Treatment With Leflunomide in Patients With Polymyalgia Rheumatica

NCT03576794 | Unknown Phase 3 DMC

• 1 other identifier: ABR57022
• Study Type: interventional
• Target: 94
• Locations: 1 country
• Sites: 2

Brief Summary

Over the last decades outcome has greatly improved for rheumatoid arthritis (RA) and spondyloarthritis (SpA). This is in sharp contrast to the situation for polymyalgia rheumatica (PMR), 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 ≥50 years. Due to population ageing, the number of PMR patients will likely double in the decades to come (CBS). Glucocorticoids (GC) are the mainstay of treatment. 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. 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. 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. Studies on tumor necrosis factor (TNF) blockers yielded negative results. The effectiveness of leflunomide has only been convincingly demonstrated in case series. 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.

Conditions

Polymyalgia Rheumatica

Keywords

PMR RCT; Leflunomide

Outcome Measures

Primary Outcomes (1)

• PMR relapse

  Relapse or recurrence will be measured according to an adaptation, based on expert opinion, to consensus criteria for PMR: * Patient global higher than 3/10 and * Physician global higher than 1/10 and * An increased CRP ( \> 5 mg/L) It is called a "relapse" if it was observed during glucocorticoid tapering and is called a "recurrence" if it was observed after glucocorticoid withdrawal.

  Within first 12 months of the study participation

Secondary Outcomes (6)

• Time till first relapse within first 24 months

  Within first 24 months of the study participation

• Percentage of patients with at least 1 relapse in the first 12 or 24 months

  Within first 24 months of the study participation

• Number of relapsing patients within the first 24 months.

  Within first 24 months of the study participation

• Time till glucocorticoid free remission

  Within first 24 months of the study participation

• Glucocorticoid-sparing effect

  Within first 24 months of the study participation

Study Arms (2)

Leflunomide treatment

ACTIVE COMPARATOR

Patients will receive prednisolone 15 mg once daily and will be randomized within 4 weeks of the start of glucocorticoid therapy (prednisolone). Prednisolon will be tapered according to a short fixed protocol with a slow gradual taper till 0 in week 27. During the first 2 weeks after randomization patients will receive Leflunomide 20 mg every other day in order to prevent early drug withdrawal due to side effects. After 2 weeks Leflunomide will be increased to 20 mg once daily and this therapy will be continued during 12 months.

Drug: Leflunomide 20 mg; Drug: Prednisolone

Placebo control

PLACEBO COMPARATOR

Patients will receive prednisolone 15 mg once daily and will be randomized within 4 weeks of the start of glucocorticoid therapy (prednisolone). Prednisolon will be tapered according to a short fixed protocol with a slow gradual taper till 0 in week 27. During the first 2 weeks after randomization patients will receive placebo 20 mg every other day in order to prevent early drug withdrawal due to side effects. After 2 weeks placebo will be increased to 20 mg once daily and this therapy will be continued during 12 months.

Drug: Prednisolone

Interventions

Leflunomide 20 mg DRUG

During the first 2 weeks after randomization patients will receive Leflunomide 20 mg every other day. After 2 weeks Leflunomide will be increased to 20 mg once daily and this therapy will be continued during 12 months.

Leflunomide treatment

Prednisolone DRUG

Patients in both groups will receive prednisolone 15 mg once daily and will be randomized within 4 weeks of the start of glucocorticoid therapy (prednisolone). Prednisolon will be tapered according to a short fixed protocol with a slow gradual taper till 0 in week 27.

Leflunomide treatment; Placebo control

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed written informed consent
• Female or male aged ≥ 50 years
• PMR according to the American College of Rheumatology (ACR)/European league Against Rheumatism (EULAR) 2012 PMR core (essential) classification criteria
• Newly diagnosed PMR being on glucocorticoids for less than 4 weeks

You may not qualify if:

• Presence of any other connective tissue disease, including vasculitis/giant-cell arteritis
• PMR on glucocorticoids for \>4 week or \>25 mg/day
• History of alcohol or drug abuse or current alcohol or drug abuse
• Transplanted organ (except corneal transplant performed more than 3 months prior to screening)
• Evidence (as assessed by the investigator) of active infection, presence of hepatitis B surface antigen or hepatitis C antibody in blood, HIV positivity.
• Malignancy within 5 years prior to screening, except for non-melanoma skin cancer
• Exposure to DMARD/biological in the last 5 years
• Pain syndromes, e.g. fibromyalgia, drug-induced myalgia
• Active thyroid disease
• Neurological diseases, e.g. Parkinson's disease
• 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)
• Laboratory abnormalities:
• Glomerular filtration rate \<50 ml/min
• Alanine-aminotransferase (ALT) or aspartate aminotransferase (AST) \>1.5x upper limit of normal
• Platelet count \<100 x 109/L (100,000/mm3)

Sponsors & Collaborators

• Elisabeth Brouwer: lead
• Dutch Arthritis Foundation Reuma Nederland: collaborator

Study Sites (2)

ZGT Almelo

Almelo, 7609 PP, Netherlands

RECRUITING

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

RECRUITING

Related Publications (22)

• Dasgupta B, Borg FA, Hassan N, Alexander L, Barraclough K, Bourke B, Fulcher J, Hollywood J, Hutchings A, James P, Kyle V, Nott J, Power M, Samanta A; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guidelines for the management of giant cell arteritis. Rheumatology (Oxford). 2010 Aug;49(8):1594-7. doi: 10.1093/rheumatology/keq039a. Epub 2010 Apr 5. No abstract available.

  PMID: 20371504 BACKGROUND

• Hernandez-Rodriguez J, Cid MC, Lopez-Soto A, Espigol-Frigole G, Bosch X. Treatment of polymyalgia rheumatica: a systematic review. Arch Intern Med. 2009 Nov 9;169(20):1839-50. doi: 10.1001/archinternmed.2009.352.

  PMID: 19901135 BACKGROUND

• 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 polymyalgia rheumatica and giant cell arteritis? Ann Rheum Dis. 1996 Apr;55(4):218-23. doi: 10.1136/ard.55.4.218.

  PMID: 8733437 BACKGROUND

• Wagener P. [Methotrexate therapy of polymyalgia rheumatica]. Z Rheumatol. 1995 Nov-Dec;54(6):413-6. German.

  PMID: 8578892 BACKGROUND

• Ferraccioli G, Salaffi F, De Vita S, Casatta L, Bartoli E. Methotrexate in polymyalgia rheumatica: preliminary results of an open, randomized study. J Rheumatol. 1996 Apr;23(4):624-8.

  PMID: 8730115 BACKGROUND

• Feinberg HL, Sherman JD, Schrepferman CG, Dietzen CJ, Feinberg GD. The use of methotrexate in polymyalgia rheumatica. J Rheumatol. 1996 Sep;23(9):1550-2.

  PMID: 8877923 BACKGROUND

• Caporali R, Cimmino MA, Ferraccioli G, Gerli R, Klersy C, Salvarani C, Montecucco C; Systemic Vasculitis Study Group of the Italian Society for Rheumatology. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2004 Oct 5;141(7):493-500. doi: 10.7326/0003-4819-141-7-200410050-00005.

  PMID: 15466766 BACKGROUND

• Cimmino MA, Salvarani C, Macchioni P, Gerli R, Bartoloni Bocci E, Montecucco C, Caporali R; Systemic Vasculitis Study Group of the Italian Society for Rheumatology. Long-term follow-up of polymyalgia rheumatica patients treated with methotrexate and steroids. Clin Exp Rheumatol. 2008 May-Jun;26(3):395-400.

  PMID: 18578959 BACKGROUND

• Catanoso MG, Macchioni P, Boiardi L, Pipitone N, Salvarani C. Treatment of refractory polymyalgia rheumatica with etanercept: an open pilot study. Arthritis Rheum. 2007 Dec 15;57(8):1514-9. doi: 10.1002/art.23095.

  PMID: 18050171 BACKGROUND

• Salvarani C, Macchioni P, Manzini C, Paolazzi G, Trotta A, Manganelli P, Cimmino M, Gerli R, Catanoso MG, Boiardi L, Cantini F, Klersy C, Hunder GG. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med. 2007 May 1;146(9):631-9. doi: 10.7326/0003-4819-146-9-200705010-00005.

  PMID: 17470831 BACKGROUND

• Kreiner F, Galbo H. Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial. Arthritis Res Ther. 2010;12(5):R176. doi: 10.1186/ar3140. Epub 2010 Sep 20.

  PMID: 20854662 BACKGROUND

• Lally L, Forbess L, Hatzis C, Spiera R. Brief Report: A Prospective Open-Label Phase IIa Trial of Tocilizumab in the Treatment of Polymyalgia Rheumatica. Arthritis Rheumatol. 2016 Oct;68(10):2550-4. doi: 10.1002/art.39740.

  PMID: 27159185 BACKGROUND

• 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. doi: 10.1136/annrheumdis-2015-208742. Epub 2016 Feb 29.

  PMID: 26929219 BACKGROUND

• Adizie T, Christidis D, Dharmapaliah C, Borg F, Dasgupta B. Efficacy and tolerability of leflunomide in difficult-to-treat polymyalgia rheumatica and giant cell arteritis: a case series. Int J Clin Pract. 2012 Sep;66(9):906-9. doi: 10.1111/j.1742-1241.2012.02981.x.

  PMID: 22897467 BACKGROUND

• Diamantopoulos AP, Hetland H, Myklebust G. Leflunomide as a corticosteroid-sparing agent in giant cell arteritis and polymyalgia rheumatica: a case series. Biomed Res Int. 2013;2013:120638. doi: 10.1155/2013/120638. Epub 2013 Sep 11.

  PMID: 24106691 BACKGROUND

• Dasgupta B, Cimmino MA, Kremers HM, Schmidt WA, Schirmer M, Salvarani C, Bachta A, Dejaco C, Duftner C, Jensen HS, Duhaut P, Poor G, Kaposi NP, Mandl P, Balint PV, Schmidt Z, Iagnocco A, Nannini C, Cantini F, Macchioni P, Pipitone N, Del Amo M, Espigol-Frigole G, Cid MC, Martinez-Taboada VM, Nordborg E, Direskeneli H, Aydin SZ, Ahmed K, Hazleman B, Silverman B, Pease C, Wakefield RJ, Luqmani R, Abril A, Michet CJ, Marcus R, Gonter NJ, Maz M, Carter RE, Crowson CS, Matteson EL. 2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum. 2012 Apr;64(4):943-54. doi: 10.1002/art.34356.

  PMID: 22389040 BACKGROUND

• Gran JT, Myklebust G. The incidence of polymyalgia rheumatica and temporal arteritis in the county of Aust Agder, south Norway: a prospective study 1987-94. J Rheumatol. 1997 Sep;24(9):1739-43.

  PMID: 9292797 BACKGROUND

• Kermani TA, Warrington KJ. Polymyalgia rheumatica. Lancet. 2013 Jan 5;381(9860):63-72. doi: 10.1016/S0140-6736(12)60680-1. Epub 2012 Oct 8. Erratum In: Lancet. 2013 Jan 5;381(9860):28.

  PMID: 23051717 BACKGROUND

• Matteson EL, Maradit-Kremers H, Cimmino MA, Schmidt WA, Schirmer M, Salvarani C, Bachta A, Dejaco C, Duftner C, Slott Jensen H, Poor G, Kaposi NP, Mandl P, Balint PV, Schmidt Z, Iagnocco A, Cantini F, Nannini C, Macchioni P, Pipitone N, Del Amo M, Espigol-Frigole G, Cid MC, Martinez-Taboada VM, Nordborg E, Direskeneli H, Aydin SZ, Ahmed K, Hazelman B, Pease C, Wakefield RJ, Luqmani R, Abril A, Marcus R, Gonter NJ, Maz M, Crowson CS, Dasgupta B. Patient-reported outcomes in polymyalgia rheumatica. J Rheumatol. 2012 Apr;39(4):795-803. doi: 10.3899/jrheum.110977. Epub 2012 Mar 15.

  PMID: 22422492 BACKGROUND

• Dasgupta B, Borg FA, Hassan N, Barraclough K, Bourke B, Fulcher J, Hollywood J, Hutchings A, Kyle V, Nott J, Power M, Samanta A; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guidelines for the management of polymyalgia rheumatica. Rheumatology (Oxford). 2010 Jan;49(1):186-90. doi: 10.1093/rheumatology/kep303a. Epub 2009 Nov 12. No abstract available.

  PMID: 19910443 BACKGROUND

• Dejaco C, Singh YP, Perel P, Hutchings A, Camellino D, Mackie S, Abril A, Bachta A, Balint P, Barraclough K, Bianconi L, Buttgereit F, Carsons S, Ching D, Cid M, Cimmino M, Diamantopoulos A, Docken W, Duftner C, Fashanu B, Gilbert K, Hildreth P, Hollywood J, Jayne D, Lima M, Maharaj A, Mallen C, Martinez-Taboada V, Maz M, Merry S, Miller J, Mori S, Neill L, Nordborg E, Nott J, Padbury H, Pease C, Salvarani C, Schirmer M, Schmidt W, Spiera R, Tronnier D, Wagner A, Whitlock M, Matteson EL, Dasgupta B; European League Against Rheumatism; American College of Rheumatology. 2015 recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheumatol. 2015 Oct;67(10):2569-80. doi: 10.1002/art.39333.

  PMID: 26352874 BACKGROUND

• Metzler C, Fink C, Lamprecht P, Gross WL, Reinhold-Keller E. Maintenance of remission with leflunomide in Wegener's granulomatosis. Rheumatology (Oxford). 2004 Mar;43(3):315-20. doi: 10.1093/rheumatology/keh009. Epub 2004 Jan 6.

  PMID: 14963200 BACKGROUND

MeSH Terms

Conditions

Polymyalgia Rheumatica

Interventions

Leflunomide; Prednisolone

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Elisabeth Brouwer

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

• E.M. Colin

  ZGT Almelo

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elisabeth Brouwer

CONTACT

+3150 3613432; e.brouwer@umcg.nl

Maria Sandovici

CONTACT

+3150 3613432; m.sandovici01@umcg.nl

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal investigator

Model Details: Prospective, randomized, double-blind, placebo controlled treatment study during 12 months (part I) and an additional open-label follow-up of 12 months (part II).

Study Record Dates

• First Submitted: April 17, 2018
• First Posted: July 3, 2018
• Study Start: March 1, 2019
• Primary Completion: November 1, 2022
• Study Completion: November 1, 2022
• Last Updated: June 3, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Within 2 years after study termination, study data will be available and published
• Access Criteria: Study data will be available upon request to the principal investigator

Locations

NL (2)