Title: A randomized double blind controlled trial comparing rituximab against intravenouscyclophosphamide in connective tissue disease associated interstitial lung disease
Funder: Department of Health (England)

Abstract: Proposed study: To compare the efficacy of rituximab against intravenous cyclophosphamide in individuals with connective tissue disease associated interstitial lung disease (CTD-ILD). Study design is randomised double blind double dummy with stratification based on specific CTD and centre.Population: Patients with extensive and/or progressive CTD-ILD for whom the caring physician would usually recommend treating with IV cyclophosphamide. Patients eligible for enrolment will have a CTD diagnosis of systemic sclerosis idiopathic inflammatory myopathy or mixed CTD (according to accepted criteria) and associated ILD.Intervention: Blinded randomisation to receive IV rituximab (1000 mg for 2 doses; day 0 and day 14) with low dose prednisolone (10mg/day) or IV cyclophosphamide (600 mg/m2 monthly for 6 months) with low dose prednisolone. At 6 months all subjects will be converted to open label oral immunosuppression (azathioprine 2-3 mg/kg up to 150 mg/day) together with continued prednisolone 10 mg/day.Primary outcome: Change in forced vital capacity (FVC) at 12 months.Secondary outcomes: Safety change in diffusing capacity for carbon monoxide (DLco) change in 6 minute walk distance change in quality of life scores (as measured by SGRQ SF-36) change in global disease activity and overall healthcare utilisation.Assessments: Monthly review for the first 6 months followed by 3 monthly reviews for the second 6 months.Sample size: 116 (aiming for 52 subjects reaching end-of-study in each arm and anticipating a 10% drop out)Statistical analysis: Previous studies of IV cyclophosphamide in systemic sclerosis showed a 1% decline in FVC at 12 months with a standard deviation of 7.8%. Our observational data and a previous non-randomised study of rituximab suggest improvements in FVC at 12 months of up to 19%. Using a 1:1 randomization a sample size of 52 subjects in each group will have a 90% power to detect a 5% difference in 12 month FVC between treatment groups with a significance level (alpha) of 0.05 (two-tailed).Economic benefit: Treatment with IV cyclophosphamide requires a minimum of 6 visits (monthly for 6 months) with drug administration laboratory tests medical and nursing review at each visit. In contrast rituximab requires 2 visits 2 weeks apart (due to the long lasting effects of the drug with B cell depletion lasting for 6-9 months). Fewer visits and considerably less patient inconvenience will be a major additional benefit if rituximab is found to be of greater efficacy than cyclophosphamide.Expertise: Our unit has previously successfully co-ordinated a multi-centre placebo controlled trial of IV cyclophosphamide in individuals with systemic sclerosis related-ILD. Our team brings together clinical expertise in respiratory medicine rheumatology and immunology together with extensive clinical trials and health economics expertise. Public/patient involvement has been embedded into design and running of the trial.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY