Safety and Efficacy of Tofacitinib in the Treatment of NSAID Refractory Axial Spondyloarthritis:A Clinical Trial
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Assessment of spondyloarthritis international society 20 response(ASAS 20)
研究概览
简要总结
Title Efficacy and Safety of Tofacitinib in the Treatment of NSAID-Refractory Axial Spondyloarthritis: A Clinical Trial
Background:
Axial spondyloarthritis (axSpA) is a chronic systemic inflammatory rheumatic disease affecting mainly sacroiliac joints and spine. There are limited options for treatment. Initial treatments are patient's education, regular physical exercise and nonsteroidal antiinflammatory drugs(NSAID). If the patients do not respond to at least two NSAIDs in full dosages for at least one month then it is called NSAID refractory axSpA. In these cases biologics like-tumor necrosis factor α blockers are the options for treatment. Tofacitinib is a new drug has been proven to be effective for treatment of rheumatoid arthritis , psoriasis , inflammatory bowel disease and supposed to be effective in spondyloarthritis. This study is aimed to assess the efficacy and safety of tofacitinib in NSAID refractory ax SpA with a view to find a safe, effective and affordable treatment modality.
Method:
This open label uncontrolled clinical trial with tofacitinib will be conducted in NSAID refractory axSpA (age >18 years) patients. Study participants will be enrolled after having informed written consent from the outpatient department of Rheumatology, Bangabandhu sheikh mujib medical university. Assessment of Spondyloarthritis International Society (ASAS) criteria will be followed for diagnosis of ax SpA. Patients failing a trial of 2 different NSAID each for at least 2 weeks with optimum dosage without response or with partial response and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥4 (range, 0-10) or Ankylosing spondylitis disease activity score-C reactive protein(ASDAS-CRP)>2.1 will be considered as primary entry criteria for this study.
Baseline evaluation will include Bath AS Disease Activity Index (BASDAI), Functional Index (BASFI) , Ankylosing spondylitis disease activity score-C reactive protein(ASDASCRP) and Ankylosing spondylitis disease activity score-erythrocyte sedimentation rate(ASDAS-ESR).
Laboratory tests like CBC, ESR, CRP, SGPT, Serum creatinine and X-ray pelvis A/P view or X-ray both SI joints modified Ferguson veiw (to see both SI and hip joints ), HLA-B27(if needed), CXR P/A view and MT test or Interferon Gamma Release Assay(IGRA) will be done.
After considering inclusion and exclusion criteria eligible patients will be included for this study. All patients will be put on 5mg tofacitinib BD. NSAID and adjuvant analgesics will be used if needed. Follow up will be done at 4th, 12th and 24th week. Response to treatment will be evaluated by assessement of spondyloarthritis society (ASAS) response criteria. More than 20% improvements from baseline will consider as primary response at the end of 12th week. Those patients who will not achieve ASAS20 response at 12th week, will be given 10 mg tofacitinib BD. Efficacy will be assessed at the end of 24th week by ASAS20, ASAS50, ASAS70, ASDAS-ESR, ASDAS-CRP, BASDAI, Bath ankylosing spondylitis functional index(BASFI). Adverse effects will be assesed by history, Physical examinations and investigations.
The entire study subjects will be informed about the nature, purpose and implication of the study as well as whole spectrum of benefits and risk of the study. Ethical clearance will be taken from the IRB of BSMMU.
详细描述
INTRODUCTION Spondyloarthritis (SpA) is one of the most prevalent forms of chronic inflammatory arthritis. It affects approximately 0.01-2.5% in the World wide. Estimated prevalence of SpA in India is between 0.1 to 0.2% and prevalence in Bangladesh is about 1.2% .
Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinase that transduce cytokine-mediated signals via theJAK-signal transduction and activation of transcriptors( JAK-STAT) pathway. The JAK-STAT signaling pathway transmits information from extracellular chemical signals to the nucleus resulting in DNA transcription and expression of genes involved in immunity, proliferation, differentiation, apoptosis and oncogenesis .
Tofacitinib acts by inhibiting JAK-STAT pathway particularly JAK1 and/JAK3 of multilineage cells thereby inhibiting lymphocytes. It inhibits interleukin IL-17, IL-21, IL-23 and interferon IFN-γ productions by CD4 T cells acts on dendritic cells(DCs) and suppressed inflammatory cytokine productions and expression of costimulatory molecules, also supprressed T cell stimulatory capacity of DCs. These indicate that wide range of biological effects of tofacitinib that directly and indirectly affect cytokine pathway thereby modulate immunue response and reduce inflammations.
Axial SpA patients treated with tofacitinib experienced clinically meaningful reductions in axial MRI inflammations and thereby an increased clinical response rates. A 16-week, phase II, randomized trial on AS patients with tofacitinib showed 80.8 % patients achieved ASAS 20 response .
As the therapeutic options of NSAID refractory axial SpA are limited, we want to assess the efficacy of tofacitinib in refractory axial SpA. In our country there are no studies of tofacitinib on axial spondyloarthritis. In Bangladesh, tofacitinib is cheaper than anti TNF biologics so it will reduce the treatment cost.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The subjects will be considered if they fulfill the following criteria
- •Subjects greater than 18 years of age
- •Patients fulfilling the ASAS classification criteria for axial SpA including both non radiographic axial spondyloarthritis (nr-Ax SpA) and ankylosing spondylitis(AS)
- •Patients with axSpA underwent a trial of at least 2 course of NSAIDs with optimum doses for at least 1 month without response or with partial response
- •Patients with BASDAI ≥4 or ASDAS-CRP>2.1
排除标准
- •The subjects will be excluded if they have any of the
- •Systemic infections requiring hospital admission during the last 6 months
- •Active infections and/or a history of chronic or recurrent serious infective diseases, opportunistic infections
- •Hemoglobin (Hb) < 9 g/dl
- •White blood cell count < 4000, Neutrophil count < 1000, Platelet count < 100000/mm3
- •Live vaccines within 3 months prior to the first dose
- •Serum creatinine > upper limit of normal reference range
- •GFR less than 50 mL/min
- •Alanine aminotransaminase (ALT) more than 2 times of ULN
- •Pregnant or breast feeding females of child-bearing potential not using highly effective contraception
- •Evidence or history of malignancy, with the exception of adequately treated or excised non-metastatic basal or squamous cell cancer of the skin or cervical carcinoma in situ
- •New York Heart Association Class III and IV congestive heart failure
- •Any lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease
研究组 & 干预措施
Open label clinical trial
NSAID refractory axial spondyloarthritis patients who are eligible after considering inclusion and exclusion crietria will be put on 5 mg tofacitinib BD ,at the end of 1st and 3rd month they will be assessed for safety and efficacy.Those who will not respond will be put on 10 mg tofacitinib BD.All patients will be assessed at the end of 6th month.If any adverse event occur they will be treated accordingly.
干预措施: Tofacitinib (Drug)
结局指标
主要结局
Assessment of spondyloarthritis international society 20 response(ASAS 20)
时间窗: At the end of 3rd month
ASAS 20:It is a composite measurement which means improvement of ≥ 20% in 3 of the following 4 domains without 20% worsening in the remaining domain Four domains 1. Bath ankylosing spondylitis functional index(BASFI)-The 10 items index of daily functional activities completed on a numerical rating scale (NRS) 0-10. The higher the BASFI score, the more severe the limitation of function due to AxSpA 2. Morning stiffness 3. Patient global assessment 4. Pain
次要结局
- Ankylosing Spondylitis Disease Activity Score- C reactive protein(ASDASCRP)(At the end of 6 month)
- Ankylosing Spondylitis Disease Activity Score-Erythrocyte sedimentation rate(ASDASESR)(At the end of 6th month)
研究者
Dr.Md.Asadul Islam
Resident
Globe Pharmaceuticals Limited