Efficacy and safety of low-dose submicron diclofenac for the treatment of osteoarthritis pain: a 12 week, phase 3 study

Abstract

Objective:

NSAIDs, such as diclofenac, are the most commonly used medications to treat osteoarthritis (OA), but they are associated with dose-related adverse events (AEs). Low-dose submicron diclofenac was developed using a new, proprietary dry milling process that creates submicron drug particles (SoluMatrix Fine Particle Technology), enabling effective treatment at lower doses than other commercially available diclofenac drug products. This phase 3 study evaluated the efficacy and safety of low-dose submicron diclofenac 35 mg three times daily (tid) and twice daily (bid) in patients with OA pain.

Research design and methods:

This double-blind study enrolled patients ≥40 years of age with clinically and radiographically confirmed (Kellgren–Lawrence grade II–III) hip or knee OA. Eligible patients were chronic NSAID and/or acetaminophen (APAP) users with baseline Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain subscale scores ≥40 mm by visual analog scale and an OA flare (≥15 mm increase in WOMAC pain subscale score following discontinuation of NSAIDs/APAP at screening). Patients were randomized to submicron diclofenac 35 mg tid, submicron diclofenac 35 mg bid, or placebo for 12 weeks.

ClinicalTrials.gov identifier:

ClinicalTrials.gov identifier: NCT01461369.

Main outcome measures:

Efficacy parameters included mean change from baseline in WOMAC pain subscale score at week 12 (primary efficacy parameter) and in average total WOMAC score over 12 weeks.

Results:

Submicron diclofenac 35 mg tid significantly improved WOMAC pain subscale scores from baseline at 12 weeks (−44.1; p = 0.0024) compared with placebo (−32.5). Submicron diclofenac 35 mg bid provided numerical improvement in pain at week 12 that did not reach statistical significance (−39.0; p = 0.0795) compared with placebo. Submicron diclofenac 35 mg tid (−35.9; p = 0.0002) and 35 mg bid (−30.3; p = 0.0363) improved the average total WOMAC score in treated patients over 12 weeks compared with placebo (−23.2). The most frequent AEs in the submicron diclofenac-treated groups were diarrhea, headache, nausea, and constipation. The inclusion of patients with a documented requirement for analgesic therapy (OA ‘flare’) at baseline and the high rates of rescue medication usage in the placebo group may have impacted the study outcome for the submicron diclofenac treatment groups.

Conclusions:

Low-dose submicron diclofenac is an effective therapeutic option for the treatment of OA pain.

Keywords::

• Chronic pain
• Diclofenac capsules
• NSAID
• Osteoarthritis
• Submicron

Transparency

Declaration of funding

This study was supported by Iroko Pharmaceuticals LLC, Philadelphia, PA, USA.

Declaration of financial/other relationships

A.G. has disclosed that he is a stock shareholder of GlaxoSmithKline plc, Bristol-Myers Squibb, Johnson & Johnson Services Inc., Amgen Inc., Pfizer Inc., and AbbVie Inc. and serves as a consultant for Takeda Pharmaceutical Company Limited, Amgen, AbbVie, UCB Inc., Genentech Inc., Horizon Pharma, and Iroko Pharmaceuticals LLC. M.C.H. has disclosed that he is a consultant for Iroko Pharmaceuticals, Amgen, AstraZeneca, Covidien, Eli Lilly and Company, EMD Serono, Genentech Inc., Merck & Co Inc., Novartis Pharma AG, Pfizer, and Pozen Inc. M.J. has disclosed that he is an employee of Summit Analytical LLC and is a consultant for Iroko Pharmaceuticals. C.L.Y. has disclosed that he is an employee of Iroko Pharmaceuticals.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank the following individuals: Jennifer Nezzer, Susan Whitcher, Aaron Danna, Michael Kuss, Garen Manvelian, Olaolu Imasogie, Daniel Solorio, Claire Sheridan, and the investigators and patients who participated in this study. Colville Brown MD of AlphaBioCom LLC (King of Prussia, PA, USA) provided editorial support for this manuscript. Funding for editorial support was provided by Iroko Pharmaceuticals LLC.

Previous presentations: Gibofsky A, Hochberg M, Young C. A phase 3 study of lower-dose diclofenac submicron particle capsules demonstrate effective pain relief in patients with osteoarthritis. World Congress on Osteoarthritis, 18–21 April 2013, Philadelphia, PA, USA. Osteoarthritis Cartilage 2013;21(Suppl):S267. Kuss M, Nezzer J, Young C. A phase 3 study of lower-dose diclofenac submicron particle capsules demonstrates effective pain relief in patients with osteoarthritis. 8th Congress of the European Federation of IASP Chapters (EFIC), 9–12 October 2013, Florence, Italy [Abstract 666]. Young C, Hochberg M. Safety of lower-dose diclofenac submicron particle capsules dosed to 12 weeks in patients with osteoarthritis. American College of Rheumatology Annual Meeting, 26–30 October 2013, San Diego, CA, USA [Abstract 2149]. Arthritis Rheum 2013;65(Suppl 10):s882. Argoff C, Parenti D, Young C. Lower-dose diclofenac submicron particle containing capsules: review of pharmacokinetic properties, efficacy, and tolerability. Eastern Pain Association Annual Meeting, 7 December 2013, New York, NY, USA. Young C, Parenti D, Hochberg M. Lower-dose diclofenac capsules developed using SoluMatrix Fine Particle Technology result in clinically meaningful improvements in pain in a phase 3 study of patients with osteoarthritis. 2014 World Congress on Osteoarthritis, 24–27 April 2014, Paris, France. Osteoarthritis Cartilage 2014; 22(Suppl): S399. Strand V, Bergman M, Parenti D, et al. A phase 3 randomized controlled trial of lower-dose diclofenac capsules developed using SoluMatrix fine particle technology in patients with osteoarthritis pain: impact on patient-reported outcomes. 2014 World Congress on Osteoarthritis, 24–27 April 2014, Paris, France. Osteoarthritis Cartilage 2014;22(Suppl):S392.

Notes

*SoluMatrix Fine Particle Technology is a trademark of iCeutica Inc., and the technology is licensed to Iroko Pharmaceuticals LLC for exclusive use in NSAIDs

†SoluMatrix Fine Particle Technology is a trademark of iCeutica Inc., and the technology is licensed to Iroko Pharmaceuticals LLC for exclusive use in NSAIDs

‡Zorvolex is a registered trademark of Iroko Pharmaceuticals LLC, Philadelphia, PA, USA