SAN FRANCISCO, California—Osteoarthritis (OA) researchers are solving the problem of how to get topical formulations of arthritis drugs into the joint. A phase III trial of a topical diclofenac/DMSO solution (Pennsaid®, Nuvo Pharmaceuticals) and a trial of a new topical ketoprofen (IDEA-033, Idea AG) reported at the 2008 meeting of the American College of Rheumatology both show efficacy similar to oral NSAIDs, and the diclofenac preparation showed significantly lower adverse effects compared to oral diclofenac.1,2
"TDS [topical solution of diclofenac] is an effective treatment option for the symptoms of knee OA with an improved safety profile as compared to oral diclofenac."—Lee S. Simon, MD

Painting knee with diclofenac/DMSO solution as good as pills, phase III RCT shows

“TDS [topical solution of diclofenac] is an effective treatment option for the symptoms of knee OA with an improved safety profile as compared to oral diclofenac,” reported lead investigator Lee S. Simon, MD,  of Harvard Medical School in Boston, Massachusetts. This trial was done to answer questions raised in the US FDA's “approvable” letter for Pennsaid, which now looks on target to become the first topical NSAID the agency will approve for OA treatment.  

Dr. Simon's double-blind, double-dummy, randomized controlled trial in 775 subjects with knee OA found that topical diclofenac was as effective as oral diclofenac for treating knee OA in the following domains:
  • Pain (P =.43)
  • Physical function (P = .32)
  • Patient overall health assessment (POHA, P = .96)
  • Stiffness (P =.46)
  • Patient global assessment (P = .60)

Patients were randomized to five treatment arms (Figure 1) that compared the topical 1.5% diclofenac in a 45.5% dimethyl sylfoxide (DMSO) vehicle plus oral placebo to placebo solution with oral placebo, to the vehicle solution plus oral placebo, to placebo solution plus oral diclofenac (100 mg slow-release), and to topical diclofenac solution plus oral diclofenac. The placebo solution included a very small amount of DMSO to compensate for the characteristic onion or garlic taste subjects report within a few minutes after DMSO is absorbed through the skin. The combination topical/oral diclofenac arm was added to the trial at the FDA's request.

Primary efficacy endpoints were WOMAC pain, WOMAC physical function, and POHA. Secondary endpoints were WOMAC stiffness and patient global assessment (PGA).

Dr. Simon said that modified intent-to-treat analysis showed that topical diclofenac solution was better than placebo for pain, physical function, POHA, and PGA, but not for stiffness, that topical diclofenac was superior to vehicle on all efficacy measures, and that there were no significant efficacy differences between vehicle and  placebo except for POHA, which favored vehicle.

The proportion of patients who dropped out due to adverse effects was 11.4%, and 9.4% dropped out due to lack of efficacy. The most common side effect with topical diclofenac solution was dry skin, which occurred in 18.2% of patients. However, topical diclofenac was associated with fewer gastrointestinal adverse effects and with fewer laboratory abnormalities than the oral formulation.

Combining the topical diclofenac with oral diclofenac did not produce any additional side effects beyond those associated with oral diclofenac alone.

RCT: Topical Diclofenac Solution for Treating Knee OA:

ARM DRUG DOSE
1. Topical diclofenac solution + placebo*† Diclofenac solution 1.5% in 45.5% DMSO vehicle, applied to 1 knee 40 drops QID for 12 weeks
  Placebo tablet 1/day for 12 weeks
2. Placebo solution + tablets Placebo solution 2.3% DMSO, applied to 1 knee 40 drops QID for 12 weeks
  Placebo tablet 1/day for 12 weeks
3. Vehicle solution + placebo Vehical solution 45.5% DMSO, applied to 1 knee 40 drops QID for 12 weeks
  Placebo tablet 1/day for 12 weeks
Oral diclofenac Placebo solution 2.3% DMSO, applied to 1 knee 40 drops QID for 12 weeks
  Oral diclofenac 100 mg slow-release/day
5. Topical diclofenac solution + oral diclofenac Diclofenac solution 1.5% in 45.5% DMSO vehicle, applied to 1 knee 40 drops QID for 12 weeks
  Oral diclofenac 100 mg slow-release/day
*P = .015 versus placebo for WOMAC pain
†P = .43 versus oral diclofenac for WOMAC pain

Adapted from Simon L, et al.1

The vehicle-only arm showed that DMSO has no effect in knee OA, although it has enjoyed some fame as an allegedly “suppressed” approach to treating arthritis.

Ketoprofen that sneaks through the skin also looks good

Pennsaid relies on DMSO's ability to penetrate the skin and to carry other chemicals along with it. IDEA-033 (IDEA  AG) uses a different strategy: the Transferosome® is an easily deformed carrier structure loaded with ketoprofen and applied in aqueous solution. Applied to the skin, the water evaporates, carriers reaching their solubility limit are attracted by the skin's high water content, and they migrate through the skin, carrying the drug with them.

Matthias Rother, MD, and colleagues from IDEA AG in Munich, Germany, reported that IDEA-033 showed the same efficacy as 500 mg naproxen BID for relief of knee OA pain.2 This was the first trial to provide 52-week safety  and efficacy data for a locally applied NSAID.

The 349 knee OA patients in the multicenter, randomized, double-blind, double-dummy study were randomized to IDEA-033 applied to the skin at a dose of 100 mg ketoprofen BID or to oral naproxen at a dose of 500 mg BID. The primary endpoints were WOMAC pain score, PGA, and WOMAC function score.  The study was designed to show noninferiority of IDEA-033 as compared with the naproxen group.

“The primary efficacy analysis for the intention-to-treat population showed proven noninferiority for all three primary efficacy criteria (LB-CI > 0.4; confirmatory result). The effect sizes of the changes from baseline of WOMAC function showed a trend for superiority of IDEA-033 (100 mg ketoprofen in IDEA-033) versus naproxen (P = .0536),” Dr. Rother reported.

Adverse effects occurred in 85 out of 138 (61.6%) naproxen patients and 106 out of 207 (51.2%) IDEA-033 patients (51.2%). Discontinuation rates due to adverse effects were 18.1% in the naproxen group and 15.9% in the IDEA-033 group. Rates of severe adverse effects were 5.07% for naproxen and 4.35% for IDEA-033. Dr. Rother commented that most of the treatment-related AEs in the IDEA-033 patients were dermal irritations.

“IDEA-033 as a topical applied NSAID showed efficacy at a level of 500 mg naproxen BID for a treatment period of up to 52 weeks. IDEA-033 seems to be a valuable option for the long-term treatment of OA of the knee,” the researchers concluded.

References

1. Simon LS, Grierson LM, Naseer Z, et al. Efficacy and safety of a topical diclofenac solution compared with topical placebo, vehicle, oral diclofenac, and oral/topical combination in the symptomatic treatment of osteoarthritis of the knee. Presented at: American College of Rheumatology 2008 Meeting; October 27, 2008; San Francisco, CA. Presentation 855.
2. Rother M, Yoeman G, Ekman E, et al. Safety and efficacy of epicutaneously applied ketoprofen in transfersome® (IDEA-033) as compared to oral naproxen after 52 weeks treatment in patients with osteoarthritis (OA) of the knee. Presented at: American College of Rheumatology 2008 Meeting; October 27, 2008. San Francisco, CA. Presentation 854.