PDF(Pubmed)
Abstract：
Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA). Treatment options for patients are limited; gene therapy based on haematopoietic stem cell transplantation is the only approved treatment for some subtypes of MLD. Any therapeutic benefit of treatments must be meaningful for patients and their families. We evaluated the clinical meaningfulness of slowing the decline in gross motor function as measured by the Gross Motor Function Classification in MLD (GMFC-MLD) from the caregiver perspective via semi-structured telephone interviews with caregivers of children with late-infantile MLD. We also evaluated the perceived significance of declines in communication abilities measured by the Expressive Language Function Classification in MLD (ELFC-MLD). This work could help to inform the endpoints of a phase 2 clinical trial (NCT03771898) assessing the efficacy of intrathecal recombinant human ASA in MLD.
Twelve caregivers were recruited, reporting on 12 children with MLD. Children had a mean age of 6.1 years; mean age at symptom onset was 17.6 months. Most children (10/12) progressed from walking without support (categories 0-1) to a loss of locomotion (categories 5-6) in ≤ 2 years. Caregivers felt that GMFC-MLD and ELFC-MLD accurately described motor and language declines in their children, respectively. Most caregivers (10/12) reported that the idea of delaying disease progression would be meaningful. Further, a slowing of motor function decline in GMFC-MLD, from category 1 to category 3 or from category 2 to category 4 over 2 years, was seen as meaningful by all caregivers asked; however, only 3/12 caregivers reported that delayed decline would be meaningful if baseline category was ≥ 3. Caregivers also reported that delaying expressive language decline at any level that did not indicate a complete loss of expressive language (indicated by categories 1-3) would be meaningful.
Caregivers of children with MLD felt that a delayed decline in gross motor function, as assessed by the GMFC-MLD, would be meaningful, supporting the selection of primary and secondary endpoints for the phase 2 clinical trial. Communication abilities were another area of significance for consideration in future clinical trial design.
Twelve caregivers were recruited, reporting on 12 children with MLD. Children had a mean age of 6.1 years; mean age at symptom onset was 17.6 months. Most children (10/12) progressed from walking without support (categories 0-1) to a loss of locomotion (categories 5-6) in ≤ 2 years. Caregivers felt that GMFC-MLD and ELFC-MLD accurately described motor and language declines in their children, respectively. Most caregivers (10/12) reported that the idea of delaying disease progression would be meaningful. Further, a slowing of motor function decline in GMFC-MLD, from category 1 to category 3 or from category 2 to category 4 over 2 years, was seen as meaningful by all caregivers asked; however, only 3/12 caregivers reported that delayed decline would be meaningful if baseline category was ≥ 3. Caregivers also reported that delaying expressive language decline at any level that did not indicate a complete loss of expressive language (indicated by categories 1-3) would be meaningful.
Caregivers of children with MLD felt that a delayed decline in gross motor function, as assessed by the GMFC-MLD, would be meaningful, supporting the selection of primary and secondary endpoints for the phase 2 clinical trial. Communication abilities were another area of significance for consideration in future clinical trial design.
摘要：
背景：异染性脑白质营养不良（MLD）是一种罕见的溶酶体贮积症，由芳基硫酸酯酶A（ASA）活性不足引起。患者的治疗选择有限；基于造血干细胞移植的基因治疗是针对某些MLD亚型的唯一批准的治疗方法。治疗的任何治疗益处都必须对患者及其家人有意义。我们通过对婴儿晚期MLD儿童的照顾者进行半结构化电话采访，从照顾者的角度评估了通过MLD粗大运动功能分类（GMFC-MLD）测量的减缓粗大运动功能下降的临床意义。我们还评估了通过MLD中的表达语言功能分类（ELFC-MLD）测量的交流能力下降的感知重要性。这项工作可以帮助告知评估鞘内重组人ASA在MLD中的功效的2期临床试验（NCT03771898）的终点。
结果：招募了12名护理人员，报告了12名患有MLD的儿童。儿童的平均年龄为6.1岁；症状发作的平均年龄为17.6个月。大多数儿童（10/12）在≤2年内从无支撑行走（0-1类）发展到失去运动能力（5-6类）。看护者认为GMFC-MLD和ELFC-MLD准确地描述了孩子的运动和语言下降，分别。大多数护理人员（10/12）报告说，延迟疾病进展的想法是有意义的。Further,GMFC-MLD运动功能下降的减慢，在2年内从类别1到类别3或从类别2到类别4，被所有被问到的护理人员认为是有意义的；然而，只有3/12的护理人员报告,如果基线类别≥3,则延迟下降是有意义的.看护者还报告说，在任何水平上延迟表达性语言下降，而这并不表明表达性语言的完全丧失（由类别1-3表示）都是有意义的。
结论：患有MLD的儿童的照顾者认为运动粗大功能的延迟下降，根据GMFC-MLD的评估，会有意义，支持选择2期临床试验的主要和次要终点.沟通能力是未来临床试验设计中需要考虑的另一个重要领域。
结果：招募了12名护理人员，报告了12名患有MLD的儿童。儿童的平均年龄为6.1岁；症状发作的平均年龄为17.6个月。大多数儿童（10/12）在≤2年内从无支撑行走（0-1类）发展到失去运动能力（5-6类）。看护者认为GMFC-MLD和ELFC-MLD准确地描述了孩子的运动和语言下降，分别。大多数护理人员（10/12）报告说，延迟疾病进展的想法是有意义的。Further,GMFC-MLD运动功能下降的减慢，在2年内从类别1到类别3或从类别2到类别4，被所有被问到的护理人员认为是有意义的；然而，只有3/12的护理人员报告,如果基线类别≥3,则延迟下降是有意义的.看护者还报告说，在任何水平上延迟表达性语言下降，而这并不表明表达性语言的完全丧失（由类别1-3表示）都是有意义的。
结论：患有MLD的儿童的照顾者认为运动粗大功能的延迟下降，根据GMFC-MLD的评估，会有意义，支持选择2期临床试验的主要和次要终点.沟通能力是未来临床试验设计中需要考虑的另一个重要领域。
