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 safety and tolerability of intravenous (IV) administration of AEB1102 in patients with Arginase I deficiency and hyperargininemia |
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E.2.2 | Secondary objectives of the trial |
1) To determine the effects of AEB1102 administered IV on plasma arginine concentrations 2)To determine the effects of AEB1102 administered IV on plasma guanidino compounds 3) To characterize the pharmacokinetic (PK) profile of AEB1102 administered IV |
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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:
PART 1 1. Is male or female: Pediatric patients ≥ 2 to < 18 years of age; and adult patients ≥ 18 years of age. 2. Has documented diagnosis of Arginase I deficiency, with: • Hyperargininemia: plasma arginine levels consistently ≥ 2-times the upper limit of normal (ULN) (> 250 μM) AND EITHER • Known mutation in the Arginase I gene OR • Known decrease in arginase activity (< 5%) in red blood cells (RBCs)
3. Has adequate organ function defined as follows: a. Bone Marrow: Hemoglobin ≥10 g/dL; absolute neutrophil count ≥ 1.5x10^9/L; platelet count ≥ 100,000/μL b. Hepatic: transaminase levels (aspartate aminotransferase/alanine aminotransferase ≤ 2.5-times ULN; total bilirubin ≤ 2.0 mg/dL c. Renal: serum creatinine < 1.5x ULN
4. If female and of child-bearing potential, has a negative serum pregnancy test within 7 days before enrollment. 5. If sexually active (male or female), must be surgically sterile, postmenopausal (female), or must agree to use a physician-approved method of birth control during the study and for a minimum of 30 days after the last study drug administration. 6. 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.
PART 2 INCLUSION CRITERION: 1. Did not experience any safety or tolerability event in Part 1 which would preclude continued participation and dosing of AEB1102 |
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E.4 | Principal exclusion criteria |
A patient is excluded from this study if he/she meets any of the following criteria
1. Had transfusion of ≥ 2 units of RBC within the 60 days before enrollment 2. Currently has an active infection of any kind requiring systemic treatment 3. Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C 4. Had severe hyperammonemia requiring hospitalization within the 14 days before enrollment. Had more than 1 episode of hyperammonemia requiring hospitalization within the 30 days prior to enrollment 5. Currently has uncontrolled hyperammonemia (ammonia ≥ 100 μmol/L) 6. Currently has any co-morbid condition that in the opinion of the investigator might compromise the patient's safety, might interfere with participation in the trial, or might interfere with the interpretation of trial results 7. Is currently participating in another therapeutic clinical trial 8. Has received any investigational agent within 30 days of enrollment 9. Has a history of hypersensitivity to polyethylene glycol (PEG) or any other component of the AEB1102 (Co-ArgI-PEG) formulation 10. 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/serious adverse events • Physical examinations • Vital signs • ECGs • Clinical laboratory studies (serum chemistries, hematology, coagulation, urinalysis) • Low plasma arginine levels associated with clinically significant symptoms • Clinically significant hyperammonemia • Immunogenicity assessments (levels of anti-drug antibodies, neutralizing anti-drug antibodies, anti-PEG antibodies) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1 At screening: Physical examinations, Vital signs, Clinical laboratory studies, ECG, Adverse events and Ammonia
At Base line: Adverse events, Arginine and ornithine
Week 1 (Dose 1), 3 (Dose 2*), 5 (Dose 3*), 7 (Dose 4*), 9 (Dose 5-7*) & Follow up (2 weeks after last dose) : All parameters
Week 2, 4, 6, 8 & 10: Vital signs, Adverse events, Plasma Arginine & ornithine
*Doses 2 to 7 only needed if arginine suppression or stopping criteria not met. Procedures would continue on an every 2 week interval.Please refer the protocol for more details.
Part 2 Each patient will receive up to 8 weeks of repeat dose therapy, primary end point measures for part 2 are detailed in the protocol No. CAEB1102-101A (Amendment 2.1, June 30, 2017) Page 18/90, Table 2. |
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E.5.2 | Secondary end point(s) |
Pharmacokinetic analyses • T1/2, Tmax, Cmax, AUC0-t, AUC0-∞, CL, and Vss
Plasma arginine levels • Magnitude, onset, and duration of changes to arginine levels after AEB1102 administration
Plasma guanidino compounds levels • Magnitude, onset, and duration of changes to guanidino compounds levels after AEB1102 administration |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1 AEB1102 PK sampling: Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and Follow up (2 weeks after last dose)
Plasma arginine levels Plasma arginine collection time points will match AEB1102 PK Sampling time points.
Plasma guanidino compounds levels At Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and Follow up (2 weeks after last dose)
Part 2 AEB1102 PK sampling: Week 1, 2, 3, 4, 5, 6, 7, 8 and Follow up (2 weeks after final dose)
Plasma arginine levels Plasma arginine collection time points will match AEB1102 PK Sampling time points.
Plasma guanidino compounds levels At Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8 and Follow up (2 weeks after final dose) |
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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 | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety and tolerability study |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
France |
Portugal |
Spain |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |