Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis
Brief summary
The purpose of this study is to determine the Efficacy, Safety, and Pharmacokinetics of MP-435 administered for 12 weeks in subjects with rheumatoid arthritis (RA) on stable doses of Methotrexate.
Interventions
DRUGMP-435(dose1) + Methotrexate
MP-435 dose1 + stable weekly dose of Methotrexate
Placebo + stable weekly dose of Methotrexate
Sponsors
Tanabe Pharma Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with a diagnosis of RA according to the diagnostic criteria of the American College of Rheumatology (ACR) (revised in 1987) for at least 6 months. * Subjects who inadequately response for stable dose of MTX.
Exclusion criteria
* Patients with Class IV functional activity by the Steinbrocker's scale. * Patients who have received a biological agent in the past. * Patients who have other rheumatic diseases, or who have other diseases with joint symptoms. * Patients with severe or uncontrolled endocrine, psychiatric, cardiac, hematological, pulmonary, hepatic, kidney, gastrointestinal, or thyroid disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 2, 4, 6, 8, 12, LOCF (Week 12 or discontinuation time) | ACR 20 response is a decrease of at least 20 per cent in both tender and swollen joint count \[TJC and SJC\] and in 3 to 5 assessments (participant's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ-DI\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving ACR 50 Response | Week 2, 4, 6, 8, 12, LOCF (Week 12 or discontinuation time) | ACR 50 response is a decrease of at least 50 per cent in both tender and swollen joint count and in 3 to 5 assessments (participant's assessment of pain VAS with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; HAQ-DI: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; CRP). |
| Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 2, 4, 6, 8, 12, LOCF (Week 12 or discontinuation time) | ACR 70 response is a decrease of at least 70 per cent in both tender and swollen joint count and in 3 to 5 assessments (participant's assessment of pain VAS with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; HAQ-DI: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; CRP). |
| Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | LOCF (Week 12 or discontinuation time) | DAS28 (CRP) is calculated using TJC, SJC C-Reactive Protein ( CRP in mg/dL ), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.36 x log (CRP+1) + 0.014 x Global Assessment of Arthritis + 0.96 where 28 joints are examined and a lower score indicates less disease activity. DAS28 (ESR) is calculated using TJC, SJC erythrocyte sedimentation rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.70 x log (ESR) + 0.014 x Global Assessment of Arthritis where 28 joints are examined and a lower score indicates less disease activity. A negative change score indicates improvement. Higher score indicated more disease activity. DAS28 =\<3.2 implied low disease activity, \>3.2 to 5.1 implied moderate disease activity, \>5.1 implied high disease activity. |
| Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | LOCF (Week 12 or discontinuation time) | ACR components are tender joints count (TJC), swollen joints count (SJC), participant assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ-DI\]); and C-Reactive Protein (CRP) or erythrocyte sedimentation rate (ESR). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo MP-435 placebo-matching tablets, orally, twice daily. And stable dose (6-8 mg/week) Methotrexate(MTX) were administered as background therapy. | 46 |
| MP-435 100mg BID MP-435 100mg, orally, twice daily. And stable dose (6-8 mg/week) MTX were administered as background therapy.
MP-435 400mg:
There were 13 patients who randomized 400 mg bid group when they were discontinued dosing. At this point, it was found that there were Four patients who increased ALT more than three times of upper limit of normal in this dosing group. Therefore, patients who randomized to this dosing group were discontinued and also new inclusion was stopped in this point.
Primary analysis of this study result was Par Protocol Set ( PPS ). Because examination for 400 mg bid group was discontinued, this arm data was excluded from PPS analysis. | 47 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 9 | 5 |
| Overall Study | Lack of Efficacy | 6 | 2 | 1 |
| Overall Study | Other reason | 0 | 0 | 5 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | MP-435 100mg BID | Total |
|---|---|---|---|
| Age, Customized 40 - 50 years | 9 participants | 7 participants | 16 participants |
| Age, Customized < 40 years | 5 participants | 8 participants | 13 participants |
| Age, Customized 50 - 60 years | 13 participants | 13 participants | 26 participants |
| Age, Customized 60 - 70 years | 15 participants | 12 participants | 27 participants |
| Age, Customized ≧ 70 years | 4 participants | 7 participants | 11 participants |
| Sex: Female, Male Female | 43 Participants | 43 Participants | 86 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 49 | 22 / 50 |
| serious Total, serious adverse events | 3 / 49 | 0 / 50 |
Outcome results
Primary
Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response
ACR 20 response is a decrease of at least 20 per cent in both tender and swollen joint count \[TJC and SJC\] and in 3 to 5 assessments (participant's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ-DI\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]).
Time frame: Week 2, 4, 6, 8, 12, LOCF (Week 12 or discontinuation time)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 2 | 10.9 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 4 | 24.4 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 6 | 23.3 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 8 | 34.9 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 12 | 39.5 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | LOCF (Week 12 or discontinuation time) | 34.8 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 12 | 39.5 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 2 | 19.1 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 8 | 45.0 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 4 | 39.1 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | LOCF (Week 12 or discontinuation time) | 42.6 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 20 (ACR 20) Response | Week 6 | 39.0 percentage of participants |
Secondary
Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components
DAS28 (CRP) is calculated using TJC, SJC C-Reactive Protein ( CRP in mg/dL ), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.36 x log (CRP+1) + 0.014 x Global Assessment of Arthritis + 0.96 where 28 joints are examined and a lower score indicates less disease activity. DAS28 (ESR) is calculated using TJC, SJC erythrocyte sedimentation rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.70 x log (ESR) + 0.014 x Global Assessment of Arthritis where 28 joints are examined and a lower score indicates less disease activity. A negative change score indicates improvement. Higher score indicated more disease activity. DAS28 =\<3.2 implied low disease activity, \>3.2 to 5.1 implied moderate disease activity, \>5.1 implied high disease activity.
Time frame: LOCF (Week 12 or discontinuation time)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | DAS 28 (CRP) Week 0 | 4.18 units on a scale | Standard Deviation 0.8 |
| Placebo | Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | DAS 28 (CRP) Week 12 or discontinuation time | 3.48 units on a scale | Standard Deviation 1.26 |
| Placebo | Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | DAS 28 (ESR) Week 0 | 5.59 units on a scale | Standard Deviation 0.82 |
| Placebo | Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | DAS 28 (ESR) Week 12 or discontinuation time | 4.87 units on a scale | Standard Deviation 1.3 |
| MP-435 100mg BID | Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | DAS 28 (ESR) Week 12 or discontinuation time | 4.94 units on a scale | Standard Deviation 1.15 |
| MP-435 100mg BID | Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | DAS 28 (CRP) Week 0 | 4.41 units on a scale | Standard Deviation 0.77 |
| MP-435 100mg BID | Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | DAS 28 (ESR) Week 0 | 5.8 units on a scale | Standard Deviation 0.76 |
| MP-435 100mg BID | Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | DAS 28 (CRP) Week 12 or discontinuation time | 3.54 units on a scale | Standard Deviation 1.15 |
Secondary
Percentage of Participants Achieving ACR 50 Response
ACR 50 response is a decrease of at least 50 per cent in both tender and swollen joint count and in 3 to 5 assessments (participant's assessment of pain VAS with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; HAQ-DI: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; CRP).
Time frame: Week 2, 4, 6, 8, 12, LOCF (Week 12 or discontinuation time)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Achieving ACR 50 Response | Week 2 | 4.3 percentage of participants |
| Placebo | Percentage of Participants Achieving ACR 50 Response | Week 4 | 8.9 percentage of participants |
| Placebo | Percentage of Participants Achieving ACR 50 Response | Week 6 | 7.0 percentage of participants |
| Placebo | Percentage of Participants Achieving ACR 50 Response | Week 8 | 9.3 percentage of participants |
| Placebo | Percentage of Participants Achieving ACR 50 Response | Week 12 | 13.2 percentage of participants |
| Placebo | Percentage of Participants Achieving ACR 50 Response | LOCF (Week 12 or discontinuation time) | 13.0 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving ACR 50 Response | Week 12 | 15.8 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving ACR 50 Response | Week 2 | 2.1 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving ACR 50 Response | Week 8 | 17.5 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving ACR 50 Response | Week 4 | 4.3 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving ACR 50 Response | LOCF (Week 12 or discontinuation time) | 14.9 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving ACR 50 Response | Week 6 | 12.2 percentage of participants |
Secondary
Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response
ACR 70 response is a decrease of at least 70 per cent in both tender and swollen joint count and in 3 to 5 assessments (participant's assessment of pain VAS with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; HAQ-DI: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; CRP).
Time frame: Week 2, 4, 6, 8, 12, LOCF (Week 12 or discontinuation time)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 2 | 0.0 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 4 | 2.2 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 6 | 2.3 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 8 | 2.3 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 12 | 2.6 percentage of participants |
| Placebo | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | LOCF (Week 12 or discontinuation time) | 2.2 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 12 | 2.6 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 2 | 0.0 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 8 | 0.0 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 4 | 0.0 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | LOCF (Week 12 or discontinuation time) | 4.3 percentage of participants |
| MP-435 100mg BID | Percentage of Participants Achieving American College of Rheumatology 70 (ACR 70) Response | Week 6 | 0.0 percentage of participants |
Secondary
Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components
ACR components are tender joints count (TJC), swollen joints count (SJC), participant assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ-DI\]); and C-Reactive Protein (CRP) or erythrocyte sedimentation rate (ESR).
Time frame: LOCF (Week 12 or discontinuation time)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | TJC | 33.72 percentage of change from baseline | Standard Deviation 52.21 |
| Placebo | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | SJC | 35.74 percentage of change from baseline | Standard Deviation 91.22 |
| Placebo | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | participant assessment | -2.14 percentage of change from baseline | Standard Deviation 76.99 |
| Placebo | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | participant global assessment of disease activity | -11.57 percentage of change from baseline | Standard Deviation 98.92 |
| Placebo | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | physician global assessment of disease activity | 21.6 percentage of change from baseline | Standard Deviation 43.85 |
| Placebo | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | HAQ-DI | 5.84 percentage of change from baseline | Standard Deviation 61.48 |
| Placebo | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | CRP | -34.13 percentage of change from baseline | Standard Deviation 147.17 |
| Placebo | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | ESR | 1.00 percentage of change from baseline | Standard Deviation 27.76 |
| MP-435 100mg BID | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | ESR | -12.01 percentage of change from baseline | Standard Deviation 46.95 |
| MP-435 100mg BID | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | TJC | 36.94 percentage of change from baseline | Standard Deviation 50.57 |
| MP-435 100mg BID | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | physician global assessment of disease activity | 33.06 percentage of change from baseline | Standard Deviation 35.39 |
| MP-435 100mg BID | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | SJC | 44.44 percentage of change from baseline | Standard Deviation 33 |
| MP-435 100mg BID | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | CRP | -46.01 percentage of change from baseline | Standard Deviation 150.97 |
| MP-435 100mg BID | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | participant assessment | -6.67 percentage of change from baseline | Standard Deviation 187.29 |
| MP-435 100mg BID | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | HAQ-DI | 14.78 percentage of change from baseline | Standard Deviation 49.8 |
| MP-435 100mg BID | Percent Changes From the Pretreatment Values in the Disease Activity Score (DAS) 28, and ACR Components | participant global assessment of disease activity | 4.53 percentage of change from baseline | Standard Deviation 128.92 |