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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,D (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
MPS IIIA (12) I/II Intrathecal heparan-N-sulfatase (rhHNS) Open label, dose escalation safety study over 6 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 48 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 (124 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
  1. Key: AAV adeno-associated virus, IMP investigational medical product, PEP-3 psychoeducational profile, 3rd edition, VABS-III Vineland Adaptive Behaviour Scale, 2nd edition, TBAQ Toddler Behaviour Assessment Questionnaire, IFNα interferon alpha, KABC-II Kaufman Assessment Battery for Children, Second Edition, BSID-III Bayley Scales of Infant and Toddler Development, Third Edition, uGAG urinary glycosaminoglycan, DMB dimethylmethylene blue, CSF cerebrospinal fluid, LC-MS/MS liquid chromatography-tandem mass spectrometry, EudraCT European Union Drug Regulating Authorities Clinical Trials, CMFT Central Manchester University Hospitals NHS Foundation Trust, PK pharmacokinetics, DQ Developmental Quotient, PD pharmacodynamics