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    Summary
    EudraCT Number:2018-003163-67
    Sponsor's Protocol Code Number:CAEB1102-102A
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-10-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPortugal - INFARMED
    A.2EudraCT number2018-003163-67
    A.3Full title of the trial
    An Open-label, Multicenter Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of AEB1102 in Patients with Arginase I Deficiency
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-label, Multicenter Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of AEB1102 in Patients with Arginase I Deficiency
    A.4.1Sponsor's protocol code numberCAEB1102-102A
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03378531
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAeglea Biotherapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAeglea Biotherapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAeglea Biotherapeutics, Inc.
    B.5.2Functional name of contact pointArg1-D Trial Information
    B.5.3 Address:
    B.5.3.1Street Address805 Las Cimas Pkwy,Suite 100, Building III
    B.5.3.2Town/ cityAustin, TX
    B.5.3.3Post code78746
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18555099921
    B.5.6E-mailarg1dtrialinfo@aegleabio.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1701
    D.3 Description of the IMP
    D.3.1Product namePegzilarginase
    D.3.2Product code AEB1102
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEGZILARGINASE
    D.3.9.1CAS number 1659310-95-8
    D.3.9.2Current sponsor codeAEB1102
    D.3.9.3Other descriptive nameCo-Arg1-PEG
    D.3.9.4EV Substance CodeSUB193532
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1701
    D.3 Description of the IMP
    D.3.1Product namePegzilarginase
    D.3.2Product code AEB1102
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEGZILARGINASE
    D.3.9.1CAS number 1659310-95-8
    D.3.9.2Current sponsor codeAEB1102
    D.3.9.3Other descriptive nameCo-Arg1-PEG
    D.3.9.4EV Substance CodeSUB193532
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Arginase 1 deficiency
    Hyperargininemia
    E.1.1.1Medical condition in easily understood language
    Arginase deficiency
    Hyperargininemia
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10062695
    E.1.2Term Arginase deficiency
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the long-term safety and tolerability of intravenous (IV) or subcutaneous (SC) Pegzilarginase administered for up to 4 years in patients with Arginase I deficiency and hyperargininemia
    E.2.2Secondary objectives of the trial
    • To evaluate the long-term effects of Pegzilarginase in patients with Arginase I deficiency and hyperargininemia on sustained reduction of arginine levels
    • To evaluate the long-term effects of Pegzilarginase on plasma guanidino compounds
    • To characterize repeat-dose pharmacokinetics (PK) of Pegzilarginase administered IV or SC
    • To evaluate the long-term effects of Pegzilarginase on stabilization or improvement of neurological/neuromotor manifestations, using objective measures:
    o Six-Minute Walk Test (6MWT)
    o Berg Balance Scale (BBS)
    o Gross Motor Function Measure (GMFM)
    o Modified Ashworth Scale (MAS)
    o Purdue Pegboard Test
    • To evaluate the long-term effects of Pegzilarginase on select manifestations of Arginase I deficiency:
    o Frequency of seizures
    o Frequency of hyperammonemic episodes
    o Incidence of disease-related transaminase elevations
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A patient must meet all of the following criteria to be enrolled in this study:
    1. Completed participation in Study CAEB1102-101A without experiencing any clinically significant AE or other unmanageable drug toxicity that precludes continued dosing
    2. After review of the patient’s data from the CAEB1102-101A study, the Investigator and the Sponsor confirm that it is acceptable for the patient to continue dosing with pegzilarginase and that the patient continues to meet the following criteria from the 101A study
    − Is male or female: pediatric patients ≥2 to <18 years of age and adult patients ≥18 years of age
    − Has documented diagnosis of Arginase 1 deficiency, with:
     Known mutation in the Arginase 1 gene
    OR
     Known deficiency in red blood cells (RBCs) arginase activity
    Has adequate organ function defined as follows:
     Bone Marrow: Hemoglobin ≥10 g/dL; absolute neutrophil count ≥1.5x10^9/L; platelet count ≥100,000/μL
     Hepatic: transaminase levels (aspartate aminotransferase/alanine aminotransferase ≤2.5-times upper limit of normal (ULN); total bilirubin ≤2.0 mg/dL
     Renal: serum creatinine <1.5 x ULN
    3. If female and of child-bearing potential, has a negative serum pregnancy test within 7 days before enrollment
    4. If the patient (male or female) is engaging in sexual activity that could lead to pregnancy, must be surgically sterile, post-menopausal (female), 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); or intrauterine hormone-releasing system (IUS).
