Modified-Release Prednisone at the ACR 2015 Meeting in San Francisco

There has been one study on Modified-Release Prednisone at the ACR 2015 Annual Meeting in San Francisco. I have voiced my concerns about Modified-Release Prednisone before and this study makes me even more confident in my views.

Maurizio Cutolo and colleagues presented: “Efficacy and Safety of Modified-Release Prednisone in Patients with Polymyalgia Rheumatica: Results of a Multicenter, Randomized, Active-Controlled Phase 3 Study”. Methods: “Patients meeting the 2012 EULAR/ACR classification criteria for PMR (excluding US) were randomized to double-blind MR prednisone or IR prednisone 15 mg/day for 4 weeks. MR prednisone/placebo was taken at approx. 10pm and IR prednisone/placebo was taken between 5am and 9am. […]” The duration of the study is too short to say anything about adverse events in long term therapy using glucocorticoids. Comparing “ approx. 10pm” with “between 5am and 9am” looks suspicious as one compares an optimized time slot with one that wasn’t optimized. Why compare approx. 10pm and approx. 5am? Results: “The study randomized 62 patients; 66% female, mean age 69 years. […].” I’d say the study is very low powered. Conclusion: “Although the primary analysis of non-inferiority was not met, the consistently positive and clinically meaningful results for MR prednisone compared with IR prednisone observed in this study provide an indication of a beneficial clinical effect of MR over IR prednisone in patients with PMR, with improvements observed as early as Week 1.”

My own conclusion is different: “Although Modified-Release Prednisone has been given an advantage, the primary analysis of non-inferiority was not met.” Especially morning stiffness, global pain, and CRP didn’t show significant differences (please look at the chart in the abstract). If you really want to test, if the modified-release mechanism has any advantage over prednisone, you would have to give both at the same time in the evening. 

References:

Cutolo M, Hopp M, Liebscher S, Dasgupta B, Buttgereit F. Efficacy and Safety of Modified-Release Prednisone in Patients with Polymyalgia Rheumatica: Results of a Multicenter, Randomized, Active-Controlled Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-modified-release-prednisone-in-patients-with-polymyalgia-rheumatica-results-of-a-multicenter-randomized-active-controlled-phase-3-study/. Accessed December 3, 2015.

http://rheumatologe.blogspot.de/2012/11/lodotra-auf-dem-kongress-der.html(Text in German)

http://rheumatologe.blogspot.de/2012/06/modified-release-prednisone.html

http://rheumatologe.blogspot.de/2010/06/lodotra-my-problems-with-new-miracle.html

Modified Release Prednisone at the EULAR 2013 http://rheumatologe.blogspot.de/2013/06/modified-release-prednisone-at-eular.html

Lodotra (modified or delayed release prednisone) at the ACR 2013 Meeting in San Diego http://rheumatologe.blogspot.de/2013/11/lodotra-modified-or-delayed-release.html

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Cowardice or icecold reckoning? A Glimpse into medical studies

Today I have read an article by R.G. Langley and colleagues on Secukinumab in Plaque Psoriasis (Link: http://www.ncbi.nlm.nih.gov/pubmed/25007392). I’m interested in Secukinumab (last blogpost is here: http://rheumatologe.blogspot.de/2014/07/secukinumab-at-eular-2014-meeting-in.html), but something came to my mind while reading. In this study secukinumab has been tested versus etanercept. Why? Why not adalimumab? Maybe because the sponsor thinks that adalimumab works better in psoriatic arthritis than etanercept? Cowardice or icecold reckoning?

M. Schiff and colleagues reported on the AMPLE trial (Link: http://www.ncbi.nlm.nih.gov/pubmed/23962455). The AMPLE trial is a head-to-head comparison of subcutaneous etanercept versus adalimumab for rheumatoid arthritis. Why not etanercept? Maybe because the sponsor thinks that etanercept works better in rheumatoid arthritis than adalimumab? Cowardice or icecold reckoning?

F. Buttgereit and colleagues published a study on modified release prednisone (Link: http://www.ncbi.nlm.nih.gov/pubmed/18207016) in rheumatoid arthritis. Under methods we read: “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.” I don’t want to dwell on the fact, that “prednisone was released with a delay of 4 h after ingestion” has nothing to do with the method, but rather on the fact that the comparator was administered in the morning and not in the evening. Why not? Maybe because the sponsor thinks that an unequal comparison works better? Cowardice or icecold reckoning?

To sum it up, I think that we have to look at studies very carefully. In the above studies I don’t question the results but the design, which might influence the results. Cowardice or icecold reckoning? I think the latter one!

Lodotra (modified or delayed release prednisone) at the ACR 2013 Meeting in San Diego

Let me talk again about modified or delayed release prednisone (Lodotra) as two studies have been presented at the ACR 2013 Meeting in San Diego.

F. Buttgereit and colleagues presented this study [Abstract # 2255]: "Threshold Analysis of Patient Reported Morning Stiffness Where Delayed-Release (DR) Prednisone Was Compared to, and Replaced, Immediate Release Prednisone in Rheumatoid Arthritis (RA) Patients Receiving Conventional Disease-Modifying Antirheumatic Drugs (DMARDs) Over 1 Year." IR-prednisone, taken in the morning, is compared to DR-prednisone, taken once daily at bedtime (e.g. 10pm). Conclusion: DR prednisone, as compared to IR prednisone, produces significantly higher MS response rates as defined by 25/50/75% improvement thresholds.  [...]."

The same patients were analysed in this study, which had been presented by R. Alten and colleagues [Abstract # 2265]: "Switching From Immediate Release (IR) Prednisone To Delayed Release (DR) Prednisone Improves Patient Reported Outcomes In Rheumatoid Arthritis (RA) Patients On Conventional Disease-Modifying Antirheumatic Drugs (DMARDs)." Conclusion: "This analysis demonstrates that RA patients on stable DMARD therapy, who have not adequately responded to IR-prednisone with respect to morning stiffness, showed statistically significant and clinically meaningful improvement in this symptom when switched to DR prednisone [...]."

Where's the catch? There's more than one. First: would you call a patient, who suffers two hours of morning stiffness, stable? Second: the advocates of Lodotra claim chronotherapy for their therapy, but we're already doing chronotherapy. We give immediate release prednisone in the morning to optimize (reduce) side effects. Lodotra is given in the evening to be released during the night to optimize (increase) therapeutic effects. In any study designed as this study DR prednisone will be better than IR prednisone. This is due to the time, when the drug is given. So the study shows that prednisone given at different times has different effects on morning stiffness. If you really want to test, if the DR mechanism has any advantage over IR prednisone, you would have to give both at the same time in the evening. My guess is that significance dwindles to a trend. Unless I see such a designed study, I won't prescribe DR prednisone.

Links to other blogposts on Lodotra on this blog:
http://rheumatologe.blogspot.de/2013/06/modified-release-prednisone-at-eular.html

http://rheumatologe.blogspot.de/2012/11/lodotra-auf-dem-kongress-der.html (Text in German)
http://rheumatologe.blogspot.de/2012/06/modified-release-prednisone.html 
http://rheumatologe.blogspot.de/2010/06/lodotra-my-problems-with-new-miracle.html

Modified Release Prednisone at the EULAR 2013

I have already published my concerns about modified release prednisone severeal times; please look for the links below.

At the EULAR 2012 Meeting there had been four studies: "To sum up these studies: Lodotra (modified-release prednisone) failed to show a clear advantage over conventional immediate-release prednisone in the studies presented at the 2012 EULAR meeting. One study failed to look at 1733 of 2661 patients, while another study only presented data on 950 of 1928 patients."

At the EULAR 2013 Meeting we could see two studies on modified release prednisone.

M. Benucci and colleagues presented [SAT0152]: "Polymyalgia rheumatica: a comparative study of methylprednisolone and the modified release prednisone". The study is non-blinded, non-randomized and looks only at N=42 in two groups. The endpoint is unclear. The objective is to " compare changes in inflammation markers and their correlations with cortisol levels ...". Conclusions: " In this non-randomized prospective observational study the response of inflammation markers to low-dose GC was similar in patients with PM treated with 6-MP or MR-P, and morning cortisol levels were unaffected. However, the patients treated with MR-P showed a greater decrease in IL-6 levels after the first month."
Does anyone treat IL-6 levels after the first month in patients with polymyalgia rheumatica? I don't! So this study rather convinces me to not use Lodotra.

D. Sola and colleagues presented a study [AB0346]: "Safety and efficacy of rheumatoid arthritis treatment with modified-release prednisone (MR-PDN), experience in “real life”". The study is retrospective! Objectives: "To assess in “real life” adherence to treatment and efficacy (morning stiffness, DAS28 score and steroid dose reduction) in RA patients who initiated treatment with MR-PDN,". "64 RA patients who initiated RM-PDN completed a 12 weeks (W) follow-up, 49 completed 24 W and 33 48W." So the study lost about 50% of it's initial patients to follow up after 48 weeks or is incomplete. "In 19 patients this was the first steroid treatment, 45 received MR-PDN after a switch from one other steroid (in this case 1 month bridging with traditional steroid was performed)." So, in about 33% of the patients we look at prednisone naive and in 66% at pretreated patients. At week 48 only 64% stayed on treatment. "The efficacy analysis was limited only to patients with DMARDs or biological therapies stable for the whole period of observation." But we don't know how many patients had been on which therapy. And in the end we look at patients, who have been doing better and measure the success. Conclusions: "In RA patients in “real life” the use of MR-PDN showed good safety profile and adherence to treatment also after switch from prolonged traditional steroid treatment. We observed a reduction in morning stiffness and disease activity similarly to that described in clinical trial. The greatest improvement occurs within the first 12 weeks confirmed by further modest improvement up to 48 weeks. Finally the use of the MR-PDN permitted a lower consumption of steroid in these patients with obvious long term benefits."
The study is a catastrophe. It looks retrospectively at a heterogenous group of patients (pretreated with steroids of steroid naive, on traditional DMARDs or on different biologics) without a well defined endpoint. Is it desirable to stay on prednisone after 48 weeks? Is the reduction of morning stiffness and disease activity due to modified release prednisone or DMARDs/biologics? What is the idea of the authors behind: lower consumption of steroid? Lower than at the beginning? That would mean modified release prednisone could be tapered like any other steroid. What are the "obvious long term benefits"?

These two studies convince me even more that modified release prednisone (Lodotra) won't be my drug of choice.

Links:
http://rheumatologe.blogspot.de/2012/11/lodotra-auf-dem-kongress-der.html (Text in German)
http://rheumatologe.blogspot.de/2012/06/modified-release-prednisone.html
http://rheumatologe.blogspot.de/2010/06/lodotra-my-problems-with-new-miracle.html

Modified-release Prednisone

Modified-release prednisone is marketed in Germany as Lodotra, which is at least fourfold as expensive as conventional immediate-release prednisone, but often it is even more expensive when it comes to tapering dosage.

C. Baerwald et al. presented a non-interventional study of patients with rheumatoid arthritis (n=2661), but looks only at a subgroup of 928 patients. The authors choose to leave the patients on conventional immediate-release prednisone without evaluation (N=1733). Did the 1733 patients on conventional immediate-release prednisone fare so well that a comparison would be destastrous? The authors concluded that patients treated with modified-release prednisone tablets benefited. I don´t doubt this, but I doubt the relevance of this study.

[AB0594] FUNCTIONAL ABILITY AND QUALITY OF LIFE IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH LOW DOSE MODIFIED-RELEASE PREDNISONE IN DAILY PRACTICE
C. Baerwald1, F. Buttgereit2, J. Währisch3, P. Flaxenberg3. 1Medical Clinic and Polyclinic, University Hospital, Leipzig; 2Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin; 3Specialist in Internal Medicine and Rheumatology, Essen, Germany
Conclusions: In this non-interventional study patients treated with modified-release prednisone tablets benefited from better functional ability and Quality of Life being shown under daily practice conditions. These results add to those obtained from previous clinical studies.

S. Zakout and colleagues looked at the circadian rhythm of IL-6 in patients with polymyalgia rheumatica and compared the effects of morning (immediate-release prednisone) and night time glucocorticoids (modified-release prednisone) on overnight IL-6 and morning stiffness. With N=10 this study is underpowered, but in the conclusions the authors only “raise the possibility” of better disease control. Maybe one can indeed start at a lower dose, but inflammation needs to be tightly controlled in patients with polymyalgia rheumatica, so that conventional immediate-release prednisone achieves the same.
For the time being conventional immediate-release prednisone is easier to taper as modified-release prednisone tablets can´t be broken. Therapy costs might increase up to sixteenfold depending on how you taper dosage.

[AB0103] POLYMYALGIA RHEUMATICA HAS A NOCTURNAL RISE IN PLASMA INTERLEUKIN-6 WHICH IS ALMOST COMPLETELY SUPPRESSED BY NIGHT TIME ADMINISTRATION OF MODIFIED-RELEASE PREDNISONE
S. Zakout1, L. Clark1, D. Jessop2, R.H. Straub3, J.R. Kirwan1. 1Rheumatology, University Hospitals Bristol; 2Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom; 3Lab of Experimental Rheumatology & Neuroendocrine Immunology, University Hospital, Regensburg, Germany
Conclusions: PMR, like RA, has a marked circadian variation in plasma IL-6. Both IL-6 and symptoms of morning stiffness are suppressed more by night time low dose glucocorticoids. This observation raises the possibility that PMR may be controlled by lower doses of glucocorticoids given at night compared to current conventional morning treatment.


L. Iaccarino1 and colleagues presented a study, which might be labeled chaotic. They looked at 1928 consecutive outpatients with documented rheumatoid arthritis, in which 950 patients were changed to modified-release prednisone for unclear reasons. Patients have been on different DMARDs and even biologics, but nothing is told on dosage variation, change of therapy. The study also fails to compare patients on modified-release prednisone with patients on conventional immediate-release prednisone.

[OP0206] EFFICACY OF MODIFIED-RELEASE PREDNISONE IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA) CHRONICALLY TREATED WITH STANDARD GLUCOCORTICOIDS: AN ITALIAN MULTICENTER SURVEY
L. Iaccarino1, I. Farina2, A. Sulli3, A. Bortoluzzi2, C. Marcassa4, A. Doria1, M. Govoni2, M. Cutolo3. 1Division of Rheumatology, University of Padova, Padova; 2Rheumatology Unit, University of Ferrara, Ferrara; 3Research Laboratory and Academic Rheumatology, University of Genova, Genova; 4Fondazione Maugeri IRCCS, Veruno (NO), Italy
Conclusions: In unselected RA patients chronically treated with standard GC, modified-release prednisone (given at bedtime) induced a significant improvement over a medium-term observation, particularly in those patients who switched from methyl-prednisolone.


S. Stisi ans colleagues presented a study, which has been constructed like the study by L. Iaccarino. The study shows that prednisone works in patients with uncontrolled activity of rheumatoid arthritis. Wow! Nobody expected this! If modified-release prednisone is necessary to do the trick or conventional immediate-release prednisone or changing DMARDs can´t be answered by this study.

[AB0610] MID-TERM EFFICACY OF MODIFIED-RELEASE PREDNISONE IN GLUCOCORTICOIDS-NAIVE PATIENTS WITH RHEUMATOID ARTHRITIS (RA)
S. Stisi1, R. De Luca Bossa2, G. Ciano3, A. Marsico4, C. Venditti1, C. Marcassa5. 1Medical Sciences, Rheumatology Division, Gaetano Rummo Hospital - Benevento, Benevento; 2Asl Sa1, Laurito; 3Medical Sciences, Division of Internal Medicine, Ariano Irpino; 4Rheumatology Unit, Taranto; 5Cardiology, S. Maugeri Fnd, IRCCS, Veruno, Italy
Conclusions: In unselected RA patients on active antirheumatic treatment, modified-release prednisone (given at bedtime) induced a substantial benefit over a medium-term observation and was well tolerated.

To sum up these studies: Lodotra (modified-release prednisone) failed to show a clear advantage over conventional immediate-release prednisone in the studies presented at the 2012 EULAR meeting. One study failed to look at 1733 of 2661 patients, while another study only presented data on 950 of 1928 patients.