Reply

To the Editor:

We thank Dr. Riddle for stating his concerns regarding potential methodologic issues in our study. We would like to address these concerns.

First, our article was prepared in compliance with the Consolidated Standards of Reporting Trials statement (1), including all prespecified methods and results; therefore, there is no concern of selective outcome reporting. Diclofenac etalhyaluronate (DF‐HA) is a developmental product and has never been on the market in any country. To protect our intellectual property, only the minimum information was provided to the registry. Therefore, some of the secondary outcomes reported in this article differ from those registered. However, the registered contents in the JapicCTI registry follow the International Federation of Pharmaceutical Manufacturers and Associations guidelines (2). We plan to add this article to the JapicCTI registry after DF‐HA becomes available in the first country to implement it.

As for the second concern, we used the WOMAC scoring system (3) correctly because we followed the instructions in the WOMAC user guide to normalize dimensions on a subscale‐by‐scale basis and express the scores on 0–10 or 0–100 scales (4). Dr. Riddle also raised the issue of incorrect reporting of scale version and type of scale, as described by Woolacott et al (5). In the outcomes section of our article, however, we clearly state that we used a 100‐mm VAS to evaluate the WOMAC pain subscale scores. Therefore, we do not inadequately report or misreport any application or explanations of the WOMAC pain subscale scoring system.

Third, it is necessary to examine multiple factors in order to evaluate the clinical importance of group differences (6). We discussed results of the responder analysis, improvement of multiple symptoms, early response to treatment with DF‐HA, and maintenance of the treatment effect. In addition, to examine the magnitude of group differences for the primary and secondary outcomes, the mean effect size over 12 weeks was calculated using the least squares mean change and the pooled SD at each time point for the post hoc analyses (7). The results indicated that the mean effect size of DF‐HA treatment on WOMAC pain subscale scores over 12 weeks was 0.30. Similar effect sizes were observed when secondary outcomes were evaluated in the DF‐HA group over 12 weeks (Table 1). Although this study was not an active treatment–controlled clinical trial, and it is difficult to evaluate the clinical importance of group differences only by effect size, the effect size of DF‐HA was in the low‐to‐moderate range for improvement in primary and secondary outcomes (8). Thus, some benefits of DF‐HA were confirmed, but further studies are needed to evaluate the clinical usefulness of DF‐HA.

Table 1.

Difference and effect size in primary and secondary outcomes of DF‐HA over 12 weeks^*

	Difference (95% CI)	Effect size, SD units
Primary outcome
WOMAC pain score, mm†	–6.1 (–9.4, –2.8)	0.30
Secondary outcomes
WOMAC stiffness score, mm†	–4.6 (–8.0, –1.2)	0.20
WOMAC physical function score, mm†	–5.7 (–8.9, –2.5)	0.29
Total score	–5.6 (–8.7, –2.4)	0.29
50‐foot walking test pain score, mm†	–6.8 (–10.5, –3.2)	0.30
Mean daily pain score‡	–0.56 (–0.82, –0.31)	0.35
Patient global assessment score, mm†	–6.5 (–9.7, –3.3)	0.31
Physician global assessment score, mm†	–4.5 (–7.2, –1.9)	0.24

^*Differences are the between‐group difference (95% confidence interval [95% CI]) in least squares mean change from baseline. DF‐HA = diclofenac etalhyaluronate; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

^†On a 100‐mm visual analog scale (0–100).

^‡On an 11‐point numeric rating scale (0–10).

Supported by Seikagaku Corporation and Ono Pharmaceutical Company, Ltd. Dr. Nishida has received consulting fees, speaking fees, and/or honoraria from Eli Lilly, Kaken, Hisamitsu, Kyowa Hakko Kirin, and Asahi Kasei (less than $10,000 each) and from Seikagaku Corporation (more than $10,000) and has received research support from Daichi Sankyo, Chugai, Novartis, Pfizer, Eisai, and Zimmer Biomet. Mr. Kano, Mr. Nobuoka, and Dr. Seo own stock or stock options in Seikagaku Corporation.