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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

Primary Purpose

Rheumatoid Arthritis

Status

Completed

Phase

Phase 3

Locations

Italy

Study Type

Interventional

Intervention

Tocilizumab

DMARDs

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Uni Degli Studi Di L Aquila; Cattedra Di Reumatologia - Dept. Di Medicina Interna E San
P. O. Spirito Santo - Asl Pescara; U.O. Complessa Di Reumatologia
Azienda Ospedaliera Bianchi Melacrino Morelli; Unità Operativa di Reumatologia
Az. Ospedaliera S. Giuseppe Moscati; Dip. Med. Gen. Struttura Semplice Reumatologia
Azienda Ospedaliera Rummo; Divisione Di Reumatologia
Azienda Ospedaliera A. Cardarelli; Medicina III - Divisione di Reumatologia
Policlinico Universitario-II Università di Napoli; Reumatologia
Osp Riuniti S.Giovanni di Dio e Ruggi d'Aragona; Rep. Medicina Interna
Irccs Fondazione Salvatore Maugeri-Istituto Scientifico Di Telese;U.O. Riabilitazione Reumatologica
A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2
A.O. Universitaria Policlinico Di Modena; Reumatologia
Arcispedale Santa Maria Nuova; Reumatologia
Policlinico Univ. Uni Degli Sudi Di Udine; Clinica Di Reumatologia
Policlinico Campus Bio-Medico Di Trigoria; Medicina Clinica E Reumatologia
Policlinico Tor Vergata; Divisione Di Reumatologia
Ospedale S.Pietro Fatebenefratelli; Divisione di Reumatologia
Ospedale La Colletta; Reparto Di Reumatologia
Università Degli Studi Di Genova - Dimi; Reumatologia
Ospedale San Paolo; Divisione di Reumatologia
Asst Papa Giovanni XXIII; Dh Reumatologia
Ospedale Civile "La Memoria" Di Gavardo;Immunoematologia Trasfusionale-Allergologia E Reumatologia
Ospedale Di Magenta Fornaroli; U.O. Di Reumatologia
Asst Centro Specialistico Ortopedico Traumato-Logico Gaetano Pini/Cto; Divisione Di Reumatologia
Ospedale Maggiore Policlinico; Unità Operativa Complessa di Allergologia e Immunologia Clinica
ASST FATEBENEFRATELLI SACCO; Reumatologia (Sacco)
Asst Grande Ospedale Metropolitano Niguarda; Reumatologia
ASST DI MONZA; Reumatologia (Medicina I)
Irccs Policlinico San Matteo; Reumatologia Adulti
ASST DI VIMERCATE; Medicina Generale
Ospedale Regionale Torrette; SOD Clinica Medica del Dipartimento di Medicina Interna e Specialisti
Ospedale Murri - Universita Politecnica Delle Marche; Clinica Reumatologica Ii
Azienda Ospedaliera Maggiore Della Carita; Day Hospital Immunologia
Azienda Ospedaliera San Giovanni Battista; Reparto Reumatologia
Ordine Mauriziano Ospedale Umberto I; Centro Di Reumatologia
Azienda Ospedaliera Policlinico; Servizio Reumatologia
ASL Lecce- Presidio Ospedaliero di Casarano-Servizio di Reumatologia ed Osteoporosi
Ospedali Riuniti di Foggia; Dipartimento Medicina Interna Reumatologia
Ospedali Riuniti Di Foggia; Struttura Di Reumatologia
A.O. Universitaria Policlinico Monserrato Di Cagliari; Reumatologia I
Azienda Ospedaliero Universitaria di Sassari; UOC Reumatologia
Ospedale Vittorio Emanuele Ii; U.O. Reumatologia Clinica Medica Condorelli
Azienda Osped. Univ. Policlinico G. Martino; Centro Prevenzione E Cura Osteoporosi
Arnas Ospedale Civico; Medicina Interna II
Ospedale Careggi Villa Monnatessa ; Sezione Di Reumatologia
Az. Osp. Pisana Ospedale S. Chiara; U.O. Di Reumatologia
Osp S. Maria Misericordia Dip. Medicina Clinica Sperimentale Cattedra Reumatologia
Ospedale Regionale Umberto Parini; Reparto Endocrinologia e Diabetologia - Amb. Reumatologia
Azienda Ospedaliera Universitaria Borgo Trento; Dipartimento di Medicina Sezione di Reumatologia
Policlinico G.B. Rossi; Divisione Immunologia Clinica Sperimentale Medicina B

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tocilizumab

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

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.

Change From Baseline in CDAI at Week 16

Change From Baseline in CDAI at Week 12

Change From Baseline in CDAI at Week 8

Change From Baseline in CDAI at Week 4

Change From Baseline in CDAI at Week 2

Secondary Outcome Measures

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Mean Tocilizumab Concentration

Mean Soluble Interleukin-6 Receptor (sIL-6R) Concentration

Full Information

NCT ID

NCT01941940

First Posted

September 2, 2013

Last Updated

June 12, 2017

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT01941940

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2017

Overall Recruitment Status

Completed

Study Start Date

September 5, 2013 (Actual)

Primary Completion Date

September 9, 2015 (Actual)

Study Completion Date

July 5, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rheumatoid Arthritis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

227 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Tocilizumab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Tocilizumab

Other Intervention Name(s)

RoActemra

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

DMARDs

Intervention Description

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

Primary Outcome Measure Information:

Title

Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24

Description

Time Frame

Baseline, Week 24

Title

Change From Baseline in CDAI at Week 20

Description

Time Frame

Baseline, Week 20

Title

Change From Baseline in CDAI at Week 16

Description

Time Frame

Baseline, Week 16

Title

Change From Baseline in CDAI at Week 12

Description

Time Frame

Baseline, Week 12

Title

Change From Baseline in CDAI at Week 8

Description

Time Frame

Baseline, Week 8

Title

Change From Baseline in CDAI at Week 4

Description

Time Frame

Baseline, Week 4

Title

Change From Baseline in CDAI at Week 2

Description

Time Frame

Baseline, Week 2

Secondary Outcome Measure Information:

Title

Number of Participants Achieving Clinical Remission According to CDAI up to Week 52

Description

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)

Title

Change From Baseline in Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (DAS28-ESR) at Weeks 2, 24, and 52

Description

Time Frame

Baseline, Weeks 2, 24, and 52

Title

Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 24, and 52

Description

Time Frame

Baseline, Weeks 2, 24, and 52

Title

Percentage of Participants With an American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) Response

Description

Time Frame

Weeks 2, 24, and 52

Title

Percentage of Participants With European League Against Rheumatism (EULAR) Response Based on DAS28

Description

Time Frame

Baseline, Weeks 2, 24, and 52

Title

Change From Baseline in Total TJC at Weeks 2, 24, and 52

Description

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

Title

Change From Baseline in Total SJC at Weeks 2, 24, and 52

Description

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

Title

Association Between Disease Activity Parameters: DAS28-ESR and CDAI, Assessed Using Correlation Coefficient

Description

Time Frame

Weeks 2, 24, 52

Title

Association Between Disease Activity Parameters: DAS28-ESR and SDAI, Assessed Using Correlation Coefficient

Description

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

Title

Association Between Disease Activity Parameters: CDAI and SDAI, Assessed Using Correlation Coefficient

Description

Time Frame

Weeks 2, 24, 52

Title

Association Between Disease Activity Parameter (DAS28-ESR) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient

Description

Time Frame

Weeks 2, 24, 52

Title

Association Between Disease Activity Parameter (DAS28-ESR) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient

Description

Time Frame

Weeks 2, 24, 52

Title

Association Between Disease Activity Parameter (CDAI) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient

Description

Time Frame

Weeks 2, 24, 52

Title

Association Between Disease Activity Parameter (CDAI) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient

Description

Time Frame

Weeks 2, 24, 52

Title

Association Between Disease Activity Parameter (SDAI) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient

Description

Time Frame

Weeks 2, 24, 52

Title

Association Between Disease Activity Parameter (SDAI) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient

Description

Time Frame

Weeks 2, 24, 52

Title

Percentage of DMARDs Dose Reductions and/or Discontinuation Events by Reasons

Description

Percentage of DMARDs dose reduction and/or discontinuation (Red/Dis) events is reported by different reasons.

Time Frame

Baseline up to Week 52

Title

Percentage of Non-DMARDs Dose Reductions and/or Discontinuation Events by Reasons

Description

Percentage of Non-DMARDs dose reduction and/or discontinuation (Red/Dis) events is reported by different reasons.

Time Frame

Baseline up to Week 52

Title

Change From Baseline in PtGDA VAS Score at Weeks 2, 24, and 52

Description

Time Frame

Baseline, Weeks 2, 24, and 52

Title

Change From Baseline in PGDA VAS Score at Weeks 2, 24, and 52

Description

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

Title

Participant Pain VAS Score at Weeks 2, 24, and 52

Description

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

Title

Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 24, and 52

Description

Time Frame

Baseline, Weeks 2, 24, and 52

Title

Missed Working Days Assessed Using Short Form-Health and Labor Questionnaire (SF-HLQ) Score at Weeks 24 and 52

Description

Time Frame

Weeks 24 and 52

Title

Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Total Score at Weeks 2, 24, and 52

Description

Time Frame

Baseline, Weeks 2, 24, and 52

Title

Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) at Weeks 24 and 52

Description

Time Frame

Baseline, Weeks 24 and 52

Title

Treatment Compliance, as Assessed Using Participant Diary Cards and Return Records

