Clinical trial NCT03921541
Conditions: Arginase I Deficiency Hyperargininemia
Keywords: ARG1-D
Sponsor: Aeglea Biotherapeutics
Start date: 2019-04-10; Completion date: 2023-01-27
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
CAEB1102-300A is a multi-center randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of pegzilarginase in patients with ARG1-D. This study will consist of a screening period; a randomized, double-blind treatment period; a long-term extension; and a follow up visit for final safety assessments.

Detailed description:
CAEB1102-300A is a multi-center randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of pegzilarginase in patients with ARG1-D. This study will consist of a screening period; a randomized, double-blind treatment period; a long-term extension; and a follow up visit for final safety assessments.

Subjects will be randomized to treatment following completion of all screening assessments and confirmation of study eligibility in a 2:1 ratio to receive weekly IV infusions of pegzilarginase plus individualized disease management (IDM) or placebo plus IDM during the 24-week double blind treatment period. After completion of the 24-week double-blind treatment period, each subject will enter the long term, open-label extension, the first 8 weeks of which are blinded. During the long-term extension, all subjects receive pegzilarginase plus IDM. After 8 weeks of the LTE study, patients have the option to receive treatment by subcutaneous administration (SC).

Arms: arm 1: Weekly IV infusions of pegzilarginase plus individualized disease management for 24 weeks arm 2: Weekly IV infusions of placebo plus individualized disease management for 24 weeks arm 3: After completion of 24 weeks DB treatment, weekly IV infusions of pegzilarginase plus individualized disease management for an additional 150 weeks, with the option to receive treatment by SC after 8 weeks of the LTE study.
Interventions: intervention 1: Pegzilarginase intervention 2: Placebo
Intervention descriptions: intervention 1: Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated intervention 2: Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated

Protocol documents:
Prot_000.pdf: 
205
NCT03921541


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
TITLE PAGE
PEACE (Pegzilarginase Effect on Arginase 1 Deficiency Clinical 
Endpoints): A Randomized, Double-Blind, Placebo-Controlled 
Phase 3 Study of the Efficacy and Safety of Pegzilarginase in 
Children and Adults with Arginase 1 Deficiency
Protocol Number: 
CAEB1102-300A 
Protocol Version: 
6.0 
Protocol Date: 
11DEC2020 
SAP Version: 
3.0
SAP Date:  
11 NOV2021 
1
NCT03921541


APPROVAL SIGNATURE PAGE
Protocol Title:
Protocol Number:
SAP Date / Version:
Author:
Sponsor Approval 
2


TABLE OF CONTENTS
 
 
 
 
 
 
3


 
 
 
 
 
 
 
 
4


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5


 
 
 
 
 
 
 
 
 
6


 
 
 
 
LIST OF TABLES
 
 
 
 
 
 
 
 
LIST OF FIGURES
 
 
7


1.
REVISION HISTORY 
8


2.
LIST OF ABBREVIATIONS
Abbreviation
Definition
9


Abbreviation
Definition
10


Abbreviation
Definition
11


3.
INTRODUCTION
12


4.
STUDY OBJECTIVES AND ENDPOINTS
4.1.
Primary
4.2.
Key Secondary
4.3.
Other Secondary
o
o
o
13


o
o
o
o
4.4.
Tertiary
14


15


5.
STUDY DESIGN AND PROCEDURES
5.1.
General Study Design
Figure 1: 
Study Design/Schema
16


5.2.
Schedule of Assessments
17


6.
STUDY TREATMENTS
6.1.
Method of Assigning Subjects to Treatment Groups
6.2.
Blinding and Unblinding
18


7.
SAMPLE SIZE AND POWER CONSIDERATIONS
Table 1: 
Power Calculations for Varying Estimates of True Treatment Difference
True Effects on Arginine at 24 Weeks
Power at 
1-S
Pegzilarginase
Placebo
Difference
19


Table 2: 
Key Secondary Endpoints Mean and Variance Assumptions Used in Power 
Simulations
Class I GMFCS
Class II and III GMFCS
Table 3: 
Key Secondary Endpoints Correlation Assumptions Used in Power 
Simulations
2MWT Baseline
2MWT Week 24
GMFM-E Baseline
GMFM-E Week 24
20


8.
DATA PREPARATION
8.1.
Input Data
8.2.
Output Data
21


9.
ANALYSIS PERIODS AND POPULATIONS
9.1.
Analysis Periods
9.1.1.
Placebo-Controlled DB Period – Baseline to Week 24 
Analysis:
Efficacy and Safety
9.1.2.
LTE Period – LTE01 subgroup to LTE150 (End of Study)
Analysis:  
Efficacy data
Safety data
22


9.2.
Analysis Populations
9.2.1.
Consented Set
9.2.2.
Randomized Set
9.2.3.
Full Analysis Set
9.2.4.
Per-Protocol Set
 
23


9.2.5.
Pharmacokinetic Set
24


10.
GENERAL STATISTICAL CONSIDERATIONS
10.1.
Missing or Inconclusive Data Handling
25


10.2.
Handling of Assessments from Re-Starting Study Due to COVID-19 
Pause
Table 4: 
Main Criteria for Repeating Assessments
Type of Assessment
Criteria
Action
10.3.
Safety Data
10.4.
Definition of Baseline
26


10.4.1.
Baseline Handling for Study Pauses and Re-Starts Due to COVID-19  
10.4.1.1.
Definition of Baseline for Subjects Who Paused During Screening
10.4.1.2.
Definition of Baseline for Subjects Who Paused During the Placebo-Controlled 
DB Period (Week 1-Week 24) 
10.4.1.3.
Definition of Baseline for Subjects Who Paused During the LTE Period 
10.4.2.
Baseline for Plasma Arginine, Ornithine, and GCs
27


10.4.3.
Analysis Visit Windows for LTE Period 
10.5.
Data Analysis Conventions
28


10.6.
Subgroup Analyses
10.7.
Adjustments for Multiplicity and Global Control of Type 1 Error
Table 5: 
Methods Used for Global Control of Type 1 Error 
Type of 
Analysis
Analysis 
Set
Endpoint
Type 1 Error Control/Multiplicity Adjustment
29


Type of 
Analysis
Analysis 
Set
Endpoint
Type 1 Error Control/Multiplicity Adjustment
10.8.
Timepoints
10.8.1.
Scheduled Visits
30


10.8.2.
Discontinuation Visit
10.8.3.
End of Specific Analysis Period Visit
31


11.
DISPOSITION OF SUBJECTS
32


12.
DEMOGRAPHIC AND PRETREATMENT VARIABLES
12.1.
Demographic Variables
12.2.
Baseline Disease Characteristics
33


34


13.
MEDICAL HISTORY AND CONCOMITANT MEDICATIONS
13.1.
Medical History
13.2.
Prior and Concomitant Medications
35


14.
DOSING COMPLIANCE AND TREATMENT EXPOSURE
14.1.
Dosing Compliance for the Placebo-Controlled DB Period
14.2.
Dosing Exposure for the Placebo-Controlled DB Period
36


Figure 2: 
Exposure Calculations 
14.3.
Dosing Compliance for the LTE Period
14.4.
Dosing Exposure for the LTE Period
37


15.
PROTOCOL DEVIATIONS
38


16.
DERIVATION OF EFFICACY MEASURES 
16.1.
Plasma Arginine Concentrations
16.2.
2-Minute Walk Test
16.3.
Gross Motor Function Measures
16.3.1.
Gross Motor Function Measure E
39


16.3.2.
Gross Motor Function Measure D 
16.4.
Functional Mobility Assessment
16.4.1.
Functional Mobility Scale
16.4.2.
Gillette Functional Assessment Questionnaire
16.5.
Vineland Adaptive Behavior Scales-II
40


16.6.
Composite Clinical Outcome: 2MWT, GMFM Part D, and 
GMFM Part E
Table 6: 
Clinical Response Definitions
Assessment
Definition of Component Improvement at 
Week 24 (Change from Baseline)
Definition of Component Worsening at 
Week 24 (Change from Baseline)
41


16.7.
Modified Ashworth Scale
Table 7: 
Modified Ashworth Scale Definitions
Score
Modified Ashworth Scale
16.8.
Assessments of Caregiver and Clinician Global Impressions 
16.8.1.
Caregiver and Clinician Global Impressions of Change 
16.8.2.
Caregiver and Clinician Global Impressions of Severity
42


16.9.
9-Hole Pegboard Test
16.10.
Quality-of-Life Assessments
16.10.1.
Pediatric Quality of Life
43


16.10.2.
36-Item Short Form Health Survey
16.10.3.
Zarit Burden Interview-12 
16.10.4.
Neurocognitive Assessments
44


Scoring
The total raw scores
Scaled scores
Composite scores
45


16.11.
Diet Management Plan and 3-Day Diary Diet Record
16.12.
Growth Assessments
-
16.13.
Electroencephalogram
46


16.14.
Psychometric (Clinical Outcomes Assessment) Analyses
47


17.
PRIMARY AND SECONDARY ANALYSES
17.1.
Primary Analysis and Sensitivity Analyses of the Primary Endpoint
48


17.2.
Key Secondary Analyses and Sensitivity Analyses of the Key 
Secondary Endpoints
49


17.3.
Other Secondary Analyses
17.3.1.
Compare Treatment Groups Whose Endpoint Arginine Value Falls Below 
200 µM
50


17.3.2.
Compare Treatment Groups Whose Endpoint Arginine Value Falls Within 40 to 
115 µM
17.3.3.
Compare Pegzilarginase With Placebo for Changes in GCs and Ornithine
17.3.4.
Compare Pegzilarginase With Placebo With Respect to Other Aspects of 
Mobility
17.3.5.
Compare Pegzilarginase With Placebo With Respect to Adaptive Behavior 
51


