Background

Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret.

Objectives

Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT).

Design

The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies.

Setting

TCT methods were applied to a randomized phase II clinical trial.

Participants

Patients with early Alzheimer’s disease (N=332).

Intervention

Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04.

Measurements

The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study’s prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes.

Results

The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg.

Conclusion

The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

中文翻译：

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“节省时间”的计算可改善进展性疾病研究中的决策

背景

疾病修饰疗法 (DMT) 可能对早期疾病最有益，此时进展缓慢且变化较小，且临床相关性难以解释。

目标

时间成分测试 (TCT) 将治疗之间的差异从平均变化、纵向轨迹之间的垂直距离转化为直观理解的节省时间、轨迹之间的水平距离，这些差异可以很容易地在全局 TCT (gTCT) 中跨端点组合。

设计

展示了复合材料的价值、节省时间的估计和优化 DMT 测量和解释的组合分数，以及施工细节和模拟研究。

环境

TCT方法应用于随机II期临床试验。

参加者

早期阿尔茨海默病患者 (N=332)。

干涉

三个治疗组使用 AFFITOPE® AD02，两个对照组使用羟基氧化铝 AD04。

测量

共同主要疗效结果是适应的 ADAS-Cog (aADAS) 和适应的 ADCS-ADL (aADL)，它们是针对认知和功能领域的优化复合量表。基于这两个分数的综合结果是该研究预先设定的主要结果。 CDR-sb 和标准的未适应 ADCS-ADL 和 ADAS-Cog 量表是预先指定的次要结果。

结果

与其他研究组相比，AD04 2 mg 组显示出一些统计学上显着的效果。目前尚不清楚观察到的 3.8 分的综合差异是否具有临床意义。 TCT 结果显示，在一项为期 18 个月的研究中，使用 AD04 2 mg 可以节省 11 个月的时间。

结论

与综合结果中 3.8 分的平均差异相比，节省 11 个月的相关性更容易被普遍理解。这些结果表明，综合方法和节省时间的解释的结合为检测和解释疾病改变效应提供了一种强大的方法。