Publication summary 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. Buttgereit F, Doering G, Schaeffler A, et al. Lancet 2008; 371(9608):205-14. Background and key findings
It was proposed that by administering glucocorticoids
of RA compared with baseline. However, this regimen
to rheumatoid arthritis (RA) patients during the night,
was considered to be impractical because it required
instead of the usual morning dosing regimen
regular waking of the patient at 2 a.m. This led to the
(e.g. 6 - 8 a.m.), this may improve the risk:benefit ratio
development of a modified-release (MR) formulation
of this class of drugs. The theory behind this was that
of prednisone which could be taken at bedtime
if the glucocorticoid could be administered in the
(around 10 p.m.) and, after a delay of approximately
early morning hours (approximately 2 a.m.) then this
4 hours, would begin to release the active drug.
would not only mimic the natural circadian rhythm of endogenous cortisol but would also allow the drug
The Circadian Administration of Prednisone in
to act at the most appropriate time point to prevent
Rheumatoid Arthritis (CAPRA-1) Phase III study found
the circadian increases of pro-inflammatory cytokine
that at 12 weeks, the MR prednisone (compared with
concentrations and, consequently, the morning
• a significantly greater relative decrease in the
duration of morning stiffness (P = 0.045);
This concept was confirmed by Arvidson et al.1 who
• a significantly greater relative decrease in serum
demonstrated that the administration of conventional
immediate-release (IR) prednisone at 2 a.m.
• no clinically relevant differences in tolerability
significantly improved the acute morning symptoms
The CAPRA-1 study was set up to assess the efficacy and safety of a modified-release (MR) prednisone tablet compared with immediate-release (IR) prednisone in patients with active rheumatoid arthritis (RA).
A total of 288 patients with active RA were randomised to receive study treatment. As is typical in RA, the patient population in this study were predominantly female (≈ 86%), of white ethnic origin (≈ 99%) and with a mean age of approximately 55 years. Around two-fifths of patients had long-standing disease with duration greater than 10 years, and a further fifth had suffered from RA for five to ten years. They also had a mean 28-joint disease activity score (DAS28) of 5.8.
The majority of patients were receiving a stable dose of disease-modifying antirheumatic drugs (DMARDs; ≈ 95%) and non-steroidal anti-inflammatory drugs (NSAIDs; ≈ 81%). All patients had been receiving glucocorticoids for at least three months with a stable dose of 2.5 mg – 10 mg prednisone (or equivalent) for at least one month before randomisation. The mean daily dose of glucocorticoids was approximately 6.6 mg of prednisone per day (or equivalent).
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This was a 12-week, multicentre, randomised, double-blind, active-control ed study. Al patients were randomised to either IR prednisone given in the morning (6 – 8 a.m.) or MR prednisone given in the evening (about 10 p.m.).
Patients continued on the same oral dose of
prednisone that they had taken before the study
(in the range of 3 – 10 mg per day). Therefore the
only difference between the study arms was the
time at which the prednisone was released from
the respective formulations (≈ 6 – 8 a.m. for IR
prednisone and ≈ 2 a.m. for MR prednisone). Primary endpoint: Relative change from baseline in
duration of morning stiffness of the joints at the end
Secondary endpoints: Recurrence of joint stiffness, pain intensity during the day, quality of sleep, DAS28, physician’s global assessment of disease, laboratory variables, health assessment questionnaire, disability index and SF36 scores. Primary endpoint: After 12 weeks of treatment (last observation carried forward method), MR prednisone resulted in a substantially greater decrease in the duration of morning stiffness than IR prednisone [mean relative change -22.7% vs. -0.4%; least square mean difference = 22.4% (95% CI 0.49 – 44.30); P = 0.045]. The absolute difference in the duration of morning stiffness between the treatment groups was 29·2 minutes (95% CI –2·59 to 61·9), in favour of modified-release prednisone (p=0·072). However, the study was not designed to show a significant difference in absolute changes. Secondary endpoints: No clinically or statistically relevant differences were noted between the two treatment groups for secondary variables with the exception of interleukin-6 (IL-6). Serum IL-6 levels decreased with MR prednisone [median relative change -28.6% (range -96.8 to 2018)] but remained constant with IR prednisone [median relative change 0.0% (range -98.1 to 3017)]. The difference between the two groups at week 12 was significant (P = 0.0322).
Figure 2: Relative changes in duration of morning stiffness of the joints from baseline over time
Safety: No clinically relevant differences were observed between the tolerability profiles of MR prednisone and IR prednisone.
Most common adverse events (occurring in 4 or more patients)
MR prednisone is well tolerated, convenient to administer, and produces a clinically relevant reduction in duration of morning stiffness of the joints. This was in addition to all the well known therapeutic effects of IR prednisone.
References:1. Arvidson NG, Gudbjornsson B, Larsson A, et al. The timing of glucocorticoid administration in rheumatoid arthritis.
Lodotra ® 1 mg, 2 mg and 5 mg modified release
and chronic bacterial infections; history of
excretion; increased appetite; weight gain;
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Presentation Cylindrical modified release tablets
disorders; glaucoma; corneal ulcers and injuries;
fragility; petechiae; ecchymoses; muscular atrophy
containing prednisone, marked NP and the strength severe ulcerative colitis with imminent perforation;
and weakness; osteoporosis. Other side-effects
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2 mg – yellowish white, 5 mg – light yellow.
postoperative). Sleep disorder occurs more
disturbed sexual hormone secretion (amenorrhoea,
Indication Treatment of moderate to severe, active frequently compared with conventional IR
impotence); thyroid function disturbance;
rheumatoid arthritis in adults, particularly when
formulation given in the morning. Not recommended depression; euphoria; psychosis; pseudotumor
for patients with galactose intolerance, Lapp lactase cerebri; latent epilepsy; increased predisposition to
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and bacterial eye inflammations; hypertension;
Adults: Initial y 10 mg once daily, with subsequent
expected. Osteoporosis prophylaxis is recommended increased risk of arteriosclerosis, thrombosis,
adjustment according to the patient’s response. Take and is particularly important if other risk factors are
vasculitis (also as withdrawal syndrome after long-
at bedtime (around 10 p.m.), with or after evening
present (including familial predisposition, advanced
term therapy); gastrointestinal ulcerations and
meal. Active substance is released 4 – 6 hours after
age, postmenopausal status, insufficient intake of
haemorrhages; pancreatitis; hypertrichosis; steroid
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protein and calcium, excessive smoking, excessive
acne; delayed healing of wounds; rosacea-like
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alcohol consumption, reduced physical activity).
(perioral) dermatitis; changes in skin pigmentation;
2 – 3 hours have passed after the meal, take with
Interactions Prednisone may interact with: cardiac
hypersensitivity reactions (e.g. drug exanthema) and
a light snack. The tablets should be swal owed
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aseptic osteonecrosis (humeral and femoral head).
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Please refer to the SPC for a ful list of side-effects.
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Date of preparation August 2010
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(JTES) Delving: Journal of Technology and Engineering Sciences “Mixed-Solvency” – A novel concept for solubilization of poorly water-soluble drugs Department of Pharmacy, Shri G.S. Institute of Technology and Science Abstract - On the basis of a large number of solubilization experiments on poorly water-soluble drugs, the author is of the opinion that hydrotropy is another type
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