2024-511971-13-00招募中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)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Co-primary pharmacodynamic efficacy endpoints: •Change in ARSA activity levels in CSF from baseline to 24 months post treatment. •Change in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain from baseline to 24 months post-treatment.
研究概览
简要总结
To evaluate the pharmacodynamic effect of OTL-200 in CSF and the brain of subject LJ MLD subjects as compared to baseline.
研究设计
- 分配方式
- Non-randomized
- 主要目的
- Single Arm
- 盲法
- None
入排标准
- 年龄范围
- 0 years 至 17 years（0-17 Years）
- 接受健康志愿者
- 是
入选标准
- •1.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 analysed with in silico prediction tool 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.
- •O/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: subject 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. 5.a) If the subject is <7 years age (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 the subject is ≥ 7 years, normal gross motor function or mild gross motor function impairment, defined by a GMFC-MLD 0 or 1 (i.e subject is able to walk independently). NOTE: The following will not be exclusionary if present alone: i.Seizures ii.Signs of the disease revealed at instrumental evaluations (Electroneurography [ENG] and brain MRI)
- •If applicable, subject willing and capable of compliance with contraceptive requirements as detailed further in Protocol Section 7.
- •Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- •Subject (or if applicable, parent/legal guardian) providing signed informed consent or assent if applicable as described in Section 17.4 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
排除标准
- •Documented HIV infection (positive HIV RNA and/or anti-p24 antibodies). 2.Malignant neoplasia (except localised skin cancer) or a documented history of hereditary cancer syndrome. Subjects 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 Orchard-MM. 3.Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) or other serious haematological disorders. 4.Subjects currently enrolled in other interventional trials. 5.Has previously undergone allogeneic HSCT and has evidence of residual cells of donor origin. 6.Previous gene therapy. 7.Has symptomatic herpes zoster, not responsive to specific treatment. 8.Evidence of active tuberculosis (TB) based upon medical examination, chest imaging and TB testing i.e. QuantiFERON-TB Gold test and microbiological evidence. 9.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. 10.Presence of positive Hepatitis C RNA test result at screening. 11.End-organ dysfunction, severe active infection not responsive to treatment, or other severe disease or clinical condition which, in the judgement of the investigator, would make the subject 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 EU Cell and Tissue Directive as clinically appropriate and results must be discussed with the Orchard-MM prior to stem cell harvest.
- •Subjects 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-MM and considered in the context of the criterion for excluding subjects 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
Co-primary pharmacodynamic efficacy endpoints: •Change in ARSA activity levels in CSF from baseline to 24 months post treatment. •Change in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain from baseline to 24 months post-treatment.
Co-primary pharmacodynamic efficacy endpoints: •Change in ARSA activity levels in CSF from baseline to 24 months post treatment. •Change in neuronal metabolite ratio NAA: Cr in white matter regions of interest of the brain from baseline to 24 months post-treatment.
次要结局
- Change in CSF ARSA, Change in neuronal metabolite ratio, Change in ARSA in PBMC, CD14+ & CD15+, Engraftment, VCN in BM & PBMC, Change in severity scale for brain MRI asses, Change in neurocog function, Full NCE, Change in GMFC-MLD, Change in NCV, Conditioning related toxicity/AEs, Non-conditioning AEs, Hem.reconstitution, Incidence of inf. related reactions, Incidence & titers of ARSA antibodies, Abn.clonal proliferation, Absence of RCL, site analysis findings, ELFC-MLD, Add Brain MRI analyses
研究者
Clinical
Scientific
Orchard Therapeutics (Europe) Limited
研究点 (1)
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