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OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)

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ClinicalTrials.gov Identifier: NCT04283227
Recruitment Status : Recruiting
First Posted : February 25, 2020
Last Update Posted : February 25, 2021
Sponsor:
Collaborator:
Ospedale San Raffaele
Information provided by (Responsible Party):
Orchard Therapeutics

Tracking Information
First Submitted Date  ICMJE February 13, 2020
First Posted Date  ICMJE February 25, 2020
Last Update Posted Date February 25, 2021
Actual Study Start Date  ICMJE December 31, 2020
Estimated Primary Completion Date January 2032   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 25, 2020)
  • Change from baseline in ARSA activity levels in Cerebrospinal Fluid (CSF) [ Time Frame: 24 months ]
  • Change from baseline in neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter regions of the brain [ Time Frame: 24 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: February 24, 2020)
  • Evaluation of OTL-200 on ARSA activity levels in Cerebrospinal Fluid (CSF) [ Time Frame: 2 years ]
    Assessment of the change in ARSA activity levels in Cerebrospinal Fluid (CSF) from baseline to 24 months post treatment
  • Evaluation of OTL-200 on the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter regions of the brain [ Time Frame: 2 years ]
    Assessment of the changes in neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter regions of interest of the brain from baseline to 24 months
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)
Official Title  ICMJE An Open Label, Non-randomized Trial to Evaluate the Safety and Efficacy of a Single Infusion of OTL-200 in Patients With Late Juvenile (LJ) Metachromatic Leukodystrophy (MLD).
Brief Summary OTL-200 is a cryopreserved dispersion for infusion containing autologous CD34+ cell enriched population that contains haematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A (ARSA) gene. MLD is an autosomal recessive lysosomal storage disorder (LSD) characterized by severe and progressive demyelination affecting the central and peripheral nervous system. The aim of this clinical study is to assess the pharmacodynamic effect and long-term clinical efficacy and safety of OTL-200 in Late Juvenile MLD patients.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
All eligible subjects will receive intravenous (IV) infusion of OTL-200 gene therapy. Subjects will also receive conditioning regimen with busulfan.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lysosomal Storage Diseases
  • Metachromatic Leukodystrophy
Intervention  ICMJE Genetic: OTL-200
All subjects will receive OTL-200 gene therapy and will be followed up for 8 years following treatment with OTL-200.
Study Arms  ICMJE Experimental: OTL-200 Gene Therapy
OTL-200 is an autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A (ARSA) gene.
Intervention: Genetic: OTL-200
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 24, 2020)
6
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2032
Estimated Primary Completion Date January 2032   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

All the following criteria need to be met:

  • Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles.
  • 0/R or R/R genotype or a genotype recognized as associated with the LJ variant of MLD.
  • a) If symptomatic: age at disease onset between ≥7 and <17 years of age (i.e. before their 17th birthday). OR
  • b) If pre-symptomatic: participant must be <17 years of age at treatment (i.e. before their 17th birthday) AND must have a sibling with a diagnosis of late-juvenile MLD variant based on age at disease onset (≥7 and <17 years of age i.e. before sibling's 17th birthday), with biochemical and molecular diagnosis.
  • Normal cognitive function as defined by an IQ≥85 on age appropriate cognitive scales.
  • a) If the participant is <7 years (i.e. before their 7th birthday): normal motor milestones achievement, normal gross motor function according to chronological age and normal neurological examination (if applicable based on the age of the subject, GMFC-MLD = 0) OR b) If participant is ≥7 years: normal gross motor function or mild gross motor function impairment, defined by a GMFC-MLD 0 or 1 (i.e. patient is able to walk independently).
  • If applicable, participant willing and capable of compliance with contraceptive use requirements.
  • Participant (or if applicable, parent/legal guardian) providing signed informed consent

Exclusion Criteria:

  • Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies).
  • Malignant neoplasia (except localised skin cancer) or a documented history of hereditary cancer syndrome
  • Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) or other serious haematological disorders.
  • Patients currently enrolled in other interventional trials
  • Has previously undergone allogeneic HSPC gene therapy (HSPC-GT) and has evidence of residual cells of donor origin.
  • Previous gene therapy.
  • Has symptomatic herpes zoster, not responsive to specific treatment.
  • Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing
  • Acute or chronic stable Hepatitis B (HBV) as evidenced by positive Hepatitis B surface antigen (HBsAg) test result at screening or within 3 months prior to onset of conditioning and/or positive HBV DNA
  • Presence of positive Hepatitis C RNA test result at screening
  • End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
  • In addition to the potential infections tested per protocol, the PI should consider testing for other transmissible infectious agents listed in the European Union (EU) Cell and Tissue Directive as clinically appropriate and results must be discussed with the Orchard medical monitor prior to stem cell harvest.
  • Participants with alanine transferase (ALT) >2x upper limit of normal (ULN) or total bilirubin >1.5xULN may be included only after discussed and agreed with the Orchard medical monitor and considered in the context of the criterion for excluding participants with other severe disease. Isolated elevation of total bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35% of total.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Orchard Clinical Trials +44 (0) 20 3808 8286 medinfo@orchard-tx.com
Contact: Orchard Clinical Trials medinfo@orchard-tx.com
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04283227
Other Study ID Numbers  ICMJE OTL-200-07
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Orchard Therapeutics
Study Sponsor  ICMJE Orchard Therapeutics
Collaborators  ICMJE Ospedale San Raffaele
Investigators  ICMJE
Study Director: Orchard Clinical Trials Orchard Therapeutics
PRS Account Orchard Therapeutics
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP