Rheumatoid Arthritis
Conditions
Brief summary
To demonstrate the efficacy of 80 mg adalimumab monthly dosing compared with placebo and demonstrate the non-inferiority of monthly dosing of 80 mg adalimumab compared with dosing of 40 mg adalimumab every other week.
Detailed description
The objective of this study is to demonstrate the efficacy of 80 mg adalimumab monthly dosing compared with placebo as measured by ACR20 response criteria following 12 weeks of therapy. The study is also designed to demonstrate the non-inferiority of monthly dosing of 80 mg adalimumab compared with dosing of 40 mg adalimumab eow as measured by ACR20 response criteria at Week 12.
Interventions
DRUGadalimumab
Pre-filled syringe. See arm for more detail
DRUGPlacebo
Pre-filled syringe. See arm for more detail
Sponsors
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject \> 18 years of age * Subject has a diagnosis of RA as defined by the 1987-revised ACR-classification criteria and has a disease duration for a minimum of three months * Subject must meet the following two criteria: a) At least 6 swollen joints out of 66 assessed, or b) At least 6 tender joints out of 68 assessed * If a subject is on MTX, the doses must be stable for at least 4 weeks prior to Screening blood draw and follow standard recommendations for MTX treatment * Subject is judged to be in generally good health as determined by the principal investigator
Exclusion criteria
* Subject has previous exposure to any systemic anti-TNF therapy (eg, infliximab, etanercept, certolizumab pegol or golimumab) including adalimumab * Subject has a history of acute inflammatory joint disease of different origin other than RA * Subject has been treated with any investigational biologic agents * Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study * Female subject who is pregnant or breast-feeding or considering becoming pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Responders According to the American College of Rheumatology (ACR) 20 Response Criteria at Week 12 Involving the Comparison of Adalimumab 80 mg Monthly Dose Versus Placebo and Adalimumab 40 mg Every Other Week (Eow) | Week 12 | Comparison of adalimumab 80 mg monthly dose versus placebo and adalimumab 40 mg eow in the number of responders with ACR criteria improvement consisting of 20%, (ACR20) reduction in tender or swollen joint counts (TJC or SJC, respectively) and 20% improvement in 3 of the following 5 criteria: \[1\] physician's global assessment of disease activity (PGA), \[2\] subject's assessment of disease activity, \[3\] subject's assessment of pain, \[4\] subject's assessment of physical disability via a health assessment questionnaire disability index(HAQ-DI), and \[5\] C-reactive protein (CRP) at each visit |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Within Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed) | Baseline and Week 12 | The HAQ-DI is a self-reported subject measure of physical function calculated as the mean of 8 category scores: Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each category score is calculated as the maximum of the scores for the questions within the category. The HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute the HAQ score. Changes to lower scores indicate improvement in physical function. |
| Within Group Mean Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF]) | Baseline and Week 12 | The HAQ-DI is a self-reported subject measure of physical function calculated as the mean of 8 category scores: Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each category score is calculated as the maximum of the scores for the questions within the category. The HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute the HAQ score. Changes to lower scores indicate improvement in physical function. |
| Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed) | Baseline and Week 12 | The HAQ-DI is a self-reported subject measure of physical function calculated as the mean of 8 category scores: Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each category score is calculated as the maximum of the scores for the questions within the category. The HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute the HAQ score. Changes to lower scores indicate improvement in physical function. |
| Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF]) | Baseline and Week 12 | The HAQ-DI is a self-reported subject measure of physical function calculated as the mean of 8 category scores: Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each category score is calculated as the maximum of the scores for the questions within the category. The HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute the HAQ score. Changes to lower scores indicate improvement in physical function. |
Countries
Australia, Canada, Germany, Puerto Rico, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 72 sites in the United States, Canada, Puerto Rico, Germany, the United Kingdom, and Australia. Subjects received over the course of 24 weeks either 80 mg adalimumab monthly, 40 mg adalimumab every other week (eow), or placebo (12 weeks) followed by 40 mg adalimumab eow (12 weeks).
Pre-assignment details
A total of 432 subjects were enrolled, randomized, and received at least 1 dose of study drug. A total of 420 subjects were defined as the Full analysis set (FAS), which excluded the 12 subjects enrolled at a non-compliant site. A total of 48 subjects were switched from placebo to adalimumab 40 mg eow and participated in Period 2.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo 40 mg every other week (eow) for 12 weeks for Period 1; Adalimumab 40 mg eow for remaining 12 weeks for Period 2 | 56 |
| Adalimumab 40 mg Eow Adalimumab 40 mg eow for Period 1 and Period 2 | 159 |
| Adalimumab 80 mg Monthly Adalimumab 80 mg monthly for Period 1 and Period 2 | 205 |
| Total | 420 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1, Placebo-control (12 Weeks) | Adverse Event | 2 | 7 | 7 |
| Period 1, Placebo-control (12 Weeks) | Lost to Follow-up | 0 | 1 | 1 |
| Period 1, Placebo-control (12 Weeks) | Other | 4 | 4 | 8 |
| Period 1, Placebo-control (12 Weeks) | Withdrawal by Subject | 2 | 1 | 7 |
| Period 2, Placebo Switched to Adalimumab | Adverse Event | 1 | 3 | 3 |
| Period 2, Placebo Switched to Adalimumab | Other | 2 | 6 | 0 |
| Period 2, Placebo Switched to Adalimumab | Withdrawal by Subject | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Total | Adalimumab 80 mg Monthly | Adalimumab 40 mg Eow | Placebo |
|---|---|---|---|---|
| Age Continuous | 56.4 years STANDARD_DEVIATION 12.58 | 56.3 years STANDARD_DEVIATION 12.43 | 57.2 years STANDARD_DEVIATION 12.79 | 54.4 years STANDARD_DEVIATION 12.46 |
| Age, Customized < 65 years | 304 participants | 148 participants | 113 participants | 43 participants |
| Age, Customized >= 65 years | 116 participants | 57 participants | 46 participants | 13 participants |
| Sex: Female, Male Female | 314 Participants | 149 Participants | 122 Participants | 43 Participants |
| Sex: Female, Male Male | 106 Participants | 56 Participants | 37 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 57 | 29 / 164 | 38 / 211 | 6 / 49 | 14 / 151 | 11 / 188 |
| serious Total, serious adverse events | 5 / 57 | 8 / 164 | 4 / 211 | 1 / 49 | 5 / 151 | 12 / 188 |
Outcome results
Primary
The Number of Responders According to the American College of Rheumatology (ACR) 20 Response Criteria at Week 12 Involving the Comparison of Adalimumab 80 mg Monthly Dose Versus Placebo and Adalimumab 40 mg Every Other Week (Eow)
Comparison of adalimumab 80 mg monthly dose versus placebo and adalimumab 40 mg eow in the number of responders with ACR criteria improvement consisting of 20%, (ACR20) reduction in tender or swollen joint counts (TJC or SJC, respectively) and 20% improvement in 3 of the following 5 criteria: \[1\] physician's global assessment of disease activity (PGA), \[2\] subject's assessment of disease activity, \[3\] subject's assessment of pain, \[4\] subject's assessment of physical disability via a health assessment questionnaire disability index(HAQ-DI), and \[5\] C-reactive protein (CRP) at each visit
Time frame: Week 12
Population: Full Analysis Set (FAS) - a subset of the intent to treat population used in all efficacy analyses excluding subjects from an Abbott identified Investigator who was non-compliant with the protocol requirements. The FAS of subjects who received at least 1 dose of study drug during Period 2 of the study was used for Period 2 efficacy analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | The Number of Responders According to the American College of Rheumatology (ACR) 20 Response Criteria at Week 12 Involving the Comparison of Adalimumab 80 mg Monthly Dose Versus Placebo and Adalimumab 40 mg Every Other Week (Eow) | Nonresponders | 37 participants |
| Placebo | The Number of Responders According to the American College of Rheumatology (ACR) 20 Response Criteria at Week 12 Involving the Comparison of Adalimumab 80 mg Monthly Dose Versus Placebo and Adalimumab 40 mg Every Other Week (Eow) | Responders | 19 participants |
| Adalimumab 40 mg Eow | The Number of Responders According to the American College of Rheumatology (ACR) 20 Response Criteria at Week 12 Involving the Comparison of Adalimumab 80 mg Monthly Dose Versus Placebo and Adalimumab 40 mg Every Other Week (Eow) | Responders | 80 participants |
| Adalimumab 40 mg Eow | The Number of Responders According to the American College of Rheumatology (ACR) 20 Response Criteria at Week 12 Involving the Comparison of Adalimumab 80 mg Monthly Dose Versus Placebo and Adalimumab 40 mg Every Other Week (Eow) | Nonresponders | 79 participants |
| Adalimumab 80 mg Monthly | The Number of Responders According to the American College of Rheumatology (ACR) 20 Response Criteria at Week 12 Involving the Comparison of Adalimumab 80 mg Monthly Dose Versus Placebo and Adalimumab 40 mg Every Other Week (Eow) | Responders | 97 participants |
| Adalimumab 80 mg Monthly | The Number of Responders According to the American College of Rheumatology (ACR) 20 Response Criteria at Week 12 Involving the Comparison of Adalimumab 80 mg Monthly Dose Versus Placebo and Adalimumab 40 mg Every Other Week (Eow) | Nonresponders | 108 participants |
Comparison: Adalimumab 80 mg monthly versus placebo: The null hypothesis associated with this comparison stated that adalimumab 80 mg monthly would be inferior to placebo with respect to ACR20 response percentage; the alternative hypothesis was that adalimumab 80 mg monthly would be superior to placebo with respect to ACR20 response.p-value: 0.07495% CI: [-13.3, 7.4]Chi-squared
Comparison: The non-inferiority of adalimumab 80 mg monthly to adalimumab 40 mg every other week (eow) was to be claimed if at least 50% of the treatment effect of adalimumab 40 mg eow over placebo was to be achieved by adalimumab 80 mg monthly over placebo.p-value: 0.74Chi-squared
Secondary
Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF])
The HAQ-DI is a self-reported subject measure of physical function calculated as the mean of 8 category scores: Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each category score is calculated as the maximum of the scores for the questions within the category. The HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute the HAQ score. Changes to lower scores indicate improvement in physical function.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS) - a subset of the intent to treat population used in all efficacy analyses excluding subjects from an Abbott identified Investigator who was non-compliant with the protocol requirements. The FAS of subjects who received at least 1 dose of study drug during Period 2 of the study was used for Period 2 efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF]) | 0 units on a score | Standard Error 0 |
| Adalimumab 40 mg Eow | Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF]) | -0.24 units on a score | Standard Error 0.077 |
| Adalimumab 80 mg Monthly | Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF]) | -0.21 units on a score | Standard Error 0.075 |
Comparison: Using a fixed-sequence multiple-testing approach at an alpha level of 0.05 to test the secondary endpoints, the testing of the null-hypothesis began with the first endpoint and stopped as soon as failure to reject a hypothesis occurred (i.e., P value \> 0.05). Using this procedure, testing stopped after secondary endpoint number 1, change from Baseline in HAQ at Week 12.p-value: 0.005ANCOVA
Secondary
Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed)
The HAQ-DI is a self-reported subject measure of physical function calculated as the mean of 8 category scores: Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each category score is calculated as the maximum of the scores for the questions within the category. The HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute the HAQ score. Changes to lower scores indicate improvement in physical function.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS) - a subset of the intent to treat population used in all efficacy analyses excluding subjects from an Abbott identified Investigator who was non-compliant with the protocol requirements. The FAS of subjects who received at least 1 dose of study drug during Period 2 of the study was used for Period 2 efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed) | 0 units on a score | Standard Error 0 |
| Adalimumab 40 mg Eow | Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed) | -0.26 units on a score | Standard Error 0.081 |
| Adalimumab 80 mg Monthly | Between Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed) | -0.24 units on a score | Standard Error 0.079 |
Comparison: Using a fixed-sequence multiple-testing approach at an alpha level of 0.05 to test the secondary endpoints, the testing of the null-hypothesis began with the first endpoint and stopped as soon as failure to reject a hypothesis occurred (i.e., P value \> 0.05). Using this procedure, testing stopped after secondary endpoint number 1, change from Baseline in HAQ at Week 12.p-value: 0.002ANCOVA
Secondary
Within Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed)
The HAQ-DI is a self-reported subject measure of physical function calculated as the mean of 8 category scores: Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each category score is calculated as the maximum of the scores for the questions within the category. The HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute the HAQ score. Changes to lower scores indicate improvement in physical function.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS)-a subset of the intent to treat population used in all efficacy analyses excluding subjects from an Abbott identified Investigator who was non-compliant with protocol requirements. The FAS of subjects who received at least 1 dose of study drug during Period 2 of the study was used for Period 2 efficacy analyses (observed).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Within Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed) | -0.11 units on a score | Standard Deviation 0.488 |
| Adalimumab 40 mg Eow | Within Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed) | -0.41 units on a score | Standard Deviation 0.508 |
| Adalimumab 80 mg Monthly | Within Group Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Observed) | -0.39 units on a score | Standard Deviation 0.536 |
Comparison: Using a fixed-sequence multiple-testing approach at an alpha level of 0.05 to test the secondary endpoints, the testing of the null-hypothesis began with the first endpoint and stopped as soon as failure to reject a hypothesis occurred (i.e., P value \> 0.05). Using this procedure, testing stopped after secondary endpoint number 1, change from Baseline in HAQ at Week 12.p-value: 0.002ANCOVA
Secondary
Within Group Mean Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF])
The HAQ-DI is a self-reported subject measure of physical function calculated as the mean of 8 category scores: Dressing and Grooming, Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities. Each category score is calculated as the maximum of the scores for the questions within the category. The HAQ-DI is expressed on a scale of 0 (without any difficulty) to 3 (unable to do) representing an average score across the category. Scores for at least 6 categories are needed to compute the HAQ score. Changes to lower scores indicate improvement in physical function.
Time frame: Baseline and Week 12
Population: Full Analysis Set (FAS)-a subset of the intent to treat population used in all efficacy analyses excluding subjects from an Abbott identified Investigator who was non-compliant with protocol requirements. The FAS of subjects who received at least 1 dose of study drug during Period 2 of the study was used for Period 2 efficacy analyses (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Within Group Mean Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF]) | -0.12 units on a score | Standard Deviation 0.484 |
| Adalimumab 40 mg Eow | Within Group Mean Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF]) | -0.40 units on a score | Standard Deviation 0.507 |
| Adalimumab 80 mg Monthly | Within Group Mean Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 (Last Observation Carried Forward [LOCF]) | -0.37 units on a score | Standard Deviation 0.537 |
Comparison: Using a fixed-sequence multiple-testing approach at an alpha level of 0.05 to test the secondary endpoints, the testing of the null-hypothesis began with the first endpoint and stopped as soon as failure to reject a hypothesis occurred (i.e., P value \> 0.05). Using this procedure, testing stopped after secondary endpoint number 1, change from Baseline in HAQ at Week 12.p-value: 0.005ANCOVA
Comparison: Using a fixed-sequence multiple-testing approach at an alpha level of 0.05 to test the secondary endpoints, the testing of the null-hypothesis began with the first endpoint and stopped as soon as failure to reject a hypothesis occurred (i.e., P value \> 0.05). Using this procedure, testing stopped after secondary endpoint number 1, change from Baseline in HAQ at Week 12.p-value: 0.002ANCOVA