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

Phase 3CompletedNCT01941940

Hoffmann-La Roche227 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

227

Conditions

Rheumatoid Arthritis

Interventions

TocilizumabDRUG

Tocilizumab at a fixed dose of 162 mg as SC injection will be administered once every week.

DMARDsDRUG

Non-biologic DMARDs according to standard of care, at a stable dose that was initiated at least 4 weeks prior to baseline.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (49)

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Baseline, Week 20

Change From Baseline in CDAI at Week 16

Time frame: Baseline, Week 16

Change From Baseline in CDAI at Week 12

Data from ClinicalTrials.gov

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Uni Degli Studi Di L Aquila; Cattedra Di Reumatologia - Dept. Di Medicina Interna E San

Coppito, Abruzzo, Italy

P. O. Spirito Santo - Asl Pescara; U.O. Complessa Di Reumatologia

Pescara, Abruzzo, Italy

Ospedale Regionale Umberto Parini; Reparto Endocrinologia e Diabetologia - Amb. Reumatologia

Aosta, Aosta Valley, Italy

Azienda Ospedaliera Policlinico; Servizio Reumatologia

Bari, Apulia, Italy

ASL Lecce- Presidio Ospedaliero di Casarano-Servizio di Reumatologia ed Osteoporosi

Casarano (LE), Apulia, Italy

Ospedali Riuniti di Foggia; Dipartimento Medicina Interna Reumatologia

Foggia, Apulia, Italy

Ospedali Riuniti Di Foggia; Struttura Di Reumatologia

Foggia, Apulia, Italy

Azienda Ospedaliera Bianchi Melacrino Morelli; Unità Operativa di Reumatologia

Reggio Calabria, Calabria, Italy

Az. Ospedaliera S. Giuseppe Moscati; Dip. Med. Gen. Struttura Semplice Reumatologia

Avellino, Campania, Italy

Azienda Ospedaliera Rummo; Divisione Di Reumatologia

Benevento, Campania, Italy

...and 39 more locations

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: Baseline, Weeks 12, 24, 38, 52, at early withdrawal (up to Week 52), at Follow-up Visit 2 (Week 76)