Clinical trial NCT02046603: A Study of Tocilizumab (RoActemra/Actemra) in Monotherapy or in Combination With Methotrexate or Other Non-Biologic DMARDs in Participants With Active Rheumatoid Arthritis and an Inadequate Response to Current Non-Biologic DMARD Therapy or the First Anti-TNF Biologic Agent
Official title: Open-Label, Phase IIIb Study to Evaluate the Efficacy and Safety of Subcutaneous (SC) Tocilizumab Monotherapy or Combination Therapy With Methotrexate (MTX) or Other Non-Biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) in Patients With Active Rheumatoid Arthritis (RA) Who Have an Inadequate Response to Current Non-Biologic DMARD Therapy or the First Anti-Tumour Necrosis Factor (Anti-TNF) Biologic Agent
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-01-28
Enrollment: 162
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This open-label study will evaluate the efficacy and safety of tocilizumab as monotherapy or in combination with methotrexate or other non-biologic disease modifying anti-rheumatic drugs (DMARDs) in participants with active rheumatoid arthritis (RA) and an inadequate response to current non-biologic DMARD therapy or the first anti-tumour necrosis factor (anti-TNF) agent. Participants will receive tocilizumab 162 milligrams (mg) subcutaneously once a week for 52 weeks.


Eligibility criteria: Inclusion Criteria:

* Active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria
* Participants who have an inadequate response to current non-biologic DMARD therapy or the first anti-TNF agent (in monotherapy or in combination with MTX or other non-biologic DMARDs). Inadequate response to anti-TNF treatment is defined as DAS28 score improvement of less than 1.2 or participants achieving a DAS28 score improvement of 1.2 but not achieving low disease activity (current DAS28-ESR above 3.2) according to a treat-to-target strategy and have not been previously exposed to treatment with tocilizumab. Inadequate response to non-biologic DMARD therapy will be assessed according to local guidelines and the participants will need to be eligible for biologic therapy according to local guidelines
* Oral corticosteroids (≤10 mg/day prednisone or equivalent) and non-steroidal anti-inflammatory drugs (NSAIDs; up to recommended dose) are permitted if on stable dose regimen for greater than or equal to \[≥\] 4 weeks prior to baseline
* Permitted non-biologic DMARDs are allowed if on stable dose for at least 4 weeks prior to baseline
* Receiving treatment on an outpatient basis, not including tocilizumab
* Females of childbearing potential and males with female partners of childbearing potential must agree to use reliable means of contraception as defined by protocol during the study and for at least 3 months following the last dose of tocilizumab

Exclusion Criteria:

* Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following baseline
* Rheumatic autoimmune disease other than RA
* Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
* Diagnosis of juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16
* Prior history of or current inflammatory joint disease other than RA
* Exposure to tocilizumab either intravenous or SC at any time prior to baseline
* Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
* Intra-articular or parenteral corticosteroids within 4 weeks prior to baseline
* History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
* Known active current or history of recurrent infections
* Major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
* Active tuberculosis (TB) requiring treatment within the previous 3 years
* Positive for hepatitis B or hepatitis C virus infection
* Primary or secondary immunodeficiency (history of or currently active)
* Pregnant or lactating women
* Inadequate hematologic, renal or liver function

Primary outcomes:
measure: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2
timeFrame: Baseline, Week 2
measure: Change From Baseline in DAS28-ESR at Week 4
timeFrame: Baseline, Week 4
measure: Change From Baseline in DAS28-ESR at Week 8
timeFrame: Baseline, Week 8
measure: Change From Baseline in DAS28-ESR at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in DAS28-ESR at Week 16
timeFrame: Baseline, Week 16
measure: Change From Baseline in DAS28-ESR at Week 20
timeFrame: Baseline, Week 20
measure: Change From Baseline in DAS28-ESR at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in DAS28-ESR at Week 28
timeFrame: Baseline, Week 28
measure: Change From Baseline in DAS28-ESR at Week 32
timeFrame: Baseline, Week 32
measure: Change From Baseline in DAS28-ESR at Week 36
timeFrame: Baseline, Week 36
measure: Change From Baseline in DAS28-ESR at Week 40
timeFrame: Baseline, Week 40
measure: Change From Baseline in DAS28-ESR at Week 44
timeFrame: Baseline, Week 44
measure: Change From Baseline in DAS28-ESR at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in DAS28-ESR at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in DAS28-ESR at Early Withdrawal
timeFrame: Baseline, early withdrawal (up to Week 52)
Secondary outcomes:
measure: Number of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Number of Participants Achieving an ACR50 Response
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Number of Participants Achieving an ACR70 Response
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Number of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Percent Change From Baseline in Total TJC on 68 Joints at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Total TJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Percent Change From Baseline in Total SJC on 66 Joints at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Total SJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Number of Participants Who Achieved Low Disease Activity as Defined by DAS28-ESR ≤3.2
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Number of Participants Who Achieved Remission as Defined by DAS28-ESR <2.6
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Number of Participants With Non-Biologic DMARD/Corticosteroid Dose Reductions and/or Discontinuation
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, at early withdrawal (up to Week 52), follow-up Week 4 (up to Week 56), and follow-up Week 8 (up to Week 60)
measure: Percentage of Methotrexate Adherence as Assessed by Methotrexate Adherence Questionnaire
timeFrame: Baseline, Weeks 12, 24, 36, 52, and at early withdrawal (up to Week 52)
measure: Patient Global Assessment of Disease Activity VAS Score
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Patient Pain VAS Score
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Health Assessment Questionnaire-Disability Index (HAQ-DI) Score
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Number of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)
measure: Number of Participants With Anti-Tocilizumab Antibodies
timeFrame: Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)
measure: Serum Levels of Tocilizumab
timeFrame: Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)
measure: Serum Levels of Soluble Interleukin-6 Receptors (sIL-6Rs)
timeFrame: Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)
Other outcomes:
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Bournemouth
country: United Kingdom
facility: Christchurch Hospital; Rheumatology
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital; Clinical Investigation Research Unit
city: Burton on Trent
country: United Kingdom
facility: Queens Hospital
city: Bury Saint Edmonds
country: United Kingdom
facility: West Suffolk Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke'S Hospital; Rheumatology Research Unit
city: Cannock
country: United Kingdom
facility: Cannock Chase Hospital; Rheumatology
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales; Dept of Rhematology
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital; Dept of Rheumatology
city: Dewsbury
country: United Kingdom
facility: Dewsbury & District Hospital; Dept of Rheumatology
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital; Rheumatology Department
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Eastbourne
country: United Kingdom
facility: Eastbourne District General Hospital; Dept of Rheumatology
city: Edinburgh
country: United Kingdom
facility: Western General Hospital; Pharmacy Department
city: Glasgow
country: United Kingdom
facility: Gartnavel General Hospital; Rheumatology
city: Grimsby
country: United Kingdom
facility: Diana Princess of Wales Hosp.
city: Harlow
country: United Kingdom
facility: Princess Alexandra Hospital
city: Harrow
country: United Kingdom
facility: Northwick Park Hospital
city: Hemel Hempstead
country: United Kingdom
facility: Hemel Hempstead General Hospital; Rheumatology Dept
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary; Rheumatology Department
city: Llandudno
country: United Kingdom
facility: Llandudno General Hospital
city: London
country: United Kingdom
facility: Whipps Cross Hospital; Rheumatology Dept
city: London
country: United Kingdom
facility: Royal Free Hospital; Department of Rheumatology
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital; Dept of Rheumatology
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital; Dept of Rheumatology
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich Hospital; Rheumatology
city: Oldham
country: United Kingdom
facility: Integrated Care Centre
city: Solihull
country: United Kingdom
facility: Solihull Hospital
city: Stoke-on-trent
country: United Kingdom
facility: Haywood Hospital; Staffordshire Rheumatology Centre
city: Swindon
country: United Kingdom
facility: Great Western Hospital; Dept of Rheumatology
city: Torquay
country: United Kingdom
facility: Torbay Hospital; Dept of Rhematology
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital; Rhuematololgy Dept
city: Warrington
country: United Kingdom
facility: Warrington Hospital
city: Wigan
country: United Kingdom
facility: Wrightington Hospital; Rheumatology
city: Wishaw
country: United Kingdom
facility: Wishaw General Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Isaacs JD, Salih A, Sheeran T, Patel YI, Douglas K, McKay ND, Naisbett-Groet B, Choy E. Efficacy and safety of subcutaneous tocilizumab in rheumatoid arthritis over 1 year: a UK real-world, open-label study. Rheumatol Adv Pract. 2019 Apr 19;3(1):rkz010. doi: 10.1093/rap/rkz010. eCollection 2019.
citation: Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Devenport J, Petho-Schramm A. Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis. Rheumatology (Oxford). 2019 Jun 1;58(6):1056-1064. doi: 10.1093/rheumatology/key393.
citation: Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Bernasconi C, Petho-Schramm A. Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries. Rheumatology (Oxford). 2018 Mar 1;57(3):499-507. doi: 10.1093/rheumatology/kex443.