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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2018-004837-34
    Trial protocol
    		 AT   DE   FR   GB   IT  
    Global end of trial date
    01 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Nov 2025
    First version publication date
    06 Nov 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CAEB1102-300A
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03921541
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aeglea BioTherapeutics, Inc.
    Sponsor organisation address
    221 Crescent Street, Waltham, Massachusetts, United States, 02453
    Public contact
    Global Integrated Evidence Generation, Immedica Pharma AB, +46 8 533 39 50, clinical@immedica.com
    Scientific contact
    Global Integrated Evidence Generation, Immedica Pharma AB, +46 8 533 39 50, clinical@immedica.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Feb 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of pegzilarginase relative to placebo based on a statistically significant decrease in plasma arginine concentrations
    Protection of trial subjects
    This trial was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the United States Food and Drug Administration regulations, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E6 guidelines for Good Clinical Practice, and the applicable regulatory requirements. Furthermore, the trial adhered to the European Union Clinical Trials Directive 2001/20/EC, as well as all relevant local and national laws and regulations governing the conduct of human clinical trials were followed. I was also performed in accordance with the United Kingdom Medicines for Human Use (Clinical Trials) Regulations 2004 and Canada Drug-Part C, Division 5 of the Food and Drugs Act and Regulation. The trial was conducted by investigators experienced in the treatment of patients (children and adults) with arginase 1 deficiency (ARG1-D). A Safety Review Committee (SRC) periodically provided independent review of the safety data during the trial.
    Background therapy
    		 The previously prescribed individualized disease management (IDM) was continued throughout the trial.
    Evidence for comparator
    		 A placebo-controlled study design was employed to demonstrate the efficacy of pegzilarginase in subjects with ARG1-D in the double-blind (DB) period. It is well recognized that improvements in disease parameters can occur in subjects not receiving active treatment due to changes in behavior and other factors resulting from participation in a clinical trial.
    Actual start date of recruitment
    01 May 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    Canada: 1
    Worldwide total number of subjects
    32
    EEA total number of subjects
    12
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    18
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 44 subjects were screened. 12 subjects were screening failures. 32 subjects were randomized, 21 to receive pegzilarginase and 11 to receive placebo.

    Pre-assignment
    Screening details
    		 Patients who met all inclusion criteria and none of the exclusion criteria were eligible to participate in the trial.

    Period 1
    Period 1 title
    Placebo-controlled 24-week DB period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Laboratory results of parameters who had the potential to unblind the investigator to subjects’ treatment groups were not provided to the investigator or other blinded individuals, including subjects, families, sponsor personnel, or assessors, until all subjects had completed the 24-week DB period and formal unblinding had occurred. Dose modifications were implemented by an unblinded pharmacist and/or physician.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pegzilarginase
    Arm description
    		 Pegzilarginase, administered once weekly for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegzilarginase
    Investigational medicinal product code
    Other name
    AEB1102, Co-ARG1-PEG
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The initial dose was 0.10 mg/kg. Dose adjustments were permitted based on the subject's pharmacodynamic response. The weekly dose was administered intravenously over approximately 30 minutes at the same time of day.

    Arm title
    		 Placebo
    Arm description
    		 Placebo, administered once weekly for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The weekly dose was administered intravenously over approximately 30 minutes at the same time of day. The volume corresponded to the pegzilarginase infusion.

    Number of subjects in period 1
    		Pegzilarginase Placebo
    Started
    21
    11
    Completed
    20
    11
    Not completed
    1
    0
         personal reasons
    1
    -
    Period 2
    Period 2 title
    Long-term extension (LTE)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    In the first 8 weeks of the LTE period, the treatment was blinded to subject and investigator. Subjects had the option to receive open-label pegzilarginase by subcutaneous (SC) administration after that.

    Arms
    Arm title
    		 Pegzilarginase
    Arm description
    		 Pegzilarginase, administered once weekly for up to 150 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegzilarginase
    Investigational medicinal product code
    Other name
    AEB1102, Co-ARG1-PEG
    Pharmaceutical forms
    Infusion, Injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    All subjects received pegzilarginase plus IDM during the LTE period. During blinded 8 weeks: Subjects initially randomized to pegzilarginase received the optimized dose they received during the 24-week DB period. Subjects initially randomized to placebo during the 24-week DB period started with 0.10 mg/kg pegzilarginase, which was adjusted during the LTE period based on arginine levels. The weekly dose was administered intravenously over approximately 30 minutes at the same time of day. During open-label LTE period after blinded 8 weeks: Subjects received weekly a SC injection of pegzilarginase. The initial mg/kg SC dose was the same as the IV dose unless dictated by the arginine level. The first 4 SC doses were given at the investigational site. Subsequent SC doses were administered outside of the investigational site by appropriately trained home health care professionals.

    Number of subjects in period 2
    		Pegzilarginase
    Started
    31
    Completed
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pegzilarginase
    Reporting group description
    		 Pegzilarginase, administered once weekly for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, administered once weekly for 24 weeks.

    Reporting group values
    		 Pegzilarginase Placebo Total
    Number of subjects
    		 21 11 32
    Age categorical
    Units: Subjects
        Children (2 to <6 years)
    		 5 1 6
        Children (6 to <12 years)
    		 8 4 12
        Children (12 to <18 years)
    		 7 4 11
        Adults (≥18 years)
    		 1 2 3
    Age continuous
    Units: years
        median (full range (min-max))
    		 8 (2 to 28) 12 (5 to 29) -
    Gender categorical
    Units: Subjects
        Female
    		 9 4 13
        Male
    		 12 7 19
    Gross motor function classification system level
    Units: Subjects
        Level I
    		 9 5 14
        Level II
    		 9 4 13
        Level III
    		 0 0 0
        Level IV
    		 3 2 5
        Level V
    		 0 0 0
    Level of spasticity
    Units: Subjects
        None
    		 8 3 11
        Mild
    		 7 2 9
        Moderate
    		 5 4 9
        Severe
    		 1 2 3
    Age at ARG1-D diagnosis
    Units: Years
        median (full range (min-max))
    		 0.7 (0 to 15) 4.6 (0 to 11) -
    Historical arginine level
    Units: µM
        median (full range (min-max))
    		 409 (173 to 724) 454 (277 to 664) -

    End points

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    End points reporting groups
    Reporting group title
    Pegzilarginase
    Reporting group description
    		 Pegzilarginase, administered once weekly for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, administered once weekly for 24 weeks.
    Reporting group title
    Pegzilarginase
    Reporting group description
    		 Pegzilarginase, administered once weekly for up to 150 weeks.

    Primary: Change from Baseline in plasma arginine after 24 weeks of study drug

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    End point title
    		 Change from Baseline in plasma arginine after 24 weeks of study drug
    End point description
    The primary analysis tested the change in the level of plasma arginine between baseline and completion of Week 24 assessments. The change from baseline in plasma arginine on Week 24 was compared between subjects treated with pegzilarginase and those treated with placebo. Log-transformed plasma arginine data were used. Baseline values for plasma arginine concentrations were defined as the mean of all logged values (analyzed at the designated central laboratory) obtained during the Screening/Baseline Period and before the first dose of blinded study treatment.
    End point type
    Primary
    End point timeframe
    From Baseline (Screening/Baseline period and before the first dose of blinded study treatment) until the end of the 24-week DB period (Week 24).
    End point values
    		 Pegzilarginase Placebo
    Number of subjects analysed
    21
    11
    Units: µM
        geometric mean (standard deviation)
    0.244 ( 1.635 )
    0.918 ( 1.371 )
    Statistical analysis title
    		 Change in plasma arginine after 24-week treatment
    Statistical analysis description
    The used mixed effect model repeated measures (MMRM) method included visit, randomized study treatment, and interaction between visit and randomized study treatment as effects and Baseline value as a covariate. Log-transformed plasma arginine data were used. The output of this model with unstructured covariance structure is shown as geometric least squares mean ratio (pegzilarginase/placebo).
    Comparison groups
    Pegzilarginase v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.233
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.165
         upper limit
    		 0.329

    Secondary: Mean change from Baseline at Week 24 in the 2-minute walk test (2MWT)

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    End point title
    		 Mean change from Baseline at Week 24 in the 2-minute walk test (2MWT)
    End point description
    The mean change from Baseline in the 2 MWT of the mobility assessments was a key secondary outcome measure. The change in distance completed in 2 minutes in meters were compared between subjects treated with pegzilarginase and those treated with placebo.
    End point type
    Secondary
    End point timeframe
    From Baseline until the end of the 24-week DB period (Week 24).
    End point values
    		 Pegzilarginase Placebo
    Number of subjects analysed
    19
    10
    Units: m
        arithmetic mean (standard deviation)
    7.3 ( 30.64 )
    2.7 ( 19.66 )
    Statistical analysis title
    		 Change in 2MWT at Week 24
    Statistical analysis description
    The used MMRM method included visit, randomized study treatment, and interaction between visit and randomized study treatment as effects and Baseline value as a covariate. The output of this model is shown as least squares (LS) mean difference (pegzilarginase - placebo).
    Comparison groups
    Placebo v Pegzilarginase
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5961
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.6
         upper limit
    		 26.7

    Secondary: Mean change from Baseline at Week 24 in the gross motor function measure-88 part E (GMFM-E)

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    End point title
    		 Mean change from Baseline at Week 24 in the gross motor function measure-88 part E (GMFM-E)
    End point description
    The mean change from Baseline in the GMFM-E of the mobility assessments was a key secondary outcome measure. The GMFM-E assessed walking, running, and jumping. The GMFM-E is scored from 0 to 72, with a higher score representing better gross motor function. The score change was compared between subjects treated with pegzilarginase and those treated with placebo.
    End point type
    Secondary
    End point timeframe
    From Baseline until the end of the 24-week DB period (Week 24).
    End point values
    		 Pegzilarginase Placebo
    Number of subjects analysed
    20
    11
    Units: score(s)
        arithmetic mean (standard deviation)
    4.2 ( 7.69 )
    -0.4 ( 6.20 )
    Statistical analysis title
    		 Change in GMFM-E score at Week 24
    Statistical analysis description
    The used MMRM method included visit, randomized study treatment, and interaction between visit and randomized study treatment as effects and Baseline value as a covariate. The output of this model is shown as LS mean difference (pegzilarginase - placebo).
    Comparison groups
    Pegzilarginase v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1087
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 10.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of the study drug (pegzilarginase or placebo) until Week 24 in the DB period and from first administration of pegzilarginase until up to 150 weeks in the LTE period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Pegzilarginase (DB period)
    Reporting group description
    		 All subjects who received pegzilarginase during the DB period.

    Reporting group title
    Placebo (DB period)
    Reporting group description
    		 All subjects who received placebo during the DB period.

    Reporting group title
    Pegzilarginase - pegzilarginase (LTE period)
    Reporting group description
    		 All subjects who received pegzilarginase during the DB and the LTE period .

    Reporting group title
    Placebo - pegzilarginase (LTE period)
    Reporting group description
    		 All subjects who received placebo during the DB period and pegzilarginase during the LTE period.

    Serious adverse events
    		 Pegzilarginase (DB period) Placebo (DB period) Pegzilarginase - pegzilarginase (LTE period) Placebo - pegzilarginase (LTE period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 21 (19.05%)
    4 / 11 (36.36%)
    5 / 20 (25.00%)
    7 / 11 (63.64%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ammonia increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    3 / 11 (27.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperammonaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 11 (27.27%)
    2 / 20 (10.00%)
    5 / 11 (45.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 2
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperammonaemic encephalopathy
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pegzilarginase (DB period) Placebo (DB period) Pegzilarginase - pegzilarginase (LTE period) Placebo - pegzilarginase (LTE period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 21 (85.71%)
    11 / 11 (100.00%)
    20 / 20 (100.00%)
    11 / 11 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of skin
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Oral papilloma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Skin papilloma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 11 (0.00%)
    9 / 20 (45.00%)
    5 / 11 (45.45%)
         occurrences all number
    4
    0
    13
    6
    Asthenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Fatigue
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    9 / 20 (45.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    9
    3
    Gait disturbance
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Influenza like illness
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    1
    Injection site pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    1
    Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Vaccination site pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 21 (19.05%)
    2 / 11 (18.18%)
    10 / 20 (50.00%)
    3 / 11 (27.27%)
         occurrences all number
    4
    2
    16
    4
    Nasal congestion
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    2 / 20 (10.00%)
    4 / 11 (36.36%)
         occurrences all number
    0
    1
    2
    8
    Rhinorrhoea
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    5 / 20 (25.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    0
    5
    0
    Catarrh
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Productive cough
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Sinus congestion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    Generalised anxiety disorder
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    4 / 20 (20.00%)
    3 / 11 (27.27%)
         occurrences all number
    6
    0
    9
    5
    Ammonia increased
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 11 (18.18%)
    3 / 20 (15.00%)
    4 / 11 (36.36%)
         occurrences all number
    5
    3
    5
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    4 / 20 (20.00%)
    3 / 11 (27.27%)
         occurrences all number
    4
    0
    7
    4
    Blood potassium decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    0
    2
    Body temperature increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    1
    Amino acid level increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    4 / 20 (20.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    6
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    3 / 20 (15.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Insulin-like growth factor decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    2
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    4 / 20 (20.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    0
    6
    3
    Transaminases increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    3 / 20 (15.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    0
    3
    0
    Contusion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    3
    Post-traumatic pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 11 (9.09%)
    5 / 20 (25.00%)
    2 / 11 (18.18%)
         occurrences all number
    3
    1
    7
    2
    Lethargy
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Hypoacusis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 11 (27.27%)
    3 / 20 (15.00%)
    4 / 11 (36.36%)
         occurrences all number
    0
    5
    4
    4
    Constipation
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 11 (9.09%)
    2 / 20 (10.00%)
    2 / 11 (18.18%)
         occurrences all number
    9
    1
    3
    2
    Diarrhoea
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    2 / 20 (10.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    2
    2
    Nausea
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 11 (36.36%)
    5 / 20 (25.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    6
    7
    10
    Vomiting
         subjects affected / exposed
    5 / 21 (23.81%)
    3 / 11 (27.27%)
    10 / 20 (50.00%)
    7 / 11 (63.64%)
         occurrences all number
    10
    8
    27
    13
    Abdominal discomfort
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    3 / 20 (15.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Dental caries
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    Osteochondrosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 11 (9.09%)
    0 / 20 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 11 (0.00%)
    5 / 20 (25.00%)
    1 / 11 (9.09%)
         occurrences all number
    4
    0
    8
    1
    Asymptomatic COVID-19
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    COVID-19
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    4 / 20 (20.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    5
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Ear infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    3 / 20 (15.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Helicobacter infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Localised infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Molluscum contagiosum
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Parasitic gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    5 / 20 (25.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Viral infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    2 / 20 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    3
    Viral skin infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 11 (18.18%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    0
    1
    Hyperammonaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 11 (0.00%)
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2019
    Protocol v2.0 with following changes to v1.0: - Schedule of Assessments was updated to clarify timing, add height assessments in the LTE period, specify that mutation analysis and arginase activity in red blood cells were required for all subjects, and for other clarifications. - Clarified that interactive web/voice response system (IXRS) evaluates arginine data and sends the dose adjustments to the unblinded pharmacist and/or physician. Also formal unblinding was defined. - Questions for caregivers were clarified. - Hypersensitivity reactions and hyperammonemic episodes were specified as adverse events of special interest (AESIs), and a guidance regarding corticosteroids was given. - Definition of hyperammonemic episodes was added.
    08 Jun 2020
    Protocol v5.0 with following changes to v2.0: - AE were to be reported from signing of informed consent continuing through the last study follow-up visit. - The objectives "compare pegzilarginase with placebo with respect to (re:) other aspects of mobility", "compare pegzilarginase with placebo re: adaptive behavior" and "compare pegzilarginase with placebo re: objective measures of neurological/neuromotor manifestations" were added; including corresponding endpoints. - Definitions were clarified and added regarding clinical response, responder and AESI. - Requirements for a stable, consistent diet through the first 8 weeks of the LTE period were added. - Measures to minimize bias were clarified. - Time period for botulinum toxin use (standard treatment for spasticity) before study treatment (exclusion criterion 8) was shortened. - Storage temperature was corrected, and description of study treatment was updated and clarified. - Initial calculation of dose was to be based on subject’s weight at Baseline. - Potential for transition to SC treatment was added. - Limitations of GMFM to parts D and E and minimum clinically important differences for these parts were added. - Subject requirement to maintain dietary protein intake levels during DB period consistent with baseline was added. - AESI terms were defined. Specifications of measures to be taken in case of hypersensitivity reaction were added. - Statistical analysis was specified. Sample Size determination with new power calculations was added. - Interim analysis after completion of the DB period was added. Analyses were completed at an overall 2-sided alpha=0.05 without adjustment for multiplicity for the interim analysis. - Personnel and level of unblinding/access was clarified. - Timings of assessments were revised and adjusted. - SC dosing and administration requirements were added. - Specified that the SRC had access to full subject data/treatment assignment in case of safety concerns.
    11 Dec 2020
    Protocol v6.0 with following changes to v5.0: - Objectives, endpoints, and analyses were clarified and reprioritized based on clinical and statistical considerations. The statistical approach was changed to specify the use of continuous rather than categorical variables, and multiple comparison procedures were specified for global control of Type 1 error. - Additional changes were made to ensure continuity and safety of study subjects despite the impact of the global pandemic. A section was added addressing the impact of COVID-19. - The key secondary objective (including corresponding endpoint) was revised to be based on key mobility and/or motor function outcome measures. - Secondary objectives and endpoints and the tertiary objectives and endpoints were clarified. - For the primary endpoint analysis, the values would be log transformed before analysis. - Sensitivity analyses were added. - Contingency for action if the primary analysis is or is not statistically significant was added. - Schedule of Assessments footnotes were clarified. - Preparation/Handling/Storage/Accountability section was revised to reflect new data. - Clarification was made re: when the IXRS would be discontinued. - Specification for reporting additional follow-up SAE information was added. - Injection site reactions was defined and added as AESI. - The hyperammonemia section was revised for accuracy and clarity. - Sample size determination was adjusted to reflect inclusion of Study CAEB1102-102A preliminary data and specification of the number of units corresponding to the log scale. - Sample size was adjusted to align with the changes in statistical analyses/endpoints/objectives. - Additional details were included for the statistical analyses consistent with the change in the statistical approach.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38292042
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