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Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency

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ClinicalTrials.gov Identifier: NCT03921541
Recruitment Status : Active, not recruiting
First Posted : April 19, 2019
Last Update Posted : May 17, 2021
Sponsor:
Information provided by (Responsible Party):
Aeglea Biotherapeutics

Tracking Information
First Submitted Date  ICMJE April 9, 2019
First Posted Date  ICMJE April 19, 2019
Last Update Posted Date May 17, 2021
Actual Study Start Date  ICMJE April 10, 2019
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 22, 2021)
Change from baseline in plasma arginine concentration after 24 weeks of treatment [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
Change in plasma arginine concentration [ Time Frame: Baseline through 24 weeks ]
The primary analysis will test the change in the level of plasma arginine between baseline and week 24. It will compare the level of plasma arginine between participants treated with pegzilarginase and those treated with placebo.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2021)
  • Mean change from baseline in the mobility assessments of the Key secondary outcome measure of the 2 Minute Walk Test [ Time Frame: Baseline and week 24 ]
    The Key Secondary outcome measure is the mean change from baseline in the 2 Minute Walk Test.
  • Mean change from baseline in the mobility assessments of the Key secondary outcome measure of GMFM-E [ Time Frame: Baseline and week 24 ]
    The Key Secondary outcome measure is the mean change from baseline in GMFM-E.
  • Proportion of participants with plasma arginine levels below target guidance [ Time Frame: 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.
  • Proportion of participants with plasma arginine levels in normal range [ Time Frame: Week 24 ]
    Proportion of participants with plasma arginine levels between 40 - 115 umol/L (normal range for plasma arginine) after 24 weeks.
  • Change in ornithine and guanidino compounds [ Time Frame: 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.
  • Mean change from baseline at week 24 in other aspects of mobility assessed by GMFM-D [ Time Frame: Baseline, week 12 and week 24 ]
    To compare pegzilarginase with placebo with respect to other aspects of mobility.
  • Mean change from baseline at week 24 in other aspects of mobility assessed by the Functional Mobility Scale (FMS) [ Time Frame: Baseline, week 12 and week 24 ]
    To compare pegzilarginase with placebo with respect to other aspects of mobility.
  • Mean change from baseline at week 24 in other aspects of mobility assessed by the Gillette Functional Assessment Questionnaire (GFAQ) [ Time Frame: Baseline, week 12 and week 24 ]
    To compare pegzilarginase with placebo with respect to other aspects of mobility.
  • Mean change from baseline at week 24 in Adaptive Behavior assessed using the Vineland Adaptive Behavior Scales (VABS)-II [ Time Frame: Baseline, week 12 and week 24 ]
    To compare pegzilarginase with placebo with respect to adaptive behavior.
  • Evaluate safety of pegzilarginase [ Time Frame: Reporting will be from signing consent through follow-up (assessed for up to 174 weeks) ]
    Number of participants developing treatment related adverse events.
  • Evaluate immunogenicity of pegzilarginase [ Time Frame: 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.
  • Pharmacokinetic profile of pegzilarginase [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 16, 2019)
  • Clinical response in any of the mobility or adaptive behavior [ Time Frame: Baseline, week 12 and week 24 ]
    The Key Secondary outcome measure will compare the proportion of participants in either the pegzilarginase or the placebo arm who have a Clinical Response after 12 and 24 weeks of treatment. A Clinical Response is defined by either a Mobility Response or an Adaptive Behavior Response in at least one of the component assessments. The component assessments are the 2 Minute Walk Test, Functional Mobility Assessment or the Vineland Adaptive Behavior Scale II.
  • Clinical Response in each individual mobility and adaptive behavior assessment [ Time Frame: Baseline, week 12 and week 24 ]
    Each participant will be measured on whether or not (yes/no) they have a Clinical Response at week 12 and week 24 on each of the individual component assessments from the Key Secondary Outcome Measure above (2). Mobility is measured by the 2 Minute Walk Test and the Functional Mobility Assessment and adaptive behavior is measured by the Vineland Adaptive Behavior Scale II."
  • Number of assessments where a Clinical Response is seen [ Time Frame: Baseline, week 12 and week 24 ]
    The number of individual components of the Key Secondary Outcome Measure where a Clinical Response is demonstrated in each participant will be measured (0, 1, 2 or 3) at week 12 and week 24 and will be compared between pegzilarginase and placebo arms.
  • Proportion of participants with plasma arginine levels below target guidance [ Time Frame: Baseline, week 12 and week 24 ]
    Proportion of participants with plasma arginine levels below 200umol/L (target level set in disease management guidelines) at week 24.
  • Proportion of participants with plasma arginine levels in normal range [ Time Frame: Week 24 ]
    Proportion of participants with plasma arginine levels between 40 - 115 umol/L (normal range for plasma arginine) at week 24.
  • Change in guanidino compounds [ Time Frame: Baseline and week 24 ]
    Guanidino compounds (direct or indirect breakdown products from arginine) have been shown to be elevated in patients with Arg1-D. This analysis will measure the change in the level of guanidino compounds between baseline and week 24.
  • Immunogenicity of pegzilarginase [ Time Frame: Baseline, week 1, week 7, week 12, week 17, week 24 ]
    The proportion of participants who develop antibodies to pegzilarginase will be measured over the period of the clinical trial.
  • Pharmacokinetic profile of pegzilarginase [ Time Frame: 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.
  • Determine if adverse events occur [ Time Frame: weekly from baseline through study completion ]
    Number of participants developing treatment related adverse events.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Pegzilarginase in Patients With Arginase 1 Deficiency
Official Title  ICMJE 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
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Arginase I Deficiency
  • Hyperargininemia
Intervention  ICMJE
  • Drug: Pegzilarginase
    Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated
    Other Name: Co-ArgI-PEG; AEB1102
  • Drug: Placebo
    Individualized disease management which includes severe protein restriction, essential amino acid supplementation and the ammonia scavengers when indicated
Study Arms  ICMJE
  • Experimental: Pegzilarginase
    Weekly IV infusions of pegzilarginase plus individualized disease management for 24 weeks
    Intervention: Drug: Pegzilarginase
  • Placebo Comparator: Placebo
    Weekly IV infusions of placebo plus individualized disease management for 24 weeks
    Intervention: Drug: Placebo
  • 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.
    Intervention: Drug: Pegzilarginase
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 13, 2021)
32
Original Estimated Enrollment  ICMJE
 (submitted: April 16, 2019)
30
Estimated Study Completion Date  ICMJE July 2024
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Canada,   France,   Germany,   Italy,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03921541
Other Study ID Numbers  ICMJE CAEB1102-300A
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Aeglea Biotherapeutics
Study Sponsor  ICMJE Aeglea Biotherapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Josie Gayton Aeglea BioTherapeutics, Inc.
PRS Account Aeglea Biotherapeutics
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP