Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency

NCT ID: NCT03921541

Last Updated: 2024-11-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-04-10
• Study Completion Date: 2023-01-27

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).

Conditions

Arginase I Deficiency; Hyperargininemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Pegzilarginase

Weekly IV infusions of pegzilarginase plus individualized disease management for 24 weeks

Group Type: EXPERIMENTAL

Pegzilarginase

Intervention Type: DRUG

Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated

Placebo

Weekly IV infusions of placebo plus individualized disease management for 24 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated

Pegzilarginase Long Term Extension

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.

Group Type: EXPERIMENTAL

Pegzilarginase

Intervention Type: DRUG

Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated

Interventions

Pegzilarginase

Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated

Intervention Type: DRUG

Placebo

Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated

Intervention Type: DRUG

Other Intervention Names

Co-ArgI-PEG; AEB1102

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.

• Minimum Eligible Age: 2 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aeglea Biotherapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Cortney Caudill

Role: STUDY_DIRECTOR

Aeglea BioTherapeutics, Inc.

Locations

Harvey Pediatrics

Rogers, Arkansas, United States

Children's Hospital of Orange County

Orange, California, United States

Stanford University School of Medicine

Stanford, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

University of Florida College of Medicine

Gainesville, Florida, United States

Emory University

Atlanta, Georgia, United States

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Cohen Children's Medical Center (Northwell Health)

Queens, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

UT Southwestern Medical Center

Dallas, Texas, United States

University of Texas Health Science Center Medical School at Houston

Houston, Texas, United States

University of Utah Hospitals & Clinics

Salt Lake City, Utah, United States

Seattle Children's Hospital

Seattle, Washington, United States

LKH Bregenz

Bregenz, , Austria

Medizinische Universität Innsbruck

Innsbruck, , Austria

McGill University Health Center

Montreal, Quebec, Canada

Hôpital Necker - Enfants Malades

Paris, , France

Hopital des Enfants

Talence, , France

Universitaetsklinikum Muenster

Münster, North Rhine-Westphalia, Germany

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz

Mainz, Rhineland-Palatinate, Germany

Fondazione MBBM

Monza, , Italy

Ospedale Pediatrico Bambino Gesù

Roma, , Italy

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Torino, , Italy

Birmingham Children's Hospital

Birmingham, , United Kingdom

University Hospital of Wales

Cardiff, , United Kingdom

Great Ormond Street Hospital for Children

London, , United Kingdom

Willink Biochemical Genetics Unit

Manchester, , United Kingdom

Salford Royal

Salford, , United Kingdom

Countries

United States; Austria; Canada; France; Germany; Italy; United Kingdom

References

Russo RS, Gasperini S, Bubb G, Neuman L, Sloan LS, Diaz GA, Enns GM; PEACE Investigators. Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial. EClinicalMedicine. 2024 Jan 12;68:102405. doi: 10.1016/j.eclinm.2023.102405. eCollection 2024 Feb.

Reference Type: DERIVED

PMID: 38292042 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

CAEB1102-300A

Identifier Type: -

Identifier Source: org_study_id