A Multicenter Randomized Placebo Controlled Treatment Study of Leflunomide in Polymyalgia Rheumatica
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 94
- 试验地点
- 2
- 主要终点
- PMR relapse
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
- •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.
研究组 & 干预措施
Leflunomide treatment
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.
干预措施: Leflunomide 20 mg (Drug)
Leflunomide treatment
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.
干预措施: Prednisolone (Drug)
Placebo control
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.
干预措施: Prednisolone (Drug)
结局指标
主要结局
PMR relapse
时间窗: 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.
次要结局
- 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)
- Number of participants with adverse events and serious adverse events as assessed by MedDRA V21.0(Within first 24 months of the study participation)
研究者
Elisabeth Brouwer
Principal investigator
University Medical Center Groningen