Targeted Treatment Early With Etanercept + Methotrexate vs.T2T Care for DMARD-naïve Early RA Patients Based on naïve T-cell Stratification (TEEMS)

Targeted Treatment Early With Etanercept Plus Methotrexate Versus T2T Care for DMARD-naïve Early RA Patients. A Prospective, Longitudinal Cohort Study With Embedded Pilot Randomised Controlled Trial to Assess Treatment Rationalisation Based on naïve T-cell Stratification.

The main aim of the study is to determine the clinical utility of naive T-cell stratification for rationalising treatment with methotrexate (MTX), for DMARD-naive early RA patients. Thus, it aims to determine whether TNFi therapy (Benepali) instituted as first-line therapy in DMARD-naive early RA patients with poor T-cell prognostication confers better outcomes (clinical, structural and immunological). Hence, this would enable early targeted treatment for those with a poorer prognosis based on their immunological status.

Study Overview

• Status: Not yet recruiting
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Benepali; Drug: Methotrexate; Drug: Sulfasalazine; Drug: Hydroxychloroquine

Detailed Description

The current optimal therapeutic approach in early RA is to start MTX to target inflammation and induce remission.Prediction of MTX therapy response remains a key clinical need to enable the identification of patients who would benefit from an alternative, more aggressive treatment strategy. Multiple predictors of remission with MTX have been reported over the years but none have entered routine clinical practice.

We previously reported that T-cell phenotyping at baseline could predict remission in DMARD-naïve early RA treated with MTX. Reduced naïve CD4+ T-cell frequency was the most predictive factor, using both a pilot and a replication cohort.These data confirmed the potential value of using naïve CD4+ T-cells as a biomarker of MTX induced remission in early RA.

The clinical utility of measuring T-cell subsets is therefore strongly indicated by these data and suggests that measurement of T- cell subsets can be used to rationalise the use of MTX as first-line therapy.Predicting response to MTX has important clinical value to identify patients who will do well on MTX but furthermore for directing those who will have a sub-optimal response to MTX to receive alternative therapy without any harmful delay and in line with the treat to target principle.

The current study aims to confirm/validate the clinical value of T-cell subset quantification for the prediction of MTX response in early RA, by stratified interventions based on baseline naïve CD4+ T-cell status.

This is a Single centre, phase IV, open-label, prospective, longitudinal cohort study with an embedded pilot randomised controlled trial that aims to assess whether MTX can be rationalised as a first-line treatment for DMARD-naïve early RA patients, according to baseline naïve CD4+ T-cell stratification.

Patients with newly diagnosed RA satisfying the inclusion criteria will be recruited from our early arthritis clinic. Eligible patients will be provided with written information on the study and will be given a minimum of 24 hours to read this information prior to being contacted by a research nurse (within one week). If interested they will be invited to a screening appointment within four weeks to confirm eligibility, obtain written consent and to collect the necessary clinical and laboratory data as per the study schedule. Following the screening visit, patients will attend a baseline assessment within four weeks.

Patients will be stratified based on their naïve CD4+ T-cell frequency (normal or abnormal based on our pre-defined cut-off values according to age and sex-matched controls). Patients with a normal T-cell frequency (Arm A) will commence MTX 15mg/week PO (+HCQ 400mg od) as per standard T2T practice. Follow-up (4, 12 and 24 weeks), dose escalation of MTX and treatment of flare will also be conducted in line with T2T care.

Patients with an abnormal T-cell frequency will be randomized 1:1 into 2 groups using randomly permuted block sizes and also followed up as per T2T care:

The first group (Arm B) will receive MTX 15mg/week PO (+HCQ 400mg od) The second group (Arm C) will receive MTX 15mg/week PO (+HCQ 400mg od) in combination with 50 mg subcutaneous Benepali® administered weekly.

Patients will be followed up for a period of 24 weeks and will undergo clinical, immunological and imaging assessments as stated in the study schedule. Following completion of the study, patients will either be followed up in our established inflammatory arthritis or biologics clinic. Patients in group C will discontinue their Benepali®.

This study will take place at the rheumatology out-patient department in Chapel Allerton Hospital, Leeds.

• Study Type: Interventional
• Enrollment (Anticipated): 106
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: James Goulding; Phone Number: 0113 392 4495; Email: j.t.r.goulding@leeds.ac.uk

Study Locations

• United Kingdom
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS7 4SA
      • Institute of Rheumatic & Musculoskeletal Medicine, Chapel Allerton Hospital
      • Contact: Paul Emery, Professor; Email: p.emery@leeds.ac.uk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subject has a diagnosis of RA as defined by the new ACR/EULAR 2010 classification criteria
• Newly diagnosed (within 12 weeks)
• Active disease at screening (DAS28ESR ≥3.2 or clinical evidence of synovitis)
• Anti-citrillunated protein antibody (ACPA) positive
• Male & female subjects ≥18 years old
• DMARD (disease modifying anti-rheumatic drug) naïve
• No use of intra-muscular, intra-articular or oral corticosteroids 4 weeks days prior to screening
• 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.
• Patients must have the capacity and be willing to provide written informed consent and comply with the requirements of the protocol
• Subjects should be deemed to be in good health with respect to clinical examination and screening blood tests, including full blood count (FBC), urea and electrolytes (U&E), and liver functions tests (LFT) - see exclusion criteria for further details

Exclusion Criteria:

• Use of any additional investigational medications or products within 28 days of screening (including prior to screening)
• Use of intra-muscular/intra-articular or oral corticosteroids within 28 days prior to screening
• 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.
• Live vaccine within <28 days prior to screening
• Pregnant/lactating women or planning pregnancy within 24 weeks of last protocol treatment
• Planned surgery within the study period (requiring omission of study medication > 28 days
• The presence of other comorbidities, which the physician deems as significant to interfere with evaluation (musculoskeletal condition such as osteoarthritis & fibromyalgia)
• Diagnosis of another inflammatory arthritis or connective tissue disease (e.g. psoriatic arthritis or Ankylosing spondylitis, primary Sjogren's syndrome, systemic sclerosis, systemic lupus erythematosus, polymyositis)
• Concomitant severe infection requiring intravenous therapy 4 weeks (28) days prior to screening
• Any contraindication to conventional DMARD's/anti-TNF therapy

• Patients with abnormal liver function at the time of screening or abnormal blood tests as shown by:

  • Aminotransferase (AST) / alanine aminotransferase (ALT) > 3x upper limit of normal (ULN) OR Bilirubin > 50µmol/L
  • Serum Creatinine > 175 umol/L
  • eGFR below 30ml/L/min/1.73m2
  • neutrophils < 2000 x 106/L
  • Platelets < 125 x 109/L
  • Haemoglobin < 90 g/L for males and < 85 g/L for females

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Abnormal T-cells: Benepali + T2T Care; Treatment Arm C will receive Benepali and methotrexate combination therapy and followed as per T2T care over a total duration of 24 weeks. Sulfasalazine or Hydroxychloroquine may be added to therapy at follow up visits in-line with T2T care. Benepali will be administered subcutaneously at a dose of 50mg weekly and discontinued at the primary endpoint (24 weeks). Methotrexate will be administered orally at a starting dose of 15mg weekly. It may be increased in line with T2T care (to a maximum of 25mg) over the 24 weeks.	Drug: Benepali; Benepali will be adminstered subcutaneously at a dose of 50mg weekly and discontinued at the primary endpoint (24 weeks).; Other Names: Etanercept; Drug: Methotrexate; Methotrexate will be administered orally at a starting dose of 15mg weekly. It may be increased in line with T2T care (to a maximum of 25mg) over the 24 weeks.
Active Comparator: Abnormal T-cells: Methotrexate + T2T Care; Treatment Arm B will receive initial methotrexate monotherapy with adoption of a treat to target protocol (standard care involving monthly DAS28-ESR assessment with escalation to combination synthetic DMARD (Including sulfasalazine and/or hydroxychloroquine). therapy if not achieving low disease activity (LDA) at, or after, 8 weeks).	Drug: Methotrexate; Methotrexate will be administered orally at a starting dose of 15mg weekly. It may be increased in line with T2T care (to a maximum of 25mg) over the 24 weeks.; Drug: Sulfasalazine; Sulfasalazine will be added at follow up visits (T2T care) if the subject fails to achieve low disease activity,administered orally at a dose of 1g twice daily.; Drug: Hydroxychloroquine; Hydroxychloroquine will be added at follow up visits (T2T care) if the subject fails to achieve low diseaseactivity, administered at a dose of 200mg daily.
Other: Normal T-cells: Methotrexate + T2T Care; Treatment Arm A will receive standard T2T care as per Arm B.	Drug: Methotrexate; Methotrexate will be administered orally at a starting dose of 15mg weekly. It may be increased in line with T2T care (to a maximum of 25mg) over the 24 weeks.; Drug: Sulfasalazine; Sulfasalazine will be added at follow up visits (T2T care) if the subject fails to achieve low disease activity,administered orally at a dose of 1g twice daily.; Drug: Hydroxychloroquine; Hydroxychloroquine will be added at follow up visits (T2T care) if the subject fails to achieve low diseaseactivity, administered at a dose of 200mg daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Remission at 24 weeks (Arms A vs B)	The difference in the proportions of patients in clinical remission (DAS28ESR ≤2.6) at 24 weeks of first-line methotrexate with T2T care between those with normal (Arm A) vs. abnormal (Arm B) naïve CD4+ T-cell frequencies	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Remission at 12 weeks (Arms A vs B)	The difference in the proportions of patients in clinical remission (DAS28ESR ≤2.6) after 12 weeks of first-line methotrexate with T2T care between those with normal (Arm A) vs. abnormal (Arm B) naïve CD4+ T-cell frequencies	12 weeks
Clinical Remission at 12 and 24 weeks (Arms B vs C)	The difference in the proportions of patients in clinical remission (DAS28ESR ≤2.6) at 12 weeks and 24 weeks for patients with abnormal baseline naïve CD4+ T-cell frequencies receiving methotrexate with T2T care (Arm B) vs. etanercept + methotrexate (Arm C)	12 and 24 weeks
Sustained Clinical Remission	The difference in the proportions of patients achieving sustained clinical remission (DAS28ESR ≤2.6 at both 12 and 24 weeks) (Arm A vs. Arm B and Arm B vs. Arm C)	12 and 24 weeks
Patient Reported Outcomes at 12 and 24 weeks (Arm A vs B)	The differences in the medians of patient-reported outcome measures (EMS, VAS scales, HAQ-DI) after 12 weeks & 24 weeks of first-line methotrexate with T2T care between those with normal (Arm A) vs. abnormal (Arm B) naïve CD4+ T-cell frequencies	12 and 24 weeks
Patient Reported Outcomes at 12 and 24 weeks (Arm B vs C)	The differences in the medians of patient-reported outcome measures (EMS, VAS scales, HAQ-DI) after 12 weeks & 24 weeks for patients with abnormal baseline naïve CD4+ T-cell frequencies receiving methotrexate with T2T care (Arm B) vs. etanercept + methotrexate (Arm C)	12 and 24 weeks
Imaging Remission at 24 weeks (Arm A vs B)	The difference in the proportions of patients in imaging remission (Total power doppler synovitis score=0) after 24 weeks of first-line methotrexate with T2T care between those with normal (Arm A) or abnormal (Arm B) naïve CD4+ T-cell frequencies	24 weeks
Imaging Remission at 24 weeks (Arm B vs C)	The difference in the proportions of patients in imaging remission (Total power doppler synovitis score = 0) at 24 weeks for patients with abnormal baseline naïve CD4+ T-cell frequencies receiving methotrexate with T2T care (Arm B) vs. etanercept + methotrexate (Arm C)	24 weeks
Immunological Remission	The difference in the proportion of patients with normal naïve CD4+ T-cells at 24 weeks for patients with abnormal baseline naïve CD4+ T-cells receiving methotrexate with T2T care (Arm B) vs. etanercept + methotrexate (Arm C)	24 weeks
Cumulative Steroid Use	The difference in the average (median) cumulative amount of intramuscular corticosteroid use at 24 weeks between study arms (Arm A vs. Arm B and Arm B vs. Arm C). This will include any administered at the 24 week visit.	24 weeks

Collaborators and Investigators

• Sponsor: University of Leeds
• Collaborators: Samsung Bioepis Co., Ltd.
• Investigators: Principal Investigator: Paul Emery, Professor, Institute of Rheumatic & Musculoskeletal Medicine, Chapel Allerton Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2019
• Primary Completion (Anticipated): February 1, 2023
• Study Completion (Anticipated): February 1, 2023

Study Registration Dates

• First Submitted: September 12, 2018
• First Submitted That Met QC Criteria: January 21, 2019
• First Posted (Actual): January 23, 2019

Study Record Updates

• Last Update Posted (Actual): January 23, 2019
• Last Update Submitted That Met QC Criteria: January 21, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: T-cells; Treat to Target; DMARD-naive; Benepali
• 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: RR16/209; 2016-002344-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No