1219 - Integrated Safety Summary of Modified-Release Prednisone and Immediate-Release Prednisone Comparing Doses ≤5mg/Day Versus >5mg/Day

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Frank Buttgereit1, Jacek Szechinski2, Gisela Doering3, Stephan Witte4, Christine Knauer4, Amy Y. Grahn5, Kenneth G. Saag6 and Rieke Alten7, 1Charité University Medicine, Berlin, Germany, 2Wroclaw Medical University, Wroclaw, Poland, 3Merck KgaA, Darmstadt, Germany, 4Horizon Pharma GmbH, Mannheim, Germany, 5Horizon Pharma, Inc., Northbrook, IL, 6University of Alabama at Birmingham, Birmingham, AL, 7Rheumatology Schlossparkklinik, Berlin, Germany
Presentation Number: 1219

Background/Purpose: Glucocorticoid (GC) chronotherapy with a modified-release (MR) prednisone tablet enables programmed delivery of prednisone during the night to target the circadian pattern of inflammatory mediators. This therapeutic approach has demonstrated both clinically relevant reduction of morning stiffness compared to conventional, immediate-release (IR) prednisone, as well as improvement in ACR response criteria (Buttgereit et al Lancet 2008, Buttgereit et al Ann Rheum Dis 2010, Alten et al J Rheumatol 2010). Adverse effects related to GCs increase with dose and duration of treatment (Da Silva et al Ann Rheum Dis 2006).  The data here describe the integrated safety summary for low-dose glucocorticoid therapy 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 MR prednisone (3-10 mg/d, average of 6.8 mg/d) to conventional IR prednisone over 12 weeks in 288 patients, the CAPRA-2 study compared 5 mg/d MR prednisone + DMARD to placebo (PBO) + DMARD over 12 weeks in 350 patients. MR prednisone or PBO was administered once daily in the evening; IR prednisone or PBO once daily in the morning. An open-label extension of CAPRA-1 provided safety data for up to 12 months. All Adverse Events (AEs) were collected in a standardized manner and categorized according to the dose of prednisone received during the study (≤5 mg/d or >5mg/d).

Results:  Overall, 41.9% of MR prednisone patients, 39.6% of IR prednisone patients, and 48.7% of PBO patients reported a treatment emergent adverse event (TEAE) during the 12 week blinded period showing comparable safety of the different formulations. In the MR prednisone group, discontinuations due to any TEAE were higher for the >5 mg/d dose, with 9.7% of patients discontinuing compared to 2.2% of patients receiving  ≤5 mg/d. In the IR prednisone group, 5.3% of patients receiving ≤5 mg/d discontinued due to any TEAE compared to 4.4% of patients receiving >5 mg/d.  The incidence of TEAEs in descending frequency are shown in Table 1.  Safety data for the open label phase were consistent and similar (not shown). 

PBO

(N=119)

MR Prednisone

IR Prednisone

≤5 mg/d
(N=313)

>5 mg/d
(N=62)

Total
(N=375)

≤5 mg/d
(N=76)

>5 mg/d
(N=68)

Total
(N=144)

Mean Daily Dose (mg ± SD)

NA

4.86 ± 0.37

8.45 ± 1.49

5.46 ± 1.50

4.93 ± 0.34

8.59 ± 1.48

6.66 ± 2.11

Any Adverse Event

48.7%

43.1%

35.5%

41.9%

42.1%

36.8%

39.6%

Frequency by Severity

Mild

29.4%

20.4%

8.1%

18.4%

18.4%

16.2%

17.4%

Moderate

15.1%

20.8%

22.6%

21.1%

19.7%

19.1%

19.4%

Severe

4.2%

1.9%

4.8%

2.4%

3.9%

1.5%

2.8%

Preferred Term

   Rheumatoid arthritis flare

 26.1%*

14.4%

4.8%

12.8%

11.8%

7.4%

9.7%

   Nasopharyngitis

3.4%

4.8%

1.6%

4.3%

6.6%

4.4%

5.6%

   Abdominal pain upper

1.7%

1.6%

1.6%

1.6%

7.9%

2.9%

5.6%

   Headache

4.2%

4.5%

1.6%

4.0%

3.9%

2.9%

3.5%

   Vertigo

0%

1.3%

0%

1.1%

3.9%

2.9%

3.5%

*p=0.0137 PBO versus MR prednisone; all other comparisons are nonsignificant; NA = not applicable, SD = standard deviation

Conclusions: Safety findings from the 12 week blinded period were similar between MR prednisone and PBO or IR prednisone, demonstrating that the MR formulation does not adversely impact the known safety profile of the active ingredient.  MR Prednisone has been shown to be more effective than IR prednisone and PBO with regard to standard RA outcome parameters. Taken together, these data support that MR prednisone may improve the benefit/risk ratio of long-term low-dose GC treatment in patients with RA on standard DMARD therapy.


Keywords: chronobiologic variation, clinical trials, drug toxicity, glucocorticoids and rheumatoid arthritis, treatment

Disclosure: F. Buttgereit, Mundipharma, 5, Horizon Pharma, 5, Merck Serono, 5, Horizon Pharma, 2, Merck Serono, 2 ; J. Szechinski, Horizon Pharma, 9 ; G. Doering, Merck KgaA, 3 ; S. Witte, Horizon Pharma GmbH, 3 ; C. Knauer, Horizon Pharma GmbH, 3 ; A. Y. Grahn, Horizon Pharma, 3 ; K. G. Saag, Horizon Pharma, 5 ; R. Alten, Bristol-Myers Squibb, Merck Pharma GmbH, Wyeth Pharmaceuticals, Pfizer, 2, Abbott Laboratories, Bristol-Myers Squibb, Horizon Pharma, Merck Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, 8, Abbott Laboratories, Horizon Pharma, Merck Pharma GmbH, Nitec Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, 5, Abbott Laboratories, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Roche, 6 .