E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main aim of the study is compare remission (absence of symptoms and signs of arthritis) achieved with very early etanercept therapy to that achieved by current standard care (methotrexate and a treat to target regimen) with or without delayed etanercept, in patients with early, untreated rheumatoid arthritis. We will compare differences in: a. the proportion of patients achieving initial remission. b. the proportion of patients who remain in sustained remission. c. the depth of remission. For example, we will look for signs of active arthritis on ultrasound scans and using sensitive MRI techniques. We will also look to see the body's immune response (in rheumatoid arthritis part of the body's defence system does not act normally and attacks its own joint tissues). We will assess if it has returned to normal using blood and urine tests and examining joint tissue (synovial biopsy tissue). |
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E.2.2 | Secondary objectives of the trial |
1. If there are differences in efficacy of very early compared to delayed etanercept therapy, what are the reasons for this? Are there differences in very early, untreated disease, compared to later disease which mean patients are more responsive to a TNF inhibitor? We will evaluate differences in the appearance of joints (on ultrasound and MRI) and the body's immune cells and chemical signalling between immune cells in blood, urine and joint tissue samples. 2. Why do some patients respond to etanercept and others do not? We will look for factors which may predict response to etanercept: in the appearance of joints (on ultrasound and MRI), the immune system (in blood, urine and joint tissue) and genetic factors (a persons DNA, the information in their body cells they inherit from their parents will be examined by a single blood test at the start of the study). 3. In patients achieving clinical remission (absence of symptoms and signs of arthritis) are there ongoing signs o |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A Prospective, Single-centre, Randomised Study Evaluating the Clinical, Imaging and Immunological Depth of Remission Achieved by Very Early versus Delayed Etanercept in patients with Rheumatoid Arthritis (VEDERA: CARDIOVASCULAR SUB-STUDY) In the cardiovascular substudy we will investigate the effect of treatment on the structure and function of blood vessels and the heart and on blood tests associated with an increased risk of cardiovascular diseases such as heart disease or stroke. |
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E.3 | Principal inclusion criteria |
Male and female patients aged between 18 and 80 years. Diagnosis of rheumatoid arthritis (new 2010 ACR/EULAR RA classification criteria). Symptom onset within the preceding 12 months. Patients with active RA at baseline: clinical evidence of synovitis (or imaging evidence of synovitis in cases of uncertainty/subclinical disease) and DAS28-ESR≥3.2. Presence of anti-citrullinated peptide antibody (ACPA) or if ACPA negative, presence of power Doppler in at least 1 joint on ultrasound imaging. Naïve to disease-modifying therapy. Active synovitis in hand and/or wrist joints evaluable by ultrasound and MRI. All male and female subjects biologically capable of having children must agree to use a reliable method of contraception for the duration of the study and 24 weeks after the end of the study period. Acceptable methods of contraception are surgical sterilisation, oral, implantable or injectable hormonal methods, intrauterine devices or barrier contraceptives. |
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E.4 | Principal exclusion criteria |
Previous treatment with disease-modifying anti-rheumatic drugs (for example, methotrexate, sulfasalazine or hydroxychloroquine). Intramuscular, oral or intra-articular (of non-target joint for synovial biopsy) corticosteroid within 28 days of the screening visit or intra-articular corticosteroid of the chosen target joint within 12 weeks of screening visit. Use of more than one non-steroidal anti-inflammatory (NSAID), change in NSAID or change in dose of NSAID within 28 days of the baseline visit. Contraindications to MRI (e.g. pacemaker) or unable or unwilling to attend for all imaging assessments. Unable or unwilling to attend for all synovial biopsies. Pregnancy or breastfeeding. Other contraindications to TNF inhibitor as determined by local prescribing guidelines and physician discretion. Whilst some of the below are absolute contraindications, physician discretion will be applied as in usual clinical practice: active infection, open leg ulcers, previously infected prosthetic joint (unless completely removed), septic arthritis in last year, HIV, Hepatitis B or Hepatitis C carriers, previous malignancy within 10 years (except basal cell carcinoma), severe heart failure (New York Heart Association grade 3 or more), any history of demyelinating disease, uncontrolled diabetes, pulmonary fibrosis, bronchiectasis, previous PUVA therapy (of >1000 Joules), history of TB or positive Purified Protein Derivative test (in this event, a TB gold quanteferon blood test will be performed: if negative a patient may be included, if positive a patient may be included if treated with isoniazid and pyridoxine one month before starting the study and for a further 6 months whilst on study treatments). History of other significant medical conditions, including: o Severe pulmonary disease, defined as requiring previous hospital admission or supplemental oxygen. o Active or severe cardiovascular disease: uncontrolled hypertension, myocardial infarction within 12 months of screening, angina within 6 months of screening. o Other immunodeficiency disorders. o Connective tissue diseases, e.g. Sjogren’s syndrome, systemic sclerosis, systemic lupus erythematosus, polymyositis. o Psoriasis. o Renal impairment (creatinine 175µmol/L). o Neutropenia (neutrophils < 2.0 x 109/L). o Thrombocytopenia (platelets < 125 x 109/L). o Abnormal liver function (alanine transaminase > 3 x upper limit of normal). o Anaemia (haemoglobin < 8 g/dL). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is the proportion of patients with early, treatment-naïve rheumatoid arthritis that achieve clinical remission at 48 weeks, following either: 1. Initial etanercept and methotrexate treatment. 2. Initial methotrexate with 'Treat to Target' regimen: escalation to combination therapy (methotrexate, sulfasalazine and hydroxychloroquine) at 12 weeks and switch to etanercept and methotrexate at/after 24 weeks if indicated by disease activity. The definition for clinical remission used in the primary endpoint will be DAS28-ESR remission (DAS28-ESR<2.6) or physician judgement of clinical remission with DAS28-ESR low disease activity (DAS28-ESR<3.2). DAS28-ESR is a composite score using: - the numbers of swollen and tender joints (out of 28 specified joints). - patient self-assessment of their current general health (using a visual analogue scale). - Erythrocyte Sedimentation Rate (marker of inflammation in blood). |
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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 | Yes |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard care(see cover letter) with treatment with the IMP if not acheiving remission at 6 months |
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E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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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Last visit of the last subject. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 61 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 61 |