E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
A diagnosis of connective tissue disease associated interstitial lung disease, based on internationally accepted criteria, in one of the following categories: o Systemic sclerosis o Idiopathic interstitial myopathy (including polymyositis/dermatomyositis) o Mixed connective tissue disease |
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E.1.1.1 | Medical condition in easily understood language |
Interstitial lung disease in individuals with systemic autoimmune disease (the conditions scleroderma, polymyositis/dermatomyositis and mixed connective tissue disease) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012503 |
E.1.2 | Term | Dermatomyositis |
E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10022611 |
E.1.2 | Term | Interstitial lung disease |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027754 |
E.1.2 | Term | Mixed connective tissue disease |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039710 |
E.1.2 | Term | Scleroderma |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036102 |
E.1.2 | Term | Polymyositis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The aim of the study is to compare the safety and effectiveness of rituximab against that of cyclophosphamide as first line therapy in patients with severe, progressive connective tissue disease associated interstitial lung disease. The study will test the hypothesis that rituximab is superior to intravenous cyclophosphamide, in terms of both safety and efficacy, as a treatment for extensive and progressive connective tissue disease associated interstitial lung disease (CTD-ILD). |
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E.2.2 | Secondary objectives of the trial |
Other main objectives will be; 1. To compare the safety profile of rituximab to intravenous cyclophosphamide in individuals with CTD-ILD 2. 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 and carer burden. 3. To evaluate a range of exploratory biomarkers for disease severity, prognosis and treatment response in CTD-ILD |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects will be recruited prospectively from rheumatology or interstitial lung disease units at 6 UK centres. Prior to enrolment potential study subjects will be assessed according to the following inclusion and exclusion criteria; Inclusion Criteria: • A diagnosis of connective tissue disease, based on internationally accepted criteria, in one of the following categories: o Systemic sclerosis o Idiopathic interstitial myopathy (including polymyositis/dermatomyositis) o 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 randomisation • 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 will stabilize or improve CTD-ILD • Written informed consent |
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E.4 | Principal exclusion criteria |
Exclusion Criteria: • 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 • Unexplained neurological symptoms (which may be suggestive of progressive mutifocal leukoencephalopathy; PML). Neurological symptoms arising as a consequence of the underlying CTD do not necessitate exclusion. • Other investigational therapy (participation in research trial) received within 8 weeks of randomisation • Immunosuppressive or CTD disease modifying therapy (other than corticosteroids) received within 2 weeks of randomisation • Pregnant or breast feeding women, or women of child-bearing potential, not using a reliable contraceptive method for up to 12 months following IMP • Unexplained haematuria, or previous bladder carcinoma • CT scan > 12 months from randomisation • Unable to provide informed written consent |
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E.5 End points |
E.5.1 | Primary end point(s) |
Absolute change in FVC (expressed in mL) at week 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Change from baseline in diffusing capacity for carbon monoxide (DLco) • Change from baseline in health related quality of life scores (SGRQ, SF-36, K-BILD) • Change from baseline in global disease activity score • Change in 6 minute walk distance over 48 weeks • Change in FVC and DLco at 24 weeks • Further analyses on FVC o Absolute categorical change of %FVC up to 48 weeks (decrease by > 5%, increase by >5% and change within <5%) o Absolute categorical change of %FVC up to 48 weeks (decrease by > 10%, increase by >10% and change within <10%) o 48 week rate of change in FVC • Disease related mortality (adjudicated by steering committee and close of study) • Overall survival • Progression free survival (composite endpoint of mortality, transplant, treatment failure or decline in FVC > 10% compared to baseline) • Treatment failure (as determined by need for transplant or rescue therapy with an alternative immunosuppressive regimen at any point until 48 weeks). • Total corticosteroid requirement over 48 weeks • Change from baseline in SpO2 • Healthcare utilisation during study period (visits to primary care, unscheduled hospital visits, emergency admissions) • Scleroderma specific endpoints (change in scleroderma HAQ, modified Rodnan Skin Score (mRSS). • Safety and tolerability |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |