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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01791153
Other study ID # WA28119
Secondary ID 2011-006022-25
Status Completed
Phase Phase 3
First received
Last updated
Start date July 22, 2013
Est. completion date June 4, 2018

Study information

Verified date February 2020
Source Hoffmann-La Roche
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Recruitment information / eligibility

Status Completed
Enrollment 251
Est. completion date June 4, 2018
Est. primary completion date April 11, 2016
Accepts healthy volunteers No
Gender All
Age group 50 Years and older
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Tocilizumab
Tocilizumab will be administered at a dose of 162 mg as SC injection qw or q2w for 52 weeks in Part 1 of the study and at a dose 162 mg as SC injection qw for 104 week at the discretion of the investigator in Part 2 of the study.
Prednisone
Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.
Tocilizumab Placebo
Tocilizumab placebo will be administered as SC injection qw or q2w for 52 weeks in Part 1 of the study.
Prednisone Placebo
Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.
Corticosteroids
Participants without sustained remission at Week 52 will receive corticosteroids at a dose and schedule at the discretion of the investigator for a maximum of 104 weeks.
Methotrexate
Participants without sustained remission at Week 52 will receive methotrexate at a dose and schedule at the discretion of the investigator for a maximum of 104 weeks.

Locations

Country Name City State
Belgium Hospital Erasme Bruxelles
Belgium UZ Leuven Gasthuisberg Leuven
Canada Clin. de Rhumatologie Trois-rivieres Quebec
Denmark Nordsjællands Hospital - Hillerød;Department of Rheumatology 0731 Hillerod
France Hopital Avicenne; Medecine Interne H5 Bobigny
France Hopital La Cavale Blanche; Rhumatologie Brest
France Hopital Claude Huriez; Internal Medicine Lille
France Hôpital de la Conception Marseille
France Hopital Emile Muller; Medecine Interne Mulhouse
France Hopital Cochin; Medecine Interne Paris
Germany Asklepios Kllinikum Bad Abbach; Klinik für Rheumatologie und Klinische Immunologie Bad Abbach
Germany Rheuma-Klinikum Bad Bramstedt Klinik fuer Rheumatologie und Immunologie Bad Bramstedt
Germany Charité Campus Mitte, Med.Klinik, Rheumatologie und Klinische Immunologie Berlin
Germany Schlosspark Klinik; Abt. Rheumatologie Berlin
Germany Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik III Dresden
Germany Universitätsklinikum Erlangen; Medizinische Klinik 3; Rheumatologie und Immunologie Erlangen
Germany Universitätsklinikum Freiburg Freiburg
Germany Medizinische Hochschule Zentrum Innere Medizin Abt.Klinische Immunologie und Rheumatologie Hannover
Germany Rheumazentrum-Ruhrgebiet, St. Josefs-Krankenhaus; Rheumatologie Herne
Germany Universitätsklinikum Jena; Klinik für Innere Medizin III Jena
Germany Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Medizinische Klinik, Pneumologie Mainz
Germany Klinikum der Universitat Munchen; Bereich Pettenkoferstr; Rheumaeinheit der medizinischen Klinik IV München
Germany Kreiskliniken Esslingen gGmbH Klinik Plochingen Medizinische Klinik Plochingen
Germany Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II Tübingen
Italy Università Degli Studi Di Genova - Dimi; Reumatologia Genova Liguria
Italy Irccs San Raffele; Div Med Gen Immunologia Clinica Milano Lombardia
Italy Azienda Ospedaliera di Padova; Cattedra e Divisione di Reumatologia Padova Veneto
Italy A.O. Universitaria Pisana; Psichiatria Pisa Toscana
Italy Arcispedale Santa Maria Nuova; Reumatologia Reggio Emilia Emilia-Romagna
Italy Policlinico Univ. Uni Degli Sudi Di Udine; Clinica Di Reumatologia Udine Friuli-Venezia Giulia
Italy Azienda Ospedaliera di Verona-Ospedale Civile Maggiore Verona Veneto
Netherlands VU Medisch Centrum; Reumatologie 4-A-A2 Amsterdam
Netherlands Ziekenhuis Rijnstate Arnhem
Netherlands Universitair Medisch Centrum Groningen Groningen
Netherlands Ziekenhuisgroep Twente, Hengelo Hengelo
Netherlands Akademisch Ziekenhuis St. Radboud; Rheumatology Nijmegen
Norway Ålesund sjukehus Ålesund
Norway Sørlandet Sykehus Kristiansand Kristiansand
Norway Rikshospitalet; Revmatologisk Avd Seksjon Barnerevmatologi Oslo
Poland Szpital Uniwersytecki; nr 2 im. Dr J. Biziela Bydgoszcz
Poland Klinika Reumatologii I Chorób Wewn. Pum W Szczecinie; Samodzielny Publiczny Szpital Kliniczny Nr 1 Szczecin
Portugal Hospital Geral de Santo Antonio; Servico de Imunologia Clinica Porto
Spain Hospital Univ A Coruna; Rheumatology A Coruna LA Coruña
Spain Hospital Universitari de Bellvitge; Servicio de Reumatologia Barcelona
Spain University of Barcelona; Dept. of Internal Medicine, Barcelona
Spain Hospital de Basurto; Servicio de Reumatologia Bilbao Vizcaya
Spain Hospital Universitario de Canarias;servicio de Reumatologia La Laguna Tenerife
Sweden Sahlgrenska Universitetssjukhuset Goteborg
Sweden Skånes Universitetssjukhus Lund
Sweden Skånes Universitetssjukhus Malmö; Reumatologkliniken Malmo
Sweden Karolinska Sjukhuset; Reumatologkliniken D2-1 Stockholm
Sweden Akademiska Sjukhuset; Lungmedicinska Kliniken Uppsala
United Kingdom Aberdeen Royal Infirmary; Medical Oncology Dept Aberdeen
United Kingdom Barnsley General Hospital; Rheumatology Barnsley
United Kingdom Old Queen Elizabeth Hospital; Pharmacy Building;Clinical Research offices Birmingham
United Kingdom Colchester General Hospital; Aseptic Dept, Pharmacy Support Unit Colchester, Essex
United Kingdom University of Edinburgh; The Queens Medical Research Institute Edinburgh
United Kingdom CHAPEL ALLERTON HOSPITAL; Unit of Musculoskeletal Disease Leeds
United Kingdom Moorfields Eye Hospital NHS Foundation Trust London
United Kingdom Freeman Hospital; Dept of Rheumatology Newcastle Upon Tyne
United Kingdom Queen's Hospital Romford
United Kingdom Haywood Hospital; Staffordshire Rheumatology Centre Stoke-on-trent
United Kingdom Royal Cornwall Hospital; Rhuematololgy Dept Truro
United Kingdom Southend Hospital; Rheumatology Department Westcliffe-on-sea
United States Asheville Arthritis & Osteoporosis Center, PA Asheville North Carolina
United States Rheumatology Assoc. of S. Florida - Clinical Research Center Boca Raton Florida
United States Massachusetts General Hospital Boston Massachusetts
United States Cedars-Sinai Medical Center Los Angeles California
United States Univ of Calif., Los Angeles; Rheumatology Los Angeles California
United States Hospital For Special Surgery; Dept of Medicine - Rheumatology New York New York
United States Four Rivers Clinical Research Inc. Paducah Kentucky
United States University of Pennsylvania Philadelphia Pennsylvania
United States Rheumatology Associates Portland Maine
United States Mayo Clinic Rochester Rochester Minnesota
United States Shores Rheumatology Saint Clair Shores Michigan
United States University of Utah; Division of Rheumatology Salt Lake City Utah
United States Sarasota Arthritis Res Center Sarasota Florida
United States Marshfield Clinic Wausau Ctr Wausau Wisconsin

Sponsors (1)

Lead Sponsor Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  France,  Germany,  Italy,  Netherlands,  Norway,  Poland,  Portugal,  Spain,  Sweden,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 26 Weeks Prednisone Taper) Remission was defined as the absence of flare and normalization of the C-reactive protein (CRP) (less than [<] 1 milligram per deciliter [mg/dL]). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit. Week 52
Secondary Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 52 Weeks Prednisone Taper) Remission was defined as the absence of flare and normalization of the CRP (<1 mg/dL). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit. Week 52
Secondary Time to First GCA Disease Flare Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. Participants who withdrew from the study prior to Week 52 were censored from the time of withdrawal. Up to 52 weeks
Secondary Total Cumulative Prednisone Dose The median total cumulative prednisone dose over the 52 weeks for each treatment group and the corresponding 95% confidence intervals are presented. Up to 52 weeks
Secondary Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52 The SF-36 is a standardized questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical Component Score (PCS) and Mental Component Score (MCS). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). A positive change from baseline indicates improvement. No imputation was used for missing data. Data was set to missing for participants who received escape therapy. Baseline, Week 52
Secondary Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52 Participants assessed their current disease activity on a 0-100 millimeter (mm) VAS, where 0 mm = no disease activity and 100 mm = maximum disease activity. A negative change from baseline indicates improvement. Baseline, Week 52
Secondary Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab AUCtau is the model-predicted area under the tocilizumab serum concentration versus time curve from time zero to the end of dosing interval. AUCtau is measured in microgram*day per milliliter (mcg*day/mL). 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])
Secondary Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab Cmax,ss is maximum model-predicted serum steady state concentration of tocilizumab measured in micrograms per milliliter (mcg/mL). 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])
Secondary Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab Cmin,ss is minimum model-predicted serum steady state concentration of tocilizumab measured in mcg/mL. 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])
Secondary Minimum Observed Serum Concentration (Ctrough) of Tocilizumab Ctrough is minimum observed serum concentration of tocilizumab measured in mcg/mL. Predose (Hour 0) at Baseline and Week 52
Secondary Serum Interleukin-6 (IL-6) Level Baseline and Week 52
Secondary Serum Soluble IL-6 Receptor (sIL-6R) Level Baseline and Week 52
Secondary Erythrocyte Sedimentation Rate (ESR) ESR is a laboratory test that provides a non-specific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 mm/hr. A higher rate is consistent with inflammation. Baseline and Week 52
Secondary C-Reactive Protein (CRP) Level The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. Baseline and Week 52
Secondary Percentage of Participants With Anti-Tocilizumab Antibodies All samples were tested by screening assay, and those samples that were positive were further analyzed by a confirmation assay to confirm specificity. Percentage of participants who has a positive confirmation assay result any time after the initial drug administration with a negative confirmation assay result at baseline was reported. Baseline up to Week 52
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