Efficacy, Safety, and Economic Evaluation of Gamidaeganghwal-Tang in Patients with Knee Osteoarthritis: Protocol for a Multicenter, Randomized, Double-Blind, Controlled Trial [Letter]

Dear editor

We read with great interest the study protocol by Kim et al regarding the efficacy, safety, and economic evaluation of Gamidaeganghwal-tang (GMDGHT) for knee osteoarthritis (KOA).¹ Before this protocol is implemented and the findings interpreted, several design choices and logical inconsistencies warrant closer scrutiny.

First, there is a logical contradiction in the sample size calculation. The study protocol specifies an 80% statistical power and an expected dropout rate of 20%, requiring approximately 100 participants per group theoretically. However, only 80 participants were actually planned for enrollment. In the event of expected dropouts, the final analytical sample size would decrease to approximately 64 participants, resulting in insufficient statistical power and potentially failing to detect genuine efficacy differences.

Second, the risk of blinding failure is significantly underestimated.² GMDGHT is a complex aqueous extract containing 12 herbal ingredients, which typically possess distinct organoleptic properties (bitterness, aroma, and texture). The placebo, however, relies solely on “ginseng flavor powder” and colorants to mimic these characteristics. As the authors acknowledge in the discussion, subtle differences in taste or texture may challenge participant blinding. For participants familiar with traditional herbal medicine, this disparity may lead to unblinding, thereby contaminating the subjective K-WOMAC scores with expectation bias.³ Assessing blinding success only at the final visit is a “post-mortem” measure that cannot correct for performance bias introduced during the 12-week treatment period.

Third, the stringent restriction on concomitant therapies introduces significant selection bias. The protocol requires participants to discontinue existing KOA treatments and prohibits the use of analgesics, NSAIDs, and physical therapy for 12 weeks. This requirement likely filters out patients with moderate-to-severe symptoms who cannot tolerate a cessation of standard care. Consequently, the study population may be limited to a highly specific subgroup with high pain tolerance or mild disease, undermining the generalizability of the findings to real-world clinical practice. Furthermore, this raises further questions regarding the applicability of the pre-specified Minimal Clinically Important Difference (MCID) of 10.55 to such a selective cohort.

Fourth, the methodological rationale lacks transparency. The introduction claims a lack of robust clinical evidence, yet also notes that GMDGHT has been used in routine clinical practice for three years. The absence of preliminary practical data undermines the empirical support for the trial design.

Finally, the 24-week time horizon for economic evaluation is insufficient.⁴ For a chronic degenerative disease like KOA, cost-utility outcomes (QALYs) often manifest over years. A 6-month window is unlikely to capture the intervention’s potential long-term value in delaying surgical requirements or sustained productivity gains.

Additionally, we noted a minor editorial oversight in Table 1, where “VAS” is defined twice in the notes. While minor, such redundancies suggest that the rigorous quality control required for a multicenter trial protocol may need further strengthening.

We urge the authors to consider these points, as addressing these vulnerabilities will significantly enhance the scientific rigor and clinical relevance of this trial.