Innovative Thinking on Endpoint Selection in Clinical Trials

ABSTRACT

In clinical trials, selection of appropriate study endpoints is critical for an accurate and reliable evaluation of safety and effectiveness of a test treatment under investigation. In practice, however, there are usually multiple endpoints available for measurement of disease status and/or therapeutic effect of the test treatment under study. For example, in cancer clinical trials, overall survival, response rate, and/or time to disease progression are usually considered as primary clinical endpoints for evaluation of safety and effectiveness of the test treatment under investigation. Once the study endpoints have been selected, sample size required for achieving a desired power is then determined. It, however, should be noted that different study endpoints may result in different sample sizes. In practice, it is usually not clear which study endpoint can best inform the disease status and measure the treatment effect. Moreover, different study endpoints may not translate one another although they may be highly correlated one another. In this article, we intend to develop an innovative endpoint namely therapeutic index based on a utility function to combine and utilize information collected from all study endpoints. Statistical properties and performances of the proposed therapeutic index are evaluated theoretically. A numerical example concerning a cancer clinical trial is given to illustrate the use of the proposed therapeutic index.     

Differences in Patient-Reported Outcomes That Are Most Frequently Detected in Randomized Controlled Trials in Patients With Solid Tumors: A Pooled Analysis of 229 Trials

ObjectivesPatient-reported outcome (PRO) measurements used in cancer research can assess a number of health domains. Our primary objective was to investigate which broad types of PRO domains (namely, functional health, symptoms, and global quality of life [QoL]) most frequently yielded significant differences between treatments in randomized controlled trials (RCTs).MethodsA total of 229 RCTs published between January 2004 and February 2019, conducted on patients diagnosed with the most common solid malignancies and assessed using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, were considered. Studies were identified systematically using literature searches in key electronic databases. Unlike other PRO measurements typically used in RCTs, the scoring algorithm of the multidimensional EORTC QLQ-C30 allowed us to clearly distinguish the 3 broad types of PRO domains.ResultsIn total, 134 RCTs (58.5%) reported statistically significant differences between treatment arms for at least 1 of the QLQ-C30 domains. Most frequently, differences were reported for 2 or all 3 broad types of PRO domains (78 of 134 trials; 58.2%). In particular, 35 trials (26.1%) found significant differences for symptoms, functional health, and global QoL, 24 trials (17.9%) for symptoms and functional health, 11 trials (8.2%) for functional health and global QoL, and 8 trials (6.0%) for symptoms and global QoL. The likelihood of finding a statistically significant difference between treatment arms was not associated with key study characteristics, such as study design (ie, open-label vs blinded trials) and industry support.ConclusionsOur findings emphasize the importance of a multidimensional PRO assessment to most comprehensively capture the overall burden of therapy from the patients’ standpoint.     

Acute GVHD: New approaches to clinical trial monitoring

Acute GVHD occurs in nearly 50% of patients receiving hematopoietic cell transplantation (HCT), and is the major driver of mortality. However, progress in the development of new acute GVHD therapeutics has been slow, in part due to heterogeneity in acute GVHD data collection and interpretation among centers. Herein, we first describe the methods used by the Mount Sinai Acute GVHD International Consortium (MAGIC) to standardize acute GVHD data collection and curation. We then review the utility of serum biomarkers, specifically the MAGIC Algorithm Probability (MAP) that combines two GI biomarkers (ST2 and REG3α) that has been shown to be more accurate than changes in clinical symptom severity after GVHD treatment. We then present preliminary data on the feasibility of a surrogate clinical trial endpoint that combines clinical response and MAP two weeks after treatment. This novel endpoint is an earlier and potentially better predictor of non-relapse mortality than the current gold standard of clinical response four weeks after treatment.     

《伤寒论》和《温病条辨》中汤剂煎煮终点的判断

煎煮时间对于保证中药汤剂临床疗效和中成药质量起着至关重要的作用，从古至今，中药汤剂煎煮终点的判断一直是困扰人们的技术难题。对中医药典籍《伤寒论》和《温病条辨》中汤剂的煎煮时间及其煎煮终点的判断经验进行了整理，发现其具有一定的规律，认为影响煎煮时间的因素主要有病证、方剂功效、药物药性、药材性状等；通过对其总结，并结合现代研究成果初步阐明传统中药汤剂煎煮终点的判断方法，以期能为中药汤剂煎煮时间及现代中药制剂的提取工艺寻求合理的科学依据，为保证中药汤剂临床疗效和中药制剂的质量提供理论基础。     

The Use of Lipoprotein-Associated Phospholipase A2 in a Chinese Population to Predict Cardiovascular Events

Objective To explore associations between lipoprotein-associated phospholipase A2(Lp-PLA2) and the risk of cardiovascular events in a Chinese population, with a long-term follow-up.Methods A random sample of 2,031 participants(73.6% males, mean age = 60.4 years) was derived from the Asymptomatic Polyvascular Abnormalities Community study(APAC) from 2010 to 2011. Serum Lp-PLA2 levels were determined by enzyme-linked immunosorbent assay(ELISA). The composite endpoint was a combination of first-eve...     

Five criteria for using a surrogate endpoint to predict treatment effect based on data from multiple previous trials

A surrogate endpoint in a randomized clinical trial is an endpoint that occurs after randomization and before the true, clinically meaningful, endpoint that yields conclusions about the effect of treatment on true endpoint. A surrogate endpoint can accelerate the evaluation of new treatments but at the risk of misleading conclusions. Therefore, criteria are needed for deciding whether to use a surrogate endpoint in a new trial. For the meta‐analytic setting of multiple previous trials, each with the same pair of surrogate and true endpoints, this article formulates 5 criteria for using a surrogate endpoint in a new trial to predict the effect of treatment on the true endpoint in the new trial. The first 2 criteria, which are easily computed from a zero‐intercept linear random effects model, involve statistical considerations: an acceptable sample size multiplier and an acceptable prediction separation score. The remaining 3 criteria involve clinical and biological considerations: similarity of biological mechanisms of treatments between the new trial and previous trials, similarity of secondary treatments following the surrogate endpoint between the new trial and previous trials, and a negligible risk of harmful side effects arising after the observation of the surrogate endpoint in the new trial. These 5 criteria constitute an appropriately high bar for using a surrogate endpoint to make a definitive treatment recommendation.     

麦芽炒制过程中近红外在线监测模型的建立及“炒香”终点判断研究

炒麦芽一直沿用"炒黄炒香"的入药传统,而"炒黄炒香"终点的判断一直是炒制研究的重点与难点。该实验建立指标成分与NIRS之间的定量校正模型用于快速检测总还原糖、总氨基酸、总黄酮、A_(420)及含水量,并提出基于"成分变化率"的炒制终点判断方法。以近红外光谱仪采集不同炒制时间样品光谱,建立基于近红外光谱的定量分析模型,并对光谱预处理、建模波段等参数进行优选;采用HCA,PLS-DA研究成分与"炒香"的关系,确定炒制终点。所建立的校正模型性能良好,采用所建模型进行在线分析,预测结果与实际测定值相关系数均大于0.9,预测相对偏差小于10%;HCA方法将在不同炒制时间的麦芽分为4类,PLS-DA分析表明总还原糖对区分不同炒制时间的麦芽具有显著的贡献率,当总还原糖的变化率为80%时,即可判断"炒香"终点的到达。结果表明,近红外光谱可快速准确地测定麦芽不同炒制时间样品中总还原糖、总氨基酸、总黄酮、A_(420)及含水量,并可判断"炒香"工艺终点,为中药炒制工艺的评价及终点判断提供新的研究方法。     

速效救心丸治疗急性冠状动脉综合征疗效和安全性的系统评价

[目的] 系统评价速效救心丸治疗急性冠状动脉综合征（ACS）的疗效和安全性。[方法] 计算机检索MEDLINE、EMbase、Cochrane Library、中国知网数据库（CNKI）、维普数据库（VIP）和万方数据库（WanFang Data）等,纳入速效救心丸联合常规西药（治疗组）与单纯常规西药（对照组）对比治疗ACS的随机对照试验（RCT）,检索时限均为从2009年1月1日—2019年7月15日。由两位评价者独立筛选文献、提取资料和评价纳入研究的偏倚风险后,采用RevMan 5.3软件进行Meta分析。[结果] 最终纳入11个RCT,共1 296例ACS患者。Meta分析结果显示：治疗组的临床终点事件发生率[RR=0.43,95% CI（0.29,0.64）,P<0.000 1]显著低于对照组,临床总有效率[RR=1.19,95% CI（1.12,1.26）,P<0.000 01]和心电图疗效[RR=1.29,95% CI（1.14,1.46）,P<0.000 1]均显著高于对照组,且差异有统计学意义;在C反应蛋白（CRP）[SMD=-0.55,95% CI（-1.09,-0.01）,P=0.05]和不良反应发生率[RR=1.68,95% CI（0.09,30.38）,P=0.73]方面,两组差异无统计学意义。[结论] 当前证据显示,速效救心丸联合常规西药治疗能有效缓解ACS患者的临床症状、改善心电图疗效和降低临床终点事件的发生率,且安全性较好。受纳入研究质量和数量所限,上述结论仍需更多高质量的RCT加以验证。     

Withdrawal reflexes in the upper limb adapt to arm posture and stimulus location

Introduction: Withdrawal reflexes in the leg adapt in a context‐appropriate manner to remove the limb from noxious stimuli, but the extent to which withdrawal reflexes adapt in the arm remains unknown. Methods: We examined the adaptability of withdrawal reflexes in response to nociceptive stimuli applied in different arm postures and to different digits. Reflexes were elicited at rest, and kinetic and electromyographic responses were recorded under isometric conditions, thereby allowing motorneuron pool excitability to be controlled. Results: Endpoint force changed from a posterior–lateral direction in a flexed posture to predominantly a posterior direction in a more extended posture [change in force angle (mean ± standard deviation) 35.6 ± 5.0°], and the force direction changed similarly with digit I stimulation compared with digit V (change = 22.9 ± 2.9°). Conclusions: The withdrawal reflex in the human upper limb adapts in a functionally relevant manner when elicited at rest. Muscle Nerve 49 : 716–723, 2014     

Three-center feasibility of lung clearance index in infants and preschool children with cystic fibrosis and other lung diseases

Background

Lung clearance index (LCI) detects early ventilation inhomogeneity and has been suggested as sensitive endpoint in multicenter intervention trials in infants and preschoolers with cystic fibrosis (CF). However, the feasibility of multicenter LCI in this age group has not been determined. We, therefore, investigated the feasibility of LCI in infants and preschoolers with and without CF in a three-center setting.