Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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: A randomized, actively controlled, open-label, assessor-blinded, multicenter 48 weeks phase IV trial. The study design includes an optional sub-study collecting tissue samples using ultrasound-guided synovial biopsies, bronchoalveolar lavage and Particles in Exhaled Air (PExA). Study population and intervention: Patients with early untreated RA with active and seropositive disease will be eligible for screening and the performance of high-resolution computed tomography (HRCT). Subjects with pulmonary abnormalities suggestive of RA-ILD will be randomized (1:1) to tofacitinib 5 mg BID (group 1) or standard-of-care methotrexate 20 mg weekly (group 2) for 48 weeks. All patients receive prednisone with tapering for 6 weeks. Patients with incomplete response at 24 weeks will escalate to combination therapy with tofacitinib+methotrexate (group 3). Intra-articular injections of cortisone will be allowed during the study. 145 subjects will be included and screened (part 1), and approximately 48 subjects will be randomized to active treatment (part 2).

Official Title
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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

Conditions
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Rheumatoid Arthritis, Interstitial Lung Disease Due to Systemic Disease (Disorder), RA, ILD

Intervention / Treatment
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* Drug: Tofacitinib
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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 SCOREx1,5. Multiple incidental solid/subsolid lung nodules of size ≥6 mm, single incidental solid lung nodules ≥8 mm.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A study in two parts: Screening with HRCT. Patients will be stratified based on the the findings to: cohort A, with pulmonary abnormalities; and cohort B, with normal findings (who will end further participation in the main trial). Randomization of cohort A to 48 weeks of active treatment. Parallel group design from baseline to week 24.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tofacitinib<br>Oral tablet tofacitinib 5 mg BID for 48 weeks | Drug: Tofacitinib<br>* Open-label tofacitinib for 48 weeks. All subjects (both arms) receive prednisone starting at 20 mg QD with tapering for 6 weeks. Patients with incomplete response at 24 weeks will escalate to combination therapy with tofacitinib 5 mg BID + methotrexate 20 mg weekly up to week 48.<br>* Other names: Xeljanz;|
| Active Comparator: Methotrexate<br>Oral tablet methotrexate 2.5 mg: 8 tablets in one dose (=20 mg) once weekly for 48 weeks | Drug: Methotrexate<br>* Open-label methotrexate for 48 weeks. All subjects (both arms) receive prednisone starting at 20 mg QD with tapering for 6 weeks. Patients with incomplete response at 24 weeks will escalate to combination therapy with tofacitinib 5 mg BID + methotrexate 20 mg weekly up to week 48.<br>* Other names: metotrexat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total interstitial disease score of pulmonary abnormalities by HRCT | 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. | Baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in extent of parenchymal lung disease by HRCT pattern | The extent of the separate parenchymal pattern (Ground glass/reticulations/honey-combing/consolidations/emphysema) by HRCT measured as percentage of pattern area to total lung area at six different anatomical level. | Baseline and 24 weeks | 
| Change in extent of parenchymal lung disease by HRCT pattern | The extent of the separate parenchymal pattern (Ground glass/reticulations/honey-combing/consolidations/emphysema) by HRCT measured as percentage of pattern area to total lung area at six different anatomical level. | Baseline and 48 weeks | 
| Change in Forced Vital Capacity (FVC) | FVC will be measured by spirometry. The proportion of patients with FVC 24wks ≤ FVC baseline will also be calculated. | Baseline and 24 weeks | 
| Change in Diffusion Capacity of Carbon Monoxide (DLCO) | DLCO will be measured according to standard protocol and corrected for haemoglobulin level. Diffusion capacity divided by alveolar volume (DLCO/VA) will also be calculated. | Baseline and 24 weeks | 
| Change in walking distance (meters) | 6-minutes walking test Diffusion capacity divided by alveolar volume (DLCO/VA) will also be calculated. | Baseline and 24 weeks | 
| Change in blood oxygen saturation (SpO2) after 6-minutes walking | 6-minutes walking test with pulse oximetry recording Diffusion capacity divided by alveolar volume (DLCO/VA) will also be calculated. | Baseline and 24 weeks | 
| Patient reported outcome of breathing and airway symptoms | Patient reported outcomes of breathing and airway symptoms will be evaluated using Saint George's Respiratory Questionnaire. | baseline, 24 and 48 weeks | 
| Disease activity score of rheumatoid arthritis (DAS28-CRP) | DAS28-CRP will be calculated as follows: 0.56*√(TJC28) +0.28*√(SJC28)+0.014*PaGH+0.36*ln(CRP+1)+0.96. TJC = number of tender joints of 28, SJC= number of swollen joints of 28, CRP=c-reactive protein level and PaGH=Patient reported global impact of disease on health on a VAS scale (0-100) | baseline, 12, 24 and 48 weeks | 
| Patient reported health assessment of physical function (HAQ index) | Patient reported function assessed by a validated questionnaire HAQ = health assessment questionnaire. The assessment gives a value/index between 0 - 3.0. | baseline, 24 and 48 weeks | 
| Proportion of patients in rheumatoid arthritis DAS remission | DAS28 remission is defined as DAS28<2.6. | 24 and 48 weeks | 
| Frequency of adverse events (AE) | Number of AE per category and serious AE will be calculated for the different treatment groups | baseline, 24 and 48 weeks | 
| Patient reported global disease activity | Patient reported global impact of disease on health on a VAS scale (0-100 mm) | baseline, 12, 24 and 48 weeks | 
| Proportion of patients in rheumatoid arthritis ACR-EULAR Boolean remission | Boolean RA remission is defined as: SJC, TJC, PaGH and CRP, all ≤1. TJC = number of tender joints of 28, SJC= number of swollen joints of 28 and PaGH=Patient reported global impact of disease on health on a VAS scale (0-10) | 24 and 48 weeks | 
| Clinical disease activity score of rheumatoid arthritis (CDAI) | Clinical disease activity score of rheumatoid arthritis (CDAI) is calculated as follows: SJC + TJC + PaGH + PhGH. TJC = number of tender joints of 28, SJC= number of swollen joints of 28, PaGH=Patient reported global impact of disease on health on a VAS scale (0-10) and PhGH=physician assessment of global impact of disease on health of patient on a VAS scale (0-10). CDAI ranges from 0 - 76. | baseline, 12, 24 and 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, Interstitial lung disease, Janus Kinase inhibition, tofacitinib, methotrexate