leukodystrophy Pelizaeus-Merzbacher disease white matter disease leukodystrophy Pelizaeus-Merzbacher disease white matter disease
Conditions
Interventions
None listed
Sponsors
Ionis Pharmaceuticals, Inc.
Eligibility
Age
2 Years to 17 Years
Inclusion criteria
Inclusion criteria: Key Inclusion Criteria 1. Participant has a holder of parental authority (parent, legal guardian, or caregiver) capable of providing informed consent (signed and dated), able to attend all scheduled study visits and provide feedback regarding the participant’s symptoms and performance as described in the protocol, and able to comply with all study requirements 2. Previous diagnosis of PMD with genetic confirmation of PLP1 gene duplication with molecular confirmation by a CLIA, CE-marked, or equivalent lab provided by the Investigator at Screening. 3. Clinical phenotype and brain imaging consistent with a diagnosis of PMD. 4. Male, 6 months to 17 years old, inclusive, at the time of informed consent. 5. No contraindications for LP’s, blood draws, neuroimaging, sedation (if necessary) or other study procedures. 6. Medically stable, able to undergo sedation or general anesthesia. 7. Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, measurements, and visits.
Exclusion criteria
Exclusion criteria: Key Exclusion Criteria 1. Clinically significant abnormalities in medical history (previous acute coronary syndrome or evidence of renal, impairment within 6 months of Screening, or major surgery within 3 months of Screening) or physical examination. 2. > 2 copies of the PLP1 gene. 3. Unwillingness or inability to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator 4. Platelet count < 100000/mm3 or any other clinically significant laboratory abnormalities that would render a participant unsuitable for inclusion. 5. History of bleeding diathesis or coagulopathy. 6. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Registration. 7. Active infection with human immunodeficiency virus (HIV), hepatitis C, or hepatitis B, diagnosed by initial serological testing and confirmed with ribonucleic acid (RNA) testing, or prior treatment for hepatitis C. Patients at Screening who test positive by serology, but negative by RNA, may be permitted to enroll by the Investigator in consultation with the Sponsor Medical Monitor. 8. Any contraindication or unwillingness to undergo MRI (eg, metal implants, claustrophobia, agitation, or motor symptoms of a severity that precludes MRI scans). 9. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor. 10. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 halflives of investigational agent, whichever is longer. 11. Previous treatment with an oligonucleotide (including siRNA) within 4 months of Screening if a single dose is received, or within 12 months of Screening if multiple doses are received., or history of hypersensitivity to ION356 or its excipients; or history of hypersensitivity to any ASO. This exclusion does not apply to vaccines (both mRNA and viral vector vaccines). 12. History of gene therapy or cell transplantation, or any experimental brain surgery. 13. Current obstructive hydrocephalus. 14. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter. 15. Known brain or spinal disease or previous spinal surgery that would interfere with the LP process, CSF circulation, or safety assessment, including tumors or abnormalities by MRI or computed tomography, subarachnoid hemorrhage, spinal stenosis or curvature, Chiari malformation, syringomyelia, tethered spinal cord syndrome, and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome. 16. Any condition that increases the risk of meningitis, unless the participant is receiving appropriate prophylactic treatment. 17. History of severe post-LP headache and/or blood patch or of hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study. 18. Have any other conditions, which, in the opinion of the Investigator, would make the participant unsuitable for inclusion, or that could interfere with their i
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Endpoints Fluid Biomarkers CSF, plasma, serum, whole blood and a blood spot collected from participants with PMD at 3 time points: Week 1, Week 53, and week 106 in Part 2. Biofluid collection at Week 106 is optional for participants enrolled in Part 1 under a previous amendment. Biofluids will be analyzed for biomarker levels that may include, but are not limited to: • Changes in PLP1 in CSF • Disease-related biomarkers in CSF and/or blood, which may include but are not limited to: • proteins potentially associated with PLP1 in CSF, serum, and plasma • Measures of neurodegeneration: neurofilament light (NfL), phosphorylated neurofilament heavy (pNfH), n-acetylaspartate (NAA), nacetylaspartylglutamate (NAAG), visinin-like protein 1(VILIP1) • Measures of myelin: myelin basic protein (MBP), myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP), sphingolipids (e.g., sphingomyelin), galactocerebrosidase (GalC), sulfatide, Insulinlike growth factor 1 (IGF-1), growth hormone • Measures of neuroinflammation: chemokine ligand 3 (CCL3), chemokine ligand 8 (CCL8), tumor necrosis factor-alpha (TNF-a), interlukin-6 (IL-6), c-x-c motif chemokine 5 (CXCL5), chemokine ligand 2 (CCL2), c-x-c motif chemokine ligand 10 (CXCL10), chitinase-3 like protein (YKL40), s100 calcium-binding protein b (S100b), glial fibrillary acidic protein (GFAP), 8-Isoprostane (8 isoPGF2a), ionized calcium binding adaptor molecule (1Iba-1)Neuroimaging Neuroimaging assessments will be performed at 3 time points: Week 1, Week 53, and week 106. Neuroimaging at Week 106 is optional for participants enrolled in Part 1 under a previous amendment. • Analysis of changes in neuroimaging parameters may include but are not limited to: - Regional brain volumes (T1-weighted, T2-weighted, fluid-attenuated inversion recovery [FLAIR] magnetic resonance imaging [MRI]) - Diffusivity and fractional anisotropy, myelin water imaging (MWI | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Endpoints The clinical presentation and disease course of patients with PMD will be evaluated through a retrospective chart review. Retrospective analysis may include, but is not limited to: • Evaluation of the onset and progression of PMD manifestations (i.e., change over time in symptoms, signs, neuroimaging, and laboratory findings as available) before a confirmed diagnosis of PMD • Evaluation of the post-PMD diagnosis disease progression (i.e., change over time in symptoms, signs, neuroimaging, and laboratory findings as available) To characterize health services utilization and economic and disease burden for the patients and caregiver(s), analysis may include, but is not limited to: • Utilization of health services including medical history, family history, hospitalizations, medical treatment, genetic diagnoses, clinical assessments, laboratory results, neuroimaging results and data (see Section 6.2.1), collected during the prospective study and extracted from medical records as part of the retrospective chart review. • Changes across caregiver impact will be analyzed for the following: - Caregiver Impact Questionnaire (CIQ) - Work Productivity and Activity Impairment Questionnaire (WPAI) | — |
Countries
France, Germany, Israel, Italy, Netherlands, United Kingdom, United States
Contacts
Public Contactclinicaltrials_ionis clinicaltrials@ionis.com
Ionis Pharmaceuticals, Inc.
Outcome results
None listed