Safety and Efficacy Study of Adalimumab in Adult Chinese Rheumatoid Arthritis Subjects Treated With Methotrexate

Study Overview
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Brief Summary
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A study to assess the safety and efficacy of adalimumab administered as a subcutaneous injection in adult Chinese subjects with rheumatoid arthritis and treated with methotrexate

Detailed Description
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This was a multi-center, Phase 2/3, randomized, double-blind (DB), parallel group, placebo controlled, safety and efficacy study in adult Chinese RA subjects. The duration of the study was approximately 116 weeks. This included a 4-week (28 days) Screening period, a 12-week Double-Blind (DB) period, a 90-week Open-Label (OL) Period, and a 10-week (70 days) Follow-up period. The 70-day Safety Follow-up period was initiated after the last dose of study medication. During the DB period, 302 Chinese subjects with RA and concomitantly treated with MTX were enrolled at 11 clinical sites located throughout China. Subjects were randomly assigned to one of the three treatment groups in a 2:2:1 ratio: 80 mg adalimumab, 40 mg adalimumab, or placebo. From Week 0 to Week 10, subjects received blinded study drug. Subjects who successfully participated and completed Week 12 of the DB portion of the study participated in the OL period. All subjects in the OL period received adalimumab 40 mg. Throughout the study, the study drug was administered subcutaneously (SC) every other week (eow). Subjects that completed the Week 24 visit, prior to the approval of Protocol Amendment 1, had 70 days from the last dose of study drug to re-enter the study. The Investigator confirmed that the subject did not develop any of the exclusion criteria and completed the procedures defined by the OL Screening visit. Results through Week 24 of this study were presented in the regulatory dossier for the marketing authorization application of Humira in China, fulfilling the requirement for clinical data in Chinese patients. However, in order to continue to provide treatment to patients who responded well to adalimumab, subjects had the option to continue in the OL extension of this study until Week 92.

Official Title
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A Multi-center Randomized, Phase 2/3, Double-blind, Parallel-group, Placebo-controlled Study to Assess the Safety and Efficacy of Adalimumab Administered as Subcutaneous Injections in Adult Chinese Rheumatoid Arthritis Subjects Treated With Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Placebo
* Biological: Adalimumab 80 mg
* Biological: Adalimumab 40 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Met ACR criteria for diagnosis of active rheumatoid arthritis (RA) and have had at both the Screening visit and Week 0 visit at least four swollen joints (out of 66 assessed) and at least six tender joints(out of 68 assessed) Subjects must have failed prior treatment with one or more disease-modifying antirheumatic drugs (DMARDs) DMARDs (other than methotrexate [MTX]) must have been discontinued for >= 28 days or at least 5 half-lives, whichever is greater, before the Week 0 visit Traditional Chinese Medicines must have been discontinued for >= 28 days before the Week 0 visit Subjects must have received at least three months of treatment with MTX (minimum 7.5 mg/week) and remained on a stable dose of MTX for >= 28 days prior to the Screening visit Glucocorticoids equivalent to <= 10 mg of prednisone and prednisone equivalent must have remained unchanged for at least 28 days prior to the Week 0 visit Must have been able and willing to give written informed consent and to comply with the requirements of this study protocol Exclusion Criteria: A history of, or current, acute inflammatory joint disease of different origin (e.g., mixed connective tissue disease, seronegative spondyloarthropathy, psoriatic arthritis, Reiter's syndrome, systemic lupus erythematosus, fibromyalgia or any arthritide with onset prior to age 16 years Wheelchair-bound or bedridden Joint surgery involving joints to be assessed within this study, within two months prior to the Screening visit Intra-articular, intramuscular or intravenous administration of corticosteroids within 28 days prior to the Screening visit Prior treatment with any TNF antagonist, including adalimumab Subject considered by the investigator, for any reason, to be an unsuitable candidate Female subject who is pregnant or breast-feeding or considering becoming pregnant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo administered subcutaneously every other week | Biological: Placebo<br>* Placebo administered subcutaneously (SC) every other week (eow) for 12 weeks, followed by adalimumab 40 mg SC eow for 92 weeks.<br>|
| Experimental: Adalimumab 80 mg<br>Adalimumab 80 mg administered subcutaneously every other week | Biological: Adalimumab 80 mg<br>* Adalimumab 80 mg administered subcutaneously (SC) every other week (eow) for 12 weeks, followed by adalimumab 40 mg SC eow for 92 weeks.<br>* Other names: Humira;|
| Experimental: Adalimumab 40 mg<br>Adalimumab 40 mg administered subcutaneously every other week | Biological: Adalimumab 40 mg<br>* Adalimumab 40 mg administered subcutaneously every other week for 104 weeks<br>* Other names: Humira;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With American College of Rheumatology (ACR)20 at Week 12 of the Double-Blind Period | American College of Rheumatology (ACR) criteria improvement consisting of 20% (ACR20) reduction in tender or swollen joint counts and 20% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. Week 12 = end of Double-Blind period. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving American College of Rheumatology (ACR)50/70 at Week 12 of the Double-Blind Period | American College of Rheumatology (ACR) criteria improvement consisting of 50% or 70% (ACR50/70) reduction in tender or swollen joint counts and 50% or 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. Week 12 = end of Double-blind period. | Week 12 | 
| Number of Participants Achieving American College of Rheumatology (ACR)20 Response Through Week 92 of Open-Label Period | American College of Rheumatology (ACR) criteria improvement in a subject's disease condition versus Baseline consisting of 20% (ACR20) reduction in tender or swollen joint counts and 20/50/70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. | Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Number of Participants Achieving American College of Rheumatology (ACR)50 Response Through Week 92 of Open-Label Period | American College of Rheumatology (ACR) criteria improvement in a subject's disease condition versus Baseline consisting of 50% (ACR50) reduction in tender or swollen joint counts and 20/50/70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. | Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Number of Participants Achieving American College of Rheumatology (ACR)70 Response Through Week 92 of Open-Label Period | American College of Rheumatology (ACR) criteria improvement in a subject's disease condition versus Baseline consisting of 70% (ACR70) reduction in tender or swollen joint counts and 20/50/70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit. | Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Mean Change in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 12 of the Double-Blind Period | Sixty-eight or 66 joints or regions (34 or 32 per body side [hip joints excluded]) were assessed by pressure and joint manipulation on physical examination for tender joint count (TJC) or swollen joint count (SJC), respectively. Both joint tenderness and swelling were classified as either present (1), absent (0), replaced (9), or no assessment (NA). The Total TJC or SJC was derived as the sum of all 1s evaluated; the range for TJC and SJC were 0 - 68 and 0 - 66, respectively. The higher the joint count, the worse the rheumatoid arthritis. Week 12 = end of Double-Blind period. | Baseline, Week 12 | 
| Mean Change in Tender Joint Count (TJC) Through Week 92 of the Open-Label Period | Sixty-eight or 66 joints or regions (34 or 32 per body side [hip joints excluded]) were assessed by pressure and joint manipulation on physical examination for tender joint count (TJC) or swollen joint count (SJC), respectively. Both joint tenderness and swelling were classified as either present (1), absent (0), replaced (9), or no assessment (NA). The Total TJC or SJC was derived as the sum of all 1s evaluated; the range for TJC and SJC were 0 - 68 and 0 - 66, respectively. The higher the joint count, the worse the rheumatoid arthritis. Week 12 = end of Double-Blind period. | Baseline, Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Mean Change in Swollen Joint Count (SJC) Through Week 92 of the Open-Label Period | Sixty-eight or 66 joints or regions (34 or 32 per body side [hip joints excluded]) were assessed by pressure and joint manipulation on physical examination for tender joint count (TJC) or swollen joint count (SJC), respectively. Both joint tenderness and swelling were classified as either present (1), absent (0), replaced (9), or no assessment (NA). The Total TJC or SJC was derived as the sum of all 1s evaluated; the range for TJC and SJC were 0 - 68 and 0 - 66, respectively. The higher the joint count, the worse the rheumatoid arthritis. Week 12 = end of Double-Blind period. | Baseline, Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Mean Change in Visual Analog Scale (VAS) Score at Week 12 of the Double-Blind Period | Visual analog scale (VAS) was used for the physician's (PhGA) and patient's (PGA) global assessment of disease activity and the patient's assessment of pain. PhGA assessed the patient's current status, PGA assessed status within the last 24 h, and patient's assessment of pain assessed pain status during the last week. All 3 assessments were scored on a 100 mm horizontal scale. The scores range from 0 (no symptoms) to 100 (maximum symptoms); therefore lower VAS scores represent a better disease state. Week 12 = end of Double-Blind period. | Baseline, Week 12 | 
| Mean Change in Physician's Global Assessment of Disease Activity (Visual Analog Scale [VAS]) Through Week 92 of the Open-Label Period | Visual analog scale (VAS) was used for the physician's (PhGA) and patient's (PGA) global assessment of disease activity and the patient's assessment of pain. PhGA assessed the patient's current status, PGA assessed status within the last 24 h, and patient's assessment of pain assessed pain status during the last week. All 3 assessments were scored on a 100 mm horizontal scale. The scores range from 0 (no symptoms) to 100 (maximum symptoms); therefore lower VAS scores represent a better disease state. | Baseline, Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Mean Change in Patient's Assessment of Pain (Visual Analog Scale [VAS]) Through Week 92 of the Open-Label Period | Visual analog scale (VAS) was used for the physician's (PhGA) and patient's (PGA) global assessment of disease activity and the patient's assessment of pain. PhGA assessed the patient's current status, PGA assessed status within the last 24 h, and patient's assessment of pain assessed pain status during the last week. All 3 assessments were scored on a 100 mm horizontal scale. The scores range from 0 (no symptoms) to 100 (maximum symptoms); therefore lower VAS scores represent a better disease state. | Baseline, Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Mean Change in Patient's Global Assessment of Disease Activity (Visual Analog Scale [VAS]) Through Week 92 of the Open-Label Period | Visual analog scale (VAS) was used for the physician's (PhGA) and patient's (PGA) global assessment of disease activity and the patient's assessment of pain. PhGA assessed the patient's current status, PGA assessed status within the last 24 h, and patient's assessment of pain assessed pain status during the last week. All 3 assessments were scored on a 100 mm horizontal scale. The scores range from 0 (no symptoms) to 100 (maximum symptoms); therefore lower VAS scores represent a better disease state. | Baseline, Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Mean Change in the Disability Index of the Health Assessment Questionnaire (HAQ) Scores From Baseline to Week 12 of the Double-Blind Period | HAQ is a self-reported, subject-oriented outcome measure. The Standard Disability Index of HAQ for a subject is calculated as the mean of the following 8 category scores (range: 0-3): dressing and grooming, rising, eating, walking, hygiene, reach, grip, and activities. The score of each category is calculated as the maximum of the scores for the questions of that category. The Disability Index cannot be computed if the patient does not have scores for at least 6 categories. A decrease in the Disability Index = improvement in disease (0 = no difficulties). Week 12 = end of Double-Blind period. | Baseline, Week 12 | 
| Mean Change in the Disability Index of the Health Assessment Questionnaire (HAQ) Through Week 92 of the Open-Label Period | HAQ is a self-reported, subject-oriented outcome measure. The Standard Disability Index of HAQ for a subject is calculated as the mean of the following 8 category scores (range: 0-3): dressing and grooming, rising, eating, walking, hygiene, reach, grip, and activities. The score of each category is calculated as the maximum of the scores for the questions of that category. The Disability Index cannot be computed if the patient does not have scores for at least 6 categories. A decrease in the Disability Index indicates an improvement in disease (0 = no difficulties). | Baseline, Week 0, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Mean Change in the SF-36 Health Survey Index Physical Component Summary (PCS) and Mental Component Summary (MCS) at Week 12 of the Double-Blind Period | SF-36 (v.2) is a standardized health survey consisting of 36 questions to measure functional health status. The SF-36 score has two components: physical (PCS) and mental (MCS). Summary scores are calculated using the following 8 scales: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. The score for a component is an average of the individual question scores, which are scaled 0 (not functioning) to 100 (highest functioning). An increase in SF-36 PCS or MCS indicates improved health status. | Baseline, Week 12 | 
| Mean Change in the SF-36 Health Survey Index Physical Component Summary (PCS) Through Week 92 of the Open-Label Period | SF-36 (v.2) is a standardized health survey consisting of 36 questions to measure functional health status. The SF-36 score has two components: physical (PCS) and mental (MCS). Summary scores are calculated using the following 8 scales: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. The score for a component is an average of the individual question scores, which are scaled 0 (not functioning) to 100 (highest functioning). An increase in SF-36 PCS or MCS indicates improved health status. | Baseline, Week 0, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 
| Mean Change in the SF-36 Health Survey Index Mental Component Summary (MCS) Through Week 92 of the Open-Label Period | SF-36 (v.2) is a standardized health survey consisting of 36 questions to measure functional health status. The SF-36 score has two components: physical (PCS) and mental (MCS). Summary scores are calculated using the following 8 scales: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. The score for a component is an average of the individual question scores, which are scaled 0 (not functioning) to 100 (highest functioning). An increase in SF-36 PCS or MCS indicates improved health status. | Baseline, Week 0, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 92 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Humira, methotrexate