LAS VEGAS – Adalimumab proved no better than placebo for the treatment of erosive hand osteoarthritis in the double-blind, placebo-controlled, randomized HUMOR trial, throwing cold water on hopes that a disease-modifying treatment for osteoarthritis might at long last have been found.
“This randomized controlled trial demonstrated that subcutaneous adalimumab at 40 mg every other week was no different from placebo for alleviation of pain, synovitis, or bone marrow lesions in patients with erosive hand osteoarthritis presenting with MRI-detected synovitis. This suggests that pain and inflammation are not responsive to TNF [tumor necrosis factor] inhibition in this patient population,” Dawn Aitken, PhD, declared at the World Congress on Osteoarthritis.
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Dr. Dawn Aitken
The primary endpoint was change in the visual analog pain score over the course of 12 weeks of therapy. Scores dropped by an average of 3.0 points from a mean baseline of 63.6 with adalimumab and by 0.7 points with placebo. That between-group difference wasn’t statistically significant, nor were those modest reductions clinically meaningful. By convention, a clinically meaningful treatment result requires at least a 15-point improvement on the self-assessed pain scale, noted Dr. Aitken of the University of Tasmania in Hobart, Australia.
It made no difference which treatment arm came first.
“There was absolutely no placebo effect,” she said.
The study proved negative for all prespecified secondary endpoints, too. These included change in the Australian/Canadian Hand OA Index pain, function, and stiffness subscales, as well as change in bone marrow lesions and synovitis. A mere 12% of patients showed improvement in synovitis scores with adalimumab, as did 10% on placebo. Five percent of the adalimumab group and 7% on placebo showed improvement in bone marrow lesion scores.
The proinflammatory cytokine TNF-alpha has been shown to play a key role in OA development and progression. However, several prior studies failed to show a benefit for anti-TNF therapy in terms of reducing pain in hand OA patients, although in one of those negative studies, a post hoc analysis found that adalimumab halted erosive progression in the subset of interphalangeal joints with palpable soft tissue swelling at baseline (Ann Rheum Dis. 2012 Jun;71[6]:891-8).
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Dr. Margreet Kloppenburg
However, there was a positive signal: In a subgroup analysis confined to the patients with inflammatory joints, the use of etanercept was associated with less structural damage of those joints over time as assessed using the quantitative Ghent University Scoring System, or GUSS, according to Dr. Kloppenburg, professor of rheumatology at Leiden (the Netherlands) University.
The emphatically negative results of the HUMOR trial were greeted with dismay by several disappointed audience members. They raised questions: Might a study featuring more than 12 weeks of treatment have brought positive results? How about a larger study? Why no placebo effect, given that patients were receiving injections? Is this area of investigation of TNF-inhibitor therapy now a dead end? Or could adalimumab and etanercept have differential efficacy in hand OA, even though they are both TNF inhibitors?
Dr. Aitken had an answer for every question.
“I think our study was big enough based on our power calculations to detect a difference of 15 mm on a visual analog scale, which is a clinically important difference. And that’s what we should be chasing in OA, that big effect. Patients are not going to be interested in a treatment that improves their pain by 5 mm,” she said.
As for the possibility that 12 weeks of adalimumab might have been too short to see a treatment effect, Dr. Aitken noted that anti-TNF therapy in rheumatoid arthritis brings a rapid response.
“Ideally, if you did have a disease-modifying drug for osteoarthritis you would want it to have a relatively quick response for pain; if patients aren’t seeing an effect after 3 months they might be less interested in taking it,” she continued.
Also, studies with a crossover design, like HUMOR, are known to have a much smaller placebo effect because patients know that at some point they’re certain to receive the active agent, Dr. Aitken observed.
As for the possibility that etanercept might be effective for erosive hand OA, while adalimumab is not, one physician commented, “That’s really scraping the bottom of the barrel.”
The HUMOR trial was sponsored by AbbVie. Dr. Aitken reported having no financial conflicts.