Conference Coverage

Baricitinib study highlights power of placebo effect in RA



– After 52 weeks of blinded adalimumab, a switch to 48 weeks of unblinded baricitinib without an adalimumab washout period resulted in an uptick in rheumatoid arthritis control with no flares and no increase in serious adverse events in the phase 3 RA-BEYOND baricitinib long-term extension study, Michael E. Weinblatt, MD, reported at the annual meeting of the American College of Rheumatology.

Dr. Michael E. Weinblatt

That’s information of practical clinical utility now that baricitinib, an oral inhibitor of Janus kinase subtypes 1 and 2, is approved as Olumiant for the treatment of moderate to severely active rheumatoid arthritis (RA). Perhaps even more interesting, however, is the way RA-BEYOND shined a spotlight on the high placebo response rate endemic to RA clinical trials, according to Dr. Weinblatt, professor of medicine at Harvard Medical School and codirector of clinical rheumatology at Brigham and Women’s Hospital, Boston.

He presented an analysis of two patient groups: 381 RA patients with moderately to severely active RA at baseline who were randomized to 52 weeks of double-blind baricitinib at 4 mg once daily in the previously reported phase 3 RA-BEAM trial (N Engl J Med. 2017 Feb 16;376[7]:652-62), after which they immediately enrolled in RA-BEYOND and were switched to 48 weeks of open-label, unblinded baricitinib; and 238 RA patients who were randomized to double-blind subcutaneous adalimumab (Humira) at 40 mg every 2 weeks in RA-BEAM before being switched to unblinded baricitinib in RA-BEYOND. All participants were on background oral methotrexate throughout.

Here’s the finding that captured Dr. Weinblatt’s attention: At the time of the switch, 28.2% of patients who’d been on blinded baricitinib for 52 weeks were nonresponders to the drug, meaning that after a full year of treatment they had a Clinical Disease Activity Index (CDAI) score greater than 10. Yet after a mere additional 4 weeks on the same drug in RA-BEYOND – this time unblinded as to their treatment – 23.4% of this group were transformed into responders, with low disease activity as defined by a CDAI of 10 or less. This finding speaks eloquently as to the power of the placebo effect. It’s a real issue for clinical trialists, the rheumatologist observed.

In the adalimumab-to-baricitinib group, 31.1% of patients were nonresponders to 52 weeks of blinded adalimumab. Four weeks after switching to open-label baricitinib, 29.7% of this group had a CDAI of 10 or less.

At week 48 of open-label baricitinib in RA-BEYOND, 54.2% of nonresponders to the 52 weeks of blinded baricitinib had become responders, as did 50% of nonresponders to a year of blinded adalimumab.

Taking a step back to describe the primary outcomes in RA-BEYOND, Dr. Weinblatt noted that at enrollment in RA-BEYOND, after 52 weeks on double-blind baricitinib, 71.8% of patients had a CDAI of 10 or less and 27% were in remission as defined by a CDAI of 2.8 or less. Subsequently, after 48 weeks on unblinded baricitinib, these rates climbed to 78.2% and 31.6%, respectively.

Similarly, in the adalimumab-to-baricitinib study arm, the low disease activity and remission rates at enrollment in RA-BEYOND were 68.9% and 24.4%, improving to 73.5% and 28.2% after 48 weeks on open-label baricitinib.

Scores on the SDAI (Simplified Disease Activity Index) and DAS28-ESR (Disease Activity Score based on 28 joints with erythrocyte sedimentation rate) followed suit in both groups.

During the 48 weeks of open-label baricitinib in RA-BEYOND, the incidence of herpes zoster was roughly 2.2% in both study arms, and the rate of adverse events leading to permanent drug discontinuation was 2.7%. During RA-BEYOND, serious infections occurred in 3.8% of the baricitinib-to-baricitinib group and 2.2% of the adalimumab-to-baricitinib group.

Dr. Weinblatt drew attention to the fact that the dose of baricitinib employed in RA-BEAM and RA-BEYOND was 4 mg/day, whereas the dose approved by the Food and Drug Administration is 2 mg/day.

The RA-BEAM and RA-BEYOND trials were sponsored by Eli Lilly. Dr. Weinblatt reported serving as a paid consultant to that pharmaceutical company and more than a dozen others.

SOURCE: Weinblatt ME et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 886.

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