Severe Mucopolysaccharidosis Type I (Hurler syndrome, MPS IH) MedDRA version: 18.1 Level: LLT Classification code 10028094 Term: Mucopolysaccharidosis IH System Organ Class: 100000004850
Conditions
Interventions
Product Name: Methotrexate
Pharmaceutical Form: Oral solution
INN or Proposed INN: Methotrexate
CAS Number: 59-05-2
Concentration unit:
Sponsors
Central Manchester University Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Written informed consent of a legally authorised guardian(s) • A diagnosis of MPS I as defined by deficient a-L-iduronidase activity in leukocytes or cultured fibroblasts, in a laboratory accepted by the investigators • Clinical status consistent with severe Hurler phenotype OR If available, mutations consistent with a classical Hurler genotype e.g. homozygosity or compound heterozygosity for nonsense mutations (Q70X, W402X) in IDUA gene • Age =3 months and =2.5 years at diagnosis • Decision to offer HSCT with an appropriate donor after a short period (minimum 4 weeks) of ERT Are the trial subjects under 18? yes Number of subjects for this age range: 4 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range 0 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: • The patient has previously received intravenous laronidase • The patient has undergone haematopoietic stem cell transplantation • The patient has a known primary immune defect • The patient has a known sensitivity or allergy to methotrexate • The patient has known contraindications to receiving methotrexate such as pre-existing hepatic or renal dysfunction, or the patient is receiving concomitant medications that interact with methotrexate • The patient has received any immunomodulatory or immunosuppressive medication within 90 days prior to enrolment • The patient has been exposed to any other investigational product within 90 days prior to enrolment in the trial • The patient has any clinically significant organic disease (with the exception of symptoms relating to MPS I), including cardiovascular, hepatic, pulmonary, neurologic or renal disease, other serious intercurrent illness or extenuating circumstances, that, in the opinion of the investigator would preclude participation in the trial or potentially decrease survival
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: n/a;Primary end point(s): Peak anti-laronidase IgG titre (between 4 weeks post-ERT and pre-HSCT) of <1:4000;Main Objective: The objective of this trial is to investigate the safety and efficacy of methotrexate as an immune tolerance induction agent in mitigating the alloimmune response to enzyme replacement therapy with laronidase in severe MPS I. ;Timepoint(s) of evaluation of this end point: Anti-laronidase IgG samples will be taken at baseline, 4 weeks post-ERT, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints: Safety and toxicity of methotrexate as measured by haematological parameters and biochemical markers of renal and hepatic function. Absolute value of peak anti-laronidase IgG titre (between 4 weeks post-ERT and pre-HSCT). Tertiary (exploratory only) endpoints: Incidence of neutralising antibodies to laronidase at time of highest anti-laronidase antibody titres Urinary glycosaminoglycans (GAGs), urinary DS/CS ratio and blood heparan/dermatan sulfate derived disaccharides Anti-laronidase IgM titres Immune phenotyping and B/T cell functional studies Sleep oximetry (oxygen desaturation index 4%) Exploratory biomarkers in blood and urine ; Timepoint(s) of evaluation of this end point: Secondary endpoints: Clinical laboratory tests for haematological parameters and liver and renal function will be taken at baseline, 1, 2, 3, 4, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT. Anti-laronidase IgG samples will be taken at baseline, 4 weeks post-ERT, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT. Tertiary endpoints: Samples for neutralising antibodies, IgM titres, urine GAGs, urine DS/CS ratio, heparan/dermatan sulfate derived disaccharides and exploratory biomarkers will be collected at baseline, 4 weeks post-ERT, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT Sleep oximetry will be performed at baseline and pre-HSCT Immune phenotyping will be performed at baseline, 1 week post-ERT, 4 weeks post-ERT, 8 weeks post-ERT, pre-HSCT and 12 weeks post-HSCT. | — |
Countries
United Kingdom
Contacts
Public ContactCMFT Research Office
Central Manchester University Hospitals NHS Foundation Trust
Outcome results
None listed