Comparison of the Effectiveness of Two Different Dosages of Cortisone Compared to Placebo in Rheumatoid Arthritis

Condition(s) targeted: Progression of Rheumatoid Arthritis

Intervention: Prednisolone (Drug); Placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Prof. Dr. rer. nat. H.J. Trampisch

Official(s) and/or principal investigator(s):
Juergen Braun, MD, Principal Investigator, Affiliation: Rheumazentrum Ruhrgebiet, Herne/Germany

Overall contact:
Hans J Trampisch, MD, Phone: +49 (0)234-3227790, Email: Hans.J.Trampisch@ruhr-uni-bochum.de

Although cortisone is widely used in the treatment of patients with early rheumatoid arthritis, the best dosage is not known. Therefore we will compare two standard prednisolon starting dosages and placebo in the treatment of patients with early active rheumatoid arthritis on the background of the established therapy with methotrexate. In total 450 patients will be included into the study. Two different treatment arms starting with 10 or 60 mg of prednisolone, and one placebo arm. Duration of intervention is 12 weeks. In parallel, all patients start medication with methotrexate, usual dosage 15 mg/week. Primary efficacy endpoint is progression of radiographic damage after one year compared to baseline. Safety monitoring is performed.

Official title: Comparison of the Efficacy and Safety of Two Different Starting Dosages of Prednisolone in Early Active Rheumatoid Arthritis: a Randomized, Placebo Controlled Trial

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Progression of radiographic damage after one year as quantified by the van der Heijde modification of the Sharp score (SHS). Determined at baseline and after one year.

Secondary outcome:

Percentage of patients in remission

Changes of functional capacity

Patient's assessment of disease activity

Detailed description: BACKGROUND: Although glucocorticoids (GCs) are widely used in the treatment of patients with early rheumatoid arthritis (RA), the best dosage for GCs, related to both, efficacy and safety, is not known. OBJECTIVE: To compare two standard p. o. GC starting dosages and the non-use of GCs in the treatment of patients with early active RA on the background of the established 'anchor' therapy with methotrexate (MTX). METHODS: Randomised double-blind placebo-controlled trial with two treatment arms (starting with 10 or 60 mg of p. o. prednisolone (P), tapered down to 5 mg P per day within 8 weeks) and one placebo arm, each arm comprising 150 patients. Duration of intervention is 12 weeks. In parallel, all patients start medication with MTX, usual dosage 15 mg/week. Primary efficacy endpoint is progression of radiographic damage after one year compared to baseline. Secondary endpoints are: percentage of patients in remission, changes of functional capacity etc. Safety monitoring is performed. The analysis is performed in three hierarchical steps. First step is an analysis of covariance to compare the group with an initial P dosage of 60 mg (V60) and the placebo group (Pl). In case of a statistical significant result (α = 0. 05), a comparison of the group starting with 10 mg P (V10) and Pl will be done in a second step (α = 0. 05). In case of superiority of V10 versus Pl, a third step will be a non-inferiority test for V10 versus V60 (α = 0. 025).

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Diagnosis of rheumatoid arthritis based on expert opinion according to the American

College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2009 criteria (Hawker 2009)

- disease duration < 3 years

- active disease: disease activity score (DAS) 28 erythrocyte sedimentation rate (ESR)

(Prevoo et al 1995) > 4 plus ≥ 3 swollen joints Exclusion Criteria:

- Prior treatment with disease-modifying antirheumatic drugs (DMARDs) (except for

hydroxychloroquine or sulfasalazine or methotrexate during the last four weeks before screening)

- Clinically relevant comorbidity:

- concurrent liver disease (ALT > 2 times upper limit of normal),

- active hepatitis B or C viral infection,

- renal disease (creatinine clearance < 30 ml/minute),

- clinically relevant haematological disease due to the judgement of the

rheumatologist,

- uncontrolled diabetes mellitus,

- uncontrolled arterial hypertension,

- relevant immunodeficiency incl. HIV-infection,

- clinically significant pulmonary fibrosis,

- history of malignant melanoma,

- complicated or refractory gastrointestinal ulcers,

- presence or history of severe infections,

- uncontrolled increased intraocular pressure,

- pregnancy or planned pregnancy,

- non-compliance,

- age < 18 years

Hans J Trampisch, MD, Phone: +49 (0)234-3227790, Email: Hans.J.Trampisch@ruhr-uni-bochum.de

Rheumatologische Schwerpunktpraxis Bielefeld, Bielefeld 33617, Germany; Recruiting
Albert Schmid, MD, Phone: +49 (0)521-15711, Email: forum.deckertstrasse@bitel.net
Albert Schmid, MD, Principal Investigator
Hans-Joachim Christoph, MD, Sub-Investigator

