E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of Hunter syndrome and cognitive impairment |
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E.1.1.1 | Medical condition in easily understood language |
Hunter Syndrome - Iduronate-2-Sulfatase enzyme defficiency |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10056889 |
E.1.2 | Term | Mucopolysaccharidosis II |
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 the safety and tolerability of ascending doses of idursulfase-IT administered via a surgically implanted intrathecal drug delivery device (IDDD) once monthly for 6 months in pediatric patients with Hunter syndrome who have cognitive impairment and who have previously received and tolerated a minimum of 6 months of treatment with Elaprase® (idursulfase for intravenous administration) |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
a) To determine the concentration of idursulfase in cerebrospinal fluid (CSF) and blood after single and repeated doses of intrathecal idursulfase-IT given in conjunction with Elaprase
b) To determine the effect of intrathecal idursulfase-IT, given in conjunction with Elaprase, on CSF biomarkers (eg, glycosaminoglycans (GAG) and GAG degradation products, sulfated HS/DS oligosaccharides, and markers of lysosomal function)
c) To determine the effects of intrathecal idursulfase-IT, given in conjunction with Elaprase, on urinary GAG and GAG degradation products
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be considered eligible for enrollment:
1a) The patient has a deficiency in iduronate-2-sulfatase enzyme activity of ≤10% of the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory)
AND
1b) The patient has a documented mutation in the iduronate-2-sulfatase gene
OR
The patient has a normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or leukocytes (based on normal range of measuring laboratory)
2) The patient is male and is ≥3 and <18 years of age
3) The patient has evidence at Screening of Hunter syndrome-related cognitive impairment, defined as
a) The patient has an IQ ≤77
OR
b) There is evidence of a change of ≥1 (15 IQ points) but ≤2 (30 IQ points) standard deviations decline from a previous protocol-defined neurodevelopmental assessment. The duration of protocol-defined neurologic involvement is at least 3 months but less than 36 months as documented in the patient’s medical history.
4) The patient has received and tolerated a minimum of 6 months of treatment with weekly intravenous idursulfase, and has received 80% of the total planned infusions within that time frame, including having received 100% of the planned infusions within 4 weeks immediately preceding the surgical implantation of the IDDD.
5) The patient must have sufficient auditory capacity, with or without hearing aids, to complete the required protocol testing, and be compliant with wearing the aid on scheduled testing days.
6) The patient, patient’s parent(s), or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board / Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient. The guardians’ consent and patient’s assent, as relevant, must be obtained. |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria are not eligible for this study:
1) The patient has clinically significant non-Hunter syndrome-related CNS involvement which is judged by the Investigator to be likely to interfere with the accurate administration and interpretation of protocol assessments.
2) The patient’s IQ is ≥ 78
3) The patient has a CNS shunt.
4) The patient has experienced infusion-related anaphylactoid event(s) or has evidence of consistent severe adverse events related to treatment with Elaprase which, in the Investigator’s opinion, may pose an unnecessary risk to the patient.
5) The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to compromised airways or other conditions.
6) The patient has a history of complications from previous lumbar punctures or technical challenges in conducting lumbar punctures such that the potential risks would exceed possible benefits for the patient.
7) The patient or patient’s family has a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns.
8) The patient has a history of poorly controlled seizure disorder.
9) The patient has a significant medical or psychiatric comorbidity(ies) that might affect study data or confound the integrity of study results.
10) The patient is currently receiving chronic psychotropic therapy (eg, neuroleptics, benzodiazepines, antidepressants, anticonvulsants, stimulants) which in the Investigator’s opinion would likely affect the neurocognitive assessments. Intermittent use of selected short half-life agents (benzodiazepine, sedatives, etc) may be permitted as long as there are 5 half-lives between last drug administered and study-related procedures including neurocognitive assessments.
11) The patient has received treatment with any investigational drug or device within the 30 days prior to study entry.
12) The patient has received a cord blood or bone marrow transplant at any time or has received blood product transfusions within 90 days prior to Screening.
13) The patient is unable to comply with the protocol, (eg, has significant hearing or vision impairment, a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, known clinically significant psychiatric/behavioral instability, is unable to return for safety evaluations, or is otherwise unlikely to complete the study), as determined by the Investigator.
14) The patient has skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD.
15) The patient has an opening CSF pressure upon lumbar puncture that exceeds 30.0 cm H2O. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety of intrathecal idursulfase-IT administration, by dose group and treatment status.
Safety will be assessed by adverse events (by type and severity), changes in clinical laboratory testing (serum chemistry including liver function tests, hematology, urinalysis), 12-lead electrocardiograms, CSF chemistries (including cell counts, protein, and glucose), and anti-idursulfase antibodies (in CSF and serum, by isotype: IgG, IgA, IgM, IgE, and antibodies having enzyme neutralizing activity). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening Day -60 to Day 0 and Weeks 3, 7,11, 15, 19, 23, 27 and 30 |
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E.5.2 | Secondary end point(s) |
• Single and repeated dose pharmacokinetic parameters of idursulfase, administered as intrathecal idursulfase-IT, given in conjunction with Elaprase, in CSF and blood • Change from baseline in CSF biomarkers (eg, GAGs, GAG-degradation products, sulfated HS/DS oligosaccharides) by dose group and in comparison with untreated patients • Change from baseline in urinary GAGs and degradation products by dose group and in comparison with untreated patients. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK Sampling in blood - several timepoints up to 24hrs after I2S IT and after Elaprase i.v. |
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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 | Yes |
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 | 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 | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Patients previously received and continue to recieve Elaprase |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
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 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |