Rheumatoid Arthritis
Conditions
Brief summary
This randomized, placebo-controlled, double-blind study will compare the safety and efficacy of tapering methotrexate (MTX) versus maintaining MTX dosage in patients with severe active rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) initiated on treatment with tocilizumab. Participants will receive tocilizumab 8 mg/kg intravenously every 4 weeks and MTX orally weekly throughout the study. At Week 24, participants achieving a good/moderate EULAR response will be randomized receiving the MTX Tapering arm or MTX Maintenance arm. Up to Week 56 participants will receive either tapering or stable dose MTX in combination with tocilizumab. From Week 56 to Week 72 participants will receive tocilizumab monotherapy.
Interventions
DRUGMethotrexate (stable dose)
Methotrexate (MTX) was administered weekly according to the subject's pre-study MTX dose
DRUGTocilizumab
8 mg/kg intravenously every 4 weeks for 72 weeks
DRUGMethotrexate (tapering dose)
Tapering doses of methotrexate (MTX) were administered weekly from Week 24 to Week 56. Tapering doses depended on dose administered to the subject during the open label period. First tapering occurred at randomization (Week 24), second tapering at Week 32, third tapering at Week 40 and final tapering at Week 48.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients, \>/= 18 years of age * Active severe rheumatoid arthritis (DAS28 \> 5.1) according to European League of Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria * Inadequate response to a trial of 2 DMARDs, including methotrexate, a trial being defined as 6 months with 2 months at standard dose; no previous treatment with a biologic agent such as a tumor necrosis factor (TNF) inhibitor * Oral corticosteroids must have been at a stable dose of \</= 10 mg/day prednisolone or equivalent for at least 25 out of 28 days prior to start of treatment (Day 1)
Exclusion criteria
* Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization * Rheumatic autoimmune disease other than rheumatoid arthritis * Functional class IV as defined by the ACR Classification of Functional Status in RA * Prior history of or current inflammatory joint disease other than RA * Previous treatment with tocilizumab * Previous treatment with any biologic drug (e.g. TNF inhibitor) that is used in the treatment of RA * Intraarticular or parenteral corticosteroids within 6 weeks prior to enrollment * Inadequate liver, bone marrow or hepatic function * Positive for hepatitis B, hepatitis C or HIV infection * Pregnant or breastfeeding women * Females of child-bearing potential who are not using reliable means of contraception * History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies * Active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections * History of, or currently active, primary or secondary immunodeficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60 | From randomization to Week 60 | Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (\<=) 3.2 and reduction of greater than (\>) 1.2 points were assessed as having a 'good' response. Participants with a score \>3.2 with reduction of \>1.2 points, or a score \<=5.1 with reduction of \>0.6 to \<=1.2 points, were assessed as having a 'moderate' response. Participants with a score \>5.1 with reduction of \>0.6 to \<=1.2 points, or any score with reduction \<=0.6 points, were assessed as non-responders with response recorded as 'none.' |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72 | Randomization (Week 24), Week 72 | The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. |
| Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | Week 60, 72 | Percentage of participants who achieve score of =1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28. |
| Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2 | Week 60, 72 | The DAS28 index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. Participants who achieve score \<=3.2 at weeks 60 and 72 were reported. |
| Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6) | Week 60, 72 | The DAS28 index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. Participants who achieve DAS28 remission score \<2.6 at weeks 60 and 72 were reported. |
| Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2 | Week 60, 72 | The DAS28 index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. Participants who achieve cDAS28 \>=1.2 score at weeks 60 and 72 were reported. |
| Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72 | Randomization (Week 24), Week 60, 72 | Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. |
| Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72 | Randomization (Week 24), Week 60, 72 | Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. |
| Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72 | Randomization (Week 24), Week 60, 72 | The HAQ-disability index (DI) evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of participants with an improvement in HAQ-DI score. |
| Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60 | Randomization (Week 24), Week 60 | The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. |
| Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72 | Randomization (Week 24), Week 60, 72 | Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score. |
| Percentage of Participants With Anemia | Week 0 up to Week 72 | — |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Week 0 up to Week 72 | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any adverse event that can be fatal, life threatening, requires long or prolong hospitalization, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator's judgment. |
| Percentage of Participants Able to Discontinue Methotrexate | Week 0 up to Week 60 | — |
| Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP) | Randomization (Week 24), Week 60, 72 | The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. |
| Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Randomization (Week 24), Week 60, Week 72 | The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72. |
| Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Randomization (Week 24), Week 60, 72 | The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact. |
| Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72 | Randomization (Week 24), Week 60, 72 | The FACIT-fatigue assessment was a 13-item questionnaire with participants scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score. |
Countries
United Kingdom
Participant flow
Pre-assignment details
The initial open label period of the study consisted of one group of 427 participants. After completion of the initial phase only participants, who achieved a good/moderate disease response, were randomized into the double blind period. 272 participants were randomized into the two arms entering the double-blind period of the study.
