E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonsense mutation Mucopolysaccharidosis Type I |
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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] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10056886 |
E.1.2 | Term | Mucopolysaccharidosis I |
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 determine whether treatment with ataluren can reduce urinary GAG levels in patients with nmMPS I, as assessed by the conventional method for assessing GAG levels in liquid urine |
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E.2.2 | Secondary objectives of the trial |
• To characterize the safety profile of ataluren in patients with nmMPS I
• To evaluate the PK of ataluren in patients with nmMPS I
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Evidence of signed and dated informed consent document(s) indicating that the study candidate (and/or a parent/legal guardian) has been informed of all pertinent aspects of the study. Note: If the study candidate is considered a child under local regulation, a parent or legal guardian must provide written consent prior to initiation of study screening procedures and the study candidate may be required to provide written assent. The rules of the responsible institutional review board/independent ethics committee (IRB/IEC) regarding whether one or both parents must provide consent and the appropriate ages for obtaining consent and assent from the patient should be followed.
2. Age ≥2 years.
3. Clinical diagnosis of MPS I, confirmed by measurable clinical signs and symptoms of MPS Iand a documented fibroblast or leukocyte α-L-iduronidase enzyme activity level of less than 10% of the lower limit of the normal range of the measuring laboratory.
4. Documentation of the presence of a nonsense mutation in at least 1 allele of the α L iduronidase (IDUA) gene.
5. Verification that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the IDUA gene.
6. Confirmed screening laboratory values within the central laboratory ranges specified in the protocol |
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E.4 | Principal exclusion criteria |
1. Prior BMT/HSCT.
2. Treatment with ERT within 2 months prior to enrollment.
3. Any change (initiation, change in type of drug, dose modifications, schedule modifications, interruption, discontinuation, or re-initiation) in chronic treatment for MPS within 2 months prior to start of Screening.
4. Exposure to another investigational drug within 3 months prior to enrollment.
5. Ongoing participation in any other therapeutic clinical trial.
6. Is pregnant or lactating. Female patients of childbearing potential must have a negative pregnancy test [β-human chronic gonadotropin (hCG)] at Screening.
7. Ongoing warfarin, phenytoin or tolbutamide therapy.
8. Ongoing IV aminoglycoside use.
9. Ongoing immunosuppressive therapy (other than corticosteroids).
10. Known portal hypertension.
11. Prior or ongoing medical condition (eg, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the patient, makes it unlikely that the course of study drug administration or follow-up would be completed, or could impair the assessment of study results.
12. Known hypersensitivity to any of the ingredients or excipients of the study drug (polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, colloidal silica, or magnesium stearate).
13. Surgery within 30 days prior to enrollment, or anticipated surgery during study participation.
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in urinary GAG levels (total and subtypes, eg, DS and HS) in each dose cycle, as assessed by the conventional method for assessing GAG levels in liquid urine. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Overall safety profile of ataluren characterized by type, frequency, severity, timing, and relationship to study drug of any adverse events; new physical examination, laboratory test, or electrocardiogram (ECG) abnormalities; drug discontinuations due to adverse events; and serious adverse events (SAEs)
• Ataluren plasma concentrations before and 2 hours after morning drug administration at the beginning of each cycle and before and 2, 4, and 6 hours after morning drug administration at the end of each cycle, as assessed by a validated bioanalytical method.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety: Every visit
PK: day 1, 42, 70, 112, 140 and 182 |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |