A Study to Evaluate Efficacy of Tocilizumab Administered as Monotherapy or in Combination With Methotrexate and/or Other Disease Modifying Antirheumatic Drugs (DMARDs) in Rheumatoid Arthritis (RA) Participants

A National, Open-Label, Single-Arm, Phase IIIb Study to Evaluate the Efficacy of Weekly Tocilizumab Subcutaneous, Administered as Monotherapy or in Combination With Methotrexate and/or Other DMARDs in Rheumatoid Arthritis (RA) Patients

This open-label, single arm, Phase 3b study will evaluate the efficacy of tocilizumab (RoActemra), administered as monotherapy or in combination with methotrexate and/or other DMARDs, in participants with moderate to severe active RA.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Tocilizumab; Drug: DMARDs

• Study Type: Interventional
• Enrollment (Actual): 227
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Abruzzo
    • Coppito, Abruzzo, Italy, 67100
      • Uni Degli Studi Di L Aquila; Cattedra Di Reumatologia - Dept. Di Medicina Interna E San
    • Pescara, Abruzzo, Italy, 65100
      • P. O. Spirito Santo - Asl Pescara; U.O. Complessa Di Reumatologia
  • Calabria
    • Reggio Calabria, Calabria, Italy, 89133
      • Azienda Ospedaliera Bianchi Melacrino Morelli; Unità Operativa di Reumatologia
  • Campania
    • Avellino, Campania, Italy, 83100
      • Az. Ospedaliera S. Giuseppe Moscati; Dip. Med. Gen. Struttura Semplice Reumatologia
    • Benevento, Campania, Italy, 82100
      • Azienda Ospedaliera Rummo; Divisione Di Reumatologia
    • Napoli, Campania, Italy, 80131
      • Policlinico Universitario-II Università di Napoli; Reumatologia
    • Napoli, Campania, Italy, 80131
      • Azienda Ospedaliera A. Cardarelli; Medicina III - Divisione di Reumatologia
    • Salerno, Campania, Italy, 84131
      • Osp Riuniti S.Giovanni di Dio e Ruggi d'Aragona; Rep. Medicina Interna
    • Telese Terme, Campania, Italy, 82037
      • Irccs Fondazione Salvatore Maugeri-Istituto Scientifico Di Telese;U.O. Riabilitazione Reumatologica
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2
    • Modena, Emilia-Romagna, Italy, 41100
      • A.O. Universitaria Policlinico Di Modena; Reumatologia
    • Reggio Emilia, Emilia-Romagna, Italy, 42100
      • Arcispedale Santa Maria Nuova; Reumatologia
  • Friuli-Venezia Giulia
    • Udine, Friuli-Venezia Giulia, Italy, 33100
      • Policlinico Univ. Uni Degli Sudi Di Udine; Clinica Di Reumatologia
  • Lazio
    • Roma, Lazio, Italy, 00128
      • Policlinico Campus Bio-Medico Di Trigoria; Medicina Clinica E Reumatologia
    • Roma, Lazio, Italy, 00133
      • Policlinico Tor Vergata; Divisione Di Reumatologia
    • Roma, Lazio, Italy, 00189
      • Ospedale S.Pietro Fatebenefratelli; Divisione di Reumatologia
  • Liguria
    • Arenzano, Liguria, Italy, 16011
      • Ospedale La Colletta; Reparto Di Reumatologia
    • Genova, Liguria, Italy, 16132
      • Università Degli Studi Di Genova - Dimi; Reumatologia
    • Savona, Liguria, Italy, 17100
      • Ospedale San Paolo; Divisione di Reumatologia
  • Lombardia
    • Bergamo, Lombardia, Italy, 24127
      • Asst Papa Giovanni XXIII; Dh Reumatologia
    • Gavardo, Lombardia, Italy, 25085
      • Ospedale Civile "La Memoria" Di Gavardo;Immunoematologia Trasfusionale-Allergologia E Reumatologia
    • Magenta, Lombardia, Italy, 20013
      • Ospedale Di Magenta Fornaroli; U.O. Di Reumatologia
    • Milano, Lombardia, Italy, 20122
      • Ospedale Maggiore Policlinico; Unità Operativa Complessa di Allergologia e Immunologia Clinica
    • Milano, Lombardia, Italy, 20157
      • ASST FATEBENEFRATELLI SACCO; Reumatologia (Sacco)
    • Milano, Lombardia, Italy, 20122
      • Asst Centro Specialistico Ortopedico Traumato-Logico Gaetano Pini/Cto; Divisione Di Reumatologia
    • Milano, Lombardia, Italy, 20162
      • Asst Grande Ospedale Metropolitano Niguarda; Reumatologia
    • Monza, Lombardia, Italy, 20052
      • ASST DI MONZA; Reumatologia (Medicina I)
    • Pavia, Lombardia, Italy, 27100
      • Irccs Policlinico San Matteo; Reumatologia Adulti
    • Vimercate, Lombardia, Italy, 20059
      • ASST DI VIMERCATE; Medicina Generale
  • Marche
    • Ancona, Marche, Italy, 60020
      • Ospedale Regionale Torrette; SOD Clinica Medica del Dipartimento di Medicina Interna e Specialisti
    • Jesi, Marche, Italy, 60035
      • Ospedale Murri - Universita Politecnica Delle Marche; Clinica Reumatologica Ii
  • Piemonte
    • Novara, Piemonte, Italy, 28100
      • Azienda Ospedaliera Maggiore Della Carita; Day Hospital Immunologia
    • Torino, Piemonte, Italy, 10126
      • Azienda Ospedaliera San Giovanni Battista; Reparto Reumatologia
    • Torino, Piemonte, Italy, 10128
      • Ordine Mauriziano Ospedale Umberto I; Centro Di Reumatologia
  • Puglia
    • Bari, Puglia, Italy, 70124
      • Azienda Ospedaliera Policlinico; Servizio Reumatologia
    • Casarano (LE), Puglia, Italy, 73042
      • ASL Lecce- Presidio Ospedaliero di Casarano-Servizio di Reumatologia ed Osteoporosi
    • Foggia, Puglia, Italy, 71100
      • Ospedali Riuniti di Foggia; Dipartimento Medicina Interna Reumatologia
    • Foggia, Puglia, Italy, 71100
      • Ospedali Riuniti Di Foggia; Struttura Di Reumatologia
  • Sardegna
    • Cagliari, Sardegna, Italy, 09042
      • A.O. Universitaria Policlinico Monserrato Di Cagliari; Reumatologia I
    • Sassari, Sardegna, Italy, 07100
      • Azienda Ospedaliero Universitaria di Sassari; UOC Reumatologia
  • Sicilia
    • Catania, Sicilia, Italy, 95124
      • Ospedale Vittorio Emanuele Ii; U.O. Reumatologia Clinica Medica Condorelli
    • Messina, Sicilia, Italy, 98100
      • Azienda Osped. Univ. Policlinico G. Martino; Centro Prevenzione E Cura Osteoporosi
    • Palermo, Sicilia, Italy, 90127
      • Arnas Ospedale Civico; Medicina Interna II
  • Toscana
    • Firenze, Toscana, Italy, 50139
      • Ospedale Careggi Villa Monnatessa ; Sezione Di Reumatologia
    • Pisa, Toscana, Italy, 56100
      • Az. Osp. Pisana Ospedale S. Chiara; U.O. Di Reumatologia
  • Umbria
    • Perugia, Umbria, Italy, 06122
      • Osp S. Maria Misericordia Dip. Medicina Clinica Sperimentale Cattedra Reumatologia
  • Valle D'Aosta
    • Aosta, Valle D'Aosta, Italy, 11100
      • Ospedale Regionale Umberto Parini; Reparto Endocrinologia e Diabetologia - Amb. Reumatologia
  • Veneto
    • Verona, Veneto, Italy, 37126
      • Azienda Ospedaliera Universitaria Borgo Trento; Dipartimento di Medicina Sezione di Reumatologia
    • Verona, Veneto, Italy, 37134
      • Policlinico G.B. Rossi; Divisione Immunologia Clinica Sperimentale Medicina B

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria
• Moderate to severe RA (CDAI at least [>/=] 10 and DAS28 >/=3.2) at screening
• Tumor necrosis factor inhibitors-inadequate responder (TNF-IR), methotrexate-inadequate responder (MTX-IR), and/or DMARDs-inadequate responder (DMARDs-IR)
• Oral corticosteroids (less than or equal to [</=] 10 mg per day prednisone or equivalent) and non-steroidal anti-inflammatory drugs (NSAIDs; up to the maximum recommended dose) are permitted if on a stable dose regimen for >/=4 weeks prior to baseline
• Permitted non-biologic DMARDs are allowed if at a stable dose for >/=4 weeks prior to baseline
• Receiving treatment on an outpatient basis, not including tocilizumab
• Females of childbearing potential and males with female partners of childbearing potential must agree to use a reliable means of contraception for at least 3 months following the last dose of tocilizumab

Exclusion Criteria:

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 12 months following baseline
• Rheumatic autoimmune disease other than RA; secondary Sjögren's syndrome with RA is permitted
• Functional Class IV as defined by the ACR Classification of Functional Status in RA
• Diagnosis of juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16
• Prior history of or current inflammatory joint disease other than RA
• Exposure to tocilizumab (either intravenous [IV] or SC) at any time prior to baseline
• 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
• Intra-articular or parenteral corticosteroids within 4 weeks prior to baseline
• History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
• Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or gastrointestinal disease
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections
• Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
• Active tuberculosis (TB) requiring treatment within the previous 3 years
• Positive for hepatitis B surface antigen or hepatitis C antibody
• Primary or secondary immunodeficiency (history of or currently active)
• Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (except for basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 20 years
• Pregnant or breast feeding women
• Neuropathies or other conditions that might interfere with pain evaluation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Tocilizumab; Tocilizumab at a fixed dose of 162 milligrams (mg) will be administered as subcutaneous (SC) injection alone or along with methotrexate and/or other non-biological DMARDs irrespective of body weight, once every week for a total of 52 weeks. After 52-weeks of treatment, at the discretion of the treating physician, participants can continue the study treatment with SC tocilizumab until it becomes commercially available in Italy.

Drug: Tocilizumab; Tocilizumab at a fixed dose of 162 mg as SC injection will be administered once every week.; Other Names: RoActemra; Drug: DMARDs; Non-biologic DMARDs according to standard of care, at a stable dose that was initiated at least 4 weeks prior to baseline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24	The CDAI is a numerical sum of 4 outcome parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint assessment, patient's global assessment of disease activity (PtGDA) and physician global assessment of disease activity (PGDA) assessed on 0-10 centimeters (cm) visual analogue scale (VAS). Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score less than or equal to (</=) 2.8 indicates disease remission, greater than (>) 2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity.	Baseline, Week 24
Change From Baseline in CDAI at Week 20	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity.	Baseline, Week 20
Change From Baseline in CDAI at Week 16	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity.	Baseline, Week 16
Change From Baseline in CDAI at Week 12	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity.	Baseline, Week 12
Change From Baseline in CDAI at Week 8	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity.	Baseline, Week 8
Change From Baseline in CDAI at Week 4	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity.	Baseline, Week 4
Change From Baseline in CDAI at Week 2	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity.	Baseline, Week 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Achieving Clinical Remission According to CDAI up to Week 52	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 during any two consecutive visits, not including the baseline visit indicates disease remission.	Baseline up to Week 52 (Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 38, and 52)
Change From Baseline in Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (DAS28-ESR) at Weeks 2, 24, and 52	DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hour) and PtGDA assessed on 0-10 cm VAS. Higher scores indicate greater affectation due to disease activity. DAS28-ESR total score= 0-9.4. DAS28-ESR </=3.2 indicates low disease activity, DAS28-ESR >3.2 to 5.1 indicates moderate to high disease activity, and DAS28-ESR </=3.2 indicates remission.	Baseline, Weeks 2, 24, and 52
Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 24, and 52	SDAI is a numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and C-reactive protein (CRP) in milligrams per deciliter (mg/dL). Higher scores indicate greater affectation due to disease activity. SDAI total score = 0-86. SDAI </=3.3 indicates disease remission, >3.4 to 11 indicates low disease activity, >11 to 26 indicates moderate disease activity, and >26 indicates high disease activity.	Baseline, Weeks 2, 24, and 52
Percentage of Participants With an American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) Response	The ACR 20, 50, and 70 responses: greater than or equal to (>/=) 20 percent (%), 50%, and 70% improvement in TJC and SJC (28 assessed joints), and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP or ESR at each visit.	Weeks 2, 24, and 52
Percentage of Participants With European League Against Rheumatism (EULAR) Response Based on DAS28	The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 </=3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to </=5.1 or change from baseline >0.6 to </=1.2 with DAS28 </=5.1; non-responders: change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28 >5.1.	Baseline, Weeks 2, 24, and 52
Change From Baseline in Total TJC at Weeks 2, 24, and 52	TJC was defined as the total number of painful joints based on 68-joint assessment (TJC-68) and 28-joint assessment (TJC-28).	Baseline, Weeks 2, 24, and 52
Change From Baseline in Total SJC at Weeks 2, 24, and 52	SJC was defined as the total number of swollen joints based on 66-joint assessment (SJC-66) and 28-joint assessment (SJC-28).	Baseline, Weeks 2, 24, and 52
Association Between Disease Activity Parameters: DAS28-ESR and CDAI, Assessed Using Correlation Coefficient	DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the ESR in mm/hour and PtGDA. DAS28-ESR total score= 0-9.4. Higher scores indicate greater affectation due to disease activity. The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. CDAI total score = 0-76. Higher scores represent greater affectation due to disease activity. Correlation coefficient for relationship between DAS28-ESR and CDAI at different time points is reported. Correlation coefficient value range= -1 to 1. Higher positive value indicates greater positive relationship and higher negative value indicates greater negative relationship.	Weeks 2, 24, 52
Association Between Disease Activity Parameters: DAS28-ESR and SDAI, Assessed Using Correlation Coefficient	DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the ESR in mm/hour and PtGDA. DAS28-ESR total score= 0-9.4. Higher scores indicate greater affectation due to disease activity. SDAI is a numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and CRP in mg/dL. SDAI total score= 0-86. Higher scores indicate greater affectation due to disease activity. Correlation coefficient for relationship between DAS28-ESR and SDAI at different time points is reported. Correlation coefficient value range= -1 to 1. Higher positive value indicates greater positive relationship and higher negative value indicates greater negative relationship.	Weeks 2, 24, 52
