马替膦酸盐治疗轻中度阿尔茨海默病的随机、安慰剂对照、3 期临床试验结果。

Masitinib for mild-to-moderate Alzheimer's disease: results from a randomized, placebo-controlled, phase 3, clinical trial.

机构信息

Alzheimer Research Center IM2A, Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France.

Cantoblanco Memory Clinic, Geriatric Department, Hospital Cantoblanco, Madrid, Spain.

出版信息

Alzheimers Res Ther. 2023 Feb 28;15(1):39. doi: 10.1186/s13195-023-01169-x.

DOI:10.1186/s13195-023-01169-x

PMID:36849969

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9972756/

Abstract

BACKGROUND

Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer's disease (AD).

METHODS

Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12-25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population.

RESULTS

Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, -1.46 (95% CI [-2.46, -0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [-0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15 (97.5% CI [-3.48, -0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [-0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [-0.48, 2.50]) (representing an overall functional improvement) versus -0.81 (95% CI [-2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed.

CONCLUSIONS

Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data.

TRIAL REGISTRATION

EudraCT: 2010-021218-50.

CLINICALTRIALS

gov : NCT01872598.

摘要

背景

马替尼是一种口服给药的酪氨酸激酶抑制剂，针对神经免疫系统（肥大细胞和小神经胶质细胞）的激活细胞。AB09004 研究评估了马替尼作为胆碱酯酶抑制剂和/或美金刚的辅助治疗药物，用于治疗因可能的阿尔茨海默病（AD）导致的轻度至中度痴呆患者。

方法

AB09004 研究是一项随机、双盲、两平行组（四组）、安慰剂对照试验。年龄≥50 岁、有临床诊断的轻度至中度可能 AD 和 MMSE 评分为 12-25 分的患者，按 1:1 随机（随机化）接受马替尼 4.5mg/kg/天（口服分两次给予）或安慰剂。第二个独立的平行组（用于统计分析和对照臂），随机患者（2:1）接受马替尼初始剂量 4.5mg/kg/天，持续 12 周，然后滴定至 6.0mg/kg/天，或等效安慰剂。主要终点是 24 周时从基线到第 24 周阿尔茨海默病评估量表认知子量表（ADAS-cog）或阿尔茨海默病合作研究日常生活活动量表（ADCS-ADL）的最小二乘均数变化。每个马替尼剂量水平的安全性均与合并安慰剂组进行比较。

结果

马替尼（4.5mg/kg/天）（n=182）与安慰剂（n=176）相比，主要终点 ADAS-cog 显示出显著益处，-1.46（95%CI[-2.46，-0.45]）（代表认知功能总体改善）与 0.69（95%CI[-0.36，1.75]）（代表认知恶化增加）相比，差异具有统计学意义（97.5%CI[-3.48，-0.81]）；p<0.001。对于 ADCS-ADL 主要终点，组间差异为 1.82（97.5%CI[-0.15，3.79]）；p=0.038（即，1.01（95%CI[-0.48，2.50]）（代表整体功能改善）与-0.81（95%CI[-2.36，0.74]）（代表功能恶化增加）相比，分别）。安全性与马替尼的已知特征一致（斑丘疹、中性粒细胞减少症、低白蛋白血症）。6.0mg/kg/天滴定马替尼与安慰剂的独立平行组的疗效结果不确定（n=186 和 91 例患者），未观察到新的安全性信号。