼ꜠ͼⱬꜜⱲꞌͼꜗͼꜚᴒᴑ᷅ͼ᷉᷇᷇˲Ɫ᷊᷿Ⱡӿ᷈᷇Ԑⱡ᷈᷇᷉ⅎ᷊᷄⅍᷅
ᴇᴢᴟԜᴤͼⱩꜙԓͼⱩԜꜜᴒᴟ꞊꞉ͼⱨԓͼⱩᴒᴟꜜᴠᴡᴒ꞉ꜜͼꜗⱨԓͼⱩᴢᴠᴠᴒͼ͟ꜗԓͼⱪⱳᴟ꞉ᴠᴡ꞉ԜꜜᴠᴒꜜͼᴀⱪԓͼⱫԜᴣ꞉ᴠ᷄ꜙꜝᴟᴡꜝꜜͼꜚԓͼᴒᴡͼԜꞌ᷅ͼᴂᴀͼ
ⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼⱨᴠᴠꜝᴐ꞉Ԝᴡ꞉ꜝꜜͼꜚᴒᴑ꞉ᴐԜꞌͼⱨᴑᴣ꞉ᴠꜝᴟᴦͼⱩꜝԜᴟᴑͼ᷊᷉᷇᷈ͼϸᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜᴠͼⱱꜝᴟͼᴡⱳᴒͼ
ꜚԜꜜԜⱲᴒꜛᴒꜜᴡͼꜝⱱͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜͼⱫᴢᴒͼᴡꜝͼⱪ᷈ͼⱷꜜⱳ꞉ԝ꞉ᴡꜝᴟͼⱫᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦ᷅ͼꜗͼⱨꞌꞌᴒᴟⱲᴦͼⱪꞌ꞉ꜜͼ
ⱷꜛꜛᴢꜜꜝꞌͼ͟ᴟԜᴐᴡ᷅ͼ᷊᷉᷇᷈Ɫ᷈ӿ᷿Ԑⱡ᷿᷾˲᷄⅍ⅎ᷅
ᴇᴢᴟԜᴤͼⱩꜙԓͼⱩᴒᴟꜜᴠᴡᴒ꞉ꜜͼꜗⱨԓͼꜙԜꜜⱲͼⱫꜚԓͼⱪᴟԜ꞉ⱲͼᴁԓͼⱫᴟᴒᴦⱱᴢᴠͼⱫԓͼⱶᴠ꞉ᴒⱳͼⱴԓͼᴒᴡͼԜꞌ᷅ͼⱨͼⱱꜝᴐᴢᴠᴒᴑͼꜞԜᴟԜꜛᴒᴡᴒᴟͼ
ᴢꜞᴑԜᴡᴒⱡͼⱶᴒᴟᴒᴑ꞉ᴡԜᴟᴦͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜԓͼԜᴐꜟᴢ꞉ᴟᴒᴑͼⱪ᷈ͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟͼᴑᴒⱱ꞉ᴐ꞉ᴒꜜᴐᴦԓͼԜꜜᴑͼԜꜜⱲ꞉ꜝᴡᴒꜜᴠ꞉ꜜ᷄ᴐꜝꜜᴣᴒᴟᴡ꞉ꜜⱲͼ
ᴒꜜᴧᴦꜛᴒͼ꞉ꜜⱳ꞉ԝ꞉ᴡꜝᴟ᷄Ԝᴠᴠꜝᴐ꞉ԜᴡᴒᴑͼԜꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷅ͼꜗͼⱨꞌꞌᴒᴟⱲᴦͼⱪꞌ꞉ꜜͼⱷꜛꜛᴢꜜꜝꞌ᷅ͼ᷊᷉᷇᷈Ɫ᷊᷈᷈ӿ⅍Ԑⱡ᷈᷾Ⱡ᷈᷄᷈᷾Ⱡ᷊ͼᴒ᷿᷉᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ᷊
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
12 APPENDICES
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷈
͟ᴟꜝᴡꜝᴐꜝꞌͼⱶ꞉ᴠᴡꜝᴟᴦ
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷉
꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠԓͼⱫ꞉ᴣ꞉ᴠ꞉ꜝꜜͼꜝⱱͼꜚ꞉ᴐᴟꜝԝ꞉ꜝꞌꜝⱲᴦͼ
Ԝꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠͼӿⱫꜚⱷⱫԐͼⱨᴑᴢꞌᴡͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒͼӿꜚꜝᴑ꞉ⱱ꞉ᴒᴑԐͼӿᴂᴀͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼ
ⱷꜜᴠᴡ꞉ᴡᴢᴡᴒᴠͼꜝⱱͼⱶᴒԜꞌᴡⱳⱢͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠ
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷊
꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠԓͼⱫ꞉ᴣ꞉ᴠ꞉ꜝꜜͼꜝⱱͼꜚ꞉ᴐᴟꜝԝ꞉ꜝꞌꜝⱲᴦͼ
Ԝꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠͼӿⱫꜚⱷⱫԐͼ͟ᴒᴑ꞉Ԝᴡᴟ꞉ᴐͼᴁꜝᴥ꞉ᴐ꞉ᴡᴦͼᴁԜԝꞌᴒᴠͼӿꜚꜝᴑ꞉ⱱ꞉ᴒᴑԐͼӿᴂᴀͼ
꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒᴠͼꜝⱱͼⱶᴒԜꞌᴡⱳⱢͼ꜠Ԝᴡ꞉ꜝꜜԜꞌͼⱷꜜᴠᴡ꞉ᴡᴢᴡᴒͼꜝⱱͼⱨꞌꞌᴒᴟⱲᴦͼԜꜜᴑͼⱷꜜⱱᴒᴐᴡ꞉ꜝᴢᴠͼⱫ꞉ᴠᴒԜᴠᴒᴠ
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷾
ⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼԜꜜᴑͼϸᴒꜞꜝᴟᴡ꞉ꜜⱲͼ͟ᴟꜝᴐᴒᴑᴢᴟᴒᴠͼӿⱶⱨⱨϸ͟Ԑ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
᷈᷾ͼᴀᴒꜞᴡᴒꜛԝᴒᴟͼ᷿᷉᷇᷈
ⱵꞌꜝԝԜꞌ
Amendment 1.0
᷈᷾ͼⱫᴒᴐᴒꜛԝᴒᴟͼ᷿᷉᷇᷈
ⱵꞌꜝԝԜꞌ
Amendment 2.0
᷉᷈ͼⱨꜞᴟ꞉ꞌͼ᷉᷇᷈⅍
ⱵꞌꜝԝԜꞌ
Amendment 3.0
᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱵꞌꜝԝԜꞌ
ᴁⱳᴒͼ͟ᴟꜝᴡꜝᴐꜝꞌͼⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷉᷅᷇ͼ꞉ꜜᴐꞌᴢᴑᴒᴠͼᴐⱳԜꜜⱲᴒᴠͼᴡꜝͼᴡⱳᴒͼ͟ᴟꜝᴡꜝᴐꜝꞌͼⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷈᷅᷇ԓͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼ
Ԝᴠͼⱱꜝꞌꞌꜝᴤᴠⱡ

ⱨꜜͼᴒᴥᴐꞌᴢᴠ꞉ꜝꜜͼᴐᴟ꞉ᴡᴒᴟ꞉ꜝꜜͼᴤԜᴠͼԜᴑᴑᴒᴑͼᴡꜝͼᴒᴥᴐꞌᴢᴑᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼꜛԜᴦͼⱳԜᴣᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼ꞉ꜜͼԜ
ꜞᴟ꞉ꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴡᴢᴑᴦͼᴡꜝͼᴒꞌ꞉ꜛ꞉ꜜԜᴡᴒͼꜜꜝꜜ᷄ꜜԜᵴᴣᴒͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼԜꜜԜꞌᴦᴠ꞉ᴠⱢͼᴐꜝꜜᴠᴒꜟᴢᴒꜜᴡꞌᴦԓͼ
ᴠᴡᴟԜᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼԝᴦͼꜜԜᵴᴣᴒͼᴣᴒᴟᴠᴢᴠͼꜜꜝꜜ᷄ꜜԜᵴᴣᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤԜᴠͼᴟᴒꜛꜝᴣᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼ
ꜞꞌԜꜜͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅

ᴀ꞉ꜜᴐᴒͼꜜꜝͼᴑԜᴡԜͼꜝꜜͼᴒꜛԝᴟᴦꜝ᷄ⱱᴒᴡԜꞌͼᴑᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦͼԜᴟᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒԓͼꜞᴒᴟͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴡᴟ꞉Ԝꞌͼ
ⱱԜᴐ꞉ꞌ꞉ᴡԜᴡ꞉ꜝꜜͼⱲᴟꜝᴢꜞᶳᴠͼӿⱪᴁⱴⱵԐͼᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜᴠͼᴟᴒꞌԜᴡᴒᴑͼᴡꜝͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼԜꜜᴑͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼ
ᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴡᴟ꞉Ԝꞌᴠԓͼᴡⱳᴒͼⱳ꞉Ⱳⱳᴒᴠᴡͼᴟ꞉ᴠꞋͼ꞉ᴠͼԜᴠᴠᴢꜛᴒᴑ᷅ͼᴁⱳᴒᴟᴒⱱꜝᴟᴒԓͼᴡⱳᴒͼ꞉ꜜᴐꞌᴢᴠ꞉ꜝꜜͼᴐᴟ꞉ᴡᴒᴟ꞉ꜝꜜͼ
ⱱꜝᴟͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼᴡꜝͼᴒꜛꜞⱳԜᴠ꞉ᴧᴒͼᴡⱳᴒᴢᴠᴒͼꜝⱱͼⱳ꞉Ⱳⱳꞌᴦͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒͼ
ᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ᴣᴒͼꜛᴒԜᴠᴢᴟᴒᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜꜜᴑͼᴢꜜᴡ꞉ꞌͼᴡⱳᴒͼᴒꜜᴑͼꜝⱱͼᴟᴒꞌᴒᴣԜꜜᴡͼᴠᴦᴠᴡᴒꜛ꞉ᴐͼ
ᴒᴥꜞꜝᴠᴢᴟᴒͼⱱꜝᴟͼᴤꜝꜛᴒꜜͼꜝⱱͼᴐⱳ꞉ꞌᴑԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌ᷅ͼⱷᴡͼᴤԜᴠͼԜꞌᴠꜝͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼᴡⱳᴒͼᴢᴠᴒͼꜝⱱͼԜͼ
ꜛԜꞌᴒͼᴐꜝꜜᴑꜝꜛͼᴤ꞉ᴡⱳͼꜝᴟͼᴤ꞉ᴡⱳꜝᴢᴡͼᴠꜞᴒᴟꜛ꞉ᴐ꞉ᴑᴒͼꜝᴟͼᴐᴒᴟᴣ꞉ᴐԜꞌͼᴐԜꜞԓͼᴑ꞉ԜꜞⱳᴟԜⱲꜛԓ ꜝᴟͼᴠꜞꜝꜜⱲᴒͼᴤ꞉ᴡⱳͼ
ᴠꜞᴒᴟꜛ꞉ᴐ꞉ᴑᴒͼꜝᴟͼԜͼᴐꜝꜛԝ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴑꜝᴢԝꞌᴒ᷄ԝԜᴟᴟ꞉ᴒᴟͼꜛᴒᴡⱳꜝᴑᴠԐͼ꞉ᴠͼꜜꜝᴡͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼⱳ꞉Ⱳⱳꞌᴦͼ
ᴒⱱⱱᴒᴐᴡ꞉ᴣᴒ᷅

ⱴꜝᴢᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡᴠͼӿᴢᴟ꞉ꜜᴒͼꜝᴟͼᴠᴒᴟᴢꜛԐͼᴤᴒᴟᴒͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼꜝꜜͼⱫԜᴦᴠͼ᷉˲ԓͼ᷿⅍ԓͼ᷈᷉⅍ԓͼ
Ԝꜜᴑͼ᷿᷈᷾ͼⱱꜝᴟͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜝⱱͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴑᴢᴟ꞉ꜜⱲͼᴡᴟᴒԜᴡꜛᴒꜜᴡ᷅
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͟ᴒᴟͼⱴꜝꜝᴡꜜꜝᴡᴒӺⅎͼ꞉ꜜͼᴡⱳᴒͼᶰᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒԓᶱͼԜͼᴐꜝᴟᴟᴒᴐᴡ꞉ꜝꜜͼᴤԜᴠͼꜛԜᴑᴒͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ
ⅎͼӿᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠԐͼᴡⱳԜᴡͼԜͼᴠᴒᴟᴢꜛ᷄ꜝᴟͼᴢᴟ꞉ꜜᴒ᷄ԝԜᴠᴒᴑͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴒᴟⱱꜝᴟꜛᴒᴑͼԜᴡͼ
ᴡⱳᴒͼⱴ꞉ꜜԜꞌͼⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴃ꞉ᴠ꞉ᴡͼӿᴀᴢԝ꞊ᴒᴐᴡᴠͼ꜠ꜝᴡͼⱪꜝꜜᴡ꞉ꜜᴢ꞉ꜜⱲͼ꞉ꜜͼ꜡ꜞᴒꜜ᷄ꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼᴀᴡᴢᴑᴦԐⱡͼ
ᴃ꞉ᴠ꞉ᴡͼ᷈⅍ԓͼⱫԜᴦͼ᷊᷉˲ͼᶐͼⱫԜᴦᴠ᷅
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ⱷᴡͼᴤԜᴠͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼꜜꜝͼ꞉ꜜᴡᴒᴟ꞉ꜛͼԜꜜԜꞌᴦᴠ꞉ᴠͼ꞉ᴠͼꜞꞌԜꜜꜜᴒᴑ᷅
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ⱨꜜͼ꞉ꜜᴑᴒꜞᴒꜜᴑᴒꜜᴡͼⱫԜᴡԜͼᴀԜⱱᴒᴡᴦͼꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼⱩꜝԜᴟᴑͼӿⱫᴀꜚⱩԐͼᴟᴒꜞꞌԜᴐᴒᴑͼᴡⱳᴒͼ꞉ꜜᴡᴒᴟꜜԜꞌͼᴠᴡᴢᴑᴦͼ
ᴠԜⱱᴒᴡᴦͼᴐꜝꜛꜛ꞉ᴡᴡᴒᴒͼӿᴀᴀⱪԐԓͼԜꜜᴑͼ꞉ᴡᴠͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴤᴒᴟᴒͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑ᷅
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ᴁⱳᴒͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼⱱ꞉ꜜԜꞌⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴣ꞉ᴠ꞉ᴡͼᴤԜᴠͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑ᷅
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ⱴꜝᴟͼᴡⱳᴒͼꜛԜꜜԜⱲᴒꜛᴒꜜᴡͼꜝⱱͼԜᴐᴢᴡᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼ꞉ᴡͼᴤԜᴠͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼ
꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼԜꜜᴑͼᴠᴡᴢᴑᴦͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴤ꞉ᴡⱳꜝᴢᴡͼԜꞌᴡᴒᴟԜᴡ꞉ꜝꜜͼᴡꜝͼᴡⱳᴒͼ
ꜞᴟꜝᴡꜝᴐꜝꞌ᷄ᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴠᴡᴢᴑᴦͼᴠᴐⱳᴒᴑᴢꞌᴒԓͼᴒᴣᴒꜜͼ꞉ⱱͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡᴟᴒᴐᴒ꞉ᴣᴒᴠͼԜꜜᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱱꜝᴟͼԜꜜͼ
ⱶⱨⱬͼԜᴡᴡԜᴐꞋ᷅
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ⱴꜝᴟͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴑԜᴡԜԓͼ꞉ᴡͼᴤԜᴠͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼᴤᴒᴒꞋꞌᴦͼᴐꜝꜛꜛᴢꜜ꞉ᴐԜᴡ꞉ꜝꜜͼ
ԝᴒᴡᴤᴒᴒꜜͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡᴠͼԜꜜᴑͼᴡⱳᴒͼᴠ꞉ᴡᴒԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴟᴒꜞꜝᴟᴡᴠͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼꜛᴢᴠᴡͼԝᴒͼ
ᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅
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ⱨͼᴡᴒᴟᴡ꞉Ԝᴟᴦͼꜝԝ꞊ᴒᴐᴡ꞉ᴣᴒͼᴡꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱᴒᴐᴡͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝꜜͼⱳᴒԜꞌᴡⱳ᷄ᴟᴒꞌԜᴡᴒᴑͼꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼ
ӿϷꜝꜙԐͼᴤԜᴠͼᴟᴒꜞⱳᴟԜᴠᴒᴑͼⱱꜝᴟͼᴐꞌԜᴟ꞉ᴡᴦ᷅
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ⱴꜝᴢᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼϷꜝꜙͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴢᴠ꞉ꜜⱲͼᴡⱳᴒͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷄ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼӿⱨⱬ᷄ϷꜝꜙԐͼ
Ϸᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼᴤᴒᴟᴒͼԜᴑᴑᴒᴑͼԜᴡͼⱫԜᴦͼ᷉˲ͼᶐ᷊ԓͼⱫԜᴦͼ᷿⅍ͼᶐ᷊ԓͼⱫԜᴦͼ᷈᷉⅍ͼᶐ᷊ԓͼⱫԜᴦͼ᷿᷈᷾ͼᶐ᷊ͼ꞉ꜜͼᴡᴒᴥᴡͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ᷿
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Ԝꜜᴑͼ꞉ꜜͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒͼⱱꜝᴟͼԜͼԝᴒᴡᴡᴒᴟͼꜛᴒԜᴠᴢᴟᴒͼԜꜜᴑͼᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼꜝⱱͼᴡⱳᴒͼᴑԜᴡԜͼ
ԜᴣԜ꞉ꞌԜԝꞌᴒͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦ᷅
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ⱷᴡͼᴤԜᴠͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼⅎ᷅᷈ͼӿᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠ᷄ᴀᴐᴟᴒᴒꜜ꞉ꜜⱲԐͼᴡⱳԜᴡͼᴡⱳᴒͼᴤԜᴠⱳꜝᴢᴡͼԜⱱᴡᴒᴟͼᴡⱳᴒͼ
ꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴐᴡ꞉ᴐͼӿꜙᴁ͟ԐͼᴡⱳᴒᴟԜꜞᴦͼ꞉ᴠͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼԜᴠͼꞌꜝꜜⱲͼԜᴠͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ
ᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼᴡⱳԜᴡͼᴑꜝ꞉ꜜⱲͼᴠꜝͼᴤꜝᴢꞌᴑͼꜜꜝᴡͼꜞꞌԜᴐᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜᴡͼԜꜜᴦͼᴢꜜᴑᴢᴒͼᴠԜⱱᴒᴡᴦͼᴟ꞉ᴠꞋͼԜꜜᴑͼ
ᴤꜝᴢꞌᴑͼԝᴒͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒͼᴡꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼԜᴡͼꞌᴒԜᴠᴡͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒ᷅
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ⱨͼᴠԜⱱᴒᴡᴦͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡԓͼ᷈᷉᷄ꞌᴒԜᴑͼᴒꞌᴒᴐᴡᴟꜝᴐԜᴟᴑ꞉ꜝⱲᴟԜꜛͼӿⱬⱪⱵԐԓͼᴤԜᴠͼԜᴑᴑᴒᴑͼԜᴡͼᴃ꞉ᴠ꞉ᴡͼ᷈⅍᷆ⱫԜᴦͼ
᷊᷉˲ͼ꞉ꜜͼᴡⱳᴒͼᴡԜԝꞌᴒᴠͼⱱꜝᴟͼᶰᴠᴡᴢᴑᴦͼԜᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴠᴐⱳᴒᴑᴢꞌᴒᴠᶱͼᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼᴀᴒᴐᴡ꞉ꜝꜜͼⅎ᷅᷈ⅎԓͼ
ⱴ꞉ꜜԜꞌͼⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴃ꞉ᴠ꞉ᴡͼӿᴠᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴐꜝꜜᴡ꞉ꜜᴢ꞉ꜜⱲͼ꞉ꜜͼ꜡ꜞᴒꜜ᷄ꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼᴀᴡᴢᴑᴦԐ᷅
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ᴁⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼᴤԜᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼԝᴒⱲ꞉ꜜͼԜᴡͼⱫԜᴦͼ᷇ͼ꞉ꜜᴠᴡᴒԜᴑͼꜝⱱͼⱫԜᴦͼ᷈᷾ͼᴡꜝͼԝᴒͼ
ᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼ꞉ꜜᴡᴒꜜᴡ᷄ᴡꜝ᷄ᴡᴟᴒԜᴡͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜞᴟ꞉ꜜᴐ꞉ꜞꞌᴒ᷅
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ᴁⱳᴒͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼⱱꜝᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼᴟԜᴡⱳᴒᴟͼᴡⱳԜꜜͼꜞᴒᴟͼᴤᴒᴒꞋͼⱱꜝᴟͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴐᴦͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼ
ꜛꜝᴑᴒꞌ᷅ͼᴁⱳᴒͼᴢꜜ꞉ᴡͼꜝⱱͼꜛᴒԜᴠᴢᴟᴒꜛᴒꜜᴡͼ꞉ᴠͼ꞉ᴟᴟᴒꞌᴒᴣԜꜜᴡͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌͼԜᴠͼᴡⱳᴒͼ
ⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡͼ꞉ᴠͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝ᷅ͼϸᴒᴠᴢꞌᴡᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴟᴒꜞꜝᴟᴡᴒᴑͼ꞉ꜜͼԝꜝᴡⱳͼᴤᴒᴒꞋᴠͼԜꜜᴑͼꜛꜝꜜᴡⱳᴠͼᴡꜝͼⱱԜᴐ꞉ꞌ꞉ᴡԜᴡᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜ᷅
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ᴁⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᶰᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋԓͼ꞉᷅ᴒ᷅ԓͼᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡᴡԜᴐꞋͼⱱᴟᴒᴒͼ
ᴢꜜᴡ꞉ꞌͼᴡⱳᴒ꞉ᴟͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋᶱͼᴤԜᴠͼᴟᴒꜛꜝᴣᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟͼԜꜜᴑͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜꜜͼ
ᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅ͼⱷᴡͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼᴡꜝͼᶰᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ԓͼ꞉ᴒԓͼ
ᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡᴡԜᴐꞋͼⱱᴟᴒᴒͼԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ᶱͼᴡꜝͼԜꞌꞌꜝᴤͼᴒꜜꜝᴢⱲⱳͼᴡ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋͼ
ⱱꜝᴟͼᴡⱳ꞉ᴠͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅

ᴁⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᶰ꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠᶱͼᴟᴒꜛꜝᴣᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼ
ᴟԜꜜꞋͼꜝᴟᴑᴒᴟͼԜꜜᴑͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜꜜͼᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅

ᴁⱳᴒͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼⱱꜝᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼᴟԜᴡⱳᴒᴟͼᴡⱳԜꜜͼꜞᴒᴟͼᴤᴒᴒꞋͼᴡꜝͼⱱꜝᴟͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴐᴦͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼ
ꜛꜝᴑᴒꞌ᷅ͼᴁⱳᴒͼᴢꜜ꞉ᴡͼꜝⱱͼꜛᴒԜᴠᴢᴟᴒꜛᴒꜜᴡͼ꞉ᴠͼ꞉ᴟᴟᴒꞌᴒᴣԜꜜᴡͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌͼԜᴠͼᴡⱳᴒͼ
ⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡͼ꞉ᴠͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝ᷅ͼϸᴒᴠᴢꞌᴡᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴟᴒꜞꜝᴟᴡᴒᴑͼ꞉ꜜͼԝꜝᴡⱳͼᴤᴒᴒꞋᴠͼԜꜜᴑͼꜛꜝꜜᴡⱳᴠͼᴡꜝͼⱱԜᴐ꞉ꞌ꞉ᴡԜᴡᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜ᷅

ᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛᴒᴡⱳꜝᴑᴠͼᴤᴒᴟᴒͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴢᴠᴒͼԜͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼᴟԜᴡⱳᴒᴟͼᴡⱳԜꜜͼ
ⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼᴒᴠᴡ꞉ꜛԜᴡ꞉ꜜⱲͼᴒꜟᴢԜᴡ꞉ꜝꜜͼꜛꜝᴑᴒꞌͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜԜꞌᴦᴠ꞉ᴠ᷅ͼᴁⱳ꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼԜꜜԜꞌᴦᴠ꞉ᴠͼ
ԜꜞꜞᴟꜝԜᴐⱳͼԜꞌᴠꜝͼԜꜞꜞꞌ꞉ᴒᴠͼᴡꜝͼᴡⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅

ꜚᴢꞌᴡ꞉ꜞꞌ꞉ᴐ꞉ᴡᴦͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴤᴒᴟᴒͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼ꞉ꜜͼⱲᴟᴒԜᴡᴒᴟͼᴑᴒᴡԜ꞉ꞌ᷅ͼᴀꜞᴒᴐ꞉ⱱ꞉ᴐԜꞌꞌᴦԓͼԜͼⱲᴒꜜᴒᴟԜꞌͼ
ⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼᴡꜝͼᴠᴡᴟꜝꜜⱲꞌᴦͼᴐꜝꜜᴡᴟꜝꞌͼᴡⱳᴒͼⱲꞌꜝԝԜꞌͼⱱԜꜛ꞉ꞌᴦ᷄ᴤ꞉ᴠᴒͼᴁᴦꜞᴒͼⱷͼ
ᴒᴟᴟꜝᴟͼᴟԜᴡᴒͼӿⱴᴄⱬϸԐͼ꞉ꜜͼᴡⱳᴒͼⱳ꞉ᴒᴟԜᴟᴐⱳ꞉ᴐԜꞌͼᴡᴒᴠᴡ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼ
ᴐꜝꜜᴑᴢᴐᴡᴒᴑͼԜᴡͼᴡⱳᴒͼ᷈᷅⅍ⅎӼͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴐꜝꜛꜞԜᴟᴒᴑͼ
ᴤ꞉ᴡⱳͼᴡⱳᴒͼꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞ᷅

ⱷꜜͼⱲᴒꜜᴒᴟԜꞌԓͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛᴒᴡⱳꜝᴑᴠͼᴤᴒᴟᴒͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼᴤ꞉ᴡⱳͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ
ᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴡⱳᴒͼⱲᴒꜜᴒᴟԜꞌͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼᴐꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠͼԜꜜᴑͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌ᷆ԜꜜԜꞌᴦᴡ꞉ᴐԜꞌͼ꞉ᴠᴠᴢᴒᴠͼӿᴒⱲԓͼ
Ԝᴑ꞊ᴢᴠᴡꜛᴒꜜᴡͼⱱꜝᴟͼᴐꜝᴣԜᴟ꞉ԜᴡᴒᴠԓͼⱳԜꜜᴑꞌ꞉ꜜⱲͼꜝⱱͼᴑᴟꜝꜞꜝᴢᴡᴠͼԜꜜᴑͼᴑԜᴡԜͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲԓͼⱳԜꜜᴑꞌ꞉ꜜⱲͼꜝⱱͼ
ᴑᴟꜝꜞꜝᴢᴡᴠͼꜝᴟͼꜛ꞉ᴠᴠ꞉ꜜⱲͼᴑԜᴡԜԓͼ꞉ꜜᴡᴒᴟ꞉ꜛͼԜꜜԜꞌᴦᴠ꞉ᴠͼԜꜜᴑͼᴑԜᴡԜͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲԓͼꜛᴢꞌᴡ꞉ᴐᴒꜜᴡᴒᴟͼᴠᴡᴢᴑ꞉ᴒᴠԓͼ
Ԝꜜᴑͼᴠᴒꜜᴠ꞉ᴡ꞉ᴣ꞉ᴡᴦͼԜꜜԜꞌᴦᴠᴒᴠԐ᷅

ᴀԜꜛꜞꞌᴒᴠ꞉ᴧᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜͼᴤԜᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴢꜞᴑԜᴡᴒᴑͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼ
ꜛᴒᴡⱳꜝᴑᴠ᷅ͼ

ᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇᷅Ⱡԓͼ͟ᴟᴒꜛԜᴡᴢᴟᴒͼⱪꞌꜝᴠᴢᴟᴒͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦԓͼᴤԜᴠͼԜᴑᴑᴒᴑͼᴡꜝͼ꞉ꜜᴐꞌᴢᴑᴒͼᴐꜝꜜᴑ꞉ᴡ꞉ꜝꜜᴠͼᴡⱳԜᴡͼ
ꜛԜᴦͼᴤԜᴟᴟԜꜜᴡͼᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼꜝᴟͼᴠ꞉ᴡᴒ᷅


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ⅍
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅

ᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇᷅᷈᷉ԓͼⱫԜᴡԜͼⱶԜꜜᴑꞌ꞉ꜜⱲͼⱪꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠԓͼᴤԜᴠͼԜᴑᴑᴒᴑͼᴡꜝͼ꞉ꜜᴐꞌᴢᴑᴒͼᴠꜞᴒᴐ꞉ⱱ꞉ᴐᴠͼ
ᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼⱳԜꜜᴑꞌ꞉ꜜⱲͼꜝⱱͼᴑԜᴡԜͼᴡꜝͼꜞᴟᴒᴣᴒꜜᴡͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼᴢꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲ᷅

ⱷꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇᷅᷈᷾ԓͼⱱ꞉ꜜԜꜜᴐ꞉Ԝꞌͼᴑ꞉ᴠᴐꞌꜝᴠᴢᴟᴒͼꞌԜꜜⱲᴢԜⱲᴒͼᴤԜᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼ᷉᷈ͼ
ⱪⱴϸͼ᷿᷾ͼ᷉ӿԝԐͼӿ᷈ⱠⱠ˲Ԑ᷅

ᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷈᷇᷅᷈ԓͼᴀᴡᴢᴑᴦͼϸᴒᴠᴢꞌᴡᴠ᷆͟ᴢԝꞌ꞉ᴐԜᴡ꞉ꜝꜜͼ͟ꜝꞌ꞉ᴐᴦԓͼᴤԜᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼ꞉ꜜᴐꞌᴢᴑᴒͼꞌԜꜜⱲᴢԜⱲᴒͼ
ᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼꜞꜝᴠᴡ꞉ꜜⱲͼꜝⱱͼԜꜞꜞᴟꜝꜞᴟ꞉Ԝᴡᴒͼᴠᴡᴢᴑᴦͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼꜝꜜͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒͼᴤᴒԝᴠ꞉ᴡᴒᴠͼԝᴦͼᴡⱳᴒͼ
ᴀꜞꜝꜜᴠꜝᴟ᷅

ᴀꜞꜝꜜᴠꜝᴟԓͼᴀꜞꜝꜜᴠꜝᴟͼᴐꜝꜜᴡԜᴐᴡԓͼꜛᴒᴑ꞉ᴐԜꞌͼᴑ꞉ᴟᴒᴐᴡꜝᴟԓͼԜꜜᴑͼꜛᴒᴑ꞉ᴐԜꞌͼꜛꜝꜜ꞉ᴡꜝᴟͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴤԜᴠͼ
ᴢꜞᴑԜᴡᴒᴑͼᴤⱳᴒᴟᴒͼᴟᴒꞌᴒᴣԜꜜᴡ᷅

ꜚ꞉ꜜꜝᴟͼᴠꜞᴒꞌꞌ꞉ꜜⱲͼᴐⱳԜꜜⱲᴒͼᴤԜᴠͼꜛԜᴑᴒͼᴐⱳԜꜜⱲ꞉ꜜⱲͼᶰԜᴡⱳꜝᴢⱲⱳᶱͼᴡꜝͼᶰԜꞌᴡⱳꜝᴢⱲⱳ᷅ᶱ
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.0
Amendment Date
21 April 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
ᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛᴒᴡⱳꜝᴑᴠͼᴤᴒᴟᴒͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴢᴠᴒͼԜͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼᴟԜᴡⱳᴒᴟͼᴡⱳԜꜜͼ
ⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼᴒᴠᴡ꞉ꜛԜᴡ꞉ꜜⱲͼᴒꜟᴢԜᴡ꞉ꜝꜜͼꜛꜝᴑᴒꞌͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜԜꞌᴦᴠ꞉ᴠ᷅ͼᴁⱳ꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼ
ԜꜜԜꞌᴦᴠ꞉ᴠͼԜꜞꜞᴟꜝԜᴐⱳͼԜꞌᴠꜝͼԜꜞꜞꞌ꞉ᴒᴠͼᴡꜝͼᴡⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅ͼ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼ
ꜚᴒᴡⱳꜝᴑᴠ
ᴀᴀⱪꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼᴟᴒꜞꞌԜᴐᴒᴑͼԝᴦͼⱫᴀꜚⱩⱢͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼꜜꜝͼ꞉ꜜᴡᴒᴟ꞉ꜛͼԜꜜԜꞌᴦᴠ꞉ᴠͼ꞉ᴠͼꜞꞌԜꜜꜜᴒᴑͼ
ⱱꜝᴟͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼᴁⱳᴒͼ
ⱫᴀꜚⱩͼᴟᴒꜞꞌԜᴐᴒᴠͼᴡⱳᴒͼᴀᴀⱪ᷅
ⱨᴑᴑ꞉ᴡ꞉ꜝꜜͼᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼⱬⱪⱵͼᴠᴐⱳᴒᴑᴢꞌᴒͼ꞉ꜜͼᴀᴒᴐᴡ꞉ꜝꜜͼⅎ᷅᷈ⅎԓͼⱴ꞉ꜜԜꞌͼⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼ
ᴃ꞉ᴠ꞉ᴡͼӿᴀᴢԝ꞊ᴒᴐᴡᴠͼꜜꜝᴡͼᴐꜝꜜᴡ꞉ꜜᴢ꞉ꜜⱲͼ꞉ꜜͼ꜡ꜞᴒꜜ᷄ꜙԜԝᴒꞌͼⱬᴥᴡᴒꜜᴠ꞉ꜝꜜͼᴀᴡᴢᴑᴦԐͼᴃ꞉ᴠ꞉ᴡ᷈⅍ԓͼ
ⱫԜᴦ᷊᷉˲ᶐ᷊ᴑԜᴦᴠ
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒͼ
ӿᴀᴦꜜꜝꜞᴠ꞉ᴠͼԜꜜᴑͼⱨꜞꜞᴒꜜᴑ꞉ᴥ᷈Ԑ
ᴂꜞᴑԜᴡᴒᴑͼᴡⱳᴒͼԜԝԝᴟᴒᴣ꞉Ԝᴡ꞉ꜝꜜͼꞌ꞉ᴠᴡͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴐⱳԜꜜⱲᴒᴠͼᴡꜝͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅
ꜙ꞉ᴠᴡͼꜝⱱͼⱨԝԝᴟᴒᴣ꞉Ԝᴡ꞉ꜝꜜᴠ
ϸᴒꜞⱳᴟԜᴠᴒᴑͼⱱꜝᴟͼᴐꞌԜᴟ꞉ᴡᴦ᷅ͼᶰᴁꜝͼᴒᴣԜꞌᴢԜᴡᴒͼᴡⱳᴒͼᴒⱱⱱᴒᴐᴡͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼꜝꜜͼⱳᴒԜꞌᴡⱳͼᴟᴒꞌԜᴡᴒᴑ
ꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼӿϷꜝꜙԐᶱ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ
᷊᷉᷅ԓͼᴁᴒᴟᴡ꞉Ԝᴟᴦͼ꜡ԝ꞊ᴒᴐᴡ꞉ᴣᴒᴠ
ϸᴒꜛꜝᴣᴒᴑͼᴡⱳᴒͼᴡᴒᴥᴡͼԜᴟꜝᴢꜜᴑͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼԝԜᴠᴒᴑͼꜝꜜͼꜜԜᵴᴣᴒͼᴣᴒᴟᴠᴢᴠͼꜜꜝꜜ᷄ꜜԜᵴᴣᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼ
ᴡꜝͼԜꞌ꞉Ⱳꜜͼᴤ꞉ᴡⱳͼᴡⱳᴒͼꜜᴒᴤͼᴒᴥᴐꞌᴢᴠ꞉ꜝꜜͼᴐᴟ꞉ᴡᴒᴟ꞉ꜝꜜͼᴡꜝͼᴒᴥᴐꞌᴢᴑᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼꜛԜᴦͼⱳԜᴣᴒͼ
ꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼ꞉ꜜͼԜͼꜞᴟ꞉ꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
᷊᷊᷅᷈᷅᷈᷅ԓͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑⱢͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷊᷅᷈ԓͼ
ϸԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜ
ᴁⱳᴒͼꜞᴒᴟ꞉ꜝᴑͼⱱꜝᴟͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠͼԜⱱᴡᴒᴟͼᴡⱳᴒͼⱱ꞉ꜜԜꞌͼⱱꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴣ꞉ᴠ꞉ᴡͼᴤԜᴠͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
᷊᷿᷅᷈᷅᷈᷅ԓͼⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼ͟ᴒᴟ꞉ꜝᴑ
ᴀᴀⱪͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼᴟᴒꜞꞌԜᴐᴒᴑͼԝᴦͼⱫᴀꜚⱩ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷊᷅᷈᷅᷉᷅᷈ԓͼⱷꜜᴡᴒᴟ꞉ꜛͼ
ⱨꜜԜꞌᴦᴠ꞉ᴠͼԜꜜᴑͼⱫԜᴡԜͼᴀԜⱱᴒᴡᴦͼ
ꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼⱩꜝԜᴟᴑͼӿⱫᴀꜚⱩԐ
ᴁᴒᴥᴡͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴟᴒⱱꞌᴒᴐᴡͼᴡⱳᴒͼᴒᴥᴐꞌᴢᴠ꞉ꜝꜜͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼꜛԜᴦͼⱳԜᴣᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼ꞉ꜜͼԜͼ
ꜞᴟ꞉ꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴡᴢᴑᴦ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
᷾᷅᷈ԓͼᴀᴡᴢᴑᴦͼ͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ
ᴁᴒᴥᴡͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴟᴒⱱꞌᴒᴐᴡͼᴡⱳᴒͼᴒᴥᴐꞌᴢᴠ꞉ꜝꜜͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼꜛԜᴦͼⱳԜᴣᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼ꞉ꜜͼԜͼ
ꜞᴟ꞉ꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴡᴢᴑᴦ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
᷾᷅᷉ԓͼⱪᴟ꞉ᴡᴒᴟ꞉Ԝͼⱱꜝᴟͼⱷꜜᴐꞌᴢᴠ꞉ꜝꜜ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠⅎ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.0
Amendment Date
21 April 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
ᴀ꞉ꜜᴐᴒͼꜜꜝͼᴑԜᴡԜͼꜝꜜͼᴒꜛԝᴟᴦꜝ᷄ⱱᴒᴡԜꞌͼᴑᴒᴣᴒꞌꜝꜞꜛᴒꜜᴡͼᴡꜝᴥ꞉ᴐ꞉ᴡᴦͼԜᴟᴒͼԜᴣԜ꞉ꞌԜԝꞌᴒԓͼꜞᴒᴟͼᴡⱳᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ
ᴡᴟ꞉ԜꞌͼⱱԜᴐ꞉ꞌ꞉ᴡԜᴡ꞉ꜝꜜͼⱲᴟꜝᴢꜞᶳᴠͼӿⱪᴁⱴⱵԐͼᴟᴒᴐꜝꜛꜛᴒꜜᴑԜᴡ꞉ꜝꜜᴠͼᴟᴒꞌԜᴡᴒᴑͼᴡꜝͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼԜꜜᴑͼ
ꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡ꞉ꜜⱲͼ꞉ꜜͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼᴡᴟ꞉Ԝꞌᴠԓͼⱳ꞉Ⱳⱳᴒᴠᴡͼᴟ꞉ᴠꞋͼ꞉ᴠͼԜᴠᴠᴢꜛᴒᴑ᷅ͼᴁⱳᴒᴟᴒⱱꜝᴟᴒԓͼᴡⱳᴒͼ
꞉ꜜᴐꞌᴢᴠ꞉ꜝꜜͼᴐᴟ꞉ᴡᴒᴟ꞉ꜝꜜͼⱱꜝᴟͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ꜝꜜͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼᴡꜝͼᴒꜛꜞⱳԜᴠ꞉ᴧᴒͼᴡⱳᴒͼ
ᴢᴠᴒͼꜝⱱͼⱳ꞉Ⱳⱳꞌᴦͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒͼᴐꜝꜜᴡᴟԜᴐᴒꜞᴡ꞉ᴣᴒͼꜛᴒԜᴠᴢᴟᴒᴠͼᴑᴢᴟ꞉ꜜⱲͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜꜜᴑͼᴢꜜᴡ꞉ꞌͼᴡⱳᴒͼᴒꜜᴑͼ
ꜝⱱͼᴟᴒꞌᴒᴣԜꜜᴡͼᴠᴦᴠᴡᴒꜛ꞉ᴐͼᴒᴥꜞꜝᴠᴢᴟᴒͼⱱꜝᴟͼᴤꜝꜛᴒꜜͼꜝⱱͼᴐⱳ꞉ꞌᴑͼԝᴒԜᴟ꞉ꜜⱲͼꜞꜝᴡᴒꜜᴡ꞉ԜꞌⱢͼⱷᴡͼᴤԜᴠͼԜꞌᴠꜝͼ
ᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼᴡⱳᴒͼᴢᴠᴒͼꜝⱱͼԜͼꜛԜꞌᴒͼᴐꜝꜜᴑꜝꜛͼᴤ꞉ᴡⱳͼꜝᴟͼᴤ꞉ᴡⱳꜝᴢᴡͼᴠꜞᴒᴟꜛ꞉ᴐ꞉ᴑᴒͼꜝᴟͼᴐᴒᴟᴣ꞉ᴐԜꞌͼ
ᴐԜꜞԓͼᴑ꞉ԜꜞⱳᴟԜⱲꜛͼꜝᴟͼᴠꜞꜝꜜⱲᴒͼᴤ꞉ᴡⱳͼᴠꜞᴒᴟꜛ꞉ᴐ꞉ᴑᴒͼꜝᴟͼԜͼᴐꜝꜛԝ꞉ꜜԜᴡ꞉ꜝꜜͼӿᴑꜝᴢԝꞌᴒͼԝԜᴟᴟ꞉ᴒᴟͼ
ꜛᴒᴡⱳꜝᴑᴠԐͼ꞉ᴠͼꜜꜝᴡͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼⱳ꞉Ⱳⱳꞌᴦͼᴒⱱⱱᴒᴐᴡ꞉ᴣᴒ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠⱢ
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷾᷅᷉ԓͼⱪᴟ꞉ᴡᴒᴟ꞉Ԝͼⱱꜝᴟͼ
ⱷꜜᴐꞌᴢᴠ꞉ꜝꜜ
ⱨᴑᴑᴒᴑͼԜͼꜜᴒᴤͼᴒᴥᴐꞌᴢᴠ꞉ꜝꜜͼᴐᴟ꞉ᴡᴒᴟ꞉ꜝꜜͼᴡꜝͼᴒᴥᴐꞌᴢᴑᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼꜛԜᴦͼⱳԜᴣᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼ
꞉ꜜͼԜͼꜞᴟ꞉ꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴡᴢᴑᴦͼ꞉ꜜͼꜝᴟᴑᴒᴟͼᴡꜝͼᴒꞌ꞉ꜛ꞉ꜜԜᴡᴒͼꜜꜝꜜ᷄ꜜԜᵴᴣᴒͼⱱᴟꜝꜛͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅ⱨꞌᴠꜝԓͼ
ᴡⱳᴒͼꜝᴡⱳᴒᴟͼᴒᴥᴐꞌᴢᴠ꞉ꜝꜜͼᴐᴟ꞉ᴡᴒᴟ꞉Ԝͼᴤᴒᴟᴒͼᴟᴒꜜᴢꜛԝᴒᴟᴒᴑ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
᷊᷾᷅ԓͼⱬᴥᴐꞌᴢᴠ꞉ꜝꜜͼⱪᴟ꞉ᴡᴒᴟ꞉Ԝ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴢꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷅᷾ԓͼⱩꞌ꞉ꜜᴑ꞉ꜜⱲͼԜꜜᴑͼ
ᴂꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲ
ⱴꜝᴟͼᴡⱳᴒͼꜛԜꜜԜⱲᴒꜛᴒꜜᴡͼꜝⱱͼԜᴐᴢᴡᴒͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼ꞉ᴡͼᴤԜᴠͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼԜᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ꜝꜜͼꜝⱱͼ
ᴡⱳᴒͼ꞉ꜜᴣᴒᴠᴡ꞉ⱲԜᴡ꞉ꜝꜜԜꞌͼꜞᴟꜝᴑᴢᴐᴡͼԜꜜᴑͼᴠᴡᴢᴑᴦͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴤ꞉ꞌꞌͼᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴤ꞉ᴡⱳꜝᴢᴡͼԜꞌᴡᴒᴟԜᴡ꞉ꜝꜜͼ
ᴡꜝͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴠᴡᴢᴑᴦͼᴠᴐⱳᴒᴑᴢꞌᴒԓͼᴒᴣᴒꜜͼ꞉ⱱͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡͼᴟᴒᴐᴒ꞉ᴣᴒᴠͼԜꜜᴦͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
ⱱꜝᴟͼԜꜜͼⱶⱨⱬͼԜᴡᴡԜᴐꞋ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼⱶⱨⱬͼ
ⱨᴡᴡԜᴐꞋͼꜚԜꜜԜⱲᴒꜛᴒꜜᴡԐⱢͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷿᷅᷅᷈ԓͼⱨꞌꞌꜝᴤᴒᴑͼ
ᴁⱳᴒᴟԜꜞ꞉ᴒᴠ
ⱫᴦԜᴥͼᴟᴒꜞꞌԜᴐᴒᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒͼⱲᴒꜜᴒᴟԜꞌͼᴡᴒᴟꜛͼᶰᴀꜞꜝꜜᴠꜝᴟᶱͼᴡⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅ͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷅˲ԓͼ͟ԜᴐꞋԜⱲ꞉ꜜⱲͼԜꜜᴑͼ
ꜙԜԝᴒꞌ꞉ꜜⱲⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷅᷈᷅⅍ԓͼ
ⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡᴠͼꜝⱱͼᴀꜞᴒᴐ꞉Ԝꞌͼ
ⱷꜜᴡᴒᴟᴒᴠᴡⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷊᷊᷅᷅ԓͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼ
ᴀ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼӿԜꜜᴑͼᴤⱳᴒᴟᴒᴣᴒᴟͼ
ᴟᴒꞌᴒᴣԜꜜᴡͼᴒᴥᴐᴒꜞᴡͼᴡⱳᴒͼᴡ꞉ᴡꞌᴒͼ
ꜞԜⱲᴒԓͼⱱ꞉ᴟᴠᴡͼᴟꜝᴤͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼ
ᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼԜꜜᴑͼᴁԜԝꞌᴒͼ᷉ͼ꞉ꜜͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇ͼᴈⱬᴢᴟꜝꜞᴒͼ
ꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼᴟᴒᴠꜞꜝꜜᴠ꞉ԝ꞉ꞌ꞉ᴡᴦᴊԐ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠ˲
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.0
Amendment Date
21 April 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
ᴁⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼᴢꜞᴑԜᴡᴒᴑͼⱱᴟꜝꜛͼⱫԜᴦͼ᷇ͼᴡꜝͼⱫԜᴦͼ᷈᷾ͼᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼ
ᴤ꞉ᴡⱳͼᴡⱳᴒͼ꞉ꜜᴡᴒꜜᴡ᷄ᴡꜝ᷄ᴡᴟᴒԜᴡͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜞᴟ꞉ꜜᴐ꞉ꜞꞌᴒ᷅ͼ
ᴁⱳᴒͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼⱱꜝᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼᴡⱳᴒͼ
ᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑͼᴟԜᴡⱳᴒᴟͼᴡⱳԜꜜͼꜞᴒᴟͼᴤᴒᴒꞋͼⱱꜝᴟͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴐᴦͼᴤ꞉ᴡⱳͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼ
ꜛꜝᴑᴒꞌ᷅ͼ
ᴁⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᶰᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋԓͼ꞉᷅ᴒ᷅ԓͼᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼ
ԜᴡᴡԜᴐꞋ᷄ⱱᴟᴒᴒͼᴢꜜᴡ꞉ꞌͼᴡⱳᴒ꞉ᴟͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋᶱͼᴤԜᴠͼᴟᴒꜛꜝᴣᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟͼԜꜜᴑͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜꜜͼᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅ͼⱷᴡͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼᴡꜝͼᶰᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ
ԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ԓͼ꞉᷅ᴒ᷅ԓͼᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡᴡԜᴐꞋ᷄ⱱᴟᴒᴒͼԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ᶱͼᴡꜝͼԜꞌꞌꜝᴤͼ
ᴒꜜꜝᴢⱲⱳͼᴡ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅
ᴁⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᶰ꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠᶱͼᴟᴒꜛꜝᴣᴒᴑͼⱱᴟꜝꜛͼ
ᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟͼԜꜜᴑͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜꜜͼᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅
ᴁⱳᴒͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼⱱꜝᴟͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡͼᴑᴢᴟ꞉ꜜⱲͼ
ᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜꜞᴒᴟ꞉ꜝᴑͼᴟԜᴡⱳᴒᴟͼᴡⱳԜꜜͼꜞᴒᴟͼᴤᴒᴒꞋͼⱱꜝᴟͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴐᴦͼᴤ꞉ᴡⱳͼᴡⱳᴒͼ
ᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌ᷅ͼᴁⱳᴒͼᴢꜜ꞉ᴡͼꜝⱱͼꜛᴒԜᴠᴢᴟᴒꜛᴒꜜᴡͼ꞉ᴠͼ꞉ᴟᴟᴒꞌᴒᴣԜꜜᴡͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌͼԜᴠͼ
ᴡⱳᴒͼⱳᴦꜞꜝᴡⱳᴒᴠ꞉ᴠͼᴡᴒᴠᴡͼ꞉ᴠͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼᴟԜᴡᴒͼᴟԜᴡ꞉ꜝ᷅ͼϸᴒᴠᴢꞌᴡᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌͼ
ᴤ꞉ꞌꞌͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼ꞉ꜜͼԝꜝᴡⱳͼᴤᴒᴒꞋᴠͼԜꜜᴑͼꜛꜝꜜᴡⱳᴠͼᴡꜝͼⱱԜᴐ꞉ꞌ꞉ᴡԜᴡᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼⱪᴟ꞉ᴡᴒᴟ꞉Ԝͼ
ⱱꜝᴟͼⱬᴣԜꞌᴢԜᴡ꞉ꜝꜜⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
⅍᷅᷾᷅᷈ԓͼ͟ᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼ
ᴀᴒᴐꜝꜜᴑԜᴟᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ
ⱴꜝᴟͼᴡⱳᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼᴑԜᴡԜԓͼ꞉ᴡͼᴤԜᴠͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼᴤᴒᴒꞋꞌᴦͼᴐꜝꜛꜛᴢꜜ꞉ᴐԜᴡ꞉ꜝꜜͼ
ԝᴒᴡᴤᴒᴒꜜͼᴡⱳᴒͼꜞԜᴡ꞉ᴒꜜᴡᴠͼԜꜜᴑͼᴡⱳᴒͼᴠ꞉ᴡᴒԓͼ꞉ꜜᴐꞌᴢᴑ꞉ꜜⱲͼᴟᴒꜞꜝᴟᴡᴠͼꜝⱱͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠԓͼꜛᴢᴠᴡͼԝᴒͼ
ᴑꜝᴐᴢꜛᴒꜜᴡᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒⱪϸⱴ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼ
ꜝⱱͼⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼⱫԜᴡԜⱢͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾᷅᷉᷅ͼⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼ
ⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜ
ϸᴒꜛꜝᴣᴒᴑͼᴡ꞉ꜛᴒͼԝꜝᴢꜜᴑͼꜝⱱͼⅎͼᴑԜᴦᴠ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜͼ
ꜝⱱͼⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼⱫԜᴡԜⱢͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾᷅᷉ԓͼⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼ
ⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜ
ᴁᴒᴥᴡͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴟᴒⱱꞌᴒᴐᴡͼᴡⱳᴒͼᴒᴥᴐꞌᴢᴠ꞉ꜝꜜͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼꜛԜᴦͼⱳԜᴣᴒͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜᴡᴒᴑͼ꞉ꜜͼԜͼ
ꜞᴟ꞉ꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼᴠᴡᴢᴑᴦ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠⱢͼᴀᴡᴢᴑᴦͼ
ⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒͼ
ӿⱴꜝꜝᴡꜜꜝᴡᴒͼ⅍ԐⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
⅍᷅˲᷅᷈᷅ⅎԓͼⱪ᷈᷄ⱷ꜠ⱶͼ
ⱴᴢꜜᴐᴡ꞉ꜝꜜԜꞌͼⱨᴠᴠԜᴦⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
⅍᷅˲᷅᷈᷅˲ԓͼⱪ᷾ͼⱨᴠᴠԜᴦⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
⅍᷅˲᷅᷈᷅Ⱡԓͼⱪ᷈ꜟͼⱨᴠᴠԜᴦ
ⱨᴑᴑᴒᴑͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼⱨꜜⱲ꞉ꜝᴒᴑᴒꜛԜ᷄ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼӿⱨⱬ᷄ϷꜝꜙԐͼϷᴢᴒᴠᴡ꞉ꜝꜜꜜԜ꞉ᴟᴒͼ
ԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼꜝꜜͼⱫԜᴦᴠͼ᷉˲ᶐ᷊ԓͼ᷿⅍ᶐ᷊ԓͼ᷈᷉⅍ᶐ᷊ԓͼԜꜜᴑͼ᷿᷈᷾ᶐ᷊ͼⱱꜝᴟͼԜͼԝᴒᴡᴡᴒᴟͼꜛᴒԜᴠᴢᴟᴒͼԜꜜᴑͼ
ᴐꜝꜛꜞԜᴟ꞉ᴠꜝꜜͼꜝⱱͼᴑԜᴡԜͼԜᴣԜ꞉ꞌԜԝꞌᴒͼⱱᴟꜝꜛͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅ͼ
ᴀᴦꜜꜝꜞᴠ꞉ᴠⱢͼᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼ
ᴀᴐⱳᴒᴑᴢꞌᴒⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷿᷅᷈ԓͼ
ϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠⱢͼᴀᴒᴐᴡ꞉ꜝꜜⱠ᷅᷈᷈ԓͼ
ⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼϷᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꜙ꞉ⱱᴒͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ
ᴀᴀⱪͼᴟᴒꜞꞌԜᴐᴒᴑͼᴤ꞉ᴡⱳͼⱫᴀꜚⱩ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷊᷊᷅᷅ԓͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡͼꜝⱱͼⱪꞌ꞉ꜜ꞉ᴐԜꞌͼ
ᴀ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒ
ᴂꜞᴑԜᴡᴒᴑͼᴐꜝꜜᴡԜᴐᴡᴠ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷿᷿᷅᷅ԓͼᴀԜⱱᴒᴡᴦͼ
ⱪꜝꜜᴡԜᴐᴡͼⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼⱠⱠ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.0
Amendment Date
21 April 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
ᴁⱳᴟꜝᴢⱲⱳꜝᴢᴡͼᴡⱳᴒꜞᴟꜝᴡꜝᴐꜝꞌԓͼԜᴠͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴒᴐᴡ꞉ꜝꜜԓͼⱫᴦԜᴥͼᴤԜᴠͼᴟᴒꜞꞌԜᴐᴒᴑͼԝᴦͼᶰᴡⱳᴒͼᴀꜞꜝꜜᴠꜝᴟ᷅ᶱ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷅᷈᷅⅍ԓͼⱨᴑᴣᴒᴟᴠᴒͼ
ⱬᴣᴒꜜᴡᴠͼꜝⱱͼᴀꜞᴒᴐ꞉Ԝꞌͼⱷꜜᴡᴒᴟᴒᴠᴡͼ
ӿⱨⱬᴀⱷԐ
ⱫᴀꜚⱩͼᴟᴒꜞꞌԜᴐᴒᴠͼᴀᴀⱪ
ᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈ⅎԓͼᴀᴢԝ꞊ᴒᴐᴡͼ
ᴄ꞉ᴡⱳᴑᴟԜᴤԜꞌ
ⱷᴡͼᴤԜᴠͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴡⱳԜᴡͼᴡⱳᴒͼᴤԜᴠⱳꜝᴢᴡͼԜⱱᴡᴒᴟͼᴡⱳᴒͼꜙᴁ͟ͼᴡⱳᴒᴟԜꜞᴦͼ꞉ᴠͼꜞᴒᴟꜛ꞉ᴡᴡᴒᴑͼԜᴠͼꞌꜝꜜⱲͼԜᴠͼᴡⱳᴒͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼᴑᴒᴡᴒᴟꜛ꞉ꜜᴒᴑͼᴡⱳԜᴡͼᴑꜝ꞉ꜜⱲͼᴠꜝͼᴤꜝᴢꞌᴑͼꜜꜝᴡͼꜞꞌԜᴐᴒͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡͼԜᴡͼԜꜜᴦͼᴢꜜᴑᴢᴒͼ
ᴠԜⱱᴒᴡᴦͼᴟ꞉ᴠꞋͼԜꜜᴑͼᴤꜝᴢꞌᴑͼԝᴒͼԜꜞꜞꞌ꞉ᴐԜԝꞌᴒͼᴡꜝͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼԜᴟᴒͼԜᴡͼꞌᴒԜᴠᴡͼ᷈˲ͼᴦᴒԜᴟᴠͼꜝⱱͼԜⱲᴒ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⅎ᷅᷈ԓͼᴀᴐᴟᴒᴒꜜ꞉ꜜⱲ
ⱴꜝᴢᴟͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴡᴒᴠᴡᴠͼӿᴢᴟ꞉ꜜᴒͼꜝᴟͼᴠᴒᴟᴢꜛԐͼᴤᴒᴟᴒͼᴠᴐⱳᴒᴑᴢꞌᴒᴑͼꜝꜜͼⱫԜᴦᴠ᷉˲ԓͼ᷿⅍ԓͼ
᷈᷉˲ԓͼԜꜜᴑͼ᷿᷈᷾ͼⱱꜝᴟͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜞᴟᴒⱲꜜԜꜜᴐᴦͼᴑᴢᴟ꞉ꜜⱲͼᴡᴟᴒԜᴡꜛᴒꜜᴡ᷅
ᴀᴡᴢᴑᴦͼⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒԓͼ
͟ᴟᴒⱲꜜԜꜜᴐᴦͼᴁᴒᴠᴡͼӿⱱᴒꜛԜꞌᴒᴠԐͼ
ԜꜜᴑͼⱴꜝꜝᴡꜜꜝᴡᴒͼӺⅎⱢͼᴀᴒᴐᴡ꞉ꜝꜜᴠͼ
ⅎ᷅⅍ԓͼⅎ᷅˲ԓͼⅎ᷅᷈᷈ԓͼԜꜜᴑͼⅎ᷅᷈᷾
ᴀꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴡⱳᴒͼ꞉ꜜᴠᴡᴟᴢꜛᴒꜜᴡᴠͼӿⱬϷ᷿ⱫͼԜꜜᴑͼⱨⱬ᷄ϷꜝꜙԐͼᴢᴠᴒᴑͼⱱꜝᴟͼꜟᴢԜꞌ꞉ᴡᴦͼꜝⱱͼꞌ꞉ⱱᴒͼ
ԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼꜝꜜͼⱫԜᴦᴠͼ᷇ԓͼⱠ˲ᶐ᷊ԓͼ᷈˲᷉ᶐ᷊ԓͼԜꜜᴑͼ᷊᷉˲ᶐ᷊᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⅎ᷊᷅ͼӿᴀᴡԜᴟᴡͼꜝⱱͼ
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼ͟ᴒᴟ꞉ꜝᴑԐⱢͼ
ᴀᴒᴐᴡ꞉ꜝꜜᴠⅎ᷅᷈᷇ͼԜꜜᴑⅎ᷿᷅᷈ͼ
ӿⱪꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ
͟ᴒᴟ꞉ꜝᴑԐⱢͼᴀᴒᴐᴡ꞉ꜝꜜⅎ᷅᷈ⅎͼ
ӿⱴ꞉ꜜԜꞌͼⱴꜝꞌꞌꜝᴤ᷄ᴢꜞͼᴃ꞉ᴠ꞉ᴡԐ
ᴀꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼᴡⱳᴒͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼⱱꜝᴟͼⱨⱬ᷄ϷꜝꜙͼꜝꜜͼⱫԜᴦᴠͼ᷉˲ᶐ᷊ԓͼ᷿⅍ᶐ᷊ԓͼ᷈᷉⅍ᶐ᷊ԓͼ
Ԝꜜᴑͼ᷿᷈᷾ᶐ᷊ͼⱱꜝᴟͼᴐꞌᴒԜᴟͼᴑᴒꜛԜᴟᴐԜᴡ꞉ꜝꜜ᷅
ᴀᴒᴐᴡ꞉ꜝꜜᴠͼⅎ᷅⅍ԓ ⅎ᷅˲ԓͼⅎ᷅᷈᷈᷅ͼͼ
ⅎ᷅᷈᷾
ⱫᴀꜚⱩͼᴟᴒꜞꞌԜᴐᴒᴠͼᴀᴀⱪ᷅
ᴀᴒᴐᴡ꞉ꜝꜜᴠⅎ᷅Ⱡԓͼⅎ᷅᷈᷇ԓͼⅎ᷅᷈᷈ԓͼ
ⅎ᷅᷈᷉ԓͼⅎ᷅᷈᷾
ᴁᴒᴥᴡͼԜᴑᴑᴒᴑͼᴡꜝͼꜞᴟꜝᴣ꞉ᴑᴒͼԜꜜͼꜝᴣᴒᴟᴣ꞉ᴒᴤͼꜝⱱͼᴡⱳᴒͼⱲᴒꜜᴒᴟԜꞌͼꜞꞌԜꜜͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼԜꜜԜꞌᴦᴠᴒᴠ᷅ͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅᷈ԓͼⱵᴒꜜᴒᴟԜꞌͼ
ⱪꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠ
ᴁᴒᴥᴡͼⱱꜝᴟᶰᴠԜꜛꜞꞌᴒͼᴠ꞉ᴧᴒͼᴑᴒᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜᶱͼᴤԜᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼᴡⱳᴒͼ
ᴢꜞᴑԜᴡᴒᴑͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛᴒᴡⱳꜝᴑᴠ᷅
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠⱢͼᴀᴒᴐᴡ꞉ꜝꜜͼ
Ⱡ᷅᷉ԓͼᴀԜꜛꜞꞌᴒͼᴀ꞉ᴧᴒͼ
Ⱬᴒᴡᴒᴟꜛ꞉ꜜԜᴡ꞉ꜝꜜͼ
ⱨᴑᴑᴒᴑͼᴐꜝꜜᴠꜝꞌ꞉ᴑԜᴡᴒᴑͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴟԜꜜᴑꜝꜛ꞉ᴧԜᴡ꞉ꜝꜜͼԜꜜᴑͼᴠᴡᴟԜᴡ꞉ⱱ꞉ᴐԜᴡ꞉ꜝꜜͼ꞉ꜜͼᴡⱳᴒͼ
ᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼⱨꜜԜꞌᴦᴠ꞉ᴠͼᴠᴒᴐᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷊᷅ԓͼꜚᴒᴡⱳꜝᴑͼꜝⱱͼ
ⱨᴠᴠ꞉Ⱳꜜ꞉ꜜⱲͼᴀᴡᴢᴑᴦͼᴀᴢԝ꞊ᴒᴐᴡᴠͼ
ᴡꜝͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼⱵᴟꜝᴢꜞᴠ
ᴁᴒᴥᴡͼԜᴑᴑᴒᴑͼᴡꜝͼᴐꞌԜᴟ꞉ⱱᴦͼᴡⱳԜᴡͼᴡⱳᴒͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤ꞉ꞌꞌͼԝᴒͼԜꜜԜꞌᴦᴧᴒᴑͼԜᴐᴐꜝᴟᴑ꞉ꜜⱲͼᴡꜝͼᴡⱳᴒ꞉ᴟͼ
ᴟԜꜜᴑꜝꜛ꞉ᴧᴒᴑͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴠᴠ꞉Ⱳꜜꜛᴒꜜᴡ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅᷾ԓͼⱨꜜԜꞌᴦᴠ꞉ᴠͼ
͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ
ⱨᴑᴑᴒᴑͼᴡⱳᴒͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜᴠͼⱱꜝᴟͼᴐꞌԜᴟ꞉ᴡᴦ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷿᷅ԓͼⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼ
Ⱬ꞉ᴠꜞꜝᴠ꞉ᴡ꞉ꜝꜜ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜞꜝꜞᴢꞌԜᴡ꞉ꜝꜜ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅⅍ԓͼⱫᴒꜛꜝⱲᴟԜꜞⱳ꞉ᴐᴠͼ
ԜꜜᴑͼⱩԜᴠᴒꞌ꞉ꜜᴒͼ
ⱪⱳԜᴟԜᴐᴡᴒᴟ꞉ᴠᴡ꞉ᴐᴠͼⱨꜜԜꞌᴦᴠᴒᴠ
ⱨᴑᴑᴒᴑͼᴡⱳᴒͼꜛᴒᴡⱳꜝᴑͼꜝⱱͼᴑᴒᴠᴐᴟ꞉ԝ꞉ꜜⱲͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴐꜝꜛꜞꞌ꞉ԜꜜᴐᴒͼԜꜜᴑͼᴒᴥᴡᴒꜜᴡͼꜝⱱͼᴒᴥꜞꜝᴠᴢᴟᴒ᷅ͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅ⅎԓͼᴁᴟᴒԜᴡꜛᴒꜜᴡͼ
ⱪꜝꜛꜞꞌ꞉ԜꜜᴐᴒͼԜꜜᴑͼⱬᴥᴡᴒꜜᴡͼꜝⱱͼ
ⱬᴥꜞꜝᴠᴢᴟᴒ
ⱬⱱⱱ꞉ᴐԜᴐᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼꜞᴒᴟ꞉ꜝᴑͼԝᴒⱲ꞉ꜜꜜ꞉ꜜⱲͼꜝꜜͼⱫԜᴦͼ᷇ͼ꞉ꜜᴠᴡᴒԜᴑͼꜝⱱͼⱫԜᴦͼ᷈᷾᷅ͼ
ϸᴒᴠᴢꞌᴡᴠͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛꜝᴑᴒꞌͼᴤ꞉ꞌꞌͼԝᴒͼᴟᴒꜞꜝᴟᴡᴒᴑͼ꞉ꜜͼԝꜝᴡⱳͼᴤᴒᴒꞋᴠͼԜꜜᴑͼꜛꜝꜜᴡⱳᴠͼᴡꜝͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅˲ԓ ⱨꜜԜꞌᴦᴠ꞉ᴠͼꜝⱱͼ
͟ᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴀᴒᴐꜝꜜᴑԜᴟᴦͼ
ⱬⱱⱱ꞉ᴐԜᴐᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈᷇᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.0
Amendment Date
21 April 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
ⱱԜᴐ꞉ꞌ꞉ᴡԜᴡᴒͼᴐꞌ꞉ꜜ꞉ᴐԜꞌͼ꞉ꜜᴡᴒᴟꜞᴟᴒᴡԜᴡ꞉ꜝꜜ᷅
ᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛᴒᴡⱳꜝᴑᴠͼᴤᴒᴟᴒͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴢᴠᴒͼԜͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌͼᴟԜᴡⱳᴒᴟͼᴡⱳԜꜜͼ
ⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼᴒᴠᴡ꞉ꜛԜᴡ꞉ꜜⱲͼᴒꜟᴢԜᴡ꞉ꜝꜜͼꜛꜝᴑᴒꞌͼⱱꜝᴟͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜԜꞌᴦᴠ꞉ᴠ᷅ͼᴁⱳ꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼ
ԜꜜԜꞌᴦᴠ꞉ᴠͼԜꜞꜞᴟꜝԜᴐⱳͼԜꞌᴠꜝͼԜꜞꜞꞌ꞉ᴒᴠͼᴡꜝͼᴡⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠ᷅
ⱬᴥꜞꞌԜ꞉ꜜᴠͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼԜꜜԜꞌᴦᴠᴒᴠͼԝԜᴠᴒᴑͼꜝꜜͼⱲᴒꜜᴒᴟԜꞌ꞉ᴧᴒᴑͼꞌ꞉ꜜᴒԜᴟͼꜛꜝᴑᴒꞌ᷅
ᴁⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᶰᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋԓͼ꞉ᴒԓͼᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡᴡԜᴐꞋͼ
ⱱᴟᴒᴒͼᴢꜜᴡ꞉ꞌͼᴡⱳᴒ꞉ᴟͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋᶱͼᴤԜᴠͼᴟᴒꜛꜝᴣᴒᴑͼⱱᴟꜝꜛͼᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟͼԜꜜᴑͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜꜜͼᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅ͼⱷᴡͼᴤԜᴠͼꜛꜝᴑ꞉ⱱ꞉ᴒᴑͼᴡꜝͼᶰᴁ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼⱶⱨⱬͼԜᴡᴡԜᴐꞋͼ
ԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ԓͼ꞉᷅ᴒ᷅ԓͼᴑᴢᴟԜᴡ꞉ꜝꜜͼᴡⱳԜᴡͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼ꞉ᴠͼԜᴡᴡԜᴐꞋ᷄ⱱᴟᴒᴒͼԜⱱᴡᴒᴟͼⱫԜᴦͼ᷈᷾ᶱͼᴡꜝͼԜꞌꞌꜝᴤͼ
ᴒꜜꜝᴢⱲⱳͼᴡ꞉ꜛᴒͼᴡꜝͼⱱ꞉ᴟᴠᴡͼԜᴡᴡԜᴐꞋͼⱱꜝᴟͼᴡⱳ꞉ᴠͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡ᷅
ᴁⱳᴒͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡͼᶰ꜠ᴢꜛԝᴒᴟͼꜝⱱͼⱳ꞉Ⱳⱳ᷄ꜛꜝᴟԝ꞉ᴑ꞉ᴡᴦͼⱶⱨⱬͼԜᴡᴡԜᴐꞋᴠᶱͼᴟᴒꜛꜝᴣᴒᴑͼⱱᴟꜝꜛ
ᴡⱳᴒͼᴟԜꜜꞋͼꜝᴟᴑᴒᴟͼԜꜜᴑͼᴤ꞉ꞌꞌͼԝᴒͼᴐꜝꜜᴠ꞉ᴑᴒᴟᴒᴑͼԜꜜͼᴒᴥꜞꞌꜝᴟԜᴡꜝᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅˲ԓͼᴀᴒᴐꜝꜜᴑԜᴟᴦͼ
ⱬⱱⱱ꞉ᴐԜᴐᴦͼⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ
ⱨᴑᴑᴒᴑͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼᴑᴒᴡԜ꞉ꞌᴠͼⱱꜝᴟͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼԜꜜԜꞌᴦᴠ꞉ᴠⱢͼᴐꞌԜᴟ꞉ⱱ꞉ᴒᴑͼꜜꜝͼꜞꞌԜꜜͼⱱꜝᴟͼ꞉ꜜᴡᴒᴟ꞉ꜛͼ
ԜꜜԜꞌᴦᴠ꞉ᴠͼԜꜜᴑͼꜞꞌԜꜜᴠͼⱱꜝᴟͼⱫᴀꜚⱩ᷅ͼ
ⱷꜜͼⱲᴒꜜᴒᴟԜꞌԓͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼꜛᴒᴡⱳꜝᴑᴠͼᴤᴒᴟᴒͼᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼᴤ꞉ᴡⱳͼԜᴑᴑ꞉ᴡ꞉ꜝꜜԜꞌͼ꞉ꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ
ᴟᴒⱲԜᴟᴑ꞉ꜜⱲͼᴡⱳᴒͼⱲᴒꜜᴒᴟԜꞌͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼᴐꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠͼԜꜜᴑͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌ᷆ԜꜜԜꞌᴦᴡ꞉ᴐԜꞌͼ꞉ᴠᴠᴢᴒᴠͼӿᴒⱲԓͼ
Ԝᴑ꞊ᴢᴠᴡꜛᴒꜜᴡͼⱱꜝᴟͼᴐꜝᴣԜᴟ꞉ԜᴡᴒᴠԓͼⱳԜꜜᴑꞌ꞉ꜜⱲͼꜝⱱͼᴑᴟꜝꜞꜝᴢᴡᴠͼԜꜜᴑͼᴑԜᴡԜͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲԓͼⱳԜꜜᴑꞌ꞉ꜜⱲͼꜝⱱͼ
ᴑᴟꜝꜞꜝᴢᴡᴠͼꜝᴟͼꜛ꞉ᴠᴠ꞉ꜜⱲͼᴑԜᴡԜԓͼ꞉ꜜᴡᴒᴟ꞉ꜛͼԜꜜԜꞌᴦᴠ꞉ᴠԜꜜᴑͼᴑԜᴡԜͼꜛꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲԓͼꜛᴢꞌᴡ꞉ᴐᴒꜜᴡᴒᴟͼ
ᴠᴡᴢᴑ꞉ᴒᴠԓͼԜꜜᴑͼᴠᴒꜜᴠ꞉ᴡ꞉ᴣ꞉ᴡᴦͼԜꜜԜꞌᴦᴠᴒᴠԐ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅᷈᷉ԓͼ
ᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌ᷆ⱨꜜԜꞌᴦᴡ꞉ᴐͼⱷᴠᴠᴢᴒᴠ
ꜚᴢꞌᴡ꞉ꜞꞌ꞉ᴐ꞉ᴡᴦͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠͼᴤᴒᴟᴒͼᴠꜞᴒᴐ꞉ⱱ꞉ᴒᴑͼ꞉ꜜͼⱲᴟᴒԜᴡᴒᴟͼᴑᴒᴡԜ꞉ꞌ᷅ͼᴀꜞᴒᴐ꞉ⱱ꞉ᴐԜꞌꞌᴦԓͼԜͼⱲᴒꜜᴒᴟԜꞌͼ
ⱲԜᴡᴒꞋᴒᴒꜞ꞉ꜜⱲͼꜞᴟꜝᴐᴒᴑᴢᴟᴒͼᴤ꞉ꞌꞌͼԝᴒͼᴢᴠᴒᴑͼᴡꜝͼᴠᴡᴟꜝꜜⱲꞌᴦͼᴐꜝꜜᴡᴟꜝꞌͼᴡⱳᴒͼⱲꞌꜝԝԜꞌͼⱴᴄⱬϸͼ꞉ꜜͼᴡⱳᴒͼ
ⱳ꞉ᴒᴟԜᴟᴐⱳ꞉ᴐԜꞌͼᴡᴒᴠᴡ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼꜞᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴠᴒᴐꜝꜜᴑԜᴟᴦͼᴒꜜᴑꜞꜝ꞉ꜜᴡᴠͼᴐꜝꜜᴑᴢᴐᴡᴒᴑͼԜᴡͼᴡⱳᴒͼ
᷈᷅⅍ⅎӼͼᴠ꞉Ⱳꜜ꞉ⱱ꞉ᴐԜꜜᴐᴒͼꞌᴒᴣᴒꞌͼⱱꜝᴟͼᴒԜᴐⱳͼԜᴐᴡ꞉ᴣᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼⱲᴟꜝᴢꜞͼᴐꜝꜛꜞԜᴟᴒᴑͼᴤ꞉ᴡⱳͼᴡⱳᴒͼ
ꜞꞌԜᴐᴒԝꜝͼⱲᴟꜝᴢꜞ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅᷈᷉ԓͼ
ᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌ᷆ⱨꜜԜꞌᴦᴡ꞉ᴐͼⱷᴠᴠᴢᴒᴠ
ⱨᴑᴑᴒᴑͼᴡꜝͼԝᴟ꞉ᴒⱱꞌᴦͼ꞉ꜜᴡᴟꜝᴑᴢᴐᴒͼᴡⱳᴒͼꜞꞌԜꜜͼⱱꜝᴟͼᴠᴒꜜᴠ꞉ᴡ꞉ᴣ꞉ᴡᴦͼԜꜜԜꞌᴦᴠ꞉ᴠԓͼᴤⱳ꞉ᴐⱳͼᴤ꞉ꞌꞌͼԝᴒͼ
ᴑᴒᴠᴐᴟ꞉ԝᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴠᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌͼԜꜜԜꞌᴦᴠ꞉ᴠͼꜞꞌԜꜜ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅᷈᷉᷅⅍ԓͼᴀᴡԜᴡ꞉ᴠᴡ꞉ᴐԜꞌ
ⱨꜜԜꞌᴦᴠᴒᴠ
ᴀᴡᴢᴑᴦͼᴐꜝꜜᴡԜᴐᴡͼԜꜜᴑͼꜚᴒᴑ꞉ᴐԜꞌͼⱫ꞉ᴟᴒᴐᴡꜝᴟͼᴢꜞᴑԜᴡᴒᴑͼ꞉ꜜͼᴁԜԝꞌᴒͼ᷉᷅ͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇ԓͼᴀᴡᴢᴑᴦ
ⱨᴑꜛ꞉ꜜ꞉ᴠᴡᴟԜᴡ꞉ᴣᴒͼᴀᴡᴟᴢᴐᴡᴢᴟᴒ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼⱫᴀꜚⱩͼꜞᴟꜝᴐᴒᴑᴢᴟᴒᴠ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇᷅ⅎԓͼⱫԜᴡԜͼᴀԜⱱᴒᴡᴦ
ꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲ
꜠ᴒᴤͼᴡᴒᴥᴡ
꜠ᴒᴤͼᴀᴒᴐᴡ꞉ꜝꜜⱡͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷇᷅Ⱡԓ
͟ᴟᴒꜛԜᴡᴢᴟᴒͼⱪꞌꜝᴠᴢᴟᴒͼꜝⱱͼᴡⱳᴒ
ᴀᴡᴢᴑᴦ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴑԜᴡԜͼⱳԜꜜᴑꞌ꞉ꜜⱲͼᴐꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠᴡꜝͼꜞᴟᴒᴣᴒꜜᴡͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼᴢꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲ᷅
꜠ᴒᴤͼᴀᴒᴐᴡ꞉ꜝꜜⱡͼᴀᴒᴐᴡ꞉ꜝꜜ
᷈᷇᷅᷈᷉ԓͼⱫԜᴡԜͼⱶԜꜜᴑꞌ꞉ꜜⱲ
ⱪꜝꜜᴠ꞉ᴑᴒᴟԜᴡ꞉ꜝꜜᴠ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈᷇᷈
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.0
Amendment Date
21 April 2016
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
ⱨᴑᴑᴒᴑͼᴡᴒᴥᴡᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼ᷉᷈ͼⱪⱴϸͼ᷿᷾ͼ᷉ӿԝԐͼӿ᷈ⱠⱠ˲Ԑ᷅ͼ
꜠ᴒᴤͼᴀᴒᴐᴡ꞉ꜝꜜⱡͼᴀᴒᴐᴡ꞉ꜝꜜ
᷈᷇᷅᷈᷾ԓͼⱴ꞉ꜜԜꜜᴐ꞉Ԝꞌ
Ⱬ꞉ᴠᴐꞌꜝᴠᴢᴟᴒ
ⱨᴑᴑᴒᴑͼᴡᴒᴥᴡͼᴡꜝͼԜꞌ꞉Ⱳꜜͼᴤ꞉ᴡⱳͼꜞꜝᴡᴒꜜᴡ꞉Ԝꞌͼᴑ꞉ᴠᴐꞌꜝᴠᴢᴟᴒͼꜝⱱͼᴠᴡᴢᴑᴦͼᴟᴒᴠᴢꞌᴡᴠ᷅
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷈᷇᷅᷈ԓͼ͟ᴢԝꞌ꞉ᴐԜᴡ꞉ꜝꜜ
ԜꜜᴑͼⱫ꞉ᴠᴐꞌꜝᴠᴢᴟᴒͼ͟ꜝꞌ꞉ᴐᴦ
ᴁⱳᴒͼ͟ᴟꜝᴡꜝᴐꜝꞌͼⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷈᷅᷇ͼ꞉ꜜᴐꞌᴢᴑᴒᴠͼᴐⱳԜꜜⱲᴒᴠᴡꜝͼᴡⱳᴒͼꜝᴟ꞉Ⱳ꞉ꜜԜꞌͼꜞᴟꜝᴡꜝᴐꜝꞌԓͼᴠᴢꜛꜛԜᴟ꞉ᴧᴒᴑͼԜᴠͼ
ⱱꜝꞌꞌꜝᴤᴠⱡ

ᴁⱳᴒͼꞌ꞉ᴠᴡͼꜝⱱͼ꞉ꜜԜᴐᴡ꞉ᴣᴒͼ꞉ꜜⱲᴟᴒᴑ꞉ᴒꜜᴡᴠͼԜꜜᴑͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴡᴟᴒԜᴡꜛᴒꜜᴡᴠͼ꞉ꜜͼᴡⱳᴒͼᴠᴦꜜꜝꜞᴠ꞉ᴠͼԜꜜᴑͼ꞉ꜜͼ
ᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷅᷈ͼ꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴟᴒⱱꞌᴒᴐᴡͼᴡⱳᴒͼᴢᴠᴒͼꜝⱱͼ᷿᷈᷇ͼꜛⱲ᷆ꜛꜙͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼ
꞉ꜜᴠᴡᴒԜᴑͼꜝⱱͼ᷈᷇᷇ͼꜛⱲ᷆ꜛꜙͼᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜͼⱫᴅ᷄᷉Ⱡ᷊᷇᷅ꜚ꞉ꜜꜝᴟͼᴢꜞᴑԜᴡᴒᴠͼԜᴟᴒͼꜛԜᴑᴒͼᴡꜝͼᴡⱳᴒͼ
ᴐꜝꜛꜞꜝꜜᴒꜜᴡᴠͼꜝⱱͼԝꜝᴡⱳͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑͼ͟ꞌԜᴐᴒԝꜝ᷅ͼᴁⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜᴠͼԜꜜᴑͼᴡⱳᴒͼᴣꜝꞌᴢꜛᴒͼ
ꜝⱱͼᴒԜᴐⱳͼ꞉ꜜ꞊ᴒᴐᴡ꞉ꜝꜜͼꜝⱱͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼԜꜜᴑͼ͟ꞌԜᴐᴒԝꜝͼԜᴟᴒͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴟᴒⱱꞌᴒᴐᴡͼᴡⱳᴒͼᴐⱳԜꜜⱲᴒͼ꞉ꜜͼ
ᴐꜝꜜᴐᴒꜜᴡᴟԜᴡ꞉ꜝꜜ᷅

ᴁⱳᴒͼ᷈ͼꜛꜝꜜᴡⱳͼꜜꜝꜜ᷄ⱳᴢꜛԜꜜͼꜞᴟ꞉ꜛԜᴡᴒͼᴑԜᴡԜͼ꞉ꜜͼᴡⱳᴒͼᴀԜⱱᴒᴡᴦͼϸԜᴡ꞉ꜝꜜԜꞌᴒͼⱱꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇ͼⱳԜᴠͼԝᴒᴒꜜͼ
ᴟᴒꜞꞌԜᴐᴒᴑͼᴤ꞉ᴡⱳͼ⅍ͼꜛꜝꜜᴡⱳͼꜜꜝꜜ᷄ⱳᴢꜛԜꜜͼꜞᴟ꞉ꜛԜᴡᴒͼᴑԜᴡԜͼԜᴠͼᴡⱳᴒͼ⅍ͼꜛꜝꜜᴡⱳͼᴑԜᴡԜͼ꞉ᴠͼԜᴣԜ꞉ꞌԜԝꞌᴒͼԜꜜᴑͼ
ꜛꜝᴟᴒͼᴟᴒꞌᴒᴣԜꜜᴡͼⱱꜝᴟͼᴡⱳ꞉ᴠͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼᴡᴟ꞉Ԝꞌ᷅ͼᴁⱳᴒͼᴑᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴡⱳᴒͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼ
꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴐꞌԜᴟ꞉ⱱᴦͼᴡⱳԜᴡͼ꞉ⱱͼԜͼᴠᴢԝ꞊ᴒᴐᴡᶳᴠͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑͼᴒᴥᴡᴒꜜᴑᴒᴑͼᴡꜝͼ˲ͼᴤᴒᴒꞋᴠͼᴡⱳᴒꜜͼ꞉ꜜͼꜝᴟᴑᴒᴟͼ
ᴡꜝͼԝᴒͼᴒꞌ꞉Ⱳ꞉ԝꞌᴒͼⱱꜝᴟͼᴒꜜᴟꜝꞌꞌꜛᴒꜜᴡͼᴡⱳᴒᴦͼꜛᴢᴠᴡͼᴐꜝꜛꜞꞌᴒᴡᴒͼᴡⱳᴒͼⱱᴢꞌꞌͼ˲ͼᴤᴒᴒꞋᴠͼꜞᴟ꞉ꜝᴟͼᴡꜝͼᴒꜜᴡᴒᴟ꞉ꜜⱲͼᴡⱳᴒͼ
ᴡᴟᴒԜᴡꜛᴒꜜᴡͼꜞᴒᴟ꞉ꜝᴑ
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ⱷꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴠᴡᴢᴑᴦͼꜞԜᴟᴡ꞉ᴐ꞉ꜞԜꜜᴡͼᴠᴡꜝꜞꜞ꞉ꜜⱲͼᴟᴢꞌᴒᴠͼԜᴟᴒͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴐꞌԜᴟ꞉ⱱᴦͼᴡⱳԜᴡͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼ
ⱳԜᴠͼᴠꜝꞌᴒͼᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼᴡꜝͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢᴒͼᴠᴢԝ꞊ᴒᴐᴡͼᴑꜝᴠ꞉ꜜⱲͼԜꜜᴑͼᴡⱳԜᴡͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼ꞉ᴠͼ
ԜᴣԜ꞉ꞌԜԝꞌᴒͼⱱꜝᴟͼᴐꜝꜜᴠᴢꞌᴡԜᴡ꞉ꜝꜜ᷅

ᴁⱳᴒͼᴒᴥꜞᴒᴐᴡᴒᴑͼꜜᴢꜛԝᴒᴟͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼԜⱲᴒͼ᷈᷉ͼᴡꜝͼ᷈ⅎͼᴡꜝͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼ꞉ᴠͼԜᴑᴑᴒᴑ᷅

ᴁⱳᴒͼԝꞌ꞉ꜜᴑ꞉ꜜⱲͼԜꜜᴑͼᴢꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲͼᴡᴒᴥᴡͼ꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴐꞌԜᴟ꞉ⱱᴦͼᴡⱳԜᴡͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼⱳԜᴠͼᴠꜝꞌᴒͼ
ᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼᴡꜝͼԝᴟᴒԜꞋͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴐꜝᴑᴒͼ꞉ꜜͼԜꜜͼᴒꜛᴒᴟⱲᴒꜜᴐᴦͼᴠ꞉ᴡᴢԜᴡ꞉ꜝꜜͼᴡⱳᴟꜝᴢⱲⱳͼ꞉ꜛꜛᴒᴑ꞉Ԝᴡᴒͼ
Ԝꜜᴑͼᴢꜜᴟᴒᴠᴡᴟ꞉ᴐᴡᴒᴑͼԜᴐᴐᴒᴠᴠͼᴡꜝͼᴡⱳᴒͼⱷᴄϸᴀͼᴠᴦᴠᴡᴒꜛ᷅ͼᴁⱳᴒͼᴡᴒᴥᴡͼ꞉ᴠͼⱱᴢᴟᴡⱳᴒᴟͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴐꞌԜᴟ꞉ⱱᴦͼᴡⱳԜᴡͼ
ᴡⱳᴒͼⱫᴦԜᴥͼ͟ⱳԜᴟꜛԜᴐꜝᴣ꞉Ⱳ꞉ꞌԜꜜᴐᴒͼӿ͟ᴃԐͼⱫᴒꜞԜᴟᴡꜛᴒꜜᴡͼᴤ꞉ꞌꞌͼԝᴒͼꜞᴟꜝᴣ꞉ᴑᴒᴑͼᴤ꞉ᴡⱳͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
Ԝᴠᴠ꞉Ⱳꜜꜛᴒꜜᴡᴠͼⱱꜝᴟͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴤⱳꜝͼᴒᴥꜞᴒᴟ꞉ᴒꜜᴐᴒͼᴑᴟᴢⱲͼᴟᴒꞌԜᴡᴒᴑԓͼᴠᴒᴟ꞉ꜝᴢᴠԓͼᴢꜜᴒᴥꜞᴒᴐᴡᴒᴑͼԜᴑᴣᴒᴟᴠᴒͼ
ᴒᴣᴒꜜᴡᴠͼⱱꜝᴟͼᴡⱳᴒͼꜞᴢᴟꜞꜝᴠᴒͼꜝⱱͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲ᷅
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ᴁⱳᴒͼꜝᴟᴑᴒᴟͼꜝⱱͼᴡⱳᴒͼᴠԜꜛꜞꞌᴒͼᴐꜝꞌꞌᴒᴐᴡ꞉ꜝꜜᴠͼᴤⱳᴒꜜͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼᴠԜꜛꜞꞌᴒͼᴡᴦꜞᴒᴠͼԜᴟᴒͼᴐꜝꞌꞌᴒᴐᴡᴒᴑͼԜᴡͼᴡⱳᴒͼ
ᴠԜꜛᴒͼᴡ꞉ꜛᴒͼꜞꜝ꞉ꜜᴡͼ꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴐꜝᴟᴟᴒᴠꜞꜝꜜᴑͼᴡꜝͼᴡⱳᴒͼꜙԜԝꜝᴟԜᴡꜝᴟᴦꜚԜꜜᴢԜꞌ᷅
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ᴁⱳᴒͼᴠᴡᴢᴑᴦͼᴑԜᴦͼᴡⱳᴟꜝᴢⱲⱳͼᴤⱳ꞉ᴐⱳͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼᴒꜛᴒᴟⱲᴒꜜᴡͼⱨⱬᴠͼԜᴟᴒͼᴑᴒⱱ꞉ꜜᴒᴑͼ꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼᴠꜝͼԜᴠͼᴡꜝͼ
ԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼꜝᴡⱳᴒᴟͼᴠᴒᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅

ᴀᴢԝ꞊ᴒᴐᴡͼᴤ꞉ᴡⱳᴑᴟԜᴤԜꞌͼᴡᴒᴥᴡͼ꞉ᴠͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼꜛꜝᴟᴒͼᴐꞌᴒԜᴟꞌᴦͼᴑ꞉ᴠᴡ꞉ꜜⱲᴢ꞉ᴠⱳͼԝᴒᴡᴤᴒᴒꜜͼ
ᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴑꜝᴠ꞉ꜜⱲͼԜꜜᴑͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴡⱳᴒͼᴠᴡᴢᴑᴦԓͼԜᴠͼᴤᴒꞌꞌͼԜᴠͼᴡꜝͼᴐꞌԜᴟ꞉ⱱᴦͼ
ᴡⱳԜᴡͼᴡⱳᴒͼᴢᴠᴒͼꜝⱱͼꜞᴟꜝⱳ꞉ԝ꞉ᴡ꞉ᴣᴒͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼꜛԜᴦͼԝᴒͼⱲᴟꜝᴢꜜᴑᴠͼⱱꜝᴟͼᴤ꞉ᴡⱳᴑᴟԜᴤԜꞌͼԝᴦͼᴡⱳᴒͼ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈᷇᷉
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅ͼᴁⱳᴒͼᴡᴒᴥᴡͼ꞉ᴠͼⱱᴢᴟᴡⱳᴒᴟͼᴢꜞᴑԜᴡᴒᴑͼᴡꜝͼᴐꞌԜᴟ꞉ⱱᴦͼᴡⱳԜᴡͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟͼⱳԜᴠͼᴠꜝꞌᴒͼ
ᴑ꞉ᴠᴐᴟᴒᴡ꞉ꜝꜜͼᴡꜝͼᴤ꞉ᴡⱳᴑᴟԜᴤͼԜͼᴠᴢԝ꞊ᴒᴐᴡͼⱱꜝᴟͼᴠԜⱱᴒᴡᴦͼᴟᴒꞌԜᴡᴒᴑ꞉ᴠᴠᴢᴒᴠͼԜꜜᴑͼᴡⱳԜᴡͼᴡⱳᴒͼꜚᴒᴑ꞉ᴐԜꞌͼꜚꜝꜜ꞉ᴡꜝᴟͼ
꞉ᴠͼԜᴣԜ꞉ꞌԜԝꞌᴒͼⱱꜝᴟͼᴐꜝꜜᴠᴢꞌᴡԜᴡ꞉ꜝꜜ᷅
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ⱨͼꜛ꞉ꜜꜝᴟͼᴠꜞᴒꞌꞌ꞉ꜜⱲͼᴐꜝᴟᴟᴒᴐᴡ꞉ꜝꜜͼ꞉ᴠͼꜛԜᴑᴒͼᴐⱳԜꜜⱲ꞉ꜜⱲͼᶲꜛᴒᴑ꞉Ԝᴡ꞉ꜝꜜᴠᶳͼᴡꜝͼᶲꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠᶳ
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.0
Amendment Date
14 December 2015
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼԜᴐᴡᴢԜꞌͼ꞉ꜜⱲᴟᴒᴑ꞉ᴒꜜᴡᴠͼᴡⱳԜᴡͼԜᴟᴒͼᴟᴒⱱᴒᴟᴒꜜᴐᴒᴑͼ꞉ꜜͼᴡⱳᴒͼᴒᴥᴐ꞉ꜞ꞉ᴒꜜᴡͼꞌ꞉ᴠᴡ᷅
͟ԜⱲᴒͼ᷊ͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼ
ᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼⱷꜜԜᴐᴡ꞉ᴣᴒͼ
ⱷꜜⱲᴟᴒᴑ꞉ᴒꜜᴡᴠ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼꜜԜᴡᴢᴟᴒͼꜝⱱͼᴡⱳᴒͼ͟ꜘͼԜꜜᴑͼ͟ⱫͼꜛᴒԜᴠᴢᴟᴒᴠͼꜝⱱͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜ᷅ͼ
͟ԜⱲᴒͼ᷊᷈ͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼ
ᴀᴦꜜꜝꜞᴠ꞉ᴠԓͼⱪᴟ꞉ᴡᴒᴟ꞉Ԝͼⱱꜝᴟͼ
ⱬᴣԜꞌᴢԜᴡ꞉ꜝꜜ
ⱫԜᴡԜͼⱱᴟꜝꜛͼᴡⱳᴒͼ⅍᷄ꜛꜝꜜᴡⱳͼᴠᴡᴢᴑᴦͼ꞉ᴠͼԜᴣԜ꞉ꞌԜԝꞌᴒͼԜꜜᴑͼꜛꜝᴟᴒͼᴟᴒꞌᴒᴣԜꜜᴡͼⱱꜝᴟͼᴡⱳ꞉ᴠͼꞌꜝꜜⱲ᷄ᴡᴒᴟꜛͼ
ꜞᴟꜝꜞⱳᴦꞌԜᴥ꞉ᴠͼᴡᴟ꞉Ԝꞌ᷅
͟ԜⱲᴒͼ᷉˲ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷅᷾ͼᴀԜⱱᴒᴡᴦͼ
ϸԜᴡ꞉ꜝꜜԜꞌᴒͼⱱꜝᴟͼⱫᴅ᷄᷉Ⱡ᷊᷇
꜠ᴒᴢᴡᴟԜꞌ꞉ᴧ꞉ꜜⱲͼԜꜜᴡ꞉ԝꜝᴑᴦͼᴑԜᴡԜͼⱱᴟꜝꜛͼⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉ͼ꞉ᴠͼꜜꜝᴤͼԜᴣԜ꞉ꞌԜԝꞌᴒ᷅ͼ
͟ԜⱲᴒͼ᷊᷈ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷈᷅⅍᷅᷉ͼ
ꜚᴢꞌᴡ꞉ꜞꞌᴒͼⱨᴠᴐᴒꜜᴑ꞉ꜜⱲͼⱫꜝᴠᴒͼ
ᴀᴡᴢᴑᴦͼ꞉ꜜͼⱶⱨⱬͼ͟Ԝᴡ꞉ᴒꜜᴡᴠͼ
ӿⱫᴅ᷄᷉Ⱡ᷊᷇᷄᷇᷉Ԑ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼᴟᴒꜟᴢ꞉ᴟᴒꜛᴒꜜᴡᴠͼⱱꜝᴟͼᴒᴥᴡᴒꜜᴑᴒᴑͼᴟᴢꜜ᷄꞉ꜜͼꜞᴒᴟ꞉ꜝᴑᴠ᷅
͟ԜⱲᴒᴠͼ᷾ԓͼ᷈᷇ͼԜꜜᴑͼ᷈ⅎͼꜝⱱͼ
ᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠ
͟ԜⱲᴒͼ᷊᷾ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷊᷅᷈᷅᷈ԓͼ
꜡ᴣᴒᴟԜꞌꞌͼᴀᴡᴢᴑᴦͼⱫᴒᴠ꞉ⱲꜜͼԜꜜᴑͼ
͟ꞌԜꜜͼӿ꜡ᴣᴒᴟᴣ꞉ᴒᴤԐ
͟ԜⱲᴒͼ᷾˲ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾᷅᷉ԓͼ
ⱶⱨⱬͼⱨᴡᴡԜᴐꞋͼⱷꜜⱱꜝᴟꜛԜᴡ꞉ꜝꜜͼ
ⱪꜝꞌꞌᴒᴐᴡ꞉ꜝꜜ
ⱨꜞꜞᴒꜜᴑ꞉ᴥͼ᷈ͼᴀᴡᴢᴑᴦͼ
ⱨᴐᴡ꞉ᴣ꞉ᴡ꞉ᴒᴠͼᴀᴐⱳᴒᴑᴢꞌᴒ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡⱳԜᴡͼꜛԜᴦͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴒᴥꜞᴒᴐᴡᴒᴑͼᴡꜝͼᴐꜝꜛꜞꞌᴒᴡᴒ᷅
͟ԜⱲᴒͼ᷿ͼꜝⱱͼᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠ
͟ԜⱲᴒͼ᷊᷾ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷊᷅᷈᷅᷈ԓͼ
꜡ᴣᴒᴟԜꞌꞌͼᴀᴡᴢᴑᴦͼⱫᴒᴠ꞉ⱲꜜͼԜꜜᴑͼ
͟ꞌԜꜜͼӿ꜡ᴣᴒᴟᴣ꞉ᴒᴤԐ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼᴟꜝꞌᴒͼ꞉ꜜͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢ꞉ꜜⱲͼᴠᴢԝ꞊ᴒᴐᴡͼᴑꜝᴠ꞉ꜜⱲ᷅
͟ԜⱲᴒͼ᷈᷉ͼꜝⱱͼᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠ
͟ԜⱲᴒͼ᷊˲ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷊᷊᷅᷈᷅᷉᷅ͼ
ⱷꜜᴑ꞉ᴣ꞉ᴑᴢԜꞌͼᴀᴡꜝꜞꜞ꞉ꜜⱲͼϸᴢꞌᴒᴠ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼᴠᴢԝ꞊ᴒᴐᴡᴠͼᴡⱳԜᴡͼꜛԜᴦͼԝᴒͼᴒꜜᴟꜝꞌꞌᴒᴑͼԝԜᴠᴒᴑͼꜝꜜͼᴡⱳᴒͼꜜᴢꜛԝᴒᴟͼꜝⱱͼ
ᴠᴢԝ꞊ᴒᴐᴡᴠͼᴒᴥꜞᴒᴐᴡᴒᴑͼᴡꜝͼᴐꜝꜛꜞꞌᴒᴡᴒ᷅
͟ԜⱲᴒͼ᷾᷇ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷾᷅᷈ͼᴀᴡᴢᴑᴦͼ
͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ
͟ᴒᴟͼᴟᴒꜟᴢᴒᴠᴡͼԝᴦͼⱬᴢᴟꜝꜞᴒԜꜜͼϸᴒⱲᴢꞌԜᴡꜝᴟᴦͼⱨᴢᴡⱳꜝᴟ꞉ᴡ꞉ᴒᴠ᷅
͟ԜⱲᴒͼ᷿ͼꜝⱱͼᴀᴡᴢᴑᴦͼᴀᴦꜜꜝꜞᴠ꞉ᴠ
͟ԜⱲᴒͼ᷾᷇ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷾᷅᷈ͼᴀᴡᴢᴑᴦͼ
͟ꜝꜞᴢꞌԜᴡ꞉ꜝꜜ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦͼ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷊᷈᷇
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.0
Amendment Date
14 December 2015
Global/Country/Site 
Specific
Global
Description of Change
Section(s) Affected by 
Change
ϸᴒⱱꞌᴒᴐᴡ꞉ᴣᴒͼꜝⱱͼᴐⱳԜꜜⱲᴒᴠͼᴡꜝͼᴡⱳᴒͼꜛԜꜜᴢⱱԜᴐᴡᴢᴟᴒͼꜝⱱͼⱷ͟ͼⱱᴟꜝꜛͼ᷈᷇᷇ͼꜛⱲ᷆ͼꜛꜙͼᴡꜝͼ᷿᷈᷇ͼꜛⱲ᷆ͼꜛꜙͼ
Ⱬᴅ᷉Ⱡ᷊᷇᷅
͟ԜⱲᴒͼⅎͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼ
ᴀᴦꜜꜝꜞᴠ꞉ᴠ
͟ԜⱲᴒͼ᷾᷉ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷅᷈ԓͼ
Ⱬᴒᴠᴐᴟ꞉ꜞᴡ꞉ꜝꜜͼꜝⱱͼᴁᴟᴒԜᴡꜛᴒꜜᴡᴠ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼᴟꜝꞌᴒͼ꞉ꜜͼԝᴟᴒԜꞋ꞉ꜜⱲͼᴡⱳᴒͼԝꞌ꞉ꜜᴑͼԜꜜᴑͼꜝԝᴡԜ꞉ꜜ꞉ꜜⱲͼᴡⱳᴒͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼ
Ԝᴠᴠ꞉Ⱳꜜꜛᴒꜜᴡͼ꞉ꜜͼᴒꜛᴒᴟⱲᴒꜜᴐᴦͼᴠ꞉ᴡᴢԜᴡ꞉ꜝꜜᴠ᷅ͼ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳԜᴡͼⱫᴦԜᴥͼ͟ᴃͼᴤ꞉ꞌꞌͼꜝԝᴡԜ꞉ꜜͼᴡᴟᴒԜᴡꜛᴒꜜᴡͼԜᴠᴠ꞉ⱲꜜꜛᴒꜜᴡͼⱱꜝᴟͼᴟᴒⱲᴢꞌԜᴡꜝᴟᴦͼᴟᴒꜞꜝᴟᴡ꞉ꜜⱲͼ
ꜝⱱͼᴑᴟᴢⱲ᷄ᴟᴒꞌԜᴡᴒᴑԓͼᴠᴒᴟ꞉ꜝᴢᴠԓͼᴢꜜᴒᴥꜞᴒᴐᴡᴒᴑͼⱨⱬᴠ᷅
͟ԜⱲᴒͼ᷊᷾ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ᷿᷅᷾ͼ
Ⱪꞌ꞉ꜜᴑ꞉ꜜⱲͼԜꜜᴑͼᴂꜜԝꞌ꞉ꜜᴑ꞉ꜜⱲ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼᴡ꞉ꜛ꞉ꜜⱲͼꜝⱱͼᴡⱳᴒͼᴒⱱⱱ꞉ᴐԜᴐᴦͼᴒᴣԜꞌᴢԜᴡ꞉ꜝꜜͼꜞᴒᴟ꞉ꜝᴑ᷅
͟ԜⱲᴒͼ᷈᷉ͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼ
ᴀᴦꜜꜝꜞᴠ꞉ᴠ
͟ԜⱲᴒͼ᷾⅍ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷾᷅᷈ͼ
͟ᴟ꞉ꜛԜᴟᴦͼԜꜜᴑͼᴀᴒᴐꜝꜜᴑԜᴟᴦͼ
ⱬꜜᴑꜞꜝ꞉ꜜᴡᴠ
ⱪꜝᴟᴟᴒᴐᴡᴠͼᴡⱳᴒͼꜝᴟᴑᴒᴟͼꜝⱱͼᴠԜꜛꜞꞌᴒͼᴑᴟԜᴤᴠͼԜᴡͼᴡ꞉ꜛᴒͼꜞꜝ꞉ꜜᴡᴠͼᴤⱳᴒꜜͼꜛᴢꞌᴡ꞉ꜞꞌᴒͼᴠԜꜛꜞꞌᴒᴠͼԜᴟᴒͼ
ᴑᴟԜᴤꜜ᷅
͟ԜⱲᴒͼ᷿᷇ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅˲᷅᷈ͼ
ꜙԜԝꜝᴟԜᴡꜝᴟᴦͼ͟ԜᴟԜꜛᴒᴡᴒᴟᴠ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴑԜᴦͼᴡⱳᴟꜝᴢⱲⱳͼᴤⱳ꞉ᴐⱳͼᴁⱬⱨⱬᴠͼԜᴟᴒͼᴐԜꜞᴡᴢᴟᴒᴑͼᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼ
ꜝᴡⱳᴒᴟͼᴠᴒᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅ͼ
͟ԜⱲᴒͼ᷿᷿ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷿᷅᷈᷅ͼ
ᴁᴟᴒԜᴡꜛᴒꜜᴡͼⱬꜛᴒᴟⱲᴒꜜᴡͼ
ⱨᴑᴣᴒᴟᴠᴒͼⱬᴣᴒꜜᴡᴠͼӿᴁⱬⱨⱬᴠԐ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼᴠᴡᴢᴑᴦͼᴑԜᴦͼᴡⱳᴟꜝᴢⱲⱳͼᴤⱳ꞉ᴐⱳͼᴁⱬⱨⱬᴠͼԜᴟᴒͼᴐԜꜞᴡᴢᴟᴒᴑͼᴡꜝͼԝᴒͼᴐꜝꜜᴠ꞉ᴠᴡᴒꜜᴡͼᴤ꞉ᴡⱳͼ
ꜝᴡⱳᴒᴟͼᴠᴒᴐᴡ꞉ꜝꜜᴠͼꜝⱱͼᴡⱳᴒͼꜞᴟꜝᴡꜝᴐꜝꞌ᷅
͟ԜⱲᴒͼ᷿⅍ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈⅍᷅᷉᷅᷈ͼ
ꜚꜝꜜ꞉ᴡꜝᴟ꞉ꜜⱲͼꜝⱱͼⱨᴑᴣᴒᴟᴠᴒͼ
ⱬᴣᴒꜜᴡᴠ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟᶳᴠͼᴟꜝꞌᴒͼ꞉ꜜͼᴤ꞉ᴡⱳᴑᴟԜᴤ꞉ꜜⱲͼᴠᴢԝ꞊ᴒᴐᴡᴠͼⱱꜝᴟͼᴠԜⱱᴒᴡᴦͼᴟᴒꞌԜᴡᴒᴑͼᴟᴒԜᴠꜝꜜᴠ᷅
͟ᴟꜝᴣ꞉ᴑᴒᴠͼԝᴒᴡᴡᴒᴟͼᴑ꞉ᴠᴡ꞉ꜜᴐᴡ꞉ꜝꜜͼԝᴒᴡᴤᴒᴒꜜͼᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴑꜝᴠ꞉ꜜⱲͼԜꜜᴑͼ
ᴑ꞉ᴠᴐꜝꜜᴡ꞉ꜜᴢԜᴡ꞉ꜝꜜͼⱱᴟꜝꜛͼᴠᴡᴢᴑᴦ᷅
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳԜᴡͼᴢᴠᴒͼꜝⱱͼꜞᴟꜝⱳ꞉ԝ꞉ᴡ꞉ᴣᴒͼꜛᴒᴑ꞉ᴐԜᴡ꞉ꜝꜜᴠͼꜛԜᴦͼԝᴒͼⱲᴟꜝᴢꜜᴑᴠͼⱱꜝᴟͼᴤ꞉ᴡⱳᴑᴟԜᴤԜꞌͼԝᴦͼ
ⱷꜜᴣᴒᴠᴡ꞉ⱲԜᴡꜝᴟ᷅
͟ԜⱲᴒͼ⅍᷈ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼ⅍᷅᷈ⅎͼ
ᴀᴢԝ꞊ᴒᴐᴡͼᴄ꞉ᴡⱳᴑᴟԜᴤԜꞌ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼꜜԜᴡᴢᴟᴒͼꜝⱱͼᴡⱳᴒͼ͟ꜘͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴡꜝͼԝᴒͼᴒᴣԜꞌᴢԜᴡᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ᷅
͟ԜⱲᴒͼⅎ᷿ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷿᷅᷅᷈ͼ
͟ⱳԜᴟꜛԜᴐꜝꞋ꞉ꜜᴒᴡ꞉ᴐͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ
ⱪꞌԜᴟ꞉ⱱ꞉ᴒᴠͼᴡⱳᴒͼꜜԜᴡᴢᴟᴒͼꜝⱱͼᴡⱳᴒͼ͟ⱫͼԜᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠͼᴡꜝͼԝᴒͼᴒᴣԜꞌᴢԜᴡᴒᴑͼ꞉ꜜͼᴡⱳ꞉ᴠͼᴠᴡᴢᴑᴦ
͟ԜⱲᴒͼⅎ᷿ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷿᷅᷅᷉ͼ
͟ⱳԜᴟꜛԜᴐꜝᴑᴦꜜԜꜛ꞉ᴐͼ
ⱨᴠᴠᴒᴠᴠꜛᴒꜜᴡᴠ
ꜚ꞉ꜜꜝᴟͼᴠꜞᴒꞌꞌ꞉ꜜⱲͼᴐꜝᴟᴟᴒᴐᴡ꞉ꜝꜜ᷅
͟ԜⱲᴒͼ᷿᷈ͼꜝⱱͼᴡⱳᴒͼᴀᴡᴢᴑᴦͼ
ᴀᴦꜜꜝꜞᴠ꞉ᴠ
͟ԜⱲᴒͼⅎ˲ԓͼᴀᴒᴐᴡ꞉ꜝꜜͼⱠ᷅ⅎͼᴀԜⱱᴒᴡᴦͼ
ⱨꜜԜꞌᴦᴠ꞉ᴠ


Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ͼⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
͟ԜⱲᴒͼ᷈᷇᷾
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅
Appendix 2
National Institute of Allergy and Infectious Diseases, 
Division of Microbiology and Infectious Diseases 
(DMID) Adult Toxicity Table (Modified) (US National 
Institutes of Health; National Institute of Allergy and 
Infectious Diseases)


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials. This toxicity table is not comprehensive and 
should not be applied directly to all trials. "
""
When selecting a toxicity table, the following are some of the items that must be taken into 
consideration:"
""
‚
The population being studied "
o
Does the clinical trial evaluate healthy subjects, subjects with a particular disease 
or condition? "
‚
The stage of test article development "
o
Is the clinical trial a Phase I, II, III or IV?"
‚
The type of test article "
o
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent? "
‚
The prior human and preclinical experience with the test article"
o
Are there any specific findings that require adjustment of the toxicity table? "
""
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal 
values at the single site. Multi-center clinical trials should reconcile among their laboratory normal 
values when evaluating a healthy volunteer population."
""
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when 
selecting or developing a toxicity table for a DMID-sponsored trial."
"
Page 105
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


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Page 106
';
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$PHQGPHQW )LQDO-DQXDU\ 
&RQILGHQWLDO
'\D[&RUS


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
"
HEMATOLOGY"
"
"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
Jgoqinqdkp"
"
;07"/"3207"io1fN"
"
:02""/";06io1fN"
"
"807"/"90;"io1fN"
"
>"807"io1fN"
"
Cduqnwvg"Pgwvtqrjkn"Eqwpv"
"
3222/37221oo5"
"
972/;;;1oo5"
"
722/96;1oo5"
"
>7221oo5"
"
Rncvgngvu"
"
97.222/
;;.;;;1oo5"
"
72.222/
96.;;;1oo5"
"
42.222/6;.;;;1oo5"
"
>42.2221oo5"
YDEu"
33.222/35.2221"
oo5"
35.222/"
37.222"1oo5"
37.222/"
52.2221oo5"
@52.222"qt"
>3.222"1oo5"
'"Rqn{oqtrjqpwengct"
Ngweqe{vgu"-"Dcpf"Egnnu"
"@":2'"
;2"Î";7'"
@;7'"
//////////"
"
"
Cdpqtocn"
Hkdtkpqigp"
Nqy<"
322/422"oi1fN""
"
Jkij<"
622/822"oi1fN"
Nqy<"
>322"oi1fN""
"
Jkij<"
@822"oi1fN"
Nqy<"
>"72"oi1fN"
"
"
""""//////////"
Hkdtkpqigp"
cuuqekcvgf"ykvj"
itquu"dnggfkpi"qt"
ykvj"
fkuugokpcvgf"
eqciwncvkqp"
"
Hkdtkp"Urnkv"Rtqfwev"
"
42/62"oei1on"
"
63/72"oei1on"
"
73/82"oei1on"
"
@"82"oei1on"
"
Rtqvjtqodkp""
Vkog"*RV+"
"
3023"/"3047"z"WNP"
"
3048/307"z"WNP"
"
3073"/502"z"WNP"
"
@5"z"WNP"
"
Cevkxcvgf"Rctvkcn"
Vjtqodqrncuvkp"*CRRV+"
"
3023"/3088"z"WNP"
"
3089"/"4055"z"
WNP"
"
4056"/"5"z"WNP"
"
@"5"z"WNP"
"
Ogvjgoqinqdkp"
"
702"/";0;"'"
"
3202"/"360;"'"
"
3702"/"3;0;'"
"
@"4202"'"
Page 107
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
"
CHEMISTRIES"
""
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
J{rqpcvtgokc"
"
352/357"oGs1N"
"
"345/34;"
oGs1N"
"
338/344"oGs1N"
"
>"338"oGs1N"qt"
cdpqtocn"uqfkwo"
with"ogpvcn"
uvcvwu"ejcpigu"qt"
ugk¦wtgu"
"
J{rgtpcvtgokc"
"
368/372"oGs1N"
"
373/379"oGs1N"
"
37:/387"oGs1N"
"
@"387"oGs1N"qt"
cdpqtocn"uqfkwo"
with ogpvcn"
uvcvwu"ejcpigu"qt"
ugk¦wtgu"
"
J{rqmcngokc"
"
502"/"506"oGs1N"
"
407"/"40;"oGs1N"
"
402"/"406"oGs1N""
qt"kpvgpukxg"
tgrncegogpv"
vjgtcr{"qt"
jqurkvcnk¦cvkqp"
tgswktgf"
"
>"402"oGs1N qt"
cdpqtocn"
rqvcuukwowith"
"rctguku."kngwu"qt"
nkhg/vjtgcvgpkpi"
cttj{vjokc"
"
J{rgtmcngokc"
"
708"/"802"oGs1N"
"
803"/"807"oGs1N"
"
808"/"902"oGs1n"
"
@"902"oGs1N"
qt"cdpqtocn"
rqvcuukwo" with 
nkhg/vjtgcvgpkpi"
cttj{vjokc"
"
J{rqin{egokc"
"
77/86"oi1fN"
"
62/76"oi1fN"
"
52/5;"oi1fN"
"
>52"oi1fN"qt"
cdpqtocn"inwequg"
with"ogpvcn"
uvcvwu"ejcpigu"qt"
eqoc"
"
J{rgtin{egokc"
*pqphcuvkpi"cpf"pq"rtkqt"
fkcdgvgu+"
"
338"/"382"oi1fN"
"
383/"472"
oi1fN"
"
473"/"722"oi1fN"
"
@"722"oi1fN qt
cdpqtocn"inwequg"
with mgvqcekfquku"
"qt"ugk¦wtgu"
"
J{rqecnegokc"
*eqttgevgf"hqt"cndwokp+"
"
:06"/"90:"oi1fN"
"
909"/"902"oi1fN"
"
80;"/"803"oi1fN"
"
>"803"oi1fN"
qt"cdpqtocn"
ecnekwo"with"nkhg"
vjtgcvgpkpi"
cttj{vjokc"qt"
vgvcp{"
"
"
"
"
"
"
Page 108
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
CHEMISTRIES (continued)"
"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
J{rgtecnegokc"
*eqttgev"hqt"cndwokp+"
"
3208"/"3307"oi1fN"
"
3308"/"3407"
oi1fN"
"
3408"/"3507"oi1fN"
"
@"3507"oi1fN"qt
cdpqtocn"ecnekwo"
with nkhg"
vjtgcvgpkpi"
cttj{vjokc"
"
J{rqocipgugokc"
"
306"/"304"oGs1N"
"
303"/"20;"oGs1N"
"
20:"/"208"oGs1N"
"
>"208"oGs1N"qt
cdpqtocn"
ocipgukwo"with 
nkhg/vjtgcvgpkpi"
cttj{vjokc"
"
J{rqrjqurjcvgokc"
"
402"/"406"oi1fN"
"
307"/30;"oi1fN"
qt"
tgrncegogpv"Tz"
tgswktgf"
"
302"/306"oi1fN""
kpvgpukxg"vjgtcr{""
qt"
jqurkvcnk¦cvkqp"
tgswktgf"
"
>"302"oi1fN"qt"
cdpqtocn"
rjqurjcvg"with 
nkhg/vjtgcvgpkpi"
cttj{vjokc"
"
J{rgtdknktwdkpgokc"*yjgp"
ceeqorcpkgf"d{"cp{"kpetgcug"
kp"qvjgt"nkxgt"hwpevkqp"vguv+"
"
303"/">3047"z"WNP"
"
3047"/">307"z"
WNP"
"
307"Î"3097"z"WNP"
"
@"3097"z"WNP"
"
J{rgtdknktwdkpgokc"*yjgp"
qvjgt"nkxgt"hwpevkqp"ctg"kp"vjg""
pqtocn"tcpig+"
"
303"/">307"z"WNP"
"
307"/">402"z"
WNP"
"
402"Î"502"z"WNP"
"
@"502"z"WNP"
"
DWP"
"
3047"/"407"z"WNP"
"
408"/"7"z"WNP"
"
703"/"32"z"WNP"
"
@"32"z"WNP"
J{rgtwtkegokc"*wtke"cekf+"
907"Î"3202"oi1fN"
3203"Î"3402"
oi1fN"
3403"Î"3702"oi1fN"
@3702"oi1fN"
"
"
"
Etgcvkpkpg"
"
303"/"307"z"WNP""
"
308"/"502"z"WNP"
"
503"/"8"z"WNP"
"
@"8"z"WNP"qt"
fkcn{uku"tgswktgf"
Page 109
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
"
ENZYMES
"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
CUV"*UIQV+"
"
303"/">402"z"WNP"
"
402"Î">502"z"WNP"
"
502"Î":02"z"WNP"
"
@":"z"WNP"
"
CNV"*UIRV+"
"
303"/">402"z"WNP"
"
402"Î">502"z"WNP"
"
502"Î":02"z"WNP"
"
@":"z"WNP"
"
IIV"
"
303"/">402"z"WNP"
"
402"Î">502"z"WNP"
"
502"Î":02"z"WNP"
"
@":"z"WNP"
"
Cnmcnkpg"Rjqurjcvcug"
"
303"/">402"z"WNP"
"
402"Î">502"z"WNP"
"
502"Î":02"z"WNP"
"
@":"z"WNP"
"
Co{ncug"
"
303"/"307"z"WNP"
"
308"/"402"z"WNP"
"
403"/"702"z"WNP"
"
@"703"z"WNP"
Nkrcug""
"
303"/"307"z"WNP"
"
308"/"402"z"WNP"
"
403"/"702"z"WNP"
"
@"703"z"WNP"
"
"
URINALYSIS
"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
Rtqvgkpwtkc"
"
3-"
"qt""
422"oi"/"3"io"
nquu1fc{"
"
4/5-""
qt""
3/"4"io"
nquu1fc{"
"
6-"
"qt""
4/507"io"nquu1fc{"
"
pgrjtqvke"
u{pftqog""
qt"
@"507"io"nquu1fc{"
Jgocvwtkc"
"
oketqueqrke"qpn{"
>32"tde1jrh"
"
itquu."pq"enqvu"
@32"tde1jrh"
"
itquu."ykvj"qt"
ykvjqwv"enqvu."QT"
tgf"dnqqf"egnn"ecuvu"
"
qduvtwevkxg"qt"
tgswktgf"
vtcpuhwukqp"
Page 110
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
"
CARDIOVASCULAR"
"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
Ectfkce"Tj{vjo"
"
"
"
cu{orvqocvke."
vtcpukgpv"ukipu."
pq"
Tz"tgswktgf"
"
tgewttgpv1rgtukuvgpv="
u{orvqocvke"Tz"
tgswktgf"
"
wpuvcdng"
f{ut{vjokc="
jqurkvcnk¦cvkqp"
cpf"vtgcvogpv"
tgswktgf"
"
J{rgtvgpukqp"
"
vtcpukgpv"kpetgcug"
@"42"oo1Ji="pq"
vtgcvogpv"
"
tgewttgpv."
ejtqpke"
kpetgcug"
"@"42oo1Ji0"
1vtgcvogpv"
tgswktgf"
"
cewvg"vtgcvogpv"
tgswktgf="qwvrcvkgpv"
vtgcvogpv"qt"
jqurkvcnk¦cvkqp"
rquukdng"
"
gpf"qticp"
fcocig"qt"
jqurkvcnk¦cvkqp"
tgswktgf"
"
J{rqvgpukqp"
"
vtcpukgpv"
qtvjquvcvke"
j{rqvgpukqp"ykvj"
jgctv"tcvg"kpetgcugf"
d{">42"dgcv1okp"qt"
fgetgcugf"d{">32"
oo"Ji"u{uvqnke"
DR."Pq"vtgcvogpv"
tgswktgf"
"
u{orvqou"fwg"
vq"qtvjquvcvke"
j{rqvgpukqp"qt"
DR"fgetgcugf"
d{">42"oo"Ji"
u{uvqnke="
eqttgevcdng"
ykvj"qtcn"hnwkf"
vtgcvogpv"
"
tgswktgu"KX"hnwkfu="
pq"jqurkvcnk¦cvkqp"
tgswktgf"
"
ogcp"ctvgtkcn"
rtguuwtg""
>82oo1"Ji qt"
gpf"qticp"
fcocig"qt"ujqem="""
tgswktgu"
jqurkvcnk¦cvkqp"
cpf"xcuqrtguuqt"
vtgcvogpv"
"
Rgtkectfkvku"
"
okpkocn"ghhwukqp"
"
oknf1oqfgtcvg"
cu{orvqocvke"
ghhwukqp."pq"
vtgcvogpv"
"
u{orvqocvke"
ghhwukqp="rckp="
GMI"ejcpigu"
"
vcorqpcfg="
rgtkectfkqegpvguku"
qt"uwtigt{"
tgswktgf"
"
Jgoqttjcig."Dnqqf"Nquu"
"
oketqueqrke1qeewnv"
"
oknf."pq"
vtcpuhwukqp"
"
itquu"dnqqf"nquu="
3/4"wpkvu"vtcpuhwugf"
"
ocuukxg"dnqqf"
nquu="@"5"wpkvu"
vtcpuhwugf"
Page 111
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
RESPIRATORY
""
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
Eqwij""
"
vtcpukgpv/"pq"
vtgcvogpv"
"
rgtukuvgpv"
eqwij="
vtgcvogpv"
tgurqpukxg"
"
Rctqz{uocn"eqwij="
wpeqpvtqnngf"ykvj"
vtgcvogpv"
////////////////////"
"
Dtqpejqurcuo."Cewvg"
"
vtcpukgpv="pq"
vtgcvogpv="
92'"/":2'"HGX3 "
qh"rgcm"hnqy"
"
tgswktgu"
vtgcvogpv="
pqtocnk¦gu"ykvj"
dtqpejqfkncvqt="
HGX3"72'"/"
92'"
*qh"rgcm"hnqy+"
"
pq"pqtocnk¦cvkqp"
ykvj"
dtqpejqfkncvqt="
HGX3"47'"/"72'"
qh"rgcm"hnqy="qt""
tgvtcevkqpu"rtgugpv"
"
e{cpquku<"HGX3"
>"47'"
qh"rgcm"hnqy"qt"
kpvwdcvkqp"
pgeguuct{"
F{urpgc"
"
f{urpgc"qp"
gzgtvkqp"
f{urpgc"ykvj"
pqtocn"cevkxkv{"
f{urpgc"cv"tguv"
f{urpgc"tgswktkpi"
Qz{igp"vjgtcr{"
Page 112
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
"
GASTROINTESTINAL"
"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
Pcwugc"
"
oknf"qt"vtcpukgpv="
ockpvckpu"
tgcuqpcdng"kpvcmg"
"
oqfgtcvg"
fkueqohqtv="
kpvcmg"
fgetgcugf"
ukipkhkecpvn{="
uqog"cevkxkv{"
nkokvgf"
"
pq"ukipkhkecpv"
kpvcmg="tgswktgu"KX"
hnwkfu"
jqurkvcnk¦cvkqp"
tgswktgf="
"
Xqokvkpi"
"
3"grkuqfg"kp"46"
jqwtu"
4/7"grkuqfgu"kp"
46"jqwtu"
@8"grkuqfgu"kp"46"
jqwtu"qt"pggfkpi"
KX"hnwkfu"
"
"
"
rj{ukqnqike"
eqpugswgpegu"
tgswktkpi"
jqurkvcnk¦cvkqp"qt"
tgswktkpi"
rctgpvgtcn"
pwvtkvkqp"
"
Eqpuvkrcvkqp"
"
tgswktkpi"uvqqn"
uqhvgpgt"qt"fkgvct{"
oqfkhkecvkqp"
tgswktkpi"
nczcvkxgu"
qduvkrcvkqp"
tgswktkpi"ocpwcn"
gxcewcvkqp"qt"
gpgoc"
"
qduvtwevkqp"qt
vqzke"ogiceqnqp"
"
Fkcttjgc"
"
oknf"qt"vtcpukgpv="
5/6"nqqug"
uvqqnu1fc{"qt"oknf"
fkcttjgc"ncuv">"3"
yggm"
"
oqfgtcvg"qt"
rgtukuvgpv="7/9"
nqqug"uvqqnu1fc{"
qt"fkcttjgc"
ncuvkpi"@3"yggm"
@9"nqqug"uvqqnu1fc{"
qt"dnqqf{"fkcttjgc="
qt"qtvjquvcvke"
j{rqvgpukqp"qt"
gngevtqn{vg"
kodcncpeg"qt"@4N"
KX"hnwkfu"tgswktgf""
"
"
j{rqvgpukxg"
ujqem qt"
rj{ukqnqike"
eqpugswgpegu"
tgswktkpi"
jqurkvcnk¦cvkqp"""
"
Qtcn"Fkueqohqtv1F{urjcikc"
"
oknf"fkueqohqtv="
pq"fkhhkewnv{"
uycnnqykpi"
"
uqog"nkokvu"qp"
gcvkpi1ftkpmkpi"
"
gcvkpi1vcnmkpi"xgt{"
nkokvgf="wpcdng"vq"
uycnnqy"uqnkf"
hqqfu"
"
wpcdng"vq"ftkpm"
hnwkfu="tgswktgu"
KX"hnwkfu"
"
"
Page 113
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
"
NEUROLOGICAL
""
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
Pgwtq/Egtgdgnnct"
"
unkijv"
kpeqqtfkpcvkqp"
f{ufkcfqejqmkpguku"
"
kpvgpvkqp"
vtgoqt."
f{uogvtkc."
unwttgf"urggej="
p{uvciowu"
"
nqeqoqvqt"cvczkc"
"
kpecrcekvcvgf"
"
Ru{ejkcvtke"
"
oknf"cpzkgv{"qt"
fgrtguukqp"
"
oqfgtcvg"
cpzkgv{"qt"
fgrtguukqp="
vjgtcr{"
tgswktgf="
ejcpig"kp"
pqtocn"tqwvkpg"
"
ugxgtg"oqqf"
ejcpigu"tgswktkpi""
vjgtcr{="qt"uwkekfcn"
kfgcvkqp=""qt"
ciitguukxg"kfgcvkqp"
"
cewvg"ru{ejquku"
tgswktkpi"
jqurkvcnk¦cvkqp=""
qt"uwkekfcn"
iguvwtg1cvvgorv"
qt"jcnnwekpcvkqpu"
"
Owueng"Uvtgpivj"
"
uwdlgevkxg"
ygcmpguu"
pq"qdlgevkxg"
u{orvqou1"ukipu"
"
oknf"qdlgevkxg""
ukipu1u{orvqou"
pq"fgetgcug"kp"
hwpevkqp"
"
qdlgevkxg"ygcmpguu"
hwpevkqp"nkokvgf"
"
rctcn{uku"
Rctguvjgukc"*dwtpkpi."vkpinkpi."
gve0+"
oknf"fkueqohqtv="
pq"vtgcvogpv""
tgswktgf"
oqfgtcvg"
fkueqohqtv="
pqp/pcteqvke"
cpcnigukc"
tgswktgf"
ugxgtg"fkueqohqtv="
qt"pcteqvke"
cpcnigukc"tgswktgf"
ykvj"u{orvqocvke"
kortqxgogpv"
kpecrcekvcvkpi="qt"
pqv"tgurqpukxg"vq"
pcteqvke"cpcnigukc"
Pgwtq/ugpuqt{"
oknf"korcktogpv"kp"
ugpucvkqp"
*fgetgcugf"
ugpucvkqp."g0i0."
xkdtcvqt{."rkprtkem."
jqv1eqnf"kp"itgcv"
vqgu+"kp"hqecn"ctgc"
qt"u{oogvtkecn"
fkuvtkdwvkqp="qt"
ejcpig"kp"vcuvg."
uognn."xkukqp"
cpf1qt"jgctkpi"
oqfgtcvg"
korcktogpv"
*oqf"fgetgcugf"
ugpucvkqp."g0i0."
xkdtcvqt{."
rkprtkem."
jqv1eqnf"vq"
cpmngu+"cpf1qt"
lqkpv"rqukvkqp"qt"
oknf"
korcktogpv"vjcv"
ku"pqv"
u{oogvtkecn"
ugxgtg"korcktogpv"
*fgetgcugf"qt"nquu"
qh"ugpucvkqp"vq"
mpggu"qt"ytkuvu+"qt"
nquu"qh"ugpucvkqp"qh"
cv"ngcuv"oqf"fgitgg"
kp"ownvkrng"
fkhhgtgpv"dqf{"
ctgcu"*k0g0."wrrgt"
cpf"nqygt"
gzvtgokvkgu+"
ugpuqt{"nquu"
kpxqnxgu"nkodu"
cpf"vtwpm="
rctcn{uku=""qt
ugk¦wtgu"
Page 114
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
"
MUSCULOSKELATEL
"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
Ctvjtcnikc"
*lqkpv"rckp+"
oknf"rckp"pqv"
kpvgthgtkpi"ykvj"
hwpevkqp"
oqfgtcvg"rckp."
cpcnigukeu"
cpf1qt"rckp"
kpvgthgtkpi"ykvj"
hwpevkqp"dwv"pqv"
ykvj"cevkxkvkgu"
qh"fckn{"nkxkpi"
ugxgtg"rckp="rckp"
cpf1qt"cpcnigukeu"
kpvgthgtkpi"ykvj"
cevkxkvkgu"qh"fckn{"
nkxkpi"
fkucdnkpi"rckp"
Ctvjtkvku"
oknf"rckp"ykvj"
kphncoocvkqp."
gt{vjgoc"qt"lqkpv"
uygnnkpi"Î"dwv"pqv"
kpvgthgtkpi"ykvj"
hwpevkqp"
oqfgtcvg"rckp"
ykvj"
kphncoocvkqp."
gt{vjgoc"qt"
lqkpv"uygnnkpi"Î"
kpvgthgtkpi"ykvj"
hwpevkqp."dwv"
pqv"ykvj"
cevkxkvkgu"qh"
fckn{"nkxkpi"
ugxgtg"rckp"ykvj"
kphncoocvkqp."
gt{vjgoc"qt"lqkpv"
uygnnkpi"Îcpf"
kpvgthgtkpi"ykvj"
cevkxkvkgu"qh"fckn{"
nkxkpi"
rgtocpgpv"cpf1qt"
fkucdnkpi"lqkpv"
fkuvtwevkqp"
O{cnikc"
o{cnikc" ykvj" pq"
nkokvcvkqp"qh""
cevkxkv{"
owueng"
vgpfgtpguu"*cv"
qvjgt"vjcp"
kplgevkqp"ukvg+"
qt"ykvj"
oqfgtcvg"
korcktogpv"qh"
cevkxkv{"
ugxgtg"owueng"
vgpfgtpguu"ykvj"
octmgf"korcktogpv"
qh"cevkxkv{"
htcpm"
o{qpgetquku"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
Page 115
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE
NOVEMBER 2007
DRAFT"
"
SKIN"
"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
Oweqewvcpgqwu"
gt{vjgoc="rtwtkvwu"
fkhhwug."ocewnq"
rcrwnct"tcuj."
ft{"
fguswcocvkqp"
xgukewncvkqp qt"
oqkuv"
fguswcocvkqp"qt"
wnegtcvkqp"
gzhqnkcvkxg"
fgtocvkvku."
oweqwu"
ogodtcpg"
kpxqnxgogpv qt"
gt{vjgoc."
ownvkhqtog"qt"
uwurgevgf"
Uvgxgpu/Lqjpuqp"
qt""pgetquku"
tgswktkpi"uwtigt{"
Kpfwtcvkqp"
< 37oo""
37/52"oo"
@52oo"
"
Gt{vjgoc"
< 37oo""
37/52"oo"
@52oo"
"
Gfgoc"
< 37oo""
37/52"oo"
@52oo"
"
Tcuj"cv"Kplgevkqp"Ukvg"
< 37oo""
37/52"oo"
@52oo"
"
Rtwtkvwu"
unkijv"kvejkpi"cv"
kplgevkqp"ukvg"
oqfgtcvg"
kvejkpi"cv"
kplgevkqp"
gzvtgokv{"
kvejkpi"qxgt"gpvktg"
dqf{"
"
"
"
"
SYSTEMIC"
"
Itcfg"3""
"
Itcfg"4""
"
Itcfg"5""
"
Itcfg"6""
"
Cnngtike"Tgcevkqp"
"
rtwtkvwu"ykvjqwv"
tcuj"
"
nqecnk¦gf"
wtvkectkc"
"
igpgtcnk¦gf"
wtvkectkc="
cpikqgfgoc"
"
cpcrj{nczku"
Jgcfcejg"
oknf."pq"vtgcvogpv"
tgswktgf"
vtcpukgpv."
oqfgtcvg="
vtgcvogpv"
tgswktgf"
ugxgtg="tgurqpfu"vq"
kpkvkcn"pcteqvke"
vjgtcr{"
kpvtcevcdng="
tgswktgu"tgrgcvgf"
pcteqvke"vjgtcr{"
"
Hgxgt<"qtcn"
"
5909"/"5:07"E"qt""
32202"/"32307"H"
"
5:08"/"5;07"E"qt"
32308"/"3240;"H"
"
5;08"/"6207"E"qt"
325"/"327"H"
"
@"62"E"qt"
@"327"H"
"
Hcvkiwg"
"
pqtocn"cevkxkv{"
tgfwegf">"6:"jqwtu"
"
"pqtocn"cevkxkv{"
fgetgcugf"47/"
72'"@"6:"jqwtu"
"
pqtocn"cevkxkv{"
fgetgcugf"@"72'"
ecpÓv"yqtm"
"
wpcdng"vq"ectg"hqt"
ugnh"
"
"
 
 
 
 
 
 
 
"
Page 116
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
Appendix 3 
National Institute of Allergy and Infectious Diseases, 
Division of Microbiology and Infectious Diseases 
(DMID) Pediatric Toxicity Tables (Modified) (US 
National Institutes of Health; National Institute of 
Allergy and Infectious Diseases)
"
"
Page 117
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
"
"
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials. This toxicity table is not comprehensive and should 
not be applied directly to all trials. "
""
When selecting a toxicity table, the following are some of the items that must be taken into consideration:"
""
‚
The population being studied "
o
Does the clinical trial evaluate healthy subjects, subjects with a particular disease or 
condition? "
‚
The stage of test article development "
o
Is the clinical trial a Phase I (is it for the fisrt time in human subjects?) , II, III or IV?"
‚
The type of test article "
o
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent? "
‚
The prior human and preclinical experience with the test article"
o
Are there any specific findings that require adjustment of the toxicity table? "
o
Has it been approved for this indication in adult population?"
""
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal values at the 
single site. Multi-center clinical trials should reconcile among their laboratory normal values when 
evaluating a healthy volunteer population."
""
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when selecting 
or developing a toxicity table for a DMID-sponsored trial."
"
Page 118
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
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ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
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DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
"
(Selected Values for children less than or equal 
to 3 months of age) 
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HEMATOLOGY (continued)"
GRADE 1
GRADE 2
GRADE 3
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Page 121
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
"
(Greater than 3 months of age) 
LOCAL REACTIONS"
GRADE 1
GRADE 2
GRADE 3
GRADE 4
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Page 122
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
 (Greater than 3 months of age)  
"
GASTROINTESTINAL"
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Page 123
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
(Greater than 3 months of age) 
"
GASTROINTESTINAL (continued)"
GRADE 1
GRADE 2
GRADE 3
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Page 124
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
 (Greater than 3 months of age)  
"
ELECTROLYTES
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GRADE 2
GRADE 3
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Page 125
Ⱬᴅ᷄᷉Ⱡ᷊᷇
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ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
"
 (Greater than 3 months of age)  
"
ELECTROLYTES"
GRADE 1
GRADE 2
GRADE 3
GRADE 4
J{rgtpcvtgokc"
>367/36;"oGs1N"
372/377"oGs1N"
@377"oGs1N"qt"
cdpqtocn"uqfkwo"
CPF"ogpvcn"uvcvwu"
ejcpigu"
J{rqpcvtgokc
"
352/357"oGs1N"
34;/346"oGs1N
>346"oGs1N"qt"
cdpqtocn"uqfkwo"
CPF"ogpvcn"uvcvwu"
ejcpigu
J{rgtmcngokc"
702/70;"oGs1N"
802/806"oGs1N"
807/902"oGs1N"
@902"oGs1N"qt"
cdpqtocn"rqvcuukwo"
CPF"ectfkce"
cttj{vjcokc"
J{rqmcngokc
502/5/7"oGs1N"
407/40;"oGs1N
402/406"oGs1N
>402"oGs1N"qt"
cdpqtocn"rqvcuukwo"
CPF"ectfkce"
cttj{vjokc
J{rgtecnegokc
3207/3304oi1fN"
3305/330;"oi1fN
3402/340;"oi1fN
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90:/:06"oi1fN"
902/909"oi1fN"
802/80;"oi1fN"
>802"oi1fN"
J{rqocipgugokc"
304/306"oGs1N"
20;/303"oGs1N"
208/20:"oGs1N"
>208"oGs1N"qt"
cdpqtocn"ocipgukwo"
CPF"ectfkce"
cttj{vjokc"
J{rqin{egokc"
77/87"oi1fN"
62/76"oi1fN"
52/5;"oi1fN"
>52"oi1fN"qt"
cdpqtocn"inwequg"
CPF"ogpvcn"uvcvwu"
ejcpigu"
J{rgtin{egokc"
338/37;"oi1fN"
382/46;"oi1fN"
472/622"oi1fN"
@622"oi1fN"qt"
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"
Itquu"jgocvwtkc"
Page 126
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
egnnu1jrh"
egnnu1jrh"
"
Page 127
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
"
 (Greater than 3 months of age) 
"
CENTRAL NERVOUS SYSTEM (CNS)
GRADE 1
GRADE 2
GRADE 3
GRADE 4
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"
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Page 128
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
kphqtocvkqp0"Cp{"uwdlgev/tgrqtvgf"cvvcem"pqv"eqphktogf"d{"vjg"Kpxguvkicvqt"owuv"jcxg"cp"
cnvgtpcvg"CG"fkcipquku"tgeqtfgf0""Cnn"uwdlgev/tgrqtvgf"cpf"Kpxguvkicvqt/eqphktogf"JCG"
cvvcemu"yknn"dg"tgeqtfgf"kp"vjg"gETH0"
4
INVESTIGATOR ATTACK ASSESSMENT 
Vjg"Rtkpekrcn"Kpxguvkicvqt"hqt"c"uvwf{"ukvg"oc{"kfgpvkh{"c"rj{ukekcp"fgukipgg"vq"cuuguu"rcvkgpv"
u{orvqo"kphqtocvkqp"cpf"ocmg"cvvcem"fgvgtokpcvkqpu0"Ukvgu"ujqwnf"dg"nkokvgf"vq"vyq"
kpfkxkfwcnu"tgurqpukdng"hqt"cuuguukpi"cvvcemu."qpg"qh"vjgo"dgkpi"vjg"Rtkpekrcn"Kpxguvkicvqt0"
Cuuguuqtu"owuv"dg"gzrgtkgpegf"ykvj"JCG"cpf"hcoknkct"ykvj"vjg"uvwf{"uwdlgevÓu"fkugcug"
jkuvqt{0""
Vjg"cuuguuqt"owuv"tgxkgy"vjg"kphqtocvkqp"cpf"fgvgtokpg"yjgvjgt"vjg"gxgpv"ku"cp"cevwcn"cvvcem"
qt"pqv0"Kh"pggfgf."vjg"cuuguuqt"ecp"eqpvcev"vjg"uwdlgev"cpf1qt"ectgikxgt"vq"enctkh{"kphqtocvkqp"
qt"cum"hqt"cp{"cffkvkqpcn"fgvckn0"Vjg"fgvgtokpcvkqp"yknn"dg"fqewogpvgf"cnqpi"ykvj"vjg"fcvg"
cpf"vkog"vjg"fgvgtokpcvkqp"ycu"ocfg0"Cp{"gxgpv"fggogf"pqv"cp"cvvcem"owuv"dg"ceeqorcpkgf"
d{"cp"gzrncpcvkqp"cpf"cnvgtpcvkxg"fkcipquku"d{"vjg"cuuguuqt0""
Yjgp"tgxkgykpi"uwdlgev"kphqtocvkqp."vjg"cuuguuqt"yknn"hqnnqy"vjg"fghkpkvkqpu"qh"cp"cvvcem"cu"
qwvnkpgf"kp"vjgug"rtqegfwtgu"cpf."vcmkpi"cnn"cxckncdng"kphqtocvkqp"cdqwv"vjg"gxgpv"kpvq"
eqpukfgtcvkqp."yknn"fgvgtokpg"kh"kv"ku"c"eqphktogf"cvvcem0"Vjg"cuuguuogpv"qh"vjg"cvvcem"ku"vjg"
Kpxguvkicvqt"qt"fgukipggÓu"qyp."cpf"pqv"vjg"qrkpkqp"qh"vjg"uwdlgev."vjg"uwdlgevÓu"ectgikxgt"qt"
cp{"qvjgt"ukvg"rgtuqppgn0"Cuuguuqtu"oc{"eqpuwnv"ykvj"qpg"cpqvjgt"cdqwv"c"rctvkewnct"uwdlgevÓu"
cvvcem"dwv"qpn{"qpg"cuuguuqt"ocmgu"vjg"fqewogpvgf"fgvgtokpcvkqp0"Kv"ku"rquukdng"hqt"dqvj"vjg"
Rtkpekrcn"Kpxguvkicvqt"cpf"rj{ukekcp"fgukipgg"vq"cuuguu"fkhhgtgpv"cvvcemu"hqt"vjg"ucog"uwdlgev0"
Page 129
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES
NOVEMBER  2007 
DRAFT"
 (Greater than 3 months of age)  
"
OTHER 
GRADE 1
GRADE 2
GRADE 3
GRADE 4
Cnngti{
Rtwtkvwu"ykvjqwv"Tcuj
Rtwtkvke"Tcuj
Oknf"Wtvkectkc
Ugxgtg"Wtvkectkc""
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Ftwi"Hgxgt"*Tgevcn+
0
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32305"Î"32602H
Itgcvgt"vjcp"6202E"
Itgcvgt"vjcp"32602H
Uwuvckpgf"Hgxgt<""
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62E"*32602H+"hqt"
nqpigt"vjcp"7"fc{u
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Nqecnk¦gf"tcuj
Fkhhwug"
ocewnqrcrwnct"
Tcuj"
Igpgtcnk¦gf"wtvkectkc
Uvgxgpu/Lqjpuqp"
U{pftqog"qt"Gt{vjgoc"
ownvkhqtog
Uvqocvkvku
Oknf"fkueqohqtv
Rckphwn."fkhhkewnv{"
uycnnqykpi."dwv"cdng"
vq"gcv"cpf"ftkpm"
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specified"kp"vjku"vcdng
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otherwise specified"kp"
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vq"tgswktg"gxcnwcvkqp"
cu"vq"ecwucnkv{"cpf"
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qh"uwhhkekgpv"ugxgtkv{"
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ejcpigu"kp"uvwf{"ftwi
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tgswktg"gxcnwcvkqp"
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ftwi"owuv"dg"uvqrrgf"
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engctn{"hgnv"vq"dg"
ecwugf"d{"uqog"qvjgt"
ogejcpkuo"vjcv"uvwf{"
ftwi
"
"
"
Page 130
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
Appendix 4 
HAE Attack Assessment and Reporting Procedures 
(HAARP) 
"
Page 131
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
"
HAE Attack Assessment and Reporting Procedures 
(HAARP)
Title:
JCG"Cvvcem"Cuuguuogpv"cpf"Tgrqtvkpi"Rtqegfwtgu"*JCCTR+"
Product Name:
FZ/4;52"
Indication:
Rtgxgpvkqp"qh"cpikqgfgoc"cvvcemu"kp"rcvkgpvu"ykvj"JCG"
Sponsor:
F{cz"Eqtr0""
77"Pgvyqtm"Ftkxg"
Dwtnkpivqp."OC"23:25"
Original Date:
36"Ugrvgodgt"4237"
Version:
x302"
"
Confidentiality Statement
Vjku"fqewogpv"ku"vjg"rtqrgtv{"qh"F{cz"Eqtr0"Vjg"kphqtocvkqp"kp"vjku"fqewogpv"eqpvckpu"vtcfg"ugetgvu"cpf"
eqoogtekcn"kphqtocvkqp"vjcv"ctg"rtkxkngigf"qt"eqphkfgpvkcn"cpf"oc{"pqv"dg"fkuenqugf"ykvjqwv"vjg"gzrtguu"ytkvvgp"
rgtokuukqp"qh"F{cz"wpnguu"tgswktgf"d{"hgfgtcn"qt"uvcvg"ncy"qt"tgiwncvkqpu0"Cp{"rgtuqp"vq"yjqo"vjg"kphqtocvkqp"
ku"fkuenqugf"owuv"dg"kphqtogf"vjcv"vjg"kphqtocvkqp"ku"rtkxkngigf"qt"eqphkfgpvkcn"cpf"oc{"pqv"dg"hwtvjgt"fkuenqugf"
d{"vjgo0"Vjgug"tguvtkevkqpu"qp"fkuenquwtg"yknn"crrn{"gswcnn{"vq"cnn"hwvwtg"kphqtocvkqp"uwrrnkgf"vq"{qw"vjcv"ku"
kpfkecvgf"cu"rtkxkngigf"qt"eqphkfgpvkcn0"
"
Page 132
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
TABLE OF CONTENTS
3 
RWTRQUG"000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000005 
4 
FGHKPKVKQP"QH"CP"CVVCEM"0000000000000000000000000000000000000000000000000000000000000000000000000000000000000005 
5 
TGRQTVKPI"CPF"CUUGUUOGPV"QH"CVVCEM"FCVC"0000000000000000000000000000000000000000000005 
503 
Uwdlgev/Tgrqtvgf"U{orvqou"000000000000000000000000000000000000000000000000000000000000000000000000000000000006 
50303 
Cvvcem"Kphqtocvkqp"000000000000000000000000000000000000000000000000000000000000000000000000000000000000000006 
50304 
Yqtugpkpi"U{orvqou"0000000000000000000000000000000000000000000000000000000000000000000000000000000000007 
50305 
Uwdlgev"Vtckpkpi"0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000007 
50306 
Tgrqtvkpi"Ownvkrng"Cvvcemu00000000000000000000000000000000000000000000000000000000000000000000000000007 
50307 
Ectgikxgt"Tgrqtv"000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000007 
50308 
Uwdlgev"Eqpvcev"ykvj"Ukvgu"000000000000000000000000000000000000000000000000000000000000000000000000000007 
504 
Ukvg"Eqpvcev"ykvj"vjg"Uwdlgev"000000000000000000000000000000000000000000000000000000000000000000000000000000000007 
50403 
Tgxkgy"qh"uwdlgev"tgrqtv"qh"u{orvqou"00000000000000000000000000000000000000000000000000000000008 
50404 
Fqewogpvkpi"c"Tgrqtvgf"Cvvcem"000000000000000000000000000000000000000000000000000000000000000000008 
50405 
Ukvg"Vtckpkpi0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000009 
505 
JCG"cvvcemu"cu"Cfxgtug"Gxgpvu"00000000000000000000000000000000000000000000000000000000000000000000000000000009 
6 
KPXGUVKICVQT"CVVCEM"CUUGUUOGPV"000000000000000000000000000000000000000000000000000000000000000000: 
"
"
Page 133
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
1 
PURPOSE 
Vjku"fqewogpv"crrnkgu"vq"enkpkecn"vtkcnu"vjcv"kpxqnxg"kpxguvkicvqt"cflwfkecvkqp1cuuguuogpv"qh"
cpikqgfgoc"cvvcemu0"Vjg"rwtrqug"qh"vjku"fqewogpv"ku"vq"rtqxkfg"c"fghkpkvkqp"qh"cp"JCG"
cvvcem"cpf"vq"fghkpg"c"uvcpfctfk¦gf"ugv"qh"rtqegfwtgu"hqt"vjg"tgrqtvkpi"cpf"cuuguuogpv"qh"
gxgpvu"tgrqtvgf"d{"uwdlgevu"vq"fgvgtokpg"yjgvjgt"vjqug"gxgpvu"ctg"vtwg"JCG"cvvcemu0"
2
DEFINITION OF AN ATTACK
Vq"dg"eqphktogf"cu"cp"JCG"cvvcem."vjg"gxgpv"owuv"jcxg"u{orvqou"qt"ukipu"eqpukuvgpv"ykvj"
cp"cvvcem"kp"cv"ngcuv"qpg"qh"vjg"hqnnqykpi"nqecvkqpu<""
‚
Rgtkrjgtcn"cpikqgfgoc<"ewvcpgqwu"uygnnkpi"kpxqnxkpi"cp"gzvtgokv{."vjg"hceg."pgem."vqtuq."
cpf1qt"igpkvqwtkpct{"tgikqp"
‚
Cdfqokpcn"cpikqgfgoc<"cdfqokpcn"rckp."ykvj"qt"ykvjqwv"cdfqokpcn"fkuvgpvkqp."pcwugc."
xqokvkpi."qt"fkcttjgc"
‚
Nct{pigcn"cpikqgfgoc<"uvtkfqt."f{urpgc."fkhhkewnv{"urgcmkpi."fkhhkewnv{"uycnnqykpi."vjtqcv"
vkijvgpkpi."qt"uygnnkpi"qh"vjg"vqpiwg."rcncvg."wxwnc."qt"nct{pz"
Fgurkvg"vjg"rtgugpeg"qh"vjgug"u{orvqou."vjg"kpxguvkicvqt"oc{"uvknn"fgvgtokpg"enkpkecnn{"vjcv"
vjg"gxgpv"fkf"pqv"tgrtgugpv"cp"JCG"cvvcem"kh"vjgtg"ctg"hgcvwtgu"vjcv"uvtqpin{"tghwvg"uwej"c"
fkcipquku0"Hqt"gzcorng."vjg"tgrqtvgf"gxgpv"ku"ceeqorcpkgf"d{"u{orvqou"vjcv"ctg"pqv"
eqpukuvgpv"ykvj"cp"cvvcem"*g0i0."wtvkectkc+."vjg"tgrqtvgf"gxgpv"rgtukuvu"ygnn"dg{qpf"vjg"v{rkecn"
vkog"eqwtug"qh"cp"cvvcem"*g0i0."itgcvgt"vjcp"9"fc{u+."qt"vjgtg"ku"c"nkmgn{"cnvgtpcvg"gvkqnqi{"hqt"
vjg"gxgpv"*g0i0."vjg"uwdlgevÓu"cdfqokpcn"u{orvqou"ctg"cvvtkdwvcdng"vq"c"xktcn"icuvtqgpvgtkvku"
qwvdtgcm"kp"vjg"jqwugjqnf+0"
Vq"dg"eqwpvgf"cu"c"wpkswg"cvvcem"fkuvkpev"htqo"vjgkt"rtgxkqwu"cvvcem."vjg"pgy"u{orvqou"owuv"
qeewt"cv"ngcuv"46"jqwtu"chvgt"tguqnwvkqp"qh"vjg"rtkqt"cvvcemÓu"u{orvqou0""
Cvvcem"tguqnwvkqp"ku"fghkpgf"cu"vjg"uwdlgev"pq"nqpigt"jcxkpi"u{orvqou"qh"vjg"cvvcem0"
Rtqftqocn"u{orvqou"d{"vjgougnxgu"ctg"pqv"eqpukfgtgf"cp"cvvcem0"
Rcvkgpv"tgrqtv"qh"wug"qh"cewvg"JCG"cvvcem"vtgcvogpv"hqt"cp"cvvcem"d{"kvugnh"ku"pqv"eqphktocvkqp"
vjcv"cp"cvvcem"qeewttgf0"
3
REPORTING AND ASSESSMENT OF ATTACK DATA
Cv"uetggpkpi"hqt"crrnkecdng"enkpkecn"vtkcnu."uwdlgev"JCG"cvvcem"jkuvqt{"yknn"dg"eqnngevgf"d{"vjg"
ukvg"hqt"gpvt{"kpvq"vjg"enkpkecn"fcvcdcug0"Kphqtocvkqp"eqnngevgf"yknn"kpenwfg"cp{"rtkqt"jkuvqt{"qh"
nct{pigcn"cvvcemu."cvvcem"htgswgpe{."cxgtcig"ugxgtkv{."rtgfqokpcpv"nqecvkqp*u+."cxgtcig"
fwtcvkqp."cewvg"cvvcem"vjgtcr{"wug."cpf"jkuvqt{"qh"nqpi/vgto"rtqrj{nczku0"
Fwtkpi"vjg"tgngxcpv"uvwf{"rgtkqfu."cu"fghkpgf"kp"vjg"crrnkecdng"uvwf{"rtqvqeqn."uwdlgevu"*qt"
ectgikxgtu."hqt"uwdlgevu">"3:"{gctu"qnf+"yknn"dg"kpuvtwevgf"vq"eqpvcev"vjg"ukvg"ykvjkp"94"jqwtu"
qh"vjg"uvctv"qh"u{orvqou"qh"cp"cvvcem0"Kp"vjg"ukvwcvkqp"vjcv"c"uwdlgev"ku"kpecrcekvcvgf"cpf"ku"
"
Page 134
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
wpcdng"vq"eqpvcev"vjg"ukvg."c"hcokn{"ogodgt"qt"qvjgt"kpfkxkfwcn"ykvj"fgvckngf"mpqyngfig"qh"
vjg"gxgpv"ecp"rtqxkfg"vjg"kphqtocvkqp0"Kh"fguktgf"d{"vjg"uwdlgev."ogoqt{"ckfu"oc{"dg"
rtqxkfgf"vq"cuukuv"kp"vtcemkpi"cp{"JCG"cvvcemu"uwdlgevÓu"gzrgtkgpeg0"Cp{"vqqnu"qt"fgxkegu"vjg"
uwdlgev"wugu"vq"vtcem"vjku"kphqtocvkqp"ctg"pqv"kpvgpfgf"vq"ugtxg"cu"uqwteg"fqewogpvu"hqt"vjg"
uvwf{0""
Ukvg"rgtuqppgn"yknn"tgxkgy"vjg"kphqtocvkqp"rtqxkfgf"d{"vjg"uwdlgev"qt"ectgikxgt"cpf"uqnkekv"
cffkvkqpcn"kphqtocvkqp"cu"pgeguuct{"vq"fqewogpv"vjg"cvvcem0""Kphqtocvkqp"fqewogpvgf"d{"vjg"
ukvg"yknn"dg"eqpukfgtgf"uqwteg"hqt"vjg"uvwf{0""
C"fgukipcvgf"kpfkxkfwcn"cv"vjg"ukvg"*vjg"eqnngevqt+"yknn"eqpvcev"vjg"uwdlgev"qt"ectgikxgt"qp"c"
tgiwnct"dcuku"cu"fghkpgf"kp"vjg"uvwf{"rtqvqeqn."tgictfnguu"qh"yjgvjgt"qt"pqv"vjg"uwdlgev"jcu"
tgrqtvgf"cp{"cvvcemu."kp"qtfgt"vq"uqnkekv"hqt"cp{"cvvcemu"vjcv"oc{"jcxg"qeewttgf"dwv"ygtg"pqv"
tgrqtvgf0"Kp"cffkvkqp."fwtkpi"gcej"uvwf{"xkukv."ukvg"rgtuqppgn"yknn"uqnkekv"hqt"cp{"pgy"cvvcem"
kphqtocvkqp"vjcv"ycu"pqv"rtqxkfgf"vjtqwij"rtgxkqwu"eqpvcev"ykvj"vjg"uwdlgev"qt"ectgikxgt0"
Vjg"Kpxguvkicvqt"qt"fgukipgg"*vjg"cuuguuqt+"yknn"tgxkgy"vjg"cvvcem"kphqtocvkqp"cpf"gxcnwcvg"kh"
vjg"gxgpv"tgrtgugpvu"c"eqphktogf"JCG"cvvcem0"Kh"pgeguuct{"hqt"vjg"gxcnwcvkqp."vjg"kpxguvkicvqt"
qt"fgukipgg"oc{"eqpvcev"vjg"uwdlgev"vq"tgegkxg"cffkvkqpcn"kphqtocvkqp0""
3.1 
Subject-Reported Symptoms 
Uwdlgevu"cpf"ectgikxgtu"ecp"wug"cp{"gzkuvkpi"ogvjqfu"d{"yjkej"vjg{"vtcem"kphqtocvkqp"cdqwv"
vjgkt"cvvcemu."qt."kh"tgswguvgf."ogoqt{"ckfu"ecp"dg"rtqxkfgf"d{"vjg"uvwf{"ukvg0"Jqygxgt."
uwdlgevu"*qt"c"ectgikxgt+"yknn"pggf"vq"vtcem"cvvcemu"kp"uwej"c"yc{"cu"vq"dg"cdng"vq"eqpvcev"vjg"
uvwf{"ukvg"cu"uqqp"cu"rquukdng."dwv"pqv"ncvgt"vjcp"94"jqwtu"*5"hwnn"fc{u+"chvgt"vjg"hktuv"
u{orvqou"crrgct."vq"tgrqtv"vjg"kphqtocvkqp0"
3.1.1
Attack Information
Vjg"hqnnqykpi"kphqtocvkqp"ujqwnf"dg"rtqxkfgf"d{"vjg"uwdlgev"*qt"ectgikxgt+"cv"vjg"vkog"vjg{"
ctg"tgrqtvkpi"cp"cvvcem"vq"vjg"ukvg<"
‚
Fcvg"cpf"vkog"u{orvqou"qh"cp"cvvcem"ygtg"hktuv"gzrgtkgpegf"
‚
Fguetkrvkqp"qh"u{orvqou"gzrgtkgpegf."kpenwfkpi"nqecvkqp*u+"
‚
Korcev"qp"cevkxkv{"cpf"yjgvjgt"cp{"cuukuvcpeg"qt"ogfkecn"kpvgtxgpvkqp"ycu"tgswktgf."
kpenwfkpi"jqurkvcnk¦cvkqpu"qt"gogtigpe{"fgrctvogpv"xkukvu"
‚
Cp{"ogfkecvkqpu"wugf"vq"vtgcv"vjg"cvvcem"
‚
Kh"vjg"cvvcem"tguqnxgf."fcvg"cpf"vkog"vjg"uwdlgev"ycu"pq"nqpigt"gzrgtkgpekpi"u{orvqou""
Uwdlgevu"fq"pqv"jcxg"vq"yckv"hqt"vjgkt"u{orvqou"vq"eqorngvgn{"tguqnxg"vq"tgrqtv"cp"cvvcem0"
Kphqtocvkqp"cdqwv"qpiqkpi"u{orvqou"ecp"dg"qdvckpgf"d{"vjg"ukvg"fwtkpi"vjg"ejgem/kp"ecnn"
cpf1"qt"cv"c"uejgfwngf"uvwf{"xkukv0"Uwdlgevu"ujqwnf"pqv"ykvjjqnf"qt"fgnc{"cp{"vtgcvogpv"vjg{"
yqwnf"pqtocnn{"tgegkxg"vq"vtgcv"vjgkt"cvvcem"kp"qtfgt"eqpvcev"vjg"ukvg0"
Page 135
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
3.1.2
Worsening Symptoms
Vjg"ukvg"oc{"tgswguv"vjg"uwdlgev"ecnn"vjgo"dcem"kh"vjg{"gzrgtkgpeg"yqtugpkpi"u{orvqou"
cpf1"qt"pgy"u{orvqou"hqt"c"tgrqtvgf"cvvcem0"Qvjgtykug."vjg"pgy"kphqtocvkqp"yknn"dg"ecrvwtgf"
fwtkpi"vjg"pgzv"ejgem/kp"ecnn"qt"uejgfwngf"uvwf{"xkukv0"Uwdlgevu"oc{"eqpvcev"vjg"ukvg"qp"vjgkt"
qyp"vq"rtqxkfg"kphqtocvkqp"cdqwv"cp{"yqtugpkpi"u{orvqou0"
3.1.3
Subject Training
Fwtkpi"uetggpkpi."ukvg"rgtuqppgn"yknn"vtckp"uwdlgevu"qp"kfgpvkh{kpi"u{orvqou"qh"cp"cvvcem."vjg"
tgswktgogpvu"hqt"tgrqtvkpi"cvvcemu"cpf"vjg"kphqtocvkqp"vjg{"yknn"dg"gzrgevgf"vq"rtqxkfg0""Vjg"
rcvkgpv"yknn"eqphkto"vjgkt"wpfgtuvcpfkpi"qh"yjcv"ku"tgswktgf"qh"vjgo"hqt"tgrqtvkpi"cvvcemu"vq"
vjg"ukvg0""Ukvgu"yknn"cuuguu"vjg"uwdlgevÓu"eqornkcpeg"ykvj"vjg"tgrqtvkpi"tgswktgogpvu"
vjtqwijqwv"vjg"uvwf{"cpf"oc{"tgvtckp"vjg"uwdlgev"kh"pgeguuct{"kp"qtfgt"vq"ockpvckp"vjg"
kpvgitkv{"qh"vjg"fcvc"rtqxkfgf"vq"vjg"ukvg0"
3.1.4
Reporting Multiple Attacks
Kh"c"uwdlgev"gzrgtkgpegu"u{orvqou"vjg{"cvvtkdwvg"vq"oqtg"vjcp"qpg"wpkswg"cvvcem"vjg{"ecp"
tgrqtv"vjku"cu"ownvkrng"cvvcemu"vq"vjg"ukvg0""Dcugf"qp"vjg"fghkpkvkqp"qh"cp"cvvcem"cu"uvcvgf"kp"
Ugevkqp"4."kv"yknn"dg"vjg"fgvgtokpcvkqp"qh"vjg"kpxguvkicvqt"qt"fgukipgg"cu"vq"yjgvjgt"gxgpvu"
tgrqtvgf"cu"dgkpi"ugrctcvg"ctg"eqphktogf"cu"ugrctcvg"cvvcemu"qt"pqv0"
3.1.5
Caregiver Report
Fwtkpi"uetggpkpi."ukvg"rgtuqppgn"yknn"vtckp"uwdlgev"ectgikxgtu"*kh"crrnkecdng+"qp"kfgpvkh{kpi"
u{orvqou"qh"cp"cvvcem."vjg"tgswktgogpvu"hqt"tgrqtvkpi"cvvcemu"cpf"vjg"kphqtocvkqp"vjg{"yknn"
dg"gzrgevgf"vq"rtqxkfg0""Vjg"ectgikxgt"yknn"eqphkto"vjgkt"wpfgtuvcpfkpi"qh"yjcv"ku"tgswktgf"qh"
vjgo"hqt"tgrqtvkpi"cvvcemu"vq"vjg"ukvg0"Ukvgu"yknn"cuuguu"vjg"ectgikxgtÓu"eqornkcpeg"ykvj"vjg"
tgrqtvkpi"tgswktgogpvu"vjtqwijqwv"vjg"uvwf{"cpf"oc{"tgvtckp"vjg"ectgikxgt"kh"pgeguuct{"kp"
qtfgt"vq"ockpvckp"vjg"kpvgitkv{"qh"vjg"fcvc"rtqxkfgf"vq"vjg"ukvg0"
3.1.6
Subject Contact with Sites
Ukvg"rgtuqppgn"yknn"guvcdnkuj"c"tgeqoogpfgf"ogvjqf"cpf"vkog"ykpfqy"hqt"gcej"uwdlgev"vq"
eqpvcev"vjg"ukvg"vq"tgrqtv"cp{"u{orvqou"qh"cp"cvvcem0"Ukvgu"yknn"guvcdnkuj"c"rtkoct{"eqpvcev"
rgtuqp"cpf."kh"rquukdng."c"dcem/wr"rgtuqp."ykvj"eqpvcev"kphqtocvkqp0"Dcem/wr"rncpu."kpenwfkpi"
ecnn"dcemu"cpf1"qt"wug"qh"dcem/wr"eqpvcevu."ujqwnf"dg"guvcdnkujgf"kp"ecug"vjg"uwdlgev"ku"wpcdng"
vq"tgcej"uqogqpg"cv"vjg"ukvg0""
3.2 
Site Contact with the Subject 
Ukvgu"yknn"guvcdnkuj"c"tgeqoogpfgf"fc{"cpf"vkog"ykpfqy"hqt"ejgem/kp"ecnnu"dgvyggp"uvwf{"
xkukvu0"Vjg"fcvg"cpf"vkog"hqt"ejgem/kpu"ecp"dg"oqfkhkgf"dcugf"qp"yjgp"vjg"ncuv"eqpvcev"ykvj"
vjg"uwdlgev"ycu"ocfg."cu"qwvnkpgf"kp"vjg"uvwf{"rtqvqeqn0"Yjgp"vjg"ukvg"ku"eqpvcevgf"d{"c"
uwdlgev"tgrqtvkpi"u{orvqou"qh"cp"cvvcem"vjg"ukvg"ujqwnf"ocmg"uwtg"vjg{"jcxg"vjg"cdknkv{"vq"
tgeqtf"vjg"kphqtocvkqp"rtqxkfgf"kp"c"eqorngvg"cpf"ceewtcvg"yc{0"Dcem/wr"rncpu"ujqwnf"dg"
Page 136
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
guvcdnkujgf"kp"ecug"vjg"uwdlgev"okuugu"c"ecnn"htqo"vjg"ukvg0"C"uvwf{"uejgfwng"hqt"gcej"uwdlgevÓu"
qp/ukvg"xkukvu"yknn"dg"rtqxkfgf"vq"vjg"uwdlgev"d{"vjg"ukvg0"
3.2.1
Review of subject report of symptoms
Fwtkpi"eqpvcev"ykvj"vjg"uwdlgev."yjgvjgt"uwdlgev/kpkvkcvgf"qt"c"tgiwnct"ejgem/kp."ukvg"
rgtuqppgn"ujqwnf"cum"vjg"uwdlgev"vq"rtqxkfg"vjgo"kphqtocvkqp"cdqwv"pgy"qt"qpiqkpi"JCG"
cvvcemu"gzrgtkgpegf0"
Vjg"ukvg"yknn"vt{"vq"qdvckp"cnn"kphqtocvkqp"pgeguuct{"vq"fqewogpv"vjg"cvvcem"eqorngvgn{0"
Okuukpi"kphqtocvkqp"oc{"korcev"vjg"cuuguuogpv"qh"cp{"cvvcem"cpf"ujqwnf"dg"cxqkfgf"
yjgpgxgt"rquukdng0"
3.2.2
Documenting a Reported Attack
Eqorngvg"cpf"ceewtcvg"fqewogpvcvkqp"qh"gcej"tgrqtvgf"cvvcem"ku"korqtvcpv"vq"ocmkpi"cp"
Kpxguvkicvqt"cuuguuogpv"qh"vjg"cvvcem0"Vjg"ukvg"ujqwnf"fqewogpv"vjg"hqnnqykpi"kphqtocvkqp"
cdqwv"gcej"cvvcem"tgrqtvgf"d{"vjg"uwdlgev"qt"ectgikxgt<""
‚
Fcvg"cpf"vkog"qh"eqpvcev"ykvj"vjg"uwdlgev"
‚
Fcvg"cpf"vkog"vjg"uwdlgev"hktuv"gzrgtkgpegf"u{orvqou"
‚
Fguetkrvkqp"qh"u{orvqou"gzrgtkgpegf."kpenwfkpi"nqecvkqp*u+"
‚
Korcev"qp"cevkxkv{"cpf"yjgvjgt"cp{"cuukuvcpeg"ycu"tgswktgf"
‚
Kh"vjg"cvvcem"jcu"tguqnxgf"qt"ku"qpiqkpi0""Kh"vjg"cvvcem"jcu"tguqnxgf."vjg"fcvg"cpf"vkog"vjg"
uwdlgev"ycu"pq"nqpigt"gzrgtkgpekpi"cp{"u{orvqou"qh"vjg"cvvcem""""
‚
Pcogu"qh"cp{"ogfkecvkqpu"wugf"vq"vtgcv"vjg"cvvcem"kpenwfkpi"JCG"cewvg"vjgtcr{"qt"qvjgt"
pqp/JCG"vtgcvogpvu"
‚
Kh"jqurkvcnk¦cvkqp"qeewttgf"
‚
Kh"c"vtkr"vq"vjg"gogtigpe{"fgrctvogpv"qeewttgf"
Cffkvkqpcn"rtqdkpi"swguvkqpu"cdqwv"yjcv"vjg"uwdlgev"gzrgtkgpegf"vq"fgvgtokpg<"
‚
Kh"vjg"uwdlgev"qpn{"gzrgtkgpegf"rtqftqocn"u{orvqou"
‚
Kh""vjg"uwdlgev"gzrgtkgpegf"cp{vjkpi"fkhhgtgpv"vjcp"vjgkt"v{rkecn"cvvcem"""
‚
Kh"vjgtg"ygtg"cp{"rquukdng"cnvgtpcvkxg"gvkqnqikgu"qh"vjg"u{orvqou0"Hqt"gzcorng."c"xktcn"
icuvtqgpvgtkvku"qwvdtgcm"kp"vjg"jqwugjqnf"eqwnf"gzrnckp"cdfqokpcn"u{orvqou""
Vjg"qxgtcnn"ugxgtkv{"qh"vjg"uwdlgevÓu"cvvcem"yknn"dg"fgvgtokpgf"d{"vjg"ukvg"wukpi"vjg"hqnnqykpi"
fghkpkvkqpu<"
/
Oknf<"Vtcpukgpv"qt"oknf"fkueqohqtv""
/
Oqfgtcvg<"Oknf"vq"oqfgtcvg"nkokvcvkqp"kp"cevkxkv{"/"uqog"cuukuvcpeg"pggfgf"
/
Ugxgtg<"Octmgf"nkokvcvkqp"kp"cevkxkv{."cuukuvcpeg"tgswktgf"
"
Page 137
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
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fgukipcvkqp"qh"vjg"gxgpv"cu"cp"cvvcem"qt"pqv."cpf"kh"crrnkecdng."vjg"tgcuqp"yj{"cp"gxgpv"ku"pqv"
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*gETH+0"
3.2.3
Site Training
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‚
tgrqtvkpi"yqtugpkpi"u{orvqou"cpf"ownvkrng"cvvcemu"
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swguvkqpu"vq"icvjgt"eqpvgzv"hqt"vjg"cvvcem"kphqtocvkqp"rtqxkfgf"
‚
cuuguuogpv"qh"cvvcem"ugxgtkv{"
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gpvt{"qh"vjg"cvvcem"fcvc"kpvq"vjg"gETH"
‚
tgrqtvkpi"JCG"cvvcemu"cu"cfxgtug"gxgpvu""
‚
tgswktgogpvu"hqt"Kpxguvkicvqt"cuuguuogpv"qh"cvvcemu"
Vtckpkpiu"yknn"dg"eqpfwevgf"rtkqt"vq"ukvgu"uetggpkpi"uwdlgevu0""Vtckpkpiu"yknn"dg"fqewogpvgf"
kp"vjg"Vtkcn"Ocuvgt"Hkng0"Kpxguvkicvqtu"cpf"fgukipggu"yknn"dg"vtckpgf"qp"vjgug"rtqegfwtgu"cu"
ygnn"cpf"owuv"rcuu"cp"ÐCuuguuqtÑ"vtckpkpi"kp"qtfgt"vq"qhhkekcnn{"cuuguu"cvvcemu"hqt"vjku"uvwf{0""
Cnn"tgurqpukdng"rgtuqpu"kpxqnxgf"kp"vjg"eqnngevkqp"qh"kphqtocvkqp"htqo"uwdlgevu"qt"cuuguukpi"
cvvcemu"owuv"dg"nkuvgf"qp"HFC"Hqto"37940"
3.3
HAE attacks as Adverse Events
Cv"vjg"vkog"qh"gcej"eqpvcev"cpf"uejgfwngf"uvwf{"xkukv."ukvg"rgtuqppgn"yknn"cum"kh"vjg"uwdlgev"
gzrgtkgpegf"cp{"cfxgtug"gxgpvu"qt"ejcpigu"vq"vjg"ogfkecvkqpu"vjg{"ctg"vcmkpi0"
JCG"cvvcemu"yknn"dg"ecrvwtgf"cu"CGu0""Cnn"CGu."tgictfnguu"qh"ugtkqwupguu."ugxgtkv{."qt"ecwucn"
tgncvkqpujkr"vq"uvwf{"ftwi."yknn"dg"tgeqtfgf"qp"vjg"CG"rcig"qh"vjg"gETH0"
Cp{"CG"tgrqtvgf"vq"vjg"ukvg"oggvkpi"etkvgtkc"hqt"c"ugtkqwu"cfxgtug"gxgpv"owuv"dg"tgrqtvgf"vq"
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cpf."kp"ceeqtfcpeg"ykvj"JCCTR."gxcnwcvg"kh"kv"tgrtgugpvgf"c"eqphktogf"JCG"cvvcem0"
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0"
Page 138
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅


"
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cnvgtpcvg"CG"fkcipquku"tgeqtfgf0""Cnn"uwdlgev/tgrqtvgf"cpf"Kpxguvkicvqt/eqphktogf"JCG"
cvvcemu"yknn"dg"tgeqtfgf"kp"vjg"gETH0"
4
INVESTIGATOR ATTACK ASSESSMENT 
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"
Page 139
Ⱬᴅ᷄᷉Ⱡ᷊᷇
ⱪꞌ꞉ꜜ꞉ᴐԜꞌͼᴁᴟ꞉Ԝꞌͼ͟ᴟꜝᴡꜝᴐꜝꞌⱡͼⱫᴅ᷄᷉Ⱡ᷊᷊᷇᷄᷇
ⱨꜛᴒꜜᴑꜛᴒꜜᴡͼ᷊᷅᷇ⱴ꞉ꜜԜꞌⱡͼ᷇ⱠͼꜗԜꜜᴢԜᴟᴦ᷉᷇᷈ⅎ
ⱪꜝꜜⱱ꞉ᴑᴒꜜᴡ꞉Ԝꞌ
ⱫᴦԜᴥͼⱪꜝᴟꜞ᷅

Prot_002.pdf: 









































































































































































































































































Prot_001.pdf: 























































































































































































































































Prot_000.pdf: 





















































































































































































SAP_005.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: 
HELP StudyTM: A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Efficacy and Safety Study to Evaluate DX-
2930 for Long-Term Prophylaxis Against Acute Attacks of 
Hereditary Angioedema (HAE) 
Protocol Number: 
DX-2930-03 
Protocol Version/Date: 
Amendment 3.0  09 January 2017  
Indication: 
Prevention of angioedema attacks in subjects with HAE 
Study Phase 
III 
SAP Analysis Type 
Final Analysis 
SAP Version/Date 
Original SAP       24 May 2016 
 
Amendment 1.0   03 May 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is the proprietary and confidential property of Dyax Corp., an indirect, 
wholly-owned subsidiary of Shire plc. 
 
 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
 TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ................................................................................................ 5 
2. 
INTRODUCTION .................................................................................................................. 7 
2.1 
Purpose of the Statistical Analysis Plan ....................................................................... 7 
2.2 
Background .................................................................................................................. 7 
2.3 
Study Rationale ............................................................................................................ 7 
3. 
STUDY OBJECTIVES .......................................................................................................... 8 
3.1 
Primary Objectives ....................................................................................................... 8 
3.2 
Secondary Objectives ................................................................................................... 8 
3.3 
Tertiary Objectives ....................................................................................................... 8 
4. 
STUDY DESIGN .................................................................................................................... 9 
4.1 
General Description ...................................................................................................... 9 
4.2 
Discussion of Study Design, Including the Choice of Control Group ....................... 10 
4.3 
Method of Assigning Subjects to Treatment Regimens ............................................. 11 
4.4 
Blinding ...................................................................................................................... 11 
4.5 
Sample Size Determination ........................................................................................ 11 
5. 
EFFICACY AND SAFETY ENDPOINTS ........................................................................ 13 
5.1 
Efficacy Endpoints ..................................................................................................... 13 
5.1.1 
Primary Efficacy Endpoint ............................................................................. 13 
5.1.2 
Secondary Efficacy Endpoints ........................................................................ 13 
5.1.3 
Exploratory Efficacy Endpoints ..................................................................... 13 
5.2 
Safety Endpoints......................................................................................................... 14 
5.3 
Other Endpoints .......................................................................................................... 14 
6. 
EFFICACY AND SAFETY VARIABLES ........................................................................ 15 
6.1 
Study Activities Schedule .......................................................................................... 15 
6.2 
Efficacy Assessments ................................................................................................. 15 
6.3 
Safety Assessments .................................................................................................... 16 
6.3.1 
Adverse Events ............................................................................................... 16 
6.3.2 
Vital Signs ...................................................................................................... 18 
6.3.3 
Physical Examination ..................................................................................... 18 
6.3.4 
Electrocardiogram (ECG) ............................................................................... 18 
6.3.5 
Clinical Laboratories ...................................................................................... 18 
6.3.6 
Concomitant Therapies ................................................................................... 20 
6.4 
Other Assessments ..................................................................................................... 20 
6.4.1 
Pharmacokinetic Assessment.......................................................................... 20 
6.4.2 
Pharmacodynamic Assessment ....................................................................... 20 
6.4.3 
Plasma Anti-Drug Antibody Testing .............................................................. 20 
6.4.4 
Quality of Life Assessments ........................................................................... 20 
7. 
STATISTICAL ANALYSIS ................................................................................................ 22 
7.1 
General Methodology ................................................................................................. 22 
7.2 
Analysis Populations .................................................................................................. 23 
7.2.1 
Intent-to-treat (ITT) Population ...................................................................... 23 
7.2.2 
Safety Population ............................................................................................ 23 
7.3 
Subject Disposition..................................................................................................... 23 
7.4 
Protocol Deviations .................................................................................................... 23 
7.5 
Demographic and Other Baseline Characteristics ...................................................... 24 
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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
7.6 
Medical History .......................................................................................................... 24 
7.7 
Treatment Compliance and Extent of Exposure ......................................................... 24 
7.8 
Analysis of Efficacy ................................................................................................... 25 
7.8.1 
Primary Efficacy Analysis .............................................................................. 25 
7.8.2 
Secondary Efficacy Analyses ......................................................................... 26 
7.8.3 
Exploratory Efficacy Analyses ....................................................................... 27 
7.9 
Analysis of Safety ...................................................................................................... 31 
7.9.1 
Adverse Events ............................................................................................... 31 
7.9.2 
Clinical Laboratory Evaluation ....................................................................... 34 
7.9.3 
Vital Signs ...................................................................................................... 35 
7.9.4 
Electrocardiography ........................................................................................ 36 
7.9.5 
Physical Examinations .................................................................................... 36 
7.9.6 
Prior and Concomitant Medications ............................................................... 36 
7.10 
Other Analyses ........................................................................................................... 37 
7.10.1 
Analysis of Pharmacokinetic Data .................................................................. 37 
7.10.2 
Analysis of Pharmacodynamic Data ............................................................... 37 
7.10.3 
Analysis of Immunogenicity Data .................................................................. 37 
7.10.4 
Analysis of Quality of Life Data .................................................................... 37 
8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ........ 38 
8.1 
Changes in the Conduct of the Study ......................................................................... 38 
8.2 
Change from the Analyses Planned in the Protocol ................................................... 38 
8.2.1 
Efficacy Evaluation Period ............................................................................. 38 
8.2.2 
ITT and Safety Population Definitions ........................................................... 38 
8.2.3 
Adverse Events ............................................................................................... 38 
8.2.4 
Laboratory Parameters .................................................................................... 38 
8.2.5 
Vital Sign Parameters ..................................................................................... 39 
9. 
STATISTICAL/ANALYTIC ISSUES ................................................................................ 40 
9.1 
Adjustment for covariates .......................................................................................... 40 
9.2 
Handling of Dropouts or Missing Data ...................................................................... 40 
9.3 
Interim Analysis and Data Monitoring ....................................................................... 40 
9.4 
Multicenter Studies..................................................................................................... 40 
9.5 
Multiple Comparisons/Multiplicity ............................................................................ 40 
9.6 
Examination of Subgroups ......................................................................................... 41 
9.7 
Sensitivity Analyses ................................................................................................... 42 
10. APPENDICIES ..................................................................................................................... 45 
10.1 
Appendix I List of Statistical Outputs ........................................................................ 45 
10.1.1 
List of Planned Tables .................................................................................... 45 
10.1.2 
List of Planned Figures ................................................................................... 58 
10.1.3 
List of Planned Listings .................................................................................. 60 
10.2 
List of Clinical Study Sites ......................................................................................... 61 
10.3 
Definitions and Programming Conventions ............................................................... 63 
10.3.1 
Age ................................................................................................................. 63 
10.3.2 
BMI ................................................................................................................. 63 
10.3.3 
LTP Prior to Study Randomization ................................................................ 63 
10.3.4 
Study Day ....................................................................................................... 63 
10.3.5 
Durations of Events ........................................................................................ 64 
10.3.6 
Baseline .......................................................................................................... 64 
10.3.7 
Analysis Periods ............................................................................................. 64 
Confidential 
 
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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
10.3.8 
Handling of Data for Subjects who Rolled-Over to the DX-2930-04 Early ... 64 
10.3.9 
Handling of HAE Attack Data ........................................................................ 65 
10.3.10 HAE Attack Rate ............................................................................................ 67 
10.3.11 Time to First HAE Attack............................................................................... 67 
10.3.12 Details of the Tipping Point Analyses ............................................................ 67 
10.3.13 Adverse Events ............................................................................................... 70 
10.3.14 Non-standard Laboratory Results ................................................................... 71 
10.3.15 GLM Model Sample SAS Code ..................................................................... 72 
10.3.16 GEE Model Sample SAS Code ...................................................................... 72 
10.3.17 Tipping Point Analysis Sample SAS Code .................................................... 73 
10.3.18 Sample Code to Derive Relative Risk and Risk Difference ........................... 74 
10.3.19 Sample Code on Time-to-Event Analyses ...................................................... 74 
10.3.20 Clinical Significance Attributions for Laboratory Results ............................. 75 
10.3.21 Angioedema Quality of Life ........................................................................... 75 
10.4 
Treatment Period Dosing Schedule ............................................................................ 77 
10.5 
Study Activity Schedule ............................................................................................. 78 
11. REFERENCES ..................................................................................................................... 81 
 
Confidential 
 
Page 4 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
1. LIST OF ABBREVIATIONS 
AE 
Adverse event 
AE-QoL 
Angioedema Quality of Life Questionnaire 
AESI  
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomic therapeutic chemical 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C1-INH 
C1-inhibitor 
CI 
Confidence interval 
cHMWK 
Cleaved High Molecular Weight Kininnogen 
CO2 
Carbon dioxide 
CPK 
Creatine phosphokinase 
CSR 
Clinical study report 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EQ5D 
EuroQoL Group 5-Dimension 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FWER 
Family-wise type I error rate 
GEE 
Generalized estimating equations 
GLM 
Generalized linear model 
HAARP 
HAE Attack Assessment and Reporting Procedures 
HAE 
Hereditary angioedema  
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IWRS 
Interactive web-based randomization system 
KM 
Kaplan-Meier 
Confidential 
 
Page 5 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
LS 
Least squares 
LTP 
Long-term prophylaxis 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed model repeated measures 
OLE 
Open-label extension 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
PT 
Preferred term 
QOL 
Quality of life 
RBC 
Red blood cell  
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SMQ 
Standardized MedDRA Queries 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
VAS 
Visual analog scale 
WBC 
White blood cell 
WHO-DD 
World Health Organization-Drug Dictionary 
 
Confidential 
 
Page 6 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
2. INTRODUCTION 
2.1 
Purpose of the Statistical Analysis Plan 
This statistical analysis plan (SAP) is being developed after review of DX-2930-03 protocol, but 
before database lock and unblinding of treatment assignment. This SAP contains detailed 
information to aid in the implementation of the statistical analysis and reporting of the study data 
for use in the clinical study report (CSR). This SAP is being written with due consideration of 
the recommendations outlined in the most recent International Conference on Harmonisation 
(ICH) E9 Guideline, entitled Guidance for Industry: Statistical Principles for Clinical Trials, and 
the most recent ICH E3 Guideline, entitled Guidance for Industry: Structure and Content of 
Clinical Study Reports. 
This SAP describes the analysis sets that will be used for analysis, as well as subject 
characteristics, efficacy, safety, pharmacokinetic (PK), pharmacodynamic (PD), and quality of 
life (QoL) parameters. The details of the specific statistical methods as stated in the protocol will 
be provided and any changes from the protocol-specified analyses will be documented in the 
SAP prior to database lock. If additional analyses are required to supplement the planned 
analyses described in this SAP after the database lock, they may be completed and will be 
described in the CSR. Table, figure, and listing specifications are provided in separate 
documents. 
2.2 
Background 
DX-2390-03 is a Phase 3, randomized, double-blind, placebo-controlled, multicenter clinical 
study evaluating the safety and efficacy of DX-2930 as a treatment for the prevention of 
hereditary angioedema (HAE) attacks. Details of the study design, rationale, and procedures are 
documented in Protocol DX-2390-03 Amendment 3.0. 
2.3 
Study Rationale 
DX-2930 is a fully human IgG1 recombinant monoclonal antibody that binds specifically to 
active plasma kallikrein. DX-2930 is being developed for prophylactic treatment of angioedema 
attacks in patients with HAE, a serious and life-threatening disease. 
Confidential 
 
Page 7 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
3. STUDY OBJECTIVES 
3.1 
Primary Objectives 
To evaluate the efficacy of DX-2930 in preventing HAE attacks. 
3.2 
Secondary Objectives 
To evaluate the safety of repeated subcutaneous administrations of DX-2930. 
3.3 
Tertiary Objectives 
• 
To evaluate the pharmacodynamic (PD) effects of chronically administered DX-2930 
• 
To assess the immunogenicity of chronically administered DX-2930 
• 
To evaluate the pharmacokinetics (PK) of chronically administered DX-2930 
• 
To evaluate the effect of DX-2930 on health related quality of life (QoL)  
 
Confidential 
 
Page 8 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
4. STUDY DESIGN 
4.1 
General Description 
This study is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate 
the efficacy and safety of DX-2930 in preventing acute angioedema attacks in subjects with Type I 
and Type II HAE. This double-blind study is planned to be followed by an open-label extension 
(OLE) that is described in a separate protocol (Protocol DX-2930-04). 
A table showing dosing is in Appendix 10.4. A table showing the Study Activities Schedule for the 
study is provided in Appendix 10.5. 
Long-Term Prophylactic (LTP) Therapy Washout:  
Following informed consent, subjects will undergo screening assessments. Screened subjects who are 
on long-term prophylactic therapy for HAE are required to undergo a minimum 2-week washout 
period prior to the start of the run-in period. This LTP washout is permitted as long as the 
Investigator determines that doing so would not place the subject at any undue safety risk and the 
subject is at least 18 years of age. The Investigator must confirm the subject has successfully 
completed the 2-week washout period before they can enter the run-in period. 
Run-In Period:  
Screened subjects who are either not on long-term prophylactic therapy for HAE, or have completed 
the required washout period, will enter a run-in period of 4 weeks to determine the baseline HAE 
attack rate. Only subjects meeting a minimum baseline rate of at least 1 investigator-confirmed HAE 
attack per 4 weeks will be eligible for enrollment and randomization. Subjects who experience 3 or 
more investigator-confirmed attacks before the end of the 4 weeks can exit the run-in period early 
and proceed to enrollment and randomization. Subjects without at least 1 investigator-confirmed 
attack after 4 weeks of run-in will have their run-in period extended for another 4 weeks, during 
which time they need to have at least 2 investigator-confirmed attacks to proceed to enrollment and 
randomization. To be eligible for enrollment, subjects who have their run-in extended must 
complete the full 8-week run-in period prior to entering the treatment period. Subjects who do 
not meet the minimum attack rate during run-in or are otherwise determined to be ineligible due 
to screening assessments will be considered screen failures. Subjects who fail screening will not 
be allowed to rescreen into the study. 
Treatment Period:  
After verification of eligibility, subjects will be randomized 2:1 to receive repeated subcutaneous 
(SC) administrations of DX-2930 or placebo in a double-blind fashion. Subjects who are 
randomized to DX-2930 will be assigned in a 1:1:1 ratio to 1 of 3 dose regimens: 300 mg every 2 
weeks, 300 mg every 4 weeks, or 150 mg every 4 weeks. Randomization into all treatment 
groups will be stratified by the baseline attack rate observed during the run-in period into the 
following groups: 1 to < 2 attacks per 4 weeks, 2 to < 3 attacks per 4 weeks, and ≥ 3 attacks per 4 
weeks. 
Each subject will undergo a treatment period consisting of 13 doses of blinded Investigational 
Medicinal Product (IMP), for a period of 26 weeks from the date of first dose on Day 0 through 
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two weeks after the final dose. Subjects randomized to one of the 4 treatment arms will either 
receive a DX-2930 or placebo dose according to the dosing schedule in Appendix 10.4.  
Open-Label Extension (OLE) Study:  
Subjects who complete the treatment period will be offered the option of enrolling in an open-
label extension (OLE) study that will be described in a separate protocol (DX-2930-04).  
Follow-up Period:  
Subjects who do not participate in the OLE will undergo safety and additional evaluations (i.e., 
PK and PD) during an 8 week follow-up period. Subjects (or caregivers) will be instructed to 
inform the site of any HAE attacks they experience for up to 30 days after the final follow-up 
visit.  
4.2 
Discussion of Study Design, Including the Choice of Control Group 
This study is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to 
evaluate the efficacy and safety of DX-2930 in preventing acute angioedema attacks in subjects 
with Type I and Type II HAE. The following is a discussion of the rationale behind the design of 
the trial. 
• Primary endpoint selection: The objective of this study is to evaluate the efficacy of DX-
2930 in preventing HAE attacks. The number of HAE attacks is a direct way to evaluate 
efficacy. 
• Dose selection: The dose rationale is based on the pharmacodynamic bioactivity, PK, safety, 
and efficacy of DX-2930 from the Phase 1 clinical studies and nonclinical studies. Together, 
these attributes provide the rationale for the selected doses and regimens to achieve drug 
levels likely to prevent a majority of HAE attacks. Based on these considerations, 300 mg 
every 2 weeks, 300 mg every 4 weeks, and 150 mg every 4 weeks were identified as the 
dosing regimens for evaluation. The 3 proposed dose-regimen combinations provide a 6-fold 
range of steady-state trough concentrations and leverage both the biomarker and efficacy data 
generated in study DX-2930-02. Evaluation of the DX-2930 plasma concentrations at the 
time of attacks reported by DX-2930-treated subjects in DX-2930-02 suggests that the 3 
planned dosing regimens will provide a meaningful range of clinical response. 
• Control group selection: This trial incorporates a placebo comparator to evaluate and 
interpret the efficacy of DX-2930. The use of placebo is justified because 1) placebo does not 
represent a reduction in current standard of care for subjects due to the availability of acute 
attack treatments and 2) none of the therapies currently used for the prevention of HAE 
attacks are suitable for use as an active comparator. 
• Study population: Subjects 12 years of age and older with a confirmed diagnosis of HAE 
(Type I or II) who experience at least 1 investigator-confirmed attack per 4 weeks during the 
run-in period. HAE diagnosis will be confirmed through documented clinical history 
consistent with HAE and diagnostic testing conducted during the screening visit.  
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• Baseline symptom severity: To be eligible to participate in the study, subjects had to meet a 
minimum baseline HAE attack rate of at least 1 investigator-confirmed HAE attack per 4 
weeks during the run-in period.  
• Stratified randomization: Randomization to treatment is stratified by the baseline HAE 
attack rate observed during the run-in period. The three levels of HAE attack rate strata are 1-
<2 attacks per 4 weeks, 2-<3 attacks per 4 weeks and 3 or more attacks per 4 weeks. 
• Safety monitoring: Adverse events (AE), clinical laboratories and vital signs will be 
monitored throughout the study. 
4.3 
Method of Assigning Subjects to Treatment Regimens 
Subjects will be randomized after confirmation of study eligibility in a 2:1 ratio to receive 
repeated SC administrations of DX-2930 or placebo in a double-blind fashion via an Interactive 
Web-based Randomization System (IWRS). Subjects who are randomized to DX-2930 will be 
assigned in a 1:1:1 ratio to 1 of 3 dose regimens: 300 mg every 2 weeks, 300 mg every 4 weeks, 
or 150 mg every 4 weeks. Randomization into all treatment groups will be stratified by the 
baseline attack rate observed during the run-in period into the following groups: 1 to < 2 attacks 
per 4 weeks, 2 to < 3 attacks per 4 weeks, and ≥ 3 attacks per 4 weeks. 
4.4 
Blinding 
Subjects will be randomized to receive 300 mg DX-2930 every 2 weeks, 300 mg DX-2930 every 
4 weeks, 150 mg DX-2930 every 4 weeks or placebo every 2 weeks in a double-blind fashion. 
The appearance of the placebo will be indistinguishable from DX-2390. Subjects, caregivers for 
subjects under 18 years of age, Investigators and site personnel will be blinded to the treatment 
administered until the study is complete. The Sponsor will be blinded to the treatment 
administered until all subject involvement in the treatment period is complete, the database has 
locked, and primary statistical analyses have been conducted. 
An Unblinded Data Team Charter will be developed to document which roles will have access to 
which data and their responsibilities. The Unblinded Data Team is independent from the blinded 
study team and is not involved in the day-to-day conduct of the study.  
4.5 
Sample Size Determination 
Power analysis and sample size estimation was based on 1000 computer simulations using a 
generalized linear model for count data assuming a Poisson distribution with Pearson chi-square 
scaling of standard errors to account for potential overdispersion. The active treatment dose in 
each active treatment arm to placebo ratio was set at 1:1.5. A 10% missing data/dropout rate for 
both active treatment and placebo was also built into the empirical sample size simulations. 
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For a treatment effect of 60% reduction in attacks as compared to placebo, assuming a placebo 
attack rate of 0.3 attacks per week over a 26 week period for an average total of 7.8 attacks 
during the treatment period, a sample size of 24 actively treated subjects for the primary active 
treatment arm and 36 placebo subjects would provide at least 95% power (at alpha=0.025, 
one-sided). A 60% reduction is well below the smallest expected reduction in attacks, for in the 
DX-2930-02 study, we observed reductions of attacks of near 100%. These sample sizes will 
also provide adequately sized safety population for evaluation. Up to 120 subjects 
(approximately 80 subjects in the 3 active treatment groups and 40 in the placebo group) may be 
enrolled to account for potential early drop-outs during the study. 
 
 
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5. EFFICACY AND SAFETY ENDPOINTS 
5.1 
Efficacy Endpoints 
Primary and secondary efficacy endpoints will be based on the treatment period spanning Day 0 
(after study drug administration) through Day 182, unless otherwise specified. 
5.1.1 
Primary Efficacy Endpoint 
• Number of investigator-confirmed HAE attacks during the treatment period (Day 0 through 
Day 182) 
5.1.2 
Secondary Efficacy Endpoints 
• Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period (Day 0 through Day 182)   
• Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period (Day 0 through Day 182)   
• Number of Investigator-confirmed HAE attacks occurring on Day 14 after administration of 
study drug through Day 182 (Day 14 through Day 182) 
5.1.3 
Exploratory Efficacy Endpoints 
• Time to first HAE attack after Day 14 
• Number of high-morbidity investigator-confirmed HAE attacks during the treatment period 
(Day 0 through Day 182) 
• Number of investigator-confirmed HAE attacks resulting in an emergency department visit 
and/or admission to hospital during the treatment period (Day 0 through Day 182) 
• Number of investigator-confirmed laryngeal HAE attacks during the treatment period (Day 0 
through Day 182) 
• Achievement of a pre-specified reduction from the run-in period in the investigator-
confirmed HAE attack rate (i.e., responder analysis) during the treatment period (Day 0 
through Day 182). 
• Characteristics of investigator-confirmed HAE attacks, including attack duration, severity, 
location, and medication use during the run-in period and treatment period (Day 0 through 
Day 182)  
• Percentage of attack free days during the treatment period (Day 0 through Day 182) 
• Achievement of investigator-confirmed HAE attack-free interval of 1 month, 3 months, or 
until the Day 182 visit during the treatment period (Day 0 through Day 182)  
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• Achievement of investigator-confirmed HAE attack-free interval of 1 month, 3 months, or 
until the Day 182 visit after Day 14 (Day 14 through Day 182) 
5.2 
Safety Endpoints 
The safety and tolerability of DX-2390 will be evaluated through the assessment of adverse 
events, clinical laboratory testing, vital sign measurements, electrocardiogram (ECG) recordings, 
concomitant medications and physical examination findings. 
5.3 
Other Endpoints 
Additional endpoints of interest in this study are the plasma concentration of DX-2930, 
pharmacodynamic biomarker assays, anti-drug antibodies and quality of life data as collected 
with the EuroQoL Group 5-Dimension (EQ5D) Questionnaire and the Angioedema Quality of 
Life (AE-QoL) Questionnaire. 
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6. EFFICACY AND SAFETY VARIABLES 
6.1 
Study Activities Schedule 
Please refer to Appendix 10.5 for details of assessments performed at each visit. 
6.2 
Efficacy Assessments 
The collection, reporting and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP). Site personnel will be trained 
on HAARP prior to screening subjects at their site. 
During the study, subjects (or caregivers, in the event the subject is < 18 years old) will be 
instructed to notify and report details of an attack to the study site within 72 hours of the onset of 
an HAE attack. In the event that a subject is incapacitated following an attack, this information 
can be provided to the site by a family member or other individual with detailed knowledge of 
the event. If desired by the subject, memory aids may be provided to assist in tracking any HAE 
attacks subjects experience. Weekly communication between the subjects and the site personnel, 
including reports of HAE attacks must be documented in the electronic case report form (eCRF). 
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack: 
• Date and time symptoms of an attack were first experienced 
• Description of symptoms experienced, including location(s) 
• Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits 
• Any medications used to treat the attack 
• If the attack resolved, date and time the subject was no longer experiencing symptoms 
Site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP.  
Sites personal will also record the severity of the attack, if the attack required acute treatment, if 
the attack resulted in an emergency department visit or hospitalization, if the attack was 
hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or associated 
with syncope or near-syncope) and whether the attack was peripheral, abdominal or laryngeal. 
In this study HAE attacks will be captured as AEs.  All AEs, regardless of seriousness, severity, 
or causal relationship to study drug, will be recorded on the AE page of the eCRF. Any AE 
reported to the site meeting criteria for a serious adverse event must be reported to the Sponsor 
using the SAE Reporting Form in the electronic data capture (EDC) system within 24 hours of 
becoming aware of the event. For all serious adverse events that are reported as HAE attacks, the 
Principal Investigator or physician designee will review the event within 24 hours of initial 
notification and, in accordance with HAARP, evaluate if it represented a confirmed HAE attack.  
For all non-serious AEs that are reported as HAE attacks, the Principal Investigator or physician 
designee will review the event within 3 days of initial notification and, in accordance with 
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HAARP, evaluate if it represented a confirmed HAE attack. If necessary for the evaluation, the 
Investigator or designee may contact the subject for additional information. Any subject-reported 
attack not confirmed by the Investigator must have an alternate AE diagnosis recorded. All 
subject-reported and investigator-confirmed HAE attacks will be recorded in the eCRF. 
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured. 
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with an 
attack in at least one of the following locations:  
• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region. 
• Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea. 
• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx. 
 
