Capability of Tofacitinib or Etanercept to Accelerate Clinical Relevant Tapering of Non-steroidal Anti-inflammatory Drugs (NSAID) and Treat-to-target Guided De-escalation of Corticosteroids in Patients With Active Rheumatoid Arthritis (RA) and an Inadequate Response to Previous csDMARD Therapy (AcceleRAte)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 92
- 试验地点
- 6
- 主要终点
- Discontinuation of Celecoxib treatment and clinically relevant improvement in pain
研究概览
简要总结
Patients with active rheumatic arthritis (RA) and lack of efficacy of at least one csDMARD (Disease-modifying anti-rheumatic drug) treatment will be randomized to receive either Tofacitinib (TOFA) or etanercept (ETA). The study will be separated into two parts: The capability to decrease and discontinue pain-reducing treatment with a NSAID (non-steroidal anti-inflammatory drug) over the first 12 weeks of treatment will be measured for primary outcome measured using a visual analogue scale (VAS) at week 12 compared to baseline between the two treatment groups.
Starting at week 12, the capability to taper corticosteroid (CS) treatment using a treat-to-target strategy, i.e. when at least low disease activity (LDA-DAS28) is achieved, will be measured in both groups.
详细描述
In this clinical study, a design was chosen to reflect European standards recommended by EULAR for treatment of active RA by comparison of a Treat-to- target (T2T) approach in two treatment groups: Patients with active RA and lack of efficacy of at least one csDMARD treatment will be randomized to receive either TOFA or ETA. The study will be separated into two parts: The capability to decrease and discontinue pain-reducing treatment with a NSAID (Celecoxib, two times 200 mg as maximum standard dosage for RA) over the first 12 weeks of treatment will be measured for primary outcome. The proportion of patients with successful discontinuation of Celecoxib and significant and clinical relevant decrease of pain-levels measured using a visual analogue scale (VAS) with a reduction of at least 30% at week 12 compared to baseline will be compared between the two treatment groups.
Starting at week 12, the capability to taper CS treatment using a treat-to-target strategy, i.e. when at least low disease activity (LDA-DAS28) is achieved, will be measured in both groups. In addition to efficacy assessments (DAS28, ACR-response, SJC, TJC), patient reported outcomes, Quality of Life (QoL) measurements and patient satisfaction will be evaluated. Safety (severity and frequency of adverse events) will be evaluated over the 24-week treatment period.
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with active RA and an inadequate response to up to two previous conventional synthetic Disease modifying anti-rheumatic drug (csDMARD) treatments (methotrexate (MTX), leflunomide (LEF),sulfasalazine (SSZ)) with or without ongoing csDMARD therapy
- •RA according to ACR classification criteria
- •Age 18 - 65 years
- •Active RA is defined as
- •DAS28 > 3.2 and
- •TJC ≥ 3 and SJC ≥ 3
- •VAS-pain ≥ 60 mm (0-100 mm)
- •Accompanying CS treatment for RA with a stable dosage of ≥ 2mg/d and ≤ 10 mg/d 2 weeks prior to BL (not more than 30% of patients without CS)
- •Accompanying need of NSAID or analgesic treatment due to arthritis and in dosages not exceeding the maximum dose according to Summary of Product characteristics (SmPC)
- •If ongoing csDMARD treatment, stable treatment will be defined as either
- •MTX treatment with a dosage of ≥ 10 mg/week and ≤ 25 mg/week, continuously for at least 12 weeks prior to Screening (SCR) with a stable dose of MTX for at least 2 weeks prior to BL or
- •LEF treatment with a dosage between 10 to 20 mg/day, continuously for at least 12 weeks prior to SCR with a stable dose of LEF for at least 2 weeks prior to BL or
- •SSZ treatment with dosage between 1 to 3 g/day, continuously for at least 12 weeks prior to SCR with a stable dose of SSZ for at least 2 weeks prior to BL
- •Presence of documented negative results for testing of Hepatitis B and C
- •Completed SARS-CoV-2-immunisation as currently recommended by the Standing Committee of Vaccination
- •Written informed consent obtained prior to the initiation of any protocol-required procedures
- •Willingness to comply to study procedures and study protocol
排除标准
- •Previous use of Tofacitinib or other Janus-Kinase (JAK)-inhibitors
- •Previous use of Etanercept
- •Previous use of any biological agent for RA
- •which was stopped due to lack of efficacy
- •one previous use of biological stopped due to intolerance will be allowed
- •CS treatment with dosages >10 mg at BL
- •Known hypersensitivity to any component of the study medication (TOFA, ETA, Celecoxib)
- •Previous use of Celecoxib as analgesic therapy which was stopped due to lack of efficacy or intolerance
- •Concomitant diseases with chronic pain syndrome or need of extended dosages or long-term treatment with the maximum dosages of NSAID/analgesics (according to SmPC) due to other concomitant diseases/pain symptoms in discretion of the treating physician Exclusion criteria related to general health
- •Patients with other chronic inflammatory articular disease or systemic autoimmune disease
- •Patients with active Tuberculosis (Tb) (evaluation of Tb according to local standards in clinical care)
- •Patients with latent Tb, that are not pre-treated for at least 1 month and planned to be treated 9 months in total with Isozid once a day
- •Any active infection, a history of recurrent clinically significant infections (e.g. human immune deficiency virus (HIV)), or a history of recurrent bacterial infections with encapsulated organisms
- •Primary or secondary immunodeficiency
- •Current malignancy or history of malignancies except adequately treated or excised basal cell or squamous cell carcinoma or cervical carcinoma in situ.
- •Patients of 50 years and older, if they have one or more cardiovascular risk factors (CVRF) defined as:
- •Current cigarette smoking,
- •Known diagnosis of hypertension,
- •HDL <40 mg/dl,
- •Diabetes mellitus,
- •History of coronary artery disease: history of revascularization procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome or
- •History of premature coronary heart disease or sudden death documented in first degree relatives (male relative before 55 years, female relative before 65 years)
- •Evidence of significant uncontrolled concomitant diseases or serious and/or uncontrolled diseases that are likely to interfere with the evaluation of the patient's safety and with the study outcome
- •History of a severe psychological illness or condition
- •Known hypersensitivity to sulfonamides
- •Active peptic ulceration or gastrointestinal (GI) bleeding
- •Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or other NSAIDs including Cyclooxigenase (COX)-2 inhibitors
- •Risk for or history of thrombotic events (e.g. pulmonary embolism or thrombosis) Severe hepatic dysfunction (serum albumin < 25 g/L or Child-Pugh score ≥ 10)
- •Patients with estimated creatinine clearance < 30 mL/min
- •Inflammatory bowel disease
- •Congestive heart failure (New York Heart Association (NYHA) II-IV)
- •Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease
- •Women lactating, pregnant, nursing or of childbearing potential with a positive pregnancy test
- •Males or females of reproductive potential not willing to use effective contraception (e.g. contraceptive pill, intrauterine device (IUD), physical barrier)
- •Alcohol, drug or chemical abuse Exclusion criteria related to prior treatments
- •Current participation in another interventional clinical trial or participation within the last 90 days Exclusion criteria related to formal aspects
- •Underage or incapable patients
研究组 & 干预措施
Tofacitinib
Tofacitinib (Xeljanz®; 5 mg twice daily, p.o.)
干预措施: Tofacitinib (Drug)
Etanercept
Etanercept (Enbrel®; 50 mg once per week, s.c.)
干预措施: Etanercept (Biological)
结局指标
主要结局
Discontinuation of Celecoxib treatment and clinically relevant improvement in pain
时间窗: Baseline to week 12
Proportion of patients who can discontinue Celecoxib treatment and in whom clinically relevant improvement in pain levels are measured, defined as reduction in VAS pain of ≥ 30%
次要结局
- re-started NSAID treatment(week 12 to week 24)
- Absolute pain levels(at week 24)
- relative (percent) pain levels(at week 24)
- Change in pain levels(at week 24)
- Determination of flares(between week 12 and week 24)
- Proportion of LDA(at week 24)
- Proportion of DAS remission(at week 24)
- Proportion of ACR20 response(at week 24)
- Proportion of ACR 50 response(at week 24)
- Proportion of ACR 70 response(at week 24)
- Changes in ACR core set(at week 24)
- DAS28 (ESR)(at week 24)
- SJC (66),(at week 24)
- TJC (68)(at week 24)
- Quality of Life: SF36 (36 items short form health survey)(at week 24)
- Change in Quality of Life: SF36 (36 items short form health survey)(at week 24)
- Quality of Life HAQ-DI (health assessment questionnaire - disability index)(at week 24)
- Change in Quality of Life HAQ-DI (health assessment questionnaire - disability index)(at week 4)
- Change of Quality of Life HAQ-DI (health assessment questionnaire - disability index)(at week 24)
- Correlation of SF36 and HAQ-DI results(through study completion, an average of 24 weeks)
- Treatment satisfaction: TSQM-14 scores(at week 24)
- Patient's expectation on treatment(at week 24)
- Correlation of TSQM-14 results and patient's expectation on treatment(through study completion, an average of 24 weeks)
- drug accountability(at week 24)
- eGFR (estimated glomerular filtration rate)(at week 24)
- change in eGFR (estimated glomerular filtration rate)(at week 24)
- blood pressure (mmHg)(at week 24)
- change in blood pressure (mmHg)(at week 24)
- pain characteristics measured by QST (quantitative sensory testing)(at week 24)
- adverse events (AEs)(through study completion, an average of 24 weeks)
- Infections(through study completion, an average of 24 weeks)
- Documentation of all lab abnormalities(through study completion, an average of 24 weeks)
- Cardiovascular events(through study completion, an average of 24 weeks)
- Malignencies(through study completion, an average of 24 weeks)
- Mean dosage of Celecoxib in patients(at 12 weeks)
- NSAID treatment(at week 24)
- discontinuation of CS-treatment(at week 24)
- rescue treatment(at week 12)
- Mean dosage of Corticosteroids (CS) in the patients who achieve Low Disease activity (LDA) in the two treatment groups(at week 24)
- Mean dosage of Corticosteroids (CS)(at week 24)
研究者
Dr. Frank Behrens
Representative of the Sponsor
Fraunhofer Institute for Molecular Biology and Applied Ecology