Takeda Development Center Americas, Inc., Cambridge, MA, USA.
Alexion Pharmaceuticals, Inc., AstraZeneca Rare Disease, Boston, MA, USA.
Orphanet J Rare Dis. 2023 Nov 2;18(1):343. doi: 10.1186/s13023-023-02957-2.
Norm-based scores used to assess cognitive ability have clinical value when describing functioning of patients with neuronopathic disorders compared with unaffected, same-age peers. However, they have limitations when used to assess change in cognitive ability between two timepoints, especially in children with severe cognitive decline. Calculation of Projected Retained Ability Scores (PRAS) is a novel method developed to characterize absolute change in norm-based ability test scores. In this analysis, PRAS were calculated post hoc for children with mucopolysaccharidosis II (MPS II; Hunter syndrome) and early cognitive impairment in a 52-week phase 2/3 randomized controlled trial (RCT) and its extension study of intrathecal idursulfase (idursulfase-IT). Patients completing the first year of the extension after receiving idursulfase-IT in the RCT and extension (n = 32 of 34 enrolled) or the extension only (n = 15 of 15 enrolled) were categorized according to changes in Differential Ability Scales, Second Edition, General Conceptual Ability (DAS-II GCA) scores and PRAS at 1 and 2 years. Analyses were conducted in the overall population and a subpopulation aged < 6 years at baseline (idursulfase-IT in the RCT and extension [n = 27] and extension only [n = 12]).
PRAS methodology differentiated patients with decreases in DAS-II GCA scores into three separate categories reflecting below-average cognitive growth rates, plateauing cognitive development, and deteriorating cognitive functioning. After 1 year in the RCT, 72.4% of patients who initiated idursulfase-IT had above-average or average cognitive growth rates in DAS-II GCA scores compared with 53.3% of those who did not receive idursulfase-IT; 6.9% versus 20.0% experienced deteriorating cognitive functioning. Similar results were seen in children aged < 6 years: 76% (idursulfase-IT group) versus 50% (no idursulfase-IT) had above-average or average cognitive growth rates in DAS-II GCA scores; 4% versus 17% had deteriorating cognitive functioning. The difference in the distributions of cognitive categories at 1 year in children aged < 6 years was significant (p = 0.048). At 2 years, the proportions of patients in different cognitive categories were more similar between treatment groups.
PRAS methodology may help to differentiate changes in cognitive development in MPS II, and therefore may represent a valuable addition to existing approaches for interpreting changes in cognitive scores over time.
ClinicalTrials.gov NCT02055118 (registration date: 4 February 2014) and NCT02412787 (registration date: 9 April 2015).
与未受影响的同龄患者相比，用于评估神经病变性疾病患者认知能力的基于标准的评分在描述患者的功能方面具有临床价值。然而，当用于评估两个时间点之间的认知能力变化时，它们存在局限性，尤其是在认知能力严重下降的儿童中。预测保留能力评分（PRAS）的计算是一种新方法，用于描述基于标准的能力测试评分的绝对变化。在这项分析中，为在一项 52 周的 2/3 期随机对照试验（RCT）及其伊杜硫酸酶鞘内给药（idursulfase-IT）扩展研究中患有黏多糖贮积症 II 型（MPS II；亨特综合征）和早期认知障碍的儿童，在试验和扩展研究的第一年结束后，通过事后计算了 PRAS（n=34 名入组患者中的 32 名，接受了 idursulfase-IT；n=15 名入组患者中的 15 名，仅接受了扩展研究）。根据差异能力量表，第二版，一般概念能力（DAS-II GCA）评分和 1 年和 2 年时的 PRAS 的变化，将接受 idursulfase-IT 的 RCT 和扩展研究（n=27）以及仅接受扩展研究的患者（n=12）的人群进行分类。在总体人群和基线时年龄<6 岁的亚组（RCT 中的 idursulfase-IT 和扩展研究[n=27]和仅扩展研究[n=12]）中进行了分析。
PRAS 方法学将 DAS-II GCA 评分下降的患者分为三个单独的类别，反映了认知增长率低于平均水平、认知发展趋于平稳和认知功能恶化。在 RCT 的第一年结束时，与未接受伊杜硫酸酶-IT 的患者相比，72.4%接受伊杜硫酸酶-IT 的患者的 DAS-II GCA 评分具有高于平均或平均的认知增长率；6.9%的患者认知功能恶化，而 20.0%的患者认知功能恶化。在年龄<6 岁的儿童中也观察到了类似的结果：76%（伊杜硫酸酶-IT 组）与 50%（未接受伊杜硫酸酶-IT）的儿童 DAS-II GCA 评分具有高于平均或平均的认知增长率；4%的儿童认知功能恶化，而 17%的儿童认知功能恶化。在年龄<6 岁的儿童中，1 年时认知类别分布的差异具有统计学意义（p=0.048）。在 2 年时，两组患者在不同认知类别的比例更为相似。
PRAS 方法学可能有助于区分 MPS II 认知发育的变化，因此可能是解释随时间推移认知评分变化的现有方法的有益补充。
ClinicalTrials.gov NCT02055118（注册日期：2014 年 2 月 4 日）和 NCT02412787（注册日期：2015 年 4 月 9 日）。
