Comparative Adverse-Event Risk in Placebo-Controlled Phase I Trials: A Systematic Review and Meta-Analysis in Healthy Korean Participants

Background/Objectives: Adverse events in phase I trials may reflect treatment, background symptoms, or study procedures. We compared investigational treatment with placebo in healthy Korean participants. Methods: We searched PubMed, Embase, Scopus, the Korea Citation Index, the Research Information Sharing Service, and Google Scholar through 30 April 2026 (PROSPERO: CRD420261426647). Outcomes were any treatment-emergent adverse event or adverse event (any TEAE/AE) and adverse drug reaction or treatment-related AE (ADR/related AE). The prespecified inverse-variance random-effects analysis used 0.5 continuity correction, Paule–Mandel variance estimation, and modified Hartung–Knapp confidence intervals (CIs). Post hoc analyses used treatment-arm correction, Mantel–Haenszel pooling without correction, and a Poisson mixed model. Results: Forty-one studies were included. Any TEAE/AE was reported in 323/929 active-treatment and 66/267 placebo recipients; ADRs/related AEs occurred in 230/960 and 53/282. Prespecified risk ratios were 1.108 (95% CI 0.885–1.388) and 0.971 (0.764–1.234). Continuity-corrected inverse-variance analyses showed no significant difference. Mantel–Haenszel and Poisson estimates for any TEAE/AE were 1.393 (1.122–1.728) and 1.396 (1.070–1.820); ADR/related AE results were borderline and method-dependent. A highly imprecise gastrointestinal signal rested on one placebo event. Most risk-of-bias assessments raised some concerns. Conclusions: This was not an equivalence or non-inferiority analysis. Comparative estimates were sensitive to sparse-data methods, and clinically important increases in risk cannot be excluded. Concurrent controls and complete arm-specific reporting remain essential for interpreting early safety signals.