    5. Patient or legal guardian is able and willing to provide written informed consent and where required assent, and to comply with all requirements of study participation (including all study procedures and continuation of prescribed diet without modification), prior to any screening procedures
    E.4Principal exclusion criteria
    A patient is excluded from this study if he/she has:
    1) Clinically significant concurrent disease, serious intercurrent illness, or other extenuating circumstances that, in the opinion of the Investigator, would preclude the patient's participation in the study including:
    a) Had transfusion of ≥ 2 units of red blood cells (RBCs) within the 60 days before enrollment
    b) Currently has an active infection requiring systemic treatment
    c) Known infection with human immunodeficiency virus (HIV), hepatitis
    B, or hepatitis C
    d) Currently has uncontrolled hyperammonemia (ammonia ≥ 100 μmol/L)
    e) Is currently participating in another therapeutic clinical trial
    f) Has received any investigational agent (other than pegzilarginase)
    within 30 days of enrollment
    g) If female, is lactating or breast feeding
    E.5 End points
    E.5.1Primary end point(s)
    Safety and tolerability will be assessed by:
    • Adverse events (AEs)/serious AEs (SAEs)
    • Physical examinations
    • Vital signs
    • Electrocardiograms (ECGs)
    • Clinical laboratory studies (serum chemistries, hematology, coagulation, urinalysis)
    • Low plasma arginine levels associated with clinically significant symptoms
    • Clinically significant hyperammonemia
    • Immunogenicity safety measures(anti-drug antibodies [ADAs], anti-polyethylene glycol [PEG] antibodies)
    E.5.1.1Timepoint(s) of evaluation of this end point
    BL=Baseline; EOT=End of Treatment; Wk= Week; QW=weekly
    Adverse events* & Vital signs: BL, QW 1-48, QW 52-192 & EOT
    (*The reporting period is from the signing of the consent form)
    Physical examinations: BL, Wk 12, Wk 24, 48, 72, 96, 144 & EOT
    ECG: BL, Wk 12, 24, 36, 48, 96, 144 & EOT
    Clinical lab studies: BL, Wk 1, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96,108, 120, 132, 144, 168, 192 & EOT
    Arginine levels: QW 1-24, QW 25-28, Wk 30, 32, 34, 36, 38, 40, 42, 44, 48, every other week for Wk 52 -96, every 12 weeks for Wk 108-144, Wk168, 192 & EOT
    Hyperammonemia: BL, Wk 1, 4, 8, 12, 16, 20, 24, 32, 36, 48, 60, 72, 84 and 96
    Immunogenicity assessments: Wk 1, 4, 8,12,20, 28, 36,48, 60, 72, 84, 96, 108, 120, 132, 144 & EOT
    E.5.2Secondary end point(s)
    • Changes in plasma arginine levels
    • Changes in plasma guanidino compound levels
    • PK parameters
    • Additional PK
    • Neurological/neuromotor manifestations, using functional and spasticity measurements:
    o Six-Minute Walk Test (6-MWT)
    o Berg Balance Scale (BBS)
    o Gross Motor Function Measure (GMFM)
    o Modified Ashworth Scale (MAS)
    o Purdue Pegboard Test
    • Other manifestations of Arginase I deficiency
    o Seizure frequency
    o Frequency of hyperammonemic episodes, as measured from laboratory evaluations of ammonia levels and relevant AEs
    o Incidence of transaminase elevations, as measured from laboratory evaluations of liver function tests and relevant AEs
    E.5.2.1Timepoint(s) of evaluation of this end point
    BL=Baseline; EOT=End of Treatment; Wk=Week; QW=weekly
    Guanidino compounds: QW1-24, QW25-28, Wk 30, 32, 34, 36, 38, 40, 42, 44, 48, 52 -96 every other wk, every 12 weeks (Wk 108-144), Wk168, 192&EOT
    PK profile: Wk 1, 8, 24, 25, 26, 27, 28, 32, 36
    Additional PK: Additional PK samples for pegzilarginase will be collected during SC dosing after the patient has received a minimum of 4 consecutive doses of the IMP with no missed doses or changes in dose levels. This sampling will occur at the subject’s next regularly scheduled visit (neuromotor &/or neurocognitive assessments) based on the subject’s availability for repeat samples.
    Neurological/neuromotor, adaptive behavior, & QOL assessments: BL, Wk 12, 24, 36, 48, 72, 96, 120, 144 &EOT
    Seizure frequency: BL, QW1-48, QW 52-144,192&EOT
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    United States
    Portugal
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS (last visit of the last subject)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 9
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 5
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patient or legal guardian is able & willing to provide written informed consent and where required assent, and to comply with all requirements of study participation, prior to any screening procedures.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3
    F.4.2.2In the whole clinical trial 14
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Drug will be made available under approved local law until Market Authorization.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-12-15
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