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Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease (PULMORA)

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ClinicalTrials.gov Identifier: NCT04311567
Recruitment Status : Recruiting
First Posted : March 17, 2020
Last Update Posted : February 25, 2021
Sponsor:
Collaborator:
Göteborg University
Information provided by (Responsible Party):
Vastra Gotaland Region

Tracking Information
First Submitted Date  ICMJE March 5, 2020
First Posted Date  ICMJE March 17, 2020
Last Update Posted Date February 25, 2021
Actual Study Start Date  ICMJE November 7, 2020
Estimated Primary Completion Date May 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2020)
Change in total interstitial disease score of pulmonary abnormalities by HRCT [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 22, 2021)
  • Change in extent of parenchymal lung disease by HRCT pattern [ Time Frame: Baseline and 24 weeks ]
    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.
  • Change in extent of parenchymal lung disease by HRCT pattern [ Time Frame: Baseline and 48 weeks ]
    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.
  • Change in Forced Vital Capacity (FVC) [ Time Frame: Baseline and 24 weeks ]
    FVC will be measured by spirometry. The proportion of patients with FVC 24wks ≤ FVC baseline will also be calculated.
  • Change in Diffusion Capacity of Carbon Monoxide (DLCO) [ Time Frame: Baseline and 24 weeks ]
    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.
  • Change in walking distance (meters) [ Time Frame: Baseline and 24 weeks ]
    6-minutes walking test Diffusion capacity divided by alveolar volume (DLCO/VA) will also be calculated.
  • Change in blood oxygen saturation (SpO2) after 6-minutes walking [ Time Frame: Baseline and 24 weeks ]
    6-minutes walking test with pulse oximetry recording Diffusion capacity divided by alveolar volume (DLCO/VA) will also be calculated.
  • Patient reported outcome of breathing and airway symptoms [ Time Frame: baseline, 24 and 48 weeks ]
    Patient reported outcomes of breathing and airway symptoms will be evaluated using Saint George's Respiratory Questionnaire.
  • Disease activity score of rheumatoid arthritis (DAS28-CRP) [ Time Frame: baseline, 12, 24 and 48 weeks ]
    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)
  • Patient reported health assessment of physical function (HAQ index) [ Time Frame: baseline, 24 and 48 weeks ]
    Patient reported function assessed by a validated questionnaire HAQ = health assessment questionnaire. The assessment gives a value/index between 0 - 3.0.
  • Proportion of patients in rheumatoid arthritis DAS remission [ Time Frame: 24 and 48 weeks ]
    DAS28 remission is defined as DAS28<2.6.
  • Frequency of adverse events (AE) [ Time Frame: baseline, 24 and 48 weeks ]
    Number of AE per category and serious AE will be calculated for the different treatment groups
  • Patient reported global disease activity [ Time Frame: baseline, 12, 24 and 48 weeks ]
    Patient reported global impact of disease on health on a VAS scale (0-100 mm)
  • Proportion of patients in rheumatoid arthritis ACR-EULAR Boolean remission [ Time Frame: 24 and 48 weeks ]
    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)
  • Clinical disease activity score of rheumatoid arthritis (CDAI) [ Time Frame: baseline, 12, 24 and 48 weeks ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2020)
  • Change in extent of parenchymal lung disease by HRCT pattern [ Time Frame: Baseline and 24 weeks ]
    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.
  • Change in extent of parenchymal lung disease by HRCT pattern [ Time Frame: Baseline and 48 weeks ]
    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.
  • Change in Forced Vital Capacity (FVC) [ Time Frame: Baseline and 24 weeks ]
    FVC will be measured by spirometry. The proportion of patients with FVC 24wks ≤ FVC baseline will also be calculated.
  • Change in Diffusion Capacity of Carbon Monoxide (DLCO) [ Time Frame: Baseline and 24 weeks ]
    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.
  • Patient reported outcome of breathing and airway symptoms [ Time Frame: baseline, 24 and 48 weeks ]
    Patient reported outcomes of breathing and airway symptoms will be evaluated using Saint George's Respiratory Questionnaire.
  • Disease activity score of rheumatoid arthritis (DAS28-CRP) [ Time Frame: baseline, 12, 24 and 48 weeks ]
    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)
  • Patient reported health assessment of physical function (HAQ index) [ Time Frame: baseline, 24 and 48 weeks ]
    Patient reported function assessed by a validated questionnaire HAQ = health assessment questionnaire. The assessment gives a value/index between 0 - 3.0.
  • Proportion of patients in rheumatoid arthritis DAS remission [ Time Frame: 24 and 48 weeks ]
    DAS28 remission is defined as DAS28<2.6.
  • Frequency of adverse events (AE) [ Time Frame: baseline, 24 and 48 weeks ]
    Number of AE per category and serious AE will be calculated for the different treatment groups
  • Patient reported global disease activity [ Time Frame: baseline, 12, 24 and 48 weeks ]
    Patient reported global impact of disease on health on a VAS scale (0-100 mm)
  • Proportion of patients in rheumatoid arthritis ACR-EULAR Boolean remission [ Time Frame: 24 and 48 weeks ]
    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)
  • Clinical disease activity score of rheumatoid arthritis (CDAI) [ Time Frame: baseline, 12, 24 and 48 weeks ]
    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.
Current Other Pre-specified Outcome Measures
 (submitted: February 22, 2021)
  • Change in cellular activity profile of clinical samples [ Time Frame: baseline and 24 weeks ]
    Exploratory sub-study: Frequencies (% of total cell populations) of subtypes of immune- and stroma cells (defined by a core set of cell surface markers) isolated from synovial biopsies and broncho-alveolar lavage samples and evaluated by flowcytometry
  • Change in molecular activity profile of clinical samples [ Time Frame: Baseline and 24 weeks ]
    Exploratory sub-study: Gene expression of bulk tissue and sorted cells of synovial biopsies and broncho-alveolar lavage samples by RNA sequencing. Levels of cytokines (IL-1β, IFN-α2, IFN-γ, TNF-α, IL-6, IL-8 (CXCL8), IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33), chemokines (CCL2, CCL3, CCL4, CCL5, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11) and growth factors (GM-CSF, PDGF and TGFbeta1) of synovial fluid, blood and broncho-alveolar lavage will be determined by bead-based immunoassay. Clinical fluid droplet samples containing lipids and proteins from small airways will be collected on a membrane using a novel non-invasive method - Particles in Exhaled Air (PExA) and analyzed using mass spectrometry.
Original Other Pre-specified Outcome Measures
 (submitted: March 15, 2020)
  • Change in cellular activity profile of clinical samples [ Time Frame: baseline and 24 weeks ]
    Exploratory sub-study: Frequencies (% of total cell populations) of subtypes of immune- and stroma cells (defined by a core set of cell surface markers) isolated from synovial biopsies and broncho-alveolar lavage samples and evaluated by flowcytometry
  • Change in molecular activity profile of clinical samples [ Time Frame: Baseline and 24 weeks ]
    Exploratory sub-study: Gene expression of bulk tissue and sorted cells of synovial biopsies and broncho-alveolar lavage samples by RNA sequencing. Levels of cytokines (IL-1β, IFN-α2, IFN-γ, TNF-α, IL-6, IL-8 (CXCL8), IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33), chemokines (CCL2, CCL3, CCL4, CCL5, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11) and growth factors (GM-CSF, PDGF and TGFbeta1) of synovial fluid, blood and broncho-alveolar lavage will be determined by bead-based immunoassay.
 
Descriptive Information
Brief Title  ICMJE Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease
Official Title  ICMJE 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
Brief Summary 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

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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A study in two parts:

  1. 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).
  2. Randomization of cohort A to 48 weeks of active treatment. Parallel group design from baseline to week 24.
Masking: Single (Outcomes Assessor)
Masking Description:
Blinded assessors of lung evaluation with HRCT and joint evaluation with joint counts (number of tender and swollen joints)
Primary Purpose: Treatment
Condition  ICMJE
  • Rheumatoid Arthritis
  • Interstitial Lung Disease Due to Systemic Disease (Disorder)
  • RA
  • ILD
Intervention  ICMJE
  • Drug: Tofacitinib
    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.
    Other Name: Xeljanz
  • Drug: Methotrexate
    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.
    Other Name: metotrexat
Study Arms  ICMJE
  • Experimental: Tofacitinib
    Oral tablet tofacitinib 5 mg BID for 48 weeks
    Intervention: Drug: Tofacitinib
  • Active Comparator: Methotrexate
    Oral tablet methotrexate 2.5 mg: 8 tablets in one dose (=20 mg) once weekly for 48 weeks
    Intervention: Drug: Methotrexate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 15, 2020)
48
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 30, 2024
Estimated Primary Completion Date May 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. The subject has given written consent to participate in the study.
  2. 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.
  3. 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.
  4. Active disease with ≥2 painful and ≥2 swollen joints in 66/68 joints and CRP ≥2.0 mg/dl
  5. Aged 18-80 years
  6. Willing to undergo HRCT and pulmonary function tests (PFTs)

Exclusion Criteria:

  1. Current active inflammatory joint disease other than RA.
  2. 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.
  3. 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.
  4. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
  5. 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.
  6. 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.
  7. Pregnant or lactating women.
  8. Positive tests for hepatitis B (HBsAg or HBV DNA) or hepatitis C serology.
  9. History of herpes zoster infection during last 10 years.
  10. History of venous thromboembolism or diverticulitis.
  11. Positive tuberculosis history and/or positive Quantiferon test.
  12. Hemoglobin <90 g/L.
  13. Absolute neutrophil count < 1500 cells/uL.
  14. ASAT or ALAT >2.0 times the upper limit of normal.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Study Coordinator +46-31-3428639 marie-louise.andersson@vgregion.se
Contact: Eva Klingberg, MD PhD +46-31-3427745 eva.klingberg@vgregion.se
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04311567
Other Study ID Numbers  ICMJE EudraCT 2019-004179-38
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Vastra Gotaland Region
Study Sponsor  ICMJE Vastra Gotaland Region
Collaborators  ICMJE Göteborg University
Investigators  ICMJE
Principal Investigator: Anna-Karin H Ekwall, MD MSc PhD The Sahlgrenska University Hospital and University of Gothenburg
PRS Account Vastra Gotaland Region
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP