An Efficacy and Safety Study of Tocilizumab (RoActemra/Actemra) in Participants With Giant Cell Arteritis (GCA)

Giant Cell Arteritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01791153
• Other study ID #: WA28119
• Secondary ID: 2011-006022-25
• Status: Completed
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Arteritis
• Giant Cell Arteritis
• Polymyalgia Rheumatica

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