Rituximab Versus Cyclophosphamide in Connective Tissue Disease-ILD

NCT01862926 | Completed Phase 2 DMC

• 2 other identifiers: RBHIPF0042012-003633-42
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

Brief Summary

Interstitial lung disease (ILD) is characterised by inflammation and scarring of the lung and is the leading cause of death in patients with systemic sclerosis, and contributes significantly to morbidity and mortality in many other connective tissue diseases (CTDs) such as polymyositis/dermatomyositis and mixed connective tissue disease. When ILD is extensive and/or progressive, immunosuppressive medication is often required to stabilize lung disease and alleviate symptoms. Current standard care for CTD associated ILD is extrapolated from studies performed in individuals with systemic sclerosis and comprises low dose corticosteroids and intravenous cyclophosphamide followed by oral azathioprine. In some individuals even this intensive immunosuppression is insufficient to prevent deterioration, and in a significant minority of affected individuals this results in respiratory failure and death. Rituximab has recently been reported as an effective 'rescue therapy' for stabilizing and even improving ILD in this patient group. Based on observations gained from this experience, the investigators believe that rituximab is a potential important alternative to current best therapy for this patient group. This study has therefore been initiated to evaluate the efficacy of rituximab (compared with standard therapy) in patients with progressive CTD related ILD.

Conditions

Interstitial Lung Disease; Scleroderma; Idiopathic Inflammatory Myositis; Mixed Connective Tissue Disease

Keywords

connective tissue disease; interstitial lung disease; pulmonary fibrosis; rituximab; scleroderma; polymyositis; dermatomyositis

Outcome Measures

Primary Outcomes (1)

• Absolute change in FVC

  48 weeks

Secondary Outcomes (5)

• • Change from baseline in diffusing capacity for carbon monoxide (DLco)

  48 weeks

• • Change from baseline in health related quality of life scores

  48 weeks

• • Change from baseline in global disease activity score

  48 weeks

• • Progression free survival

  48 weeks

• • Adverse and serious adverse events (as defined in GCP)

  48 weeks

Study Arms (2)

Rituximab

EXPERIMENTAL

1g given at baseline and two weeks.

Drug: Rituximab

Cyclophosphamide

ACTIVE COMPARATOR

Intravenous dose of 600 mg/m2 body surface area. 6 doses given 4 weekly.

Drug: Cyclophosphamide

Interventions

Rituximab DRUG

Rituximab

Cyclophosphamide DRUG

Cyclophosphamide

Eligibility Criteria

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

You may qualify if:

• Age 18 to 80 years at visit 1
• A diagnosis of connective tissue disease, based on internationally accepted criteria, in one of the following categories21-24: (see Appendix 1 for details)
• Systemic sclerosis
• Idiopathic interstitial myopathy (including polymyositis/dermatomyositis)
• Mixed connective tissue disease
• Severe and/or progressive interstitial lung disease associated with the underlying connective tissue disease.
• Chest HRCT performed within 12 months of study visit 1
• Intention of the caring physician to treat the ILD with intravenous cyclophosphamide (with treatment indications including deteriorating symptoms attributable to ILD, deteriorating lung function tests, worsening gas exchange or extent of ILD at first presentation) and where there is a reasonable expectation that immunosuppressive treatment with stabilize or improve CTD-ILD. In individuals with scleroderma it is anticipated that subjects will fulfil the criteria for extensive disease defined by Goh et al19
• Able to provide written informed consent

You may not qualify if:

• Age \<18 or \>80 years.
• Previous treatment with rituximab and/or intravenous cyclophosphamide
• Known hypersensitivity to rituximab or cyclophosphamide or their components
• Significant (in the opinion of the investigator) other organ co-morbidity including cardiac, hepatic or renal impairment
• Co-existent obstructive pulmonary disease (e.g. asthma, COPD, emphysema) with pre bronchodilator FEV1/FVC \< 70%
• Patients at significant risk for infectious complications following immunosuppression, including; HIV positive or other immunodeficiency syndromes (including hypogammaglobulineamia)
• Suspected or proven untreated tuberculosis
• Viral hepatitis
• Infection requiring antibiotic treatment in the preceding four weeks
• Other investigational therapy (participation in research trial) received within 8 weeks of visit 1
• Immunosuppressive therapy (other than corticosteroids) received within 2 weeks of visit 1 (randomization)
• Pregnant or breast feeding women, or women of child-bearing potential, not using a reliable contraceptive method
• Unexplained haematuria, or previous bladder carcinoma
• Unable to provide informed written consent

