Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease

NCT04311567 | Terminated Phase 4 DMC

• 1 other identifier: EudraCT 2019-004179-38
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 3

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (14)

• Change in extent of parenchymal lung disease by HRCT pattern

  Baseline and 24 weeks

• 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

Other Outcomes (2)

• Change in cellular activity profile of clinical samples

  baseline and 24 weeks

• Change in molecular activity profile of clinical samples

  Baseline and 24 weeks

Study Arms (2)

Tofacitinib

EXPERIMENTAL

Oral tablet tofacitinib 5 mg BID for 48 weeks

Drug: Tofacitinib

Methotrexate

ACTIVE COMPARATOR

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

Drug: Methotrexate

Interventions

Tofacitinib DRUG

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.

Also known as: Xeljanz

Tofacitinib

Methotrexate DRUG

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.

Also known as: metotrexat

Methotrexate

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Vastra Gotaland Region: lead
• Göteborg University: collaborator

Study Sites (3)

Skåne University Hospital, Department of Rheumatology

Lund, Skåne County, 20502, Sweden

Location

Clinical Rheumatology Research Center, The Sahlgrenska University Hospital

Gothenburg, Västra Götaland County, 41345, Sweden

Location

Karolinska University Hospital, Department of Rheumatology

Stockholm, 17176, Sweden

Location

MeSH Terms

Conditions

Arthritis, Rheumatoid; Lung Diseases, Interstitial

Interventions

tofacitinib; Methotrexate

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Anna-Karin H Ekwall, MD MSc PhD

  The Sahlgrenska University Hospital and University of Gothenburg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Blinded assessors of lung evaluation with HRCT and joint evaluation with joint counts (number of tender and swollen joints)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 5, 2020
• First Posted: March 17, 2020
• Study Start: November 7, 2020
• Primary Completion: November 30, 2023
• Study Completion: March 26, 2024
• Last Updated: May 23, 2024

Record last verified: 2022-04

Locations

SE (3)