Participants by arm
| Arm | Count |
|---|---|
| Initial Phase At Week 0 participants started open-label tocilizumab and open-label MTX for 24 weeks. | 427 |
| Total | 427 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Period | Administrative/Other | 0 | 7 | 6 |
| Double-Blind Period | Adverse Event | 0 | 16 | 18 |
| Double-Blind Period | Investigator's Decision | 0 | 1 | 2 |
| Double-Blind Period | Protocol Violation | 0 | 2 | 3 |
| Double-Blind Period | Refused Treatment | 0 | 0 | 1 |
| Double-Blind Period | Sponsor Termination | 0 | 14 | 17 |
| Double-Blind Period | Withdrawal by Subject | 0 | 1 | 3 |
| Open-Label Period | Administrative/Other | 1 | 0 | 0 |
| Open-Label Period | Adverse Event | 44 | 0 | 0 |
| Open-Label Period | Death | 1 | 0 | 0 |
| Open-Label Period | Did not meet EULAR criteria | 1 | 0 | 0 |
| Open-Label Period | Investigator Decision | 3 | 0 | 0 |
| Open-Label Period | Lost to Follow-up | 2 | 0 | 0 |
| Open-Label Period | Protocol Violation | 3 | 0 | 0 |
| Open-Label Period | Sponsor termination | 16 | 0 | 0 |
| Open-Label Period | Withdrawal by Subject | 5 | 0 | 0 |
Baseline characteristics
| Characteristic | Initial Phase |
|---|---|
| Age, Continuous | 55.0 years STANDARD_DEVIATION 12.03 |
| Sex: Female, Male Female | 326 Participants |
| Sex: Female, Male Male | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 263 / 427 | 62 / 136 | 70 / 136 |
| serious Total, serious adverse events | 21 / 427 | 9 / 136 | 3 / 136 |
Outcome results
Primary
Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60
Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (\<=) 3.2 and reduction of greater than (\>) 1.2 points were assessed as having a 'good' response. Participants with a score \>3.2 with reduction of \>1.2 points, or a score \<=5.1 with reduction of \>0.6 to \<=1.2 points, were assessed as having a 'moderate' response. Participants with a score \>5.1 with reduction of \>0.6 to \<=1.2 points, or any score with reduction \<=0.6 points, were assessed as non-responders with response recorded as 'none.'
Time frame: From randomization to Week 60
Population: Intention to treat (ITT) population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60 | 76.5 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60 | 65.4 percentage of participants |
Comparison: Comparison was Tapering MTX : MTX maintenance. Last post-baseline EULAR response recorded used for participants with a missing result at Week 60.p-value: 0.03695% CI: [1.037, 3.133]Analysis by logistic regression
Secondary
Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60
The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
Time frame: Randomization (Week 24), Week 60
Population: ITT population included all randomized participants. Here, number of participants analyzed signifies those participants who were evaluable for this end point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60 | Baseline (n= 135, 136) | 2.572 units on a scale | Standard Deviation 1.3218 |
| Methotrexate (MTX) Tapering Group | Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60 | Change at Week 60 (n= 134, 135) | -0.179 units on a scale | Standard Deviation 1.1702 |
| Methotrexate (MTX) Maintenance Group | Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60 | Baseline (n= 135, 136) | 2.573 units on a scale | Standard Deviation 1.3017 |
| Methotrexate (MTX) Maintenance Group | Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60 | Change at Week 60 (n= 134, 135) | -0.233 units on a scale | Standard Deviation 1.5156 |
Secondary
Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72
The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
Time frame: Randomization (Week 24), Week 72
Population: ITT population included all randomized participants. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72 | -0.105 units on a scale | Standard Deviation 1.2262 |
| Methotrexate (MTX) Maintenance Group | Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72 | -0.224 units on a scale | Standard Deviation 1.4961 |
Secondary
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP
The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact.
Time frame: Randomization (Week 24), Week 60, 72
Population: Participants in the ITT population with available data at the respective time points were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Productivity (P), Week 60 (n=34, 18) | 2.0 units on a scale |
| Methotrexate (MTX) Tapering Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Change in P from Week 24 at Week 60 (n=30, 16) | 1.0 units on a scale |
| Methotrexate (MTX) Tapering Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Regular Daily Activities (RDA), Week 60 (n=60, 45) | 3.0 units on a scale |
| Methotrexate (MTX) Tapering Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Change in RDA from Week 24 at Week 60 (n=59, 44) | 0.0 units on a scale |
| Methotrexate (MTX) Tapering Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Productivity (P), Week 72 (n=24, 12) | 3.0 units on a scale |
| Methotrexate (MTX) Tapering Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Change in P from Week 24 at Week 72 (n=21, 11) | 0.0 units on a scale |
| Methotrexate (MTX) Tapering Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Regular Daily Activities (RDA), Week 72 (n=42, 31) | 3.0 units on a scale |
| Methotrexate (MTX) Tapering Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Change in RDA from Week 24 at Week 72 (n=41, 29) | 0.0 units on a scale |
| Methotrexate (MTX) Maintenance Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Regular Daily Activities (RDA), Week 72 (n=42, 31) | 3.0 units on a scale |
| Methotrexate (MTX) Maintenance Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Productivity (P), Week 60 (n=34, 18) | 2.0 units on a scale |
| Methotrexate (MTX) Maintenance Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Productivity (P), Week 72 (n=24, 12) | 3.0 units on a scale |
| Methotrexate (MTX) Maintenance Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Change in P from Week 24 at Week 60 (n=30, 16) | 0.0 units on a scale |
| Methotrexate (MTX) Maintenance Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Change in RDA from Week 24 at Week 72 (n=41, 29) | -1.0 units on a scale |
| Methotrexate (MTX) Maintenance Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Regular Daily Activities (RDA), Week 60 (n=60, 45) | 3.0 units on a scale |
| Methotrexate (MTX) Maintenance Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Change in P from Week 24 at Week 72 (n=21, 11) | 0.0 units on a scale |
| Methotrexate (MTX) Maintenance Group | Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP | Change in RDA from Week 24 at Week 60 (n=59, 44) | 0.0 units on a scale |
Secondary
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP
The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72.
Time frame: Randomization (Week 24), Week 60, Week 72
Population: Participants in the ITT population with available data were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Work hours missed (WHM) to RA, Week 60 (n=33, 17) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Hours actually worked (HAW), Week 60 (n=33, 17) | 25.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 in WHM RA, Week 72 (n=21, 11) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 in WHM RA, Week 60 (n=30, 16) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | WHM other, Week 60 (n=33, 17) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | WHM other, Week 72 (n=23, 13) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 WHM other, Week 60 (n=30, 16) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 in HAW, Week 72, (n=20, 12) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | HAW, Week 72 (n=23, 13) | 30.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 WHM other, Week 72 (n=21, 11) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | WHM to RA, Week 72 (n=23, 13) | 0.0 hours |
| Methotrexate (MTX) Tapering Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 in HAW, Week 60 (n=29, 17) | -1.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | WHM to RA, Week 72 (n=23, 13) | 0.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 in HAW, Week 60 (n=29, 17) | 2.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Work hours missed (WHM) to RA, Week 60 (n=33, 17) | 0.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 in HAW, Week 72, (n=20, 12) | 2.5 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 in WHM RA, Week 72 (n=21, 11) | 0.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | WHM other, Week 72 (n=23, 13) | 0.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 WHM other, Week 72 (n=21, 11) | 0.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Hours actually worked (HAW), Week 60 (n=33, 17) | 28.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 in WHM RA, Week 60 (n=30, 16) | 0.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | WHM other, Week 60 (n=33, 17) | 0.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | Change from Week 24 WHM other, Week 60 (n=30, 16) | 0.0 hours |
| Methotrexate (MTX) Maintenance Group | Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP | HAW, Week 72 (n=23, 13) | 16.0 hours |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any adverse event that can be fatal, life threatening, requires long or prolong hospitalization, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator's judgment.
Time frame: Week 0 up to Week 72
Population: Safety population included all the randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 98 participants |
| Methotrexate (MTX) Tapering Group | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 9 participants |
| Methotrexate (MTX) Maintenance Group | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 98 participants |
| Methotrexate (MTX) Maintenance Group | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 participants |
Secondary
Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP)
The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities.
Time frame: Randomization (Week 24), Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP) | Week 60 | 33 participants |
| Methotrexate (MTX) Tapering Group | Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP) | Week 72 | 23 participants |
| Methotrexate (MTX) Maintenance Group | Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP) | Week 60 | 17 participants |
| Methotrexate (MTX) Maintenance Group | Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP) | Week 72 | 14 participants |
Secondary
Percentage of Participants Able to Discontinue Methotrexate
Time frame: Week 0 up to Week 60
Population: Data were not collected for this outcome measure.
Secondary
Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2
The DAS28 index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. Participants who achieve score \<=3.2 at weeks 60 and 72 were reported.
Time frame: Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2 | Week 60 | 59.6 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2 | Week 72 | 61.0 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2 | Week 60 | 62.5 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2 | Week 72 | 60.3 percentage of participants |
Secondary
Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2
The DAS28 index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. Participants who achieve cDAS28 \>=1.2 score at weeks 60 and 72 were reported.
Time frame: Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2 | Week 60 | 9.6 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2 | Week 72 | 9.6 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2 | Week 60 | 16.2 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2 | Week 72 | 15.4 percentage of participants |
Secondary
Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72
Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity.
Time frame: Randomization (Week 24), Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72 | Week 72 | 1.5 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72 | Week 60 | 2.9 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72 | Week 60 | 1.5 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72 | Week 72 | 3.7 percentage of participants |
Secondary
Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6)
The DAS28 index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. Participants who achieve DAS28 remission score \<2.6 at weeks 60 and 72 were reported.
Time frame: Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6) | Week 60 | 51.5 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6) | Week 72 | 50.0 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6) | Week 60 | 47.1 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6) | Week 72 | 51.5 percentage of participants |
Secondary
Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72
Percentage of participants who achieve score of =1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28.
Time frame: Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | TJC <=1, Week 60 | 39.0 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | SJC <=1, Week 60 | 44.1 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | TJC <=1, Week 72 | 37.5 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | SJC <=1, Week 72 | 55.9 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | SJC <=1, Week 72 | 60.3 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | TJC <=1, Week 60 | 39.0 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | TJC <=1, Week 72 | 40.4 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 | SJC <=1, Week 60 | 58.1 percentage of participants |
Secondary
Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72
Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity.
Time frame: Randomization (Week 24), Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72 | Week 60 | 2.9 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72 | Week 72 | 2.9 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72 | Week 60 | 0.7 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72 | Week 72 | 0.7 percentage of participants |
Secondary
Percentage of Participants With Anemia
Time frame: Week 0 up to Week 72
Population: Safety population included all the randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants With Anemia | 1.5 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants With Anemia | 0.7 percentage of participants |
Secondary
Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72
Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score.
Time frame: Randomization (Week 24), Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72 | Improvement at Week 60 | 22.2 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72 | Improvement at Week 72 | 23.8 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72 | Improvement at Week 60 | 10.4 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72 | Improvement at Week 72 | 15.6 percentage of participants |
Secondary
Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72
The FACIT-fatigue assessment was a 13-item questionnaire with participants scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score.
Time frame: Randomization (Week 24), Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72 | Improvement at Week 60 | 54.0 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72 | Improvement at Week 72 | 45.2 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72 | Improvement at Week 60 | 50.0 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72 | Improvement at Week 72 | 56.3 percentage of participants |
Secondary
Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72
The HAQ-disability index (DI) evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of participants with an improvement in HAQ-DI score.
Time frame: Randomization (Week 24), Week 60, 72
Population: ITT population included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methotrexate (MTX) Tapering Group | Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72 | Improvement at Week 60 | 27.0 percentage of participants |
| Methotrexate (MTX) Tapering Group | Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72 | Improvement at Week 72 | 40.5 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72 | Improvement at Week 60 | 39.6 percentage of participants |
| Methotrexate (MTX) Maintenance Group | Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72 | Improvement at Week 72 | 50.0 percentage of participants |