Very Early Versus Delayed Etanercept in Patients With RA

NCT02433184 | Completed Phase 4

• 1 other identifier: RR10/9592
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

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.

Conditions

Rheumatoid Arthritis

Keywords

Etanercept; treat to target; Disease Modifying Antirheumatic Drugs (DMARDs)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• Change in MRI synovitis

  baseline and week 48

• CDAI (clinical disease activity index)

  weeks 12, 24, 48 and 96

• SDAI (simplified disease activity index)

  weeks 12, 24, 48 and 96

• ACR(American College of Rheumatology) response scores

  weeks 12, 24, 48 and 96

• EULAR(European League Against Rheumatism)response criteria

  weeks 12, 24, 48 and 96

Study Arms (2)

Etanercept

EXPERIMENTAL

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

Drug: Etanercept; Drug: Methotrexate

Methotrexate-treat to target

ACTIVE COMPARATOR

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; Drug: Sulfasalazine; Drug: Hydroxychloroquine; Drug: Etanercept

Interventions

Etanercept DRUG

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

Etanercept

Methotrexate DRUG

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

Methotrexate-treat to target

Sulfasalazine DRUG

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.

Methotrexate-treat to target

Hydroxychloroquine DRUG

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.

Methotrexate-treat to target

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Leeds: lead

Study Sites (1)

Institute of Rheumatic & Musculoskeletal Medicine, Chapel Allerton Hospital

Leeds, West Yorkshire, LS7 4SA, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 31996367 DERIVED

• 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.

  PMID: 26847108 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Etanercept; Methotrexate; Sulfasalazine; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Chloroquine; Aminoquinolines; Quinolines

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: NIHR Clinician Scientist, Senior Lecturer/Honorary Consultant Rheumatologist

Study Record Dates

• First Submitted: April 23, 2015
• First Posted: May 4, 2015
• Study Start: July 1, 2011
• Primary Completion: August 1, 2017
• Study Completion: July 1, 2019
• Last Updated: September 9, 2019

Record last verified: 2019-09

Locations

GB (1)