The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 50% response (ACR50) at Week 12. Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria:

1. ≥ 50% improvement in 68-tender joint count;

2. ≥ 50% improvement in 66-swollen joint count; and

3. ≥ 50% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was clinical remission, based on a Disease Activity Score 28 (DAS28)-CRP score of < 2.6 at Week 24.

The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity.

A DAS28 score less than 2.6 indicates clinical remission.

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom DAS28 data were missing at Week 24 were considered non-responders.

The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The primary endpoint for Japan/Pharmaceuticals and Medical Devices Agency (PMDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria:

1. ≥ 20% improvement in 68-tender joint count;

2. ≥ 20% improvement in 66-swollen joint count; and

3. ≥ 20% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The global analysis includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The second primary endpoint for Japan/PMDA regulatory purposes was change from baseline in mTSS at Week 24.

The mTSS measures the level of joint damage from radiographs of the hands and feet. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers.

Joint erosion was assessed in 16 joints in each hand/wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst).

JSN was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst).

The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst). A change from Baseline greater than 0 indicates progression.

Full analysis set participants with available data at Baseline; linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing at Week 24.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.

Full analysis set participants with available data at Baseline; multiple imputation was used for missing post-baseline data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability.

A negative change from Baseline in the overall score indicates improvement.

Full analysis set participants with available data at Baseline; multiple imputation was used for missing data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The DAS28(CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity.

A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity.

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).

The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement.

Full analysis set participants with available data at Baseline; multiple imputation was used for missing data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.

Full analysis set participants with available data at Baseline; multiple imputation was used for missing post-baseline data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability.

A negative change from Baseline in the overall score indicates improvement.

Full analysis set participants with available data at Baseline; multiple imputation was used for missing data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria:

1. ≥ 50% improvement in 68-tender joint count;

2. ≥ 50% improvement in 66-swollen joint count; and

3. ≥ 50% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The DAS28(CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity.

A DAS28(CRP) score less than or equal to 3.2 indicates low disease activity.

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom DAS28 data were missing at Week 24 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health).

The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement.

Full analysis set participants with available data at Baseline; multiple imputation was used for missing data.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

No radiographic progression is defined as a change from Baseline in mTSS ≤ 0. The mTSS measures the level of joint damage from radiographs of the hands and feet. Joint erosion and joint space narrowing (JSN) were assessed by two independent, blinded readers.

Joint erosion severity was assessed in 16 joints in each hand and wrist and 6 joints in each foot. Each joint was scored from 0 (no erosion) to 5 for hands/wrists or to 10 for feet (complete collapse). The total erosion score ranges from 0 to 280 (worst).

Joint space narrowing (JSN) was assessed in 15 joints of each hand and wrist, and 6 joints of each foot, including subluxation, from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation). The total JSN score ranges from 0 to 168 (worst).

The mTSS is the sum of the joint erosion and JSN scores and ranges from 0 (normal) to 448 (worst).

Full analysis set participants with available data at Baseline; linear extrapolation was used for participants who discontinued prior to Week 24 or for whom x-ray data were missing at Week 24.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria:

1. ≥ 70% improvement in 68-tender joint count;

2. ≥ 70% improvement in 66-swollen joint count; and

3. ≥ 70% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria:

1. ≥ 20% improvement in 68-tender joint count;

2. ≥ 20% improvement in 66-swollen joint count; and

3. ≥ 20% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria:

1. ≥ 70% improvement in 68-tender joint count;

2. ≥ 70% improvement in 66-swollen joint count; and

3. ≥ 70% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom ACR data were missing at Week 24 were considered non-responders.

The global analysis population includes participants enrolled under the methotrexate and upadacitinib 15 mg and 30 mg treatment groups.

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria:

1. ≥ 20% improvement in 68-tender joint count;

2. ≥ 20% improvement in 66-swollen joint count; and

3. ≥ 20% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria:

1. ≥ 50% improvement in 68-tender joint count;

2. ≥ 50% improvement in 66-swollen joint count; and

3. ≥ 50% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria:

1. ≥ 70% improvement in 68-tender joint count;

2. ≥ 70% improvement in 66-swollen joint count; and

3. ≥ 70% improvement in at least 3 of the 5 following parameters:

   • Physician global assessment of disease activity
   • Patient global assessment of disease activity
   • Patient assessment of pain
   • Health Assessment Questionnaire - Disability Index (HAQ-DI)
   • High-sensitivity C-reactive protein (hsCRP).

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.

Full analysis set participants with available data at Baseline; multiple imputation was used for missing post-baseline data.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability.

A negative change from Baseline in the overall score indicates improvement.

Full analysis set participants with available data at Baseline; multiple imputation was used for missing data.

The Japan sub-study analysis includes participants enrolled in Japan under the methotrexate and upadacitinib 7.5 mg, 15 mg, and 30 mg treatment groups.