Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency

• Sponsor: Aeglea Biotherapeutics (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03921541
• Collaborator: (none)
• Enrollment: 32
• Locations: 32
• Arms: 3
• Anticipated Duration (Months): 69.8
• Patient Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Arginase I Deficiency; Hyperargininemia	Drug: Pegzilarginase; Drug: Placebo; Drug: Pegzilarginase	Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 10, 2019
• Anticipated Primary Completion Date: Aug 1, 2024
• Anticipated Study Completion Date: Feb 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pegzilarginase Weekly IV infusions of pegzilarginase plus individualized disease management for 24 weeks	Drug: Pegzilarginase; Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated; Other Names: Co-ArgI-PEG; AEB1102
Placebo Comparator: Placebo Weekly IV infusions of placebo plus individualized disease management for 24 weeks	Drug: Placebo; Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated
Experimental: 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.	Drug: Pegzilarginase; Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated; Other Names: Co-ArgI-PEG; AEB1102

Outcome Measures

Primary Outcome Measures

1. Change from baseline in plasma arginine concentration after 24 weeks of treatment [Baseline through week 24]

   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.

Secondary Outcome Measures

1. Mean change from baseline in the mobility assessments of the Key secondary outcome measure of the 2 Minute Walk Test [Baseline and week 24]

   The Key Secondary outcome measure is the mean change from baseline in the 2 Minute Walk Test.

2. Mean change from baseline in the mobility assessments of the Key secondary outcome measure of GMFM-E [Baseline and week 24]

   The Key Secondary outcome measure is the mean change from baseline in GMFM-E.

3. Proportion of participants with plasma arginine levels below target guidance [Baseline and week 24]

   Proportion of participants with plasma arginine levels below 200umol/L (target level set in disease management guidelines) after 24 weeks of treatment.

4. Proportion of participants with plasma arginine levels in normal range [Week 24]

   Proportion of participants with plasma arginine levels between 40 - 115 umol/L (normal range for plasma arginine) after 24 weeks.

5. Change in ornithine and guanidino compounds [Baseline and week 24]

   This analysis will measure the change from baseline in the level of ornithine and guanidino compounds after 24 weeks of treatment.

6. Mean change from baseline at week 24 in other aspects of mobility assessed by GMFM-D [Baseline, week 12 and week 24]

   To compare pegzilarginase with placebo with respect to other aspects of mobility.

7. Mean change from baseline at week 24 in other aspects of mobility assessed by the Functional Mobility Scale (FMS) [Baseline, week 12 and week 24]

   To compare pegzilarginase with placebo with respect to other aspects of mobility.

8. Mean change from baseline at week 24 in other aspects of mobility assessed by the Gillette Functional Assessment Questionnaire (GFAQ) [Baseline, week 12 and week 24]

   To compare pegzilarginase with placebo with respect to other aspects of mobility.

9. Mean change from baseline at week 24 in Adaptive Behavior assessed using the Vineland Adaptive Behavior Scales (VABS)-II [Baseline, week 12 and week 24]

   To compare pegzilarginase with placebo with respect to adaptive behavior.

10. Evaluate safety of pegzilarginase [Reporting will be from signing consent through follow-up (assessed for up to 174 weeks)]

    Number of participants developing treatment related adverse events.

11. Evaluate immunogenicity of pegzilarginase [Baseline, week 2, week 7, week 12, week 17, week 24]

    The proportion of participants who develop (ADA) anti-drug antibodies to pegzilarginase will be measured over the period of the clinical trial.

12. Pharmacokinetic profile of pegzilarginase [Baseline, week 12, week 24]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

3. 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

4. If a subject is re-screened, the only values that are considered for eligibility assessment are those in the current screening period

5. Subjects must be ≥ 2 years of age on the date of informed consent/assent

6. 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

7. 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

8. 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

9. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harvey Pediatrics	Rogers	Arkansas	United States	72758
2	Children's Hospital of Orange County	Orange	California	United States	92868
3	Stanford University School of Medicine	Stanford	California	United States	94305
4	Children's National Medical Center	Washington	District of Columbia	United States	20010
5	University of Florida College of Medicine	Gainesville	Florida	United States	32610
6	Emory University	Atlanta	Georgia	United States	30322
7	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
8	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
9	Cohen Children's Medical Center (Northwell Health)	Queens	New York	United States	11040
10	Duke University Medical Center	Durham	North Carolina	United States	27710
11	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
12	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15224
13	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
14	UT Southwestern Medical Center	Dallas	Texas	United States	75390
15	University of Texas Health Science Center Medical School at Houston	Houston	Texas	United States	77030
16	University of Utah Hospitals & Clinics	Salt Lake City	Utah	United States	84108
17	Seattle Children's Hospital	Seattle	Washington	United States	98105
18	LKH Bregenz	Bregenz		Austria
19	Medizinische Universität Innsbruck	Innsbruck		Austria
20	McGill University Health Center	Montreal	Quebec	Canada
21	Hôpital Necker - Enfants Malades	Paris		France
22	Hopital des Enfants	Talence		France
23	Universitaetsklinikum Muenster	Muenster	Nordrhein Westfalen	Germany
24	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz	Mainz	Rheinland Pfalz	Germany
25	Fondazione MBBM	Monza		Italy
26	Ospedale Pediatrico Bambino Gesù	Roma		Italy
27	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino		Italy
28	Birmingham Children's Hospital	Birmingham		United Kingdom
29	University Hospital of Wales	Cardiff		United Kingdom
30	Great Ormond Street Hospital for Children	London		United Kingdom
31	Willink Biochemical Genetics Unit	Manchester		United Kingdom
32	Salford Royal	Salford		United Kingdom

Sponsors and Collaborators

• Aeglea Biotherapeutics

Investigators

• Study Director: Josie Gayton, Aeglea BioTherapeutics, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Aeglea Biotherapeutics
• ClinicalTrials.gov Identifier: NCT03921541
• Other Study ID Numbers: CAEB1102-300A
• First Posted: Apr 19, 2019
• Last Update Posted: Aug 10, 2022
• Last Verified: Aug 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Aeglea Biotherapeutics: ARG1-D
• Additional relevant MeSH terms: Hyperargininemia

Study Results

No Results Posted as of Aug 10, 2022