Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
New York Medical College, Valhalla, NY, USA.
J Alzheimers Dis. 2022;86(3):1221-1229. doi: 10.3233/JAD-215545.
In pre-clinical studies of Alzheimer's disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and reduced neurofibrillary tangles.
Within pre-specified cohorts of advanced AD patients in two double-blind placebo-controlled bryostatin Phase II trials, to conduct exploratory statistical analyses of patients with identical conditions of enrollment and treatment.
Severe Impairment Battery (SIB) scores above baseline at 5, 9, and 13 weeks were analyzed initially in the complete cases, with multiple imputation methods based on an iterative Markov chain Monte Carlo algorithm used for missing SIB scores. To mitigate confounding by a chance imbalance of 4.9 SIB baseline scores (Study #203), each patient was used as their own control with differences in 13-week SIB from baseline in single trial and pooled analyses to measure benefit at 13 weeks using general estimating equations (GEE) modeling.
Patients treated with bryostatin pre-specified at Mini-Mental State Examination scores 10-14, without memantine, showed baseline balance, complete safety, and SIB improvements at 13 weeks with multiple imputation analysis: Study #203 = 4.1 SIB points above baseline (p = 0.005), and Study #202 = 4.2 SIB points above baseline (p = 0.016). An increased power (N = 95) "pooled analysis" showed an increased SIB over time and a higher mean SIB at 13 weeks in the bryostatin treatment group (p < 0.001) but not significant (NS) for the placebo patients.
Pre-specified exploratory analyses for the individual trials and the pooled trials confirmed significant bryostatin-induced improvement over baseline (treatment p < 0.001, placebo NS).
在阿尔茨海默病（AD）转基因小鼠的临床前研究中，海鞘素恢复了突触连接，防止了神经元死亡，减少了淀粉样斑块，减少了神经原纤维缠结。
在两项双盲安慰剂对照海鞘素二期临床试验中，对预先指定的晚期 AD 患者亚组进行探索性统计分析，这些患者的入组和治疗条件相同。
在完全病例中，首先分析严重损害电池（SIB）评分在 5、9 和 13 周时高于基线，采用基于迭代马尔可夫链蒙特卡罗算法的多次插补方法对缺失的 SIB 评分进行处理。为了减轻因 SIB 基线评分 4.9 个单位的偶然不平衡而产生的混杂影响（研究#203），每个患者都被用作自身对照，在单一试验和汇总分析中，使用广义估计方程（GEE）模型，从基线到 13 周的 SIB 差值来衡量 13 周时的获益。
在 Mini-Mental State Examination 评分 10-14 分的患者中预先指定接受海鞘素治疗，未接受美金刚治疗，在基线平衡、完全安全和 13 周 SIB 改善方面具有多重插补分析的优势：研究#203 为 4.1 个 SIB 点高于基线（p=0.005），研究#202 为 4.2 个 SIB 点高于基线（p=0.016）。增加的功率（N=95）“汇总分析”显示，海鞘素治疗组随时间推移 SIB 增加，13 周时平均 SIB 更高（p<0.001），而安慰剂组无显著差异（NS）。
对各试验和汇总试验的预先指定探索性分析证实，海鞘素诱导的改善明显优于基线（治疗 p<0.001，安慰剂 NS）。