Rheumatologische Schwerpunktpraxis Bocholt, Bocholt 46397, Germany; Recruiting
Anna M Hund, MD, Phone: +49 (0)2871-2904200, Email: mhundbocholt@aol.com
Anna M Hund, MD, Principal Investigator
Frank Schumann, MD, Sub-Investigator

MVZ Endokrinologikum Ruhr, Bochum 44866, Germany; Active, not recruiting

Rheumatologische Schwerpunktpraxis Bochum, Bochum 44787, Germany; Recruiting
Manfred Igelmann, MD, Phone: +49 (0)234 60631, Email: rheuma.igelmann@t-online.de
Manfred Igelmann, MD, Principal Investigator
Elmar Schmitz-Bortz, MD, Sub-Investigator

MVZ Dr. Kretzmann und Kollegen, Dortmund 44147, Germany; Recruiting
Ulrich Risse, MD, Phone: +49 (0)231-8602370
Ulrich Risse, MD, Principal Investigator
Manfred Igelmann, MD, Sub-Investigator

Rheumapraxis Dortmund, Dortmund 44137, Germany; Recruiting
Judith Guenzel, Phone: +49 (0)231 95727305, Email: guenzel@labmed.de
Judith Guenzel, Principal Investigator
Annette Rittstieg, MD, Sub-Investigator

Rheumatologische Schwerpunktpraxis Dortmund, Dortmund 44263, Germany; Recruiting
Hans-Juergen Menne, MD, Phone: +49 (0)231-102535, Email: menne@rheumapraxis-dortmund.de
Hans-Juergen Menne, MD, Principal Investigator
Dietmar Krause, MD, Sub-Investigator

Rheumapraxis Duisburg, Duisburg 47057, Germany; Recruiting
Claas Fendler, MD, Phone: +49 (0)203-2890150, Email: rheumapraxis-duisburg@gmx.de
Claas Fendler, MD, Principal Investigator
Ertan Saracbasi-Zender, MD, Sub-Investigator

Rheumapraxis Gelsenkirchen, Gelsenkirchen 45891, Germany; Active, not recruiting

Internistische und rheumatologische Praxis Gladbeck, Gladbeck 45964, Germany; Recruiting
Dietmar Krause, MD, Phone: +49 (0)2043-206111, Email: gundi.krause@t-online.de
Dietmar Krause, MD, Principal Investigator
Claudia Klink, MD, Sub-Investigator

Facharztzentrum Hagen, Hagen 58089, Germany; Recruiting
Cornelia Schweder, MD, Phone: +49 (0)2331-3757715
Cornelia Schweder, MD, Principal Investigator
Udo Rosendahl, MD, Sub-Investigator

Rheumatologische Schwerpunktpraxis Hamm, Hamm 59065, Germany; Withdrawn

Orthopädisch-rheumatologische Schwerpunktpraxis, Hattingen 45525, Germany; Recruiting
Juergen Bachmann, MD, Phone: +49 (0)2324-925953, Email: jbachmann@augusta-clinic.de
Juergen Bachmann, MD, Principal Investigator
Elmar Schmitz-Bortz, MD, Sub-Investigator

Rheumapraxis Hattingen, Hattingen 45527, Germany; Recruiting
Elmar Schmitz-Bortz, MD, Phone: +49 (0)2324-919648, Email: esb@rheumapraxis-hattingen.de
Elmar Schmitz-Bortz, MD, Principal Investigator
Manfred Igelmann, MD, Sub-Investigator

Rheumapraxis Herne, Herne 44652, Germany; Recruiting
Friedrich Dybowski, MD, Phone: +49 (0)2323-9190740, Email: empfang@rheumapraxis-ruhr.de
Friedrich Dybowski, MD, Principal Investigator
Ludwig Kalthoff, MD, Sub-Investigator

Rheumatologische Schwerpunktpraxis Herne, Herne 44623, Germany; Recruiting
Ludwig Kalthoff, MD, Phone: +49 (0)2323-91900740, Email: kalthoff@rheumapraxis-ruhr.de
Ludwig Kalthoff, MD, Principal Investigator
Gunda-Liane Hein, MD, Sub-Investigator

Rheumazentrum Ruhrgebiet, Herne 44652, Germany; Recruiting
Juergen Braun, MD, Phone: +49 (0)2325-592131, Email: j.braun@rheumazentrum-ruhrgebiet.de
Juergen Braun, MD, Principal Investigator
Frank Heldmann, MD, Sub-Investigator

Rheumatologische Schwerpunktpraxis Lingen, Lingen 49808, Germany; Active, not recruiting

Rheumapraxis am EVK, Lippstadt 59555, Germany; Recruiting
Andreas Goebel, MD, Phone: +49 (0)2941-97575, Email: dr.a.goebel@t-online.de
Andreas Goebel, MD, Principal Investigator
Ernst Scheibl, MD, Sub-Investigator

