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 |
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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 demonstrate the efficacy of pegzilarginase relative to placebo based on a statistically significant decrease in plasma arginine concentrations |
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E.2.2 | Secondary objectives of the trial |
1) To demonstrate the efficacy of pegzilarginase relative to placebo based on a statistically significantly greater proportion of clinical responders.
2)To compare the proportions of subjects with response in the individual components of the key secondary endpoint between pegzilarginase and placebo.
3)To compare pegzilarginase with placebo with respect to the number of individual components of the key secondary endpoint exhibiting response.
4)To compare pegzilarginase with placebo with respect to the proportion of subjects whose endpoint arginine value falls below target guidance of 200 μmol/L.
5) To compare pegzilarginase with placebo with respect to the proportions of subjects whose endpoint arginine value falls within the normal range of 40-115μmol/L.
6) To compare pegzilarginase with placebo for changes in guanidino compounds.
7) To evaluate the safety and immunogenicity of pegzilarginase.
8) To further characterize the pharmacokinetic profile of pegzilarginase. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
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. For entry into this study, subjects must also fulfill the following plasma arginine criterion:
a. The average of all measured values of plasma arginine during the screening period prior to the randomization visit (Visit 1, Study Day 0) is ≥ 250 μmol/L.
b. 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 endpoint. To be considered assessable, the subject must be able to complete the assessment, and must have a baseline deficit in the specific component as defined in the protocol.
5. Have received documented confirmation from the investigator and/or dietician that the subject is capable of maintaining their diet in accordance with dietary information presented in the protocol, i.e., is capable of maintaining their current level of protein consumption including natural protein and essential amino acid supplementation.
6. Subjects receiving ammonia scavenger therapy, anti-epileptic drugs, and/or medications for spasticity (e.g., 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 child-bearing 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 (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). |
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E.4 | Principal exclusion criteria |
1. Hyperammonemic episode (defined as an event in which a subject has an ammonia level ≥100 umol/L 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 (e.g., 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 within last 6 months for spasticity related complications.
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 on this study.
10. Previous liver or hematopoietic transplant procedure. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in plasma arginine after 24 weeks of study treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 24 weeks of study treatment |
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E.5.2 | Secondary end point(s) |
1) Clinical response is defined as a subject exhibiting
either a mobility response or an adaptive behavior
response as defined in the protocol.
2)Response for each component is defined in the protocol.
3)For each subject, the endpoint is the number of
components with response (0, 1, 2, 3, …)
4)A subject is considered a responder if their
endpoint arginine value is <200 μmol/L, and a non-responder otherwise
5)A subject is considered a responder if their
endpoint arginine value is ≤115 μmol/L, and a non-responder otherwise.
6)Change from baseline in guanidino compounds
after 24 weeks of study treatment
7)Adverse events and anti-drug antibodies will be
collected.
8)Pharmacokinetic data will be collected for use in a
population pharmacokinetics (PK) model. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 24 weeks of study treatment. |
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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 | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Austria |
France |
Germany |
Italy |
Portugal |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 1 |