Efficacy and Mechanism Evaluation (Feb 2024)
Rituximab compared to intravenous cyclophosphamide in adults with connective tissue disease-associated interstitial lung disease: the RECITAL RCT
Abstract
Background Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials. Objectives To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease. Methods This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m2 body surface area. The primary end point for the study was the change in forced vital capacity at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, forced vital capacity change at 48 weeks and patient-reported quality of life. A cost-effectiveness analysis was undertaken to assess the impact of rituximab use in the United Kingdom National Health Service. Results One hundred and one subjects (70 females) with a mean age of 56.3 years were randomised; 51 to rituximab and 50 to cyclophosphamide. Ninety-seven were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the cyclophosphamide group). 38.6% had scleroderma, 44.6% idiopathic inflammatory myositis and 16.8% mixed connective tissue disease. Four subjects withdrew prior to the first dose of therapy (two in each arm). At 24 weeks, both rituximab and cyclophosphamide improved forced vital capacity from baseline [(mean ± standard deviation) 97 ± 234 and 99 ± 329 ml, respectively]. Using an adjusted mixed-effects model corrected for diagnosis and baseline forced vital capacity the difference in forced vital capacity at 24 weeks between rituximab and cyclophosphamide was −40 ml (95% CI −153 to 74 ml), p = 0.49. Other physiological and quality-of-life parameters improved in both arms following treatment but were not statistically significantly different between groups. Numerically fewer adverse events were reported by subjects receiving rituximab. Corticosteroid exposure over the 48 weeks of the trial was numerically less in the rituximab arm [13,291 (±14,657) mg of hydrocortisone equivalent per subject in the cyclophosphamide arm versus 11,469 (±10,041) mg per subject in the rituximab group; these differences did not reach statistical significance]. Limitations of the study include a disproportionate number of subjects being recruited from a single centre and insufficient subjects in each subgroup to determine whether there were treatment differences between individual connective tissue diseases. Based on the results of the trial, from a UK healthcare payer perspective, rituximab is more cost-effective than cyclophosphamide as a treatment for severe or progressive connective tissue disease-interstitial lung disease. Conclusions Rituximab improved forced vital capacity and patient-reported quality of life at 24 weeks but was not superior to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with connective tissue disease-associated interstitial lung disease requiring systemic therapy. Future work should explore the role of repeated dosing of rituximab and the use of rituximab earlier in the course of connective tissue disease-associated interstitial lung disease. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary Interstitial lung disease, a condition characterised by inflammation and scarring of the lungs, is the leading cause of death in systemic sclerosis (an autoimmune disease that typically causes thickening and scarring of the skin and which is associated with internal organ problems such as interstitial lung disease and kidney failure), and a major cause of morbidity (illness) in many other connective tissue diseases; a group of conditions that are caused by over activity of the immune system. When interstitial lung disease associated with connective tissue disease gets worse over time, treatment such as intravenous cyclophosphamide is required to slow down lung scarring. Occasionally, standard immunosuppressive drugs fail to control lung inflammation and scaring and this can result in death. Rituximab, a novel therapy, has been proven to be of benefit in suppressing inflammation associated with immune system over activity. Observational studies suggest that rituximab may be an effective treatment for pulmonary inflammation in connective tissue diseases. The study was designed to determine how well rituximab works compared to cyclophosphamide in treating patients with severe connective tissue disease-associated interstitial lung disease. We recruited 101 participants from 11 hospitals throughout the UK who were randomly allocated to one of two groups. Those in the first group were given rituximab on day 1 of the study and then on day 14. They were then given a placebo every 4 weeks for the next 18 weeks. Those in the second group were given cyclophosphamide every 4 weeks from day 1 of the study to week 20. On day 14, they were given a placebo. Lung function for all participants was assessed at 24 weeks. Our results suggest that rituximab improved lung function and quality of life but was not better than cyclophosphamide. Rituximab was associated with fewer unexpected medical