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

Primary Purpose

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

Status

Recruiting

Phase

Phase 4

Locations

Sweden

Study Type

Interventional

Intervention

Tofacitinib

Methotrexate

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Rheumatoid arthritis, Interstitial lung disease, Janus Kinase inhibition, tofacitinib, methotrexate

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Skåne University Hospital, Department of Rheumatology
Clinical Rheumatology Research Center, The Sahlgrenska University HospitalRecruiting
Karolinska University Hospital, Department of Rheumatology

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tofacitinib

Methotrexate

Arm Description

Oral tablet tofacitinib 5 mg BID for 48 weeks

Oral tablet methotrexate 2.5 mg: 8 tablets in one dose (=20 mg) once weekly for 48 weeks

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Change in extent of parenchymal lung disease by HRCT pattern

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.

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.

Change in walking distance (meters)

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

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

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)

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)

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

DAS28 remission is defined as DAS28<2.6.

Frequency of adverse events (AE)

Number of AE per category and serious AE will be calculated for the different treatment groups

Patient reported global disease activity

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

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)

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.

Full Information

NCT ID

NCT04311567

First Posted

March 5, 2020

Last Updated

April 26, 2022

Sponsor

Vastra Gotaland Region

Collaborators

Göteborg University

1. Study Identification

Unique Protocol Identification Number

NCT04311567

Brief Title

Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease

Acronym

PULMORA

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Recruiting

Study Start Date

November 7, 2020 (Actual)

Primary Completion Date

May 30, 2024 (Anticipated)

Study Completion Date

November 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Vastra Gotaland Region

Collaborators

Göteborg University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Rheumatoid arthritis, Interstitial lung disease, Janus Kinase inhibition, tofacitinib, methotrexate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

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

Outcomes Assessor

Masking Description

Blinded assessors of lung evaluation with HRCT and joint evaluation with joint counts (number of tender and swollen joints)

Allocation

Randomized

Enrollment

48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Tofacitinib

Arm Type

Experimental

Arm Description

Oral tablet tofacitinib 5 mg BID for 48 weeks

Arm Title

Methotrexate

Arm Type

Active Comparator

Arm Description

Oral tablet methotrexate 2.5 mg: 8 tablets in one dose (=20 mg) once weekly for 48 weeks

Intervention Type

Drug

Intervention Name(s)

Tofacitinib

Other Intervention Name(s)

Xeljanz

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Methotrexate

Other Intervention Name(s)

metotrexat

Intervention Description

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.

Primary Outcome Measure Information:

Title

Change in total interstitial disease score of pulmonary abnormalities by HRCT

Description

Time Frame

Baseline and 24 weeks

Secondary Outcome Measure Information:

Title

Change in extent of parenchymal lung disease by HRCT pattern

Description

Time Frame

Baseline and 24 weeks

Title

Change in extent of parenchymal lung disease by HRCT pattern

Description

Time Frame

Baseline and 48 weeks

Title

Change in Forced Vital Capacity (FVC)

Description

FVC will be measured by spirometry. The proportion of patients with FVC 24wks ≤ FVC baseline will also be calculated.

Time Frame

Baseline and 24 weeks

Title

Change in Diffusion Capacity of Carbon Monoxide (DLCO)

Description

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.

Time Frame

Baseline and 24 weeks

Title

Change in walking distance (meters)

Description

6-minutes walking test Diffusion capacity divided by alveolar volume (DLCO/VA) will also be calculated.

Time Frame

Baseline and 24 weeks

Title

Change in blood oxygen saturation (SpO2) after 6-minutes walking

Description

6-minutes walking test with pulse oximetry recording Diffusion capacity divided by alveolar volume (DLCO/VA) will also be calculated.

Time Frame

Baseline and 24 weeks

Title

Patient reported outcome of breathing and airway symptoms

Description

Patient reported outcomes of breathing and airway symptoms will be evaluated using Saint George's Respiratory Questionnaire.

Time Frame

baseline, 24 and 48 weeks

Title

Disease activity score of rheumatoid arthritis (DAS28-CRP)

Description

Time Frame

baseline, 12, 24 and 48 weeks

Title

Patient reported health assessment of physical function (HAQ index)

Description

Patient reported function assessed by a validated questionnaire HAQ = health assessment questionnaire. The assessment gives a value/index between 0 - 3.0.

Time Frame

baseline, 24 and 48 weeks

Title

Proportion of patients in rheumatoid arthritis DAS remission

Description

DAS28 remission is defined as DAS28<2.6.

Time Frame

24 and 48 weeks

Title

Frequency of adverse events (AE)

Description

Number of AE per category and serious AE will be calculated for the different treatment groups

Time Frame

baseline, 24 and 48 weeks

Title

Patient reported global disease activity

Description

Patient reported global impact of disease on health on a VAS scale (0-100 mm)

Time Frame

baseline, 12, 24 and 48 weeks

Title

Proportion of patients in rheumatoid arthritis ACR-EULAR Boolean remission

Description

Time Frame

24 and 48 weeks

Title

Clinical disease activity score of rheumatoid arthritis (CDAI)

Description

Time Frame

baseline, 12, 24 and 48 weeks

Other Pre-specified Outcome Measures:

Title

Change in cellular activity profile of clinical samples

Description

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

Time Frame

baseline and 24 weeks

Title

Change in molecular activity profile of clinical samples

Description

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.

Time Frame

Baseline and 24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Study Coordinator

Phone

+46-31-3428639

marie-louise.andersson@vgregion.se

First Name & Middle Initial & Last Name or Official Title & Degree

Eva Klingberg, MD PhD

Phone

+46-31-3427745

eva.klingberg@vgregion.se

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Anna-Karin H Ekwall, MD MSc PhD

Organizational Affiliation

The Sahlgrenska University Hospital and University of Gothenburg

Official's Role

Principal Investigator

Facility Information:

Facility Name

Skåne University Hospital, Department of Rheumatology

City

Lund

State/Province

Skåne

ZIP/Postal Code

20502

Country

Sweden

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Meliha C Kapetanovic, MD PhD

meliha.c_kapetanovic@med.lu.se

Facility Name

Clinical Rheumatology Research Center, The Sahlgrenska University Hospital

City

Göteborg

State/Province

Västra Götaland

ZIP/Postal Code

41345

Country

Sweden

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Study coordinator

Phone

+46-31-3428639

marie-louise.andersson@vgregion.se

First Name & Middle Initial & Last Name & Degree

Anna-Karin H Ekwall, MD MSc PhD

Phone

+46-3429360

anna-karin.ekwall@vgregion.se

Facility Name

Karolinska University Hospital, Department of Rheumatology

City

Stockholm

ZIP/Postal Code

17176

Country

Sweden

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Anca I Catrina, MD PhD

anca.catrina@ki.se

12. IPD Sharing Statement

Learn more about this trial

Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease

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