No registrations found.
ID
Source
Brief title
Health condition
Polymyalgia Rheumatica
PMR
Spierreuma
Sponsors and support
Intervention
Outcome measures
Primary outcome
PMR relaps, timepoint: first 12 months of the study
Secondary outcome
Efectiveness concerning disease activity
a.Time till first relaps within first 24 months
b.Percentage of patients with at least 1 relaps in the first 12 or 24 months
c.Total relapses within the first 12 and 24 months
d.Time till gucocorticoid free remission
Gucocorticoid-sparing effect
a.Gucocorticoid dose after 6, 12, 18 and 24 months.
b.Cumulative glucocorticoid dose after 12, 18 and 24 months
Safety/side-effects
a.Amount of side effects
b.Amount of severe side effects
Background summary
Over the last decades outcome has greatly improved for RA and SpA. This is in sharp contrast to the situation for PMR (polymyalgia rheumatica), with a lifetime prevalence of 2.4% for women and 1.7% for men, PMR is the commonest auto-inflammatory musculoskeletal disease in adults aged ¡Ý50 years. Due to population ageing, the number of PMR patients will likely double in the decades to come (CBS).
Glucocorticoids are the mainstay of treatment [1] [2]. However, there is an unmet medical need of alternatives in the treatment of PMR as 50% of patients will relapse or have difficulties to reduce the corticosteroid doses [3]. Also, there is increasing awareness of steroid related toxicity and in addition, long-term toxicity is a well-known side-effect of glucocorticoids in PMR[3].
Low dose methotrexate (< 10 mg per week) has been tested in two blinded randomized control trials and 4 open label studies and has shown low to moderate efficacy as corticosteroid-sparing agent [4] [5] [6] [7] [8] [9]. Studies on TNF blockers yielded negative results [10-12]. The effectiveness of leflunomide has only been convincingly demonstrated in case series [13] [14].
The high rate of relapses and adverse events in steroid treated patients indicate that alternative adjuvant agents are needed.
There is evidence that leflunomide could serve as steroid sparing agent and that leflunomide can be used to prevent relapses in the clinical management of polymyalgia rheumatica.
We will perform a randomized placebo controlled trial. Eligible patients will be randomly assigned in a 1:1 ratio receiving either leflunomide 20 mg once daily + glucocorticoids , or placebo + glucocorticoids.
Study objective
Leflunomide is able to reduce the relapses, the glucocorticoid use and the adverse events associated with glucocorticoid s use in PMR patients.
Study design
Time Frame: 24 months of the study
Intervention
Leflunomide
E Brouwer
Groningen
The Netherlands
+3150 3613432
e.brouwer@umcg.nl
E Brouwer
Groningen
The Netherlands
+3150 3613432
e.brouwer@umcg.nl
Inclusion criteria
1.Signed written informed consent
2.Female or male aged ¡Ý 50 years
3.PMR according to the ACR/EULAR 2012 PMR core (essential) classification criteria
4.Newly diagnosed PMR being on glucocorticoids for less than 4 weeks
Exclusion criteria
1.Presence of any other connective tissue disease, including vasculitis/giant-cell arteritis
2.PMR on glucocorticoids for >4 week or >25 mg/day
3.History of alcohol or drug abuse or current alcohol or drug abuse
4.Transplanted organ (except corneal transplant performed more than 3 months prior to screening)
5.Evidence (as assessed by the investigator) of active infection, presence of hepatitis B surface antigen or hepatitis C antibody in blood, HIV positivity.
6.Malignancy within 5 years prior to screening, except for non-melanoma skin cancer
7.Exposure to DMARD/biological in the last 5 years
8.Pain syndromes, e.g. fibromyalgia, drug-induced myalgia
9.Active thyroid disease
10.Neurological diseases, e.g. Parkinson's disease
11.Contraindications for Leflunomide (serious immunodeficiency, e.g. AIDS, cytopenia as defined under 12, moderate to severe kidney failure (as defined under 12), liver test abnormality (as defined under 12)
12.Laboratory abnormalities:
◦EGFR<50 ml/min
◦ALT or AST >1.5x upper limit of normal
◦Platelet count <100 x 109/L (100,000/mm3)
◦Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L)
◦White blood cells <3.0 x 109/L (3,000/mm3)Absolute neutrophil count <2.0 x 109/L (2,000/mm3)
◦Absolute lymphocyte count <0.5 x 109/L (500/mm3)
13.Uncontrolled or poorly controlled hypertension
14.Major surgery or hospitalization within 3 month prior to screening
15.Any medical condition that could interfere with the implementation or interpretation of the study or with the safety of the patient during the study.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL6930 |
| NTR-old | NTR7126 |
| Other | UMCG : ABR57022 |
Summary results
2. Dasgupta B, et al. BSR and BHPR guidelines for the management of GCA. Rheumatology2010: 8:1594-1597.
3. Hernandez-Rodriguez J,et al. Treatment of PMR: a review. ArchIntMed 2009 Nov 9;169(20):1839-1850.
4. van der Veen MJ, Dinant HJ, van Booma-Frankfort C, van Albada-Kuipers GA, Bijlsma JW. Can methotrexate be used as a steroid sparing agent in the treatment of PMR and GCA? ARD 1996 Apr;55(4):218-223.
5. Wagener P. MTX therapy of PMR . Zeitschrift fur Rheumatologie 1995 Nov-Dec;54(6):413-416.
6. Ferraccioli G, et al. MTX in PMR : preliminary results of an open, RCT. JRheum1996 Apr;23(4):624-628.
7. Feinberg HL, et al. The use of methotrexate in PMR. JRheum 1996 Sep;23(9):1550-1552.
8. Caporali R, Cimmino MA, et al. Prednisone plus MTX for PMR: a RCT. AnnIntMed2004 Oct 5;141(7):493-500.
9. Cimmino MA, Salvarani C, Macchioni P, et al. Long-term follow-up of PMR patients treated with methotrexate and steroids. Clinical and experimental rheumatology 2008 May-Jun;26(3):395-400.
10. Catanoso MG, Macchioni P, Boiardi L, Pipitone N, Salvarani C. Treatment of refractory polymyalgia rheumatica with etanercept: an open pilot study. Arthritis and Rheumatism 2007 Dec 15;57(8):1514-1519.
11. Salvarani C, Macchioni P, Manzini C,. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of PMR: a randomized trial. Annals of Internal Medicine 2007 May 1;146(9):631-639.
12. Kreiner F, Galbo H. Effect of etanercept in PMR: a RCT. Arthritis research & therapy 2010;12(5):R176.
13. Lally L, Forbess L, Hatzis C, Spiera R. A prospective open-label phase II trial of tocilizumab in the treatment of Polymyalgia Rheumatica. Arthritis Rheumatology 2016; Oct;68(10):2550-4
14. Devauchelle-Pensec V, Berthelot JM, Cornec D, Renaudineau Y, Marhadour T, Jousse-Joulin S, Querellou S, Garrigues F, De Bandt M, Gouillou M, Saraux A. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. Ann Rheum Dis. 2016 Aug;75(8):1506-10
15. Adizie T, Christidis D, Dharmapaliah C, Borg F, Dasgupta B. Efficacy and tolerability of Leflunomide in difficult-to-treat PMR and GCA: a case series. International journal of clinical practice 2012 Sep;66(9):906-909.
16. Diamantopoulos AP, Hetland H, Myklebust G. Leflunomide as a corticosteroid-sparing agent in giant cell arteritis and polymyalgia rheumatica: a case series. BioMed research international 2013;2013:120638.
17. Dasgupta B, Cimmino MA, Kremers HM, Schmidt WA, Schirmer M, Salvarani C, et al. 2012 Provisional classification criteria for PMR: a EULAR/ACR collaborative initiative. AR 2012 Apr;64(4):943-954.
18. Gran JT, Myklebust G. The incidence of PMR and temporal arteritis in the county of Aust Agder, south Norway: a prospective study 1987-94. The Journal of rheumatology 1997 Sep;24(9):1739-1743.
19. Kermani TA, Warrington KJ. Polymyalgia rheumatica. Lancet 2013 Jan 5;381(9860):63-72.
20. Matteson EL, Maradit-Kremers H, Cimmino MA, Schmidt WA, Schirmer M, Salvarani C, et al. Patientreported outcomes in polymyalgia rheumatica. The Journal of rheumatology 2012 Apr;39(4):795-803.
21. Dasgupta B, Borg FA, Hassan N, Barraclough K, Bourke B, Fulcher J, et al. BSR and BHPR guidelines for the management of polymyalgia rheumatica. Rheumatology (Oxford, England) 2010 Jan;49(1):186-190.
22. Dejaco C, Singh YP, Perel P, Hutchings A et al. 2015 Recommendations for the Management of Polymyalgia Rheumatica. A European League Against Rheumatism/American College of Rheumatology Collaborative Initiative. Arthritis & Rheumatology, 2015, 67(10):2569�C2580.
23. Metzler, C., Fink, C., Lamprecht, P., Gross, W. L. & Reinhold-Keller, E. Maintenance of remission with Leflunomide in Wegener's granulomatosis. Rheumatology (Oxford) 43, 315�C320 (2004).