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Trial record 1 of 1 for:    telethon | MPS I | Italy
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Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant (TigetT10_MPSIH)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03488394
Recruitment Status : Active, not recruiting
First Posted : April 5, 2018
Last Update Posted : August 13, 2021
Sponsor:
Collaborator:
Fondazione Telethon
Information provided by (Responsible Party):
Alessandro Aiuti, IRCCS San Raffaele

Brief Summary:
This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem and progenitor cells genetically modified with IDUA lentiviral vector encoding for the human α-L-iduronidase gene for the treatment of patients affected by Mucopolysaccharidosis Type I, Hurler variant

Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis IH Genetic: Frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the α-L-iduronidase cDNA, in their final formulation medium. Phase 1 Phase 2

Detailed Description:

Pediatric patients with mucopolysaccharidosis type I will be treated with genetically modified autologous hematopoietic stem cells collected from mobilized peripheral blood (or bone marrow if mobilization is not feasible) and transduced with IDUA lentiviral vector encoding for the human α-L-iduronidase gene.

Patients will be followed for 5 years after gene therapy. After completing participation in this study, subjects will be offered enrollment into an approved long term follow-up (LTFU) study which will enable continued follow-up for up to 15 years post-treatment (per regulatory guidelines for follow up of patients treated with ATMPs).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study Evaluating Safety and Efficacy of Autologous Hematopoietic Stem and Progenitor Cells Genetically Modified With IDUA Lentiviral Vector Encoding for the Human α-L-iduronidase Gene for the Treatment of Patients Affected by Mucopolysaccharidosis Type I, Hurler Variant
Actual Study Start Date : May 11, 2018
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : January 2025


Arm Intervention/treatment
Experimental: Treatment
Gene therapy (autologous, CD34+ cell enriched cells fraction containing HSCs, transduced with the IDUA LV encoding for the human IDUA gene and cryopreserved in cryoformulation medium)
Genetic: Frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the α-L-iduronidase cDNA, in their final formulation medium.

The drug product target dose is more or equal to 8x10^6 CD34+ cells/Kg, with a minimum dose of 4x10^6 CD34+ cells/Kg and a maximum dose of 35x10^6 CD34+ cells/Kg.

The product will be injected intravenously.





Primary Outcome Measures :
  1. Overall survival [ Time Frame: 5 year ]
    Number of subjects alive at the end of the trial

  2. Achievement of haematological engraftment [ Time Frame: within day +45 after gene therapy ]
    First day of neutrophil count more than 500/mm3 and platelets more than 20,000/mm3 on 3 consecutive days (in the absence of transfusions).

  3. Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability [ Time Frame: 0-24 hours from injection ]
    Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions

  4. Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus [ Time Frame: 0-5 years after gene therapy ]
    Percentage of subjects without Replication Competent Lentivirus

  5. Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation [ Time Frame: 0-5 years after gene therapy ]
    Percentage of subjects without abnormal clonal proliferation

  6. Overall safety and tolerability (AE) [ Time Frame: 0-5 years after gene therapy ]
    The number of AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) and the percentage of subjects experiencing AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) will be summarized by severity and within body system involved. Narratives will also be presented. The rate of occurrence of these events will also be estimated.

  7. IDUA activity in blood [ Time Frame: 1, 3 and 5 years post treatment ]
    IDUA activity measured on peripheral blood dried spot


Secondary Outcome Measures :
  1. Anti-IDUA antibody immune response [ Time Frame: 0-5 years after gene therapy ]
    Presence and titer of anti-IDUA antibody on serum

  2. Achievement of supraphysiologic IDUA activity in blood [ Time Frame: 1, 3 and 5 years after gene therapy ]
    IDUA activity measured on peripheral blood dried spot up to supraphysiologic levels as compared with healthy donors. A supraphysiologic IDUA level is defined as >24.31 μmol/L/h, which is the 97.5 percentile of the IDUA distribution in healthy children.

  3. IDUA activity in plasma [ Time Frame: 1, 3 and 5 years after gene therapy ]
    IDUA activity measured on plasma samples from peripheral blood.

  4. Engraftment of transduced cells at levels above 30% [ Time Frame: by year 1 and after 3 and 5 years from gene therapy ]
    Engraftment will be assessed by vector-specific quantitative PCR on peripheral blood mononuclear cells (PBMC) and/or bone marrow (BM). Adequate engraftment is defined as ≥ 0.30 VCN/genome

  5. Normalization of urinary GAGs [ Time Frame: 1, 3 and 5 years after gene therapy ]
    Proportion of subjects achieving normalization of urinary GAG levels (heparansulfate and dermatansulfate) measured by HPLC

  6. Normalization of spleen and liver [ Time Frame: 1, 3 and 5 years after gene therapy ]
    Proportion of subjects achieving normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound

  7. Growth velocity [ Time Frame: 1, 3 and 5 years after gene therapy ]
    length/height for age and cm/year percentiles



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 11 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent by parent/legal guardian
  • Sex: Males and Females
  • Age: ≥ 28 days and ≤ 11 years old
  • Biochemically and molecularly proven MPS IH
  • Lansky index >80%
  • Indication to hematopoietic stem cell transplant
  • Lack of a non-heterozygous (for mutated IDUA) HLA-matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5 x 10^7 Total Nucleated Cells (TNC)/Kg after 1-month search.(This criterion will not apply to patients whose country of origin does not offer unrelated donor cord blood transplantion).
  • Adequate cardiac, renal, hepatic and pulmonary functions

Exclusion Criteria:

  • Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
  • Severe, active viral, bacterial or fungal infection at eligibility evaluation
  • Patients affected by neoplasia or family history of familial cancer syndromes
  • Cytogenetic alterations associated with high risk of developing hematological malignancies
  • History of uncontrolled seizures
  • Patients with end-organ damage or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
  • Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or Treponema Pallidum or Mycoplasma active infection
  • Patients with DQ/IQ <70
  • Previous allogeneic hematopoietic stem cells transplantation or gene therapy with a different product
  • Contraindications to PeIMP (G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab)

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): NCT03488394


Locations
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Italy
Ospedale San Raffaele
Milano, Italy, 20132
Sponsors and Collaborators
IRCCS San Raffaele
Fondazione Telethon
Publications:

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Responsible Party: Alessandro Aiuti, Professor, IRCCS San Raffaele
ClinicalTrials.gov Identifier: NCT03488394    
Other Study ID Numbers: 2017-002430-23
First Posted: April 5, 2018    Key Record Dates
Last Update Posted: August 13, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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 Alessandro Aiuti, IRCCS San Raffaele:
Mucopolysaccharidosis IH
Gene Therapy
Transplantation, Autologous
Lentiviral vector
Additional relevant MeSH terms:
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Mucopolysaccharidoses
Mucopolysaccharidosis I
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases