Clinical trial NCT02573012: Study to Compare the Efficacy of Tocilizumab With or Without Glucocorticoid Discontinuation in Rheumatoid Arthritis Participants
Official title: Prospective, Multicentre, Placebo-controlled, Double-blind Interventional Study to Compare the Efficacy of Maintenance Treatment With Tocilizumab With or Without Glucocorticoid Discontinuation in Rheumatoid Arthritis Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-10-09
Enrollment: 314
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This Phase IIIb/IV, two-arm, randomized, double-blind, placebo-controlled, parallel-group, international, multicenter trial compares the change in disease activity (as assessed by Disease Activity Score in 28 joints \[DAS28\] erythrocyte sedimentation rate \[ESR\]) from randomization to Week 24 post-randomization, in participants with stable low disease activity \[LDA\] (DAS28 ESR score less than or equal to \[\<=\] 3.2) who receive tocilizumab, and have been randomized to either continue or taper prednisone in a double-blinded fashion.


Eligibility criteria: Inclusion Criteria:

Tocilizumab-experienced participants:

* Comply with the requirements of the study protocol (including treatment on an outpatient basis)
* Rheumatoid arthritis (RA) of greater than or equal to (\>=) 6 months duration diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria or 2010 ACR / European League Against Rheumatism (EULAR) criteria
* Have received tocilizumab either subcutaneous (162 milligram \[mg\] once in a week) or intravenously (8 milligram per kilogram \[mg/kg\] once every 4 weeks) for the treatment of RA for at least 24 weeks prior to randomization
* Have received 5 - 15 milligrams per day \[mg/day\] of glucocorticoids (prednisone or equivalent) for the treatment of RA for at least 20 weeks prior to screening
* Currently receiving 5 mg/day of prednisone
* Have attained and maintained LDA (DAS28 ESR score \<=3.2) or remission (DAS28 ESR score less than \[\<\] 2.6) for at least 4 weeks prior to randomization

Tocilizumab-naïve participants:

* Comply with the requirements of the study protocol (including treatment on an outpatient basis)
* RA of \>=6 months duration diagnosed according to the revised 1987 ACR criteria or 2010 ACR / EULAR criteria
* Have active RA (defined as DAS28 ESR score greater than \[\>\] 3.2)
* Are considered by the investigator as inadequate responders to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or biologic disease-modifying anti-rheumatic drugs (bDMARDs)
* Are receiving 5 - 15 mg/day prednisone (or equivalent) for the treatment of RA

Exclusion Criteria:

General

* Major surgery (including joint surgery) within 8 weeks prior to screening, or planned major surgery during the study and up to 6 months after randomization
* Pregnant women or nursing (breastfeeding) mothers
* In females of childbearing potential, a positive serum pregnancy test at screening
* Females of childbearing potential unwilling or unable to use a reliable means of contraception (for example, physical barrier \[participant or partner\], contraceptive pill or patch, spermicide and barrier, or intrauterine device) during study treatment and for a minimum of 3 months after the last dose of tocilizumab
* Body weight of \>=150 kilogram (kg)
* Lack of peripheral venous access

Disease-related

* RA of functional Class 4, as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
* Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to RA (for example, vasculitis, pulmonary fibrosis, or Felty syndrome). Secondary Sjögren syndrome with RA may be allowed per the discretion of the investigator
* Diagnosed with juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16 years
* Prior or current inflammatory joint disease other than RA (for example, gout, Lyme disease, sero-negative spondyloarthropathy, including reactive arthritis, psoriatic arthritis, arthropathy of inflammatory bowel disease), or prior or current joint infections
* Previous history of primary or secondary adrenal insufficiency

Previous or Concomitant Prohibited Therapy

* Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
* Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies (for example, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD20)
* Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of screening
* Intraarticular (IA) or parenteral glucocorticoids for the treatment of RA within 4 weeks prior to screening
* Previous treatment with glucocorticoids for conditions other than RA, at any dose and in any formulation used continuously for \>1 week, during the last 1 year prior to screening. Topical glucocorticoid creams or ointments for the treatment of skin conditions (for example eczema) are allowed
* Immunization with a live/attenuated vaccine within 30 days prior to screening. Participants must agree not to take live attenuated vaccines (including seasonal nasal flu vaccine, varicella vaccine for shingles or chickenpox, vaccines for measles, mumps or rubella without or with varicella \[MMR or MMRV\], oral polio vaccine and vaccines for yellow fever), within 30 days before the Screening Visit, throughout the duration of the trial and for 60 days following the last dose of study drug
* Any previous treatment with alkylating agents such as chlorambucil or with total lymphoid irradiation