Description

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

Title

Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) of Special Interest

Description

Time Frame

Baseline up to 95 weeks

Title

Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to Tocilizumab

Description

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)

Title

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)

Title

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)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Hoffmann-La Roche

Official's Role

Study Director

Facility Information:

Facility Name

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

City

Coppito

State/Province

Abruzzo

ZIP/Postal Code

67100

Country

Italy

Facility Name

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

City

Pescara

State/Province

Abruzzo

ZIP/Postal Code

65100

Country

Italy

Facility Name

Azienda Ospedaliera Bianchi Melacrino Morelli; Unità Operativa di Reumatologia

City

Reggio Calabria

State/Province

Calabria

ZIP/Postal Code

89133

Country

Italy

Facility Name

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

City

Avellino

State/Province

Campania

ZIP/Postal Code

83100

Country

Italy

Facility Name

Azienda Ospedaliera Rummo; Divisione Di Reumatologia

City

Benevento

State/Province

Campania

ZIP/Postal Code

82100

Country

Italy

Facility Name

Azienda Ospedaliera A. Cardarelli; Medicina III - Divisione di Reumatologia

City

Napoli

State/Province

Campania

ZIP/Postal Code

80131

Country

Italy

Facility Name

Policlinico Universitario-II Università di Napoli; Reumatologia

City

Napoli

State/Province

Campania

ZIP/Postal Code

80131

Country

Italy

Facility Name

Osp Riuniti S.Giovanni di Dio e Ruggi d'Aragona; Rep. Medicina Interna

City

Salerno

State/Province

Campania

ZIP/Postal Code

84131

Country

Italy

Facility Name

Irccs Fondazione Salvatore Maugeri-Istituto Scientifico Di Telese;U.O. Riabilitazione Reumatologica

City

Telese Terme

State/Province

Campania

ZIP/Postal Code

82037

Country

Italy

Facility Name

A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2

City

Bologna

State/Province

Emilia-Romagna

ZIP/Postal Code

40138

Country

Italy

Facility Name

A.O. Universitaria Policlinico Di Modena; Reumatologia

City

Modena

State/Province

Emilia-Romagna

ZIP/Postal Code

41100

Country

Italy

Facility Name

Arcispedale Santa Maria Nuova; Reumatologia

City

Reggio Emilia

State/Province

Emilia-Romagna

ZIP/Postal Code

42100

Country

Italy

Facility Name

Policlinico Univ. Uni Degli Sudi Di Udine; Clinica Di Reumatologia

City

Udine

State/Province

Friuli-Venezia Giulia

ZIP/Postal Code

33100

Country

Italy

Facility Name

Policlinico Campus Bio-Medico Di Trigoria; Medicina Clinica E Reumatologia

City

Roma

State/Province

Lazio

ZIP/Postal Code

00128

Country

Italy

Facility Name

Policlinico Tor Vergata; Divisione Di Reumatologia

City

Roma

State/Province

Lazio

ZIP/Postal Code

00133

Country

Italy

Facility Name

Ospedale S.Pietro Fatebenefratelli; Divisione di Reumatologia

City

Roma

State/Province

Lazio

ZIP/Postal Code

00189

Country

Italy

Facility Name

Ospedale La Colletta; Reparto Di Reumatologia

City

Arenzano

State/Province

Liguria

ZIP/Postal Code

16011

Country

Italy

Facility Name

Università Degli Studi Di Genova - Dimi; Reumatologia

City

Genova

State/Province

Liguria

ZIP/Postal Code

16132

Country

Italy

Facility Name

Ospedale San Paolo; Divisione di Reumatologia

City

Savona

State/Province

Liguria

ZIP/Postal Code

17100

Country

Italy

Facility Name

Asst Papa Giovanni XXIII; Dh Reumatologia

City

Bergamo

State/Province

Lombardia

ZIP/Postal Code

24127

Country

Italy

Facility Name

Ospedale Civile "La Memoria" Di Gavardo;Immunoematologia Trasfusionale-Allergologia E Reumatologia

City

Gavardo

State/Province

Lombardia

ZIP/Postal Code

25085

Country

Italy

Facility Name

Ospedale Di Magenta Fornaroli; U.O. Di Reumatologia

City

Magenta

State/Province

Lombardia

ZIP/Postal Code

20013

Country

Italy

Facility Name

Asst Centro Specialistico Ortopedico Traumato-Logico Gaetano Pini/Cto; Divisione Di Reumatologia

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20122

Country

Italy

Facility Name

Ospedale Maggiore Policlinico; Unità Operativa Complessa di Allergologia e Immunologia Clinica

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20122

Country

Italy

Facility Name

ASST FATEBENEFRATELLI SACCO; Reumatologia (Sacco)

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20157

Country

Italy

Facility Name

Asst Grande Ospedale Metropolitano Niguarda; Reumatologia

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20162

Country

Italy

Facility Name

ASST DI MONZA; Reumatologia (Medicina I)

City

Monza

State/Province

Lombardia

ZIP/Postal Code

20052

Country

Italy

Facility Name

Irccs Policlinico San Matteo; Reumatologia Adulti

City

Pavia

State/Province

Lombardia

ZIP/Postal Code

27100

Country

Italy

Facility Name

ASST DI VIMERCATE; Medicina Generale

City

Vimercate

State/Province

Lombardia

ZIP/Postal Code

20059

Country

Italy

Facility Name

Ospedale Regionale Torrette; SOD Clinica Medica del Dipartimento di Medicina Interna e Specialisti

City

Ancona

State/Province

Marche

ZIP/Postal Code

60020

Country

Italy

Facility Name

Ospedale Murri - Universita Politecnica Delle Marche; Clinica Reumatologica Ii

City

Jesi

State/Province

Marche

ZIP/Postal Code

60035

Country

Italy

Facility Name

Azienda Ospedaliera Maggiore Della Carita; Day Hospital Immunologia

City

Novara

State/Province

Piemonte

ZIP/Postal Code

28100

Country

Italy

Facility Name

Azienda Ospedaliera San Giovanni Battista; Reparto Reumatologia

City

Torino

State/Province

Piemonte

ZIP/Postal Code

10126

Country

Italy

Facility Name

Ordine Mauriziano Ospedale Umberto I; Centro Di Reumatologia

City

Torino

State/Province

Piemonte

ZIP/Postal Code

10128

Country

Italy

Facility Name

Azienda Ospedaliera Policlinico; Servizio Reumatologia

City

Bari

State/Province

Puglia

ZIP/Postal Code

70124

Country

Italy

Facility Name

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

City

Casarano (LE)

State/Province

Puglia

ZIP/Postal Code

73042

Country

Italy

Facility Name

Ospedali Riuniti di Foggia; Dipartimento Medicina Interna Reumatologia

City

Foggia

State/Province

Puglia

ZIP/Postal Code

71100

Country

Italy

Facility Name

Ospedali Riuniti Di Foggia; Struttura Di Reumatologia

City

Foggia

State/Province

Puglia

ZIP/Postal Code

71100

Country

Italy

Facility Name

A.O. Universitaria Policlinico Monserrato Di Cagliari; Reumatologia I

City

Cagliari

State/Province

Sardegna

ZIP/Postal Code

09042

Country

Italy

Facility Name

Azienda Ospedaliero Universitaria di Sassari; UOC Reumatologia

City

Sassari

State/Province

Sardegna

ZIP/Postal Code

07100

Country

Italy

Facility Name

Ospedale Vittorio Emanuele Ii; U.O. Reumatologia Clinica Medica Condorelli

City

Catania

State/Province

Sicilia

ZIP/Postal Code

95124

Country

Italy

Facility Name

Azienda Osped. Univ. Policlinico G. Martino; Centro Prevenzione E Cura Osteoporosi

City

Messina

State/Province

Sicilia

ZIP/Postal Code

98100

Country

Italy

Facility Name

Arnas Ospedale Civico; Medicina Interna II

City

Palermo

State/Province

Sicilia

ZIP/Postal Code

90127

Country

Italy

Facility Name

Ospedale Careggi Villa Monnatessa ; Sezione Di Reumatologia

City

Firenze

State/Province

Toscana

ZIP/Postal Code

50139

Country

Italy

Facility Name

Az. Osp. Pisana Ospedale S. Chiara; U.O. Di Reumatologia

City

Pisa

State/Province

Toscana

ZIP/Postal Code

56100

Country

Italy

Facility Name

Osp S. Maria Misericordia Dip. Medicina Clinica Sperimentale Cattedra Reumatologia

City

Perugia

State/Province

Umbria

ZIP/Postal Code

06122

Country

Italy

Facility Name

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

City

Aosta

State/Province

Valle D'Aosta

ZIP/Postal Code

11100

Country

Italy

Facility Name

Azienda Ospedaliera Universitaria Borgo Trento; Dipartimento di Medicina Sezione di Reumatologia

City

Verona

State/Province

Veneto

ZIP/Postal Code

37126

Country

Italy

Facility Name

Policlinico G.B. Rossi; Divisione Immunologia Clinica Sperimentale Medicina B

City

Verona

State/Province

Veneto

ZIP/Postal Code

37134

Country

Italy

12. IPD Sharing Statement

Citations:

PubMed Identifier

30649524

Citation

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.

Results Reference

derived

PubMed Identifier

29244149

Citation

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.

Results Reference

derived

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