A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression

IF 2 3区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Seth C. Hopkins, Sasagu Tomioka, Steven T. Szabo, Kenneth S. Koblan
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引用次数: 0

Abstract

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials.

Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710

临床试验纳入标准,以丰富双相抑郁症患者的典型症状结构。
由于患者群体的异质性以及使用症状评分量表测量神经精神疾病结构的不确定性,精神病学的临床药物开发面临着挑战。在此,我们介绍了一种丰富算法的开发和实施情况,该算法可根据筛查和基线时获得的 MADRS 评分,在单个受试者水平上识别典型症状与异常症状表现。研究采用了 5 项针对双相情感障碍 I 的随机、安慰剂对照、3 期试验的数据(N = 2026 例受试者,15239 次 MADRS 评估)。利用两次连续评估中的 10 个 MADRS 项目,开发了一个方差-协方差(VCD)向量来编码个体症状结构。从每个受试者的 VCD 向量中计算出的异常得分通过隔离林来量化与假设的典型项目结构的差异程度。该算法的回顾性应用可靠地确定了异常分值的阈值,超过该阈值,MADRS 的心理测量特性就会恶化。与提高MADRS评分确定性相一致的是,在一项治疗双相抑郁症的非消旋氨磺必利(SEP-4199)2期安慰剂对照试验中,基线时具有典型症状结构的受试者在基线后表现出更大的效应量。我们的分析表明,所开发的算法可以减少基线症状结构的异质性,从而提高临床试验中精神症状测量的确定性。这种新颖的富集方法已在SEP-4199的3期临床研究中得到前瞻性应用,并符合旨在提高临床试验统计能力和减轻患者负担的监管指南。临床试验注册:NCT00868452、NCT00868699、NCT01284517、NCT01986101、NCT03543410、NCT05169710。
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来源期刊
CiteScore
3.70
自引率
4.50%
发文量
281
审稿时长
44 days
期刊介绍: Contemporary Clinical Trials is an international peer reviewed journal that publishes manuscripts pertaining to all aspects of clinical trials, including, but not limited to, design, conduct, analysis, regulation and ethics. Manuscripts submitted should appeal to a readership drawn from disciplines including medicine, biostatistics, epidemiology, computer science, management science, behavioural science, pharmaceutical science, and bioethics. Full-length papers and short communications not exceeding 1,500 words, as well as systemic reviews of clinical trials and methodologies will be published. Perspectives/commentaries on current issues and the impact of clinical trials on the practice of medicine and health policy are also welcome.
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