events and a trend towards reduction in corticosteroid use and should be considered as a therapeutic alternative to cyclophosphamide. Scientific summary Background Interstitial lung disease (ILD) is characterised by inflammation and/or fibrosis within the parenchymal compartment bounded by the alveolar epithelium and capillary endothelium and frequently results in breathlessness progressing over time to respiratory failure. Autoimmune injury to the lung is a frequent cause of ILD. As such, the connective tissue diseases (CTDs), including systemic sclerosis (SSc), the inflammatory myopathies and mixed connective tissue disease (MCTD), are important causes of ILD. For individuals with CTD the development of ILD is an important cause of morbidity and mortality; for people with scleroderma, ILD is now the leading cause of death. Despite this there are few evidence-based treatments for CTD-associated ILD. At the time of planning this research there were no approved therapies available for CTD-ILD and all of the trial data which existed had been generated in the context of scleroderma-associated ILD. The Scleroderma Lung Study I assessed the efficacy of 52 weeks of treatment with oral cyclophosphamide (CP) compared to placebo in individuals with systemic sclerosis-associated ILD and evidence of an active inflammatory cell infiltrate on bronchoalveolar lavage. The trial demonstrated a positive effect of CP at 52 weeks but the drug was poorly tolerated and the benefit compared with placebo had disappeared by 2 years. A smaller 52-week study, also conducted in individuals with scleroderma-associated ILD, compared placebo to once-monthly intravenous CP given for 6 months followed by azathioprine and low dose prednisolone for the subsequent 6 months and showed a trend towards benefit in the active treatment arm. In the absence of treatment guidelines or evidence generated in other forms of CTD-ILD, most centres in the UK were routinely using intravenous CP as first-line therapy for individuals with clinically advanced or rapidly progressive ILD arising in the context of CTD. Rituximab, a chimeric (human/mouse) monoclonal antibody with a high affinity for the CD20 surface antigen expressed on B-lymphocytes, results in rapid depletion of B cells from the peripheral circulation for 6–9 months. Evidence for the efficacy of B cell depletion exists in a number of immune-mediated conditions, including rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated vasculitis and immune thrombocytopenic purpura. Several case series suggest rituximab may also be effective in ILD occurring in the context of immunological over-activity, with favourable responses reported in antisynthetase-associated ILD and SSc-ILD. Our own clinical experience suggested that rituximab is an effective, potentially life-saving therapeutic intervention in the treatment of very severe, progressive CTD-ILD unresponsive to conventional immunosuppression. In head-to-head studies in the context of other autoimmune diseases rituximab has been shown to have a favourable safety and tolerability profile compared to CP. The absence of high-quality evidence to guide treatment of CTD-ILD provided an opportunity to assess the efficacy of rituximab compared to the accepted standard of care, CP. Objectives The primary objective of the study was to demonstrate that intravenous rituximab has superior efficacy compared to current best treatment (intravenous CP) for CTD-ILD as measured by assessment of change in forced vital capacity (FVC) at 24 weeks. Secondary objectives were: to compare the safety profile of rituximab to intravenous CP in individuals with CTD-ILD to assess the health economic benefits of rituximab compared to current standard of care for CTD-ILD – including measurements of healthcare utilisation, quality of life (QoL) and carer burden to evaluate a range of exploratory biomarkers for disease severity, prognosis and treatment response in CTD-ILD. Methods The study was a Phase IIb, UK multicentre, prospective, randomised, double-blind, double-dummy trial of intravenous rituximab compared with intravenous CP in patients with severe, progressive CTD-ILD. Patients were randomised 1 : 1 to two groups, both groups received placebo to match the different regimens. Patients were followed for 48 weeks after first treatment; after 24 weeks subjects were permitted additional immunotherapy as determined by their treating physician. Study settings The study was conducted in rheumatology or ILD units at 11 UK centres. Participant inclusion criteria A diagnosis of CTD, based on internationally accepted criteria, in one of the following categories: systemic sclerosis idiopathic interstitial myopathy (including polymyositis/dermatomyositis) MCTD. Severe and/or progressive ILD associated with the underlying CTD. Chest high-resolution computer tomography performed within 12 months of randomisation. Intention of the caring physician to treat the ILD with intravenous CP. Able to provide written informed consent. Participant exclusion criteria Previous treatment with rituximab and/or intravenous CP. Age 80 years. Known hypersensitivity to rituximab or CP or their components. Significant (in the opinion of the investigator) other organ comorbidity including cardiac, hepatic or renal impairment. Coexistent obstructive pulmonary disease (e.g. asthma, chronic obstructive pulmonary disease, emphysema) with pre-bronchodilator forced expiratory volume in 1 second (FEV1) and FVC ratio 12 months from randomisation. Unable to provide informed written consent. Interventions Patients were randomised to receive either: Rituximab 1000 mg for two doses at day 0 and day 14. Placebo was administered monthly from week 4 to week 20. CP given at a dose of 600 mg/m2 body surface area rounded to the nearest 100 mg every 4 weeks from day 0 to week 20. Placebo was given at day 14. Patients were pre-medicated on day 0 with hydrocortisone, paracetamol, chlorpheniramine and mesna, at day 14 with hydrocortisone, paracetamol and chlorpheniramine and at visits from week 4 to 20 with mesna. Measurements Wherever possible, even if treatment could not be given, spirometry was undertaken at the time of each planned visit and performed according to standards outlined in the American Thoracic Society/European Respiratory Society guidelines. Lung function tests (plethysmography and gas transfer) were measured at screening, baseline, week 12, week 24 and week 48. Assessment for adverse events (AEs) and clinical end points began from randomisation and continued for the individual patient until they completed their follow-up at 48 weeks. At each study visit the investigator or designee made an assessment of safety and reviewed the clinical history and investigation findings with regard to the occurrence of adverse or serious adverse events (SAEs). Peripheral blood was taken at the time of each planned visit. Collection of blood for laboratory analyses included full blood count, erythrocyte sedimentation rate, urea and electrolytes, glucose, hepatitis A, B and C serology (screening only) and liver function tests. Blood for lymphocyte subsets and biomarker analysis was taken at day 0, week 12, 24 and 48 only. Quality of life was assessed by self-administered validated questionnaires undertaken at baseline and repeated at the primary end point visit at 24 weeks and at the final follow-up visit at 48 weeks. The instruments used were: the Short Form 36 (SF36) questionnaire EuroQol-5 Dimensions (EQ-5D) St George’s Respiratory Questionnaire (SGRQ) King’s Brief Interstitial Lung Disease (K-BILD) Scleroderma Health Assessment (SHA) Questionnaire which was disease-specific. For individuals with scleroderma, assessment of skin thickening was undertaken using the modified Rodnan skin score at baseline, 24 and 48 weeks. Sample size The primary outcome was changed in FVC at 24 weeks. The trial was designed to have 90% power to detect a 5% difference in 24-week FVC between treatment groups with a significance level (alpha) of 0.05 (two-tailed). The target sample size was 116 with the anticipation that 52 patients would reach the end-of-study in each arm with an expected 10% drop out. Because of the COVID-19 pandemic and an anticipated prolonged interruption to recruitment, trial enrolment was halted in March 2020 after randomisation of 101 subjects. Statistical analysis No formal interim analysis was planned. A statistical analysis plan was produced and agreed prior to analysis. Analysis of the primary outcome was by modified intention to treat. In other words, data were included in respect of all subjects who met all the entry criteria for the trial and had been randomised and received at least one dose of study drug. Results The study recruitment period was from December 2014 until March 2020 from 11 sites. In total 145 subjects were assessed for eligibility and of these 104 participants were enrolled. Three of these failed screening and were excluded. One hundred and one subjects were therefore randomised and 97 subjects received at least one dose of study drug and were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the CP group). Overall, baseline characteristics between the rituximab and CP arms were well balanced albeit with slightly more male participants in the rituximab arm. For the total cohort the mean ± S.D. age was 56 ± 11.4 years. Seventy subjects (69.3%) were female, 70 (69.3%) were white, 16 (15.8%) Asian and 12 (11.9%) black. The most frequently encountered CTD was idiopathic inflammatory myopathy (44.6%), followed by scleroderma (38.6%) and then MCTD (16.8%). Primary outcome At week 24 the unadjusted mean [± standard deviation (SD)] change in FVC in the CP treatment arm was a gain of 99 ± 329 ml. In the rituximab arm the change was 97 ± 234 ml. The relative change from baseline for each arm was 4.35 ± 15.67% for CP and for rituximab 4.31 ± 11.80%. Using a mixed-effects model adjusted for baseline FVC and diagnosis the difference (and 95% confidence interval) at 24 weeks between rituximab and CP was −40 ml [95% confidence interval (CI) −153 to 74 ml], p = 0.49. Secondary outcomes The unadjusted change in FVC at 48 weeks was 138 ± 440 ml in the CP arm and 112 ± 249 ml in the rituximab group. In relative terms, over 48 weeks, the improvement in the CP group was 5.08 ± 19.96% and in the rituximab group 4.22 ± 10.31%. An adjusted mixed-effects model demonstrated a −58 (95% CI −178 to 62) ml difference at 48 weeks between the rituximab and CP arms (p = 0.251). At week 24 the mean relative change in diffusing capacity of the lung for carbon monoxide (DLco) in the CP arm was 1.43 ± 23.05% compared to 6.98 ± 17.19% in the rituximab arm. At 48 weeks the changes in DLco were 3.00 ± 31.35% and 7.43 ± 16.08% in the CP and rituximab arms, respectively. For 6-minute walk distance the 24-week change in the CP and rituximab arms was 10.4 ± 78.6 and 10.9 ± 74.2 m, respectively. At week 48 the changes were 15.1 ± 82.8 and −6.8 ± 69.8 m. Using an adjusted mixed-effects model the differences between the rituximab and CP arms were −0.72 (−24.76 to 23.32) m, p = 0.953 at 24 weeks and −22.46 (−48.43 to 3.51) m, p = 0.090 at 48 weeks. Quality of life was assessed using the K-BILD questionnaire. Change at 24 weeks was 9.4 ± 20.8 in the CP arm and 8.8 ± 17.0 in the rituximab arm. At 48 weeks the difference compared to baseline was 5.6 ± 25.6 and 6.4 ± 16.2 in the CP and rituximab arms, respectively. Analysis in an adjusted mixed-effects model showed the difference between rituximab and CP was 0.4 (−5.73 to 6.52) and 1.15 (−5.34 to 7.64) at weeks 24 and 48, respectively. Survival Over the 48-week course of the study there were five deaths. All were deemed to be due to complications of either CTD or ILD. Three occurred in subjects receiving rituximab and two in subjects receiving CP. There was no difference between groups in time to death as assessed by an adjusted Cox proportional hazards model [hazard ratio (HR) 1.72 (95% CI 0.311 to 9.56, p = 0.534)]. The rates of progression-free survival [HR 1.11 (95% CI 0.625 to 1.99, p = 0.715)], and time to treatment failure [HR 1.25 (95% CI 0.34 to 4.65, p = 0.742)] did not differ between treatment arms. Corticosteroids The mean per-subject total steroid exposure during the study (measured in hydrocortisone equivalents) was 13,291 (±14,657) mg in the CP and 11,469 (±10,041) mg in the rituximab group; a 12% reduction in corticosteroid exposure in the rituximab arm. The daily mean dose per patient was 42.89 mg hydrocortisone/day in the CP and 37.61 mg hydrocortisone/day in the rituximab group. Safety All subjects in both arms experienced at least one AE. There were more AEs reported in the CP arm (646) than in the rituximab arm (445). The imbalance was less marked for SAEs with 33 and 29 in the CP and rituximab arms, respectively. Gastrointestinal disorders (170 vs. 71), general disorders and administration site reactions (91 vs. 52) and nervous system disorders (72 vs. 35) were more common in the CP arm. The frequency of other AEs was balanced between groups including infections and infestations (50 vs. 46). One patient in each arm withdrew because of side effects. There were no reported cases of COVID-19 during the trial. Cost-effectiveness Over the 48-week trial period treatment with CP was associated with a cost of £94,338 compared with a cost of £93,227 for rituximab; a difference of £1110 in favour of rituximab. Rituximab was associated with a 0.022 gain in quality-adjusted life-years over that seen with CP. The incremental net monetary benefit was significantly higher in the rituximab group under a wide range of monetary values and quality-adjusted life-years. Conclusion This study demonstrated that both rituximab and CP improve FVC and QoL in patients with CTD-ILD. There were numerically fewer AEs and a trend towards reduction in corticosteroid exposure in the rituximab-treated subjects. Rituximab should therefore be considered as a treatment option in patients with severe or rapidly progressive CTD-associated ILD. Implications for health care Although this study failed to show superiority of rituximab over CP in improving FVC when used as first-line treatment for CTD-ILD, the consistent positive effects of rituximab on physiological end points, QoL, and corticosteroid requirements support the clinical use of this drug in what is a population of patients with high unmet need (especially in situations where CP is contraindicated or likely to cause deleterious effects such as gonad failure or bladder malignancy). Implications for research Further trials will be necessary to confirm whether repeated dosing with rituximab confers additional benefit as compared to a single baseline dose. Similarly, additional studies are necessary to confirm findings in individual CTDs and to assess the optimal longer-term therapeutic regimen following initial intravenous therapy. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information.
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