A Study of Tocilizumab as Monotherapy and in Combination... | NCT01007435

NCT01007435

ID	Type	Description	Link
2009-012759-12

Status Module

Sponsor/Collaborators Module

Oversight Module

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No data is available for this block.

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
(A) Tocilizumab 8 mg/kg + placebo to methotrexate	Experimental	Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.	Drug: Tocilizumab Drug: Placebo to methotrexate
(B) Tocilizumab 8 mg/kg + methotrexate	Experimental	Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.	Drug: Tocilizumab Drug: Methotrexate
(C) Tocilizumab 4 mg/kg + methotrexate	Experimental	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.	Drug: Tocilizumab Drug: Methotrexate
(D) Placebo to tocilizumab + methotrexate	Active Comparator	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.	Drug: Placebo to tocilizumab Drug: Methotrexate

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Tocilizumab	Drug	Tocilizumab was supplied in vials.	(A) Tocilizumab 8 mg/kg + placebo to methotrexate (B) Tocilizumab 8 mg/kg + methotrexate (C) Tocilizumab 4 mg/kg + methotrexate

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 24	A participant has a DAS28 remission response if their DAS28 < 2.6. The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog scale (left end = no disease activity [symptom-free and no arthritis symptoms], right end = maximum disease activity [maximum arthritis disease activity]). When ESR equaled 0 mm/hr, it was set to 1 mm/hr. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.	Week 24

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 52		Week 52
Percentage of Patients With an Improvement ≥ 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline to Weeks 24 and 52

Eligibility Module

Contacts/Locations Module

Name	Affiliation	Role
Clinical Trials	Hoffmann-La Roche	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Pinnacle Research Group; Llc, Central		Anniston	Alabama	36207	United States
Rheumatology Associates of North Alabama

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
28389552	Derived	Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Blanco R, Kadva A, Dimonaco S. Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial. Ann Rheum Dis. 2017 Jul;76(7):1279-1284. doi: 10.1136/annrheumdis-2016-210561. Epub 2017 Apr 7.
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IPD Sharing Statement Module

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No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
FG001	Tocilizumab 4 mg/kg + Methotrexate

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

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No data is available for this block.

Document Section

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No data is available for this block.

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

Improvement must be seen in tender (68) and swollen (66) joint counts. Joints were assessed and classified as swollen/not swollen and tender/not tender by pressure and joint manipulation. Improvement must also be seen in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, the extreme left end of the line "no disease activity" [symptom-free and no arthritis symptoms] and the extreme right end "maximum disease activity"; patient assessment of pain in previous the 24 hours on a VAS (extreme left end of the line "no pain" and the extreme right end "unbearable pain"); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C-reactive protein (CRP), or erythrocyte sedimentation rate if CRP was missing.

Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.

Baseline Characteristics were based on the intent-to-treat (ITT) population. Five of 1162 randomized patients (2 placebo + methotrexate, 2 tocilizumab 4 mg/kg + methotrexate, 1 tocilizumab 8 mg/kg + methotrexate) did not receive any study treatment and were excluded from all analysis populations. The ITT population therefore included 1157 patients.

Arm/Group Information

ID	Title	Description
BG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
BG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
BG002	Tocilizumab 8 mg/kg + Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
BG003	Tocilizumab 8 mg/kg + Placebo to Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.
BG004	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	OG00015.0(10.9 to 19.1) OG00131.9(26.6 to 37.3) OG00244.8(39.1 to 50.6) OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002	The null hypothesis is that there is no difference in the DAS28 remission response at Week 24 between the placebo to tocilizumab + methotrexate and the tocilizumab 8 mg/kg + methotrexate treatment groups.	Regression, Logistic	The stratification factors, region and serologic status, were included in the model.	<0.0001	A hierarchy of statistical testing was implemented in order to control the type I error rate for multiple comparisons.	Odds Ratio (OR)	4.77			2-Sided	95	3.19	7.14			Last observation carried forward was used for TJC and SJC. No imputation was used for ESR and GH. Patients who withdrew prematurely or where a DAS28 could not be calculated were set to "non-responder".

Secondary

Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 52

Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.

Posted

Number

Percentage of participants

Week 52

ID	Title	Description
OG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
OG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG002	Tocilizumab 8 mg/kg + Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG003	Tocilizumab 8 mg/kg + Placebo to Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.

Secondary

Percentage of Patients With an Improvement ≥ 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline to Weeks 24 and 52

Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.

Posted

Number

Percentage of participants

Baseline to Weeks 24 and 52

ID	Title	Description
OG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
OG001	Tocilizumab 4 mg/kg + Methotrexate

Secondary

Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52

The mTSS is a measure of joint damage and includes measures of joint erosion (JE) and joint space narrowing (JSN). The JE score, using the van der Heijde modification, measures erosion severity in 32 hand joints and 12 foot joints. Each hand joint is scored from 0 to 5 and each foot joint is scored from 0 to 10; the total score ranges from 0 to 280. Each joint is scored according to the surface area involved. A score of 10 indicates extensive loss of bone from more than one-half of the articulating bone; a score of 0 indicates no erosion. The JSN score measures the severity of JSN in 30 hand joints (15 per hand) and 12 foot joints (6 per foot). Each joint, including subluxation, is scored from 0 to 4; the total score ranges from 0 to 168. A higher score indicates more joint space narrowing. The mTSS ranges from 0 to 448 (280+168). A higher mTSS score indicates greater damage. A negative change score indicates improvement.

Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Week 52

ID	Title	Description
OG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
OG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.

Secondary

Change From Baseline in Modified Sharp Erosion Score at Week 52

Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Week 52

ID	Title	Description
OG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
OG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG002	Tocilizumab 8 mg/kg + Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG003	Tocilizumab 8 mg/kg + Placebo to Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.

Secondary

Change From Baseline in Sharp Joint Space Narrowing Score at Week 52

Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Week 52

ID	Title	Description
OG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
OG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG002	Tocilizumab 8 mg/kg + Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG003	Tocilizumab 8 mg/kg + Placebo to Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.

Secondary

Percentage of Participants With a Major Clinical Response at Week 52

A major clinical response is defined as an ACR70 response that is maintained for 6 consecutive months (24 weeks) for any 24-week period between Week 2 and Week 52.

Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.

Posted

Number

Percentage of participants

Baseline to Week 52

ID	Title	Description
OG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
OG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG002	Tocilizumab 8 mg/kg + Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG003	Tocilizumab 8 mg/kg + Placebo to Methotrexate

Secondary

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

The Stanford HAQ-DI is a patient completed questionnaire specific for rheumatoid arthritis. The HAQ-DI assesses how well the patient is able to perform 8 activities: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The patient answers 20 questions with 1 of 4 responses with the past week as the time frame: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The highest score for any question in a category determines the category score. The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.

Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Weeks 24 and 52

ID	Title	Description
OG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
OG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG002	Tocilizumab 8 mg/kg + Methotrexate

Secondary

Change From Baseline in Short Form 36 (SF-36) Physical Component Summary (PCS) Scores at Weeks 24 and 52

The SF-36 Health Survey (Version 2) is a standardized questionnaire consisting of 36 questions that measures patient-reported symptoms on 8 dimensions; it is used to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role-Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role-Emotional, and Mental Health. Each score was scaled from 0 to 100. A positive change score indicates better HRQoL.

Intent-to-treat population: All randomized participants who received at least 1 tocilizumab/placebo infusion.

Posted

Mean

Standard Deviation

Units on a scale

Baseline to Weeks 24 and 52

ID	Title	Description
OG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.
OG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.
OG002	Tocilizumab 8 mg/kg + Methotrexate

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo to Tocilizumab + Methotrexate	Patients received placebo tocilizumab intravenously (iv) every 4 weeks + methotrexate orally once a week for 104 weeks.	24	282	177	282
EG001	Tocilizumab 4 mg/kg + Methotrexate	Patients received tocilizumab 4 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.	29	289	182	289
EG002	Tocilizumab 8 mg/kg + Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.	31	290	201	290
EG003	Tocilizumab 8 mg/kg + Placebo to Methotrexate	Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.	25	292	163	292

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Pneumonia	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0014 affected289 at risk EG0021 affected290 at risk EG0031 affected292 at risk
Cellulitis	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0021 affected290 at risk EG003
Appendicitis	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0023 affected290 at risk EG003
Bronchopneumonia	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0011 affected289 at risk EG0021 affected290 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Appendicitis perforated	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Arthritis bacterial	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Erysipelas	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Herpes zoster	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Lower respiratory tract infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Lung infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Lyme disease	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Pneumococcal infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Pneumonia bacterial	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Pneumonia influenzal	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Sepsis	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Staphylococcal infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Tuberculosis	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Viral infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Breast cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Colon cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Endometrial cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Endometrial cancer stage I	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Hepatic neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Lung neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Metastatic bronchial carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Ovarian germ cell teratoma benign	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Renal cancer stage II	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Renal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0012 affected289 at risk EG0020 affected290 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Pulmonary fibrosis	Respiratory, thoracic and mediastinal disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Haemothorax	Respiratory, thoracic and mediastinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Femur fracture	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Ankle fracture	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Fibula fracture	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Infusion related reaction	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Intentional overdose	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Meniscus lesion	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Tendon rupture	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Tibia fracture	Injury, poisoning and procedural complications	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Cerebral ischaemia	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Cerebral haemorrhage	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Convulsion	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Hypoglycaemic coma	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Peroneal nerve palsy	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Syncope	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Transient ischaemic attack	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
VIth nerve paralysis	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Acute myocardial infarction	Cardiac disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Myocardial infarction	Cardiac disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0021 affected290 at risk EG003
Angina pectoris	Cardiac disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Myocardial fibrosis	Cardiac disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Sick sinus syndrome	Cardiac disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Silent myocardial infarction	Cardiac disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Rheumatoid arthritis	Musculoskeletal and connective tissue disorders	MedDRA (15.0)	Systematic Assessment	EG0002 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Gouty arthritis	Musculoskeletal and connective tissue disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Intervertebral disc protrusion osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Osteonecrosis	Musculoskeletal and connective tissue disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Abdominal discomfort	Gastrointestinal disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Anal fissure	Gastrointestinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Colitis	Gastrointestinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Food poisoning	Gastrointestinal disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Pregnancy	Pregnancy, puerperium and perinatal conditions	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0022 affected290 at risk EG003
Deep vein thrombosis	Vascular disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0021 affected290 at risk EG003
Arteriosclerosis	Vascular disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Hypertension	Vascular disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Peripheral ischaemia	Vascular disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Peripheral vascular disorder	Vascular disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Cholelithiasis	Hepatobiliary disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0011 affected289 at risk EG0021 affected290 at risk EG003
Biliary dyskinesia	Hepatobiliary disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Diabetes mellitus inadequate control	Metabolism and nutrition disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Endometrial hyperplasia	Reproductive system and breast disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Epididymal cyst	Reproductive system and breast disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Metrorrhagia	Reproductive system and breast disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Blood bilirubin increased	Investigations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Transaminases increased	Investigations	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003
Renal cyst	Renal and urinary disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Renal failure acute	Renal and urinary disorders	MedDRA (15.0)	Systematic Assessment	EG0001 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Neurosensory hypoacusis	Ear and labyrinth disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Anaphylactic reaction	Immune system disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0011 affected289 at risk EG0020 affected290 at risk EG003
Suicide attempt	Psychiatric disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0020 affected290 at risk EG003
Oteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA (15.0)	Systematic Assessment	EG0000 affected282 at risk EG0010 affected289 at risk EG0021 affected290 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Upper respiratory tract infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG00040 affected282 at risk EG00137 affected289 at risk EG00230 affected290 at risk EG00339 affected292 at risk
Nasopharyngitis	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG00038 affected282 at risk EG00140 affected289 at risk EG00228 affected290 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG00013 affected282 at risk EG00118 affected289 at risk EG00214 affected290 at risk EG003
Bronchitis	Infections and infestations	MedDRA (15.0)	Systematic Assessment	EG0006 affected282 at risk EG00118 affected289 at risk EG00220 affected290 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA (15.0)	Systematic Assessment	EG00029 affected282 at risk EG00139 affected289 at risk EG00255 affected290 at risk EG003
Transaminases increased	Investigations	MedDRA (15.0)	Systematic Assessment	EG00023 affected282 at risk EG00135 affected289 at risk EG00240 affected290 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA (15.0)	Systematic Assessment	EG0008 affected282 at risk EG0018 affected289 at risk EG00217 affected290 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (15.0)	Systematic Assessment	EG00046 affected282 at risk EG00141 affected289 at risk EG00243 affected290 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (15.0)	Systematic Assessment	EG00018 affected282 at risk EG00116 affected289 at risk EG00219 affected290 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA (15.0)	Systematic Assessment	EG00016 affected282 at risk EG00117 affected289 at risk EG00211 affected290 at risk EG003
Rheumatoid arthritis	Musculoskeletal and connective tissue disorders	MedDRA (15.0)	Systematic Assessment	EG00021 affected282 at risk EG0019 affected289 at risk EG00216 affected290 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (15.0)	Systematic Assessment	EG0007 affected282 at risk EG00110 affected289 at risk EG0028 affected290 at risk EG003
Hypertension	Vascular disorders	MedDRA (15.0)	Systematic Assessment	EG00021 affected282 at risk EG00116 affected289 at risk EG00223 affected290 at risk EG003
Headache	Nervous system disorders	MedDRA (15.0)	Systematic Assessment	EG00012 affected282 at risk EG00120 affected289 at risk EG00218 affected290 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA (15.0)	Systematic Assessment	EG0003 affected282 at risk EG00118 affected289 at risk EG00212 affected290 at risk EG003

ID	Term
D001172	Arthritis, Rheumatoid

Ancestor Terms

ID	Term
D001168	Arthritis
D007592	Joint Diseases
D009140	Musculoskeletal Diseases
D012216	Rheumatic Diseases
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases

ID	Term
C502936	tocilizumab
D008727	Methotrexate

Units	Counts
Participants	OG000287 OG001288 OG002290 OG003292

Units	Counts
Participants	OG000267 OG001267 OG002273 OG003275

Units	Counts
Participants	OG000267 OG001268 OG002273 OG003275

Patients received tocilizumab 8 mg/kg iv every 4 weeks + placebo to methotrexate orally once a week for 104 weeks.

Patients received tocilizumab 8 mg/kg iv every 4 weeks + methotrexate orally once a week for 104 weeks.

ID	Term
D000630	Aminopterin
D011622	Pterins
D011621	Pteridines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds