Journal Article

Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial

Flather, Marcus D., Renzoni, Elisabetta A., Babalis, Daphne, Denton, Christopher P., Maher, Toby M., Keir, Gregory J., Parfrey, Helen, Saunders, Peter, Ashby, Deborah, Tsipouri, Vicky, Wells, Athol U.

2017

Overview

Background Interstitial lung disease (ILD) frequently complicates systemic autoimmune disorders resulting in considerable morbidity and mortality. The connective tissue diseases (CTDs) most frequently resulting in ILD include: systemic sclerosis, idiopathic inflammatory myositis (including dermatomyositis, polymyositis and anti-synthetase syndrome) and mixed connective tissue disease. Despite the development, over the last two decades, of a range of biological therapies which have resulted in significant improvements in the treatment of the systemic manifestations of CTD, the management of CTD-associated ILD has changed little. At present there are no approved therapies for CTD-ILD. Following trials in scleroderma-ILD, cyclophosphamide is the accepted standard of care for individuals with severe or progressive CTD-related ILD. Observational studies have suggested that the anti-CD20 monoclonal antibody, rituximab, is an effective rescue therapy in the treatment of refractory CTD-ILD. However, before now, there have been no randomised controlled trials assessing the efficacy of rituximab in this treatment population. Methods/design RECITAL is a UK, multicentre, prospective, randomised, double-blind, double-dummy, controlled trial funded by the Efficacy and Mechanism Evaluation Programme of the Medical Research Council and National Institute for Health Research. The trial will compare rituximab 1 g given intravenously, twice at an interval of 2 weeks, with intravenously administered cyclophosphamide given monthly at a dose of 600 mg/m 2 body surface area in individuals with ILD due to systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) or mixed connective tissue disease. A total of 116 individuals will be randomised 1:1 to each of the two treatment arms, with stratification based on underlying CTD, and will be followed for a total of 48 weeks from first dose. The primary endpoint for the study will be change in forced vital capacity (FVC) at 24 weeks. Key secondary endpoints include: safety, change in FVC at 48 weeks as well as survival, change in oxygen requirements, total 48-week corticosteroid exposure and utilisation of health care resources. Discussion This is the first randomised control trial to study the efficacy of rituximab as first-line treatment in CTD-associated ILD. The results generated should provide important information on the treatment of a life-threatening complication affecting a rare group of CTDs. Trial registration ClinicalTrials.gov, NCT01862926. Registered on 22 May 2013.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Administration, Intravenous / Adrenal Cortex Hormones - administration & dosage / Analysis / Biomarkers / Biomedicine / Care and treatment / Clinical Protocols / Clinical trials / Comparative analysis / Connective tissue diseases / Connective Tissue Diseases - diagnosis / Connective Tissue Diseases - drug therapy / Connective Tissue Diseases - immunology / Connective Tissue Diseases - physiopathology / Cyclophosphamide / Cyclophosphamide - administration & dosage / Cyclophosphamide - adverse effects / Dosage and administration / Double-Blind Method / Drug Administration Schedule / Drug dosages / Health Sciences / Humans / Immunosuppressive Agents - administration & dosage / Immunosuppressive Agents - adverse effects / Immunotherapy / Inflammation / Inflammatory diseases / Lung - drug effects / Lung - immunology / Lung - physiopathology / Lung diseases / Lung Diseases, Interstitial - diagnosis / Lung Diseases, Interstitial - drug therapy / Lung Diseases, Interstitial - immunology / Lung Diseases, Interstitial - physiopathology / Medical prognosis / Medicine / Medicine & Public Health / Mixed connective tissue disease / Monoclonal antibodies / Mortality / Musculoskeletal diseases / Myositis / Oxygen Inhalation Therapy / Pneumonia / Prospective Studies / Pulmonary fibrosis / Recovery of Function / Research Design / Respiratory failure / Rituximab / Rituximab - administration & dosage / Rituximab - adverse effects / Scleroderma / Scleroderma (Disease) / Statistics for Life Sciences / Study Protocol / Time Factors / Treatment Outcome / United Kingdom / Vital Capacity