Effects of Tofacitinib vs Methotrexate on Clinical and Molecular Disease Activity Markers in Joints and Lungs in Early Rheumatoid Arthritis (PULMORA) - A Randomized, Controlled, Open-label, Assessor-blinded, Phase IV Trial
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 发起方
- 入组人数
- 3
- 试验地点
- 3
- 主要终点
- Change in total interstitial disease score of pulmonary abnormalities by HRCT
研究概览
简要总结
Pulmonary abnormalities are present in up to 60% of patients with early rheumatoid arthritis (RA), and up to 10% of the patients will develop clinical interstitial lung disease (ILD). Recent data indicate that inhibition of Janus kinase is beneficial for this extra-articular manifestation. Our goal is to determine whether tofacitinib is an effective and safe treatment, compared to standard-of-care methotrexate, for subclinical and clinical ILD in patients with early RA. The study also explores disease mechanisms in lungs and joints, to identify potential biomarkers for diagnosis, prognosis, and response to treatment of RA-ILD.
详细描述
Study objectives:
Primary objective: Effects of tofacitinib compared to that of methotrexate on interstitial pulmonary abnormalities at 24 weeks.
Secondary objectives: Effects of tofacitinib compared to that of methotrexate on pulmonary abnormalities and function, RA disease activity and remission rates and patient reported outcome measures at different time points. Frequency of adverse events.
Exploratory objectives: Effects of tofacitinib compared to that of methotrexate on cellular and molecular activity profiles of clinical samples from joints and lungs.
Study design:
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
- Single (Outcomes Assessor)
盲法说明
Blinded assessors of lung evaluation with HRCT and joint evaluation with joint counts (number of tender and swollen joints)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of seropositive (i.e., presence of RF and/or anti-CCP antibodies) rheumatoid arthritis (RA) according to the ACR/EULAR 2010 criteria within 24 months.
- •No previous treatment with disease modifying anti-rheumatic drugs (DMARDs). History of prednisone use is allowed but should have been discontinued 2 weeks before baseline measurement.
- •Active disease with ≥2 painful and ≥2 swollen joints in 66/68 joints and CRP ≥2.0 mg/L
- •Aged 18-80 years
- •The subject has given written consent to participate in the study.
排除标准
- •Current active inflammatory joint disease other than RA.
- •Significant and/or uncontrolled cardiac, pulmonary disease, nervous system, renal, hepatic, endocrine or gastrointestinal disorders or severe RA which in the investigator's opinion would preclude patient participation.
- •Malignancy within the past 5 years, except for successfully treated cervical carcinoma in situ, basal cell and squamous cell carcinoma of the skin, with no evidence of recurrence or metastatic disease for at least 3 years.
- •Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
- •Pregnant or lactating women.
- •For subjects in part II the following exclusion criteria also apply:
- •Women of childbearing potential not willing or able to use highly effective methods of birth control per ICH M3 (R2) for 28 days prior and 3 months after end of study.
- •Active infection (excluding fungal infections of nail beds) requiring i.v. anti-infectives within 4 weeks, or oral anti-infectives within 2 weeks prior to baseline.
- •Positive tests for hepatitis B (HBsAg or HBV DNA),hepatitis C serology or SARS-CoV2
- •History of herpes zoster infection during last 10 years.
- •History or risk of venous thromboembolism or diverticulitis.
- •Positive tuberculosis history and/or positive Quantiferon test.
- •Hemoglobin <90 g/L.
- •Absolute neutrophil count < 1500 cells/uL.
- •ASAT or ALAT >2.0 times the upper limit of normal.
- •High or very high risk (≥ 5%) of cardiovascular death within 10 years by SCOREx1,
- •Multiple incidental solid/subsolid lung nodules of size ≥6 mm, single incidental solid lung nodules ≥8 mm.
研究组 & 干预措施
Tofacitinib
Oral tablet tofacitinib 5 mg BID for 48 weeks
干预措施: Tofacitinib (Drug)
Methotrexate
Oral tablet methotrexate 2.5 mg: 8 tablets in one dose (=20 mg) once weekly for 48 weeks
干预措施: Methotrexate (Drug)
结局指标
主要结局
Change in total interstitial disease score of pulmonary abnormalities by HRCT
时间窗: Baseline and 24 weeks
Total interstitial disease score will be calculated as the mean of six (anatomical levels) interstitial disease scores. Each level's interstitial disease score will be calculated as the sum of the extent of five different parenchymal patterns (Ground glass, reticulations, honey-combing, consolidations and emphysema) measured as percentage of pattern area to total lung area at a specified anatomical level.
次要结局
- Change in extent of parenchymal lung disease by HRCT pattern(Baseline and 48 weeks)
- Change in Forced Vital Capacity (FVC)(Baseline and 24 weeks)
- Change in Diffusion Capacity of Carbon Monoxide (DLCO)(Baseline and 24 weeks)
- Change in walking distance (meters)(Baseline and 24 weeks)
- Change in blood oxygen saturation (SpO2) after 6-minutes walking(Baseline and 24 weeks)
- Patient reported outcome of breathing and airway symptoms(baseline, 24 and 48 weeks)
- Disease activity score of rheumatoid arthritis (DAS28-CRP)(baseline, 12, 24 and 48 weeks)
- Patient reported health assessment of physical function (HAQ index)(baseline, 24 and 48 weeks)
- Proportion of patients in rheumatoid arthritis DAS remission(24 and 48 weeks)
- Frequency of adverse events (AE)(baseline, 24 and 48 weeks)
- Patient reported global disease activity(baseline, 12, 24 and 48 weeks)
- Proportion of patients in rheumatoid arthritis ACR-EULAR Boolean remission(24 and 48 weeks)
- Clinical disease activity score of rheumatoid arthritis (CDAI)(baseline, 12, 24 and 48 weeks)