Despite the presence of these symptoms, the Investigator may still clinically determine that the 
event did not represent an HAE attack if there are features that strongly refute such a diagnosis. 
For example, the reported event is accompanied by symptoms that are not consistent with an 
HAE attack (e.g., urticaria), the reported event persists well beyond the typical time course of an 
HAE attack, or there is a likely alternate etiology for the event (e.g., the subject’s abdominal 
symptoms are attributable to a viral gastroenteritis outbreak in the household).  
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms. 
6.3 
Safety Assessments 
6.3.1 
Adverse Events 
Adverse events will be collected from signing of the informed consent through the last study 
visit. For a detailed definition on AEs, Serious AEs (SAEs), severity of AEs, and relatedness of 
AEs and SAEs, please refer to the protocol. 
Treatment-emergent AEs (TEAEs) are defined as AEs with onset at the time of or following the 
start of treatment with study medication, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. 
In this study, the severity of AEs will be assessed according to Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table, Draft, November 2007 (US National 
Institutes of Health: National Institute of Allergy and Infectious Diseases) and the Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Table, Draft, November 2007 
(US National Institutes of Health: National Institute of Allergy and Infectious Diseases). For 
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abnormalities not specifically found in the Toxicity Tables, the following general scale will be 
used to estimate grade of severity: 
• GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required 
• GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
• GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible  
• GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
Any treatment-emergent ECG abnormality that is considered by the Investigator as clinically 
significant and requiring intervention/therapy will be assessed as a severe AE. 
The causal relationship between the study IMP and the AE will be assessed as Not Related or 
Related. 
6.3.1.1 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) will be captured and monitored during this study.  
AESI include hypersensitivity reactions and events of disordered coagulation.  
Hypersensitivity Reactions 
 
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the reactions 
are suspected to be related to study drug.   
Events of Disordered Coagulation 
 
Bleeding AESI 
Although aPTT prolongation due to plasma kallikrein inhibition is an artifactual in vitro 
phenomenon, as a precautionary measure in evaluating the safety of DX-2930, bleeding events 
will be reported as AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with a clinical event of 
bleeding. Coagulation testing (aPTT, PT, INR) should be performed when possible, and when 
temporally reasonable, with any reports of bleeding or for clinical conditions possibly indicative 
of bleeding. 
Hypercoagulable AESI 
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology.  
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6.3.2 
Vital Signs 
Vital signs will be assessed by the Investigator or his/her qualified designee according to the 
Study Activities Schedule (Appendix 10.5). Routine vital sign assessments will be taken with the 
subject in the sitting or supine position after 5 minutes at rest and will include body temperature, 
heart rate (HR), blood pressure (BP) and respiratory rate (RR). BP should be determined using 
the same arm and the same equipment for each assessment. There is a ±15 minute window for all 
vital signs. 
At study visits in which IMP is administered, vital signs will be obtained prior to dosing, 1 hour 
after dosing, and 2 hours after dosing for the first 4 doses with the ability to eliminate the 2 hour 
vitals for the remaining doses based on the discretion of the Investigator and the absence of 
safety signals. 
6.3.3 
Physical Examination 
A physical examination including height, weight and calculation of Body Mass Index (BMI) will 
be performed by the Investigator or his/her qualified designee according to the Study Activities 
Schedule (Appendix 10.5). Height and weight will be collected at the screening visit only. 
6.3.4 
Electrocardiogram (ECG) 
A standard 12-lead ECG (single recording) will be performed at screening, baseline prior to 
Dose 1, Day 56, and Day 144±1 day (to capture the estimated Cmax), and Day 182. The ECG 
assessment at Cmax on Day 144±1 day may be performed via at-home nurse or technician in lieu 
of a subject visit to the study site. For subjects that do not rollover into OLE (DX-2930-04), an 
ECG will be performed on Day 238. The date and time of each ECG and its results will be 
documented in the source documents and eCRF. Electrocardiograms will be sent to a central 
reading vendor for assessment. 
6.3.5 
Clinical Laboratories 
Laboratory testing will be performed according to the Study Activities Schedule (Appendix 
10.5). 
Laboratory testing includes general safety parameters (hematology, coagulation, urinalysis, and 
serum chemistry), serology, pregnancy tests, C1-INH functional assay, C4 assay, C1q assay, PK 
samples, PD samples, and plasma anti-drug antibody testing. All laboratory tests will be 
performed using established and validated methods.  
6.3.5.1 
Hematology 
• Hemoglobin 
• Hematocrit 
• Red blood cell (RBC) count 
• White blood cell (WBC) count with differential 
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• Mean corpuscular volume (MCV) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration (MCHC) 
• Absolute platelet count 
 
6.3.5.2 
Coagulation 
• Prothrombin time (PT) 
• Activated partial thromboplastin time (aPTT) 
• International Normalized Ratio (INR) 
 
6.3.5.3 
Chemistry 
• Albumin 
• Alkaline phosphatase 
• Alanine aminotransferase (ALT; SGPT) 
• Aspartate aminotransferase (AST; SGOT) 
• Bilirubin (total and direct) 
• Blood urea nitrogen (BUN) 
• Calcium 
• Carbon dioxide (CO2) 
• Chloride 
• Creatinine 
• Creatine phosphokinase (CPK) 
• Glucose 
• Phosphate 
• Magnesium 
• Potassium 
• Sodium 
• Total protein 
• Uric acid 
 
6.3.5.4 
Urinalysis 
• Bilirubin 
• Glucose 
• Ketones 
• Blood  
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• Nitrite 
• pH 
• Protein 
• Specific gravity 
• Microscopy (if indicated by macroscopic findings) 
 
6.3.6 
Concomitant Therapies 
The Sponsor representatives and Investigator at the site conducting the trial will review and 
evaluate prior and concomitant medication usage on an ongoing basis. All prescription, over-the-
counter medications, herbals, and supplements that are being taken or have been taken by 
subjects from the time of screening through the duration of the study will be regarded as 
concomitant medications and must be documented in the source documents and eCRF. 
6.4 
Other Assessments 
6.4.1 
Pharmacokinetic Assessment 
Blood samples for the measurement of plasma DX-2930 concentration will be obtained at 
pre-dose on Days 0, 56±3, 98±3, 140±3, and 182±3. Additional samples will be collected on 
Days 210±3 and 238±3 during the follow-up period for any subjects not entering OLE. 
6.4.2 
Pharmacodynamic Assessment 
To evaluate the PD effects of DX-2930 upon plasma kallikrein activity, blood samples will be 
obtained at pre-dose on Days 0, 56±3, 98±3, 140±3, and 182±3. Additional samples will be 
collected on Days 210±3 and 238±3 during the follow-up period for any subjects not entering 
OLE. 
6.4.3 
Plasma Anti-Drug Antibody Testing  
Plasma samples for testing for formation of antibodies to DX-2930 will be obtained at pre-dose 
on Days 0, 56±3, 98±3, 140±3, and 182±3. Additional samples will be collected on Days 238±3 
during the follow-up period for any subjects not entering OLE. 
6.4.4 
Quality of Life Assessments 
Quality of life data will be obtained using the EuroQoL Group 5-Dimension (EQ5D) 
Questionnaire at pre-dose on Days 0, 98±3, and 182±3 and using Angioedema Quality of Life 
(AE-QoL) Questionnaire at pre-dose on Days 0, 28 ±3, 56 ±3, 98±3, 126 ±3, 154 ±3, and 182±3. 
An additional quality of life assessment will be conducted on Day 238±3 for subjects not 
entering OLE. 
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ED-5D-5L 
The EQ-5D-5L consists of 2 parts: descriptive questions and a visual analog scale (VAS).  The 
descriptive questions comprise 5 dimensions: Mobility, Self-care, Usual activities, 
Pain/discomfort, and Anxiety/depression. Each dimension is divided into 5 levels of perceived 
problems: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The VAS records the subject’s self-rated health on a 20-cm vertical VAS with 
endpoints labelled “the best health you can imagine” and “the worst health you can imagine”.  
AE-QoL 
The AE-QoL consists of 4 domains (functioning, fatigue/mood, fears/shame and nutrition) and 
17 questions. Details of how to compute scores for the domains and the total score are included 
in Section 10.3.21.  
 
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7.2 
Analysis Populations 
The analysis populations will be defined as follows:  
7.2.1 
Intent-to-treat (ITT) Population  
The ITT population will include all randomized subjects who received any study drug. The 
primary efficacy analyses will be carried out with the ITT population. Subjects will be analyzed 
according to their randomized treatment assignment regardless of the treatment actually received. 
7.2.2 
Safety Population  
The Safety population will include all subjects who received any study drug. All safety analyses 
will use the Safety population. Subjects will be analyzed according to the treatment actually 
received, regardless of the treatment assigned.  
7.3 
Subject Disposition 
The number of subjects screened, randomized, treated with study drug, treated as randomized, 
and included in each analysis population will be summarized by randomized treatment 
assignment, overall DX-2930, and overall for all subjects. This summary will be provided by 
study site as well. See Section 10.2  for a list of study sites.  
For each analysis population, the number of subjects included in the population, completing the 
study, completing the treatment period (by roll-over status to the long term extension DX-2930-
04 study), completing the follow-up period, and those that discontinued prematurely by reason, 
will be summarized by treatment group, overall DX-2930, and overall for all subjects.  
Listings of all disposition data will be provided. A Kaplan-Meier (KM) plot showing the time to 
withdrawal will be presented by treatment group for the ITT population. 
7.4 
Protocol Deviations 
Protocol deviations will be collected at both the site and subject level.  
Deviations at the site level will be applied to all subjects who were enrolled at that site at the 
time of the deviation. Deviation types for site level deviations are: Use of incorrect equipment, 
use of incorrect forms, use of expired laboratory samples, use of equipment with expired 
maintenance, study procedure completed by non-authorized personnel, site personnel did not 
complete training prior to completing study procedure, amendment implementation without 
approval/notification or IRB/EC, temperature excursion for IP and other.  
Deviation types for subject level deviations are: eligibility criteria, informed 
consent/assent/HIPAA, concomitant medication, investigational product (IP), study visit 
(missed/out of window), study procedure (missed/out of window), site personnel/assessor error, 
randomization, safety reporting, IRB/EC reporting, EQ-5D, Angioedema Quality of Life, lab 
collection, and other (not otherwise defined). 
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Summary tables of protocol deviation type by treatment group, overall DX-2930, and overall 
will be provided for the ITT Population. All protocol deviations will be included in a subject 
listing.  
7.5 
Demographic and Other Baseline Characteristics 
Baseline and demographic variables will be descriptively summarized by treatment group, 
overall DX-2930, and overall for each analysis population.  
Demographic and baseline characteristic variables to be presented include age (years), age 
category (<18, 18 to <40, 40 to <65, ≥65 years), sex (male, female), ethnicity (Hispanic, Non-
Hispanic), race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White and Other), race group (White, Other), geographical 
region (US, Canada, Europe and Jordan), height (cm), weight (kg), weight group (<50, 50 to 
<75, 75 to <100, ≥100 kg), BMI (kg/m2), BMI group for subjects ≥ 18 years of age (<18.5, 18.5 
to <25, 25 to <30, ≥30 kg/m2), BMI percentile group for subjects < 18 years of age 
(Underweight: <5th percentile, Healthy or Overweight: 5th to <95th percentile, Obese: >=95th 
percentile), long term prophylactic (LTP) therapy use prior to study randomization (C1-INH, 
Androgens, Anti-fibrinolytics, or not on LTP), and type of LTP therapy prior to study 
randomization (C1-INH, Oral Therapy, C1-INH and Oral Therapy, Not on LTP).  
A separate table will be created for baseline HAE characteristics and will include age at onset of 
angioedema symptoms, HAE type (Type I, Type II, Unspecified), history of laryngeal attacks, 
primary attack locations, number of attacks in the last 1, 3, and 12 months, run-in period HAE 
attack rate (attacks/4 weeks), run-in period HAE attack rate group (1 to <2, 2 to <3, ≥3 attacks/4 
weeks) and run-in period HAE attack rate strata (1 to <2, 2 to <3, ≥3 attacks/4 weeks).  
All baseline and demographic data will be presented in subject listings. 
7.6 
Medical History 
Medical history will be coded using Medical Dictionary for regulatory Activities (MedDRA) 
version 20.0 and summarized by system organ class (SOC) and preferred term (PT) by treatment 
group, overall DX-2930 and overall for each analysis population. Tabulations will be presented 
sorted by SOC in alphabetical order and by PT within each SOC by descending frequency.   
All medical history will be presented in subject listings. 
7.7 
Treatment Compliance and Extent of Exposure 
All planned study drug administrations will be recorded in the case report form, including 
whether a full, partial, or no dose was given; date and time of dose; and location of the injection. 
Regardless of treatment assignment, all subjects are to receive two injections of blinded study 
drug given in the same upper arm, with at least 2 cm separation between each injection site.  
It is anticipated that all subjects will be compliant with treatment because the study drug will be 
administered by qualified site personnel. Treatment compliance and the extent of exposure will 
be described by the percentage of planned doses received by the subject, total number of doses 
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received by the subject, and the number and percentage of subjects that received at least 80% of 
planned doses, summarized by treatment group for each analysis population. Listings of study 
administrations by subject will also be provided. 
7.8 
Analysis of Efficacy 
All efficacy analyses will be performed on the ITT population.  
7.8.1 
Primary Efficacy Analysis 
The primary efficacy endpoint, number of investigator-confirmed HAE attacks during the 
treatment period (Day 0 through Day 182), will be compared for each active treatment group 
(DX-2930) to the placebo group using a generalized linear model (GLM) for count data 
assuming a Poisson distribution with a log link function and Pearson chi-square scaling of 
standard errors to account for potential overdispersion. The model will include fixed effects for 
treatment group (categorical) and the normalized baseline attack rate (continuous), and the 
logarithm of time in days each subject was observed during the treatment period will be used as 
an offset variable in the model. See Section 10.3.10.1 for the calculation of the normalized run-in 
period attack rate. 
From this model, the least squares mean rate and standard error for each treatment group as well 
as, the mean rate ratios relative to the placebo group and corresponding 95% confidence intervals 
for each active treatment group will be estimated. These estimates will be reported as mean event 
rates per unit of time (week and monthly) by transforming the estimates using the exponential 
function and scaling by the unit of time.  
The primary endpoint will be tested by the following hypothesis: 
H0: λDX-2930 / λplacebo = 1 versus H1: λDX-2930 / λplacebo ≠ 1 
λDX-2930 refers to the mean investigator-confirmed HAE attack rate in the DX-2930 group and 
λPlacebo refers to the mean investigator-confirmed HAE attack rate in the placebo group. The null 
hypothesis is that the mean investigator-confirmed HAE attack rate ratio is 1 (no difference 
between treatment groups), versus the alternative hypothesis that the HAE attack rate ratio is not 
1. Estimated attack rate ratios less than one would indicate that subjects treated with DX-2930, 
on average, have a lower incidence of investigator-confirmed HAE attacks during the treatment 
period. The hypothesis will be tested using the model-based least squares means estimate of the 
treatment difference using a Wald-based chi-square test. 
The percentage difference in mean investigator-confirmed HAE attack rate of each active 
treatment group from the attack rate of placebo will be calculated as 100% * (mean rate ratio – 
1). Similarly, the estimated upper and lower confidence limits for the mean rate ratio can be 
transformed by subtracting 1 and multiplying by 100% to calculate 95% confidence intervals for 
the percentage change.  The mean rate ratios and corresponding 95% confidence intervals will be 
estimated from the generalized linear model as described previously.  
In order to maintain the overall Type I error at 0.05, a conservative Bonferroni-based procedure 
will be used for the comparisons of each of the active treatment groups with the placebo group 
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with equal weights for each test set at 1.67% significance level (α/3). See Section 9.5 for more 
information. 
Unadjusted monthly investigator-confirmed HAE attack rates will be calculated for the run-in 
and treatment periods.  See Section 10.3.10 for details.  The run-in period, treatment period, and 
treatment period change from run-in period in the monthly investigator-confirmed HAE attack 
rate will be summarized by treatment group. This summary will include the total number of 
investigator-confirmed HAE attacks reported and the subject-time in months each subject 
contributed to the run-in and treatment periods. Figures by treatment group plotting the on-study 
investigator-confirmed HAE attacks reported during the treatment period with timing relative to 
randomization for each subject will be created (i.e., “birds on a wire” plots).   
In addition to the data summaries for the primary analysis of the primary efficacy endpoint 
described above, the number of investigator-confirmed HAE attacks per month (defined as 28 
days) will be summarized descriptively by month (per 28 day interval) and treatment group. The 
summary will include the monthly investigator-confirmed HAE attack rate, change from run-in 
period, and percent change from run-in period of investigator-confirmed HAE attack rate. 
Investigator-confirmed HAE attacks will be grouped into 28-day intervals using the start date of 
the HAE attack. The date of the first exposure to study drug will be used as the start of the first 
interval and end of the interval will be the date of first exposure to study drug plus 28 days. Each 
successive interval will start the last day of the prior interval plus 1 day and end 28 days later. 
See Section 10.3.7.2 for the definition of the run-in period. 
All HAE attacks will be presented in listings.  
7.8.2 
Secondary Efficacy Analyses 
The rank ordered secondary efficacy endpoints are as follows: 
1. Number of investigator-confirmed HAE attacks requiring acute treatment during the 
treatment period (Day 0 through Day 182) 
2. Number of moderate or severe investigator-confirmed HAE attacks during the treatment 
period (Day 0 through Day 182)  
3. Number of Investigator-confirmed HAE attacks occurring on Day 14 after administration of 
study drug through Day 182 (Day 14 through Day 182) 
The secondary endpoints will be analyzed using the same method as described for the primary 
efficacy endpoint. Data summaries will parallel those described for the primary analysis of the 
primary efficacy endpoint. 
To adjust for the potential of inflated overall type-I error rate, the rank ordered secondary 
endpoints will be tested in a fixed sequence for each active treatment group to placebo group 
comparison using a general gatekeeping approach consistent with the logical restrictions of the 
rank ordering of the endpoints. Secondary endpoints will not be declared statistically significant 
unless the primary endpoint for that active treatment group to placebo group comparison is found 
to be statistically significant. A summary table will be provided to tabulate the statistical testing 
results for the primary and secondary endpoints, including the rate ratio and its 95% CI, 
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unadjusted p-value estimated from the Poisson GLM model, and adjusted p-value corrected for 
multiple comparisons, for each endpoint and each comparison between a DX-2930 treatment 
group and the placebo group in the multiple testing hierarchy. See Section 9.5 for more 
information on the multiple testing strategy. 
7.8.3 
Exploratory Efficacy Analyses 
Exploratory analyses will include data summaries for the following: 
• Time to first HAE attack after Day 14, i.e., duration that a subject is attack free after Day 14 
• Number of high-morbidity investigator-confirmed HAE attacks during the treatment period 
(Day 0 through Day 182) 
• Number of investigator-confirmed HAE attacks resulting in an emergency department visit 
or admission to the hospital during the treatment period (Day 0 through Day 182) 
• Number of investigator-confirmed HAE attacks resulting in an emergency department visit 
during the treatment period (Day 0 through Day 182) 
• Number of investigator-confirmed HAE attacks resulting in admission to the hospital during 
the treatment period (Day 0 through Day 182) 
• Number of investigator-confirmed laryngeal HAE attacks during the treatment period (Day 0 
through Day 182)  
• Achievement of a pre-specified reduction from the run-in period in the investigator-
confirmed HAE attack rate (i.e., responder analysis) during the treatment period (Day 0 
through Day 182) 
• Characteristics of investigator-confirmed HAE attacks, including attack duration, severity, 
and rescue mediation use during the run-in period and treatment period (Day 0 through Day 
182) 
• Percentage of attack free days during the treatment period (Day 0 through Day 182) 
• Achievement of investigator-confirmed HAE attack-free period of 1 month , 3 months, or 
until the Day 182 visit during the treatment period (Day 0 through Day 182)  
• Achievement of investigator-confirmed HAE attack-free period of 1 month, 3 months, or 
until the Day 182 visit after Day 14 (Day 14 through Day 182) 
The exploratory efficacy endpoints are considered supportive and any statistical tests comparing 
treatments will be made without adjustment for multiplicity. The resulting p-values from these 
supportive analyses will be interpreted descriptively as summarizing the weight of evidence for a 
treatment effect. 
Time to first HAE attack after Day 14 
The time to first HAE attack (days) will be calculated from the date of Day 14 visit to the date of 
the first attack after Day 14 visit. Subjects who do not have an attack will be censored at the date 
of discontinuation (if prior to completion of the treatment period) or the date of the Day 182 
visit. Time to the first HAE attack after Day 14 will be summarized using Kaplan-Meier 
methods. A log-rank test comparing each active treatment group to the placebo group will be 
included.  
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Number of high-morbidity investigator-confirmed HAE attacks during the treatment period 
A high-morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation < 24 
hours), hemodynamically significant (systolic blood pressure < 90, requires IV hydration, or 
associated with syncope or near-syncope) or laryngeal. If the length of hospitalization can’t be 
determined due to missing dates and times, then that hospitalization will be conservatively 
counted as being greater than 24 hours. The number of high-morbidity investigator-confirmed 
HAE attacks during the treatment period (Day 0 through Day 182) will be analyzed using the 
same method as for the primary efficacy endpoint. Data summaries will parallel those described 
for the primary analysis of the primary efficacy endpoint. 
Number of investigator-confirmed HAE attacks resulting in an emergency department visit or 
admission to the hospital during the treatment period 
For each HAE attack, the site records if the attack resulted in a visit to the emergency department 
or admission to the hospital. The number of investigator-confirmed HAE attacks resulting in an 
emergency department visit or admission to the hospital during the treatment period (Day 0 
through Day 182) will be analyzed using the same method as for the primary efficacy endpoint. 
Data summaries will parallel those described for the primary analysis of the primary efficacy 
endpoint. 
Number of investigator-confirmed HAE attacks resulting in an emergency department visit 
during the treatment period 
For each HAE attack, the site records if the attack resulted in a visit to the emergency 
department. The number of investigator-confirmed HAE attacks resulting in an emergency 
department visit during the treatment period (Day 0 through Day 182) will be analyzed using the 
same method as for the primary efficacy endpoint. Data summaries will parallel those described 
for the primary analysis of the primary efficacy endpoint. 
Number of investigator-confirmed HAE attacks resulting in admission to the hospital during the 
treatment period 
For each HAE attack, the site records if the attack resulted in hospitalization. The number of 
investigator-confirmed HAE attacks resulting in admission to the hospital during the treatment 
period (Day 0 through Day 182) will be analyzed using the same method as for the primary 
efficacy endpoint. Data summaries will parallel those described for the primary analysis of the 
primary efficacy endpoint. 
Number of investigator-confirmed laryngeal HAE attacks during the treatment period 
For each HAE attack, the investigator records a primary location and up to 3 secondary 
location(s). In this analysis, a laryngeal HAE attack will be defined as an attack with either the 
primary or secondary location indicated as laryngeal. 
The number of investigator-confirmed laryngeal HAE attacks during the treatment period (Day 0 
through Day 182) will be analyzed using the same method as for the primary efficacy endpoint, 
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with an addition of the history of laryngeal HAE attacks (categorical) as a fixed effect in the 
model. Data summaries will parallel those described for the primary analysis of the primary 
efficacy endpoint. 
Achievement of a pre-specified reduction from run-in period in the investigator-confirmed HAE 
attack rate (i.e., responder analysis) 
There will be five classes of responders based on pre-specified percentage reduction in the 
investigator-confirmed HAE attack rate from the run-in period attack rate: 50% or more 
reduction, 60% or more reduction, 70% or more reduction, 80% or more reduction and 90% or 
more reduction. For each subject, a treatment period HAE attack rate and run-in period HAE 
attack rate will be calculated. See Section 10.3.10  for details. The percentage reduction will be 
calculated as the run-in period HAE attack rate minus the treatment period HAE attack rate 
divided by the run-in period HAE attack rate. Summary statistics will be presented for each of 
the five classes of responders by treatment. The five classes of responders are nested within each 
other and not mutually exclusive. 
Characteristics of investigator-confirmed HAE attacks, including attack duration, severity, 
location and mediation use during the run-in and treatment periods 
Attack characteristics at subject level and event level, as described below, will be summarized by 
treatment group and overall DX-2930 for the run-in period and treatment period. 
Subject level HAE attack characteristics 
HAE Attack Duration 
For each subject, the mean duration of all investigator-confirmed HAE attacks will be calculated 
in hours and summarized. See Section 10.3.9 for details on handling HAE attack data. The 
subject-level average attack duration will be categorized into 12 hour intervals and tabulated by 
category (<12 hours, 12-24 hours, >24-48 hours, and >48 hours).   
HAE Attack Severity 
For each subject, the mean and maximum severity of all investigator-confirmed HAE attacks will 
be calculated using a numerical rating and summarized. See Section 10.3.9.6 for details. The 
number and percentage of subjects will be tabulated by maximum attack severity (no attacks, 
mild, moderate, and severe).   
Event level HAE attack characteristics 
HAE Attack Location 
The number and percentage of subjects with attacks, as well as the number of events, will be 
tabulated by the primary attack location (peripheral, abdominal, and laryngeal) as determined by 
the investigator. Additionally, the attack location will be re-classified and summarized with an 
emphasis on the laryngeal attack. In this summary, an attack with either the primary or secondary 
location(s) identified as laryngeal will be considered as a laryngeal attack; otherwise attacks will 
be classified by their reported primary attack location.   
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Rescue Medication Use 
The number and percentage of subjects with rescue medication use for an HAE attack, as well as 
the number of events, will be tabulated by rescue medication by type (ecallantide, icatibant, 
nano-filtered C1-INH, plasma-derived C1-INH, recombinant C1-INH, fresh frozen plasma, and 
other) as reported in the AE CRF.  
Supportive Treatment Use 
The number and percentage of subjects with supportive treatment use for an HAE attack, as well 
as the number of events, will be tabulated by supportive treatment by type (IV fluids, pain 
medication, oxygen, anti-emetic, and other) as reported in the AE CRF.  
Percentage of HAE attack free days during the treatment period 
The percentage of HAE attack free days during the treatment period (Day 0 through Day 182) 
will be calculated by counting the number of days in the treatment period without an HAE attack 
and dividing by the number of days the subject was in the treatment period. An attack-free day is 
defined as a calendar day with no investigator-confirmed HAE attack. 
Descriptive statistics for the percentage of HAE attack free days will be summarized by 
treatment group. 
Achievement of investigator-confirmed HAE attack-free interval of 1 month, 3 months, or until 
the Day 182 Visit during the treatment period 
A subject is considered as attack free during a time period if the subject has no investigator-
confirmed HAE attacks during that time period. Subjects who discontinued during a time period 
are considered as non-responders for that time period. 
The number and percentage of subjects who achieve investigator-confirmed HAE attack free 
intervals of 1 month (4 weeks; ‘Day 0 to one day before Day 28 visit’), 3 months (12 weeks; 
‘Day 0 to one day before Day 70 visit’), or until the Day 182 visit (approximately 6 months or 
24 weeks; ‘Day 0 to Day 182 visit’) during the treatment period will be tabulated by treatment 
group. Risk difference comparing each active DX-2930 treatment group to the placebo treatment 
group, and corresponding exact 95% confidence interval (Santner, 1980) will be provided.  
Achievement of investigator-confirmed HAE attack-free interval of 1 month, 3 months, or until 
the Day 182 Visit after Day 14 during the treatment period 
A subject is considered as attack free during a time period if this subject has no investigator-
confirmed HAE attacks during that time period. Subjects who discontinued during a time period 
are considered as a non-responder for that time period. 
The number and percentage of subjects who achieve investigator-confirmed HAE attack free 
intervals of 1 month (4 weeks; ‘Day 14 visit to one day before Day 42 visit’), 3 months (12 
weeks; ‘Day 14 visit to one day before Day 84 visit’), or until the Day 182 visit (approximately 6 
months or 24 weeks; ‘Day 14 visit to Day 182 visit’) after Day 14 during the treatment period 
will be tabulated by treatment group. Risk differences comparing each active DX-2930 treatment 
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group to the placebo treatment group, and corresponding exact 95% confidence intervals 
(Santner, 1980) will be provided.  
7.9 
Analysis of Safety 
All safety analyses will be performed on the safety population. No inferential statistics are 
planned. 
7.9.1 
Adverse Events 
Adverse events (AEs) will be coded using the MedDRA coding dictionary version 20.0.  
Treatment-emergent AEs (TEAEs) are defined as AEs with onset at the time of or following the 
start of treatment with study medication, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.   
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.   
Related AEs are AEs classified as related to study drug by the investigator.  Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator. 
In this study, the primary endpoint is based on an AE.  If DX2930 is efficacious, it will result in 
a systematic difference in the incidence of AEs by treatment group which will complicate the 
interpretation of the safety.  Thus, the collection of tabulations described in this section (with the 
exception of the analyses of AEs of special interest (AESI) and injection site reaction (ISR))  will 
be produced for 2 mutually exclusive subgroups of AEs based on if the AE was identified in 
EDC as a subject-reported HAE attack or not, and defined as follows: 
• Non-HAE Attack Reported AEs will include the subset of AEs identified in EDC as not a 
reported HAE attack.  Essentially, this will be all AEs excluding HAE attack reported events. 
• HAE Attack Reported AEs will include the subset of AEs identified in EDC as a reported 
HAE attack.  Note that this includes investigator-confirmed HAE attacks; all investigator-
confirmed HAE attacks will be coded to the PT of HAE. 
For this analysis, AEs will be classified to one of three analysis periods: 
• Pretreatment Period AEs will include AEs starting at or after informed consent to those 
starting before the first exposure to study drug (AEs starting prior to treatment on Day 0). 
• Treatment Period AEs will include all AEs starting at or after the first exposure to study drug 
to those starting before or at the subject’s last visit date during the treatment period (AEs 
starting at or after treatment on Day 0 to the Day 182 visit).  
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• Follow-up Period AEs will include all AEs starting at or after the subject’s last visit date of 
the treatment period (AEs starting after the Day 182 visit).  
For AEs with partial onset times, non-missing date parts will be used to determine if the AE falls 
within the period. If a determination cannot be made using the non-missing date parts as to if the 
AE falls within the period, the AE will be conservatively counted as a treatment-period AE.  
The number and percentage of subjects with any AE, any related AE,  any severe AE, any related 
severe AE, any SAE, and any related SAE, as well as the total number of events for each 
category, will be summarized by treatment group. The number of deaths due to an AE, 
hospitalization due to an AE and study discontinuation due to an AE will be summarized by 
treatment group and overall DX-2930. This tabulation will be repeated for each of the analysis 
periods. For serious AEs and investigator-reported AESI during the treatment period and follow-
up period, relative risks and risk differences, and their associated exact 95% CI (Santner, 1980) 
will be provided for the comparison between each active DX-2930 dose group and the placebo 
group, and overall DX-2930 group and the placebo group.   
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized for each treatment group and overall DX-2930 by SOC, and PT for each analysis 
period. This tabulation will be repeated for related AEs, severe AEs, related severe AEs, SAEs, 
and related SAEs, for treatment period and follow-up period AEs. This tabulation will be 
repeated for SAEs for pretreatment period. Tabulations will be presented sorted by SOC in 
alphabetical order and by PT within each SOC by descending frequency in the overall DX-2930 
group and then the placebo group. For serious AEs during the treatment period and follow-up 
period, risk difference and corresponding exact 95% CI (Santner, 1980) will be provided for the 
comparison between each active DX-2930 dose group and the placebo group, and overall DX-
2930 group and the placebo group, by SOC and PT. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized for each treatment group and overall DX-2930 by PT for treatment period AEs only. 
This tabulation will be repeated for related AEs and severe AEs, for treatment period AEs. 
Tabulations will be presented sorted by PT by descending frequency in the overall DX-2930 
group and then the placebo group.  
All AEs will be provided in subject listings. Listings will be presented separately for each 
analysis period. In addition, subject listings of AEs causing discontinuation of study medication, 
AEs leading to death, SAEs, related AEs, and severe AEs will be produced.  
Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions and 
disordered coagulation (hypercoagulability events and bleeding events). Investigators are 
required to document any potential AESI AEs on the CRF page, and notify the sponsor within 24 
hours. These AESI AEs are collectively referred to as investigator-reported AESI. 
In addition to investigator-reported AESI, standardized MedDRA Queries (SMQ) for each AESI 
will be performed using the study data. The algorithm to define SMQ-defined AESI is provided 
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in Section 10.3.13.5. For SMQ-defined AESI, separate summary tables will be created for AESI 
categories of hypersensitivity events, hypercoagulable events, and bleeding events.  
Investigator-reported AESI and SMQ-defined AESI will be summarized separately, as shown 
below: 
• Summary of AESI: The number and percentage of subjects with any AESI AE, any 
related AESI AE, any severe AESI AE, any related severe AESI AE, any AESI SAE, and 
any related AESI SAE, as well as the total number of events for each category, will be 
summarized by treatment group. The number of deaths due to an AESI AE, 
hospitalization due to an AESI AE and study discontinuation due to an AESI AE will be 
summarized by treatment group and overall DX-2930 for each analysis period. 
• AESI by SOC and PT: The number and percentage of subjects with an AESI, as well as 
the total number of AESIs, will be summarized for each treatment group and overall DX-
2930 by SOC and PT for each analysis period. Risk difference and corresponding exact 
95% CI (Santner, 1980) will be provided for the comparisons between each active DX-
2930 dose group and the placebo group, and overall DX-2930 group and the placebo 
group. This tabulation will be repeated for related AESI for the treatment period and 
follow-up period AEs. Tabulations will be presented sorted by SOC in alphabetical order 
and by PT within each SOC by descending frequency in the overall DX-2930 group and 
then the placebo group. 
• Related AESI by SOC and PT: The number and percentage of subjects with a related 
AESI, as well as the total number of related AESIs, will be summarized for each 
treatment group and overall DX-2930 by SOC and PT for the treatment period and 
follow-up period. Tabulations will be presented sorted by SOC in alphabetical order and 
by PT within each SOC by descending frequency in the overall DX-2930 group and then 
the placebo group. 
SMQ-defined hypersensitivity AESI during the treatment period include some terms of injection 
site reactions. It was considered by the Data Safety Monitoring Board (DSMB) that including 
these terms in the tabulation would take away focus on systemic AESIs. Therefore, tables on 
SMQ-defined hypersensitivity AESI during the treatment period will be summarized in two 
ways: a display with all injection site reaction terms (PTs containing ‘Injection site’, 
‘Administration site’, or ‘Application site’) included, and a display with all injection site reaction 
terms excluded. 
A listing of investigator-reported AESI will be provided.  
Injection Site Reactions (ISR) 
ISR AEs were not predefined in the protocol, but instead are identified using the algorithm 
detailed in Section 10.3.13.6 based on the spontaneous reporting of adverse events.  
The number and percentage of subjects with any ISR AE, any related ISR AE, any severe ISR 
AE, any related severe ISR AE, any ISR SAE, and any related ISR SAE, as well as the total 
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number of events for each category, will be summarized by treatment group. The number of 
deaths due to an ISR AE, hospitalization due to an ISR AE and study discontinuation due to an 
ISR AE will be summarized by treatment group and overall DX-2930. This tabulation will be 
performed for the treatment period only.   
The number and percentage of subjects with an ISR AE, as well as the total number of ISR AEs, 
will be summarized for each treatment group and overall DX-2930 by SOC, and PT for the 
treatment period. The number and percentage of subjects with an ISR AE will be summarized for 
each treatment group and overall DX-2930 by SOC, PT, and maximum severity for the treatment 
period.  Tabulations will be presented sorted by SOC in alphabetical order and by PT within each 
SOC by descending frequency in the overall DX-2930 group and then the placebo group. 
The duration of ISR AEs overall and by PT will be summarized numerically (summary statistics) 
and categorically (0 - 0.5 hour, >0.5 - 1 hour, >1- 12 hours, >12 – 24 hours, ≤1 day - unclear, >1 
– 14 days, and >14 days). The definition of the duration of ISR is provided in Section 10.3.13.7.   
A Listing of ISR AEs during the treatment period will be provided. 
Table 1 provides a summary of the AE tabulations by analysis period as described in this section. 
Table 1: Adverse Event Tabulations by Analysis Period 
 
Pretreatment 
Period 
Treatment 
Period 
Follow-up 
Period 
AE summary 
x 
x 
x 
AE by SOC and PT 
x 
x 
x 
AE by PT 
 
x 
 
Related AE by SOC and PT 
 
x 
x 
Related AE by PT 
 
x 
 
Severe AE by SOC and PT 
x 
x 
x 
Related Severe AE by SOC and PT 
 
x 
x 
SAE by SOC and PT 
x 
x 
x 
SAE by PT 
 
x 
 
Related SAE by SOC and PT  
 
x 
x 
Summary of Investigator-reported AESI 
x 
x 
x 
Investigator-reported AESI by SOC and PT 
x 
x 
x 
Related Investigator-reported AESI by SOC and PT 
 
x 
x 
Summary of SMQ-defined AESI 
x 
xa 
x 
SMQ-defined AESI by SOC and PT 
x 
xa 
x 
Related SMQ-defined AESI by SOC and PT 
 
xa 
x 
Summary of ISR AEs 
 
x 
 
ISR AEs by SOC and PT 
 
x 
 
ISR AEs by SOC, PT, and Severity 
 
x 
 
Number and duration of ISR AEs 
 
x 
 
aFor SMQ-defined hypersensitivity AESI during the treatment period, two sets of summary tables will be provided for the AEs including or 
excluding injection site reactions (PTs start with ‘Injection site’) 
7.9.2 
Clinical Laboratory Evaluation 
Laboratory test results will be presented in conventional units.  
 
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Baseline is defined as the last non-missing value prior to the first exposure to study drug. 
Continuous laboratory test results (serum chemistry, hematology, and urine pH) will be 
summarized as described below.  
Actual values and changes from baseline in clinical laboratory tests for hematology, coagulation, 
chemistries, and urinalysis will be summarized for each treatment group and overall DX-2930 by 
study visit. If more than one laboratory result is reported per study visit per parameter, the last 
non-missing result will be selected for analysis. All laboratory results will be presented in subject 
listings. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. See Section 10.3.20 for details on handling 
clinical significance attribution for lab values. The number of subjects with a non-missing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal, non-clinically significant result less than the lower limit of normal, within the 
normal range, non-clinically significant result more than the upper limit of normal, and clinically 
significant result more than the upper limit of normal will be summarized for each treatment 
group and overall DX-2930 by study visit. If more than one laboratory result is reported per 
study visit per parameter, the result yielding the most severe classification will be selected for 
analysis.  
Categorical laboratory test results (urinalysis excluding pH) will be summarized for treatment 
group and overall DX-2930 by study visit. If more than one laboratory result is reported per 
study visit per parameter, the result yielding the most severe classification will be selected for 
analysis.  
Subjects with clinically significant abnormal laboratory test results will be listed. This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the investigator for a subject across study visit to identify any trends. 
7.9.3 
Vital Signs 
Baseline is defined as the last non-missing value prior to the first exposure to study drug. 
Actual values and changes from baseline in vital signs will be summarized for each treatment 
group and DX-2930 overall by study visit and study time point. All vital sign data will be 
presented in subject listings. 
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage 
of subjects with a non-clinically significant result and clinically significant result will be 
summarized for each treatment group and overall DX-2930 by study visit and study time point. If 
more than one vital sign result is reported per study visit and study time point per parameter, the 
result yielding the most severe classification will be selected for analysis. Subjects with clinically 
significant vital sign values will be listed. This listing will include all results of the vital sign 
parameter that was determined by the investigator to be clinically significant for a subject across 
study time points to identify any trends. 
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7.9.4 
Electrocardiography 
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG not performed, will be summarized for each 
treatment group and overall DX-2930 by study visit. Subjects with abnormal ECG results will be 
listed. This listing will include all results for a subject across study time points to identify any trends. 
All ECG data will be provided in subject listings. 
7.9.5 
Physical Examinations 
Physical examination findings by body system will be classified as normal, abnormal not 
clinically significant, abnormal clinically significant or not performed by the investigator and 
will be summarized for each treatment group and DX-2930 overall by study visit. Subjects with 
clinically significant abnormal physical examination findings will be listed. This listing will 
include all results of the body system that was determined by the investigator to be clinically 
significant for a subject across study time points to identify any trends. 
All physical examination findings will be provided in subject listings. 
7.9.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) Version 2017 Q1. 
Prior medications are defined as medications with start and stop times at or prior to the time of 
study drug administration.  
 
Concomitant medications are defined as medications with a start times after the time of study drug 
administration or medications with a start times prior to study drug administration but continuing 
after treatment.  
 
For medications with partial onset times, non-missing date parts will be used to determine if the 
medication is concomitant or prior medication. If a determination cannot be made using the non-
missing date parts as to when the medication occurred relative to study drug administration then the 
medication will be classified as concomitant medication.  
The number and percentage of subjects with prior or concomitant medications excluding medications 
taken for an HAE attack will be summarized for each treatment group and overall DX-2930 by 
therapeutic class and preferred term. Therapeutic class will be based on the Therapeutic Subgroup 
corresponding to level 2 of the Anatomic Therapeutic Chemical (ATC) classification system. 
Tabulations will be presented sorted by therapeutic class in alphabetical order and by PT within each 
therapeutic class by descending frequency in the overall DX-2930 group and then the placebo group. 
A separate, similar table will be provided for concomitant medications taken for an HAE attack. 
All medications will be presented in subject listings. 
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7.10 
Other Analyses 
Additional analyses of pharmacokinetic (PK) and pharmacodynamic (PD) data will be described 
in a separate PK/PD report. 
Additional analysis of quality of life (QoL) data will be described in a separate QoL report.  
7.10.1 
Analysis of Pharmacokinetic Data 
Plasma concentrations of DX-2930 will be summarized for each treatment group by nominal PK 
sampling time and listed by subject using the safety population. 
Plasma concentrations reported as BLQ (below the limit of quantification) of the assay will be 
reported as zero in the data listings, and BLQ concentrations are treated as zero in the calculation 
of summary statistics. 
7.10.2 
Analysis of Pharmacodynamic Data 
Plasma kallikrein activity measured by percentage of cleaved high molecular weight kininnogen 
(%cHMWK) will be summarized for each treatment group by nominal PD sampling time and 
listed by subject using the safety population. 
7.10.3 
Analysis of Immunogenicity Data 
The number and percentage of subjects with neutralizing antibody, positive, negative, or not 
evaluable antibody results will be summarized for each treatment group and DX-2930 overall by 
study visit and overall and all immunogenicity data for subjects with any positive 
immunogenicity result will be listed by subject using the safety population. 
7.10.4 
Analysis of Quality of Life Data 
The number and percentage of subjects at each level of the EQ-5D-5L dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) for each treatment group and 
DX-2930 overall by study visit using the safety population. In addition, the VAS score for the 
subject’s self-rated health will be summarized for each treatment group and DX-2930 overall by 
study visit using the safety population.   
The responses to the AE-QoL for each item will be tabulated for each treatment group and DX-
2930 overall by study visit using the safety population. In addition, the domain scores 
(functioning, fatigue/mood, fears/shame, nutrition) and total score will be summarized for each 
treatment group and DX-2930 overall by study visit using the safety population.  
All QoL data will be provided in subject listings. 
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8. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
8.1 
Changes in the Conduct of the Study 
There was no change in the conduct of the study. 
8.2 
Change from the Analyses Planned in the Protocol 
8.2.1 
Efficacy Evaluation Period 
The phase “Efficacy Evaluation Period” was used in the protocol to describe the time interval for 
which efficacy would be evaluated and was defined as Day 0 through Day 182. This phase was 
changed to treatment period for consistency with the Study Activities Schedule. The definition of 
the duration of the interval remains Day 0 through Day 182.   
8.2.2 
ITT and Safety Population Definitions 
The definition of the ITT population specified in the protocol stated that the population will 
include all randomized subjects who are administered at least 1 dose of active IMP or placebo.  
The definition in the SAP was modified from “at least 1 dose of active IMP or placebo” to “any 
exposure to study drug”. This change was made to clarify that a subject did not need to receive 
the full dose to be included in this analysis population, but that subjects receiving partial doses 
would be included. 
A similar modification was applied to the definition of the safety population. 
8.2.3 
Adverse Events 
The protocol stated that incidence of AEs and rate of study discontinuation among the four 
treatments arms would be compared, the SAP clarified that this comparison would be based on 
descriptive statistics.    
Additionally, the analysis of the incidence of AEs by month from start of study drug was 
omitted. Because subjects are repeatedly exposed to study drug on at least a monthly basis, it is 
not expected that the type or frequency of AE would vary by month.   
The protocol stated that an AE is treatment-emergent if the onset time is after first administration 
of IMP; the SAP clarified that an AE is treatment-emergent if the onset time is on or after first 
administration of study drug. 
8.2.4 
Laboratory Parameters 
The protocol specified that for laboratory parameters the change from screening would be 
summarized. Instead, a change from baseline will be summarized and a definition of baseline 
was included in the SAP.  
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The protocol specified that laboratory parameters would be summarized using shift tables. This 
summary was omitted and replaced with a summary of results based on reference ranges and 
clinical significance as determined by the investigator. 
8.2.5 
Vital Sign Parameters 
The protocol specified that for vital sign parameters the change from screening would be 
summarized. Instead, a change from baseline will be summarized and a definition of baseline 
was included in the SAP.  
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9. STATISTICAL/ANALYTIC ISSUES 
9.1 
Adjustment for covariates 
The analysis of the primary and secondary efficacy adjusts for the normalized pretreatment HAE 
attack rate.  No additional covariate adjustment is planned. 
9.2 
Handling of Dropouts or Missing Data 
All available data will be included in the analysis.  The length of time a subject was observed 
during the treatment period will be included as a variable in the generalized linear model to 
adjust for differences in follow-up time. 
9.3 
Interim Analysis and Data Monitoring 
No interim analyses are planned. However, an independent Data Safety Monitoring Board 
(DSMB) will be established to provide ongoing, independent review and assessment of the safety 
data, and to safeguard the interests and safety of the participating subjects in the study. Analysis 
of the data for DSMB review will be conducted according to the DSMB Charter and DSMB 
SAP. Because no formal hypothesis testing for safety assessments is planned, multiplicity 
concerns regarding repeated analyses are not an issue. 
9.4 
Multicenter Studies 
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis. 
9.5 
Multiple Comparisons/Multiplicity 
The global family-wise type I error rate (FWER) for the statistical tests of the primary and rank 
ordered secondary efficacy endpoints (rank specified in Section 7.8.2) will be controlled at 0.05. 
To strongly control the global FWER at this level, a general gatekeeping approach with branches 
for each active treatment group to placebo group comparison will be utilized in which each 
family of statistical tests will be conducted in a sequential manner. Specifically, a three-branch 
general gatekeeping procedure with three families of hypotheses will be defined as follows: 
Family 1 (F1): Hypothesis tests for the primary efficacy endpoint, one test for each active 
treatment to placebo comparison ordered by highest total monthly dose (H11, H12, and H13). 
Family 2 (F2): Hypothesis tests for the first ranked secondary endpoint, one test for each active 
treatment to placebo comparison ordered by highest total monthly dose (H21, H22, and H23). 
Family 3 (F3): Hypothesis tests for the second ranked secondary endpoint, one test for each 
active treatment to placebo comparison ordered by highest total monthly dose (H31, H32, and 
H33). 
Family 4 (F4): Hypothesis tests for the third ranked secondary endpoint, one test for each active 
treatment to placebo comparison ordered by highest total monthly dose (H41, H42, and H43). 
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The 4 sets of hypotheses in F1, F2, F3, and F4 will be tested in a fixed sequence within each 
active treatment group to placebo group comparison or branch. Testing within a branch will 
continue in sequence until the first test that the null hypothesis cannot be rejected; statistical 
significance cannot be declared for that test or for any of the remaining tests within the branch.  
Within a family, hypotheses will be tested using a conservative Bonferroni-based procedure with 
equal weights for each test set at 1.67% significance level (α/3). If the null hypothesis for a test is 
rejected, α will be propagated entirely to the next test in the sequence, which will then be tested 
at the 1.67% significance level. 
To further illustrate this approach, the test for the primary endpoint will be conducted first at the 
1.67% significance level for each active treatment group compared with the placebo group and, 
if significant, the first secondary endpoint will be similarly tested at the 1.67% significance level. 
The testing sequence will continue in order through the remaining secondary endpoints for each 
active treatment group to placebo comparison or branch as long as the null hypothesis is rejected 
at the 1.67% significance level.  
Testing within the last family (F4) will utilize the remaining α by applying the Holm-Bonferroni 
procedure.  
9.6 
Examination of Subgroups  
Subgroup analyses are planned to be conducted for the primary efficacy endpoint and adverse 
events (non-HAE attack treatment period AEs, related AEs, and severe AEs).  In addition, a 
subgroup analysis by history of laryngeal attacks will be performed for the exploratory efficacy 
endpoint, number of investigator-confirmed laryngeal HAE attacks during the treatment period.  
Any p-values that are presented will be descriptive. 
The following subgroups will be used: 
• Age Group (<18, 18 to <40, 40 to <65, ≥65 years) 
• Sex (Male, Female) 
• Race Group (White, Other) 
• Weight Group (<50, 50 to <75, 75 to <100, ≥100 kg) 
• BMI Group (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2) 
• Run-in Period HAE Attack Rate Group (1 to <2, 2 to <3, ≥3 attacks/4 weeks) 
• HAE Type (Type I, Type II, Unspecified) 
• Geographic Region (US, Canada, Jordan, Europe) 
• Type of Long-term Prophylactic Therapy Prior to Study Randomization (C1-INH, Oral 
Therapy, C1-INH and Oral Therapy, Not on LTP) 
• History of laryngeal HAE attack (history laryngeal attack, no history of laryngeal attack) 
 
The subgroups will be analyzed using the same method as described for the primary efficacy 
endpoint. Data summaries will parallel those described for the primary analysis of the primary 
efficacy endpoint and the primary analysis of the adverse events. For the subgroup analyses 
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conducted for the primary efficacy endpoint, a forest plot depicting the rate ratio and 
corresponding 95% CI estimated from the Poisson generalized linear model will be provided for 
each active treatment group versus placebo group comparison within each subgroup. 
 
9.7 
Sensitivity Analyses 
The following sensitivity analyses will be performed on the primary efficacy endpoint and/or 
secondary and exploratory endpoints to evaluate the robustness of the results. See Table 2 for 
details.  
1. The primary analysis will be repeated using the safety population. Subjects will be analyzed 
according to the treatment actually received.  This analysis will only be presented if the 
safety population is different from the ITT population or if subjects did not receive treatment 
as randomized. 
2. The primary analysis will be repeated counting HAE attacks occurring on Day 7 after 
administration of study drug through Day 182, instead of Day 0 to Day 182. 
3. The primary analysis will be repeated using all subject reported HAE attacks instead of 
limiting the analysis to those attacks that were investigator-confirmed. 
4. The primary analysis will be repeated using a generalized estimating equations (GEE) 
analysis method counting HAE attacks occurring on Day 14 after administration of study 
drug through Day 182 in order to descriptively compare the results from this study with those 
from DX-2930-02 study. The methods for this analysis are listed below. 
HAE attack rates for each active treatment group will be compared to the placebo group 
using a mixed-model repeated measures (MMRM) analysis of covariance (ANCOVA) for 
count data (assuming a Poisson distribution with log link function) using GEE. The model 
will include a fixed effect for treatment (categorical), pretreatment period attack rate 
(continuous), and a random effect for subject.  
 
Repeated measurement analysis will be employed, with a 7-day time period (i.e., 168 hours) 
serving as the discrete unit of measurement. Subject weeks for which completed observation 
is less than the full 168 hours within a week will be treated as a full week if at least 3 or more 
days of data were recorded during the week. Weeks with fewer than 3 days will not be 
included. 
In the event that there are 0 events in one of the treatment groups, a small value of 0.000001 
will be added in order to calculate event rates. 
5. The impact of missing data on the primary analysis will be explored using a tipping point 
analysis.   
Subjects who do not complete the treatment period (Day 0 through Day 182) but who were 
dosed and have contributed any amount of time to the treatment period will be included in 
the primary analysis. These subjects will have some portion of the treatment period observed 
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and the remainder of the treatment period, after study discontinuation, will be unobserved.  
The model used for the primary analysis assumes that events occur at a constant rate within 
an individual, and uses only the number of events in the observed portion of the treatment 
period with an offset parameter to account for the length of time in which those events were 
observed to derive the event rate for that individual.   
To better understand the impact of unobserved portion of the treatment period generated by 
subjects who discontinue early on the results of our primary analysis, a tipping point analysis 
will be conducted.  In this analysis, a range of progressively more conservative assumptions 
about the number of events occurring in the unobserved portion of the treatment period will 
be explored in order to find the assumption which will reverse the conclusion (i.e., yield a 
non-significant p-value) of the primary analysis.  The assumption that will reverse the 
conclusion is referred to as the tipping point.  Once the tipping point is identified, the clinical 
plausibility of the assumption can be assessed.   
The tipping point analysis will employ the same model as specified for the primary analysis 
including progressively conservative assumptions about the unobserved portion of time 
generated by subjects who discontinue early. The exact range of assumptions will be 
determined after treatment unblinding to ensure an appropriate range is explored based on the 
magnitude of treatment effect and pattern of missing data.  The results of the various 
assumptions will be summarized with attack rate ratios, corresponding 95% confidence 
intervals and p-values in both tabular and graphical presentations.  The details of this method 
are described in Section 10.3.12. 
6. The primary analysis will be repeated counting HAE attacks occurring on Day 14 after 
administration of study drug through Day 182, instead of Day 0 to Day 182. 
Table 2 details which sensitivity analyses will be performed for each efficacy endpoint.  Data 
summaries will parallel those described for the each of the endpoints. 
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Table 2: Sensitivity Analysis for Efficacy Endpoints 
Efficacy Endpoint 
Sensitivity Analysis Item 
1 
2 
3 
4 
5 
6 
Number of HAE attacks 
x 
x 
x 
x 
x 
x 
Number of HAE attacks requiring acute treatment 
x 
x 
x 
 
 
x 
Number of moderate or severe HAE attacks  
x 
x 
x 
 
 
x 
Number of Investigator confirmed HAE attacks occurring on Day 
14 after administration of study drug through Day 182 
x 
- 
x 
 
 
- 
Time to first HAE attack after Day 14 
x 
x 
x 
 
 
- 
Number of high-morbidity HAE attacks 
x 
x 
x 
 
 
x 
Number of HAE attacks resulting in visit to emergency department 
or admission to the hospital  
x 
x 
x 
 
 
x 
Number of HAE attacks resulting in visit to emergency department  
x 
x 
x 
 
 
x 
Number of HAE attacks resulting in admission to the hospital 
x 
x 
x 
 
 
x 
Number of investigator-confirmed laryngeal HAE attacks 
x 
x 
x 
 
 
x 
Responder Analysis 
x 
x 
x 
 
 
x 
Characteristics of HAE attacks 
x 
x 
x 
 
 
x 
Percentage of attack-free days 
x 
x 
x 
 
 
x 
Achievement of attack-free during treatment period or after Day 14 
x 
 
 
 
 
- 
 
 
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10. APPENDICIES 
10.1 
Appendix I List of Statistical Outputs 
10.1.1 
List of Planned Tables 
Table No. 
Title 
14.1.1.1 
Analysis Population by Treatment Group – All Subjects 
14.1.1.2 
Analysis Populations by Treatment Group and Site – All Subjects 
14.1.2.1 
Subject Disposition by Treatment Group – ITT Population 
14.1.2.2 
Subject Disposition by Treatment Group – Safety Population 
14.1.3.1 
Demographics and Baseline Characteristics by Treatment Group – ITT Population 
14.1.3.2 
Demographics and Baseline Characteristics by Treatment Group – Safety Population 
14.1.4.1 
HAE Attack History by Treatment Group – ITT Population 
14.1.4.2 
HAE Attack History by Treatment Group – Safety Population 
14.1.5.1 
Medical History by System Organ class, Preferred Term, and Treatment Group – ITT Population 
14.1.5.2 
Medical History by System Organ class, Preferred Term, and Treatment Group – Safety 
Population 
14.1.6.1 
Prior Medications by Treatment Group – Safety Population 
14.1.6.2 
Concomitant Medications and Therapies (Excluding Medications taken for an HAE Attack) by 
Treatment Group – Safety Population 
14.1.6.3 
Concomitant Medications taken for an HAE Attack by Treatment Group – Safety Population  
14.1.7.1 
Summary of Protocol Deviation Type by Treatment Groups – ITT Population 
14.1.8.1 
Treatment Compliance and Study Drug Exposure by Treatment Group – ITT Population 
14.1.8.2 
Treatment Compliance and Study Drug Exposure by Treatment Group – Safety Population 
14.2.1.1 
Summary of the Multiple Comparison Procedure Result – ITT Population 
14.2.2.1 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Treatment Group – ITT Population 
14.2.2.2 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Treatment Group – Safety Population 
14.2.2.3 
Poisson Regression of Investigator-confirmed HAE Attacks during Day 8 to Day 182 by 
Treatment Group – ITT Population 
14.2.2.4 
Poisson Regression of All HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group – ITT Population 
14.2.2.5 
GEE Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period 
(Day 14 to Day 182) by Treatment Group – ITT Population 
14.2.2.6 
Tipping Point Analysis: Poisson Regression of Investigator-confirmed HAE Attacks during the 
Treatment Period (Day 0 to Day 182) after Missing Data Imputation by Treatment Group– ITT 
Population 
14.2.2.7 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Age Group and Treatment Group – ITT Population 
14.2.2.8 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Sex and Treatment Group – ITT Population 
14.2.2.9 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
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to Day 182) by Race Group and Treatment Group – ITT Population 
14.2.2.10 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Weight Group and Treatment Group – ITT Population 
14.2.2.11 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by BMI Group and Treatment Group – ITT Population 
14.2.2.12 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Run-in Period HAE Attack Rate Group and Treatment Group – ITT Population 
14.2.2.13 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by HAE Type and Treatment Group – ITT Population 
14.2.2.14 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Geographic Region and Treatment Group – ITT Population 
14.2.2.15 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by Type of Long-term Prophylactic Therapy Prior to Study Randomization and 
Treatment Group – ITT Population 
14.2.2.16 
Poisson Regression of Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 
to Day 182) by History of Laryngeal HAE Attack and Treatment Group – ITT Population 
14.2.2.17 
Summary of Investigator-confirmed HAE Attacks by Treatment Group – ITT Population 
14.2.2.18 
Investigator-Confirmed HAE Attacks per Month by Study Month and Treatment Group – ITT 
Population 
14.2.3.1 
Poisson Regression of Investigator-confirmed HAE Attacks Requiring Acute Treatment during 
the Treatment Period (Day 0 to Day 182) – ITT Population 
14.2.3.2 
Poisson Regression of Investigator-confirmed HAE Attacks Requiring Acute Treatment during 
the Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.2.3.3 
Poisson Regression of Investigator-confirmed HAE Attacks Requiring Acute Treatment during 
Day 14 to Day 182 by Treatment Group – ITT Population 
14.2.3.4 
Poisson Regression of Investigator-confirmed HAE Attacks Requiring Acute Treatment during 
Day 8 to Day 182 by Treatment Group – ITT Population 
14.2.3.5 
Poisson Regression of All HAE Attacks Requiring Acute Treatment during the Treatment Period 
(Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.3.6 
Summary of Investigator-confirmed HAE Attacks Requiring Acute Treatment by Treatment 
Group – ITT Population 
14.2.4.1 
Poisson Regression of Moderate and Severe Investigator-confirmed HAE Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.4.2 
Poisson Regression of Moderate and Severe Investigator-confirmed HAE Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.2.4.3 
Poisson Regression of Moderate and Severe Investigator-confirmed HAE Attacks during Day 14 
to Day 182 by Treatment Group – ITT Population 
14.2.4.4 
Poisson Regression of Moderate and Severe Investigator-confirmed HAE Attacks during Day 8 
to Day 182 by Treatment Group – ITT Population 
14.2.4.5 
Poisson Regression of All Moderate and Severe HAE Attacks during the Treatment Period (Day 
0 to Day 182) by Treatment Group – ITT Population 
14.2.4.6 
Summary of Moderate and Severe Investigator-confirmed HAE Attacks by Treatment Group – 
ITT Population 
14.2.5.1 
Poisson Regression of Investigator-confirmed HAE Attacks during Day 14 to Day 182 by 
Treatment Group – ITT Population 
14.2.5.2 
Poisson Regression of Investigator-confirmed HAE Attacks during Day 14 to Day 182 by 
Confidential 
 
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Treatment Group – Safety Population 
14.2.5.3 
Poisson Regression of All HAE Attacks during Day 14 to Day 182 by Treatment Group – ITT 
Population 
14.2.5.4 
Summary of Investigator-confirmed HAE Attacks during Day 14 to Day 182 by Treatment 
Group – ITT Population 
14.2.6.1 
Time to First Investigator-confirmed HAE Attack after Day 14 – ITT Population 
14.2.6.2 
Time to First Investigator-confirmed HAE Attack after Day 14 – Safety Population 
14.2.6.3 
Time to First Investigator-confirmed HAE Attack after Day 7 – ITT Population 
14.2.6.4 
Time to First HAE Attack after Day 14 – ITT Population 
14.2.7.1 
Poisson Regression of Investigator-confirmed High-Morbidity HAE Attacks  during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population  
14.2.7.2 
Poisson Regression of Investigator-confirmed High-Morbidity HAE Attacks  during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population  
14.2.7.3 
Poisson Regression of Investigator-confirmed High-Morbidity HAE Attacks  during Day 14 to 
Day 182 by Treatment Group – ITT Population  
14.2.7.4 
Poisson Regression of Investigator-confirmed High-Morbidity HAE Attacks  during Day 7 to 
Day 182 by Treatment Group – ITT Population  
14.2.7.5 
Poisson Regression of High-Morbidity HAE Attacks  during the Treatment Period (Day 0 to Day 
182) by Treatment Group – ITT Population  
14.2.7.6 
Summary of Investigator-confirmed High-Morbidity HAE Attacks by Treatment Group – ITT 
Population 
14.2.8.1 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency 
Department Visit or Admission to the Hospital during the Treatment Period (Day 0 to Day 182) 
by Treatment Group – ITT Population  
14.2.8.2 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency 
Department Visit or Admission to the Hospital during the Treatment Period (Day 0 to Day 182) 
by Treatment Group – Safety Population  
14.2.8.3 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency 
Department Visit or Admission to the Hospital during Day 14 to Day 182 by Treatment Group – 
ITT Population  
14.2.8.4 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency 
Department Visit or Admission to the Hospital during Day 7 to Day 182 by Treatment Group – 
ITT Population  
14.2.8.5 
Poisson Regression of HAE Attacks resulting in an Emergency Department Visit or Admission to 
the Hospital during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT 
Population  
14.2.8.6 
Summary of Investigator-confirmed HAE Attacks resulting in an Emergency Department Visit or 
Admission to the Hospital by Treatment Group – ITT Population 
14.2.9.1 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency 
Department Visit during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT 
Population  
14.2.9.2 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency 
Department Visit during the Treatment Period (Day 0 to Day 182) by Treatment Group – Safety 
Population  
14.2.9.3 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency 
Department Visit during Day 14 to Day 182 by Treatment Group – ITT Population  
14.2.9.4 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in an Emergency 
Confidential 
 
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Department Visit during Day 7 to Day 182 by Treatment Group – ITT Population  
14.2.9.5 
Poisson Regression of HAE Attacks resulting in an Emergency Department Visit during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population  
14.2.9.6 
Summary of Investigator-confirmed HAE Attacks resulting in an Emergency Department Visit 
by Treatment Group – ITT Population 
14.2.10.1 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in Admission to the 
Hospital during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population  
14.2.10.2 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in Admission to the 
Hospital during the Treatment Period (Day 0 to Day 182) by Treatment Group – Safety 
Population  
14.2.10.3 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in Admission to the 
Hospital during Day 14 to Day 182 by Treatment Group – ITT Population  
14.2.10.4 
Poisson Regression of Investigator-confirmed HAE Attacks resulting in Admission to the 
Hospital during Day 7 to Day 182 by Treatment Group – ITT Population  
14.2.10.5 
Poisson Regression of HAE Attacks resulting in Admission to the Hospital during the Treatment 
Period (Day 0 to Day 182) by Treatment Group – ITT Population  
14.2.10.6 
Summary of Investigator-confirmed HAE Attacks resulting in Admission to the Hospital by 
Treatment Group – ITT Population 
14.2.11.1 
Poisson Regression of Investigator-confirmed Laryngeal HAE Attacks during the Treatment 
Period (Day 0 to Day 182) by Treatment Group – ITT Population  
14.2.11.2 
Poisson Regression of Investigator-confirmed Laryngeal HAE Attacks during the Treatment 
Period (Day 0 to Day 182) by Treatment Group – Safety Population  
14.2.11.3 
Poisson Regression of Investigator-confirmed Laryngeal HAE Attacks during Day 14 to Day 182 
by Treatment Group – ITT Population  
14.2.11.4 
Poisson Regression of Investigator-confirmed Laryngeal HAE Attacks during Day 7 to Day 182 
by Treatment Group – ITT Population  
14.2.11.5 
Poisson Regression of Laryngeal HAE Attacks during the Treatment Period (Day 0 to Day 182) 
by Treatment Group – ITT Population  
14.2.11.6 
Summary of Investigator-confirmed Laryngeal HAE Attacks by Treatment Group – ITT 
Population 
14.2.11.7 
Poisson Regression of Investigator-confirmed Laryngeal HAE Attacks during the Treatment 
Period (Day 0 to Day 182) by History of Laryngeal Attack and Treatment Group – ITT 
Population  
14.2.12.1 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
(Day 0 to Day 182) vs. Run-in Period by Responder Threshold and Treatment Group– ITT 
Population 
14.2.12.2 
Responder Analysis using Investigator-confirmed HAE Attacks during the Treatment Period 
(Day 0 to Day 182) vs. Run-in Period by Responder Threshold and Treatment Group– Safety 
Population 
14.2.12.3 
Responder Analysis using Investigator-confirmed HAE Attacks during Day 14 to Day 182 vs. 
Run-in Period by Responder Threshold and Treatment Group– ITT Population 
14.2.12.4 
Responder Analysis using Investigator-confirmed HAE Attacks during Day 7 to Day 182 by 
Responder Threshold and Treatment Group– ITT Population 
14.2.12.5 
Responder Analysis using All HAE Attacks during the Treatment Period (Day 0 to Day 182) vs. 
Run-in Period by Responder Threshold and Treatment Group– ITT Population 
14.2.13.1 
Subject Level Characteristics of Investigator-confirmed HAE attacks during the Treatment Period 
(Day 0 to Day 182) – ITT Population 
Confidential 
 
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14.2.13.2 
Subject Level Characteristics of Investigator-confirmed HAE attacks during the Treatment Period 
(Day 0 to Day 182) – Safety Population 
14.2.13.3 
Subject Level Characteristics of Investigator-confirmed HAE attacks during Day 14 to Day 182 – 
ITT Population 
14.2.13.4 
Subject Level Characteristics of Investigator-confirmed HAE attacks during Day 7 to Day 182 – 
ITT Population 
14.2.13.5 
Subject Level Characteristics of All HAE attacks during the Treatment Period (Day 0 to Day 
182) – ITT Population 
14.2.13.6 
Event Level Characteristics of Investigator-confirmed HAE attacks during the Treatment Period 
(Day 0 to Day 182) – ITT Population 
14.2.13.7 
Event Level Characteristics of Investigator-confirmed HAE attacks during the Treatment Period 
(Day 0 to Day 182) – Safety Population 
14.2.13.8 
Event Level Characteristics of Investigator-confirmed HAE attacks during Day 14 to Day 182 – 
ITT Population 
14.2.13.9 
Event Level Characteristics of Investigator-confirmed HAE attacks during Day 7 to Day 182 – 
ITT Population 
14.2.13.10 
Event Level Characteristics of All HAE attacks during the Treatment Period (Day 0 to Day 182) 
– ITT Population 
14.2.14.1 
Percentage of Investigator-confirmed HAE Attack-free Days during the Treatment Period (Day 0 
to Day 182) – ITT Population 
14.2.14.2 
Percentage of Investigator-confirmed HAE Attack-free Days during the Treatment Period (Day 0 
to Day 182) – Safety Population 
14.2.14.3 
Percentage of Investigator-confirmed HAE Attack-free Days during Day 14 to Day 182 – ITT 
Population 
14.2.14.4 
Percentage of Investigator-confirmed HAE Attack-free Days during Day 7 to Day 182 – ITT 
Population 
14.2.14.5 
Percentage of HAE Attack-free Days during the Treatment Period (Day 0 to Day 182) – ITT 
Population 
14.2.15.1 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, or 
until the Day 182 Visit during the Treatment Period – ITT Population 
14.2.15.2 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, or 
until the Day 182 Visit during the Treatment Period – Safety Population 
14.2.15.3 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, or 
until the Day 182 Visit after Day 14 during the Treatment Period – ITT Population 
14.2.15.4 
Achievement of Investigator-Confirmed HAE Attack-Free Interval of 1 Month, 3 Months, or 
until the Day 182 Visit after Day 14 during the Treatment Period – Safety Population 
14.2.16.1 
Subject Listing of Efficacy Parameters – Part 1 – ITT Population 
14.2.16.2 
Subject Listing of Efficacy Parameters – Part 2 – ITT Population 
14.2.17.1 
Plasma Concentrations of DX-2390 by Treatment Group and Study Visit – Safety Population 
14.2.18.1 
Plasma Kallikrein Activity Measured by %cHMWK by Treatment Group and Study Visit – 
Safety Population 
14.2.19.1 
Summary of EQ-5D-5L Dimensions and VAS Score by Treatment Group and Study Visit – 
Safety Population 
14.2.19.2 
Summary of Angioedema Quality of Life Items, Domains and Total Score by Treatment Group 
and Study Visit – Safety Population 
14.3.1.1.1 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
Confidential 
 
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during the Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.3.1.1.2 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by Age Group and Treatment Group – Safety 
Population 
14.3.1.1.3 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by Sex and Treatment Group – Safety 
Population 
14.3.1.1.4 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by Race Group and Treatment Group – Safety 
Population 
14.3.1.1.5 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by Weight Group and Treatment Group – Safety 
Population 
14.3.1.1.6 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by BMI Group and Treatment Group – Safety 
Population 
14.3.1.1.7 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by Run-in Period HAE Attack Rate Group  and 
Treatment Group – Safety Population 
14.3.1.1.8 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by HAE Type and Treatment Group – Safety 
Population 
14.3.1.1.9 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by Geographic Region and Treatment Group – 
Safety Population 
14.3.1.1.10 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by Type of Long-term Prophylactic Therapy 
Prior to Study Randomization and Treatment Group – Safety Population 
14.3.1.1.11 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by History of Laryngeal HAE attack and 
Treatment Group – Safety Population  
14.3.1.2.1 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred 
Term – Safety Population 
14.3.1.2.2 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Treatment Group and Preferred Term – Safety 
Population 
14.3.1.2.3 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Age Group, Treatment Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.2.4 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Sex, Treatment Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.2.5 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Race Group, Treatment Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.2.6 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Weight Group, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
Confidential 
 
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14.3.1.2.7 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by BMI Group, Treatment Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.2.8 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Run-in Period HAE Attack Rate Group, Treatment 
Group, System Organ Class and Preferred Term – Safety Population 
14.3.1.2.9 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by HAE Type, Treatment Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.2.10 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Geographic Region, Treatment Group, System Organ 
Class and Preferred Term – Safety Population 
14.3.1.2.11 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by Type of Long-term Prophylactic Therapy Prior to Study 
Randomization, Treatment Group, System Organ Class and Preferred Term – Safety Population 
14.3.1.2.12 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Treatment Period (Day 0 to Day 182) by History of Laryngeal HAE attack, Treatment Group, 
System Organ Class and Preferred Term – Safety Population 
14.3.1.3.1 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and 
Preferred Term – Safety Population 
14.3.1.3.2 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Treatment Group and Preferred Term – Safety 
Population 
14.3.1.3.3 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Age Group, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
14.3.1.3.4 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Sex, Treatment Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.3.5 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Race Group, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
14.3.1.3.6 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Weight Group, Treatment Group, System Organ 
Class and Preferred Term – Safety Population 
14.3.1.3.7 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by BMI Group, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
14.3.1.3.8 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Run-in Period HAE Attack Rate Group, Treatment 
Group, System Organ Class and Preferred Term – Safety Population 
14.3.1.3.9 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by HAE Type, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
14.3.1.3.10 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Geographic Region, Treatment Group, System 
Organ Class and Preferred Term – Safety Population 
14.3.1.3.11 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
Confidential 
 
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the Treatment Period (Day 0 to Day 182) by Type of Long-term Prophylactic Therapy Prior to 
Study Randomization, Treatment Group, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.3.12 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by History of Laryngeal HAE attack, Treatment Group, 
System Organ Class and Preferred Term – Safety Population 
14.3.1.4.1 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and 
Preferred Term – Safety Population 
14.3.1.4.2 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Treatment Group and Preferred Term – Safety 
Population 
14.3.1.4.3 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Age Group, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
14.3.1.4.4 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Sex, Treatment Group, System Organ Class and 
Preferred Term – Safety Population 
14.3.1.4.5 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Race Group, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
14.3.1.4.6 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Weight Group, Treatment Group, System Organ 
Class and Preferred Term – Safety Population 
14.3.1.4.7 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by BMI Group, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
14.3.1.4.8 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Run-in Period HAE Attack Rate Group, Treatment 
Group, System Organ Class and Preferred Term – Safety Population 
14.3.1.4.9 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by HAE Type, Treatment Group, System Organ Class 
and Preferred Term – Safety Population 
14.3.1.4.10 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Geographic Region, Treatment Group, System 
Organ Class and Preferred Term – Safety Population 
14.3.1.4.11 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by Type of Long-term Prophylactic Therapy Prior to 
Study Randomization, Treatment Group, System Organ Class and Preferred Term – Safety 
Population 
14.3.1.4.12 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Treatment Period (Day 0 to Day 182) by History of Laryngeal HAE attack, Treatment Group, 
System Organ Class and Preferred Term – Safety Population 
14.3.1.5.1 
Related Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and 
Preferred Term – Safety Population 
14.3.1.6.1 
Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 182) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.6.2 
Risk Difference of Serious Treatment Emergent Adverse Events during the Treatment Period 
Confidential 
 
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(Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.7.1 
Related Serious Treatment Emergent Adverse Events during the Treatment Period (Day 0 to Day 
182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.8.1 
Summary of Adverse Events (Excluding HAE Attack Reported Events) during the Pretreatment 
Period (Prior to Day 0) by Treatment Group – Safety Population 
14.3.1.8.2 
Adverse Events (Excluding HAE Attack Reported Events) during the Pretreatment Period (Prior 
to Day 0) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.8.3 
Severe Adverse Events (Excluding HAE Attack Reported Events) during the Pretreatment Period 
(Prior to Day 0) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.8.4 
Serious Adverse Events (Excluding HAE Attack Reported Events) during the Pretreatment 
Period (Prior to Day 0) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.9.1 
Summary of Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Follow-up Period (>Day 182) by Treatment Group – Safety Population 
14.3.1.9.2 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – 
Safety Population 
14.3.1.9.3 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term 
– Safety Population 
14.3.1.9.4 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term 
– Safety Population 
14.3.1.9.5 
Related Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and 
Preferred Term – Safety Population 
14.3.1.9.6 
Serious Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) during 
the Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term 
– Safety Population 
14.3.1.9.7 
Risk Difference of  Serious Treatment Emergent Adverse Events (Excluding HAE Attack 
Reported Events) during the Follow-up Period (>Day 182) by Treatment Group, System Organ 
Class, and Preferred Term – Safety Population 
14.3.1.9.8 
Related Serious Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) 
during the Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and 
Preferred Term – Safety Population 
14.3.1.10.1 
Summary of Treatment-Emergent HAE Attack Reported Adverse Events during the Treatment 
Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.3.1.10.2 
Treatment Emergent HAE Attack Reported Adverse Events during the Treatment Period (Day 0 
to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.10.3 
Related Treatment Emergent HAE Attack Reported Adverse Events during the Treatment Period 
(Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.10.4 
Severe Treatment Emergent HAE Attack Reported Adverse Events during the Treatment Period 
(Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.10.5 
Related Severe Treatment Emergent HAE Attack Reported Adverse Events during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – 
Confidential 
 
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Safety Population 
14.3.1.10.6 
Serious Treatment Emergent HAE Attack Reported Adverse Events during the Treatment Period 
(Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.10.7 
Risk Difference of Serious Treatment Emergent HAE Attack Reported Adverse Events during 
the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and 
Preferred Term – Safety Population 
14.3.1.10.8 
Related Serious Treatment Emergent HAE Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred 
Term – Safety Population 
14.3.1.11.1 
Summary of HAE Attack Reported Adverse Events during the Pretreatment Period (Prior to Day 
0) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.11.2 
HAE Attack Reported Adverse Events during the Pretreatment Period (Prior to Day 0) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.11.3 
Severe HAE Attack Reported Adverse Events during the Pretreatment Period (Prior Day 0) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.11.4 
Serious HAE Attack Reported Adverse Events during the Pretreatment Period (Prior Day 0) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.1 
Summary of Treatment-Emergent HAE Attack Reported Adverse Events during the Follow-up 
Period (>Day 182) by Treatment Group – Safety Population 
14.3.1.12.2 
Treatment Emergent HAE Attack Reported Adverse Events during the Follow-up Period (>Day 
182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.3 
Related Treatment Emergent HAE Attack Reported Adverse Events during the Follow-up Period 
(>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.4 
Severe Treatment Emergent HAE Attack Reported Adverse Events during the Follow-up Period 
(>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.5 
Related Severe Treatment Emergent HAE Attack Reported Adverse Events during the Follow-up 
Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.12.6 
Serious Treatment Emergent HAE Attack Reported Adverse Events during the Follow-up Period 
(>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.12.7 
Risk Difference of Serious Treatment Emergent HAE Attack Reported Adverse Events during 
the Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term 
– Safety Population 
14.3.1.12.8 
Related Serious Treatment Emergent HAE Attack Reported Adverse Events during the Follow-
up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.13.1 
Summary of Treatment Emergent Adverse Events of  Investigator-Reported AESI during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.3.1.13.2 
Treatment Emergent Adverse Events of  Investigator-Reported AESI during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term– 
Safety Population 
14.3.1.13.3 
Risk Difference of Treatment Emergent Adverse Events of  Investigator-Reported AESI during 
the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and 
Preferred Term– Safety Population 
14.3.1.13.4 
Related Treatment Emergent Adverse Events of Investigator-Reported AESI during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred 
Term– Safety Population  
Confidential 
 
Page 54 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
14.3.1.13.5 
Summary of Adverse Events of Investigator-Reported AESI during the Pretreatment Period 
(Prior to Day 0) by Treatment Group – Safety Population 
14.3.1.13.6 
Adverse Events of Investigator-Reported AESI during the Pretreatment Period (Prior to Day 0) 
by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.13.7 
Summary of Treatment Emergent Adverse Events of Investigator-Reported AESI during the 
Follow-up Period (>Day 182) by Treatment Group – Safety Population 
14.3.1.13.8 
Treatment Emergent Adverse Events of Investigator-Reported AESI during the Follow-up Period 
(>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.13.9 
Related Treatment Emergent Adverse Events of Investigator-Reported AESI during the Follow-
up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.14.1 
Summary of Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Treatment Period (Day 0 to Day 182) by Treatment Group– Safety Population 
14.3.1.14.2 
Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term– 
Safety Population 
14.3.1.14.3 
Risk Difference of Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity 
during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and 
Preferred Term– Safety Population 
14.3.1.14.4 
Related Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred 
Term– Safety Population  
14.3.1.14.5 
Summary of Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Excluding ISR) – Safety Population 
14.3.1.14.6 
Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term 
(Excluding ISR) – Safety Population 
14.3.1.14.7 
Risk Difference of Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity 
during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and 
Preferred Term (Excluding ISR) – Safety Population 
14.3.1.14.8 
Related Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred 
Term (Excluding ISR) – Safety Population  
14.3.1.14.9 
Summary of Adverse Events of SMQ-Defined Hypersensitivity during the Pretreatment Period 
(Prior to Day 0) by Treatment Group  – Safety Population 
14.3.1.14.10 
Adverse Events of SMQ-Defined Hypersensitivity during the Pretreatment Period (Prior to Day 
0) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.14.11 
Summary of Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Follow-up Period (>Day 182) by Treatment Group – Safety Population 
14.3.1.14.12 
Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the Follow-up 
Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.14.13 
Related Treatment Emergent Adverse Events of SMQ-Defined Hypersensitivity during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – 
Safety Population 
14.3.1.15.1 
Summary of Treatment Emergent Adverse Events of SMQ-Defined Bleeding during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.3.1.15.2 
Treatment Emergent Adverse Events of SMQ-Defined Bleeding during the Treatment Period 
Confidential 
 
Page 55 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
(Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.15.3 
Risk Difference of Treatment Emergent Adverse Events of SMQ-Defined Bleeding during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred 
Term – Safety Population 
14.3.1.15.4 
Related Treatment Emergent Adverse Events of SMQ-Defined Bleeding during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – 
Safety Population  
14.3.1.15.5 
Summary of Adverse Events of SMQ-Defined Bleeding during the Pretreatment Period (Prior to 
Day 0) by Treatment Group – Safety Population 
14.3.1.15.6 
Adverse Events of SMQ-Defined Bleeding during the Pretreatment Period (Prior to Day 0) by 
Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.15.7 
Summary of Treatment Emergent Adverse Events of SMQ-Defined Bleeding during the Follow-
up Period (>Day 182) by Treatment Group – Safety Population 
14.3.1.15.8 
Treatment Emergent Adverse Events of SMQ-Defined Bleeding during the Follow-up Period 
(>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.15.9 
Related Treatment Emergent Adverse Events of SMQ-Defined Bleeding during the Follow-up 
Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.16.1 
Summary of Treatment Emergent Adverse Events of SMQ-Defined Hypercoagulable during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.3.1.16.2 
Treatment Emergent Adverse Events of SMQ-Defined Hypercoagulable during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – 
Safety Population 
14.3.1.16.3 
Risk Difference of Treatment Emergent Adverse Events of SMQ-Defined Hypercoagulable 
during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and 
Preferred Term – Safety Population 
14.3.1.16.4 
Related Treatment Emergent Adverse Events of SMQ-Defined Hypercoagulable during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class, and Preferred 
Term – Safety Population  
14.3.1.16.5 
Summary of Adverse Events of SMQ-Defined Hypercoagulable during the Pretreatment Period 
(Prior to Day 0) by Treatment Group – Safety Population 
14.3.1.16.6 
Adverse Events of SMQ-Defined Hypercoagulable during the Pretreatment Period (Prior to Day 
0) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.16.7 
Summary of Treatment Emergent Adverse Events of SMQ-Defined Hypercoagulable during the 
Follow-up Period (>Day 182) by Treatment Group – Safety Population 
14.3.1.16.8 
Treatment Emergent Adverse Events of SMQ-Defined Hypercoagulable during the Follow-up 
Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety 
Population 
14.3.1.16.9 
Related Treatment Emergent Adverse Events of SMQ-Defined Hypercoagulable during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class, and Preferred Term – 
Safety Population 
14.3.1.17.1 
Summary of Treatment Emergent Adverse Events of Injection Site Reaction during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – Safety Population 
14.3.1.17.2 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period (Day 
0 to Day 182) by Treatment Group, System Organ Class, and Preferred Term – Safety Population 
14.3.1.17.3 
Treatment Emergent Adverse Events of Injection Site Reaction during the Treatment Period (Day 
0 to Day 182) by Treatment Group, System Organ Class, Preferred Term, and Maximum Severity 
Confidential 
 
Page 56 of 81 


 
 
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May 03, 2017 
– Safety Population 
14.3.1.17.4 
Summary on Duration of Injection Site Reaction Treatment Emergent Adverse Events during the 
Treatment Period (Day 0 to Day 182) – Safety Population 
14.3.2.1 
Listing of Adverse Events Resulting in Death – All Subjects 
14.3.2.2 
Listing of Serious Adverse Events – All Subjects 
14.3.2.3 
Listing of Adverse Events Resulting in Study Drug Interrupted or Withdrawn – All Subjects 
14.3.2.4 
Listing of Related Adverse Events – All Subjects 
14.3.2.5 
Listing of Severe Adverse Events – All Subjects 
14.3.2.6 
Listing of Investigator-Reported AESI – All Subjects 
14.3.2.7 
Listing of Injection Site Reaction Adverse Events – All Subjects 
14.3.3 
No statistical table will be generated.  Numbering reserved for SAE narratives per ICH. 
14.3.4.1.1 
Actual Values and Change from Baseline in Hematology Results by Treatment Group and Study 
Visit – Safety Population 
14.3.4.1.2 
Categorical Hematology Results by Treatment Group and Study Visit – Safety Population 
14.3.4.1.3 
Listing of Clinically Significant Abnormal Hematology Results – Safety Population 
14.3.4.2.1 
Actual Values and Change from Baseline in Coagulation Results by Treatment Group and Study 
Visit – Safety Population 
14.3.4.2.2 
Categorical Coagulation Results by Treatment Group and Study Visit – Safety Population 
14.3.4.2.3 
Listing of Clinically Significant Abnormal Coagulation Results – Safety Population 
14.3.4.3.1 
Actual Values and Change from Baseline in Chemistry Results by Treatment Group and Study 
Visit – Safety Population 
14.3.4.3.2 
Categorical Chemistry Results by Treatment Group and Study Visit – Safety Population 
14.3.4.3.3 
Listing of Clinically Significant Abnormal Chemistry Results – Safety Population 
14.3.4.4.1 
Actual Values and Change from Baseline in Urinalysis Results by Treatment Group and Study 
Visit – Safety Population 
14.3.4.4.2 
Categorical Urinalysis Results by Treatment Group and Study Visit – Safety Population 
14.3.4.4.3 
Listing of Clinically Significant Abnormal Urinalysis Results – Safety Population 
14.3.4.5.1 
Actual Values and Change from Baseline in Vital Signs by Treatment Group, Study Visit and 
Study Time Point – Safety Population 
14.3.4.5.2 
Categorical Vital Signs Results by Treatment Group, Study Visit and Study Time Point – Safety 
Population 
14.3.4.5.3 
Listing of Clinically Significant Vital Signs – Safety Population 
14.3.4.6.1 
Categorical Electrocardiogram Results by Treatment Group  and Study Visit – Safety Population 
14.3.4.6.2 
Listing of Abnormal Electrocardiogram Results – Safety Population 
14.3.4.7.1 
Categorical Physical Examination Findings by Treatment Group and Study Visit – Safety 
Population  
14.3.4.7.2 
Listing of Clinically Significant Physical Examination Findings – Safety Population 
14.3.4.8.1 
Immunogenicity by Treatment Group and Study Visit – Safety Population 
14.3.4.8.2 
Listing of Positive Immunogenicity Results – Safety Population 
 
 
Confidential 
 
Page 57 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
10.1.2 
List of Planned Figures 
Figure No. 
Title 
14.2.1.1 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group – ITT Population 
14.2.1.2 
All HAE Attacks during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT 
Population 
14.2.1.3 
Investigator-confirmed HAE Attacks during Day 14 to Day 182 by Treatment Group – ITT 
Population 
14.2.1.4 
Investigator-confirmed HAE Attacks during Day 8 to Day 182 by Treatment Group – ITT 
Population 
14.2.1.5 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Age Group – ITT Population 
14.2.1.6 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Sex – ITT Population 
14.2.1.7 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Race Group – ITT Population 
14.2.1.8 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and Weight Group – ITT Population 
14.2.1.9 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and BMI Group – ITT Population 
14.2.1.10 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182)  by 
Treatment Group and Run-in Period HAE Attack Rate Group – ITT Population 
14.2.1.11 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182) by 
Treatment Group and HAE Type – ITT Population 
14.2.1.12 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182)  by 
Treatment Group and Geographic Region – ITT Population 
14.2.1.13 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182)  by 
Treatment Group and Type of Long-term Prophylactic Therapy Prior to Study Randomization – 
ITT Population 
14.2.1.14 
Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 182)  by 
Treatment Group and History of Laryngeal Attack – ITT Population 
14.2.1.15 
Forest Plot of Rate Ratio on Number of Investigator-Confirmed HAE Attacks by Subject 
Subgroups  – ITT Population 
14.2.2.1 
Investigator-confirmed HAE Attacks Requiring Acute Treatment during the Treatment Period 
(Day 0 to Day 182) by Treatment Group – ITT Population 
14.2.3.1 
Moderate and Severe Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to 
Day 182) by Treatment Group – ITT Population 
14.2.4.1 
Time to First HAE Attack After Day 14 by Treatment Group – ITT Population 
14.2.5.1 
High-morbidity Investigator-confirmed HAE Attacks during the Treatment Period (Day 0 to Day 
182) by Treatment Group – ITT Population 
14.2.6.1 
Investigator-confirmed HAE Attacks Requiring an Emergency Department Visit or Admission to 
the Hospital during the Treatment Period (Day 0 to Day 182) by Treatment Group – ITT 
Population 
14.2.7.1 
Investigator-confirmed HAE Attacks Requiring an Emergency Department Visit during the 
Treatment Period (Day 0 to Day 182) by Treatment Group – ITT Population 
Confidential 
 
Page 58 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
14.2.8.1 
Investigator-confirmed HAE Attacks  Requiring Admission to the Hospital during the Treatment 
Period (Day 0 to Day 182) by Treatment Group – ITT Population 
 
 
Confidential 
 
Page 59 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
10.1.3 
List of Planned Listings 
Listing No. 
Title 
16.2.1 
Disposition 
16.2.2 
Protocol Deviations 
16.2.3.1 
Analysis Populations 
16.2.3.2 
Inclusion and Exclusion Criteria 
16.2.4.1 
Demographics  
16.2.4.2 
Baseline Disease Characteristics 
16.2.4.3 
Medical History 
16.2.4.4 
Prior and Concomitant Medications 
16.2.5.1 
Study Drug Administration 
16.2.5.2 
Treatment Compliance and Exposure 
16.2.6.1 
HAE Attacks 
16.2.6.2 
Plasma Concentration of DX-2930 
16.2.6.3 
Kallikrein Activity 
16.2.6.4 
EQ5D 
16.2.6.5 
Angioedema Quality of Life 
16.2.7 
Adverse Events 
16.2.8.1 
Hematology Values 
16.2.8.2 
Coagulation Values 
16.2.8.3 
Chemistry Values 
16.2.8.4 
Urinalysis Values 
16.2.8.5 
Vital Signs 
16.2.8.6 
ECGs 
16.2.8.7 
Immunogenicity 
16.2.8.8 
Physical Examinations 
 
Confidential 
 
Page 60 of 81 


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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
 
10.3 
Definitions and Programming Conventions 
10.3.1 
Age 
Age will be calculated as the date of birth minus the date of informed consent, divided by 
365.25, and truncated to years. 
10.3.2 
BMI 
BMI will be calculated as: 
 
The mass and height collected at the screening visit will be used to calculate baseline BMI. 
10.3.3 
LTP Prior to Study Randomization 
The LTP (C1-INH, Androgens, or Anti-fibrinolytics) treatment a subject was on prior to study 
randomization will be determined by applying the algorithm presented in Table 3 to prior 
medications (i.e., medications with start and stop date prior to study enrollment) reported for that 
subject that lasted for ≥4 days.  
Table 3 LTP Prior to Study Randomization 
LTP 
Algorithm to Identify Medications 
C1-INH 
ATC level 4 in (‘B06AC’) and preferred drug term not in 
(‘icatibant’, ‘ecallantide’, ‘icatibant acetate’) 
Androgens 
ATC level 4 in (‘G03BA’, ‘G03BB’, ‘A14AA’) or 
preferred drug term in (‘danazol’, ‘oxandrolone’)  
Anti-fibrinolytics 
ATC level 4 in (‘B02AA’, ‘B02AB’) 
Subjects will be further classified into four LTP subgroup, based on the LTP use prior to study 
randomization. Table 4 provides the algorithm to classify subjects by type of LTP use prior to 
study randomization. 
Table 4 LTP Subgroup 
LTP Subgroup 
Subject 
C1-INH 
Subjects who took only C1-INH as LTP 
Oral Therapy 
Subjects who took either Androgens and/or Anti-
fibrinolytics as LTP but not C1-INH   
C1-INH and Oral Therapy 
Subjects who took C1-INH and androgens and/or anti-
fibrinolytics as LTP   
Not on LTP  
Subjects who didn’t take any LTP medications prior to 
study randomization 
10.3.4 
Study Day 
The study day is calculated as start or stop date – date of randomization + 1 for dates on or after 
randomization, or start or stop date – date of randomization for dates prior to randomization. 
Confidential 
 
Page 63 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
10.3.5 
Durations of Events 
The duration of an event is calculated as stop date/time – start date/time if time is not missing, 
and stop date – start date + 1 if either the start or stop time is missing. 
10.3.6 
Baseline 
Baseline is defined as the last non-missing value prior to first exposure to study drug. 
10.3.7 
Analysis Periods 
10.3.7.1 
Pretreatment Period 
The pretreatment period is defined as the interval of time that starts at the date/time informed 
consent is signed and ends prior to the date/time of first exposure to study drug (Day 0 visit).   
[date/time of informed consent, date/time of first exposure to study drug) 
10.3.7.2 
Run-in Period 
The run-in period is defined as the interval of time that starts at the start date for the run-in 
period and ends on the end date for the run-in period.   
[start date of run-in period, end date of run-in period] 
10.3.7.3 
Treatment Period 
The treatment period is defined as the interval of time that starts on the date/time of first 
exposure to study drug (Day 0 visit) and ends on the date of Day 182 visit.     
[date/time of first exposure to study drug, date of Day 182 visit] 
10.3.7.4 
Follow-up Period 
The follow-up period is defined as the interval of time that starts on the date of the Day 182 visit 
+ 1 and ends on the date of the subject’s last date of contact for the study.     
[date of Day 182 visit + 1, date of last study contact] 
10.3.8 
Handling of Data for Subjects who Rolled-Over to the DX-2930-04 Early  
Two subjects (subject ID 107007 and 108001) rolled-over to DX-2930-04 (long-term extension 
study) prior to the Day 182 visit due to study site error. These two subjects were considered to 
have completed the DX-2930-03 study as the early discontinuation of the treatment period was in 
error. For these two subjects, the following data handling conventions were employed: 
• The planned number of doses used in the compliance and extent of exposure calculations 
will be based on the planned number of doses at their last visit instead of the Day 182 
visit. 
Confidential 
 
Page 64 of 81 


 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
• For the tipping point analysis these subjects will be treated as study completers. No 
imputation will be performed for these subjects. The shorten duration of observation will 
be accounted for in the model with the use of the offset parameter.  
10.3.9 
Handling of HAE Attack Data 
The following rules apply to the handling of HAE attack data for efficacy analyses only. HAE 
attacks starting prior to the run-in period are not processed by these rules. For safety analyses, 
HAE attacks will be analyzed as reported. 
10.3.9.1 
Imputing Missing Start or End Date and Time for HAE Attacks 
In general, missing start time will be imputed as 0:00 and missing end time will be imputed as 
23:59. However, the following rules will be applied for the attacks satisfying the corresponding 
conditions, in order to conservatively classify the attacks as separate, distinct attacks with at least 
24 hours in-between: 
• For HAE attacks with a missing start time and a non-missing start date one calendar day 
after the end date of the previous attack, the start time will be imputed using the end time 
of the previous HAE attack to ensure there are 24 hours in between the two attacks.  
• For HAE attacks with a missing start time and a non-missing end date/time within 24 
hours from the end date/time of the previous attack, the attack should be considered as 
one attack with the previous attack (see Section 10.3.9.2 for details on combining HAE 
attacks)  
• For HAE attacks with missing end time and a non-missing end date one calendar day 
before the start date of the next attack, the end time will be imputed as the start time of 
the next HAE attack to ensure there are 24 hours in between the two attacks.  
• For HAE attacks with a missing end time and non-missing start date/time within 24 hours 
from the start date/time of the next attack, the attack should be considered as one attack 
with the next attack (see Section 10.3.9.2 for details on combining HAE attacks)  
For HAE attacks with a non-missing start date and time and a missing stop date and time: 
• If the event is not indicated as ongoing, the stop date and time will be imputed as start 
date and time + 48 hours or 24 hours before the start date and time of the next attack, 
whichever is earlier. 
• If the event is indicated as ongoing, the stop date and time will be imputed as the earlier 
of the following two date and time: 
 Start date and time + 48 hours or study completion date and the stop time of 
23:59, whichever is later. 
 24 hours before the start date and time of the next attack. 
Confidential 
 
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May 03, 2017 
10.3.9.2 
Unique HAE Attacks 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.   
Specifically, there must be at least 24 hours between the stop date/ time of the first event and the 
start date/time of the next event, for the attacks to be considered distinct. If there is less than 24 
hours between the stop date/time of the first event and the start date/time of the next event, the 
events will be counted as one attack.  
When two or more attacks are combined for efficacy analysis, the parameters of the attacks will 
be conservatively chosen. The start date and time of the combined attack will take the earliest 
start date and time from the individual attacks; and the end date and time of the combined attack 
will take the latest end date and time of the individual attacks. The severity of the combined 
attack will take the highest severity from the individual attacks. The primary location of the 
combined attack will be determined by the primary location of the individual attacks, and by 
following the hierarchy of laryngeal attack, abdominal attack, and peripheral attack. One primary 
location will be taken; and all the other primary location(s) and secondary locations will be 
considered as secondary location for the combined attack. The rescue medications and 
supportive treatment for the combined attack will include all the records from individual attacks. 
Also, the combined attack will be considered as an investigator-confirmed attack if any of the 
individual attack being combined is an investigator-confirmed attack.  
10.3.9.3 
HAE Attack Duration 
The duration of an HAE attack is calculated as stop date/time – start date/time.  
10.3.9.4 
Investigator-confirmed HAE Attacks Requiring Acute Therapy 
Investigator-confirmed HAE attacks requiring acute therapy are those attacks identified as 
‘treated for HAE attack with acute therapy’ on the CRF.  
10.3.9.5 
Moderate and Severe Investigator-confirmed HAE Attacks  
Moderate and severe investigator-confirmed HAE attacks are those attacks that were classified as 
of moderate or severe according to the HARRP defined severity and reported as such on the 
CRF. 
10.3.9.6 
HAE Attack Severity 
The overall severity of the subject’s attack was to be determined by the investigator using the 
following definitions provided as part of HARRP: 
• Mild: Transient or mild discomfort  
• Moderate: Mild to moderate limitation in activity - some assistance needed 
• Severe: Marked limitation in activity, assistance required 
Confidential 
 
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DX-2930-03 Statistical Analysis Plan 
 
 
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The average attack severity will be calculated per subject by attributing a numeric value to each 
severity as follows: 1=Mild, 2=Moderate, and 3=Severe. Higher values will indicate more severe 
attacks, while lower values will indicate less severe attacks. 
10.3.10 
HAE Attack Rate 
10.3.10.1 
Run-in Period HAE Attack Rate 
The run-in period HAE attack rate will be presented as the normalized number of attacks per 
month (4 weeks) and calculated for each subject as number of HAE attacks occurring during the 
run-in period divided by the number of days the subject contributed to the run-in period 
multiplied by 28 days. 
Due to a slightly longer than planned run-in period, four of the randomized subjects had a 
calculated run-in period HAE attack rate that is lower than 1 (0.97). The actual value of the 
calculated run-in period attack rate will be used as the run-in period attack rate for these subjects. 
However, these subjects will be included in the 1-2 attacks/month group in the run-in period 
HAE attack rate group categorization. 
10.3.10.2 
Treatment Period HAE Attack Rate 
The treatment period HAE attack rate will be presented as the normalized number of attacks per 
month and calculated for each subject as the number of HAE attacks occurring during the 
treatment period divided by number of days the subject contributed to the treatment period 
multiplied by 28 days.   
10.3.11 
Time to First HAE Attack 
The time to first HAE attack (days) will be calculated as the earliest of the date of the HAE 
attack after the Day 14, date of study discontinuation or completion, or date of Day 182 visit for 
subjects who do not roll-over into the OLE visit minus the date of Day 14 visit plus 1.   
Subjects with attacks occurring first will be events. Subjects who discontinue/complete the study 
or roll-over into the OLE prior to having a post-Day 14 visit HAE attack will be censored. 
10.3.12 
Details of the Tipping Point Analyses 
Figure 1 illustrates the missing data pattern generated from subjects who discontinue early from 
the treatment period of the DX-2930-03 study.  Subject i receives first dose of the study drug at 
Day 0 and discontinues the study at Day ti prior to the end of the treatment period at Day 182.  
The pre-withdrawal period for Subject i is defined as Day 0 through Day ti and the post-
withdrawal period is defined as Day ti + 1 through Day 182.  In the pre-withdrawal period, we 
know both the length of the period (ni1) and the number of investigator-confirmed HAE attacks 
during the period (yi1), and can calculate the observed attack rate (yi1/ni1) for the period.  In the 
post-withdrawal period, we know only the length of the period (ni2), however, both the number 
of investigator-confirmed HAE attacks during the period (yi2) and the unobserved attack rate 
(yi2/ni2) for the period are unknown. 
Confidential 
 
Page 67 of 81 


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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
Steps 1a – 1c detail the multiple imputation approach to generate complete data for subjects who 
discontinued the study prior to completing the treatment period: 
Step 1a: 1000 independent samples are drawn from the posterior distribution of model 
parameters fit using a Bayesian analysis of the model defined for the primary analysis.  The 
sampled set of values of the model parameters are then used to generate a set of values for 
the expected unobserved attack rate (yi2/ni2) for each subject who discontinued the study prior 
to completing the treatment period using each subjects covariate values.  This will result in 
1000 imputed values for the unobserved attack rate for each discontinued subject. 
Step 1b: The expected unobserved attack rate (yi2/ni2) for each subject who discontinued the 
study prior to completing the treatment period is then multiplied by the length of the post-
withdrawal period (ni2) for that subject to get the expected number of attacks for the post-
withdrawal period (yi2).   
Step 1c: The expected number of attacks for the post-withdrawal period (yi2) is added to the 
observed number of attacks in the pre-withdrawal period (yi1) to get the total number of 
attacks over the entire treatment period (yi1 + yi2) for subjects who discontinued the study 
prior to completing the treatment period.  
Step 2:  Analyze the MI Datasets with Primary Analysis Model 
The primary regression model will be run using each of the 1000 multiply imputed complete data 
sets.  The primary regression model is the Poisson regression generalized linear model with 
covariates for run-in period attack rate, treatment group, and an offset variable for the log 
number of days observed.   
Step 3:  Combine Estimates using Rubin’s Rules 
From each of 1000 runs of the primary analysis model, the estimates will be combined using 
Rubin’s rules (Rubin, 1987) to get one estimate for each of the rate ratios comparing the active 
treatment groups to placebo and corresponding 95% confidence intervals and p-values.  These 
values will be summarized in both a tabular and graphical form. 
Step 4: Pattern Imputation with Delta Adjustment 
Steps 1 through 3 will be repeated with a slight modification at Step 1b to explore the impact of 
progressively worse assumptions (defined by δ) on the unobserved attack rate for subjects who 
discontinue early from the active treatment arms.  In this study, δ represents a rate ratio 
comparing the rate of investigator-confirmed HAE attacks in the treatment group to the rate of 
investigator-confirmed HAE attacks in the placebo. 
Modified Step 1b:  For subjects that discontinue the study prior to completing the treatment 
period from the active treatment arms, the expected unobserved attack rate (yi2/ni2) for each 
discontinued subject is first multiplied by a specific rate ratio δ, then multiplied by the length 
of post-withdrawal period (ni2) for that subject to get the expected number of attacks for the 
post-withdrawal period (yi2).  For subjects that discontinue the study prior to completing the 
treatment period from the placebo arm, Step 1b is followed without modification. 
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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
Steps 1 through 4 are repeated for values of δ that represent progressively worse assumptions on 
the unobserved attack rate for subjects who discontinue the study prior to completing the 
treatment period from the active treatment arms until the tipping point is identified (value of δ 
that yields a non-significant p-value). As the value of δ increases, the overall attack rate imputed 
for subjects in the active treatment arm increases.  Values of δ > 1 will be determined post-hoc in 
order to define reasonable increments for which to increase δ given the magnitude of treatment 
effect and the pattern of missing data.   
Note that the imputed results generated following Steps 1 through 3 without modification 
represent the case when δ=1, corresponding to missing at random (MAR) imputation. The 
estimates generated from the case when δ=1, should be very similar if not exactly the same as the 
estimates generated from the primary analysis model.  
If the value of δ which causes the study results to be reversed is plausible, then the missing data 
assumptions used are questionable.  However, if the value of δ is not plausible, then the missing 
data assumptions are reasonable.  
In the DX-2930-03 study, the protocol specifies that there must be 24 hours in between each 
investigator-confirmed HAE attack.  Therefore, the total number of attacks during the treatment 
period is restricted to about 1 attack per day.  If δ allows for more attacks than 1 per day, then the 
value of δ is not plausible under the study specifications and the missing data assumptions will 
be declared reasonable. 
10.3.13 
Adverse Events  
10.3.13.1 
Treatment-emergent Adverse Events 
Treatment-emergent AEs (TEAEs) are defined as AEs with onset at the time of or following the 
start of treatment with study medication, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.   
10.3.13.2 
Related Adverse Events 
Related AEs are AEs classified as related to study drug by the investigator.   
10.3.13.3 
Severe Adverse Events 
Severe AEs are AEs classified as severe (grade 3) or life threatening (grade 4) by the 
investigator. 
10.3.13.4 
Investigator-reported AESI 
An investigator-reported AESI is an adverse event identified by the investigator on the CRF as 
an adverse event of special interest. 
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May 03, 2017 
10.3.13.5 
SMQ-Defined AESI 
The broad terms from MedDRA 20.0 SMQ will be used to identify an SMQ-defined AESI. 
Table 5 shows the SMQ’s used to identify AESI of hypersensitivity, hypercoagulable, and 
bleeding. 
Table 5 SMQs Used to Identify AESI 
AESI 
SMQ 
Hypersensitivity 
Hypersensitivity 
Hypercoagulable 
Embolic and thrombotic events, arterial 
Embolic and thrombotic events, venous 
Embolic and thrombotic events, vessel type unspecified and 
mixed arterial and venous 
Bleeding 
Haemorrhage laboratory terms 
Haemorrhage terms (excl laboratory terms) 
 
10.3.13.6 
Injection Site Reaction AEs 
Injection site reaction (ISR) AEs will be identified by adverse events with the preferred terms 
starting with ‘Injection site’, ‘Application site’, or ‘Administration site’.  
10.3.13.7 
Duration of Injection Site Reaction AEs 
Duration of ISR AEs is calculated as ‘stop date/time – start date/time’ for the ISR AEs with non-
missing start and stop date/time.  
The missing start or stop date/time for ISR AEs will not be imputed. ISR AEs with missing start 
or stop date/time will be excluded from the summary statistics analysis and reported as number 
missing in the continuous analysis of ISR AE duration. For the categorical analyses on ISR AE 
duration, the following rules will be applied: 
• ISR AE with non-missing start and stop date/time: duration of the AE will be calculated 
as ‘stop date/time – start date/time’ and mapped to a duration category. 
• ISR AE with non-missing start and stop dates and missing time: duration of the AE will 
be calculated as ‘stop date – start date +1’. If the calculated duration is 1 day, then the 
duration category for this AE is ≤ 1 day - unclear. If the calculated duration is greater 
than 1 day, then it will be mapped to a >1 Day category. 
• ISR AE with missing start or stop date: The ISR AE will be excluded from the 
categorical analyses on duration. 
10.3.14 
Non-standard Laboratory Results 
The non-standard laboratory results will be converted to numeric values using the rules shown in 
Table 6. 
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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
Table 6 Convention for Converting Non-Standard Laboratory Results 
Non-Standard Lab Values 
 
Standardized Numeric Values 
<0.1 
Deduct 0.01 from the reference value. i.e., 0.09 
>1.045 
Add 0.001 to the reference value. i.e. 1.046 
10.3.15 
GLM Model Sample SAS Code 
Sample code for the primary efficacy analysis of the primary endpoint. 
PROC GENMOD DATA=eff_data; 
CLASS trtgrp; 
MODEL no_attks = trtgrp bl_rate / DIST=poisson LINK=log OFFSET=logdays PSCALE; 
LSMEANS trt / DIFF CL EXP ILINK; 
ESTIMATE ‘300mg every 2 wk vs pbo’ trtgrp 1 0 0 -1 / EXP; 
ESTIMATE ‘300mg every 4 wk vs pbo’ trtgrp 0 1 0 -1 / EXP; 
ESTIMATE ‘150mg every 4 wk vs pbo’ trtgrp 0 0 1 -1 / EXP; 
RUN; 
Where: 
eff_data = efficacy analysis dataset 
trtgrp = treatment group (categorical) 
no_attks = number of HAE attacks during the analysis period 
bl_rate = normalized pretreatment HAE attack rate (continuous) 
logdays = logarithm of time in days each subject was observed during the analysis period 
 
10.3.16 
GEE Model Sample SAS Code 
Sample code for a sensitivity analysis of the primary endpoint. 
PROC GENMOD DATA=eff_data; 
 
CLASS trtgrp subject; 
   MODEL no_attks = trtgrp bl_rate / DIST=poisson LINK=log; 
 
REPEATED SUBJECT=subject / CORR=IND; 
  LSMEANS trtgrp / DIFF CL EXP ILINK; 
   ESTIMATE ‘300mg every 2 wk vs pbo’ trtgrp 1 0 0 -1 / EXP; 
  ESTIMATE ‘300mg every 4 wk vs pbo’ trtgrp 0 1 0 -1 / EXP; 
 
 
ESTIMATE ‘150mg every 4 wk vs pbo’ trtgrp 0 0 1 -1 / EXP; 
RUN; 
Where: 
eff_data = efficacy analysis dataset 
trtgrp = treatment group (categorical) 
no_attks = number of HAE attacks per week 
bl_rate = normalized pretreatment HAE attack rate (continuous) 
 
Confidential 
 
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May 03, 2017 
10.3.17 
Tipping Point Analysis Sample SAS Code 
Step 1: Use multiple imputation to impute the unobserved rate of attacks by completing the 
following process: 
1a. Sample code that draws 1000 independent samples from the posterior distribution of model 
parameters which are fit using a Bayesian analysis. 
proc genmod data = prim_eff_all order = data; 
   class trtpn; *treatment group; 
   model NUM_ATTKS = trtpn runbase /DIST= poisson LINK = log OFFSET = 
LNUMDAYS ;  
   bayes outpost=bayes_prim thin=1 nmc=1000 nbi=200; 
 run; 
Sample code for the sampled set of values being used to generate values for the unobserved 
attack rate for subjects who discontinued the study prior to completing the treatment period.  The 
values are generated using the model parameter estimates from Step 1a and each subjects 
covariate values.  There should be 1000 imputed values for each discontinued subject.    
The variable miss_treat is an indicator for not completing the treatment period and attk_rate is 
the unobserved attack rate for the post-withdrawal period. 
%macro mi_data; 
%do i = 1 %to 1000; 
*estimate lambda for poisson distribution; 
data prim_eff_all&i; 
   set prim_eff_all; 
    
   *calculate the rate for each sample of coefficients from the model in Step 1a using each 
subjects covariate values; 
   if TRTPN = 1 then lambda = exp(&&INTERCEPT&i + &&RUNBASE&i + 
&&TRTPN1&i); 
   if TRTPN = 2 then lambda = exp(&&INTERCEPT&i + &&RUNBASE&i + 
&&TRTPN2&i); 
   if TRTPN = 3 then lambda = exp(&&INTERCEPT&i + &&RUNBASE&i + 
&&TRTPN3&i); 
   if TRTPN = 4 then lambda = exp(&&INTERCEPT&i + &&RUNBASE&i + 
&&TRTPN4&i); 
*calculate the attack rate; 
 if miss_treat = 1 then attk_rate = RAND('POISSON', lambda); 
run; 
%end; 
%mend mi_data; 
1b. The expected unobserved attack rate (from step 1b) for each subject who discontinued early 
is then multiplied by the length of the post-withdrawal period for that subject to get the expected 
number of attacks for the post-withdrawal period. 
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1c. The expected number of attacks for the post-withdrawal period is added to the observed 
number of attacks in the pre-withdrawal period to get the total number of attacks over the entire 
treatment period. 
Step 2:  The sample code shows the for primary regression model being  run using each of the 
1000 multiply imputed complete data sets.  The imputation variable is the indicator for the which 
imputation dataset is being analyzed and prim_ efficacy is the dataset that includes the 1000 
datasets that have been imputed using step 1. 
proc genmod data = prim_efficacy order = data; 
   by imputation; 
   class trtpn; *treatment group; 
  model num_attks_final = trtpn runbase /DIST= poisson LINK = log PSCALE; *model;  
  lsmeans trtpn/ diff cl exp ilink; 
run; 
Step 3: Combine the results from the multiply imputed datasets using Rubin’s rules (then 
exponentiate the estimate and the 95% confidence interval for the estimate of the rate ratios).  
Below is the code used to combine the results across imputations (note: the estimates and the 
95% CI of the estimates need to be exponentiated). 
proc mianalyze data = Diffs; 
   by trtpn; 
   where _trtpn = 1; 
   modeleffects estimate; 
   stderr stderr; 
run; 
10.3.18 
Sample Code to Derive Relative Risk and Risk Difference 
proc freq data=adae; 
   tables trt*SAE / riskdiff relrisk; 
   exact relrisk riskdiff; 
run; 
10.3.19 
Sample Code on Time-to-Event Analyses 
proc lifetest data = time_attk; 
   time attk14*cnsr(0); 
   strata trt01p/ diff = control('Placebo')  test = (logrank); 
run; 
 
where attk14 is the time to the first attack after day 14  
cnsor is the indicator for being an event 
Confidential 
 
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May 03, 2017 
10.3.20 
Clinical Significance Attributions for Laboratory Results 
The EDC system design permitted attribution of clinical significance for all laboratory values, 
not just those that are outside of the reference range. Therefore, many data points have an 
attribution of clinical significance when none is expected.  
The laboratory results will be programmatically classified for analysis due to the database 
limitation using the following algorithm: 
1. Lab results within the reference range will be classified as Normal. 
2. Lab results outside of the reference range will be classified as a) CS Low, b) NCS Low, 
c) NCS High, or d) CS High using a combination of the CS/NCS classification by the 
investigator and the Low/High classification based on the central lab reference range. 
10.3.21 
Angioedema Quality of Life 
Below are instructions for how to calculate AE-QoL domain scores and total score. 
AE-QoL is meant to be evaluated by determining its four individual domain scores (profile 
instrument), but it may also be used to determine a total score (index instrument). 
Each item answered by the subject scores between 0 and 4 points depending on the answer 
option chosen by the subject. The first answer option gets 0 points, the second option 1 point, the 
third option 2 points, etc. The AE-QoL domain scores and total score are calculated by using the 
following formula: 
(Sum of all completed items)  / (maximum sum of all possible items)*100  
 
Computation of AE-QoL Total Score 
Example 1: All items were completed (maximum possible sum: 68 points)  
Sum of all 17 completed items: 41 points. 
Total score = 100*(41/68) = 60 (out of a possible 100 points) 
 
Example 2: 2 items were not completed (maximum possible sum: 60 points).  
Sum of all 15 completed items: 41 points. 
Total score = 100*(41/60) = 68 (out of a possible 100 points) 
 
Computation of Domain Scores (Example: Fears/Shame) 
Example: Sum of all 6 completed items: 14 points  
Maximum possible sum: 24 points 
Domain Score = 100*(14/24) = 58 (out of a possible 100 points) 
 
Remarks 
Since only answered items are included in the computation (and the calculated domain and total 
scores are not raw scores but linear transformations to a 0-to-100 scale), the calculated scores are 
not or only little influenced by missing items. 
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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
An AE-QoL domain score should not be calculated if more than one item is left unanswered in 
that domain. The AE-QoL total score should not be calculated if more than 25% of items (>4 
items) are left unanswered. 
The minimal and highest possible domain and total scores are 0 and 100, respectively. 
 
Confidential 
 
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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
10.4 
Treatment Period Dosing Schedule 
Treatment Period 
Treatment Arms: DX-2930 or Placebo 
Dose 
Number 
Dose Day/ Week/Visit 
300 mg 
every 2 weeks 
300 mg 
every 4 weeks 
150 mg 
every 4 weeks 
Placebo 
1 
Day 0/ Week 0/Visit 1 
DX-2930 
DX-2930 
DX-2930 
Placebo 
2 
Day 14/ Week 2/Visit 2 
DX-2930 
Placebo 
Placebo 
Placebo 
3 
Day 28/ Week 4/Visit 3 
DX-2930 
DX-2930 
DX-2930 
Placebo 
4 
Day 42/ Week 6/Visit 4 
DX-2930 
Placebo 
Placebo 
Placebo 
5 
Day 56/ Week 8/Visit 5 
DX-2930 
DX-2930 
DX-2930 
Placebo 
6 
Day 70/ Week 10/Visit 6 
DX-2930 
Placebo 
Placebo 
Placebo 
7 
Day 84/ Week 12/Visit 7 
DX-2930 
DX-2930 
DX-2930 
Placebo 
8 
Day 98/ Week 14/Visit 8 
DX-2930 
Placebo 
Placebo 
Placebo 
9 
Day 112/ Week 16/Visit 9 
DX-2930 
DX-2930 
DX-2930 
Placebo 
10 
Day 126/ Week 18/Visit 10 
DX-2930 
Placebo 
Placebo 
Placebo 
11 
Day 140/ Week 20/Visit 11 
DX-2930 
DX-2930 
DX-2930 
Placebo 
12 
Day 154/ Week 22/Visit 12 
DX-2930 
Placebo 
Placebo 
Placebo 
13 
Day 168/ Week 24/Visit 13 
DX-2930 
DX-2930 
DX-2930 
Placebo 
-- 
Day 182/ Week 26/Visit 14 
No Dose 
No Dose 
No Dose 
No Dose 
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DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
10.5 
Study Activity Schedule 
 
Study Activities Schedule 
 
Screening 
Visit 
Run-in 
Period 1 
Treatment Period2  
Follow-up 
Period3 
Tests and 
Assessments 
 
 
Visit 1 
Dose 1 
Day 0 
Site 
Check-
in4 
Visit 2 
Dose 2 
Day 14 
Visit 3 
Dose 3 
Day 28 
Visit 4 
Dose 4 
Day 42 
Visit 5 
Dose 5 
Day 56 
Visits 6 and 7  
Doses 6 and 7 
Days 70 and 
84 
Visit 8 
Dose 8 
Day 98 
Visits 9 and 10  
Doses 9 and 10 
Days 112 and 
126 
Visit 11 
Dose 11 
Day 140 
Day 
144±1 
Visits 12 and 13  
Doses 12 and 13 
Days 154 and 
168 
Visit 
14 
 Day 
182 
 
Visit 
15 
Day 
210 
Visit 
16 
Day 
238 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Long-term 
Prophylactic 
Therapy 
Washout5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded IMP 
Treatment 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Demographic and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C1-INH, C1q and 
C4 Testing6  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test7 
(females)  
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
 
X 
Vital Signs8 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Physical 
Examination9 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
12-Lead ECG10 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Clinical 
Laboratory 
Testing11 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Serologies: 
HBsAg, HCV, and 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Confidential 
 
Page 78 of 81 


 
 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
Study Activities Schedule 
 
Screening 
Visit 
Run-in 
Period 1 
Treatment Period2  
Follow-up 
Period3 
Tests and 
Assessments 
 
 
Visit 1 
Dose 1 
Day 0 
Site 
Check-
in4 
Visit 2 
Dose 2 
Day 14 
Visit 3 
Dose 3 
Day 28 
Visit 4 
Dose 4 
Day 42 
Visit 5 
Dose 5 
Day 56 
Visits 6 and 7  
Doses 6 and 7 
Days 70 and 
84 
Visit 8 
Dose 8 
Day 98 
Visits 9 and 10  
Doses 9 and 10 
Days 112 and 
126 
Visit 11 
Dose 11 
Day 140 
Day 
144±1 
Visits 12 and 13  
Doses 12 and 13 
Days 154 and 
168 
Visit 
14 
 Day 
182 
 
Visit 
15 
Day 
210 
Visit 
16 
Day 
238 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
HAE Attack 
Data12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Quality of Life 
Assessments13 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
 
X 
PK Blood 
Sampling 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
PD Sample 
Collection 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Plasma Anti-Drug 
Antibody Testing 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Discharge from 
Study14,15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
BP = blood Pressure; C1-INH = C1 Inhibitor; Cmax = Maximum plasma drug concentration; ECG = Electrocardiogram; HAE = hereditary Angioedema; HbsAg = 
Hepatitis B Surface Antigen; HCV = Hepatitis C Virus; HIV = Human Immunodeficiency virus; HR = Heart Rate; IMP = Investigational Medicinal Product; 
LTP = Long-term Prophylactic; OLe = Open-label Extension; PD = Pharmacodynamic; PK = Pharmacokinetic; RR = Resting Rate 
1. 
Subjects will undergo a run-in period to determine their baseline HAE attack rate. Only subjects with a baseline rate of at least 1 Investigator-confirmed 
HAE attack per 4 weeks will be eligible for enrollment and randomization. Subjects who experience 3 or more Investigator-confirmed attacks before the 
end of the 4 weeks can exit the run-in period early and proceed to enrollment and randomization. Subjects without at least 1 Investigator-confirmed attack 
after 4 weeks of run-in will have their run-in period extended for another 4 weeks, during which time they need to have at least 2 Investigator-confirmed 
attacks to proceed to enrollment and randomization. To be eligible for enrollment, subjects who have their run-in extended must complete the full 8-week 
run-in period prior to entering the treatment period. Subjects who do not meet the minimum attack rate during run-in or are otherwise determined to be 
ineligible due to screening assessments will be considered a screen fail. 
2. 
Treatment Period visits have a ±3 day window, with a maximum of 17 days or a minimum of 11 days between any two doses, starting with Dose 2, Day 14 
through Day 182. 
3. 
For subjects who do not rollover into OLE (DX-2930-04). Follow-up visits have a ±3 day window. 
4. 
Site personnel contact the subject to solicit for any attacks not already reported by the subject once between scheduled site visits or approximately 7 days 
after last contact with subject. 
5. 
Subjects who are on long-term prophylactic (LTP) therapy for HAE are required to undergo a minimum 2 week washout period prior to the start of the run-
in period. This LTP washout is permitted as long as the Investigator determines that doing so would not place the subject at any undue safety risk and the 
subject is at least 18 years of age. The Investigator must confirm that the subject has successfully completed the 2 week washout period before they can 
Confidential 
 
Page 79 of 81 


 
 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
Study Activities Schedule 
 
Screening 
Visit 
Run-in 
Period 1 
Treatment Period2  
Follow-up 
Period3 
Tests and 
Assessments 
 
 
Visit 1 
Dose 1 
Day 0 
Site 
Check-
in4 
Visit 2 
Dose 2 
Day 14 
Visit 3 
Dose 3 
Day 28 
Visit 4 
Dose 4 
Day 42 
Visit 5 
Dose 5 
Day 56 
Visits 6 and 7  
Doses 6 and 7 
Days 70 and 
84 
Visit 8 
Dose 8 
Day 98 
Visits 9 and 10  
Doses 9 and 10 
Days 112 and 
126 
Visit 11 
Dose 11 
Day 140 
Day 
144±1 
Visits 12 and 13  
Doses 12 and 13 
Days 154 and 
168 
Visit 
14 
 Day 
182 
 
Visit 
15 
Day 
210 
Visit 
16 
Day 
238 
enter the run-in period. 
6. 
Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment.  
7. 
The pregnancy test will only be conducted in females of childbearing potential. Tests performed on Day 0 and Day 182 must be urine-based. Tests 
performed at screening, Days 28, 56, 98, 126, 154, and Day 238 can be serum- or urine-based. 
8. 
There is a ±15 minute window for all vital signs. At study visits in which IMP is administered, vital signs including sitting or supine BP, HR, body 
temperature, and RR, will be obtained prior to dosing, 1 hour after dosing, and 2 hours after dosing for the first 4 doses with the ability to eliminate the 2 
hour vitals for the remaining doses based on the discretion of the Investigator and the absence of safety signals. 
9. 
Height and weight will be collected at the Screening visit only. 
10. ECGs (single recordings) are collected at screening, baseline prior to Dose 1, Day 56, Day 144±1 day to capture the estimated Cmax and Day 182. The ECG 
assessment at Cmax on Day 144±1 day may be performed via at-home nurse or technician in lieu of a subject visit to the study site. 
11. Clinical laboratory testing will include Hematology, Coagulation, Serum Chemistry, and Urinalysis.  
12. Historical attack information will be collected at screening. During the study subjects (or caregivers, in the event the subject is < 18 years old or is 
incapacitated) are instructed to report details of the attack to the study site within 72 hours of the onset of the attack. Site personnel will also contact the 
subject once a week or at approximately 7 days after last contact with the subject during the run-in period and once between study visits or approximately 7 
days after last contact with the subject during the treatment period in order to solicit for any attack that may have occurred. In addition, during study visits, 
site personnel will solicit for any new HAE attack information that was not given through prior subject contact with the site. 
13. Quality of life data will be obtained using the EuroQoL Group 5-Dimension (EQ5D) Self-Report Questionnaire at pre-dose on Days 0, 98±3, and 182±3 
and using the Angioedema Quality of Life Questionnaire (AE-QoL) at pre-dose on Days 0, 28±3, 56±3, 98±3, 126±3, 154±3, and 182±3. An additional 
quality of life assessment (EQ5D and AE-QoL) will be conducted on Day 238±3 for subjects not entering OLE.  
14. Subjects who rollover into the Open-Label Extension protocol (DX-2930-04) will provide consent by Day 182 and receive their first open-label dose 
following the completion of all DX-2930-03 assessments scheduled on Day 182. At the completion of these assessments, the subject will be discharged 
from DX-2930-03 and roll into the DX-2930-04 study.  
15. Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures as Day 182 at their final study visit. 
 
 
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Page 80 of 81 


 
 
 
DX-2930-03 Statistical Analysis Plan 
 
 
May 03, 2017 
11. REFERENCES 
Keene, O. R. (2014). Missing Data Sensitivity Analysis for Recurrent Event Data Using 
Controlled Imputation. Pharmaceutical Statistics, 13, 258-264. 
Ratich, B. O. (2013). Missing Data in Clinical Trials: From Clinical Assumptions to Statistical 
Analysis Using Pattern Mixture Models. Pharmaceutical Statistics, 12, 337-347. 
Rubin, D. B. (1976). Inference and Missing Data. Biometrika, 63, 581–592. 
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons. 
Santner, T. S. (1980). Small-sample confidence intervals for p1 − p2 and p1/p2 in 2 × 2 
contingency tables. . J. Amer. Statist. Assoc., 75, 386–394. 
 
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