Association Between Disease Activity Parameters: CDAI and SDAI, Assessed Using Correlation Coefficient	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. CDAI total score = 0-76. Higher scores represent greater affectation due to disease activity. SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and CRP in mg/dL. SDAI total score= 0-86. Higher scores indicate greater affectation due to disease activity. Correlation coefficient for relationship between CDAI and SDAI at different time points is reported. Correlation coefficient value range= -1 to 1. Higher positive value indicates greater positive relationship and higher negative value indicates greater negative relationship.	Weeks 2, 24, 52
Association Between Disease Activity Parameter (DAS28-ESR) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient	DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the ESR in mm/hour and PtGDA. DAS28-ESR total score= 0-9.4. The ACR 20, 50, and 70 responses: >/=20%, 50%, and 70% improvement in TJC and SJC, and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP at each visit. Regression coefficients for relationship between DAS28-ESR and ACR responses (ACR20, ACR50, and ACR70) at different time points are reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship.	Weeks 2, 24, 52
Association Between Disease Activity Parameter (DAS28-ESR) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient	DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the ESR in mm/hour and PtGDA. DAS28-ESR total score= 0-9.4. EULAR response criteria (based on DAS28 score): Good responders (change from baseline >1.2 with DAS28 </=3.2); Moderate responders (change from baseline >1.2 with DAS28 >3.2 to </=5.1 or change from baseline >0.6 to </=1.2 with DAS28 </=5.1); Non-responders (change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28 >5.1). Regression coefficient for relationship between DAS28-ESR and EULAR Good response at different time points is reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship.	Weeks 2, 24, 52
Association Between Disease Activity Parameter (CDAI) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. CDAI total score = 0-76. The ACR 20, 50, and 70 responses: >/=20%, 50%, and 70% improvement in TJC and SJC, and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP at each visit. Regression coefficients for relationship between CDAI and ACR responses (ACR20, ACR50, and ACR70) at different time points are reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship.	Weeks 2, 24, 52
Association Between Disease Activity Parameter (CDAI) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient	The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. CDAI total score = 0-76. EULAR response criteria (based on DAS28 score): Good responders (change from baseline >1.2 with DAS28 </=3.2); Moderate responders (change from baseline >1.2 with DAS28 >3.2 to </=5.1 or change from baseline >0.6 to </=1.2 with DAS28 </=5.1); Non-responders (change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28 >5.1). Regression coefficient for relationship between CDAI and EULAR Good response at different time points is reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship.	Weeks 2, 24, 52
Association Between Disease Activity Parameter (SDAI) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient	SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and CRP in mg/dL. SDAI total score= 0-86. The ACR 20, 50, and 70 responses: >/=20%, 50%, and 70% improvement in TJC and SJC, and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP at each visit. Regression coefficients for relationship between SDAI and ACR responses (ACR20, ACR50, and ACR70) at different time points are reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship.	Weeks 2, 24, 52
Association Between Disease Activity Parameter (SDAI) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient	The SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and CRP in mg/dL. SDAI total score= 0-86. EULAR response criteria (based on DAS28 score): Good responders (change from baseline >1.2 with DAS28 </=3.2); Moderate responders (change from baseline >1.2 with DAS28 >3.2 to </=5.1 or change from baseline >0.6 to </=1.2 with DAS28 </=5.1); Non-responders (change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28 >5.1). Regression coefficient for relationship between SDAI and EULAR Good response at different time points is reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship.	Weeks 2, 24, 52
Percentage of DMARDs Dose Reductions and/or Discontinuation Events by Reasons	Percentage of DMARDs dose reduction and/or discontinuation (Red/Dis) events is reported by different reasons.	Baseline up to Week 52
Percentage of Non-DMARDs Dose Reductions and/or Discontinuation Events by Reasons	Percentage of Non-DMARDs dose reduction and/or discontinuation (Red/Dis) events is reported by different reasons.	Baseline up to Week 52
Change From Baseline in PtGDA VAS Score at Weeks 2, 24, and 52	Participants answered the following question: "Considering all the ways your arthritis affects you, how are you feeling today." Participants responded by using a 0 - 100 millimeter (mm) VAS, where 0 mm = very well and 100 mm = very poorly.	Baseline, Weeks 2, 24, and 52
Change From Baseline in PGDA VAS Score at Weeks 2, 24, and 52	The physician assessed participant's current disease activity on a 0-100 mm VAS, where 0 mm = no disease activity and 100 mm = maximum disease activity.	Baseline, Weeks 2, 24, and 52
Participant Pain VAS Score at Weeks 2, 24, and 52	Participants assessed their pain using a 0-100 mm VAS. Intensity of pain range (over past week): 0 mm = no pain to 100 mm = worst possible pain.	Weeks 2, 24, and 52
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 24, and 52	HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.	Baseline, Weeks 2, 24, and 52
Missed Working Days Assessed Using Short Form-Health and Labor Questionnaire (SF-HLQ) Score at Weeks 24 and 52	The SF-HLQ assessed productivity losses related to health problems in individuals with paid or unpaid work and consisted of three modules (absenteeism from paid work, production losses without absenteeism from paid work and hindrance in the performance of paid and unpaid work). Any missed working days or number of worked days with reduced efficiency during the last month were reported.	Weeks 24 and 52
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Total Score at Weeks 2, 24, and 52	FACIT total score is sum of Functional Assessment of Cancer Therapy-General (FACT-G) score and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; additional concerns) score. FACT-G is a core questionnaire that evaluates quality of life (QoL) in cancer population. FACT-G consists of 27 questions grouped in 4 domains of general health-related QoL: physical well-being, social/family well-being, emotional well-being, and functional well-being; each item ranges from 0 (not at all) to 4 (very much). FACT-G score ranges between 0-108. FACIT-F is a 13-item questionnaire that evaluates self-reported fatigue and its impact upon daily activities. Each item ranges from 0 (Not at all) to 4 (Very much). The sum of all responses result in the FACIT total score with a total possible range of 0 (better score) to 160 (worse score). Negative change from baseline represents a better QoL.	Baseline, Weeks 2, 24, and 52
Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) at Weeks 24 and 52	PSQI is a questionnaire with 18 questions to assess sleep quality. The 18 questions are distributed to 7 elements (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction). A participant indicates how frequently each item was experienced on a scale from 0 to 3. The global score is the sum score of all 7 elements and ranges from 0-21 with higher values indicating worse sleep quality. A score of >/=5 indicates poor sleepers.	Baseline, Weeks 24 and 52
Treatment Compliance, as Assessed Using Participant Diary Cards and Return Records	Treatment Compliance was calculated as (total actual doses taken for the period) / (total planned or prescribed dose for the period) x 100.	Weeks 24 and 52
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) of Special Interest	An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are AEs occurring between the first dose of study drug and up to 28 days after the last dose that were absent before treatment or that worsened relative to pre-treatment state. Following AEs were considered as AEs of special interest: anaphylactic reaction, hypersensitivity, stress cardiomyopathy, Gilbert's syndrome, gastrointestinal perforation, injection site erythema, injection site hypersensitivity, injection site irritation, injection site pruritus, arthritis bacterial, cellulitis, klebsiella infection, oral candidiasis, pneumonia, skin infection, vulvovaginal candidiasis, alanine aminotransferase increased, hepatic enzyme increased, brain neoplasm malignant, and urticaria.	Baseline up to 95 weeks
Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to Tocilizumab	Percentage of participants with positive results for ATA against tocilizumab at different time points is reported.	Baseline, Weeks 12, 24, 38, 52, at 8 weeks after last dose (up to Week 60), at early withdrawal (up to Week 52), at Follow-up Visits 1 (Week 64), 2 (Week 76), and 3 (Week 88)
Mean Tocilizumab Concentration		Baseline, Weeks 12, 24, 38, 52, at early withdrawal (up to Week 52), at Follow-up Visit 2 (Week 76)
Mean Soluble Interleukin-6 Receptor (sIL-6R) Concentration		Baseline, Weeks 12, 24, 38, 52, at early withdrawal (up to Week 52), at Follow-up Visit 2 (Week 76)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Devenport J, Petho-Schramm A. Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis. Rheumatology (Oxford). 2019 Jun 1;58(6):1056-1064. doi: 10.1093/rheumatology/key393.
• Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Bernasconi C, Petho-Schramm A. Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries. Rheumatology (Oxford). 2018 Mar 1;57(3):499-507. doi: 10.1093/rheumatology/kex443. Erratum In: Rheumatology (Oxford). 2018 Jun 1;57(6):1129.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 5, 2013
• Primary Completion (ACTUAL): September 9, 2015
• Study Completion (ACTUAL): July 5, 2016

Study Registration Dates

• First Submitted: September 2, 2013
• First Submitted That Met QC Criteria: September 10, 2013
• First Posted (ESTIMATE): September 13, 2013

Study Record Updates

• Last Update Posted (ACTUAL): July 11, 2017
• Last Update Submitted That Met QC Criteria: June 12, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: ML28699; 2013-001569-17 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No