Rome, 18 June 2010: Lodotra – a unique modified-release formulation designed to be taken before bed and release low-dose prednisone in the early hours when inflammatory cytokines peak – achieves clinically significant improvements in ACR20, morning stiffness and pain in patients with rheumatoid arthritis (RA), according to results from clinical trials presented at the 11th Annual European League Against Rheumatism (EULAR) congress.
The phase 3 CAPRA-2 (Circadian Administration of Prednisone in Rheumatoid Arthritis-2) study randomised 350 patients with active rheumatoid arthritis to modified-release (MR) prednisone chronotherapy (5mg once daily) or placebo, in addition to their pre-existing disease modifying antirheumatic drug (DMARD). The MR tablet is taken at bedtime and releases prednisone four hours after ingestion, timed to synchronise with the circadian rhythm of RA in which cytokines peak in the early morning hours.
Results reported at EULAR showed that ACR20 was achieved by nearly twice as many patients treated with Lodotra (48.5%) as in those given placebo in addition to their DMARD (28.6%, p=0.0002) after twelve weeks’ treatment. MR prednisone-treated patients showed improvements in all core elements of ACR20, which is a 20% reduction in the number of swollen and tender joints, and a reduction of 20% in three of the following: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in the Health Assessment Questionnaire score.
Further results from the CAPRA-1 study (in 288 RA patients) showed the reduction in duration of morning stiffness was much greater with Lodotra after 12 weeks, compared to placebo in addition to DMARDs (22.7% vs 0.4% mean relative change to baseline; p=0.045). Patients who continued with Lodotra in an open-label extension phase showed even greater reduction in morning stiffness by 12 months (55%). They also achieved a clinically significant reduction in pain intensity and DAS 28 score. Lodotra was well tolerated and adverse events were similar to the same dose of conventional prednisone.
A survey of 750 RA patients from 11 European countries presented during EULAR showed that more than one-quarter (29%) find that it takes one and a half to three hours before they are able to start their day because of pain and stiffness in the morning resulting from their RA. This impacts directly on ability to work, with 74% of the patients suffering morning stiffness reporting that they are either unemployed, or on sick leave, or have had to take early retirement because of their RA. Nearly two-thirds (60%) say their pain and stiffness in the morning controls their lives.
Reporting the survey findings, Maurizio Cutolo, professor of rheumatology at the University of Genova, Italy, explained that levels of pro-inflammatory cytokines, particularly IL-6 and TNF-alpha, rise in the early morning, peaking between 1.00-5.00am, which follows the circadian rhythms of RA symptoms. This explains why many patients find their joint stiffness, pain and functional disability are most severe in the early morning.
“Patients with RA have higher peaks of inflammatory cytokines, which are shifted towards the morning compared with people without RA. They have inadequate nocturnal serum cortisol relative to inflammation, so require replacement low-dose glucocorticoid therapy,” Professor Cutolo said. “Glucocorticoid treatment is optimised when given at the time pro-inflammatory cytokines are elevated,” he added, noting that Lodotra achieves this by providing programmed delivery of prednisone about four hours after a patient has taken a tablet before going to bed.
Written by Susan Mayor