STUDY TO EVALUATE THE SAFETY AND ESTABLISH A SAFE DOSE OF DNL310 IN PEDIATRIC SUBJECTS WITH HUNTER SYNDROME
- Conditions
- Hunter Syndrome (Mucopolysaccharidosis Type II [MPS II])MedDRA version: 20.0Level: LLTClassification code 10056917Term: Hunter's syndromeSystem Organ Class: 100000004850Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
- Registration Number
- EUCTR2019-004909-27-GB
- Lead Sponsor
- Denali Therapeutics Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- Male
- Target Recruitment
- 16
1) Informed consent signed by the subject, if able to legally provide consent, or signed by the parent(s) or LAR and subject assent if required based on local regulations, Ethics Committee (EC), and subject age
2) Body weight at screening as follows:
• Cohort A: = 19 kg
• Cohort B: = 10 kg
3) Age at study entry as follows:
• Cohort A (first 4 subjects): nMPS II subjects aged 5 to 10 years, inclusive, at screening
• Cohort B: subjects aged 2 to 18 years, inclusive, at screening, after DMC recommendation and MHRA approval to expand both the age range and include all phenotypes of MPSII (e.g., nMPS II, non-neuronopathic, or unknown).
Cohort B will have 3 subcohorts (B1, B2, B3) based on starting dose. Subjects will be assigned sequentially to subcohort B1, B2, and B3, but stratified by age, with the first 2 subjects aged 2 to < 5 years enrolled to B1 and a minimum of one subject aged 10 to 18 years in each group.
4) Subject and parent(s) or LAR are willing and have the ability to comply with protocol requirements, according to the investigator’s judgment
5) Male subjects with a confirmed diagnosis of MPS II based on the following:
• Reduced IDS activity in plasma, white blood cells, and/or skin fibroblasts consistent with MPS II (= 10% of the lower limit of the normal range, based on the testing laboratory’s range), and
• A documented mutation in the IDS gene
6) Subjects enrolled prior to DMC and MHRA approval of enrolling non-neuronopathic subjects must have nMPS II based on at least one of the following:
• Cognitive ability standard score = 85 at the screening assessment and/or a documented decline of at least 7.5 points in the standard score in the previous 6 to 18 months based on any one of the following tests, all performed without clinically significant hearing loss or with hearing aids present:
o BSID (BSID-III preferred; BSID-II is acceptable if BSID-III unavailable)
o NVI of the KABC-II
o DAS-II
o Mullen Scales of Early Learning
o Wechsler Preschool and Primary Scale of Intelligence IV
• The subject has the same genetic mutation as a blood relative with confirmed nMPS II. Confirmed nMPS II requires a genetic diagnosis of MPS II and clinically established cognitive delay or regression based on a standard score of cognitive ability = 85, and/or a documented decline of at least 7.5 points in the standard score in the previous 6 to 18 months based on any one of the following tests, all performed without clinically significant hearing loss or with hearing aids present:
o BSID (BSID-III preferred; BSID-II is acceptable if BSID-III unavailable)
o NVI of the KABC-II
o DAS-II
o Mullen Scales of Early Learning
o Wechsler Preschool and Primary Scale of Intelligence IV
• The subject has a large deletion(s) or rearrangement(s) in the IDS gene or other definitive mutation indicative of nMPS II as determined by an independent external review panel
7) For subjects receiving IV IDS ERT (e.g., Elaprase): tolerated a minimum of 4 months of therapy during the period immediately prior to screening
8) For subjects with hearing impairment requiring hearing aids, every effort has been made to encourage compliance with the use of functioning hearing aid(s) before baseline neurocognitive assessments, and parent/LAR or subject agrees to encourage wearing them during the study and on neurocognitive testing days.
9) When engaging in sex with a woman of childbearing potential, both the male subject and his female partner must use h
1) Unstable or poorly controlled medical condition(s) or significant medical or psychological comorbidity or comorbidities) based on medical history, screening laboratory values, ECGs, or other screening procedures that, in the opinion of the investigator, would interfere with safe participation in the trial or interpretation of study assessments
2) Use of any CNS-targeted MPS II ERT (e.g., IT IDS, transferrin- or insulin receptor–mediated IDS delivery to CNS) within 3 months before Study Day 1 for subjects aged = 5 years, and within 6 months before Study Day 1 for subjects aged < 5 years. Subjects may be rescreened for this study after the appropriate washout has been completed.
3) Use of an IDS gene therapy or stem cell therapy, including hematopoietic stem cell transplantation, at any time
4) Use of genistein within 30 days of screening, or intended use of genistein during the study. Subjects who discontinue genistein may be rescreened after a 30-day washout has been completed.
5) Participation in any other investigational drug trial or use of an investigational drug within 60 days prior to screening and thereafter. Subjects may rescreen for this study after the 60-day washout has been completed.
6) Documented mutation of other genes, including loci adjacent to the IDS gene (e.g., fragile X mental retardation 1 [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
7) Documented loss of activity of sulfatases other than IDS, indicating multiple sulfatase deficiency
8) Clinically significant thrombocytopenia (< 100 GI/L [100,000/mm3]), other clinically significant coagulation abnormality, or significant active bleeding, or require treatment with an anticoagulant or more than two antiplatelet agents. Subjects excluded for this reason may be rescreened for this study at least 30 days after the coagulopathy, anticoagulant, or antiplatelet treatments have stopped.
9) Contraindication for LPs, for any reason
10) Have a clinically significant history of stroke, status epilepticus, head trauma with loss of consciousness, or any CNS disease that is not Hunter syndrome–related within 1 year of screening
11) Have had a ventriculoperitoneal (VP) shunt placed or any other brain surgery, or have a clinically significant VP shunt malfunction within 30 days of screening. Subjects may be rescreened after the 30-day waiting period has elapsed.
Note: subjects who have newly diagnosed intracranial hypertension (e.g., CSF opening pressure > 30 cm H2O) requiring placement of a VP shunt may rescreen 30 days after shunt placement.
12) Have any clinically significant CNS trauma or disorder, including severe untreated intracranial hypertension, that, in the opinion of the investigator, may interfere with assessment of study endpoints or make participation in the study unsafe
13) History of serious adverse reaction to IDS enzyme or any component of the IMP, e.g., hypersensitivity or anaphylaxis requiring hospitalization, that cannot be managed with SOC treatment for infusion reactions
14) Have had a donation or loss of more than 10% total blood volume over 8 weeks preceding entry into the treatment period. Subjects excluded for this reason may be rescreened after the 8 weeks have elapsed.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method