Very Early Versus Delayed Etanercept in Patients With RA (VEDERA)

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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Etanercept; Drug: Methotrexate; Drug: Etanercept; Drug: Methotrexate; Drug: Sulfasalazine; Drug: Hydroxychloroquine

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS7 4SA
      • Institute of Rheumatic & Musculoskeletal Medicine, Chapel Allerton Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 and will be increased to 25mg weekly at 2 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); 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: 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 and will be increased to 25mg weekly at 2 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); 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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical remission	Proportion of patients that achieve clinical remission (Disease activity Score, DAS28 <2.6) at 48 weeks, following either treatment strategy.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in MRI synovitis	Change in MRI synovitis between baseline and 48 weeks.	baseline and week 48
CDAI (clinical disease activity index)	Change in CDAI score from baseline at weeks 12, 24, 48 and 96	weeks 12, 24, 48 and 96
SDAI (simplified disease activity index)	Change in SDAI score from baseline at weeks 12, 24, 36 & 48.	weeks 12, 24, 48 and 96
ACR(American College of Rheumatology) response scores	ACR response score from baseline at weeks 12, 24, 48 and 96	weeks 12, 24, 48 and 96
EULAR(European League Against Rheumatism)response criteria	EULAR response score from baseline	weeks 12, 24, 48 and 96
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)	Change in HRUS from baseline	weeks 0, 12, 24 and 48
Radiographic scores	Change in joint damage assessed by modified Sharp score.	weeks 48 and 96
Immunological parameters in blood sample	Change in immunological markers of inflammation between baseline and weeks 12, 24 and 48.	weeks 0, 12, 24 and 48
Immunological parameters in synovial tissue	Change in immunological markers of inflammation between baseline and weeks 24 and 48.	weeks 0, 24, +/- 48

Collaborators and Investigators

• Sponsor: University of Leeds

Publications and helpful links

General Publications

• Emery P, Horton S, Dumitru RB, Naraghi K, van der Heijde D, Wakefield RJ, Hensor EMA, Buch MH. Pragmatic randomised controlled trial of very early etanercept and MTX versus MTX with delayed etanercept in RA: the VEDERA trial. Ann Rheum Dis. 2020 Apr;79(4):464-471. doi: 10.1136/annrheumdis-2019-216539. Epub 2020 Jan 29. Erratum In: Ann Rheum Dis. 2021 Mar;80(3):e45.
• Dumitru RB, Horton S, Hodgson R, Wakefield RJ, Hensor EMA, Emery P, Buch MH. 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). BMC Musculoskelet Disord. 2016 Feb 5;17:61. doi: 10.1186/s12891-016-0915-0.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2011
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): July 1, 2019

Study Registration Dates

• First Submitted: April 23, 2015
• First Submitted That Met QC Criteria: April 28, 2015
• First Posted (Estimate): May 4, 2015

Study Record Updates

• Last Update Posted (Actual): September 9, 2019
• Last Update Submitted That Met QC Criteria: September 5, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Etanercept; treat to target; Disease Modifying Antirheumatic Drugs (DMARDs)
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Reproductive Control Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Etanercept; Methotrexate; Hydroxychloroquine; Sulfasalazine
• Other Study ID Numbers: RR10/9592