RITACT: A Long-term Safety Extension Study of Tocilizumab in Brazilian Participants With Rheumatoid Arthritis (RA) Who Completed the Studies ML21530 and MA21488

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01715831
• Collaborator: (none)
• Enrollment: 26
• Locations: 9
• Arm: 1
• Actual Duration (Months): 40.7
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This multicenter, open-label, single-arm extension study will evaluate the long-term safety of tocilizumab (RoActemra/Actemra) in participants with RA. Participants who have completed the MA21488 (NCT00810199) core study and the ML21530 (NCT00754572) study and who could benefit from the study drug, according to the opinion of the investigator, will receive 8 milligrams per kilogram (mg/kg) of intravenous (IV) tocilizumab every 4 weeks. The anticipated time on study treatment is 104 weeks.

Condition or Disease	Intervention/Treatment	Phase
Arthritis, Rheumatoid	Drug: DMARDs; Drug: Tocilizumab	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-Label, Single-Arm Extension Study to Describe the Safety of Tocilizumab Treatment In Brazilian Patients With DMARDs Refractory Rheumatoid Arthritis Which Completed Studies ML21530 and MA21488 and Presenting an Indication of Maintaining the Tocilizumab Treatment
• Actual Study Start Date: Jan 15, 2013
• Actual Primary Completion Date: Jun 6, 2016
• Actual Study Completion Date: Jun 6, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Tocilizumab Participants will receive tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant will be of 800 mg of tocilizumab. Participants may also receive disease-modifying anti-rheumatic drugs (DMARDs) in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.

Drug: DMARDs; DMARDs may be added to the tocilizumab treatment in any visit, at the discretion of the investigator, according to the local prescription information and participant's tolerance. Study protocol does not specify any particular DMARD.; Drug: Tocilizumab; Tocilizumab will be administered at 8 mg/kg IV dose every 4 weeks for 104 weeks; Other Names: RoActemra; Actemra

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (NSAEs) [From Baseline up to approximately 2 years]

   An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; significant medical event, according to the investigator discretion (e.g., may represent a risk to the participant or may require medical/surgical intervention to prevent one of the outcomes mentioned above).

2. Number of Participants With AEs Leading to Dose Modification or Study Discontinuation [From Baseline up to approximately 2 years]

3. Number of Participants With AEs of Special Interest [From Baseline up to approximately 2 years]

   Adverse events of special interest included following events: Infections (including opportunistic infections); myocardial infarction / acute coronary syndrome; gastrointestinal (GI) perforations and related events; malignancies; anaphylaxis/hypersensitivity reactions; demyelinating disorders; stroke; hemorrhagic events; and hepatic events. Overall number of participants who experienced any of these AEs of special interest was reported.

Secondary Outcome Measures

1. Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and follow-up (FU) Visit 1 (Week 108), FU Visit 2 (Week 116)]

   DAS28 score is a measure of participant's disease activity calculated using tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), participant's global assessment of disease activity (general health [GH]) using visual analog scale (VAS), 0 millimeter (mm)=no disease activity to 100 mm=maximum disease activity, displayed on the 100 mm horizontal VAS, and acute phase response (erythrocyte sedimentation rate [ESR] in millimeters per hour [mm/hr]) for a total possible score of 0 to 10. The score is calculated using the following formula: DAS28 = [0.56 multiplied by (*) square root (√) of TJC28] plus (+) [0.28*√SJC28]+[0.70*the natural logarithm (ln) ESR]+[0.014*GH]. DAS28-ESR score varies from 0 to 10, where higher scores represent greater disease activity.

2. Tender Joint Count (TJC) [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

   An assessment of 28 joints was conducted for tenderness. Joints were assessed and classified as tender/not tender by pressure and joint manipulation after a physical examination. Artificial joints, arthrodesis or fused joints were not taken into consideration for tenderness.

3. Swollen Joint Count (SJC) [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

   An assessment of 28 joints was conducted for swelling. Joints were assessed and classified as swollen/not swollen by pressure and joint manipulation after a physical examination. Artificial joints, arthrodesis or fused joints were not taken into consideration for swelling.

4. Global Evaluation of Disease Activity by the Participant Using VAS Score [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

   Participant's global assessment of disease activity was measured on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as "inactive disease" (free of symptoms and without symptoms of arthritis) and 100 mm (right end of the line) as "disease maximum activity" (maximum activity of arthritis). The participant marked the line according to their assessment and the distance from the left edge was measured.

5. Global Evaluation of Disease Activity by the Physician Using VAS Score [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

   Physician global assessment of disease activity was measured on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as "inactive disease" (free of symptoms and without symptoms of arthritis) and 100 mm (right end of the line) as "disease maximum activity" (maximum activity of arthritis). The physician marked the line according to their assessment and the distance from the left edge was measured.

6. Participant's Pain Assessment Using VAS Score [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

   Participant's pain assessment was made on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as "no pain" and 100 mm (right end of the line) as "unbearable pain". The participant marked the line according to their assessment and the distance from the left edge was measured.

7. Health Assessment Questionnaire - Disability Index (HAQ-DI) Score [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

   The Stanford HAQ-DI is a participant-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/personal care, ability to stand-up, eating, walking, hygiene, reaching, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where 0 represents 'no disability' and 3 represents 'very severe, high-dependency disability'.

8. Health Assessment Questionnaire (HAQ) Pain VAS Score [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

   The HAQ pain VAS is a measure of pain on a continuous 100 mm scale. Participants were asked to indicate how much pain they had in the past week as a result of their illness on a horizontal line from 0 (no pain) to 100 mm (severe pain).

9. C-Reactive Protein (CRP) Level [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

   CRP is an acute phase reactant and is a measure of inflammation.

10. ESR Level [Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)]

    ESR is an acute phase reactant and is a measure of inflammation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants who have completed their last visit in the core studies ML21530 and MA21488 and that might benefit from treatment using the study drug according to the investigator's evaluation

• Absence of an AE or current or recent laboratory finding that would prevent the use of the 8 mg/kg dose of the tocilizumab

• Receiving outpatient treatment

• For women who are not postmenopausal and are not surgically sterile: agreement to use at least one adequate method of contraception

Exclusion Criteria:

• Participants who have prematurely discontinued the core studies ML21530 and MA21488 for any reason

• MA21488 study participants who remained untreated with tocilizumab after it's discontinuation according to the treatment-free remission criteria of MA21488 study

• Immunization with a live/attenuated vaccine since the last administration of the study drug in the core studies ML21530 and ML21488

• Diagnosis after the last visit of the study ML21530 or after the last visit of the study MA21488 of a rheumatic autoimmune disease other than RA, including systemic erythematous lupus (SEL), mixed connective tissue disease (MCTD), scleroderma and polymyositis, or a significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty's syndrome). Secondary Sjogren's Syndrome and/or nodulosis with RA are allowed

• Diagnosis after the last visit of the core study ML21530 or of the study MA21488 of an inflammatory joint disease other than RA

• Abnormal laboratory parameters at the baseline

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies

• Evidences of a concomitant, serious and uncontrolled illness

• Known active condition or a history of recurrent infections by bacteria, viruses, fungi, mycobacteria or other agents

• Evidence of an active malignant disease, malignancies diagnosed in the last 10 years or breast cancer diagnosed in the last 20 years

• Uncontrolled disease status, such as asthma or inflammatory bowel disease in which acute crises are usually treated with oral or parenteral corticosteroids

• Current hepatic disease, as determined by the investigator

• Active tuberculosis (TB) requiring treatment in the previous three years. Participants should be screened for latent TB according to local practice guidelines and should not be admitted into the study if latent TB is detected. Participants must not present any evidence of active TB infection at the enrollment. Participants treated for tuberculosis without recurrence in three years are allowed

• History of alcohol, drugs or chemical abuse since the inclusion in the core studies ML21530 and MA21488

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Santa Casa de Misericordia de Salvador; Reumatologia	Salvador	BA	Brazil	40050-410
2	Hospital Universitario Cassiano Antonio Moraes - UFES; Reumatologia	Vitoria	ES	Brazil	29043-910
3	Centro Mineiro de Pesquisa - CMIP	Juiz de Fora	MG	Brazil	36036-330
4	Hospital das Clinicas - UNICAMP	Campinas	SP	Brazil	13083-888
5	Hospital de Base de Sao Jose do Rio Preto	Sao Jose do Rio Preto	SP	Brazil	15090-000
6	Universidade Federal de Sao Paulo - UNIFESP; Reumatologia	Sao Paulo	SP	Brazil	04026-000
7	Hospital Abreu Sodre - AACD;Reumatologia	Sao Paulo	SP	Brazil	04027-000
8	Hospital Estadual do Servidor Publico; Reumatologia	Sao Paulo	SP	Brazil	04039-004
9	Centro Paulista de Investigacao Clinica - CEPIC	Sao Paulo	SP	Brazil	04266-010

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01715831
• Other Study ID Numbers: ML28091
• First Posted: Oct 29, 2012
• Last Update Posted: Jun 12, 2017
• Last Verified: May 1, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received disease-modifying anti-rheumatic drugs (DMARDs) in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Period Title: Overall Study
STARTED	26
COMPLETED	25
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Overall Participants	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.0 (12.6)
Sex: Female, Male (Count of Participants)
Female	25 96.2%
Male	1 3.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs) and Non-Serious Adverse Events (NSAEs)
Description	An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; significant medical event, according to the investigator discretion (e.g., may represent a risk to the participant or may require medical/surgical intervention to prevent one of the outcomes mentioned above).
Time Frame	From Baseline up to approximately 2 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
SAEs	4 15.4%
NSAEs	24 92.3%

2. Primary Outcome

Title	Number of Participants With AEs Leading to Dose Modification or Study Discontinuation
Time Frame	From Baseline up to approximately 2 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
AEs leading to dose modification	7 26.9%
AEs leading to study discontinuation	1 3.8%

3. Primary Outcome

Title	Number of Participants With AEs of Special Interest
Description	Adverse events of special interest included following events: Infections (including opportunistic infections); myocardial infarction / acute coronary syndrome; gastrointestinal (GI) perforations and related events; malignancies; anaphylaxis/hypersensitivity reactions; demyelinating disorders; stroke; hemorrhagic events; and hepatic events. Overall number of participants who experienced any of these AEs of special interest was reported.
Time Frame	From Baseline up to approximately 2 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Number [participants]	0 0%

4. Secondary Outcome

Title	Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR)
Description	DAS28 score is a measure of participant's disease activity calculated using tender joint count in 28 joints (TJC28), swollen joint count in 28 joints (SJC28), participant's global assessment of disease activity (general health [GH]) using visual analog scale (VAS), 0 millimeter (mm)=no disease activity to 100 mm=maximum disease activity, displayed on the 100 mm horizontal VAS, and acute phase response (erythrocyte sedimentation rate [ESR] in millimeters per hour [mm/hr]) for a total possible score of 0 to 10. The score is calculated using the following formula: DAS28 = [0.56 multiplied by (*) square root (√) of TJC28] plus (+) [0.28*√SJC28]+[0.70*the natural logarithm (ln) ESR]+[0.014*GH]. DAS28-ESR score varies from 0 to 10, where higher scores represent greater disease activity.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and follow-up (FU) Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	2.76 (1.19)
Week 12 (n=24)	2.23 (0.86)
Week 24 (n=25)	2.43 (1.01)
Week 36 (n=25)	2.04 (0.85)
Week 48 (n=21)	2.32 (1.23)
Week 56 (n=24)	1.82 (0.55)
Week 68 (n=23)	2.21 (0.84)
Week 80 (n=24)	2.06 (0.64)
Week 92 (n=24)	2.23 (0.96)
Week 104 (n=25)	1.92 (0.93)
FU Visit 1 (n=13)	1.70 (1.02)
FU Visit 2 (n=24)	3.21 (1.35)

5. Secondary Outcome

Title	Tender Joint Count (TJC)
Description	An assessment of 28 joints was conducted for tenderness. Joints were assessed and classified as tender/not tender by pressure and joint manipulation after a physical examination. Artificial joints, arthrodesis or fused joints were not taken into consideration for tenderness.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	2.8 (3.6)
Week 12 (n=24)	1.8 (2.3)
Week 24 (n=25)	2.0 (3.6)
Week 36 (n=25)	1.9 (2.5)
Week 48 (n=21)	2.8 (3.8)
Week 56 (n=24)	1.1 (1.2)
Week 68 (n=23)	2.0 (2.6)
Week 80 (n=24)	1.6 (2.0)
Week 92 (n=24)	1.5 (1.7)
Week 104 (n=25)	1.5 (1.8)
FU Visit 1 (n=13)	1.8 (3.7)
FU Visit 2 (n=24)	2.8 (4.7)

6. Secondary Outcome

Title	Swollen Joint Count (SJC)
Description	An assessment of 28 joints was conducted for swelling. Joints were assessed and classified as swollen/not swollen by pressure and joint manipulation after a physical examination. Artificial joints, arthrodesis or fused joints were not taken into consideration for swelling.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	1.4 (2.0)
Week 12 (n=24)	1.0 (2.0)
Week 24 (n=25)	0.6 (1.2)
Week 36 (n=25)	0.9 (1.0)
Week 48 (n=21)	1.4 (2.5)
Week 56 (n=24)	0.8 (1.8)
Week 68 (n=23)	0.9 (1.5)
Week 80 (n=24)	0.4 (0.8)
Week 92 (n=24)	0.8 (1.2)
Week 104 (n=25)	0.6 (1.3)
FU Visit 1 (n=13)	0.2 (0.4)
FU Visit 2 (n=24)	1.5 (2.2)

7. Secondary Outcome

Title	Global Evaluation of Disease Activity by the Participant Using VAS Score
Description	Participant's global assessment of disease activity was measured on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as "inactive disease" (free of symptoms and without symptoms of arthritis) and 100 mm (right end of the line) as "disease maximum activity" (maximum activity of arthritis). The participant marked the line according to their assessment and the distance from the left edge was measured.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	35.2 (25.3)
Week 12 (n=26)	36.4 (26.4)
Week 24 (n=26)	38.4 (27.2)
Week 36 (n=25)	31.8 (25.0)
Week 48 (n=23)	32.8 (28.8)
Week 56 (n=25)	30.6 (22.7)
Week 68 (n=24)	32.4 (24.6)
Week 80 (n=24)	36.1 (26.2)
Week 92 (n=25)	36.2 (25.5)
Week 104 (n=25)	33.4 (25.2)
FU Visit 1 (n=15)	37.1 (28.0)
FU Visit 2 (n=25)	42.6 (29.9)

8. Secondary Outcome

Title	Global Evaluation of Disease Activity by the Physician Using VAS Score
Description	Physician global assessment of disease activity was measured on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as "inactive disease" (free of symptoms and without symptoms of arthritis) and 100 mm (right end of the line) as "disease maximum activity" (maximum activity of arthritis). The physician marked the line according to their assessment and the distance from the left edge was measured.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	20.6 (18.7)
Week 12 (n=26)	11.4 (14.1)
Week 24 (n=26)	13.8 (14.7)
Week 36 (n=25)	13.1 (10.4)
Week 48 (n=23)	9.1 (11.3)
Week 56 (n=25)	13.0 (13.3)
Week 68 (n=24)	11.6 (11.9)
Week 80 (n=24)	11.3 (11.2)
Week 92 (n=25)	13.7 (11.7)
Week 104 (n=25)	10.0 (9.7)
FU Visit 1 (n=15)	11.7 (11.5)
FU Visit 2 (n=25)	15.3 (18.4)

9. Secondary Outcome

Title	Participant's Pain Assessment Using VAS Score
Description	Participant's pain assessment was made on a horizontal 0-100 mm VAS, with 0 mm (left end of the line) described as "no pain" and 100 mm (right end of the line) as "unbearable pain". The participant marked the line according to their assessment and the distance from the left edge was measured.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	31.9 (21.7)
Week 12 (n=26)	29.0 (25.1)
Week 24 (n=26)	33.7 (25.4)
Week 36 (n=25)	28.6 (21.5)
Week 48 (n=23)	27.8 (25.2)
Week 56 (n=25)	27.4 (23.1)
Week 68 (n=24)	27.8 (23.1)
Week 80 (n=24)	31.9 (24.3)
Week 92 (n=25)	29.5 (22.7)
Week 104 (n=25)	28.6 (22.6)
FU Visit 1 (n=15)	28.9 (25.8)
FU Visit 2 (n=25)	42.6 (30.1)

10. Secondary Outcome

Title	Health Assessment Questionnaire - Disability Index (HAQ-DI) Score
Description	The Stanford HAQ-DI is a participant-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/personal care, ability to stand-up, eating, walking, hygiene, reaching, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where 0 represents 'no disability' and 3 represents 'very severe, high-dependency disability'.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	0.68 (0.61)
Week 12 (n=26)	0.49 (0.43)
Week 24 (n=26)	0.49 (0.38)
Week 36 (n=25)	0.49 (0.45)
Week 48 (n=23)	0.48 (0.49)
Week 56 (n=24)	0.53 (0.60)
Week 68 (n=24)	0.52 (0.47)
Week 80 (n=24)	0.53 (0.48)
Week 92 (n=23)	0.43 (0.44)
Week 104 (n=24)	0.48 (0.50)
FU Visit 1 (n=15)	0.56 (0.42)
FU Visit 2 (n=23)	0.63 (0.59)

11. Secondary Outcome

Title	Health Assessment Questionnaire (HAQ) Pain VAS Score
Description	The HAQ pain VAS is a measure of pain on a continuous 100 mm scale. Participants were asked to indicate how much pain they had in the past week as a result of their illness on a horizontal line from 0 (no pain) to 100 mm (severe pain).
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	31.9 (22.6)
Week 12 (n=26)	30.8 (24.5)
Week 24 (n=26)	37.8 (26.3)
Week 36 (n=25)	30.1 (23.4)
Week 48 (n=23)	32.7 (29.4)
Week 56 (n=24)	31.3 (24.0)
Week 68 (n=24)	32.9 (25.1)
Week 80 (n=24)	34.4 (27.2)
Week 92 (n=23)	38.2 (30.3)
Week 104 (n=24)	29.0 (23.9)
FU Visit 1 (n=15)	30.9 (24.8)
FU Visit 2 (n=22)	43.3 (32.8)

12. Secondary Outcome

Title	C-Reactive Protein (CRP) Level
Description	CRP is an acute phase reactant and is a measure of inflammation.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=24)	0.51 (0.91)
Week 12 (n=26)	3.13 (6.17)
Week 24 (n=25)	1.08 (1.58)
Week 36 (n=25)	2.58 (3.00)
Week 48 (n=21)	0.21 (0.27)
Week 56 (n=24)	0.41 (0.92)
Week 68 (n=24)	0.43 (0.74)
Week 80 (n=24)	0.64 (1.91)
Week 92 (n=23)	1.86 (7.11)
Week 104 (n=25)	0.12 (0.16)
FU Visit 1 (n=13)	0.10 (0.11)
FU Visit 2 (n=24)	1.46 (5.05)

13. Secondary Outcome

Title	ESR Level
Description	ESR is an acute phase reactant and is a measure of inflammation.
Time Frame	Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, and FU Visit 1 (Week 108), FU Visit 2 (Week 116)

Outcome Measure Data

Analysis Population Description

ITT population. Here, n=Number of participants analyzed for this outcome measure at specified timepoint.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
Measure Participants	26
Baseline (n=26)	9.8 (10.2)
Week 12 (n=24)	4.9 (3.1)
Week 24 (n=25)	8.5 (7.6)
Week 36 (n=25)	4.6 (3.2)
Week 48 (n=21)	5.1 (4.7)
Week 56 (n=24)	4.9 (5.3)
Week 68 (n=23)	6.7 (7.2)
Week 80 (n=24)	6.4 (9.1)
Week 92 (n=24)	7.5 (9.2)
Week 104 (n=25)	5.5 (6.3)
FU Visit 1 (n=13)	4.8 (5.0)
FU Visit 2 (n=24)	21.9 (29.7)

Adverse Events

Time Frame	From Baseline up to approximately 2 years
Adverse Event Reporting Description	ITT population
Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 104 weeks. The maximum single dose administered to any participant was 800 mg of tocilizumab. Participants might have also received DMARDs in addition to the tocilizumab treatment in any visit, at the investigator discretion, according to the local prescription information and participant's tolerance.
All Cause Mortality
	Tocilizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Tocilizumab
	Affected / at Risk (%)	# Events
Total	4/26 (15.4%)
Gastrointestinal disorders
Diverticulitis	1/26 (3.8%)
Injury, poisoning and procedural complications
Corneal perforation	1/26 (3.8%)
Investigations
Nervous system disorders
Ischaemic stroke	1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Lung disorder	1/26 (3.8%)
Other (Not Including Serious) Adverse Events
	Tocilizumab
	Affected / at Risk (%)	# Events
Total	24/26 (92.3%)
Cardiac disorders
Chest pain	2/26 (7.7%)
Ear and labyrinth disorders
Labyrinthitis	2/26 (7.7%)
Gastrointestinal disorders
Dyspepsia	4/26 (15.4%)
Diarrhoea NOS	2/26 (7.7%)
Gastritis	2/26 (7.7%)
Periodontitis	2/26 (7.7%)
Infections and infestations
Respiratory tract infection NOS	12/26 (46.2%)
Urinary tract infection	7/26 (26.9%)
Tonsillitis	4/26 (15.4%)
Dengue fever	2/26 (7.7%)
Influenza	2/26 (7.7%)
Injury, poisoning and procedural complications
Injury	2/26 (7.7%)
Metabolism and nutrition disorders
Dyslipidaemia	6/26 (23.1%)
Hypercholesterolemia	3/26 (11.5%)
Hyperglycaemia	2/26 (7.7%)
Osteopenia	2/26 (7.7%)
Osteoporosis	2/26 (7.7%)
Vitamin D deficiency	2/26 (7.7%)
Musculoskeletal pain	8/26 (30.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/26 (7.7%)
Back pain	2/26 (7.7%)
Myalgia	2/26 (7.7%)
Osteoarthritis	2/26 (7.7%)
Nervous system disorders
Headache	5/26 (19.2%)
Psychiatric disorders
Anxiety	3/26 (11.5%)
Renal and urinary disorders
Leukocyturia	2/26 (7.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	4/26 (15.4%)
Nasopharyngitis	2/26 (7.7%)
Dermatitis	3/26 (11.5%)
Skin and subcutaneous tissue disorders
Urticaria	3/26 (11.5%)
Pruritus	2/26 (7.7%)
Hypertension NOS	3/26 (11.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.