Elsevier

The Lancet

Volume 371, Issue 9608, 19–25 January 2008, Pages 205-214
The Lancet

Articles
Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial

https://doi.org/10.1016/S0140-6736(08)60132-4Get rights and content

Summary

Background

Circadian rhythms are changed in patients with rheumatoid arthritis. A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit–risk ratio of glucocorticoid therapy in rheumatoid arthritis. We aimed to assess the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with this disease.

Methods

In a 12-week, multicentre, randomised, double-blind trial, 288 patients with active rheumatoid arthritis were randomly assigned to either a modified-release prednisone tablet (n=144) or to an immediate-release prednisone tablet (n=144). The modified-release tablet was taken at bedtime and prednisone was released with a delay of 4 h after ingestion. This treatment was compared with morning administration of immediate-release prednisone as an active comparator. The primary outcome measure was duration of morning stiffness of the joints. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00146640.

Findings

The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone (−22·7% vs −0·4%; difference=22·4% [95% CI 0·49–44·30]; p=0·045). Patients in the prednisone modified-release group achieved a mean reduction of 44·0 (SD 136·6) min compared with baseline. The absolute difference between the treatment groups was 29·2 min (95% CI −2·59 to 61·9) in favour of modified-release prednisone (p=0·072). The safety profile did not differ between treatments.

Interpretation

Modified-release prednisone is well tolerated, convenient to administer, and produces a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone.

Introduction

Glucocorticoids exceed many other drugs in terms of use, variety of applications, pharmacological experience, and effectiveness (both clinical and cost).1 Almost 60 years after their introduction into clinical practice, they still represent the most important and most frequently used class of anti-inflammatory drugs, with a steady rise in their therapeutic use.2 The list of diseases that standard glucocorticoids can be used to treat is long and includes disorders such as allergic airway disease, rheumatic diseases (such as rheumatoid arthritis), dermatological diseases, and other local and systemic diseases.

However, glucocorticoids have a considerable potential for frequent and sometimes serious side-effects that restrict their use.3, 4, 5 Early strategies to improve the benefit–risk ratio were the synthesis of drugs with lower mineralocorticoid but higher anti-inflammatory activity.6 Moreover, glucocorticoids have been applied directly at the site of inflammation to keep systemic effects to a minimum wherever possible. Nevertheless, a general rule, that glucocorticoids should be used as much as necessary, but as little as possible, has evolved from increased experience of their use.6

Although glucocorticoids still have substantial risks they are essential for successful treatment of some disorders. This dilemma is a strong driving force for basic science and clinical research to optimise glucocorticoid therapy—ie, to “sharpen the old spear”.6 Intensive research is underway to develop innovative glucocorticoid receptor ligands with an improved benefit–risk ratio. Selective glucocorticoid receptor agonists and nitrosoglucocorticoids are examples, but their clinical relevance still needs to be shown.1, 3, 6

The challenge is whether we can further improve treatment with conventional glucocorticoid drugs. Promising developments include the targeted delivery of conventional glucocorticoids via liposomal glucocorticoids or inhibition of 11β-hydroxysteroid dehydrogenase to increase circulating concentrations and thus the action of endogenous glucocorticoids.6 However, clinical evidence for the efficacy and safety of these approaches in human beings is still missing.

To optimise conventional glucocorticoid therapy a modified-release system has been developed and studied in human beings. The tablet releases prednisone about 4 h after ingestion—ie, at about 0200 h if given at bedtime. This timing allows glucocorticoid release to be adapted to the circadian rhythms of endogenous cortisol and symptoms of the disease, both of which have their peaks during the early morning hours. This circadian rhythm of symptoms is inadequately controlled by the routine regimen for glucocorticoid dosing, with drug intake in the morning. Therefore a modified-release prednisone tablet to be taken in the evening was expected to improve the benefit–risk ratio of prednisone treatment in rheumatoid arthritis. The Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) study (EMR 62 215-003) assessed the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with rheumatoid arthritis.

Section snippets

Study design and patients

Male and female patients aged between 18 and 80 years with a documented history of rheumatoid arthritis according to the criteria of the American College of Rheumatology7 were eligible for this study. Patients had to have had active symptoms of disease to allow assessment of the inflammatory component of morning stiffness of the joints. Inclusion criteria therefore included an average daily duration of morning stiffness of the joints of 45 min or more, an average daily maximum pain intensity

Results

Figure 1 shows the trial profile. Of the 375 screened patients, 288 were enrolled and randomly assigned to treatment groups (144 per group). The most common reason for non-inclusion was low disease activity on the standard prestudy treatments (morning stiffness of the joints <45 min or inflammatory activity too low). All 288 randomised patients constituted the intention-to-treat population. 251 (87%) patients completed the double-blind phase of the study, 121 in the modified-release prednisone

Discussion

Our double-blind, randomised study has shown that the new modified-release formulation of prednisone was better than standard immediate-release prednisone in reducing the duration of morning stiffness of the joints in patients with rheumatoid arthritis. Interleukin 6 serum concentrations were also significantly reduced by modified-release prednisone after 3 months but were unchanged by immediate-release prednisone. The evening administration of modified-release prednisone did not affect the

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