Sponsors & Collaborators

• Royal Brompton & Harefield NHS Foundation Trust: lead
• Imperial College London: collaborator
• University of East Anglia: collaborator
• University College London Hospitals: collaborator

Study Sites (1)

Royal Brompton Hospital

London, SW3 6NP, United Kingdom

Location

Related Publications (6)

• Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Muller-Ladner U, Distler O, Iannone F, Pellerito R, Pileckyte M, Miniati I, Ananieva L, Gurman AB, Damjanov N, Mueller A, Valentini G, Riemekasten G, Tikly M, Hummers L, Henriques MJ, Caramaschi P, Scheja A, Rozman B, Ton E, Kumanovics G, Coleiro B, Feierl E, Szucs G, Von Muhlen CA, Riccieri V, Novak S, Chizzolini C, Kotulska A, Denton C, Coelho PC, Kotter I, Simsek I, de la Pena Lefebvre PG, Hachulla E, Seibold JR, Rednic S, Stork J, Morovic-Vergles J, Walker UA. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010 Oct;69(10):1809-15. doi: 10.1136/ard.2009.114264. Epub 2010 Jun 15.

  PMID: 20551155 BACKGROUND

• Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts C, Desai S, Herrick AL, McHugh NJ, Foley NM, Pearson SB, Emery P, Veale DJ, Denton CP, Wells AU, Black CM, du Bois RM. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006 Dec;54(12):3962-70. doi: 10.1002/art.22204.

  PMID: 17133610 BACKGROUND

• Keir GJ, Maher TM, Hansell DM, Denton CP, Ong VH, Singh S, Wells AU, Renzoni EA. Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy. Eur Respir J. 2012 Sep;40(3):641-8. doi: 10.1183/09031936.00163911. Epub 2012 Jan 26.

  PMID: 22282550 BACKGROUND

• Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, Corte TJ, Sander CR, Ratoff J, Devaraj A, Bozovic G, Denton CP, Black CM, du Bois RM, Wells AU. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008 Jun 1;177(11):1248-54. doi: 10.1164/rccm.200706-877OC. Epub 2008 Mar 27.

  PMID: 18369202 BACKGROUND

• Maher TM, Tudor VA, Saunders P, Gibbons MA, Fletcher SV, Denton CP, Hoyles RK, Parfrey H, Renzoni EA, Kokosi M, Wells AU, Ashby D, Szigeti M, Molyneaux PL; RECITAL Investigators. Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med. 2023 Jan;11(1):45-54. doi: 10.1016/S2213-2600(22)00359-9. Epub 2022 Nov 11.

  PMID: 36375479 DERIVED

• Saunders P, Tsipouri V, Keir GJ, Ashby D, Flather MD, Parfrey H, Babalis D, Renzoni EA, Denton CP, Wells AU, Maher TM. Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial. Trials. 2017 Jun 15;18(1):275. doi: 10.1186/s13063-017-2016-2.

  PMID: 28619061 DERIVED

MeSH Terms

Conditions

Lung Diseases, Interstitial; Scleroderma, Diffuse; Myositis; Mixed Connective Tissue Disease; Connective Tissue Diseases; Pulmonary Fibrosis; Polymyositis; Dermatomyositis

Interventions

Rituximab; Cyclophosphamide

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Scleroderma, Systemic; Skin and Connective Tissue Diseases; Skin Diseases; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Toby M Maher, MD PhD

  Royal Brompton and Harefield Foundation NHS Trust

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2013
• First Posted: May 27, 2013
• Study Start: November 1, 2014
• Primary Completion: January 1, 2021
• Study Completion: January 1, 2021
• Last Updated: October 7, 2021

Record last verified: 2021-10

Locations

GB (1)