Mucopolysaccharidosis IH Clinical Trial
— TigetT10_MPSIHOfficial 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
| Verified date | August 2021 |
| Source | IRCCS San Raffaele |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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
| Status | Active, not recruiting |
| Enrollment | 8 |
| Est. completion date | January 2025 |
| Est. primary completion date | January 2025 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | N/A to 11 Years |
| Eligibility | 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) |
| Country | Name | City | State |
|---|---|---|---|
| Italy | Ospedale San Raffaele | Milano |
| Lead Sponsor | Collaborator |
|---|---|
| IRCCS San Raffaele | Fondazione Telethon |
Italy,
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* Note: There are 12 references in all — Click here to view all references
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Overall survival | Number of subjects alive at the end of the trial | 5 year | |
| Primary | Achievement of haematological engraftment | 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). | within day +45 after gene therapy | |
| Primary | Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability | Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions | 0-24 hours from injection | |
| Primary | Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus | Percentage of subjects without Replication Competent Lentivirus | 0-5 years after gene therapy | |
| Primary | Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation | Percentage of subjects without abnormal clonal proliferation | 0-5 years after gene therapy | |
| Primary | Overall safety and tolerability (AE) | 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. | 0-5 years after gene therapy | |
| Primary | IDUA activity in blood | IDUA activity measured on peripheral blood dried spot | 1, 3 and 5 years post treatment | |
| Secondary | Anti-IDUA antibody immune response | Presence and titer of anti-IDUA antibody on serum | 0-5 years after gene therapy | |
| Secondary | Achievement of supraphysiologic IDUA activity in blood | 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. | 1, 3 and 5 years after gene therapy | |
| Secondary | IDUA activity in plasma | IDUA activity measured on plasma samples from peripheral blood. | 1, 3 and 5 years after gene therapy | |
| Secondary | Engraftment of transduced cells at levels above 30% | 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 | by year 1 and after 3 and 5 years from gene therapy | |
| Secondary | Normalization of urinary GAGs | Proportion of subjects achieving normalization of urinary GAG levels (heparansulfate and dermatansulfate) measured by HPLC | 1, 3 and 5 years after gene therapy | |
| Secondary | Normalization of spleen and liver | Proportion of subjects achieving normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound | 1, 3 and 5 years after gene therapy | |
| Secondary | Growth velocity | length/height for age and cm/year percentiles | 1, 3 and 5 years after gene therapy |