Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Safety of a Novel Modified-Release (MR) Prednisone Formulation: Results of the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA) Studies.

Buttgereit1,  Frank, Szechinski5,  Jacek, Doring6,  Gisela, Witte2,  Stephan, Knauer3,  Christine, Grahn4,  Amy, Saag8,  Kenneth G.

Charite University Med-Berlin, Berlin, Germany
Horizon Pharma GmbH, Mannheim, Germany
Horizon Pharma GmbH, Mannheim, Germany
Horizon Pharma, Inc., Northbrook, IL
Med. Uni. Department of Rheumatology, Wroclaw, Poland
Merck KGaA
Schlosspark-Klinik, UnivMed, Berlin, Germany
University of Alabama-Birmingham, Birmingham, AL

Background:

In patients with rheumatoid arthritis (RA), nocturnal increases in proinflammatory cytokines are implicated in the typical early morning symptoms, joint stiffness and pain. Glucocorticoid (GC) chronotherapy with a novel modified-release (MR) prednisone tablet enables delivery of prednisone during the night to specifically target the nocturnal rises in inflammatory mediators and symptoms. This novel approach showed both clinically relevant reduction of morning stiffness (MS) compared to conventional, immediate-release (IR) prednisone, as well as clinically relevant improvements according to the ACR response criteria. The data here describes the safety and tolerability of low-dose prednisone chronotherapy in patients from two phase 3 clinical studies.

Methods:

The CAPRA studies investigated safety and efficacy of MR prednisone in patients with RA, not adequately controlled by disease-modifying antirheumatic drug (DMARD) therapy. The CAPRA-1 study compared the novel formulation (3–10 mg/day, average of 6.8 mg/day) in 288 patients to conventional immediate release prednisone over 12 weeks, the CAPRA-2 study compared 5 mg/day MR prednisone + DMARD in 350 patients to placebo + DMARD over 12 weeks. An open-label extension of CAPRA-1 provided safety data for up to 12 months. In addition, the effect of MR prednisone on the Hypothalamus-Pituitary-Adrenal (HPA) axis was investigated in a CRH test subgroup study, as part of CAPRA-1 (62 tests in 28 patients under treatment with MR prednisone or IR prednisone). All Adverse Events (AEs) from these studies were collected by neutral questioning in a standardized manner.

Results:

The incidence of serious adverse events (SAEs) and adverse events (AEs) in all treatments was low and comparable between MR prednisone and IR prednisone and comparable to the placebo arm, with more AEs related to RA signs and symptoms (arthralgia and RA flare) in the PBO arm than in the MR prednisone arm. In all studies MR prednisone was shown to be safe and well tolerated. The most frequent AEs are shown in Table 1. CRH tests in patients on treatment with MR prednisone or IR prednisone showed no evidence for a different effect on the HPA axis.

Table 1. Adverse Events occurring in >=2% of MR Prednisone in patients of the CAPRA studies.

 CAPRA-2 (3 Months)CAPRA-1 (3 Months)CAPRA-1 (9 Months)
Preferred termPrednisone MR 5mg (%) N=231Placebo (%) N=119Prednisone MR 3–10mg (%) N=144Prednisone IR 3–10mg (%) N=144Prednisone MR 3–10mg (%) N=249
Worsening of rheumatoid arthritis6.59.27.69.014.5
Arthralgia10.420.20.72.12.4
Nasopharyngitis4.83.42.85.62.4
Headache3.94.24.22.81.2
Abdominal pain upper0.41.73.55.61.6
Bronchitis1.34.20.73.52.4
Upper respiratory tract infection0.40.80.72.12.8
Hypertension2.20.82.12.1<1
Back pain1.30.8<1<12.8
Nausea1.30.03.52.8<1
Chest pain/discomfort0.40.02.12.1<1
Hypercholesterolemia0.41.7<1<12.4
Feeling hot0.00.0<1<12.0
Weight increased0.00.0<1<12.8

Conclusion:

Two large phase 3 clinical trials established a favorable safety profile of low-dose chronotherapy with MR prednisone. MR Prednisone has been shown to reduce duration of morning stiffness and to be more effective than placebo with regard to standard RA outcome parameters.

To cite this abstract, please use the following information:
Buttgereit, Frank, Szechinski, Jacek, Doring, Gisela, Witte, Stephan, Knauer, Christine, Grahn, Amy, et al; Safety of a Novel Modified-Release (MR) Prednisone Formulation: Results of the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA) Studies. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1123
DOI: 10.1002/art.28890

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