Clinical trial NCT01791153: An Efficacy and Safety Study of Tocilizumab (RoActemra/Actemra) in Participants With Giant Cell Arteritis (GCA)
Official title: A Phase III, Multicenter, Randomized, Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab in Subjects With Giant Cell Arteritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Giant Cell Arteritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-02-13
Enrollment: 251
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of tocilizumab in participants with GCA. The study will consist of 2 parts: a 52-week double-blind treatment period (Part 1) followed by a 104-week open label long-term follow-up period (Part 2). In Part 1 of the study eligible participants will be randomized to receive either tocilizumab every week (qw) or every 2 weeks (q2w) or placebo for 52 weeks, with tapering oral daily doses of prednisone. After Week 52, participants in remission will stop study treatment and enter long-term follow-up, whereas participants with disease activity or flares will receive open-label tocilizumab or other treatment at the discretion of the investigator for a maximum period of 104 weeks.


Eligibility criteria: Inclusion Criteria:

* Diagnosis of GCA classified according to age \>/=50 years; history of ESR \>/=50 mm/hr or history of CRP \>/=2.45 mg/dL; and at least one of the following: unequivocal cranial symptoms of GCA or symptoms of polymyalgia rheumatica \[PMR\]; and at least one of the following: temporal artery biopsy revealing features of GCA or evidence of large-vessel vasculitis by angiography or cross-sectional imaging
* New onset (diagnosis within 6 weeks of baseline) or refractory (diagnosis greater than \[\>\] 6 weeks before baseline and previous treatment with \>/= 40 milligrams per day prednisone \[or equivalent\] for at least 2 consecutive weeks at any time) GCA
* Active disease (presence of clinical signs and symptoms \[cranial or PMR\] and ESR \>/=30 mm/hour or CRP \>/=1 mg/dL) within 6 weeks of baseline visit

Exclusion Criteria:

* Major surgery within 8 weeks prior to screening or planned within 12 months after randomization
* Transplanted organs (except corneas with transplant performed \>3 months prior to screening)
* Major ischemic event, unrelated to GCA, within 12 weeks of screening
* Prior treatment with any of the following: investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening; cell-depleting therapies including investigational agent; intravenous (IV) gamma globulin or plasmapheresis within 6 months of baseline; alkylating agents or with total lymphoid irradiation; tocilizumab; hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate mofetil within 4 weeks of baseline; etanercept within 2 weeks of baseline; infliximab, certolizumab, golimumab, abatacept, or adalimumab within 8 weeks of baseline; anakinra within 1 week of baseline; tofacitinib; cyclophosphamide within 6 months of baseline; \>100 milligrams of daily IV methylprednisolone within 6 weeks of baseline
* Participants requiring systemic glucocorticoids for conditions other than GCA, which, in the opinion of the investigator, would interfere with adherence to the fixed glucocorticoid taper regimen and/or to assessment of efficacy in response to the test article
* History of severe allergic reactions to monoclonal antibodies or to prednisone
* Evidence of serious uncontrolled concomitant disease (for example, cardiovascular, respiratory, renal, endocrine, psychiatric, corneal ulcers/injuries, or gastrointestinal \[GI\] disease)
* Current liver disease, as determined by the investigator
* History of diverticulitis, inflammatory bowel disease, or other symptomatic GI tract condition that might predispose to bowel perforation
* Known active or history of recurrent bacterial, viral fungal, mycobacterial, or other infection
* Primary or secondary immunodeficiency
* Evidence of malignancies diagnosed within previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and cured)
* Inadequate hematologic, renal or liver function
* Positive for hepatitis B or hepatitis C infection

Primary outcomes:
measure: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 26 Weeks Prednisone Taper)
timeFrame: Week 52
Secondary outcomes:
measure: Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 52 Weeks Prednisone Taper)
timeFrame: Week 52
measure: Time to First GCA Disease Flare
timeFrame: Up to 52 weeks
measure: Total Cumulative Prednisone Dose
timeFrame: Up to 52 weeks
measure: Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52
timeFrame: Baseline, Week 52
measure: Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52
timeFrame: Baseline, Week 52
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab
timeFrame: Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])
measure: Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab
timeFrame: Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])
measure: Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab
timeFrame: Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0])
measure: Minimum Observed Serum Concentration (Ctrough) of Tocilizumab
timeFrame: Predose (Hour 0) at Baseline and Week 52
measure: Serum Interleukin-6 (IL-6) Level
timeFrame: Baseline and Week 52
measure: Serum Soluble IL-6 Receptor (sIL-6R) Level
timeFrame: Baseline and Week 52
measure: Erythrocyte Sedimentation Rate (ESR)
timeFrame: Baseline and Week 52
measure: C-Reactive Protein (CRP) Level
timeFrame: Baseline and Week 52
measure: Percentage of Participants With Anti-Tocilizumab Antibodies
timeFrame: Baseline up to Week 52
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Univ of Calif., Los Angeles; Rheumatology
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Boca Raton
country: United States
facility: Rheumatology Assoc. of S. Florida - Clinical Research Center
state: Florida
city: Sarasota
country: United States
facility: Sarasota Arthritis Res Center
state: Florida
city: Paducah
country: United States
facility: Four Rivers Clinical Research Inc.
state: Kentucky
city: Portland
country: United States
facility: Rheumatology Associates
state: Maine
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Clair Shores
country: United States
facility: Shores Rheumatology
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: Hospital For Special Surgery; Dept of Medicine - Rheumatology
state: New York
city: Asheville
country: United States
facility: Asheville Arthritis & Osteoporosis Center, PA
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah; Division of Rheumatology
state: Utah
city: Wausau
country: United States
facility: Marshfield Clinic Wausau Ctr
state: Wisconsin
city: Bruxelles
country: Belgium
facility: Hospital Erasme
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Trois-rivieres
country: Canada
facility: Clin. de Rhumatologie
state: Quebec
city: Hillerod
country: Denmark
facility: Nordsjællands Hospital - Hillerød;Department of Rheumatology 0731
city: Bobigny
country: France
facility: Hopital Avicenne; Medecine Interne H5
city: Brest
country: France
facility: Hopital La Cavale Blanche; Rhumatologie
city: Lille
country: France
facility: Hopital Claude Huriez; Internal Medicine
city: Marseille
country: France
facility: Hôpital de la Conception
city: Mulhouse
country: France
facility: Hopital Emile Muller; Medecine Interne
city: Paris
country: France
facility: Hopital Cochin; Medecine Interne
city: Bad Abbach
country: Germany
facility: Asklepios Kllinikum Bad Abbach; Klinik für Rheumatologie und Klinische Immunologie
city: Bad Bramstedt
country: Germany
facility: Rheuma-Klinikum Bad Bramstedt Klinik fuer Rheumatologie und Immunologie
city: Berlin
country: Germany
facility: Charité Campus Mitte, Med.Klinik, Rheumatologie und Klinische Immunologie
city: Berlin
country: Germany
facility: Schlosspark Klinik; Abt. Rheumatologie
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik III
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen; Medizinische Klinik 3; Rheumatologie und Immunologie
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Hannover
country: Germany
facility: Medizinische Hochschule Zentrum Innere Medizin Abt.Klinische Immunologie und Rheumatologie
city: Herne
country: Germany
facility: Rheumazentrum-Ruhrgebiet, St. Josefs-Krankenhaus; Rheumatologie
city: Jena
country: Germany
facility: Universitätsklinikum Jena; Klinik für Innere Medizin III
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Medizinische Klinik, Pneumologie
city: München
country: Germany
facility: Klinikum der Universitat Munchen; Bereich Pettenkoferstr; Rheumaeinheit der medizinischen Klinik IV
city: Plochingen
country: Germany
facility: Kreiskliniken Esslingen gGmbH Klinik Plochingen Medizinische Klinik
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova; Reumatologia
state: Emilia-Romagna
city: Udine
country: Italy
facility: Policlinico Univ. Uni Degli Sudi Di Udine; Clinica Di Reumatologia
state: Friuli-Venezia Giulia
city: Genova
country: Italy
facility: Università Degli Studi Di Genova - Dimi; Reumatologia
state: Liguria
city: Milano
country: Italy
facility: Irccs San Raffele; Div Med Gen Immunologia Clinica
state: Lombardia
city: Pisa
country: Italy
facility: A.O. Universitaria Pisana; Psichiatria
state: Toscana
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova; Cattedra e Divisione di Reumatologia
state: Veneto
city: Verona
country: Italy
facility: Azienda Ospedaliera di Verona-Ospedale Civile Maggiore
state: Veneto
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum; Reumatologie 4-A-A2
city: Arnhem
country: Netherlands
facility: Ziekenhuis Rijnstate
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Hengelo
country: Netherlands
facility: Ziekenhuisgroep Twente, Hengelo
city: Nijmegen
country: Netherlands
facility: Akademisch Ziekenhuis St. Radboud; Rheumatology
city: Kristiansand
country: Norway
facility: Sørlandet Sykehus Kristiansand
city: Oslo
country: Norway
facility: Rikshospitalet; Revmatologisk Avd Seksjon Barnerevmatologi
city: Ålesund
country: Norway
facility: Ålesund sjukehus
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki; nr 2 im. Dr J. Biziela
city: Szczecin
country: Poland
facility: Klinika Reumatologii I Chorób Wewn. Pum W Szczecinie; Samodzielny Publiczny Szpital Kliniczny Nr 1
city: Porto
country: Portugal
facility: Hospital Geral de Santo Antonio; Servico de Imunologia Clinica
city: A Coruna
country: Spain
facility: Hospital Univ A Coruna; Rheumatology
state: LA Coruña
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias;servicio de Reumatologia
state: Tenerife
city: Bilbao
country: Spain
facility: Hospital de Basurto; Servicio de Reumatologia
state: Vizcaya
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge; Servicio de Reumatologia
city: Barcelona
country: Spain
facility: University of Barcelona; Dept. of Internal Medicine,
city: Goteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Lund
country: Sweden
facility: Skånes Universitetssjukhus
city: Malmo
country: Sweden
facility: Skånes Universitetssjukhus Malmö; Reumatologkliniken
city: Stockholm
country: Sweden
facility: Karolinska Sjukhuset; Reumatologkliniken D2-1
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset; Lungmedicinska Kliniken
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary; Medical Oncology Dept
city: Barnsley
country: United Kingdom
facility: Barnsley General Hospital; Rheumatology
city: Birmingham
country: United Kingdom
facility: Old Queen Elizabeth Hospital; Pharmacy Building;Clinical Research offices
city: Colchester, Essex
country: United Kingdom
facility: Colchester General Hospital; Aseptic Dept, Pharmacy Support Unit
city: Edinburgh
country: United Kingdom
facility: University of Edinburgh; The Queens Medical Research Institute
city: Leeds
country: United Kingdom
facility: CHAPEL ALLERTON HOSPITAL; Unit of Musculoskeletal Disease
city: London
country: United Kingdom
facility: Moorfields Eye Hospital NHS Foundation Trust
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital; Dept of Rheumatology
city: Romford
country: United Kingdom
facility: Queen's Hospital
city: Stoke-on-trent
country: United Kingdom
facility: Haywood Hospital; Staffordshire Rheumatology Centre
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital; Rhuematololgy Dept
city: Westcliffe-on-sea
country: United Kingdom
facility: Southend Hospital; Rheumatology Department
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Stone JH, Spotswood H, Unizony SH, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Spiera R, Bao M. New-onset versus relapsing giant cell arteritis treated with tocilizumab: 3-year results from a randomized controlled trial and extension. Rheumatology (Oxford). 2022 Jul 6;61(7):2915-2922. doi: 10.1093/rheumatology/keab780.
citation: Unizony SH, Bao M, Han J, Luder Y, Pavlov A, Stone JH. Treatment failure in giant cell arteritis. Ann Rheum Dis. 2021 Nov;80(11):1467-1474. doi: 10.1136/annrheumdis-2021-220347. Epub 2021 May 28.
citation: Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schulze-Koops H, Schett G, Spiera R, Unizony SH, Collinson N. Glucocorticoid Dosages and Acute-Phase Reactant Levels at Giant Cell Arteritis Flare in a Randomized Trial of Tocilizumab. Arthritis Rheumatol. 2019 Aug;71(8):1329-1338. doi: 10.1002/art.40876. Epub 2019 Jul 3.
citation: Strand V, Dimonaco S, Tuckwell K, Klearman M, Collinson N, Stone JH. Health-related quality of life in patients with giant cell arteritis treated with tocilizumab in a phase 3 randomised controlled trial. Arthritis Res Ther. 2019 Feb 20;21(1):64. doi: 10.1186/s13075-019-1837-7.
citation: Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med. 2017 Jul 27;377(4):317-328. doi: 10.1056/NEJMoa1613849.