Rheumatologische Schwerpunktpraxis Marl, Marl 45768, Germany; Recruiting
Stephanie Boeddeker, MD, Phone: +49 (0)2365-2045720, Email: dr.boeddeker@die-rheuma-praxis.de
Stepahnie Boeddeker, MD, Principal Investigator
Frank Schumann, MD, Sub-Investigator

Rheumatologische Schwerpunktpraxis Minden, Minden 32425, Germany; Recruiting
Hans-Joachim Christoph, MD, Phone: +49 (0)571-8292007, Email: dr.christoph@rheumapraxis-minden.de
Hans-Joachim Christoph, MD, Principal Investigator
Albert Schmid, MD, Sub-Investigator

Rheumapraxis Mülheim, Mülheim 45468, Germany; Withdrawn

Rheumatologische Schwerpunktpraxis Münster, Münster 48143, Germany; Active, not recruiting

Rheumapraxis Oberhausen, Oberhausen 46145, Germany; Recruiting
Ertan Saracbasi-Zender, MD, Phone: +49 (0)208-74011891, Email: saracbasi@t-online.de
Ertan Saracbasi-Zender, MD, Principal Investigator
Claas Fendler, MD, Sub-Investigator

Rheumapraxis Paderborn, Paderborn 33098, Germany; Active, not recruiting

Rheumatologische Gemeinschaftspraxis Ratingen, Ratingen 40882, Germany; Recruiting
Siegfried Wassenberg, MD, Phone: +49 (0)2102-206233, Email: info@rheumazentrum-ratingen.de
Siegfried Wassenberg, MD, Principal Investigator
Ralf Weier, MD, Sub-Investigator

Rheumatologische Schwerpunktpraxis Reken, Reken 48734, Germany; Withdrawn

Rheumatologische Schwerpunktpraxis Rheine, Rheine 48431, Germany; Recruiting
Ulrich Schoo, MD, Phone: +49 (0)5971-913842, Email: u.schoo@t-online.de
Ulrich Schoo, MD, Principal Investigator
Georg Huebner, MD, Sub-Investigator

Rheumapraxis Schwerte, Schwerte 58239, Germany; Withdrawn

Rheumapraxis Siegen, Siegen 57072, Germany; Withdrawn

Rheumapraxis Warendorf, Warendorf 48231, Germany; Active, not recruiting

Related publications:

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81. doi: 10.1002/art.27584.

Bakker MF, Jacobs JW, Welsing PM, Verstappen SM, Tekstra J, Ton E, Geurts MA, van der Werf JH, van Albada-Kuipers GA, Jahangier-de Veen ZN, van der Veen MJ, Verhoef CM, Lafeber FP, Bijlsma JW; Utrecht Rheumatoid Arthritis Cohort Study Group. Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2012 Mar 6;156(5):329-39. doi: 10.7326/0003-4819-156-5-201203060-00004.

Bijlsma JW, van der Goes MC, Hoes JN, Jacobs JW, Buttgereit F, Kirwan J. Low-dose glucocorticoid therapy in rheumatoid arthritis: an obligatory therapy. Ann N Y Acad Sci. 2010 Apr;1193:123-6. doi: 10.1111/j.1749-6632.2009.05342.x. Review.

Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, van Zeben D, Dijkmans BA, Peeters AJ, Jacobs P, van den Brink HR, Schouten HJ, van der Heijde DM, Boonen A, van der Linden S. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997 Aug 2;350(9074):309-18. Erratum in: Lancet 1998 Jan 17;351(9097):220.

Breedveld FC, Han C, Bala M, van der Heijde D, Baker D, Kavanaugh AF, Maini RN, Lipsky PE. Association between baseline radiographic damage and improvement in physical function after treatment of patients with rheumatoid arthritis. Ann Rheum Dis. 2005 Jan;64(1):52-5. Epub 2004 Jul 29.

Capell HA, Madhok R, Hunter JA, Porter D, Morrison E, Larkin J, Thomson EA, Hampson R, Poon FW. Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial. Ann Rheum Dis. 2004 Jul;63(7):797-803.

Choy EH, Smith CM, Farewell V, Walker D, Hassell A, Chau L, Scott DL; CARDERA (Combination Anti-Rheumatic Drugs in Early Rheumatoid Arhritis) Trial Group. Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis. 2008 May;67(5):656-63. Epub 2007 Sep 3.

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005 Nov;52(11):3381-90.

Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, Kincaid W, Porter D. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004 Jul 17-23;364(9430):263-9.

Gorter SL, Bijlsma JW, Cutolo M, Gomez-Reino J, Kouloumas M, Smolen JS, Landewé R. Current evidence for the management of rheumatoid arthritis with glucocorticoids: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2010 Jun;69(6):1010-4. doi: 10.1136/ard.2009.127332. Epub 2010 May 6. Review.

Hoes JN, Jacobs JW, Verstappen SM, Bijlsma JW, Van der Heijden GJ. Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis. Ann Rheum Dis. 2009 Dec;68(12):1833-8. doi: 10.1136/ard.2008.100008. Epub 2008 Dec 9. Review.

Hoes JN, Jacobs JW, Buttgereit F, Bijlsma JW. Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nat Rev Rheumatol. 2010 Dec;6(12):693-702. doi: 10.1038/nrrheum.2010.179. Review.

Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. N Engl J Med. 1995 Jul 20;333(3):142-6.

Möttönen T, Hannonen P, Leirisalo-Repo M, Nissilä M, Kautiainen H, Korpela M, Laasonen L, Julkunen H, Luukkainen R, Vuori K, Paimela L, Blåfield H, Hakala M, Ilva K, Yli-Kerttula U, Puolakka K, Järvinen P, Hakola M, Piirainen H, Ahonen J, Pälvimäki I, Forsberg S, Koota K, Friman C. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet. 1999 May 8;353(9164):1568-73.

Mouterde G, Dernis E, Ruyssen-Witrand A, Claudepierre P, Schaeverbeke T, Cantagrel A, Gaudin P, Maillefert JF, Pham T, Saraux A, Tebib J, Wendling D, Fautrel B, Le Loët X. Indications of glucocorticoids in early arthritis and rheumatoid arthritis: recommendations for clinical practice based on data from the literature and expert opinion. Joint Bone Spine. 2010 Dec;77(6):597-603. doi: 10.1016/j.jbspin.2009.12.011. Epub 2010 Jul 1.

Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, Combe B, Cutolo M, de Wit M, Dougados M, Emery P, Gibofsky A, Gomez-Reino JJ, Haraoui B, Kalden J, Keystone EC, Kvien TK, McInnes I, Martin-Mola E, Montecucco C, Schoels M, van der Heijde D; T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010 Apr;69(4):631-7. doi: 10.1136/ard.2009.123919. Epub 2010 Mar 9. Erratum in: Ann Rheum Dis. @011 Jul;70(7):1349. van der Heijde, Desirée [corrected to van der Heijde, Désirée]. Ann Rheum Dis. 2011 Aug;70(8):1519.

Smolen JS, Landewé R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, Gorter S, Knevel R, Nam J, Schoels M, Aletaha D, Buch M, Gossec L, Huizinga T, Bijlsma JW, Burmester G, Combe B, Cutolo M, Gabay C, Gomez-Reino J, Kouloumas M, Kvien TK, Martin-Mola E, McInnes I, Pavelka K, van Riel P, Scholte M, Scott DL, Sokka T, Valesini G, van Vollenhoven R, Winthrop KL, Wong J, Zink A, van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010 Jun;69(6):964-75. doi: 10.1136/ard.2009.126532. Epub 2010 May 5. Review. Erratum in: Ann Rheum Dis. 2011 Aug;70(8):1519.

Sokka T, Abelson B, Pincus T. Mortality in rheumatoid arthritis: 2008 update. Clin Exp Rheumatol. 2008 Sep-Oct;26(5 Suppl 51):S35-61. Review.

Svensson B, Boonen A, Albertsson K, van der Heijde D, Keller C, Hafström I. Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Arthritis Rheum. 2005 Nov;52(11):3360-70.

van der Goes MC, Jacobs JW, Boers M, Andrews T, Blom-Bakkers MA, Buttgereit F, Caeyers N, Cutolo M, Da Silva JA, Guillevin L, Kirwan JR, Rovensky J, Severijns G, Webber S, Westhovens R, Bijlsma JW. Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice. Ann Rheum Dis. 2010 Nov;69(11):1913-9. doi: 10.1136/ard.2009.124958. Epub 2010 Aug 6.

van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med. 2002 Jan 1;136(1):1-12.

van Vollenhoven RF, Cifaldi MA, Ray S, Chen N, Weisman MH. Improvement in work place and household productivity for patients with early rheumatoid arthritis treated with adalimumab plus methotrexate: work outcomes and their correlations with clinical and radiographic measures from a randomized controlled trial companion study. Arthritis Care Res (Hoboken). 2010 Feb;62(2):226-34. doi: 10.1002/acr.20072.

Wassenberg S, Rau R, Steinfeld P, Zeidler H. Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2005 Nov;52(11):3371-80.

Wolfe F, Michaud K. The risk of myocardial infarction and pharmacologic and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: a cohort and nested case-control analysis. Arthritis Rheum. 2008 Sep;58(9):2612-21. doi: 10.1002/art.23811.

Dachverband Osteologie e.V., DVO-Leitlinie 2009 zur Prophylaxe, Diagnostik und Therapie der Osteoporose bei Erwachsenen, Osteologie 4/2009: 304 -324.

Starting date: January 2014
Last updated: May 5, 2015