Polymyalgia RheumaticaPhase 3PMRLEFRCTNCT03576794
Treatment With Leflunomide in Patients With Polymyalgia Rheumatica
A Phase 3 study testing Leflunomide 20 mg and Prednisolone in people with Polymyalgia Rheumatica, run by Elisabeth Brouwer at 2 sites in Netherlands.
Trial 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… Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Polymyalgia Rheumatica
- What is being tested?
- Leflunomide 20 mg and Prednisolone
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 94 participants
- Where
- 2 sitesNetherlands
- Study dates
- 1 Mar 2019to 1 Nov 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
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- 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)
- 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)
- Uncontrolled or poorly controlled hypertension
- Major surgery or hospitalization within 3 month prior to screening
- Any medical condition that could interfere with the implementation or interpretation of the study or with the safety of the patient during the study.
Trial locations and contacts
2 sites in 1 country.
Netherlands2 sites, 2 recruiting
- Recruiting
ZGT Almelo
Almelo, 7609 PP
Edgar Colin, MDPhD
Celina Alves, MDPhD
- Recruiting
University Medical Center Groningen
Groningen, 9713 GZ
Elisabeth Brouwer, dr, +3150 3613432, e.brouwer@umcg.nl
Maria Sandovici, dr, +3150 3613432, m.sandovici01@umcg.nl
About this study
Official title: A Multicenter Randomized Placebo Controlled Treatment Study of Leflunomide in Polymyalgia Rheumatica
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.
Read more
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.
Read the detailed description
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 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.
Primary endpoint The clinically relevant lower total number of relapses in leflunomide treated PMR patients as compared to placebo treated patients at 18 months.
Secondary endpoints
- Steroid sparing capacity of leflunomide in patients with newly diagnosed PMR. Glucocorticoid sparing is expressed as a reduction of the cumulative glucocorticoid dose in the first 2 years of treatment.
- Less time needed to reach both remission on glucocorticoids and glucocorticoid free remission
- Less GC side effects in leflunomide PMR patient group
The first 2 weeks 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 per day.
In case leflunomide has to be stopped due to side effects or inefficacy methotrexate will be used as rescue therapy 10 mg per week open label, based on the evidence that 10 mg methotrexate per week is steroid sparing. Those patients will be classified as non-responder.
Randomization will be stratified by age, gender and weight. Therefore, blocked randomization with variable block size will be performed.
Patients in both groups will be started on prednisolone 15 mg once daily and will be randomized within 2 weeks of the start of steroid therapy. The steroids will be tapered according to a short fixed protocol starting with 15 mg a day with a slow gradual taper till 0 in week 27.
Criteria for relapse or recurrence of PMR Relapse or recurrence will be measured according to an adaptation, based on expert opinion, to consensus criteria for PMR.
Relapse / recurrence Patient global higher than 3/ 10 and Physician global higher than 1/10 and An increased C reactive protein (CRP) ( > 5 mg/L) Is called a relapse if it was observed during steroid tapering, and is called a Recurrence if it was observed after steroid withdrawal.
Criteria for remission Patient global 3/ 10 or less and Physician global 1/10 or less and A normal CRP ( < 5 mg/L)
Secondary outcome measure PMR-AS The PMR-AS (Leeb and Bird) is a composite score with the following items: Physician global, Pt global, CRP, ability to raise the shoulders on examination, and duration of morning stiffness in minutes.
This randomized controlled trial (RCT) will assess:
- Time to relapse and steroid-sparing capacity of leflunomide
- PMR disease activity including patient reported outcome
- Treatment related complications of steroids
- Safety and tolerability of leflunomide
This blinded RCT in PMR is a unique study involving 5 centres in 4 different countries. It is the first study to use the recently developed consensus and outcome criteria in PMR which were developed by multidisciplinary groups including patients input. It is both timely and needed to fund a study in PMR since due to ageing in especially Western Europe the expectancy is that the incidence and prevalence of PMR will increase in the coming years. In brief: It is time to take PMR seriously and treat the patients with steroid sparing agents in order to prevent co-morbidities like diabetes, hypertension and osteoporosis in an ageing population.
