E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Arginase 1 deficiency Hyperargininemia |
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E.1.1.1 | Medical condition in easily understood language |
Arginase deficiency Hyperargininemia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10062695 |
E.1.2 | Term | Arginase deficiency |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the long-term safety and tolerability of intravenous (IV) or subcutaneous (SC) pegzilarginase administered for up to 3 years in patients with Arginase I deficiency and hyperargininemia |
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E.2.2 | Secondary 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 guanidinocompounds • 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 o Berg Balance Scale o Gross Motor Function Measure o Modified Ashworth Scale 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 AEB1102 and that the patient continues to meet the following criteria from the 101A study: a) Is male or female: pediatric patients ≥ 2 to < 18 years of age and adult patients ≥ 18 years of age b) Has documented diagnosis of Arginase I deficiency, with: i) Known mutation in the Arginase I gene OR ii) Known deficiency in red blood cells (RBCs) arginase activity c) Has adequate organ function defined as follows: i) Bone Marrow: Hemoglobin ≥10 g/dL; absolute neutrophil count ≥ 1.5x10^9/L; platelet count ≥ 100,000/μL ii) Hepatic: transaminase levels (aspartate aminotransferase/alanine aminotransferase ≤ 2.5-times ULN; total bilirubin ≤ 2.0 mg/dL iii) Renal: serum creatinine < 1.5x 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 |
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E.4 | Principal 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 RBC 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 (confirmed 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 |
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E.5 End points |
E.5.1 | Primary 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 (levels of anti-drug antibodies [ADAs] and anti-polyethylene glycol [PEG] antibodies) |
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E.5.1.1 | Timepoint(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 52-144 & EOT Physical examinations: BL, Wk 12, Wk 24, 48, 72, 96, 120, 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, 104, 112, 120, 128, 136, 144 & EOT Arginine levels: QW 1-24, QW 25-28, Wk 30, 32, 34, 36, 38, 40, 42, 44, 48, prior to dosing every 2nd dose during Wk 52 -140, 144 & EOT Hyperammonemia: BL, Wk 1, 4, 8, 12, 16, 20, 24, 32, 36, 44, 48, 60, 72, 84, 96, 108, 120, 132, 144 & EOT Immunogenicity assessments: Wk 1, 4, 8,12,20, 28, 36,48, 60, 72, 84, 96, 108, 120, 132, 144 & EOT |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints: • Changes in plasma arginine levels • Changes in plasma guanidino compound levels • PK parameters • 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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
BL= Baseline; EOT=End of Treatment; Wk= Week; QW=weekly
Guanidino compounds: QW 1-24, QW 25-28, Wk 30, 32, 34, 36, 38, 40, 42, 44, 48, prior to dosing every 2nd dose during Wk 52 -140, 144 & EOT
PK profile: Wk 1, 8, 24, 25, 26, 27, 28, 32 and Wk 144
Neurological/neuromotor, adaptive behavior, and QOL assessments: BL, Wk 12, 24, 36, 48, 72, 96, 120, 144 & EOT
Seizure frequency: BL, QW 1-48, QW 52-144 & EOT |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Portugal |
United Kingdom |
United States |
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E.8.7 | Trial 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
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LVLS (last visit of the last subject) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |