Background/Purpose: A transfersome is an ultradeformable lipid vesicle originally developed to deliver high concentrations of drug (eg NSAIDs) transdermally. Large interventional trials in osteoarthritis (OA) of the knee comparing ketoprofen-containing vesicles (IDEA-033) to vesicles without active drug (called Sequessome, TDT 064) showed conflicting results for IDEA-033^1-3 but all demonstrated pronounced treatment effects of the vehicle itself (TDT 064) that, in one study,⁴ were comparable to 100 mg b.i.d. celecoxib and statistically significantly superior to oral placebo.⁴ Objectives were to investigate how the treatment effects seen with TDT 064 compare with the results reported for the placebo arm of other OA interventional studies using a meta-analytic approach.

Methods: The efficacy of TDT 064 gel has been evaluated in four randomized, double-blind, parallel-group multicenter, 12-week Phase III studies of IDEA-033 in knee OA that included TDT 064 as a drug-free vesicle control group. The meta-analysis combines the results of the WOMAC pain subscales from the studies which were standardized to a 0–100 scale. The resulting pre-post effect size (ES) is the standardized difference (Cohen)⁵ of the changes from baseline of the WOMAC pain subscale score at Week 12 (based on the standard deviation of the changes of the corresponding TDT 064 group). Effect sizes of 0.2, 0.5, and 0.8 are used to represent small, medium, and large effect sizes, respectively.⁵ The results of the meta-analysis are presented as two-sided tests with two-sided 95.0% confidence intervals (CIs; Hedges’g). The results of this analysis are compared with those of a meta-analysis of placebo responses from other conventional trials as published by Zhang et al.⁶

Results: The ES calculated for a total of 1061 patients with OA of the knee treated with TDT 064 gel was 1.15 (CI: 1.09–1.21). The respective values for the individual 4 studies were 1.33 (CI: 1.18–1.47)¹, 1.12 (CI: 1.03–1.21)², 1.05 (CI: 0.87–1.24)³, and 1.12 (CI: 1.00–1.24)⁴. The results were comparable irrespective of whether 2.2 g or 4.4 g of TDT 064 gel was used (ES 2.2 g: 1.17 [CI: 1.07–1.28]; ES 4.4 g: 1.12 [CI: 1.04–1.20]). This compares to an ES of 0.51 (CI: 0.46–0.55) reported for all placebo applications and an ES of 0.63 (CI: 0.47–0.80) for the topical placebo arm investigated with topical formulations in the meta-analysis of Zhang et al.⁶

Conclusion: Pain reduction reported in 4 comparative, double-blind studies in knee OA using TDT 064 is substantially higher than the reduction reported for the topical placebo arm of other interventional trials. The magnitude of the difference indicates that this effect is unlikely to be due to a placebo response alone. 

References

1. Stucki G, et al. Ann Rheum Dis 2007;66(Suppl. II):510.
2. Rother M, et al. EULAR Annual European Congress of Rheumatology 2012. Abst #12-3375.
3. Rother M, et al. EULAR Annual European Congress of Rheumatology 2012. Abst #12-3378.
4. Conaghan P, et al. EULAR Annual European Congress of Rheumatology 2012. Abst #12-3366.
5. Cohen J. Statistical power analysis for the behavioural sciences (2^nd ed). Lawrence Erlbaum Associate Publishers: Hillsdale, NJ (1988).
6. Zhang W, et al. Ann Rheum Dis 2008;67:1716-23.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/meta-analysis-of-four-12-week-phase-iii-clinical-trials-investigating-the-effect-of-tdt-064-a-transdermal-gel-in-osteoarthritis-of-the-knee/