VEDERA: Very Early Versus Delayed Etanercept in Patients With RA

Sponsor

University of Leeds (Other)

Overall Status

Completed

CT.gov ID

NCT02433184

Collaborator

(none)

120

Enrollment

Location

Arms

Actual Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main aim of the study is to determine whether TNFi instituted as first-line therapy in early RA confers better outcomes (clinical, structural and immunological) compared to delayed TNFi start; implying particular dominance of TNF in early disease, a changing role of TNF with disease duration and hence, confirmation of a biological window of opportunity.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Etanercept Drug: Methotrexate Drug: Sulfasalazine Drug: Hydroxychloroquine Drug: Etanercept Drug: Methotrexate	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 1, 2011

Actual Primary Completion Date :

Aug 1, 2017

Actual Study Completion Date :

Jul 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Etanercept Treatment Arm 1 will receive etanercept and methotrexate combination therapy administered for a total duration of 48 weeks.	Drug: Etanercept Etanercept will be administered subcutaneously at a dose of 50 mg weekly and will be discontinued at the primary endpoint (48 weeks). Drug: Methotrexate Methotrexate will be administered orally at a starting dose of 15 mg weekly, increasing to 20mg and 25mg weekly at weeks 4 and 8 respectively.
Active Comparator: Methotrexate-treat to target Treatment Arm 2 will receive initial methotrexate monotherapy with adoption of a treat to target protocol (standard care involving monthly DAS28-ESR assessment with escalation to combination sDMARD therapy if not achieving LDA at, or after, 8 weeks) and step-up to etanercept and methotrexate at 24 weeks if failing to achieve clinical remission	Drug: Methotrexate Methotrexate will be administered orally at a starting dose of 15 mg and will be increased to 25mg weekly at 2 weeks. Drug: Sulfasalazine Sulfasalazine will be added at weeks 8,12,16 or 20 if the subject fails to achieve low disease activity, administered orally at a dose of 1g twice daily. Will be discontinued if starting etanercept at 24 weeks. Drug: Hydroxychloroquine Hydroxychloroquine will be added at weeks 8,12,16 or 20 if the subject fails to achieve low disease activity, administered at a dose of 200mg daily. Will be discontinued if starting etanercept at 24 weeks. Drug: Etanercept Etanercept will be added at 24 weeks, if a subject fails to achieve clinical remission,at a dose of 50 mg weekly and will be discontinued at 48 weeks with the exception of those patients who are eligible to continue according to local prescribing guidelines (NICE guidelines)

Arm

Intervention/Treatment

Experimental: Etanercept

Treatment Arm 1 will receive etanercept and methotrexate combination therapy administered for a total duration of 48 weeks.

Drug: Etanercept

Etanercept will be administered subcutaneously at a dose of 50 mg weekly and will be discontinued at the primary endpoint (48 weeks).

Drug: Methotrexate

Methotrexate will be administered orally at a starting dose of 15 mg weekly, increasing to 20mg and 25mg weekly at weeks 4 and 8 respectively.

Active Comparator: Methotrexate-treat to target

Treatment Arm 2 will receive initial methotrexate monotherapy with adoption of a treat to target protocol (standard care involving monthly DAS28-ESR assessment with escalation to combination sDMARD therapy if not achieving LDA at, or after, 8 weeks) and step-up to etanercept and methotrexate at 24 weeks if failing to achieve clinical remission

Drug: Methotrexate

Methotrexate will be administered orally at a starting dose of 15 mg and will be increased to 25mg weekly at 2 weeks.

Drug: Sulfasalazine

Sulfasalazine will be added at weeks 8,12,16 or 20 if the subject fails to achieve low disease activity, administered orally at a dose of 1g twice daily. Will be discontinued if starting etanercept at 24 weeks.

Drug: Hydroxychloroquine

Hydroxychloroquine will be added at weeks 8,12,16 or 20 if the subject fails to achieve low disease activity, administered at a dose of 200mg daily. Will be discontinued if starting etanercept at 24 weeks.

Drug: Etanercept

Etanercept will be added at 24 weeks, if a subject fails to achieve clinical remission,at a dose of 50 mg weekly and will be discontinued at 48 weeks with the exception of those patients who are eligible to continue according to local prescribing guidelines (NICE guidelines)

Outcome Measures

Primary Outcome Measures

Clinical remission [48 weeks]
Proportion of patients that achieve clinical remission (Disease activity Score, DAS28 <2.6) at 48 weeks, following either treatment strategy.

Secondary Outcome Measures

Change in MRI synovitis [baseline and week 48]
Change in MRI synovitis between baseline and 48 weeks.
CDAI (clinical disease activity index) [weeks 12, 24, 48 and 96]
Change in CDAI score from baseline at weeks 12, 24, 48 and 96
SDAI (simplified disease activity index) [weeks 12, 24, 48 and 96]
Change in SDAI score from baseline at weeks 12, 24, 36 & 48.
ACR(American College of Rheumatology) response scores [weeks 12, 24, 48 and 96]
ACR response score from baseline at weeks 12, 24, 48 and 96
EULAR(European League Against Rheumatism)response criteria [weeks 12, 24, 48 and 96]
EULAR response score from baseline
Physical function, assessed by HAQ(health assessment questionnaire) [weeks 12, 24, 48 and 96]
Quality of life scores assessed by RA-QoL(RA quality of life questionnaire) [weeks 12, 24, 48 and 96]
Work instability, assessed by RA-WIS(RA work instability questionnaire) [weeks 12, 24, 48 and 96]
HRUS (High Resolution Ultrasound) [weeks 0, 12, 24 and 48]
Change in HRUS from baseline
Radiographic scores [weeks 48 and 96]
Change in joint damage assessed by modified Sharp score.
Immunological parameters in blood sample [weeks 0, 12, 24 and 48]
Change in immunological markers of inflammation between baseline and weeks 12, 24 and 48.
Immunological parameters in synovial tissue [weeks 0, 24, +/- 48]
Change in immunological markers of inflammation between baseline and weeks 24 and 48.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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) in hand and/or wrist joints evaluable by ultrasound and MRI, and DAS28-ESR>3.2.
Seropositivity for anti-citrullinated peptide antibody (ACPA) and/or rheumatoid factor. If ACPA and rheumatoid factor are both negative, presence of power Doppler in at least 1 joint on ultrasound imaging.
DMARD-naive (with the exception of previous exposure to hydroxychloroquine for an indication other than RA).
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.

Exclusion Criteria:

Previous treatment with DMARDs for the management of RA.
Intramuscular or intra-articular (of non-target joint) corticosteroid within 28 days of the screening visit; intra-articular steroid of the chosen target joint within 12 weeks of screening.
Oral steroid of greater than 10mg prednisolone daily, or change in oral steroid dose within 28 days of study drug initiation at the baseline visit.
Use (including use as required) of more than one 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. In patients with previous penetrating trauma to the eye, or patients at high risk of previous metal foreign body injury to the eye (e.g. welding), skull x-ray will be performed; these patients may be included in the absence of residual metal fragments on x-ray.
Pregnancy or breastfeeding.
Other contraindications to TNFi as determined by local prescribing guidelines and physician discretion, including:
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 evidence of latent TB on chest x-ray/TB testing (in the latter event, 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:
Severe pulmonary disease, defined as requiring previous hospital admission or supplemental oxygen.
Active or severe cardiovascular disease: uncontrolled hypertension, myocardial infarction within 12 months of screening, unstable angina within 6 months of screening.
Other immunodeficiency disorders.
Connective tissue diseases, e.g. primary Sjogren's syndrome, systemic sclerosis, systemic lupus erythematosus, polymyositis.
Psoriasis.
Renal impairment (creatinine ≥ 175µmol/L).
Blood disorders: neutropenia (neutrophils < 2.0 x 109/L), thrombocytopenia (platelets < 125 x 109/L), or anaemia (haemoglobin < 8 g/dL).
Abnormal liver function (alanine transaminase, ALT > 3 x upper limit of normal).
Planned surgery within the study period which is expected to require omission of any study medication of 28 days or more.