Laboratory Exclusion Criteria

* Inadequate haematological, renal and liver function
* Positive hepatitis B surface antigen or hepatitis C antibody Previous or Concomitant Conditions
* History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
* Evidence of current serious uncontrolled cardiovascular (including uncontrolled hyperlipidemia), nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or gastrointestinal (GI) disease
* Current liver disease as determined by the investigator
* History of diverticulitis, peptic ulcer disease, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower gastrointestinal conditions that might predispose to perforations
* Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other opportunistic infections (including, but not limited to, tuberculosis \[TB\] and atypical mycobacterial disease, hepatitis B and C, Epstein-Barr virus, cytomegalovirus and herpes zoster, but excluding fungal infections of nail beds)
* Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation
* Any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
* Active TB requiring treatment within the previous 3 years (participants previously treated for TB with no recurrence within 3 years are permitted). All Track tocilizumab-naïve participants must be screened for latent TB and if positive, should be treated following local practice guidelines prior to initiating tocilizumab
* History of or currently active, primary or secondary immunodeficiency
* Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including haematological malignancies and solid tumours, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that was excised and cured), or breast cancer diagnosed within the previous 20 years
* History of alcohol, drug or chemical abuse within 1 year prior to screening
* Pre-existing central nervous system (CNS) demyelination or seizure disorders
* Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial

Primary outcomes:
measure: Change From Baseline in Disease Activity Score in 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24 Post-randomization
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: Treatment Success
timeFrame: Week 24
measure: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24
timeFrame: Baseline and Week 24
measure: Percentage of Participants With >=1 Flare
timeFrame: 24 weeks
measure: Time to First RA Flare
timeFrame: Randomization to 24 weeks
measure: Percentage of Visits With RA Flares
timeFrame: Randomization to 24 weeks
measure: Percentage of Participants With >=1 Administration of Flare Rescue Medication
timeFrame: Randomization to 24 weeks
measure: Time to First Administration of Flare Rescue Medication
timeFrame: Randomization to 24 weeks
measure: Number of Administrations of Flare Rescue Medication
timeFrame: Randomization to 24 weeks
measure: Cumulative Prednisone Exposure (Dose)
timeFrame: Randomization to 24 weeks
measure: Percentage of Participants Who Maintain LDA (DAS28 ESR Score <=3.2) or Remission (DAS28 ESR Score <2.6) and the Percentage of Participants Who Maintain the Baseline Disease Activity Level
timeFrame: Randomization to Week 24
measure: Percentage of Participants Who Permanently Discontinue Study Treatment Due to Insufficient Flare Control
timeFrame: 24 weeks
measure: Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Swollen 66 Joint Counts
timeFrame: Baseline to Week 24
measure: Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Tender 68 Joint Counts
timeFrame: Baseline to Week 24
measure: Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Patient's Assessment of Pain
timeFrame: Baseline to Week 24
measure: Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Patient's Global Assessment of Disease Activity
timeFrame: Baseline to Week 24
measure: Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Physician's Global Assessment of Disease Activity
timeFrame: Baseline to Week 24
measure: Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Health Assessment Questionnaire-Disability Index (HAQ-DI)
timeFrame: Baseline to Week 24
measure: Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: High Sensitivity C-Reactive Protein (hsCRP)
timeFrame: Baseline to Week 24
measure: Changes From Baseline in American College of Rheumatology (ACR) Core Set Components at Week 24: Erythrocyte Sedimentation Rate (ESR)
timeFrame: Baseline to Week 24
measure: Changes From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) Final Score
timeFrame: Baseline and Week 24
measure: Changes From Baseline in Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) Score
timeFrame: Baseline and Week 24
measure: Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 24
timeFrame: Randomization to Week 24
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Hopital Pellegrin; Rhumatologie
city: Orleans
country: France
facility: Hopital de La Source
city: Paris
country: France
facility: Hopital Cochin; Rhumatologie B
city: Strasbourg
country: France
facility: Hopital Hautepierre; Rhumatologie
city: Toulouse
country: France
facility: Hopital Purpan; Rhumatologie
city: Aachen
country: Germany
facility: Praxis Dr. med. Reiner Kurthen
city: Bad Abbach
country: Germany
facility: Asklepios Kllinikum Bad Abbach; Klinik für Rheumatologie und Klinische Immunologie
city: Bad Neuenahr-Ahrweiler
country: Germany
facility: Rheumatologische Gemeinschaftspraxis Grafschaft, Dr. med. Dorothea Pick, Dr. med. Christopher Amberg
city: Berlin
country: Germany
facility: Charité Campus Mitte, Med.Klinik, Rheumatologie und Klinische Immunologie
city: Berlin
country: Germany
facility: SchlossPark-Klinik Berlin; Int. Med. II, Rheum. Osteo
city: Dresden
country: Germany
facility: Rheumatologisches MVZ Dresden GmbH, Dres. Holger Schwenke, Reiner Schwenke, Annekatrin Georgi
city: Erfurt
country: Germany
facility: MVZ Ambulantes Rheumazentrum
city: Erlangen
country: Germany
facility: Dres. Florian Schuch, Ruediger de la Camp, Martin Hammerschmidt u.w.
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf Zentrum f.Innere Medizin Med.Klinik III
city: Hamburg
country: Germany
facility: Praxis Dr.med. Maria Höhle
city: Heidelberg
country: Germany
facility: Rheumapraxis PD Dr.med. Bernhard Heilig
city: Köln
country: Germany
facility: Klinik der Uni zu Köln; Klinik für Innere Medizin
city: Magdeburg
country: Germany
facility: Rheumatologische Facharztpraxis Maren Sieburg
city: Magdeburg
country: Germany
facility: SMO.MD GmbH, Zentrum für klinische Studien
city: Muenchen
country: Germany
facility: Praxiszentrum St. Bonifatius
city: München
country: Germany
facility: Klinikum der Universitat Munchen; Bereich Pettenkoferstr; Rheumaeinheit der medizinischen Klinik IV
city: Osnabrück
country: Germany
facility: Rheumapraxis an der Hase
city: Ratingen
country: Germany
facility: Rheumazentrum Ratingen - Studienambulanz
city: Stuttgart
country: Germany
facility: Rheumatologische Schwerpunktpraxis am Feuersee
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg; Medizinische Klinik und Poliklinik II; Rheumatologie/Immunologie
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova; Reumatologia
state: Emilia-Romagna
city: Pavia
country: Italy
facility: Irccs Policlinico San Matteo; Reumatologia Adulti
state: Lombardia
city: Firenze
country: Italy
facility: Ospedale Careggi Villa Monnatessa ; Sezione Di Reumatologia
state: Toscana
city: Novosibirsk
country: Russian Federation
facility: FSBI Scientific Research Institute of Clinical and Experimental Lymphology of SB of RAMS
city: Perm
country: Russian Federation
facility: Perm Regional Clinical Hospital
city: Saint-Petersburg
country: Russian Federation
facility: SBEI of HPE "Northwestern State Medical University n.a. I.I.Mechnikov" of MoH of RF
city: UFA
country: Russian Federation
facility: Republican clinical hospital named after G.G. Kuvatov
city: Vladivostok
country: Russian Federation
facility: City Clinical Hospital # 2
city: Belgrade
country: Serbia
facility: Institute of Rheumatology
city: Belgrade
country: Serbia
facility: Military Medical Academy; Clinic of Rheumatology
city: Niska Banja
country: Serbia
facility: Institute of Rheumatology and Cardiovascular Diseases; Rheumatology
city: Novi Sad
country: Serbia
facility: Clinical Center of Vojvodina
city: Novi Sad
country: Serbia
facility: Special hospital for rheumatic diseases Novi Sad
city: Sousse
country: Tunisia
facility: Hopital Farhat Hached; Service Rhumatologie
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Burmester GR, Buttgereit F, Bernasconi C, Alvaro-Gracia JM, Castro N, Dougados M, Gabay C, van Laar JM, Nebesky JM, Pethoe-Schramm A, Salvarani C, Donath MY, John MR; SEMIRA collaborators. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. Lancet. 2020 Jul 25;396(10246):267-276. doi: 10.1016/S0140-6736(20)30636-X.