Trial Outcomes & Findings for A Study of the Impact of Methotrexate (MTX) Discontinuation on the Efficacy of Subcutaneous (SC) Tocilizumab (TCZ) With MTX (NCT NCT01855789)

Last Updated: 2017-12-26

Results Overview

The DAS28 was derived from assessments of erythrocyte sedimentation rate (ESR) measured in millimeters per hour (mm/h), tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), and Patient's Global Assessment of disease activity according to 100--millimeter (mm) Visual Analog Scale (VAS). DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity. The change from Week 24 to Week 40 was averaged among all participants, where negative changes indicated an improvement in disease activity.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

718 participants

Primary outcome timeframe

Week 24, Week 40

Results posted on

2017-12-26

Participant Flow

Randomized participants constituted the primary analysis population for the efficacy assessments, while all other analyses including safety assessments were performed on overall study population. An MRI sub-study was planned to evaluate joint inflammation in conjunction with other clinical signs and symptoms.

Participant milestones

Participant milestones
Measure	Period 1: All Participants (TCZ + MTX) All enrolled participants received tocilizumab (TCZ) at a dose of 162 milligrams (mg) via subcutaneous (SC) injection weekly (qw; if body weight was greater than or equal to \[\>/=\] 100 kilograms \[kg\]) or every 2 weeks (q2w; if body weight was less than \[\<\] 100 kg) along with methotrexate (MTX) at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a disease activity score based on 28 joints (DAS28) less than or equal to (\</=) 3.2 at Week 24, were randomized and received double-blind treatment according to the arm in which they were randomized (TCZ + MTX or TCZ + PBO \[placebo\]) up to Week 52. Participants who did not achieve a DAS28 score \</=3.2 at Week 24 continued the same treatment in a non-randomized open-label manner up to Week 52.	Period 2: Randomized Participants (TCZ + MTX) Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.	Period 2: Non-Randomized Participants (TCZ + MTX) Participants, who completed the initial 24-week treatment with TCZ + MTX and did not achieve a DAS28 score \</=3.2 at Week 24, continued receiving TCZ at a dose of 162 mg via SC injection qw along with MTX in open label manner orally up to Week 52.
1) Baseline up to Week 24 STARTED	718	0	0	0
1) Baseline up to Week 24 COMPLETED	602	0	0	0
1) Baseline up to Week 24 NOT COMPLETED	116	0	0	0
2) Week 24 up to End of Study STARTED	0	147	147	308
2) Week 24 up to End of Study COMPLETED	0	132	129	250
2) Week 24 up to End of Study NOT COMPLETED	0	15	18	58

Reasons for withdrawal

Reasons for withdrawal
Measure	Period 1: All Participants (TCZ + MTX) All enrolled participants received tocilizumab (TCZ) at a dose of 162 milligrams (mg) via subcutaneous (SC) injection weekly (qw; if body weight was greater than or equal to \[\>/=\] 100 kilograms \[kg\]) or every 2 weeks (q2w; if body weight was less than \[\<\] 100 kg) along with methotrexate (MTX) at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a disease activity score based on 28 joints (DAS28) less than or equal to (\</=) 3.2 at Week 24, were randomized and received double-blind treatment according to the arm in which they were randomized (TCZ + MTX or TCZ + PBO \[placebo\]) up to Week 52. Participants who did not achieve a DAS28 score \</=3.2 at Week 24 continued the same treatment in a non-randomized open-label manner up to Week 52.	Period 2: Randomized Participants (TCZ + MTX) Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.	Period 2: Non-Randomized Participants (TCZ + MTX) Participants, who completed the initial 24-week treatment with TCZ + MTX and did not achieve a DAS28 score \</=3.2 at Week 24, continued receiving TCZ at a dose of 162 mg via SC injection qw along with MTX in open label manner orally up to Week 52.
1) Baseline up to Week 24 Adverse Event	37	0	0	0
1) Baseline up to Week 24 Death	2	0	0	0
1) Baseline up to Week 24 Lack of Efficacy	16	0	0	0
1) Baseline up to Week 24 Lost to Follow-up	11	0	0	0
1) Baseline up to Week 24 Protocol Violation	4	0	0	0
1) Baseline up to Week 24 Withdrawal by Subject	31	0	0	0
1) Baseline up to Week 24 Physician Decision	4	0	0	0
1) Baseline up to Week 24 Pregnancy	1	0	0	0
1) Baseline up to Week 24 Participant Non-compliance	3	0	0	0
1) Baseline up to Week 24 Sponsor Decision	3	0	0	0
1) Baseline up to Week 24 Other	4	0	0	0
2) Week 24 up to End of Study Adverse Event	0	4	5	21
2) Week 24 up to End of Study Serious Hypersensitivity Reaction	0	0	0	1
2) Week 24 up to End of Study Lack of Efficacy	0	2	5	16
2) Week 24 up to End of Study Lost to Follow-up	0	1	1	4
2) Week 24 up to End of Study Protocol Violation	0	0	0	1
2) Week 24 up to End of Study Withdrawal by Subject	0	7	5	8
2) Week 24 up to End of Study Physician Decision	0	0	2	4
2) Week 24 up to End of Study Participant Non-compliance	0	1	0	1
2) Week 24 up to End of Study Sponsor Decision	0	0	0	1
2) Week 24 up to End of Study Other	0	0	0	1

Baseline Characteristics

A Study of the Impact of Methotrexate (MTX) Discontinuation on the Efficacy of Subcutaneous (SC) Tocilizumab (TCZ) With MTX

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall Study Population n=711 Participants All enrolled participants received TCZ at a dose of 162 mg via SC injection qw (if body weight was \>/=100 kg) or q2w (if body weight was \<100 kg) along with MTX at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a DAS28 score \</=3.2 at Week 24, were randomized and received double-blind treatment according to the arm in which they were randomized (TCZ + MTX or TCZ + PBO) up to Week 52. Participants who did not achieve a DAS28 score \</=3.2 at Week 24 continued the same treatment in a non-randomized open-label manner up to Week 52.
Age, Continuous	55.8 years STANDARD_DEVIATION 12.31 • n=93 Participants
Sex: Female, Male Female	556 Participants n=93 Participants
Sex: Female, Male Male	155 Participants n=93 Participants

PRIMARY outcome

Timeframe: Week 24, Week 40

Population: Analysis was performed on randomized group which included participants in ITT population who were randomized and received blinded treatment at Week 24. Missing Week 40 values were imputed using last available assessment obtained after Week 24. Here, 'Number Analyzed' signifies number of participants with assessment at specified time point.

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40 Week 24	2.13 units on a scale Standard Deviation 0.816	2.11 units on a scale Standard Deviation 0.822
Change From Week 24 in Disease Activity Score Based on 28 Joints (DAS28) Score at Week 40 Change at Week 40	0.15 units on a scale Standard Deviation 1.127	0.48 units on a scale Standard Deviation 1.275

SECONDARY outcome

Timeframe: Weeks 24, 40, and 52

Population: Analysis was performed on randomized group. Missing assessments of response were treated as no response.

The ACR20 response at any time was defined as \>/=20% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 20% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via a Health Assessment Questionnaire-Disability Index (HAQ-DI), and 5) Acute phase reactant (ESR in mm/h or C-Reactive Protein \[CRP\] in milligrams per deciliter \[mg/dL\]).

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response Week 24	91.2 percentage of participants 0.816	83.0 percentage of participants 0.822
Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response Week 40	78.9 percentage of participants 1.127	68.7 percentage of participants 1.275
Percentage of Participants Achieving 20% Improvement in American College of Rheumatology (ACR20) Response Week 52	74.1 percentage of participants	65.3 percentage of participants

SECONDARY outcome

Timeframe: Weeks 24, 40, and 52

Population: Analysis was performed on randomized group. Missing assessments of response were treated as no response.

The ACR50 response at any time was defined as \>/=50% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 50% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL).

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response Week 24	74.1 percentage of participants 0.816	63.3 percentage of participants 0.822
Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response Week 40	63.9 percentage of participants 1.127	50.3 percentage of participants 1.275
Percentage of Participants Achieving 50% Improvement in American College of Rheumatology (ACR50) Response Week 52	62.6 percentage of participants	47.6 percentage of participants

SECONDARY outcome

Timeframe: Weeks 24, 40, and 52

Population: Analysis was performed on randomized group. Missing assessments of response were treated as no response.

The ACR70 response at any time was defined as \>/=70% improvement compared to baseline in TJC (assessed on 68 joints) and SJC (assessed on 66 joints); and 70% improvement compared to baseline in 3 of the following 5 criteria, respectively: 1) Patient's global assessment of disease activity according to 100-mm VAS, 2) Physician's global assessment of disease activity according to 100-mm VAS, 3) participant's global assessment of pain according to 100-mm VAS, 4) Participant's assessment of functional ability via HAQ-DI, and 5) Acute phase reactant (ESR in mm/h or CRP in mg/dL).

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response Week 24	45.6 percentage of participants 0.816	37.4 percentage of participants 0.822
Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response Week 40	42.2 percentage of participants 1.127	34.0 percentage of participants 1.275
Percentage of Participants Achieving 70% Improvement in American College of Rheumatology (ACR70) Response Week 52	48.3 percentage of participants	36.7 percentage of participants

SECONDARY outcome

Timeframe: Week 24, 40, and 52

Population: Analysis was performed on randomized group. Missing assessments of DAS28 were treated as worsening.

The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28- score could range from 0 to 10, where higher score represented higher disease activity.

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52 Week 40	21.1 percentage of participants 0.816	28.6 percentage of participants 0.822
Percentage of Participants With >/=1.2 Points Increase (Worsening) From Week 24 in DAS28 Score at Week 40 and 52 Week 52	26.5 percentage of participants 1.127	29.9 percentage of participants 1.275

SECONDARY outcome

Timeframe: Week 40, Week 52

Population: Analysis was performed on randomized group. Missing assessments of DAS28 were treated as no response.

The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28 score could range from 0 to 10, where higher score represented higher disease activity.

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission) Week 40	59.2 percentage of participants 0.816	49.7 percentage of participants 0.822
Percentage of Participants With DAS28 Score <2.6 (DAS28 Remission) Week 52	55.1 percentage of participants 1.127	48.3 percentage of participants 1.275

SECONDARY outcome

Timeframe: Week 40, Week 52

Population: Analysis was performed on randomized group. Missing assessments of DAS28 were treated as no response.

The DAS28 was derived from assessments of ESR measured in mm/h, TJC28, SJC28, and Patient's global assessment of disease activity according to 100-mm VAS. DAS28 score was calculated as \[0.56 × square root of TJC\] + \[0.28 × square root of SJC\] + \[0.70 × natural log (ESR)\] + \[0.014 × VAS\]. DAS28-ESR score could range from 0 to 10, where higher score represented higher disease activity.

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) n=147 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Percentage of Participants With DAS28 Score </=3.2 (Low DAS28) Week 40	76.9 percentage of participants 0.816	63.3 percentage of participants 0.822
Percentage of Participants With DAS28 Score </=3.2 (Low DAS28) Week 52	68.0 percentage of participants 1.127	62.6 percentage of participants 1.275

SECONDARY outcome

Timeframe: Weeks 24, Week 40

Population: Analysis was performed on MRI subset which included all participants in the randomized group who passed MRI eligibility requirements and who had an MRI performed on or after the Week 24 visit. Here, 'Number Analyzed' signifies participants with assessment at specified time point.

Bones from the wrist regions (carpal bones, distal radius, distal ulna, and metacarpal bases) and the metacarpophalangeal (MCP) joints (metacarpal heads and phalangeal bases) were assessed for erosion via MRI and scored separately based on the proportion of eroded bone compared to the 'assessed bone volume' judged from all available images. Scoring ranged from 0 (no erosion) to 10 (91-100%). Results were summed, resulting in scores from 0 to 80 for the wrist region, 0 to 150 for the MCP joints, and 0 to 230 on aggregate. A negative value for change from Week 24 in bone erosion score indicated an improvement.

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=41 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) n=38 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy Week 24	10.66 units on a scale Standard Deviation 11.217	9.05 units on a scale Standard Deviation 7.926
Change From Week 24 in Bone Erosion Score at Week 40 for Participants in the Magnetic Resonance Imaging (MRI) Substudy Change at Week 40	-0.10 units on a scale Standard Deviation 0.844	0.17 units on a scale Standard Deviation 1.067

SECONDARY outcome

Timeframe: Baseline, Post-baseline (assessed at Weeks 12, 24, 36, 52 and at follow up [Week 60])

Population: Analysis was performed on safety population which included all participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment. The analysis included overall study population and was not intended to compare the 2 randomized groups. 'Number Analyzed' = participants with ATA assessment at specified time points.

Percentage of participants with positive results for ATA against TCZ at Baseline and at any of the post-baseline assessment time-points was reported. Participants positive at any post-baseline time points were participants who had no positivity at baseline for the same assay.

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=713 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ Baseline	1.8 percentage of participants	—
Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TCZ Post-baseline	1.5 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)

Population: Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups. 'Number Analyzed' = number of participants with assessment at specified time points.

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=713 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Mean TCZ Serum Concentration Baseline	0.01 micrograms per milliliter Standard Deviation 0.223	—
Mean TCZ Serum Concentration Week 12	8.66 micrograms per milliliter Standard Deviation 10.590	—
Mean TCZ Serum Concentration Week 24	23.38 micrograms per milliliter Standard Deviation 22.979	—
Mean TCZ Serum Concentration Week 36	25.58 micrograms per milliliter Standard Deviation 23.133	—
Mean TCZ Serum Concentration Week 52	16.46 micrograms per milliliter Standard Deviation 20.976	—
Mean TCZ Serum Concentration Week 60	6.16 micrograms per milliliter Standard Deviation 15.768	—

SECONDARY outcome

Timeframe: Baseline, Weeks 12, 24, 36, 52 and follow up (Week 60)

Outcome measures

Outcome measures
Measure	Period 2: Randomized Participants (TCZ + MTX) n=713 Participants Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX at a stable dose orally up to Week 52.	Period 2: Randomized Participants (TCZ + PBO) Participants, who completed the initial 24-week treatment with TCZ + MTX and achieved a DAS28 score \</=3.2 at Week 24, were randomized and received TCZ at a dose of 162 mg via SC injection qw or q2w along with MTX matched placebo (PBO) orally up to Week 52.
Mean Soluble Interleukin-6 (IL-6) Receptor Concentration Baseline	40.4 nanograms per milliliter Standard Deviation 18.14	—
Mean Soluble Interleukin-6 (IL-6) Receptor Concentration Week 12	366.4 nanograms per milliliter Standard Deviation 179.21	—
Mean Soluble Interleukin-6 (IL-6) Receptor Concentration Week 24	441.3 nanograms per milliliter Standard Deviation 190.78	—
Mean Soluble Interleukin-6 (IL-6) Receptor Concentration Week 36	468.9 nanograms per milliliter Standard Deviation 211.73	—
Mean Soluble Interleukin-6 (IL-6) Receptor Concentration Week 52	336.3 nanograms per milliliter Standard Deviation 267.20	—
Mean Soluble Interleukin-6 (IL-6) Receptor Concentration Week 60	166.8 nanograms per milliliter Standard Deviation 211.39	—

Adverse Events

Overall Study Population

Serious events: 72 serious events

Other events: 348 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Overall Study Population n=713 participants at risk All enrolled participants received TCZ at a dose of 162 mg via SC injection qw (if body weight was \>/=100 kg) or q2w (if body weight was \<100 kg) along with MTX at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a DAS28 score \</=3.2 at Week 24, were randomized and received double-blind treatment according to the arm in which they were randomized (TCZ + MTX or TCZ + PBO) up to Week 52. Participants who did not achieve a DAS28 score \</=3.2 at Week 24 continued the same treatment in a non-randomized open-label manner up to Week 52.
Infections and infestations Pneumonia	1.4% 10/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Cellulitis	0.42% 3/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Arthritis infective	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Diverticulitis	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Urosepsis	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Abscess neck	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Bronchitis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Encephalitis viral	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Gastritis viral	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Influenza	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Localised infection	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Meningitis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Pyelonephritis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Sepsis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Thrombophlebitis septic	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Cardiac disorders Myocardial infarction	0.70% 5/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Cardiac disorders Angina unstable	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Cardiac disorders Atrial fibrillation	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Cardiac disorders Acute myocardial infarction	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Cardiac disorders Bradycardia	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Cardiac disorders Bundle branch block right	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Cardiac disorders Cardiac arrest	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Cardiac disorders Cardiac failure congestive	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.56% 4/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Cough	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Laryngeal oedema	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Respiratory, thoracic and mediastinal disorders Respiratory tract oedema	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Abdominal pain	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Colitis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Colitis ischaemic	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Crohn's disease	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Diverticular perforation	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Hiatus hernia	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Impaired gastric emptying	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Intestinal obstruction	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Pancreatitis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
General disorders Chest pain	0.70% 5/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
General disorders Death	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
General disorders Non-cardiac chest pain	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
General disorders Pain	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Nervous system disorders Cerebrovascular accident	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Nervous system disorders Presyncope	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Nervous system disorders Seizure	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Nervous system disorders Syncope	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Nervous system disorders Transient ischaemic attack	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Nervous system disorders Vertebrobasilar insufficiency	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign lung neoplasm	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder papilloma	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive lobular breast carcinoma	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of lung	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Hepatobiliary disorders Cholecystitis	0.28% 2/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Hepatobiliary disorders Cholecystitis acute	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Hepatobiliary disorders Cholelithiasis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Injury, poisoning and procedural complications Ankle fracture	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Injury, poisoning and procedural complications Fall	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Injury, poisoning and procedural complications Incisional hernia	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Injury, poisoning and procedural complications Overdose	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Musculoskeletal and connective tissue disorders Myalgia	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Musculoskeletal and connective tissue disorders Myopathy	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Vascular disorders Aortic stenosis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Vascular disorders Deep vein thrombosis	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Vascular disorders Hypotension	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Psychiatric disorders Mental status changes	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Psychiatric disorders Suicide attempt	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Reproductive system and breast disorders Dysmenorrhoea	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Reproductive system and breast disorders Menorrhagia	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Immune system disorders Drug hypersensitivity	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Investigations Hepatic enzyme increased	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Metabolism and nutrition disorders Hyperuricaemia	0.14% 1/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.

Other adverse events

Other adverse events
Measure	Overall Study Population n=713 participants at risk All enrolled participants received TCZ at a dose of 162 mg via SC injection qw (if body weight was \>/=100 kg) or q2w (if body weight was \<100 kg) along with MTX at a stable dose (15 mg to 25 mg per week) in an open-label manner orally for 24 weeks. Participants, who achieved a DAS28 score \</=3.2 at Week 24, were randomized and received double-blind treatment according to the arm in which they were randomized (TCZ + MTX or TCZ + PBO) up to Week 52. Participants who did not achieve a DAS28 score \</=3.2 at Week 24 continued the same treatment in a non-randomized open-label manner up to Week 52.
Investigations Alanine aminotransferase increased	14.2% 101/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Investigations Hepatic enzyme increased	9.7% 69/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Investigations Aspartate aminotransferase increased	9.1% 65/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Investigations Liver function test increased	7.3% 52/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Upper respiratory tract infection	13.0% 93/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Urinary tract infection	7.6% 54/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Infections and infestations Sinusitis	5.6% 40/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.
Gastrointestinal disorders Nausea	7.4% 53/713 • From Baseline up to Week 60 Analysis was performed on safety population. The analysis included overall study population and was not intended to compare the 2 randomized groups.

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER