Clinical trial NCT03921541: Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Arginase I Deficiency
Hyperargininemia
Keywords: ARG1-D
Lead sponsor: Aeglea Biotherapeutics
Sponsor class: INDUSTRY
First posted: 2019-04-19
Enrollment: 32
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: Inclusion Criteria:

Subjects are eligible to be included in the study only if all the following criteria apply:

1. The subject and/or parent/guardian provides written informed consent/assent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
2. A current diagnosis of ARG1 D as documented in medical records, which must include 1 of the following: elevated plasma arginine levels, a mutation analysis that results in a pathogenic variant, or reduced RBC arginase activity. For entry into this study, subjects must also fulfill the following plasma arginine criteria:

   1. The average of all measured values of plasma arginine during the screening period prior to the randomization visit (Visit 1, Study Day 1) is ≥ 250 µmol/L
   2. If a subject is re-screened, the only values that are considered for eligibility assessment are those in the current screening period
3. Subjects must be ≥ 2 years of age on the date of informed consent/assent
4. The subject must be assessable for clinically meaningful within-subject change (clinical response) on at least one component of one assessment included in the key secondary/other secondary endpoints. To be considered assessable, the subject must be able to complete the assessment, and must have a baseline deficit in at least one component as defined in the protocol
5. Have received documented confirmation from the investigator and/or dietician that the subject can maintain their diet in accordance with dietary information presented in the protocol, ie, can maintain the current level of protein consumption, including natural protein and EAA supplementation
6. Subjects receiving ammonia scavenger therapy, anti-epileptic drugs, and/or medications for spasticity (eg, baclofen) must be on a stable dose of the medication for at least 4 weeks prior to randomization and be willing to remain on a stable dose during the double-blind portion and blinded follow-up portions of the study
7. Female and male subjects may participate. Female subjects of childbearing potential must have a negative serum pregnancy test during the screening period before receiving the first dose of study treatment, and a negative urine pregnancy test on the day of the first dose, prior to the first dose. If the subject (male or female) is engaging in sexual activity that could lead to pregnancy, must be surgically sterile, postmenopausal (no menses for 12 months without an alternative medical cause or a high FSH level in the postmenopausal range in women not using hormonal contraception or hormonal replacement therapy), or must agree to use a highly effective method of birth control during the study and for a minimum of 30 days after the last study drug administration. Highly effective methods of contraception include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation; progesterone-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); or abstinence (refraining from heterosexual intercourse during the entire period of risk associated with study treatment).

Exclusion Criteria:

1. Hyperammonemic episode (defined as an event in which a subject has an ammonia level ≥100 µM with one or more symptoms related to hyperammonemia requiring hospitalization or emergency room management) within the 6 weeks before the first dose of study drug is administered
2. Active infection requiring anti-infective therapy within 3 weeks prior to first dose
3. Known active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
4. Extreme mobility deficit, defined as either the inability to be assessed on the GFAQ or a score of 1 on the GFAQ
5. Other medical conditions or comorbidities that, in the opinion of the investigator would interfere with study compliance or data interpretation (eg, severe intellectual disability precluding required study assessments)
6. Has participated in a previous interventional study with pegzilarginase
7. Has a history of hypersensitivity to polyethylene glycol (PEG) that, in the judgment of the investigator, puts the subject at unacceptable risk for adverse events
8. Subject is being treated with botulinum toxin-containing regimens or plans to initiate such regimens during the double-blind or blinded follow-up portions of the study or received surgical or botulinum-toxin treatment for spasticity-related complications within the 16 weeks prior to the first dose of study treatment in this study
9. Is currently participating in another therapeutic clinical trial or has received any investigational agent within 30 days (or 5 half-lives whichever is longer) prior to the first dose of study treatment in this study
10. Previous liver or hematopoietic transplant procedure.

Primary outcomes:
measure: Change From Baseline in Plasma Arginine Concentration After 24 Weeks of Treatment
timeFrame: Baseline through Week 24
Secondary outcomes:
measure: Mean Change From Baseline in the Mobility Assessments of the Key Secondary Outcome Measure of the 2 Minute Walk Test
timeFrame: Baseline through Week 24
measure: Mean Change From Baseline in the Mobility Assessments of the Key Secondary Outcome Measure of GMFM-E
timeFrame: Baseline through Week 24
measure: Proportion of Participants With Plasma Arginine Levels Below Target Guidance
timeFrame: Baseline and week 24
measure: Proportion of Participants With Plasma Arginine Levels in Normal Range
timeFrame: Baseline to Week 24
measure: Change in Ornithine
timeFrame: Baseline and week 24
measure: Change in Guanidino Compound-ARGA
timeFrame: Baseline to week 24
measure: Change in Guanidino Compound - GAA
timeFrame: Baseline to week 24
measure: Change in Guanidino Compound - GVA
timeFrame: Baseline to week 24
measure: Change in Guanidino Compound - NAArg
timeFrame: Baseline to week 24
measure: Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by GMFM-D
timeFrame: Baseline to week 24
measure: Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Functional Mobility Scale (FMS)
timeFrame: Baseline to week 24
measure: Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Functional Mobility Scale (FMS)
timeFrame: Baseline to week 24
measure: Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Functional Mobility Scale (FMS)
timeFrame: Baseline to week 24
measure: Mean Change From Baseline at Week 24 in Other Aspects of Mobility Assessed by the Gillette Functional Assessment Questionnaire (GFAQ)
timeFrame: Baseline to week 24
measure: Mean Change From Baseline at Week 24 in Adaptive Behavior Assessed Using the Vineland Adaptive Behavior Scales (VABS)-II
timeFrame: Baseline to week 24
measure: Evaluate Safety of Pegzilarginase
timeFrame: Reporting will be from signing consent through follow-up (Baseline to Week 24)
measure: Evaluate Immunogenicity of Pegzilarginase
timeFrame: Baseline to week 24
Other outcomes:
Locations:
city: Rogers
country: United States
facility: Harvey Pediatrics
state: Arkansas
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Queens
country: United States
facility: Cohen Children's Medical Center (Northwell Health)
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center Medical School at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospitals & Clinics
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Bregenz
country: Austria
facility: LKH Bregenz
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Montreal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Paris
country: France
facility: Hôpital Necker - Enfants Malades
city: Talence
country: France
facility: Hopital des Enfants
city: Muenster
country: Germany
facility: Universitaetsklinikum Muenster
state: Nordrhein Westfalen
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
state: Rheinland Pfalz
city: Monza
country: Italy
facility: Fondazione MBBM
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
city: Manchester
country: United Kingdom
facility: Willink Biochemical Genetics Unit
city: Salford
country: United Kingdom
facility: Salford Royal
Study officials:
affiliation: Aeglea BioTherapeutics, Inc.
name: Cortney Caudill
role: STUDY_DIRECTOR
References: