Trial Outcomes & Findings for A Study of Tocilizumab and Methotrexate in Combination or as Monotherapy in Treatment-Naïve Patients With Early Rheumatoid Arthritis (NCT NCT01034137)

A total of 360 participants were screened at 21 centers in the Netherlands from 04 JAN 2010 to 30 JUL 2012.

Of 360 participants, 43 failed screening.

A Study of Tocilizumab and Methotrexate in Combination or as Monotherapy in Treatment-Naïve Patients With Early Rheumatoid Arthritis

Sustained remission rate (SRR) is defined as Disease Activity Score 28 (DAS28) \<2.6 during ≥ 23 weeks and no more than 4 swollen joints (28 joint count) due to RA at Week 24 of remission, with the exception of up to 2 in-between DAS28 values which could be between 2.6 and 3.2. The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (ESR in mm/hr), and general health status (participant global assessment of disease activity using VAS, range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening. DAS28 \<2.6 equals (=) remission.

It is the time to event analysis for the first period of sustained remission. Sustained remission is defined as DAS28 \<2.6 during ≥23 weeks and no more than 4 swollen joints (28 joint count) due to RA at Week 24 of remission, with the exception of up to 2 in-between DAS28 values which could be between 2.6 and 3.2. The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint counts (range 0-28), acute phase response (ESR in mm/hr), and general health status (participant global assessment of disease activity using VAS, range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening. DAS28 \<2.6 equals (=) remission.

It is the duration of the first period of sustained DAS28 remission. Participants who switch treatment strategy before reaching sustained remission considered failures.

The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (ESR in mm/hr), and general health status (participant global assessment of disease activity using VAS, range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening. DAS28 \<2.6 equals (=) remission. Participants with missing data at visits before early study termination or who stopped the study prematurely because of insufficient therapeutic response or safety reasons considered non-responders or who stopped the study for other reasons, response set to missing after early withdrawal.

It is the time to event analysis for the first DAS28 remission.

The DAS28 score is a measure of the subject's disease activity. DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. Participants with missing data at visits before early study termination or who stopped the study prematurely because of insufficient therapeutic response or safety reasons considered non-responders or who stopped the study for other reasons, response set to missing after early withdrawal.

It is the duration of the first period of DAS28 remission.

The DAS28 score is a measure of the participant's disease activity. DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. Participants with missing data at visits before early study termination or who stopped the study prematurely because of insufficient therapeutic response or safety reasons considered non-responders or who stopped the study for other reasons, response set to missing after early withdrawal.

The clinical disease activity index (CDAI) are continuous measures of RA disease activity. The CDAI is the numerical sum of four outcome parameters: tender joint count (TJC), swollen joint count (SJC) based on a 28-joint assessment; and patient's global assessment (PtGA) and physician's global assessment (PhGA) assessed on 0-10 cm visual analog scale (VAS). CDAI total score ranges from 0 to 76. CDAI \<= 2.8 indicates clinical remission, \>2.8 to 10 = low disease activity, \>10 to 22 = moderate disease activity, and \>22 = high (or severe) disease activity.

The simplified disease activity index (SDAI ) are continuous measures of RA disease activity.The SDAI is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (assessed on 0-10 cm VAS), and C-Reactive Protein (CRP) (mg/dL). SDAI total score ranges from 0-86. SDAI \<=3.3 indicates disease remission, \>3.4 to 11 = low disease activity, \>11 to 26 = moderate disease activity, and \>26 = high disease activity.

European league against rheumatism (EULAR) response criteria classify each participant as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual participant's DAS28 as the measure of severity of disease. Good or moderate response is defined as follows: Good response : DAS28 at the time point =\<3.2 and improvement from baseline \> 1.2. Moderate response : DAS28 at the time point \> 3.2 and improvement from baseline \> 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline \> 0.6 and =\<1.2.

It is the time to first EULAR response. EULAR response criteria classify each participant as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual participant's DAS28 as the measure of severity of disease.Good or moderate response is defined as follows: Good response : DAS28 at the time point ≤ 3.2 and improvement from baseline \> 1.2. Moderate response : DAS28 at the time point \> 3.2 and improvement from baseline \> 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline \> 0.6 and ≤ 1.2. Response 1 is defined as yes (good) versus no (moderate or no response). Response 2 is defined as yes (good or moderate) versus no (no response).

American College of Rheumatology (ACR) 20 response is defined as a \>= 20% improvement (reduction) compared with baseline for both tender joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: patient's assessment of pain over the previous 24 hours: using a Visual Analog Scale (VAS) with left end of the line 0=no pain to right end of the line 100=unbearable pain; patient's global assessment of disease activity and physician's global assessment of disease activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant, either C-reactive protein or Erythrocyte Sedimentation Rate.

ACR50 response is defined as a \>=50% improvement (reduction) compared with baseline for both TJC68 and SJC66, as well as for three of the additional five ACR core set variables: patient's assessment of pain over the previous 24 hours: using a VAS with left end of the line 0=no pain to right end of the line 100=unbearable pain; patient's Global assessment of disease activity and physician's global assessment of disease activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant, either C-reactive protein or Erythrocyte Sedimentation Rate.

ACR70 response is defined as a \>=70% improvement (reduction) compared with baseline for both TJC68 and SJC66, as well as for three of the additional five ACR core set variables: patient's Assessment of pain over the previous 24 hours: using a VAS with left end of the line 0=no pain to right end of the line 100=unbearable pain; patient's global assessment of disease activity and physician's global assessment of disease activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; health assessment questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant, either C-reactive protein or Erythrocyte Sedimentation Rate.

ACR90 response is defined as a \>=90% improvement (reduction) compared with baseline for both tender joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a VAS with left end of the line 0=no pain to right end of the line 100=unbearable pain; patient's global assessment of disease activity and physician's global assessment of disease activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; health assessment questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant, either C-reactive protein or erythrocyte sedimentation rate.

The number of swollen joints among 22 anatomical joints for both the right and left side of the body were assessed by a joint evaluator where the presence of a swollen joint was scored as 1 and absence as 0. The total SJC was derived by the sum of the scores for a range of SJC from 0 (best possible score; no swollen joints) to 44 (worse possible score; all joints swollen).

The number of tender joints among 22 anatomical joints for both the right and left side of the body were assessed by a joint evaluator where the presence of a tender joint was scored as 1 and absence as 0. The total TJC was derived by the sum of the scores for a range of TJC from 0 (best possible score; no tender joints) to 44 (worse possible score; all tender joints).

Patient health visual analog scale is a component of ACR. It is measured using a visual analogue scale with scores ranging from 0 to 100 (higher scores indicate worse disease activity). An improvement (decrease) in the patient's global assessment based on disease activity relative to respective baseline values was analyzed.

Physician health visual analog scale is a component of ACR. It is measured using a visual analogue scale with scores ranging from 0 to 100 (higher scores indicate worse disease activity).An improvement (decrease) in the physician's global assessment based on disease activity parameter relative to respective baseline values was analyzed.

Pain VAS is a component of ACR. VAS pain score calculated as 0 to 10 cm; where 0 = no pain, and 10 = worst possible pain.

CRP is a component of ACR. CRP is a marker of inflammation.

The degree of joint damage was assessed using the van der Heijde modified total Sharp score (mTSS). The methodology quantifies the extent of bone erosions for 44 joints and joint space narrowing (JSN) for 42 joints, with higher scores representing greater damage. The independent read of X-ray images was performed by 2 primary readers. In case of discrepancy between the 2 primary readers, an adjudicator was involved. The mTSS can range from 0 to 448 with a higher score indicating more joint damage. A negative change score indicates improvement.

Insufficient therapeutic response (participants not responding to the drug as assessed by the physician) was selected by the investigator as a reason for the participant to withdraw from the study.

Participants who switched treatment strategy from monotherapy (TCZ+ placebo MTX or MTX+ placebo TCZ treatment) to combination therapy (TCZ+MTX treatment) was reported. Also, participants who switched from verum therapy to standard of care was reported in the below table.

The Dutch Consensus Health Assessment Questionnaire (DC-HAQ) disability index is a self-completed participant questionnaire with 8 domains specific for RA. It assesses a participant functional ability, with scores ranging from 0 (without any difficulty) to 3 (unable to do). A change from baseline of -0.22 is considered to be the minimal clinically important difference.

"EuroQol (EQ-5D) is a standard self-completed participant questionnaire that measures health outcome. The EQ-5D questionnaire consists of 2 parts: 1) EQ-5D with five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale as 1 = no problems, 2 = some/moderate problems, 3 = extreme problems. The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, where '1' indicating full health and '0' representing dead. The positive values indicate that during the study the health status improved. 2) EQ-VAS on a scale of 0 to 100, where 0 = worst possible health status and 100 = best possible health status."

The 36-Item Short Form Health Survey (SF-36) is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical Component Summary (PCS) and Mental Component Summary (MCS) measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.

Patient global health VAS score ranges from 0 to 100 and a higher score indicates worse QoL. Patient global health VAS is a component of DAS28.

Physician global health VAS score ranges from 0 to 100 and a higher score indicates worse QoL. Physician global health VAS is a component of DAS28.

Participants assessed their pain using a 0 to 10 horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 and is described as "no pain" and the right-hand extreme equals 10 as "unbearable pain" .The final VAS score will be derived by multiplying the original scores by 10.

Participants assessed their general wellbeing using a 0 to 10 horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 and is described as " not active at all " and the right-hand extreme equals 10 as " very active " .The final VAS score will be derived by multiplying the original scores by 10.

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participants response to the questions (with the exception of 2 negatively stated), the greater the participants fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the participant's health status.

The IPQ-R includes 9 domains (identity, acute or chronic timeline, consequences, personal and treatment control, illness coherence, timeline cyclical, emotional representations, and cause). For first 8 domains it scores as: 1(strongly disagree), 2(disagree), 3(neither agree/disagree), 4(agree), and 5(strongly agree), except identity as 1(yes) and 0(no). The sum of scores for identity, timeline, consequences, and cyclical domains are ranged from 0-16. High score represent strongly held beliefs about the number of symptoms attributed to RA, the chronicity of the condition, the negative consequences of the illness and the cyclical nature of the condition. The sum of scores for personal and treatment control, coherence dimensions, and emotional representations are ranged from 0-15. High score represent positive beliefs about the number of controllability of RA and a personal understanding of the condition. The data for 'Cause' domain was not considered for analysis in this study.

The IPQ-R includes 9 domains (identity, acute or chronic timeline, consequences, personal and treatment control, illness coherence, timeline cyclical, emotional representations, and cause). For first 8 domains it scores as: 1(strongly disagree), 2(disagree), 3(neither agree/disagree), 4(agree), and 5(strongly agree), except identity as 1(yes) and 0(no). The sum of scores for identity, timeline, consequences, and cyclical domains are ranged from 0-16. High score represent strongly held beliefs about the number of symptoms attributed to RA, the chronicity of the condition, the negative consequences of the illness and the cyclical nature of the condition. The sum of scores for personal and treatment control, coherence dimensions, and emotional representations are ranged from 0-15. High score represent positive beliefs about the number of controllability of RA and a personal understanding of the condition. The data for 'Cause' domain was not considered for analysis in this study.

The IPQ-R includes 9 domains (identity, acute or chronic timeline, consequences, personal and treatment control, illness coherence, timeline cyclical, emotional representations, and cause). For first 8 domains it scores as: 1(strongly disagree), 2(disagree), 3(neither agree/disagree), 4(agree), and 5(strongly agree), except identity as 1(yes) and 0(no). The sum of scores for identity, timeline, consequences, and cyclical domains are ranged from 0-16. High score represent strongly held beliefs about the number of symptoms attributed to RA, the chronicity of the condition, the negative consequences of the illness and the cyclical nature of the condition. The sum of scores for personal and treatment control, coherence dimensions, and emotional representations are ranged from 0-15. High score represent positive beliefs about the number of controllability of RA and a personal understanding of the condition. The data for 'Cause' domain was not considered for analysis in this study.

The IPQ-R includes 9 domains (identity, acute or chronic timeline, consequences, personal and treatment control, illness coherence, timeline cyclical, emotional representations, and cause). For first 8 domains it scores as: 1(strongly disagree), 2(disagree), 3(neither agree/disagree), 4(agree), and 5(strongly agree), except identity as 1(yes) and 0(no). The sum of scores for identity, timeline, consequences, and cyclical domains are ranged from 0-16. High score represent strongly held beliefs about the number of symptoms attributed to RA, the chronicity of the condition, the negative consequences of the illness and the cyclical nature of the condition. The sum of scores for personal and treatment control, coherence dimensions, and emotional representations are ranged from 0-15. High score represent positive beliefs about the number of controllability of RA and a personal understanding of the condition. The data for 'Cause' domain was not considered for analysis in this study.

An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign , symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. A serious adverse event is defined as any event which was fatal (resulted in death), lifethreatening (with immediate risk of death), resulted in a new or prolongation of a current hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, considered medically significant by the investigator, required intervention to prevent one or more of the outcomes listed above.

Laboratory parameters included hematology, chemistry and lipids. Any treatment-emergent abnormal laboratory result accompanied by clinical symptoms or leading to a change in study medication or requiring a change in concomitant therapy was considered clinically significant. Participants with clinically significant laboratory values are reported in the below table.

Laboratory parameters included hematology, chemistry and lipids. Any treatment-emergent abnormal laboratory result accompanied by clinical symptoms or leading to a change in study medication or requiring a change in concomitant therapy was considered clinically significant. Participants with clinically significant laboratory values are reported in the below table.

Laboratory parameters included hematology, chemistry and lipids. Any treatment-emergent abnormal laboratory result accompanied by clinical symptoms or leading to a change in study medication or requiring a change in concomitant therapy was considered clinically significant. Participants with clinically significant laboratory values are reported in the below table.

Laboratory parameters included hematology, chemistry and lipids. Any treatment-emergent abnormal laboratory result accompanied by clinical symptoms or leading to a change in study medication or requiring a change in concomitant therapy was considered clinically significant. Participants with clinically significant laboratory values are reported in the below table.