Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency

Hyperargininemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03921541
• Other study ID #: CAEB1102-300A
• Status: Completed
• Phase: Phase 3
• Start date: April 10, 2019
• Est. completion date: January 27, 2023

Study information

• Verified date: July 2023
• Source: Aeglea Biotherapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: January 27, 2023
• Est. primary completion date: January 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Arginase I Deficiency
• Hyperargininemia

Intervention

Drug:
• Pegzilarginase
Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated
• Placebo
Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated

Locations

Country	Name	City	State
Austria	LKH Bregenz	Bregenz
Austria	Medizinische Universität Innsbruck	Innsbruck
Canada	McGill University Health Center	Montreal	Quebec
France	Hôpital Necker - Enfants Malades	Paris
France	Hopital des Enfants	Talence
Germany	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz	Mainz	Rheinland Pfalz
Germany	Universitaetsklinikum Muenster	Muenster	Nordrhein Westfalen
Italy	Fondazione MBBM	Monza
Italy	Ospedale Pediatrico Bambino Gesù	Roma
Italy	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino
United Kingdom	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 States	Emory University	Atlanta	Georgia
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida College of Medicine	Gainesville	Florida
United States	University of Texas Health Science Center Medical School at Houston	Houston	Texas
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Cohen Children's Medical Center (Northwell Health)	Queens	New York
United States	Harvey Pediatrics	Rogers	Arkansas
United States	University of Utah Hospitals & Clinics	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington
United States	Stanford University School of Medicine	Stanford	California
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Aeglea Biotherapeutics

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in plasma arginine concentration after 24 weeks of treatment	The primary analysis will test the change in the level of plasma arginine between baseline and completion of week 24 assessments. It will compare the change from baseline in plasma arginine between participants treated with pegzilarginase and those treated with placebo.	Baseline through week 24
Secondary	Mean change from baseline in the mobility assessments of the Key secondary outcome measure of the 2 Minute Walk Test	The Key Secondary outcome measure is the mean change from baseline in the 2 Minute Walk Test.	Baseline and week 24
Secondary	Mean change from baseline in the mobility assessments of the Key secondary outcome measure of GMFM-E	The Key Secondary outcome measure is the mean change from baseline in GMFM-E.	Baseline and week 24
Secondary	Proportion of participants with plasma arginine levels below target guidance	Proportion of participants with plasma arginine levels below 200umol/L (target level set in disease management guidelines) after 24 weeks of treatment.	Baseline and week 24
Secondary	Proportion of participants with plasma arginine levels in normal range	Proportion of participants with plasma arginine levels between 40 - 115 umol/L (normal range for plasma arginine) after 24 weeks.	Week 24
Secondary	Change in ornithine and guanidino compounds	This analysis will measure the change from baseline in the level of ornithine and guanidino compounds after 24 weeks of treatment.	Baseline and week 24
Secondary	Mean change from baseline at week 24 in other aspects of mobility assessed by GMFM-D	To compare pegzilarginase with placebo with respect to other aspects of mobility.	Baseline, week 12 and week 24
Secondary	Mean change from baseline at week 24 in other aspects of mobility assessed by the Functional Mobility Scale (FMS)	To compare pegzilarginase with placebo with respect to other aspects of mobility.	Baseline, week 12 and week 24
Secondary	Mean change from baseline at week 24 in other aspects of mobility assessed by the Gillette Functional Assessment Questionnaire (GFAQ)	To compare pegzilarginase with placebo with respect to other aspects of mobility.	Baseline, week 12 and week 24
Secondary	Mean change from baseline at week 24 in Adaptive Behavior assessed using the Vineland Adaptive Behavior Scales (VABS)-II	To compare pegzilarginase with placebo with respect to adaptive behavior.	Baseline, week 12 and week 24
Secondary	Evaluate safety of pegzilarginase	Number of participants developing treatment related adverse events.	Reporting will be from signing consent through follow-up (assessed for up to 174 weeks)
Secondary	Evaluate immunogenicity of pegzilarginase	The proportion of participants who develop (ADA) anti-drug antibodies to pegzilarginase will be measured over the period of the clinical trial.	Baseline, week 2, week 7, week 12, week 17, week 24
Secondary	Pharmacokinetic profile of pegzilarginase	The pharmacokinetic profile of pegzilarginase will be characterized by measuring plasma concentration at several time points at baseline, week 12 and week 24. The time points are pre-infusion and then 1 hr, 2 hr, 4 hr, 24 hr, 96 hr and 168 hr after infusion.	Baseline, week 12, week 24