Efficacy and Safety of Rituximab versus Placebo in Patients with Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Randomized Controlled Trial

Trial ID: 2025-524872-51-00
Protocol: BELLRA
Sponsor: Vaestra Goetalandsregionen

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Diseases & Conditions

Rheumatoid arthritis Interstitial lung disease

Objectives

The primary objective is to evaluate the superiority of rituximab compared to placebo in preserving pulmonary function, specifically measured by the percentage of predicted forced vital capacity, in patients with rheumatoid arthritis-associated interstitial lung disease receiving stable conventional therapy. Secondary objectives include:

Comparison of efficacy using additional pulmonary measures, including diffusion capacity of the lung for carbon monoxide, 6-minute walking test, and radiographic extent through visual assessment and lung texture analysis.
Assessment of patient-reported outcomes regarding lung disease activity, function, and health-related quality of life.
Evaluation of rheumatoid arthritis disease control via erythrocyte sedimentation rate, clinical disease activity index, disease activity scores based on 28 joints, C-reactive protein, and remission rates.
Monitoring of safety through the frequency of adverse events, serious adverse events, morbidity, and mortality.
Exploration of efficacy via subgroup analyses based on usual interstitial pneumonia patterns, baseline physiologic parameters, clinical joint activity, and MUC5B genotype, alongside the profiling of plasma biomarkers.

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of adult patients diagnosed with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Eligible individuals must be positive for rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA) according to the 2010 ACR/EULAR classification criteria. Inclusion requires radiographic evidence of interstitial lung disease (ILD) on a high resolution computed tomography (HRCT) scan. Participants must demonstrate a forced vital capacity (% predicted FVC) of at least 50% and a diffusing capacity of the lungs for carbon monoxide (% predicted DLCO) between 40% and 80%. The population includes both males and females. All subjects must be on a stable background of conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) therapy for at least 12 weeks prior to baseline, which may include low-dose prednisone.

Plans and Procedures

This multicentre, randomized, double-blind, placebo-controlled superiority study is designed to evaluate the efficacy and safety of rituximab compared to placebo in patients with rheumatoid arthritis-associated interstitial lung disease. The trial focuses on preserving pulmonary function, specifically measured by the percentage of predicted forced vital capacity. The study duration is 48 weeks. Following an initial screening visit to confirm eligibility based on radiographic evidence of disease and pulmonary function thresholds, participants will receive either rituximab via infusion or a placebo. The study includes assessment periods at 24 weeks and concludes with an end-of-study visit at 48 weeks. Primary and secondary endpoints involve changes in lung function, radiographic abnormalities, quality of life measures, and disease activity. Participant involvement is expected to last for the 48-week duration of the treatment period.

Treatment

The experimental medication is rituximab, which is administered via infusion at a dosage of 1000 mg. This intervention is evaluated for its efficacy in patients with rheumatoid arthritis-associated interstitial lung disease receiving stable conventional therapy.

The control group receives a placebo consisting of 0.9% sodium chloride, which contains no active substance.

Efficacy

The primary efficacy endpoint is the difference in the mean absolute change of % predicted forced vital capacity (%pFVC) from baseline to 48 weeks between the rituximab treatment group and the placebo group. Secondary efficacy assessments include the absolute change in forced vital capacity (FVC) in mL and the absolute change in % predicted diffusing capacity of the lungs for carbon monoxide (%pDLCO, Hb-corrected) at 24 and 48 weeks. The trial evaluates clinically meaningful progression based on the proportion of patients experiencing an absolute decline of ≥5% in %pFVC at 48 weeks, as well as the OMERACT definition of progression involving specific relative declines in %pFVC and %pDLCO. Additional metrics include the proportion of patients with stable or improved FVC and the time-to-event for progression defined as ≥10% of %pFVC.

Pulmonary status is further assessed using the six-minute walk test (6MWT) and high-resolution computed tomography (HRCT) of the lungs at 48 weeks. HRCT evaluations involve visual assessment by radiologists to measure the extent of interstitial lung disease (ILD) abnormalities, such as reticulations, ground glass, fibrosis, traction bronchiectasis, and honeycombing, as well as lung texture analysis based on CALIPER. Patient-reported outcomes are collected at 24 and 48 weeks using the Health Assessment Questionnaire – disability index (HAQ-DI), the King’s Brief Interstitial Lung Disease Questionnaire (K-BILD), the Dyspnea-12 Questionnaire (D-12), the Short Form 36 (SF36), and the Euro-Qol 5-dimension (EQ-5D) measure. Rheumatoid arthritis disease activity is monitored at 24 and 48 weeks through swollen and tender joint counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), disease activity score 28 (DAS28), DAS28-CRP, clinical disease activity index (CDAI), and global assessments using a visual analog scale (VAS). Remission rates are assessed via DAS28, CDAI, and ACR/EULAR Boolean 2.0 criteria at 48 weeks. Plasma biomarkers, including KL-6, surfactant protein-D, MMP-7, CXCL10, and unbiased protein profiles, are measured at 24 and 48 weeks.

Inclusion and Exclusion Criteria

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Inclusion Criteria

The subject has given their written consent to participate in the trial.
The subject is an adult with rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) positive RA fulfilling the 2010 ACR/EULAR RA classification criteria.
The subject has radiographic signs of ILD (defined as non-dependent abnormalities in ≥5% of a lung zone (upper, middle or lower) including ground glass opacities, reticulations, lung distortion, traction bronchiectasis, honey combing and non-emphysematous cysts) on a chest high resolution computed tomography (HRCT) scan (reviewed and concluded by two thoracic radiologists in consensus).
The subject has pulmonary function ≥ 50 %pFVC and 40-80 %pDLCO. Participants may be asymptomatic or symptomatic with respect to ILD.
The subject has a stable background conventional synthetic (cs) disease modifying anti-rheumatic drug (DMARD) therapy with or without a low dose prednisone since ≥ 12 weeks prior to baseline.

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Exclusion Criteria

Subjects with other chronic rheumatic disease, except for secondary Sjögrens syndrome.
Subjects with previous treatment with anti-B cell targeted therapy for RA.
Subjects with hypersensitivity towards murine proteins or excipients of rituximab drugs.
Subjects with inborn error of immunity or acquired severe immunodeficiency including but not limited to total immunoglobulin G < 6g/L.
Subjects with active infection (excluding fungal infections of nail beds) requiring hospitalization and/or i.v. anti-infectives ≤ 4 weeks, or oral anti-infectives* ≤ 2 weeks prior to baseline. *Prophylactic anti-viral therapy for chronic Hepatitis B and valaciclovir for Herpes Simplex type 2 are exempt (see exclusion criteria 6 and 7).
Subjects with a history of severe infection(s) including but not limited to disseminated and/or recurrent severe Herpes Simplex or Herpes Zoster infections.
Subjects with chronic hepatitis B without proper prophylactic therapy. Subjects with chronic hepatitis B can be included only if monitored with Hepatitis B DNA, aminotransferases (ALT and AST) every 12 weeks and treated with anti-viral drug for at least 7 days before RTX infusion and for at least 18 months after last RTX infusion.
Subjects with suspected or diagnosed active or latent tuberculosis and/or positive QuantiFERON (or TB-spot) test. Subjects with latent tuberculosis can be included if successfully treated or have initiated prophylaxis therapy ≥ 1 months of baseline.
Subjects with biologic or targeted synthetic DMARDs, anti-fibrotic therapy or cyclophosphamide ≤ 12 weeks prior to baseline.
Subjects with a history of malignancy ≤ 5 years prior to baseline (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).
Subjects with severe congestive heart failure (NYHA class 4) or severe uncontrolled heart disease.
Subjects with asthma or COPD with FEV1/FVC < 0.7.
Subjects with any significant comorbidity or disorder (including clinically significant pathological lab results) that according to the investigator will preclude study participation.
Subjects with any other factors (such as significant psychiatric or mental disorder, alcohol or other substance abuse, language barriers) that will make adherence to the protocol difficult.
Women of childbearing potential i.e. any female who has experienced menarche and does not meet the criteria for "women not of childbearing potential” defined as: women who are postmenopausal (12 months with no menses without an alternative medical cause) or who are permanently sterilized (e.g. hysterectomy, bilateral oophorectomy, or bilateral salpingectomy)) not willing or able to use highly effective methods of birth control (resulting in a low failure rate of less than 1% per year when used consistently and correctly) from 14 days prior to IMP administration, throughout the duration of the study and up to 6 months after end-of-study (i.e. 12 months after last RTX/Placebo IMP dose).
Subject who is, or wish to become, pregnant or lactating during and ≤ 6 months after the study.
Subjects with current or recent (≤30 days prior to baseline) participation in a clinical trial with an investigational product.
Subjects with absolute neutrophil count <1.5 x10^9/L.
Subjects with absolute thrombocyte count <75 x10^9/L.