Heterogeneity of participants in interventional trials of systemic sclerosis worldwide

Abstract

Heterogeneity of participants in clinical trials distorts intervention efficacy. However, factors associated with participant heterogeneity in randomized clinical trials (RCTs) focusing on systemic sclerosis (SSc) are not clear. We conducted this systematic review to establish normative standards for future research and help develop management guidelines. Three databases and four registries were searched to identify characteristics of SSc RCTs across different countries. Risk of bias was assessed by the Cochrane Collaboration’s tool and logistic regression was performed to calculate crude and adjusted ORs. In total, 261 trials met our inclusion criteria. The quality of SSc RCTs worldwide was relatively poor, with no trend of improvement in recent years, and only 12.2% were ranked as having a low risk of bias. Trials with a low risk of bias as well as single-center, single-country, or open-label trials tended to have better participant adherence than trials with a high risk of bias and multiple-center, multiple-country, or double-blind trials. Interestingly, trial registration and primary outcome definition contributed to high withdrawal. National income was also relevant; participant adherence in high-income countries, but not in upper- and lower-middle-income countries, was significantly altered by different variables. Overall, the risk of bias, national income, and trial design may lead to participant heterogeneity of SSc RCTs and ultimately confound the general clinical utility of the results. Trials with a rigorous design and transparent conduction protocol are crucial for obtaining unbiased data that can serve as a reference and for maintaining the fundamental repeatability of SSc RCTs.