Table 1 Summary of published and ongoing interventional studies in humans and endpoints selected
From: Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III
Reference / clinical trial registry identifier and sponsor | Subtype (n) | Phase | Intervention | Design | Comparator group | Primary endpoint | Additional endpoints |
|---|---|---|---|---|---|---|---|
Guffon et al. (2011) [104] Hospices Civiles de Lyon (IMP supplied by Actelion) | MPS III A,B,C,DÂ (25) | II/III | Oral miglustat | Randomised, double blinded, placebo controlled efficacy study | Placebo | Behavioural disturbance using VABS-II | Sleep disturbance (questionnaire) Hyperactivity (Conners scale) Developmental age (Borel Maisonny Petit test) Brain MRI GM2 ganglioside and Miglustat concentrations in CSF |
Tardieu et al. (2014) [51] Lysogene | MPS IIIA (4) | I/II | Gene therapy: intracerebral AAV rh.10-SGSH-IRES-SUMF1 vector | Open label tolerance/safety study over 1 year follow up | None | Tolerance and safety of IMP and procedure: - frequency of adverse events - formal clinical and neurological examinations - standard haematological and biochemical parameters - immunovirology - CSF protein, glucose, cell count and IFNα titer - routine urinalysis | Changes in brain atrophy evaluated by MRI Neuropsychological meaures: PEP-3, VABS-II, TBAQ, Brunet-Lezine revised test Viral titres in urine Anti-AAV rh.10 antibodies CSF stored for future biomarker analysis |
Jones et al. (2016) [38] Shire | MPSÂ IIIA (12) | I/II | Intrathecal heparan-N-sulfatase (rhHNS) | Open label, dose escalation safety study over 6Â month follow up | None | Safety and tolerability of intrathecal administration of rhHNS: - adverse events - CSF cell counts and chemistries - echocardiography - anti-rhHNS antibodies in CSF and serum | Neurocognitive assessments (Eligibility determined by VABS-II, enrolled patients tested using BSID-III or KABC-II depending on age or developmental age from VABS-II) Cortical grey matter volume by MRI Serum PK CSF HS (by LC-MS/MS) uGAG by DMB assay |
NCT01299727 (ClinicalTrials.gov) [105] Shire | MPS IIIA (12) | I/II | Intrathecal heparan-N-sulfatase (rhHNS) | Open label, long term safety and tolerability study | None | Adverse events Clinical laboratory including liver function tests, haematology, and urinalysis Electrocardiography CSF chemistries, cell counts and inflammatory markers Anti-rhHNS antibodies in CSF and serum | Standardized neurocognitive and behavioural assessments (Sanfilippo-specific behavioural rating scales, gross and fine motor assessments, functional adaptive rating scales, quality of life questionnaires, and Children’s Sleep Habits Rating Scale) rhHNS concentration in CSF and serum Inflammatory cytokines in serum and CSF Safety and potential surrogate efficacy biomarkers in CSF, urine, and serum HS and HS derivatives in urine, plasma and serum Brain (MRI) and auditory brainstem response |
NCT02060526 (ClinicalTrials.gov) [98] Shire | MPS IIIA (21, 7 in each arm) | II | Intrathecal heparan-N-sulfatase (rhHNS) | Randomised, controlled, open label safety and efficacy study in patients with early stage MPS IIIA | 3 arms: Placebo 2-weekly rhHNS 4-weekly rhHNS | Maximum decline in DQ of 10 points over 48Â weeks, assessed by neurocognitive testing | Adverse events Anti-rhHNS antibodies in serum Adaptive behavioural function assessed by neurocognitive testing Total cortical grey matter volume by MRI GAG concentrations in CSF and urine rhHNS concentrations in CSF and serum |
2013–001479-18 (EudraCT) [56] CMFT | MPS III A,B,C (21) | III | High dose oral genistein aglycone | Randomised, double blinded placebo controlled efficacy study with partial crossover design | Placebo controlled for 12 months followed by open label treatment phase | Change in CSF HS at 52 weeks | CSF HS at 104 weeks uGAG by DMB assay HS in urine and plasma Cognitive function using BSID-III and adaptive behaviour using VABS-II, MPS symptom checklist Actigraphy |
NCT02324049 (ClinicalTrials.gov) [55] Alexion | MPS IIIB (9) | I/II | Intravenous recombinant human alpha-N-acetylglucosaminidase (rhNAGLU) | Open label safety/efficacy study | None | Safety and tolerability - physical examinations - electrocardiography - clinical laboratory tests - concomitant medications - anti-drug antibodies | PK/PD effects Neurocognitive and developmental function Brain structure volumetric assessment Indices of microstructural integrity |
NCT02618512 (ClinicalTrials.gov) [106] Alexion | MPS IIIB (5) | I/II | Intravenous recombinant human alpha-N-acetylglucosaminidase (rhNAGLU) | Open label safety/efficacy study | None | Safety and tolerability - physical examinations - electrocardiography - clinical laboratory tests - concomitant medications - anti-drug antibodies | PK/PD effects Neurocognitive and developmental function Brain structure volumetric assessment Indices of microstructural and blood-brain barrier integrity |
NCT02754076 ClinicalTrials.gov [107] Biomarin | MPS IIIB (33) | I/II | Intracerebroventricular infusion of recombinant human alpha-N-acetylglucosaminidase and truncated human insulin-like growth factor 2 (rhNAGLU-IGF2) | Open label dose escalation safety and efficacy study | None | Safety evaluation - treatment related adverse events or abnormal clinical laboratory tests Rate of change of DQ score on treatment vs. rate of change of DQ score prior to treatment assessed at study end (124Â weeks) | Concentrations of IMP in CSF and plasma Anti-drug antibodies in CSF and serum GAG concentrations in CSF, plasma and urine Brain structure by MRI |
NCT02716246 ClinicalTrials.gov [54] Kevin Flanigan / Abeona Therapeutics | MPS IIIA (9) | I/II | Gene therapy: intravenous scAAV9.U1a.hSGSH vector | Open label, dose escalation safety and efficacy study | None | Development of unacceptable toxicity | CSF and leukocyte SGSH enzyme activity Liver and spleen volumes by MRI Adaptive functioning by VABS-II Cognitive function by Leiter International Performance Scale and Mullen Scales of Early Learning uGAG and urine HS |