A 30-WEEK RANDOMIZED CONTROLLED TRIAL OF HIGH-DOSE TACRINE IN PATIENTS WITH ALZHEIMERS-DISEASE
A 30-WEEK RANDOMIZED CONTROLLED TRIAL OF HIGH-DOSE TACRINE IN PATIENTS WITH ALZHEIMERS-DISEASE
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DOI：
10.1001/jama.271.13.985
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发表时间：
1994-04-06
影响因子：
120.7
通讯作者：
KELLEY, CK
中科院分区：
文献类型：
--
作者：
KNAPP, MJ;KNOPMAN, DS;KELLEY, CK
目标。目的：评价大剂量盐酸他克林治疗阿尔茨海默病患者30周的疗效和安全性。一项为期30周的随机、双盲、安慰剂对照、平行组试验。-美国33个中心的门诊病人。- 50岁以上的男性和女性，患有轻度至中度阿尔茨海默病，其他健康状况良好。-第一组给予安慰剂；2组先给予他克林40 mg/d，连续6周，再给予80 mg/d，连续24周；3、4组分别给予他克林40 mg/d， 80 mg/d， 6周，120 mg/d， 6周。第三组继续给药120 mg/d，共18周；第4组给药120 mg/d 6周后，最后12周滴药至160 mg/d。主要结果测量。临床医生访谈印象（CIBI）、阿尔茨海默病评估量表-认知子量表（ADAS-Cog）和最终综合共识评估（FCCA）。-共有663名患者进入研究；653名患者被纳入意向治疗（ITT）分析；263例在30周时具有可评价的数据。ITT分析的结果显示显著（P小于或等于）。2005) CIBI和ADAS-Cog的剂量反应趋势和组间比较。在可评估的患者中，所有三个主要测量指标均观察到显著的剂量-反应趋势（P <或等于0.001）。在CIBI中观察到支持160 mg/d的他克林与安慰剂的显著差异（P小于或等于）。002)和ADAS-Cog和FCCA (P小于或等于。001)，以及护理者整体和生活质量评估（P <或等于0.05）。在CIBI中，ITT组和可评估患者群体中分别有23%和42%的他克林治疗患者被评为改善，而安慰剂组的这一比例分别为17%和18%。他克林治疗患者停药的主要原因是无症状性肝转氨酶升高（28%）和胃肠道不适（16%）。这些不良事件在停药后是可逆的，并且许多患者能够重新使用他克林。-他克林在基于客观表现的测试、临床医生和护理人员评分的整体评估和生活质量测量方面产生了统计学上显著的剂量相关改善。没有证据表明大量患者退出会影响研究的总体结论。
Objective.-To evaluate the efficacy and safety of high-dose tacrine hydrochloride over 30 weeks in patients with probable Alzheimer's disease.Design.-A 30-week randomized, double-blind, placebo-controlled, parallel-group trial.Setting.-Outpatients at 33 US centers.Patients.-Men and women at least 50 years of age with mild to moderate Alzheimer's disease and otherwise in good health.Interventions.-Group 1 received placebo; group 2 received 40 mg/d of tacrine for 6 weeks, then 80 mg/d for 24 weeks; groups 3 and 4 received 40 mg/d of tacrine for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 remained on a dosage of 120 mg/d for a total of 18 weeks; after 6 weeks at 120 mg/d, group 4 titrated to 160 mg/d for the last 12 weeks.Primary Outcome Measures.-Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and Final Comprehensive Consensus Assessment (FCCA).Results.-A total of 663 patients entered the study; 653 patients were included in an intent-to-treat (ITT) analysis; 263 had evaluable data at 30 weeks. The results of the ITT analysis revealed significant (P less-than-or-equal-to .05) dose-response trends and between-group comparisons on CIBI and ADAS-Cog. In evaluable patients, significant dose-response trends were observed for all three primary measures (P less-than-or-equal-to .001). Significant differences in favor of 160 mg/d of tacrine vs placebo were observed on the CIBI (P less-than-or-equal-to .002) and ADAS-Cog and FCCA (P less-than-or-equal-to .001), as well as caregiver-global and quality-of-life assessments (P less-than-or-equal-to .05). On the CIBI, 23% and 42% of tacrine-treated patients in the ITT and evaluable-patient populations, respectively, were rated improved compared with 17% and 18% of placebo patients, respectively. The primary reasons for withdrawal of tacrine-treated patients were asymptomatic liver transaminase elevations (28%) and gastrointestinal complaints (1 6%). These adverse events were reversible on discontinuation of treatment, and many patients were able to restart tacrine.Conclusions.-Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study.