17.3.6.
Evaluate the Safety and Immunogenicity of Pegzilarginase 
17.3.7.
Characterize the Pharmacokinetic Profile of Pegzilarginase 
52


18.
TERTIARY ANALYSES
18.1.
Compare the Response on Pegzilarginase With Placebo With Respect 
to Mobility Assessments (2MWT, GMFM-E, and GMFM-D)
18.2.
Compare the Response on Pegzilarginase With Placebo With Respect 
to the FMS 5, FMS 50, FMS 500, and GFAQ
18.3.
Compare the Response on Pegzilarginase With Placebo With Respect 
to the VABS-II Overall Composite and Individual Domains
53


18.4.
Compare Pegzilarginase With Placebo With Respect to 
Improvement of Spasticity and Objective Measures of 
Neurological/Neuromotor Manifestations
 
18.5.
Describe the Impact of Global Impression of Change/Severity on 
Motor Function and Adaptive Behavior
54


18.6.
Describe the Impact of Pegzilarginase on Fine Motor Behavior
-
18.7.
Describe the Impact of Pegzilarginase on QoL 
55


18.8.
Describe the Impact of Pegzilarginase on Neurocognition 
56


18.9.
Describe the Diets Maintained by Subjects 
18.10.
Describe the Effect of Pegzilarginase Associated With Plasma 
Ammonia Levels
18.11.
Evaluate the Effects of Pegzilarginase on Growth in Pediatric 
Subjects
18.12.
Electroencephalogram 
57


18.13.
Psychometric (Clinical Outcome Assessment) Analyses
18.14.
Characterize the Long-Term Treatment Effects of Pegzilarginase 
Administration Once Weekly
18.15.
Patient Profiles
58


19.
SAFETY ANALYSES
59


19.1.
Adverse Events
Mild 
Moderate 
Severe 
60


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19.1.1.
Adverse Events of Special Interest
Hypersensitivity reactions, injection site reactions (ISRs), and hyperammonemic episodes
Hypersensitivity reactions:
ISRs:
Hyperammonemia episodes: 
62


 
19.2.
Physical and Neurological Examinations
19.3.
Vital Signs
19.4.
Electrocardiogram 
19.5.
Clinical Laboratory Data
63


19.5.1.
Ammonia Increases
19.5.2.
Liver Function Test Abnormalities
64


Table 8: 
Liver Function Test Abnormality Categories 
ALT, AST or either ALT or AST
Total Bilirubin 
Combined LFTs
ALT or AST >3
ULN, total bilirubin >2 
ULN and no ALP >2 
ULN*
65


20.
PHARMACOKINETIC, PHARMACODYNAMIC, AND 
IMMUNOGENICITY ANALYSES
66


21.
INTERIM ANALYSES
21.1.
Safety Review Committee
67


22.
CHANGES TO THE ANALYSIS PLAN
22.1.
Changes to Protocol-Stated Analyses
22.2.
Changes to the Statistical Analysis Plan
22.2.1.
Version 2.0 
Whole Document
Description of change:
Rationale for change:
Whole document
Description of change:
Rationale for change:
3. Composite Clinical Outcome: 2MWT, GMFM Part D, and GMFM Part E
Description of change:
68


Rationale for change:
4. Section 19.1 
Description of change:
Rationale for change:
5. Section 19.5.2 
Description of change:
Rationale for change:
22.2.2.
Version 2.0 
Section 7, Sample Size and Power Considerations
Description of change:
Rationale for change:
Section 9, Analysis Periods and Populations; Section 10.8, Timepoints; Section 21, 
Interim Analyses
Description of change:
Rationale for change:
Section 11, Disposition of Subjects; Section 12, Demographic and Pretreatment 
Variables; Section 13.2, Prior and Concomitant Medications; Section 14, Dosing 
Compliance and Treatment Exposure
Description of change:
69


Rationale for change:
Section 15, Protocol Deviations 
Description of change:
Rationale for change:
Section 16, Derivation of Efficacy Measures; Section 17, Efficacy Analyses;
Section 18, Tertiary Analyses; Section 19, Safety Analyses 
Description of change:
Rationale for change:
Section 22, Changes to the Analysis Plan 
Description of change:
Rationale for change:
Incorporation of administrative changes.
22.2.3.
Version 1.0 
70


23.
REFERENCES
71