STATISTICAL ANALYSIS PLAN

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
   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
    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

1. LIST OF ABBREVIATIONS

2. INTRODUCTION

2.1 Purpose of the Statistical Analysis Plan

2.2 Background

2.3 Study Rationale

3. STUDY OBJECTIVES

3.1 Primary Objectives

3.2 Secondary Objectives

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)

4. STUDY DESIGN

4.1 General Description

Long-Term Prophylactic (LTP) Therapy Washout:

Run-In Period:

Treatment Period:

Open-Label Extension (OLE) Study:

Follow-up Period:

4.2 Discussion of Study Design, Including the Choice of Control Group

• Primary endpoint selection: The objective of this study is to evaluate the efficacy of DX2930 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.
• 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 attacks per 4 weeks, 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

4.4 Blinding

4.5 Sample Size Determination

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

5.3 Other Endpoints

6. EFFICACY AND SAFETY VARIABLES

6.1 Study Activities Schedule

6.2 Efficacy Assessments

• 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

• 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.

6.3 Safety Assessments

6.3.1 Adverse Events

• 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

6.3.1.1 Adverse Events of Special Interest

Hypersensitivity Reactions

Events of Disordered Coagulation

Bleeding AESI

Hypercoagulable AESI

6.3.2 Vital Signs

6.3.3 Physical Examination

6.3.4 Electrocardiogram (ECG)

6.3.5 Clinical Laboratories

6.3.5.1 Hematology

• Hemoglobin
• Hematocrit
• Red blood cell (RBC) count
• White blood cell (WBC) count with differential
• 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
• Nitrite
• pH
• Protein
• Specific gravity
• Microscopy (if indicated by macroscopic findings)

6.3.6 Concomitant Therapies

6.4 Other Assessments

6.4.1 Pharmacokinetic Assessment

6.4.2 Pharmacodynamic Assessment

6.4.3 Plasma Anti-Drug Antibody Testing

6.4.4 Quality of Life Assessments

AE-QoL

7. STATISTICAL ANALYSIS

7.1 General Methodology

7.2 Analysis Populations

7.2.1 Intent-to-treat (ITT) Population

7.2.2 Safety Population

7.3 Subject Disposition

7.4 Protocol Deviations

7.5 Demographic and Other Baseline Characteristics

7.6 Medical History

7.7 Treatment Compliance and Extent of Exposure

7.8 Analysis of Efficacy

7.8.1 Primary Efficacy Analysis

7.8.2 Secondary Efficacy Analyses

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.

7.8.3 Exploratory Efficacy Analyses

• 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.
• 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

Time to first HAE attack after Day 14

Number of high-morbidity investigator-confirmed HAE attacks

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

Achievement of reduction from pretreatment in the investigator-confirmed HAE attack rate (i.e., responder analysis)

Characteristics of investigator-confirmed HAE attacks, including attack duration, severity, location and mediation use

Percentage of HAE attack free days

7.9 Analysis of Safety

7.9.1 Adverse Events

• 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).
• 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).

7.9.2 Clinical Laboratory Evaluation

7.9.3 Vital Signs

7.9.4 Electrocardiography

7.9.5 Physical Examinations

7.9.6 Prior and Concomitant Medications

7.10 Other Analyses

7.10.1 Analysis of Pharmacokinetic Data

7.10.2 Analysis of Pharmacodynamic Data

7.10.3 Analysis of Immunogenicity Data

7.10.4 Analysis of Quality of Life Data

8. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES

8.1 Changes in the Conduct of the Study

8.2 Change from the Analyses Planned in the Protocol

8.2.1 Efficacy Evaluation Period

8.2.2 ITT and Safety Population Definitions

8.2.3 Adverse Events

8.2.4 Laboratory Parameters

8.2.5 Vital Sign Parameters

9. STATISTICAL/ANALYTIC ISSUES

9.1 Adjustment for covariates

9.2 Handling of Dropouts or Missing Data

9.3 Interim Analysis and Data Monitoring

9.4 Multicenter Studies

9.5 Multiple Comparisons/Multiplicity

9.6 Examination of Subgroups

• Age Group ( , 18 to , 40 to years)
• Sex (Male, Female)
• Race Group (White, Other)
• Weight Group ( to to )
• BMI Group ( , 18.5 to , 25 to )
• Run-in Period HAE Attack Rate (1 to to attacks/month)
• Pretreatment Period HAE Attack Rate ( 1 to to 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)

9.7 Sensitivity Analyses

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.

10. APPENDICIES

10.1 Appendix I List of Statistical Outputs

10.1.1 List of Planned Tables

10.1.3 List of Planned Listings

10.2 Definitions and Programming Conventions

10.2.1 Age

10.2.2 BMI

10.2.3 Study Day

10.2.4 Durations of Events

10.2.5 Baseline

10.2.6 Analysis Periods

10.2.6.1 Pretreatment Period

10.2.6.2 Run-in Period

10.2.6.3 Treatment Period

10.2.6.4 Follow-up Period

10.2.7 HAE Attack Characteristics

10.2.7.1 HAE Attack Duration

10.2.7.2 HAE Attack Severity

• Mild: Transient or mild discomfort
• Moderate: Mild to moderate limitation in activity - some assistance needed
• Severe: Marked limitation in activity, assistance required

10.2.8 Unique HAE Attacks

10.2.9 HAE Attack Rate

10.2.9.1 Pretreatment HAE Attack Rate

10.2.9.2 Run-in Period HAE Attack Rate

10.2.9.3 Treatment Period HAE Attack Rate

10.2.10 Time to First HAE Attack

10.2.11 Adverse Events

10.2.11.1 Treatment-emergent Adverse Events

10.2.11.2 Related Adverse Events

10.2.11.3 Severe Adverse Events

10.2.12 GLM Model Sample SAS Code

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 ' }300\textrm{mg every 2 wk vs pbo' trtgrp 1 0 0-1 / EXP;
    ESTIMATE ' }300\textrm{mg every 4 wk vs pbo' trtgrp 0 1 0-1 / EXP;
    ESTIMATE ' }150\textrm{mg 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

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 ' }300\textrm{mg 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

Computation of AE-QoL Total Score

References

10.3 Treatment Period Dosing Schedule

10.4 Study Activity Schedule

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 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 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 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 day to capture the estimated and Day 182. The ECG assessment at on Day 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 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 , and and using the Angioedema-Quality of Life (AE-QoL) Questionnaire at pre-dose on Days , and . An additional quality of life assessment (EQ5D and AE-QoL) will be conducted on Day 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.