Study to Compare the Efficacy of Tocilizumab With or Without Glucocorticoid Discontinuation in Rheumatoid Arthritis Participants

NCT ID: NCT02573012

Last Updated: 2019-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 314 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-03-29
• Study Completion Date: 2018-02-09

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.

Conditions

Rheumatoid Arthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Tocilizumab+prednisone (constant dose)

Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) or matching placebo orally for 24 weeks.

Group Type: EXPERIMENTAL

Placebo matched to prednisone

Intervention Type: DRUG

Participants will receive placebo matched to prednisone orally for 24 weeks.

Prednisone

Intervention Type: DRUG

Participants will receive prednisone either at a constant dose of 5 mg/day, or 5 mg/day with 1 mg decrements every 4 weeks orally for 24 weeks.

Tocilizumab

Intervention Type: BIOLOGICAL

Participants will receive tocilizumab at a dose of 162 mg once a week subcutaneously for 24 weeks.

Tocilizumab+prednisone (tapering dose)

Participants will receive tocilizumab at a dose of 162 milligram (mg) once a week subcutaneously; and prednisone at a dose of 5 milligram per day (mg/day) with 1 mg decrements every 4 weeks or matching placebo orally for 24 weeks.

Group Type: EXPERIMENTAL

Placebo matched to prednisone

Intervention Type: DRUG

Participants will receive placebo matched to prednisone orally for 24 weeks.

Prednisone

Intervention Type: DRUG

Participants will receive prednisone either at a constant dose of 5 mg/day, or 5 mg/day with 1 mg decrements every 4 weeks orally for 24 weeks.

Tocilizumab

Intervention Type: BIOLOGICAL

Participants will receive tocilizumab at a dose of 162 mg once a week subcutaneously for 24 weeks.

Interventions

Placebo matched to prednisone

Participants will receive placebo matched to prednisone orally for 24 weeks.

Intervention Type: DRUG

Prednisone

Participants will receive prednisone either at a constant dose of 5 mg/day, or 5 mg/day with 1 mg decrements every 4 weeks orally for 24 weeks.

Intervention Type: DRUG

Tocilizumab

Participants will receive tocilizumab at a dose of 162 mg once a week subcutaneously for 24 weeks.

Intervention Type: BIOLOGICAL

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

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Hopital Pellegrin; Rhumatologie

Bordeaux, , France

Hopital de La Source

Orléans, , France

Hopital Cochin; Rhumatologie B

Paris, , France

Hopital Hautepierre; Rhumatologie

Strasbourg, , France

Hopital Purpan; Rhumatologie

Toulouse, , France

Praxis Dr. med. Reiner Kurthen

Aachen, , Germany

Asklepios Kllinikum Bad Abbach; Klinik für Rheumatologie und Klinische Immunologie

Bad Abbach, , Germany

Rheumatologische Gemeinschaftspraxis Grafschaft, Dr. med. Dorothea Pick, Dr. med. Christopher Amberg

Bad Neuenahr-Ahrweiler, , Germany

Charité Campus Mitte, Med.Klinik, Rheumatologie und Klinische Immunologie

Berlin, , Germany

SchlossPark-Klinik Berlin; Int. Med. II, Rheum. Osteo

Berlin, , Germany

Klinik der Uni zu Köln; Klinik für Innere Medizin

Cologne, , Germany

Rheumatologisches MVZ Dresden GmbH, Dres. Holger Schwenke, Reiner Schwenke, Annekatrin Georgi

Dresden, , Germany

MVZ Ambulantes Rheumazentrum

Erfurt, , Germany

Dres. Florian Schuch, Ruediger de la Camp, Martin Hammerschmidt u.w.

Erlangen, , Germany

Universitätsklinikum Hamburg-Eppendorf Zentrum f.Innere Medizin Med.Klinik III

Hamburg, , Germany

Praxis Dr.med. Maria Höhle

Hamburg, , Germany

Rheumapraxis PD Dr.med. Bernhard Heilig

Heidelberg, , Germany

Rheumatologische Facharztpraxis Maren Sieburg

Magdeburg, , Germany

SMO.MD GmbH, Zentrum für klinische Studien

Magdeburg, , Germany

Klinikum der Universitat Munchen; Bereich Pettenkoferstr; Rheumaeinheit der medizinischen Klinik IV

München, , Germany

Praxiszentrum St. Bonifatius

München, , Germany

Rheumapraxis an der Hase

Osnabrück, , Germany

Rheumazentrum Ratingen - Studienambulanz

Ratingen, , Germany

Rheumatologische Schwerpunktpraxis am Feuersee

Stuttgart, , Germany

Universitätsklinikum Würzburg; Medizinische Klinik und Poliklinik II; Rheumatologie/Immunologie

Würzburg, , Germany

Arcispedale Santa Maria Nuova; Reumatologia

Reggio Emilia, Emilia-Romagna, Italy

Irccs Policlinico San Matteo; Reumatologia Adulti

Pavia, Lombardy, Italy

Ospedale Careggi Villa Monnatessa ; Sezione Di Reumatologia

Florence, Tuscany, Italy

FSBI Scientific Research Institute of Clinical and Experimental Lymphology of SB of RAMS

Novosibirsk, , Russia

Perm Regional Clinical Hospital

Perm, , Russia

SBEI of HPE "Northwestern State Medical University n.a. I.I.Mechnikov" of MoH of RF

Saint Petersburg, , Russia

Republican clinical hospital named after G.G. Kuvatov

Ufa, , Russia

City Clinical Hospital # 2

Vladivostok, , Russia

Institute of Rheumatology

Belgrade, , Serbia

Military Medical Academy; Clinic of Rheumatology

Belgrade, , Serbia

Institute of Rheumatology and Cardiovascular Diseases; Rheumatology

Niška Banja, , Serbia

Clinical Center of Vojvodina

Novi Sad, , Serbia

Special hospital for rheumatic diseases Novi Sad

Novi Sad, , Serbia

Hopital Farhat Hached; Service Rhumatologie

Sousse, , Tunisia

Countries

France; Germany; Italy; Russia; Serbia; Tunisia

References

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.

Reference Type: DERIVED

PMID: 32711802 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2014-004673-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MA29585

Identifier Type: -

Identifier Source: org_study_id