Ignite Creation Date:
2024-05-06 @ 11:40 AM
Last Modification Date:
2024-10-26 @ 12:48 PM
Study NCT ID:
NCT03576794
Status:
UNKNOWN
Last Update Posted:
2019-06-03
First Post:
2018-04-17
Brief Title:
Treatment With Leflunomide in Patients With Polymyalgia Rheumatica
Sponsor:
Elisabeth Brouwer
Organization:
University Medical Center Groningen
Study Overview
Official Title:
A Multicenter Randomized Placebo Controlled Treatment Study of Leflunomide in Polymyalgia Rheumatica
Status:
UNKNOWN
Status Verified Date:
2019-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PMRLEFRCT
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 24 for women and 17 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 11 ratio receiving either leflunomide 20 mg once daily glucocorticoids or placebo glucocorticoids
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 11 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 24 for women and 17 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 11 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
1 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
2 Less time needed to reach both remission on glucocorticoids and glucocorticoid free remission
3 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 110 and An increased C reactive protein CRP 5 mgL 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 110 or less and A normal CRP 5 mgL
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
1 Time to relapse and steroid-sparing capacity of leflunomide
2 PMR disease activity including patient reported outcome
3 Treatment related complications of steroids
4 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 Jamess 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
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 11 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
1 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
2 Less time needed to reach both remission on glucocorticoids and glucocorticoid free remission
3 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 110 and An increased C reactive protein CRP 5 mgL 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 110 or less and A normal CRP 5 mgL
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
1 Time to relapse and steroid-sparing capacity of leflunomide
2 PMR disease activity including patient reported outcome
3 Treatment related complications of steroids
4 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 Jamess 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None