E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mucopolysaccharidosis Type II [MPS II] |
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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] - Nervous System Diseases [C10] |
MedDRA Classification |
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 |
1. To evaluate the CNS activity of DNL310 vs idursulfase as measured by the cerebrospinal fluid (CSF) concentration of heparan sulfate (HS) in participants with the neuronopathic form of mucopolysaccharidosis type II (nMPS II)
2. To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on adaptive behavior as assessed by the Vineland Adaptive Behavior Scale, Third Edition (Vineland-3), in nMPS II participants |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on neurocognitive development, as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), in nMPS II participants
2. To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on adaptive behavior as assessed by the Vineland-3 ABC in nMPS II participants
3. To evaluate the efficacy of DNL310 vs idursulfase on neuronal injury in nMPS II participants
4. To evaluate the clinical efficacy of DNL310 vs idursulfase on physical endurance as measured by the Six-Minute Walk Test (6MWT) in participants with the nnMPS II
5. To evaluate the onset and durability of peripheral efficacy of DNL310 vs idursulfase as measured by the urine concentration of total glycosaminoglycans (GAGs) by a massspectrometry–based detection method in nMPS II and nnMPS II participants
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participants aged ≥2 to <6 years (Cohort A) or ≥6 to <26 years (Cohort B)
2. Confirmed diagnosis of MPS II (for Cohort A, nMPS II; for Cohort B, nnMPS II)
3. For non-run-in Cohort A and Cohort B only: Be on maintenance ERT and have tolerated a minimum of 4 months (ie, 16 weeks) of idursulfase therapy during the period immediately prior to screening. |
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E.4 | Principal exclusion criteria |
1. Have documented pathogenic or likely pathogenic variants that are known to cause developmental delay or decline, cognitive dysfunction, seizures, or other significant CNS disorders.
2. Previously received an IDS gene therapy or stem cell therapy
3. Received any CNS-targeted MPS ERT within 6 months prior to screening
4. Have a contraindication for lumbar punctures and/or magnetic resonance imaging (MRIs)
5. Participated in any other investigational drug study or used an investigational drug within 60 days prior to screening or intend to receive another investigational drug during the study
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Percent change from baseline in CSF HS concentration at Week 24 (Cohort A only)
2. Change from baseline in the Vineland-3 ABRS-8 at Week 96 (Cohort A only) |
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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) |
1. Change from baseline in the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at Week 96 (Cohort A only)
2. Change from baseline in the Vineland-3 ABC at Week 96 (Cohort A only)
3. Change from baseline in serum NfL at Week 96 (Cohort A only)
4. Change from baseline in distance walked (meters) in the 6MWT at Week 48 (Cohort B only)
5. Percent change from baseline in the sum of urine HS and DS concentrations at Week 48 (Cohorts A and B) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Week 96 2. Week 96 3. Week 96 4. Week 48 5. Week 48 |
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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 | 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 |
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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 | 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 | 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) | 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 | 12 |
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 |
Australia |
Brazil |
Canada |
Mexico |
United Kingdom |
United States |
Belgium |
Czechia |
France |
Germany |
Italy |
Netherlands |
Spain |
Sweden |
Türkiye |
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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 end of this study is defined as the date on which LPLV occurs. LPLV is expected to occur approximately 2 years or 2.5 years (for run-in participants) after the last participant is enrolled if the last participant is in Cohort A, or approximately 1 year or 1.5 years (for run-in participants) after the last participant is enrolled if the last participant is in Cohort B, whichever has the later last study visit assessment. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |