NCT04283227进行中（未招募）3 期
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).
Orchard Therapeutics2 个研究点 分布在 1 个国家目标入组 6 人开始时间: 2022年1月17日最近更新:
适应症
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 6
- 试验地点
- 2
- 主要终点
- Evaluation of OTL-200 Arylsulfatase A (ARSA) activity levels in Cerebrospinal Fluid (CSF)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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. Novel mutations will be analyzed with in silico prediction tools and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.
- •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).
- •NOTE: The following will not be exclusionary if present alone: 1.) Seizures 2.) Signs of the disease revealed at instrumental evaluations (Electroneurography [ENG] and brain MR)
- •If applicable, participant willing and capable of compliance with contraceptive use requirements.
- •Participant (or if applicable, parent/legal guardian) providing signed informed consent or assent as applicable
排除标准
- •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. Participants with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the Medical Monitor.
- •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. NOTE: Participants with a recent history of herpes zoster may be included in the study. In such cases, inclusion, additional monitoring and treatment of the condition must be discussed and approved by the Medical Monitor.
- •Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing. Participants with latent tuberculosis, as documented by medical history and/or TB testing may be included in the study if receiving antibiotic prophylaxis (e.g. isoniazid). Inclusion, monitoring and treatment of TB in such participants must be discussed and approved by the Medical Monitor.
- •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. NOTE: Participants with positive Hepatitis B core antibody due to prior resolved disease may be enrolled, only if a confirmatory negative HBsAg and negative Hepatitis B DNA test are obtained. Inclusion, monitoring and treatment of hepatitis in such participants must be discussed and approved by the Medical Monitor.
- •Presence of positive Hepatitis C RNA test result at screening. NOTE: Patients who have previously tested positive for antibodies to hepatitis C can be treated, provided they demonstrate absence of ongoing infection using a nucleic acid test with a limit of quantification of ≤15 international units/ml. Negative test results are required on at least 3 sequential occasions over a period of at least 4 weeks, after completion of treatment for Hepatitis C, with the final test conducted no more than 3 days prior to cell harvest. Inclusion, monitoring and treatment of hepatitis in such participants must be discussed and approved by the Medical Monitor.
- •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.
结局指标
主要结局
Evaluation of OTL-200 Arylsulfatase A (ARSA) activity levels in Cerebrospinal Fluid (CSF)
时间窗: 24 months after treatment
Change from baseline in ARSA activity levels in CSF
Evaluation of OTL-200 on the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter regions of the brain
时间窗: 24 months after treatment
Change from baseline in neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter regions of interest of the brain
次要结局
- Change in neurocognitive function(24 months and multiple visits up to 8 years post gene-therapy as compared to baseline)
- Vineland Adaptive Behavior Scale (VABS)(24 months and multiple visits up to 8 years post gene-therapy)
- Change from baseline in ARSA levels in total peripheral blood mononuclear cells (PBMCs)(24 months and multiple visits up to 8 years post gene-therapy)
- Engraftment as measured by percent lentiviral positive (%LV+) in bone marrow (BM) progenitors(At D30 and multiple visits up to 8 years post gene-therapy)
- Change in full neurological clinical examination (NCE)(24 months and multiple visits up to 8 years post gene-therapy)
- Change in ARSA activity levels in CSF from baseline(multiple visits up to 8 years post gene-therapy)
- Change from baseline in neuronal metabolite ratio of NAA: Cr in white matter regions of interest of the brain(multiple visits up to 8 years post gene-therapy)
- Neuronal metabolite ratios as compared to baseline, siblings and/or untreated historical controls (may include but not limited to Cho:Cr, mIns:Cr, Lac: Cr, Cho: NAA, NAA: H2O, Cho: H2O, mIns: H2O, Lac: H2O) in white matter regions of interest(24 months and multiple visits up to 8 years post gene-therapy)
- VCN in Peripheral blood PBMCs(At D60 and multiple visits up to 8 years post gene-therapy)
- Change in severity scale for brain magnetic resonance imaging (MRI)(24 months and multiple visits up to 8 years post gene-therapy)
- Conditioning regimen related toxicity and AEs(up to 8 years post gene-therapy)
- Immune response (e.g. anti-ARSA antibodies)(up to 8 years post gene-therapy)
- Integration Site analysis findings(6, 12 months, then once a year up to 8 years post gene-therapy)
- Change from baseline in ARSA levels in PB CD14+(24 months and multiple visits up to 8 years post gene-therapy)
- Change from baseline in ARSA levels in PB CD15+(24 months and multiple visits up to 8 years post gene-therapy)
- Vector copy number (VCN) in BM mononuclear cells(At D30 and multiple visits up to 8 years post gene-therapy)
- Change in Gross Motor Function Classification (GMFC)-MLD(24 months and multiple visits up to 8 years post gene-therapy)
- Replication Competent Lentivirus (RCL(baseline, 1, 3, 6, and 12 months, then once a year up to 8 years post gene-therapy)
- Change in NCV(24 months and multiple visits up to 8 years post gene-therapy)
- Non-conditioning related AEs(up to 8 years post gene-therapy)
- Incidence of infusion related reactions(up to 8 years post gene-therapy)
- Abnormal Clonal Proliferation (ACP)(up to 8 years post gene-therapy)
- Hematological reconstitution(By Day 60 post-gene therapy)
研究者
研究点 (2)
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