The 5 centres (Department of Rheumatology and Immunology, Medical University Graz, Department of Rheumatology, Hospital of Southern Norway Trust Kristiansand, Kristiansand, Norway, The Department of Rheumatology, Southend University Hospital, Westcliff-on-sea, Chapel Allerton Hospital and St James's University Hospital Leeds and the University Medical Centre Groningen) participating in this study also set up an immediate early access outpatient clinic for PMR patients.
We will keep close contact with patients and their organizations to check whether our aims are in line with their expectations.
The relevance and gain for patients will be a different approach to PMR on the level of
- Early recognition/ making an appropriate diagnosis
- Starting steroid sparing treatment in an adequate dose at baseline
- Better outcome and earlier control of PMR with less relapses and cumulative dosis of steroids (benefit of thight control).
Our study can provide substantial benefit to the society. We seek to demonstrate that relatively cheap drug like leflunomide can improve the treatment of these PMR patients and limit the occurrence of relapses and GC-related side effects. Since leflunomide is an old and cheap drug the pharmaceutical companies are not interested in funding, we hope therefore that the Dutch Arthritis Association will fund our study.
- Conditions
- Polymyalgia Rheumatica
- Being tested
- Leflunomide 20 mg, Prednisolone
- Keywords
- PMR RCT, Leflunomide
- Medical subject headings
- Polymyalgia Rheumatica
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Leflunomide 20 mgDrug
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.
PrednisoloneDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Prednisolone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Within first 12 months of the study participation
Secondary outcomes (6)
Time till first relapse within first 24 months
Time measured in days
Measured: Within first 24 months of the study participation
Percentage of patients with at least 1 relapse in the first 12 or 24 months
Percentage: patients with relapse in the first 12 or 24 months divided by total participating patients.
Measured: Within first 24 months of the study participation
Number of relapsing patients within the first 24 months.
Measured: Within first 24 months of the study participation
Time till glucocorticoid free remission
Total days until patient has no glucocorticoid treatment and no signs of PMR.
Measured: Within first 24 months of the study participation
Glucocorticoid-sparing effect
- Glucocorticoid dose after 6, 12, 18 and 24 months.
- Cumulative glucocorticoid dose after 12, 18 and 24 months
Measured: Within first 24 months of the study participation
Number of participants with adverse events and serious adverse events as assessed by MedDRA V21.0
Measured: Within first 24 months of the study participation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jul 2018
- Study start1 Mar 2019
- Primary completion1 Nov 2022 (estimated)
- Study completion1 Nov 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (22)Papers the sponsor has linked to this study.
- Other trials for Polymyalgia RheumaticaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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).
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 94 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Elisabeth Brouwer
- Sponsor type
- University, hospital or other
- Collaborators
- Dutch Arthritis Foundation Reuma Nederland
- Responsible party
- Sponsor-investigator, Elisabeth Brouwer, University Medical Center Groningen
- Investigators
- Elisabeth Brouwer, Principal investigator, University Medical Center GroningenE.M. Colin, Principal investigator, ZGT Almelo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03576794
- Sponsor's protocol ID
- ABR57022
- Acronym
- PMRLEFRCT
- Status last verified
- May 2019
- First submitted
- 17 Apr 2018
- Last updated
- 3 Jun 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Manuscript after publication
Publications
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.
PubMed 20371504Hernandez-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.
PubMed 19901135van 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.
PubMed 8733437Wagener P. [Methotrexate therapy of polymyalgia rheumatica]. Z Rheumatol. 1995 Nov-Dec;54(6):413-6. German.
PubMed 8578892Ferraccioli 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.
PubMed 8730115Feinberg HL, Sherman JD, Schrepferman CG, Dietzen CJ, Feinberg GD. The use of methotrexate in polymyalgia rheumatica. J Rheumatol. 1996 Sep;23(9):1550-2.
PubMed 8877923Caporali 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.
PubMed 15466766Cimmino 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.
PubMed 18578959Catanoso 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.
PubMed 18050171Salvarani 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.
PubMed 17470831Kreiner 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.
PubMed 20854662Lally 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.
PubMed 27159185Devauchelle-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.
PubMed 26929219Adizie 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.
PubMed 22897467Diamantopoulos 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.
PubMed 24106691
Study at a glance
From the registry record, last updated by the sponsor on 3 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter Randomized Placebo Controlled Treatment Study of Leflunomide in Polymyalgia Rheumatica
- ClinicalTrials.gov ID
- NCT03576794
- Acronym / sponsor ID
- PMRLEFRCT / ABR57022
- Conditions
- Polymyalgia Rheumatica
- Keywords
- PMR RCT, Leflunomide
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 94 participants (estimated)
- Lead sponsor
- Elisabeth BrouwerUniversity, hospital or other
- Collaborators
- Dutch Arthritis Foundation Reuma Nederland
- Study start
- 1 Mar 2019 (actual)
- Primary completion
- 1 Nov 2022 (estimated)
- Study completion
- 1 Nov 2022 (estimated)
- First posted
- 3 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 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.
Primary endpoint The clinically relevant lower total number of relapses in leflunomide treated PMR patients as compared to placebo treated patients at 18 months.
Secondary endpoints
- Steroid sparing capacity of leflunomide in patients with newly diagnosed PMR. Glucocorticoid sparing is expressed as a reduction of the cumulative glucocorticoid dose in the first 2 years of treatment.
- Less time needed to reach both remission on glucocorticoids and glucocorticoid free remission
- Less GC side effects in leflunomide PMR patient group
The first 2 weeks 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 per day.
In case leflunomide has to be stopped due to side effects or inefficacy methotrexate will be used as rescue therapy 10 mg per week open label, based on the evidence that 10 mg methotrexate per week is steroid sparing. Those patients will be classified as non-responder.
Randomization will be stratified by age, gender and weight. Therefore, blocked randomization with variable block size will be performed.
Patients in both groups will be started on prednisolone 15 mg once daily and will be randomized within 2 weeks of the start of steroid therapy. The steroids will be tapered according to a short fixed protocol starting with 15 mg a day with a slow gradual taper till 0 in week 27.
Criteria for relapse or recurrence of PMR Relapse or recurrence will be measured according to an adaptation, based on expert opinion, to consensus criteria for PMR.
Relapse / recurrence Patient global higher than 3/ 10 and Physician global higher than 1/10 and An increased C reactive protein (CRP) ( > 5 mg/L) Is called a relapse if it was observed during steroid tapering, and is called a Recurrence if it was observed after steroid withdrawal.
Criteria for remission Patient global 3/ 10 or less and Physician global 1/10 or less and A normal CRP ( < 5 mg/L)
Secondary outcome measure PMR-AS The PMR-AS (Leeb and Bird) is a composite score with the following items: Physician global, Pt global, CRP, ability to raise the shoulders on examination, and duration of morning stiffness in minutes.
This randomized controlled trial (RCT) will assess:
- Time to relapse and steroid-sparing capacity of leflunomide
- PMR disease activity including patient reported outcome
- Treatment related complications of steroids
- Safety and tolerability of leflunomide
This blinded RCT in PMR is a unique study involving 5 centres in 4 different countries. It is the first study to use the recently developed consensus and outcome criteria in PMR which were developed by multidisciplinary groups including patients input. It is both timely and needed to fund a study in PMR since due to ageing in especially Western Europe the expectancy is that the incidence and prevalence of PMR will increase in the coming years. In brief: It is time to take PMR seriously and treat the patients with steroid sparing agents in order to prevent co-morbidities like diabetes, hypertension and osteoporosis in an ageing population.
The 5 centres (Department of Rheumatology and Immunology, Medical University Graz, Department of Rheumatology, Hospital of Southern Norway Trust Kristiansand, Kristiansand, Norway, The Department of Rheumatology, Southend University Hospital, Westcliff-on-sea, Chapel Allerton Hospital and St James's University Hospital Leeds and the University Medical Centre Groningen) participating in this study also set up an immediate early access outpatient clinic for PMR patients.
We will keep close contact with patients and their organizations to check whether our aims are in line with their expectations.
The relevance and gain for patients will be a different approach to PMR on the level of
- Early recognition/ making an appropriate diagnosis
- Starting steroid sparing treatment in an adequate dose at baseline
- Better outcome and earlier control of PMR with less relapses and cumulative dosis of steroids (benefit of thight control).
Our study can provide substantial benefit to the society. We seek to demonstrate that relatively cheap drug like leflunomide can improve the treatment of these PMR patients and limit the occurrence of relapses and GC-related side effects. Since leflunomide is an old and cheap drug the pharmaceutical companies are not interested in funding, we hope therefore that the Dutch Arthritis Association will fund our study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
- Model description
- 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).
| Arm | Type | Receives |
|---|---|---|
| Leflunomide treatment | Active comparator | Drug: Leflunomide 20 mg, Drug: PrednisolonePatients 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. |
| Placebo control | Placebo comparator | Drug: PrednisolonePatients 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. |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (21 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Leflunomide 20 mgDuring 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. | Drug | Leflunomide treatment |
| PrednisolonePatients 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. | Drug | Leflunomide treatment, Placebo control |
Primary outcome
PMR relapse
Time frame: Within first 12 months of the study participation
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.
6 secondary outcomes
Time till first relapse within first 24 months
Time frame: Within first 24 months of the study participation
Percentage of patients with at least 1 relapse in the first 12 or 24 months
Time frame: Within first 24 months of the study participation
Number of relapsing patients within the first 24 months.
Time frame: Within first 24 months of the study participation
Time till glucocorticoid free remission
Time frame: Within first 24 months of the study participation
Glucocorticoid-sparing effect
Time frame: Within first 24 months of the study participation
Number of participants with adverse events and serious adverse events as assessed by MedDRA V21.0
Time frame: Within first 24 months of the study participation
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jun 2019.
- Background: PubMed 20371504Dasgupta 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.
- Background: PubMed 19901135Hernandez-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.
- Background: PubMed 8733437van 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.
- Background: PubMed 8578892Wagener P. [Methotrexate therapy of polymyalgia rheumatica]. Z Rheumatol. 1995 Nov-Dec;54(6):413-6. German.
- Background: PubMed 8730115Ferraccioli 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.
- Background: PubMed 8877923Feinberg HL, Sherman JD, Schrepferman CG, Dietzen CJ, Feinberg GD. The use of methotrexate in polymyalgia rheumatica. J Rheumatol. 1996 Sep;23(9):1550-2.
- Background: PubMed 15466766Caporali 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.
- Background: PubMed 18578959Cimmino 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.
- Background: PubMed 18050171Catanoso 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.
- Background: PubMed 17470831Salvarani 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.
- Background: PubMed 20854662Kreiner 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.
- Background: PubMed 27159185Lally 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.
- Individual participant dataSharing planned: Yes. Manuscript after publication
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Elisabeth Brouwer principal investigator
University Medical Center Groningen
E.M. Colin principal investigator
ZGT Almelo
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Leflunomide 20 mg and Prednisolone in people with Polymyalgia Rheumatica, run by Elisabeth Brouwer at 2 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Elisabeth Brouwer (+3150 3613432, e.brouwer@umcg.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PMR relapse (time frame: Within first 12 months of the study participation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03576794, which also lists 22 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jun 2019.