E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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 deficiency |
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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 | 19.1 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056917 |
E.1.2 | Term | Hunter's syndrome |
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 |
The primary objective of this study is to evaluate long-term safety in patients with Hunter syndrome and cognitive impairment who are receiving intrathecal idursulfase-IT and intravenous (IV) Elaprase® enzyme replacement therapy (ERT) |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate long term clinical efficacy outcomes in patients with Hunter syndrome and cognitive impairment who are treated with idursulfase-IT in conjunction with Elaprase therapy with respect to the following:
• Cognitive function as measured by General Conceptual Ability (GCA), the cluster areas and subtests of the Differential Abilities Scale, 2nd edition (DAS-II) or the British Abilities Scales, Second Edition (BAS-II), or domains of the Bayley Scales of Infant Development, Third Edition (BSID-III)
• Adaptive behavior as measured by the Adaptive Behavior Composite (ABC) score and standard domain scores of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
• Brain structure volume as measured by magnetic resonance imaging (MRI)
For PK/PD, health economics and outcome research and device objectives see protocol section 2.3 - 2.5.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must have completed Visit Week 52 assessments in Study HGT-HIT-094
2. The patient’s parent(s) or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent form after all relevant aspects of the study have been explained and
discussed. Consent of the patient’s parent(s) or legally authorized guardian(s) and the patient’s assent, as relevant, must be obtained
3. The patient has continued to receive Elaprase on a regular basis in Study HGT-HIT-094 |
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E.4 | Principal exclusion criteria |
1. The patient has experienced, in the opinion of the Investigator, a safety or medical issue that contraindicates treatment with idursulfase-IT, including, but not limited to, uncontrolled seizure disorder, bleeding disorder, and clinically relevant hypertension
2. The patient has a known hypersensitivity to any of the components of idursulfase-IT
3. The patient has clinically relevant intracranial hypertension
4. The patient is enrolled in another clinical study, other than HGT-HIT-094, that involves clinical investigations or use of any investigational product (drug or [intrathecal/spinal] device) within 30 days prior to study enrollment or at any time during the study
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 condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use, including:
a. The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device
b. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the Investigator
c. The patient’s drug therapy requires substances known to be incompatible with the materials of construction
d. The patient has a known or suspected local or general infection
e. The patient is at risk of abnormal bleeding due to a medical condition or therapy
f. The patient has one or more spinal abnormalities that could complicate safe implantation or fixation
g. The patient has a functioning CSF shunt device
h. The patient has shown an intolerance to an implanted device |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety will be assessed during the study by the following:
• adverse events (AEs) (by type, severity, and relationship to treatment [idursulfase-IT, the IDDD, device surgical procedure, or IT administration process] and IV Elaprase infusion)
• changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)
• vital signs
• 12-lead ECG recordings
• CSF laboratory parameters (chemistries, cell counts)
• anti-idursulfase antibodies in CSF and serum, including determination of anti-idursulfase antibodies having enzyme neutralizing activity |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse events (AEs) will be assessed during all the study. CSF assessments (other than standard chemistry) and clinical laboratory tests of blood and urine will be performed every 12 weeks. 12-lead ECG will be performed every 48 weeks.
For all other endpoints please refer to Appendix 1 to 12 of the protocol.
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E.5.2 | Secondary end point(s) |
• Change from baseline in standard scores in cluster areas of the DAS-II/BAS-II: GCA, Verbal, Nonverbal, Spatial, and Special Nonverbal Composite (SNC), or the age equivalents and Development Quotient (DQ) from the BSID-III domains: Cognitive and Language
• Change from baseline in standard scores of the VABS-II domains: ABC, Communication, Daily Living Skills, Socialization, and Motor Skills
• Change from baseline in age equivalents, developmental quotients, and T-scores for the subtests of the DAS-II: Verbal Comprehension, Picture Similarities, Naming Vocabulary,
Pattern Construction, Matrices, and Copying for the DAS-II/Early Years and Recall of Designs, Word Definitions, Pattern Construction, Matrices, Verbal Similarities, and Sequential and Quantitative Reasoning for the DAS-II/BAS-II/School School Years
• Change from baseline in age equivalents, developmental quotients, and V-scale scores of the VABS-II subdomains: Communication (Receptive, Expressive, Written), Daily Living Skills
(Personal, Domestic, Community), Socialization (Interpersonal Relationships, Play and Leisure Time, Coping Skills), Motor Skills (Gross, Fine)
• Change from baseline in the V-scale scores and observed maladaptive levels of the VABS-II Maladaptive Behavior Index and its subscales (Internalizing, Externalizing)
• Change from baseline in Brain Total Intracranial Volume, Brain Total Tissue Volume, Brain Total White Matter, Brain Total Gray Matter, and Total CSF Volume
Health Economics and Outcomes Research Endpoints:
• Health status dimensions as obtained by the EQ-5D questionnaire
• Health care resource utilization will be assessed using the Healthcare Utilization Questionnaire (HCUQ) and Caregiver Impact Questionnaire
• Functional status as obtained by the HS-FOCUS form
Pharmacokinetic and Pharmacodynamic Endpoints:
• Serum concentration of idursulfase and serum PK parameters after IT administration
• CSF concentration of idursulfase
• Change from baseline in the concentration of GAG in CSF
• Change from baseline in the concentration of GAG in urine
SOPH-A-PORT Mini S Assessments:
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, device function, device longevity, and AEs associated with the implant surgery or device. These data will be collected on the patient’s eCRF from the time of initial implantation. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
*Initial Treatment Phase: Patients not treated in Study HGT-HIT-094 undergo neurodevelopmental assessment at week 16, 28, 40; EQ-5D at week 4, 16, 28 and 40; Health Resource Utilization and Impact Questionnaire and HS-FOCUS at baseline, week 4, 16, 28 and 40.
*Extended Treatment Phase:
- Patients not treated in Study HGT-HIT-094 undergo all assessment above at week 52 and thereafter every 24 weeks.
- Patients treated in Study HGT-HIT-094 do not undergo neurodevelopmental assessment and EQ-5D at week 52 but thereafter every 24 weeks. Health Resource Utilization and Impact Questionnaire and HS-FOCUS will be performed at week 52 and thereafter every 24 weeks.
For all other endpoints please refer to Appendix 1 to 12 of the protocol. |
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of Life and Health Economics |
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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) | Yes |
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.8.2.4 | 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 | 4 |
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 |
Argentina |
Australia |
Canada |
Colombia |
France |
Mexico |
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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The study will conclude after the last patient has completed his last visit. |
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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 | 5 |
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 | 5 |
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 |