Rheumatoid Arthritis
Conditions
Keywords
Methotrexate, Adalimumab, Autoimmune Disease, Connective Tissue Diseases, Rheumatic Disease, Rheumatoid Arthritis
Brief summary
This study will be conducted in Japan, South Korea and Taiwan to evaluate the optimal dosage of methotrexate (MTX) as an add-on therapy to adalimumab (ADA) in participants with rheumatoid arthritis (RA) who have not achieved remission by MTX monotherapy.
Detailed description
The erythrocyte MTX-polyglutamates (MTX-PG) concentration will be measured to evaluate its relationship to the efficacy and safety of MTX therapy.
Interventions
DRUGMethotrexate
Route of Administration: Oral
DRUGAdalimumab
Route of Administration: Subcutaneous
Sponsors
Eisai Co., Ltd.
Keio University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients aged ≥18 years (≥20 years in Taiwan) at the time of informed consent 2. Patients who meet the 1987 revised ACR criteria or 2010 ACR/EULAR criteria 3. Patients who have RA within 2 years from initial diagnosis to informed consent 4. Patients who were previously untreated with MTX, JAK inhibitor, or bDMARDs 5. Patients who have disease activity of SDAI \>11 at screening 6. Patients who are no need for concomitant use of DMARDs other than hydroxychloroquine (only in South Korea and Taiwan) and study drugs during the study as judged by principal investigator/sub-investigator at screening 7. Patients who are no need for concomitant use of corticoid steroid equivalent to \>10 mg/day prednisolone during the study as judged by principal investigator/sub-investigator at screening. 8. Female of child-bearing potential who can use appropriate contraceptive during the study, female in whom time from menopause to informed consent is ≥1 year, or female of no child-bearing potential through sterilization (bilateral tubal ligation, bilateral ovariectomy or hysterectomy, etc.) 9. Virile male who can use appropriate contraceptive during the study 10. Patients who can adequately understand this study procedures, and voluntarily consent in writing to take part in this study (consent of a legally-acceptable representative is also required for patients aged \<20 years in Japan and aged \<19 years in South Korea)
Exclusion criteria
1. Patients who currently have a malignant tumor, except for non-melanoma forms of skin cancer limited within epidermis, and uterine cervix cancer limited within epidermis 2. Patients who have serious infections such as sepsis 3. Patients who have active tuberculosis 4. Patients who have a history or current complication of demyelinating disease such as multiple sclerosis 5. Patients who have congestive heart failure 6. Pregnant female, or female who intend to conceive during the study period 7. Patients who have bone marrow depression and whom investigator considered ineligible 8. Patients who have chronic liver disease and whom investigator considered ineligible, and who is positive for HBs antigen 9. Patients who have nephropathy and whom investigator considered ineligible 10. Lactating female 11. Patients who have pleural effusion or ascites 12. Patients with a known hypersensitivity to MTX or ADA 13. Patients otherwise whom principal investigator/sub-investigator considered medically ineligible to participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in mFAS | Week 48 | SDAI is a validated combined index of rheumatoid arthritis disease activity, defined as the sum of Swollen Joint Count (0-28), Tender Joint Count (0-28), Patient's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), Physician's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), and C-reactive protein (mg/dL). Higher scores represent higher disease activity. SDAI ≤ 3.3 indicates disease remission, \> 3.4 to 11 = low disease activity, \> 11 to 26 = moderate disease activity, and \> 26 = high disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| American College of Rheumatology (ACR) 20 Response Rate at Week 48 | Week 48 | ACR 20 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 20 response will be referred to as ACR 20 response rate. * ≥20% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment * ≥20% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment * ≥20% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment |
| American College of Rheumatology (ACR) 50 Response Rate at Week 48 | Week 48 | ACR 50 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 50 response will be referred to as ACR 50 response rate. * ≥50% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment * ≥50% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment * ≥50% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment |
| Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in PPS | Week 48 | SDAI is a validated combined index of rheumatoid arthritis disease activity, defined as the sum of Swollen Joint Count (0-28), Tender Joint Count (0-28), Patient's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), Physician's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), and C-reactive protein (mg/dL). Higher scores represent higher disease activity. SDAI ≤ 3.3 indicates disease remission, \> 3.4 to 11 = low disease activity, \> 11 to 26 = moderate disease activity, and \> 26 = high disease activity. |
| Health Assessment Questionnaire - Disability Index ≤0.5 at Week 48 | Week 48 | HAQ-DI is a patient-reported questionnaire, consists of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week as: without any difficulty (0); with some difficulty (1); with much difficulty (2); unable to do (3). Scores on each task were summed and averaged to provide an overall score from 0 to 3, where 0=no disability and 3=very severe, high-dependency disability. Normal physical function is defined by HAQ-DI score of \< 0.5. |
| Change in Modified Total Sharp Score ≤ 0.5 at Week 48 | Week 48 | Bone erosions will be evaluated for each region from a scale of 0 (no damage) to 5 (complete collapse of the joint). The score will be 0 to 5 for each hand joint, and 0 to 10 for each foot joint. The maximum total erosion score of both hands will be 160 points, and that of both feet will be 120 points. Joint space narrowing will be evaluated for each region from a scale of 0 (no damage) to 4 (ankylosis or luxation). The maximum total joint space narrowing score of both hands will be 120 points, and that of both feet will be 48 points. Erosion scores and joint space narrowing scores were added to obtain the mTSS (range from 0 to 448). |
| American College of Rheumatology (ACR) 70 Response Rate at Week 48 | Week 48 | ACR 70 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 70 response will be referred to as ACR 70 response rate. * ≥70% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment * ≥70% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment * ≥70% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment |
Countries
Japan, South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Full-analysis Set Participants will receive Methotrexate (MTX) at a starting dose of 6 to 8 mg/week, which will be promptly escalated to the maximum tolerated dose (MTD) of ≤25 mg/week up to Week 12, and maintained until Week 24.
Methotrexate: Route of Administration: Oral | 291 |
| Total | 291 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| After Week 24 Randomization | Adverse Event | 0 | 1 | 2 | 2 |
| After Week 24 Randomization | Lack of Efficacy | 0 | 2 | 3 | 1 |
| After Week 24 Randomization | Lost to Follow-up | 0 | 1 | 0 | 2 |
| After Week 24 Randomization | Protocol Violation | 0 | 0 | 1 | 0 |
| After Week 24 Randomization | Withdrawal by Subject | 0 | 0 | 3 | 3 |
| Before Week 24 Randomization | Adverse Event | 10 | 0 | 0 | 0 |
| Before Week 24 Randomization | Complication | 1 | 0 | 0 | 0 |
| Before Week 24 Randomization | Inadequate Methotrexate Adherence | 1 | 0 | 0 | 0 |
| Before Week 24 Randomization | Lack of Efficacy | 8 | 0 | 0 | 0 |
| Before Week 24 Randomization | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Before Week 24 Randomization | Methotrexate <10 mg/week at Week 24 | 5 | 0 | 0 | 0 |
| Before Week 24 Randomization | Physician Decision | 2 | 0 | 0 | 0 |
| Before Week 24 Randomization | Withdrawal by Subject | 24 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Full-analysis Set |
|---|---|
| 28-Joint Disease Activity Score of Erythrocyte Sedimentation Rate (DAS28-ESR) | 5.2 scores on a scale STANDARD_DEVIATION 1.1 |
| Age, Continuous | 57.7 years STANDARD_DEVIATION 15.2 |
| Anti-cyclic Citrullinated Peptide Antibody Positive | 211 Participants |
| Bodyweight | 58.2 kg STANDARD_DEVIATION 11.4 |
| Comorbidities | 127 Participants |
| Current or Past Smoker | 102 Participants |
| Duration from the Diagnosis of Rheumatoid Arthritis | 21.1 days STANDARD_DEVIATION 56.2 |
| Estimated Glomerular Filtration Rate (eGFR) | 82.0 mL/min/1.73m² STANDARD_DEVIATION 20.2 |
| Health Assessment Questionnaire - Disability Index (HAQ-DI) | 0.9 scores on a scale STANDARD_DEVIATION 0.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 290 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment Japan | 194 Participants |
| Region of Enrollment South Korea | 55 Participants |
| Region of Enrollment Taiwan | 42 Participants |
| Rheumatoid Factor Positive | 213 Participants |
| Sex: Female, Male Female | 217 Participants |
| Sex: Female, Male Male | 74 Participants |
| Simplified Disease Activity Index (SDAI) | 26.5 scores on a scale STANDARD_DEVIATION 12.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 291 | 0 / 291 | 0 / 105 | 0 / 68 | 0 / 66 |
| other Total, other adverse events | 122 / 291 | 94 / 291 | 25 / 105 | 14 / 68 | 6 / 66 |
| serious Total, serious adverse events | 23 / 291 | 9 / 291 | 6 / 105 | 5 / 68 | 3 / 66 |
Outcome results
Primary
Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in mFAS
SDAI is a validated combined index of rheumatoid arthritis disease activity, defined as the sum of Swollen Joint Count (0-28), Tender Joint Count (0-28), Patient's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), Physician's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), and C-reactive protein (mg/dL). Higher scores represent higher disease activity. SDAI ≤ 3.3 indicates disease remission, \> 3.4 to 11 = low disease activity, \> 11 to 26 = moderate disease activity, and \> 26 = high disease activity.
Time frame: Week 48
Population: In the modified Full Analysis Set based on non-responder imputation. The modified Full Analysis Set was defined as those with evaluable data set at one or more timepoints after randomization including 66 of 68 subjects in ADA/MTX-Maximum Tolerated Dose Group and 61 of 66 subjects in ADA/MTX-Reduced Dose Group.~Primary and secondary analysis were performed in subjects randomized at week 24 and planed to receive ADA, not including MTX-Monotherapy Group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADA/MTX-Maximum Tolerated Dose Group | Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in mFAS | 25 Participants |
| ADA/MTX-Reduced Dose Group | Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in mFAS | 27 Participants |
Secondary
American College of Rheumatology (ACR) 20 Response Rate at Week 48
ACR 20 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 20 response will be referred to as ACR 20 response rate. * ≥20% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment * ≥20% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment * ≥20% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment
Time frame: Week 48
Population: In the Full Analysis Set based on non-responder imputation. Primary and secondary analysis were performed in subjects randomized at week 24 and planed to receive ADA, not including MTX-Monotherapy Group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADA/MTX-Maximum Tolerated Dose Group | American College of Rheumatology (ACR) 20 Response Rate at Week 48 | 47 Participants |
| ADA/MTX-Reduced Dose Group | American College of Rheumatology (ACR) 20 Response Rate at Week 48 | 47 Participants |
Secondary
American College of Rheumatology (ACR) 50 Response Rate at Week 48
ACR 50 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 50 response will be referred to as ACR 50 response rate. * ≥50% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment * ≥50% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment * ≥50% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment
Time frame: Week 48
Population: In the Full Analysis Set based on non-responder imputation. Primary and secondary analysis were performed in subjects randomized at week 24 and planed to receive ADA, not including MTX-Monotherapy Group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADA/MTX-Maximum Tolerated Dose Group | American College of Rheumatology (ACR) 50 Response Rate at Week 48 | 36 Participants |
| ADA/MTX-Reduced Dose Group | American College of Rheumatology (ACR) 50 Response Rate at Week 48 | 38 Participants |
Secondary
American College of Rheumatology (ACR) 70 Response Rate at Week 48
ACR 70 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 70 response will be referred to as ACR 70 response rate. * ≥70% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment * ≥70% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment * ≥70% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment
Time frame: Week 48
Population: In the Full Analysis Set based on non-responder imputation. Primary and secondary analysis were performed in subjects randomized at week 24 and planed to receive ADA, not including MTX-Monotherapy Group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADA/MTX-Maximum Tolerated Dose Group | American College of Rheumatology (ACR) 70 Response Rate at Week 48 | 22 Participants |
| ADA/MTX-Reduced Dose Group | American College of Rheumatology (ACR) 70 Response Rate at Week 48 | 26 Participants |
Secondary
Change in Modified Total Sharp Score ≤ 0.5 at Week 48
Bone erosions will be evaluated for each region from a scale of 0 (no damage) to 5 (complete collapse of the joint). The score will be 0 to 5 for each hand joint, and 0 to 10 for each foot joint. The maximum total erosion score of both hands will be 160 points, and that of both feet will be 120 points. Joint space narrowing will be evaluated for each region from a scale of 0 (no damage) to 4 (ankylosis or luxation). The maximum total joint space narrowing score of both hands will be 120 points, and that of both feet will be 48 points. Erosion scores and joint space narrowing scores were added to obtain the mTSS (range from 0 to 448).
Time frame: Week 48
Population: In the Full Analysis Set based on non-responder imputation. Primary and secondary analysis were performed in subjects randomized at week 24 and planed to receive ADA, not including MTX-Monotherapy Group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADA/MTX-Maximum Tolerated Dose Group | Change in Modified Total Sharp Score ≤ 0.5 at Week 48 | 45 Participants |
| ADA/MTX-Reduced Dose Group | Change in Modified Total Sharp Score ≤ 0.5 at Week 48 | 41 Participants |
Secondary
Health Assessment Questionnaire - Disability Index ≤0.5 at Week 48
HAQ-DI is a patient-reported questionnaire, consists of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week as: without any difficulty (0); with some difficulty (1); with much difficulty (2); unable to do (3). Scores on each task were summed and averaged to provide an overall score from 0 to 3, where 0=no disability and 3=very severe, high-dependency disability. Normal physical function is defined by HAQ-DI score of \< 0.5.
Time frame: Week 48
Population: In the Full Analysis Set based on non-responder imputation. Primary and secondary analysis were performed in subjects randomized at week 24 and planed to receive ADA, not including MTX-Monotherapy Group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADA/MTX-Maximum Tolerated Dose Group | Health Assessment Questionnaire - Disability Index ≤0.5 at Week 48 | 40 Participants |
| ADA/MTX-Reduced Dose Group | Health Assessment Questionnaire - Disability Index ≤0.5 at Week 48 | 41 Participants |
Secondary
Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in PPS
SDAI is a validated combined index of rheumatoid arthritis disease activity, defined as the sum of Swollen Joint Count (0-28), Tender Joint Count (0-28), Patient's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), Physician's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), and C-reactive protein (mg/dL). Higher scores represent higher disease activity. SDAI ≤ 3.3 indicates disease remission, \> 3.4 to 11 = low disease activity, \> 11 to 26 = moderate disease activity, and \> 26 = high disease activity.
Time frame: Week 48
Population: In the Per Protocol Set based on non-responder imputation. The Per Protocol Set is defined as a group of subjects among modified Full Analysis Set who adequately complied with the protocol including 58 of 66 subjects in ADA/MTX-Maximum Tolerated Dose Group and 61 of 61 subjects in ADA/MTX-Reduced Dose Group.~Primary and secondary analysis were performed in subjects randomized at week 24 and planed to receive ADA, not including MTX-Monotherapy Group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ADA/MTX-Maximum Tolerated Dose Group | Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in PPS | 23 Participants |
| ADA/MTX-Reduced Dose Group | Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in PPS | 27 Participants |