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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04283227
Recruitment Status : Recruiting
First Posted : February 25, 2020
Last Update Posted : May 4, 2020
Sponsor:
Collaborator:
Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
Information provided by (Responsible Party):
Orchard Therapeutics

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.

Condition or disease Intervention/treatment Phase
Lysosomal Storage Diseases Metachromatic Leukodystrophy Genetic: OTL-200 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
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
Official Title: 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).
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : January 2032
Estimated Study Completion Date : January 2032


Arm Intervention/treatment
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.
Genetic: OTL-200
All subjects will receive OTL-200 gene therapy and will be followed up for 8 years following treatment with OTL-200.




Primary Outcome Measures :
  1. Change from baseline in ARSA activity levels in Cerebrospinal Fluid (CSF) [ Time Frame: 24 months ]
  2. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04283227


Contacts
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Contact: Orchard Clinical Trials +44 (0) 20 3808 8286 medinfo@orchard-tx.com
Contact: Orchard Clinical Trials medinfo@orchard-tx.com

Locations
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Italy
Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET) Recruiting
Milan, Italy, 20132
Contact: Francesca Fumagalli    +39 0226434472    fumagalli.francesca@hsr.it   
Principal Investigator: Francesca Fumagalli, MD         
Sponsors and Collaborators
Orchard Therapeutics
Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
Investigators
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Study Director: Orchard Clinical Trials Orchard Therapeutics
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Responsible Party: Orchard Therapeutics
ClinicalTrials.gov Identifier: NCT04283227    
Other Study ID Numbers: OTL-200-07
First Posted: February 25, 2020    Key Record Dates
Last Update Posted: May 4, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Orchard Therapeutics:
OTL-200
Cryopreserved formulation
Gene therapy
MLD
late juvenile
Additional relevant MeSH terms:
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Leukodystrophy, Metachromatic
Lysosomal Storage Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Hereditary Central Nervous System Demyelinating Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sulfatidosis
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Leukoencephalopathies
Demyelinating Diseases
Lipidoses
Lipid Metabolism, Inborn Errors
Lipid Metabolism Disorders