| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mucopolysaccharidosis type II |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.1 |
| 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 |
|
| 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 JR-141 on CNS symptoms in MPS II patients
* To demonstrate the efficacy of JR-141 on somatic symptoms in MPS II patients
* To evaluate the safety of JR-141 in MPS II patients
* To evaluate the PKs of JR-141 in MPS II patients
|
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A patient who voluntarily signs an IRB or Independent Ethics Committee (IEC)-approved written ICF. If the patient is aged under 18 years (aged under 16 years in the UK) at the time of enrollment or willingness to participate in the study cannot be confirmed due to MPS II-related intellectual disability, the patient’s legally acceptable representative (e.g., his parents or guardians) may sign the informed consent on behalf of the patient. Written informed assent should be obtained from the patient, wherever possible.
2. Patients with confirmed diagnosis of MPS II, based on all of the following criteria:
1) Deficient activity of IDS in leucocytes, plasma or fibroblasts defined by 10% or less of the lower limit of the measuring laboratory normal range unless the hospital or laboratory has established different criteria
2) Documented mutation identified in the IDS gene
3) Increased levels of urinary glycosaminoglycans (GAGs) (or uronic acid) or clinical symptoms and signs consistent with MPS II (such as dysostosis multiplex, coarse facies, cardiac valve disease, neuronopathic, chronic pulmonary disease, hernias, kyphosis, joint contractures, carpal tunnel syndrome, etc)
3. Naïve patients or patients who are receiving stable enzyme replacement therapy (ERT) with idursulfase for more than 12 weeks before starting administration of JR-141 or idursulfase for this study.
4. Cohort A
- Patients aged 36-42 months old at the time of ICF signing: patients must have a standard score on the cognitive domain measured by the BSID-III of 85 or less at screening
- Patients aged 43-71 months old at the time of ICF signing: patients must EITHER have
1. A development quotient (DQ) on the cognitive domain measured by the BSID-III between 20 and 85 at screening
2. A composite standard score on Nonverbal Index (NVI) measured by the KABC-II of 85 or less at screening for only who are able to perform the KABC-II
- Patients aged 30-35 months old at the time of randomization and who are judged as having the severe phenotype by the Expert Board based on presence of one of the following mutations in the IDS gene and other information such as high CSF HS concentrations:
1) Large deletion or rearrangement
2) Small insertions or deletions that are out of frame
3) Missense mutations, nonsense mutations, in frame inserts or deletions that involve neuronopathic disease in either another family or the patient's family members.
5. Cohort B
-Patients 6 years of age or older at the time of ICF signing.
-Intelligence quotient (IQ) measured by Wechsler test (WISC-V or WAIS-IV) is 70 or higher at screening.
-Enrollment of subjects in Cohort B is contingent on the availability in that country of a validated country-specific version of the test (either WISC-V, WAIS-IV, T.O.V.A).
-Patients with 1SD deficiency in the omission errors or variability domains of the T.O.V.A. test or Processing Speed or Working memory on the Wechsler tests at screening.
6. Patients or patients whose partners are of child-bearing potential agree to use a medically accepted, highly effective method of contraception being use of condoms from the time of informed consent to 90 days after the final administration or vasectomy at least 13 weeks prior to signing informed consent. Alternatively, true abstinence is acceptable when it is in line with the subject's preferred and usual lifestyle. If a subject is usually not sexually active but becomes active, they, must comply with the contraceptive requirements detailed above. Study participants are strongly encouraged to discuss with their Partners the use of an additional approved method of effective contraception such as:
• Partner’s use of combined (estrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation:
- oral
- intravaginal
- transdermal
• Partner’s use of progestogen-only hormonal contraception:
- oral
- injectable/implantable
- intrauterine hormone-releasing system (IUS)
• Partner’s use of implantable intrauterine device (IUD)
• Surgical sterilization (for example, vasectomy or bilateral tubal occlusion)
• Partner’s use of female cap or diaphragm (double barrier)
7. For subjects with hearing impairment requiring hearing aid(s), every effort has been made to encourage compliance with the use of functioning hearing aid(s) before baseline neurocognitive assessments, and parent/legally acceptable representative or subject agrees to encourage wearing them during the study and on neurocognitive testing days. |
|
| E.4 | Principal exclusion criteria |
1. A patient with a history of engrafted hematopoietic stem cell transplantation (HSCT), with successful engraftment.
2. A patient who has received gene therapy treatment at any point.
3. A patient who is judged by the principal investigator or sub-investigator as being unable to undergo lumbar puncture, including those who has difficulties in taking position for lumbar puncture due to joint contracture or those who is likely to experience breathing difficulties during the lumbar puncture process.
4. A patient who is enrolled in another clinical study that involves clinical investigations or use of any investigational product (drug or device) within 4 months before obtaining informed consent.
5. A patient who is unable to comply with the protocol (e.g., is unable to return for safety evaluations or is otherwise unlikely to complete the study) as determined by the principal investigator or sub-investigator.
6. A patient who is judged by the principal investigator or sub-investigator to be ineligible to participate in the study due to a history of serious drug allergy or sensitivity including anesthesia or hypersensitivity to any component of JR-141 or idursulfase.
7. A patient who has a known or suspected local or general infection or is at risk of abnormal bleeding due to medical conditions* or therapies the investigator classifies as causing the patient to be ineligible to participate in the study.
8. A patient who has documented mutation of other genes, including loci adjacent to the IDS gene (e.g., fragile X mental retardation [FMR1] or AF4/FMR2 family member 2[i.e., AFF2 or FMR2]), that are known to be associated with developmental delay, seizures, or other significant CNS disorders.
9. A patient who has documented loss of activity of sulfatases other than IDS, indicating multiple sulfatase deficiency.
10. A patient who has had a ventriculoperitoneal (VP) shunt placed or any other brain surgery, or has a clinically significant VP shunt malfunction within 30 days of screening (Patients may be rescreened after the 30-day waiting period has elapsed).
11. A patient who is full time employee of the Sponsor or research site personnel directly affiliated with this study or their immediate family members, defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
12. A patient who otherwise is judged by the principal investigator or sub-investigator to be ineligible to participate in the study.
[Only in France]
13. Persons deprived of their liberty by a judicial or administrative decision, according to article L. 1121-6 of the Public Health Code (Code de la santé publique, CSP), adults who are the subject of a measure of legal protection or unable to express their consent according to article L. 1121-8 of the CSP.
* Medical Conditions:
1. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis)
2. Evidence or history of significant active bleeding or coagulation disorder or use of non-steroidal anti-inflammatory drugs or other drugs that affect coagulation or platelet function within 14 days prior to lumbar catheter insertion
3. Allergy to lidocaine (Xylocaine®) or its derivatives
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Change in level of CSF HS from baseline to Week 53 in Cohort A
- Change in the raw scores from baseline to Week 105 measured by the BSID-III (cognitive domain) in Cohort A
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Change in the growth scores of cognitive domain measured by the BSID-III from baseline to Week 105 in Cohort A
- Change in the age equivalent scores of adaptive behavior measured by the VABS-II -from baseline to Week 105 in Cohort A
- Relative change in liver volume relative to body weight from baseline to Week 53 in Cohort A and Cohort B
- Relative change in spleen volume relative to body weight from baseline to Week 53 in Cohort A and Cohort B
- Relative change in distance walked using the 6-minute walk test from baseline to Week 53 in Cohort B |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Central Nervous System symptom: Week 105
Somatic symptom: Week 53 |
|
| 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 | 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 |
|
| 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 | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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
| 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 | 11 |
| 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 |
| Colombia |
| Brazil |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| Türkiye |
|
| 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
|
The end of the study is defined as the date of the last visit of the last subject in the study or last scheduled procedure shown in the Schedule of Activities for the last subject in the trial globally. Eligible subjects who complete the trial will be invited to participate in the follow on JR-141 long term 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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