Targeted Treatment Early With Etanercept Plus Methotrexate Versus T2T Care for DMARD-naïve Early RA Patients. A Prospective, Longitudinal Cohort Study With Embedded Pilot Randomised Controlled Trial to Assess Treatment Rationalisation Based on naïve T-cell Stratification.
试验速览
- 阶段
- 4 期
- 入组人数
- 106
- 试验地点
- 1
- 主要终点
- Clinical Remission at 24 weeks (Arms A vs B)
研究概览
简要总结
The main aim of the study is to determine the clinical utility of naive T-cell stratification for rationalising treatment with methotrexate (MTX), for DMARD-naive early RA patients. Thus, it aims to determine whether TNFi therapy (Benepali) instituted as first-line therapy in DMARD-naive early RA patients with poor T-cell prognostication confers better outcomes (clinical, structural and immunological). Hence, this would enable early targeted treatment for those with a poorer prognosis based on their immunological status.
详细描述
The current optimal therapeutic approach in early RA is to start MTX to target inflammation and induce remission.Prediction of MTX therapy response remains a key clinical need to enable the identification of patients who would benefit from an alternative, more aggressive treatment strategy. Multiple predictors of remission with MTX have been reported over the years but none have entered routine clinical practice.
We previously reported that T-cell phenotyping at baseline could predict remission in DMARD-naïve early RA treated with MTX. Reduced naïve CD4+ T-cell frequency was the most predictive factor, using both a pilot and a replication cohort.These data confirmed the potential value of using naïve CD4+ T-cells as a biomarker of MTX induced remission in early RA.
The clinical utility of measuring T-cell subsets is therefore strongly indicated by these data and suggests that measurement of T- cell subsets can be used to rationalise the use of MTX as first-line therapy.Predicting response to MTX has important clinical value to identify patients who will do well on MTX but furthermore for directing those who will have a sub-optimal response to MTX to receive alternative therapy without any harmful delay and in line with the treat to target principle.
The current study aims to confirm/validate the clinical value of T-cell subset quantification for the prediction of MTX response in early RA, by stratified interventions based on baseline naïve CD4+ T-cell status.
This is a Single centre, phase IV, open-label, prospective, longitudinal cohort study with an embedded pilot randomised controlled trial that aims to assess whether MTX can be rationalised as a first-line treatment for DMARD-naïve early RA patients, according to baseline naïve CD4+ T-cell stratification.
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
- 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
- •Subject has a diagnosis of RA as defined by the new ACR/EULAR 2010 classification criteria
- •Newly diagnosed (within 12 weeks)
- •Active disease at screening (DAS28ESR ≥3.2 or clinical evidence of synovitis)
- •Anti-citrillunated protein antibody (ACPA) positive
- •Male & female subjects ≥18 years old
- •DMARD (disease modifying anti-rheumatic drug) naïve
- •No use of intra-muscular, intra-articular or oral corticosteroids 4 weeks days prior to screening
- •All male and female subjects biologically capable of having children must agree to use a reliable method of contraception for the duration of the study and 24 weeks after the end of the study period. Acceptable methods of contraception are surgical sterilisation, oral, implantable or injectable hormonal methods, intrauterine devices or barrier contraceptives.
- •Patients must have the capacity and be willing to provide written informed consent and comply with the requirements of the protocol
- •Subjects should be deemed to be in good health with respect to clinical examination and screening blood tests, including full blood count (FBC), urea and electrolytes (U&E), and liver functions tests (LFT) - see exclusion criteria for further details
排除标准
- •Use of any additional investigational medications or products within 28 days of screening (including prior to screening)
- •Use of intra-muscular/intra-articular or oral corticosteroids within 28 days prior to screening
- •Use (including use as required) of more than one NSAID, change in NSAID or change in dose of NSAID within 28 days of the baseline visit.
- •Live vaccine within <28 days prior to screening
- •Pregnant/lactating women or planning pregnancy within 24 weeks of last protocol treatment
- •Planned surgery within the study period (requiring omission of study medication > 28 days
- •The presence of other comorbidities, which the physician deems as significant to interfere with evaluation (musculoskeletal condition such as osteoarthritis & fibromyalgia)
- •Diagnosis of another inflammatory arthritis or connective tissue disease (e.g. psoriatic arthritis or Ankylosing spondylitis, primary Sjogren's syndrome, systemic sclerosis, systemic lupus erythematosus, polymyositis)
- •Concomitant severe infection requiring intravenous therapy 4 weeks (28) days prior to screening
- •Any contraindication to conventional DMARD's/anti-TNF therapy
- •Patients with abnormal liver function at the time of screening or abnormal blood tests as shown by:
- •Aminotransferase (AST) / alanine aminotransferase (ALT) > 3x upper limit of normal (ULN) OR Bilirubin > 50µmol/L
- •Serum Creatinine > 175 umol/L
- •eGFR below 30ml/L/min/1.73m2
- •neutrophils < 2000 x 106/L
- •Platelets < 125 x 109/L
- •Haemoglobin < 90 g/L for males and < 85 g/L for females
研究组 & 干预措施
Abnormal T-cells: Benepali + T2T Care
Treatment Arm C will receive Benepali and methotrexate combination therapy and followed as per T2T care over a total duration of 24 weeks. Sulfasalazine or Hydroxychloroquine may be added to therapy at follow up visits in-line with T2T care.
Benepali will be administered subcutaneously at a dose of 50mg weekly and discontinued at the primary endpoint (24 weeks).
Methotrexate will be administered orally at a starting dose of 15mg weekly. It may be increased in line with T2T care (to a maximum of 25mg) over the 24 weeks.
干预措施: Benepali (Drug)
Abnormal T-cells: Benepali + T2T Care
Treatment Arm C will receive Benepali and methotrexate combination therapy and followed as per T2T care over a total duration of 24 weeks. Sulfasalazine or Hydroxychloroquine may be added to therapy at follow up visits in-line with T2T care.
Benepali will be administered subcutaneously at a dose of 50mg weekly and discontinued at the primary endpoint (24 weeks).
Methotrexate will be administered orally at a starting dose of 15mg weekly. It may be increased in line with T2T care (to a maximum of 25mg) over the 24 weeks.
干预措施: Methotrexate (Drug)
Abnormal T-cells: Methotrexate + T2T Care
Treatment Arm B will receive initial methotrexate monotherapy with adoption of a treat to target protocol (standard care involving monthly DAS28-ESR assessment with escalation to combination synthetic DMARD (Including sulfasalazine and/or hydroxychloroquine).
therapy if not achieving low disease activity (LDA) at, or after, 8 weeks).
干预措施: Sulfasalazine (Drug)
Abnormal T-cells: Methotrexate + T2T Care
Treatment Arm B will receive initial methotrexate monotherapy with adoption of a treat to target protocol (standard care involving monthly DAS28-ESR assessment with escalation to combination synthetic DMARD (Including sulfasalazine and/or hydroxychloroquine).
therapy if not achieving low disease activity (LDA) at, or after, 8 weeks).
干预措施: Methotrexate (Drug)
Abnormal T-cells: Methotrexate + T2T Care
Treatment Arm B will receive initial methotrexate monotherapy with adoption of a treat to target protocol (standard care involving monthly DAS28-ESR assessment with escalation to combination synthetic DMARD (Including sulfasalazine and/or hydroxychloroquine).
therapy if not achieving low disease activity (LDA) at, or after, 8 weeks).
干预措施: Hydroxychloroquine (Drug)
Normal T-cells: Methotrexate + T2T Care
Treatment Arm A will receive standard T2T care as per Arm B.
干预措施: Sulfasalazine (Drug)
Normal T-cells: Methotrexate + T2T Care
Treatment Arm A will receive standard T2T care as per Arm B.
干预措施: Methotrexate (Drug)
Normal T-cells: Methotrexate + T2T Care
Treatment Arm A will receive standard T2T care as per Arm B.
干预措施: Hydroxychloroquine (Drug)
结局指标
主要结局
Clinical Remission at 24 weeks (Arms A vs B)
时间窗: 24 weeks
The difference in the proportions of patients in clinical remission (DAS28ESR ≤2.6) at 24 weeks of first-line methotrexate with T2T care between those with normal (Arm A) vs. abnormal (Arm B) naïve CD4+ T-cell frequencies
次要结局
- Clinical Remission at 12 weeks (Arms A vs B)(12 weeks)
- Clinical Remission at 12 and 24 weeks (Arms B vs C)(12 and 24 weeks)
- Sustained Clinical Remission(12 and 24 weeks)
- Patient Reported Outcomes at 12 and 24 weeks (Arm A vs B)(12 and 24 weeks)
- Patient Reported Outcomes at 12 and 24 weeks (Arm B vs C)(12 and 24 weeks)
- Imaging Remission at 24 weeks (Arm A vs B)(24 weeks)
- Imaging Remission at 24 weeks (Arm B vs C)(24 weeks)
- Immunological Remission(24 weeks)
- Cumulative Steroid Use(24 weeks)