Rheumatoid Arthritis (RA)
Conditions
Keywords
Rheumatoid Arthritis (RA), ABBV-3373, Adalimumab
Brief summary
This study will assess the safety, tolerability, and efficacy of ABBV-3373 in participants with moderately to severely active rheumatoid arthritis (RA) on background methotrexate (MTX) compared with adalimumab.
Detailed description
This study consists of a 12-week double-blind active-controlled phase and a 12 week double-blind extension period. In the active-controlled period of the first 12 weeks of treatment, participants are randomized to receive either ABBV-3373 100 mg intravenously (IV) every other week (EOW) or adalimumab 80 mg subcutaneously (SC) EOW according to a 2:1 ratio. At Week 12, the administration of ABBV-3373 was to stop to assess the durability of the observed clinical effects up to 24 weeks. Participants randomized to ABBV-3373 were to receive placebo injections, whereas participants randomized into the adalimumab arm were to continue their 80 mg dosing.
Interventions
DRUGABBV-3373
ABBV-3373 is administered as intravenous (IV) infusion
DRUGPlacebo for ABBV-3373
Placebo for ABBV-3373 is administered as IV infusion
DRUGAdalimumab
Adalimumab is administered as subcutaneous (SC) injection
Placebo for adalimumab is administered as subcutaneous (SC) injection
Sponsors
AbbVie
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Participant has the clinical diagnosis of RA for \> 3 months based on the 1987 American College of Rheumatology (ACR) classification criteria or 2010 ACR/European League against Rheumatism (EULAR) criteria. * Participant meets the following disease activity criteria: \>= 4 swollen joints (based on 28 joint count) and \>= 4 tender joints (based on 28 joint count) at Screening and Baseline visits and disease activity score (28 joints) (DAS28) C-reactive protein (CRP) \>= 3.2 at Screening. * Participant has an incomplete response to methotrexate. Participants must have been on oral or parental MTX therapy \>= 3 months and on a stable prescription of 15 to 25 mg/week (or \>= 10 mg/week in participants intolerant of MTX at doses \>= 15 mg/week) for \>= 4 weeks prior to the first dose of study drug. Participant must be expected to be able to continue on stable dose of MTX for the duration of study participation.
Exclusion criteria
* Participants previously exposed to adalimumab or other anti-tumor necrosis factor (TNF) biologics. * Participants previously exposed to non-anti-TNF biologics or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for RA, with exception of participants exposed for less than 3 months and terminated not due to lack of efficacy or intolerability.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Disease Activity Score (DAS) 28 (C-reactive Protein [CRP]) | Baseline and Week 12 | 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 (measured on a visual analog scale \[VAS\] from 0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 (CRP) range from 0.96 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Clinical Disease Activity Index (CDAI) | Baseline and Week 12 | The clinical disease activity index (CDAI) is a composite index for assessing disease activity based on the summation of the counts of tender joint count (out of 28 evaluated joints) and swollen joint count (out of 28 evaluated joints), Patient Global Assessment of Disease Activity and Physician Global Assessment of Disease Activity both measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 76 with higher scores indicating higher disease activity. A negative change from Baseline indicates improvement in disease activity. |
| Change From Baseline in Simplified Disease Activity Index (SDAI) | Baseline and Week 12 | The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), Patient Global Assessment of Disease Activity and Physician Global Assessment of Disease Activity both measured on a VAS from 0-10 cm and level of CRP (in mg/dL; normal \< 1 mg/dL). The SDAI has a range from 0 to 86, with higher scores indicating higher disease activity. A negative change from Baseline indicates improvement in disease activity. |
| Change From Baseline to Week 12 in DAS28 (Erythrocyte Sedimentation Rate [ESR]) | Baseline and Week 12 | The DAS28 (ESR) 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 (measured on a VAS from 0-100 mm), and ESR (in mm/hr). Scores on the DAS28 (ESR) range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline indicates improvement in disease activity. |
| Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28 (CRP) at Week 12 | Week 12 | 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 (measured on a VAS from 0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 (CRP) range from 0.96 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. |
| Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 | Baseline and 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). |
Countries
Germany, Hungary, Israel, Netherlands, Poland, Puerto Rico, United States
Participant flow
Recruitment details
Participants with moderately to severely active rheumatoid arthritis (RA) on background methotrexate (MTX) were enrolled at 14 sites in the United States and Puerto Rico, Poland, Hungary, and Israel.
Pre-assignment details
Participants were randomly assigned in a 2:1 ratio to either ABBV-3373 or adalimumab. Randomization was stratified by current use of systemic glucocorticoid (≤ 7.5 mg/d prednisone equivalent) for treatment of RA at Baseline (yes/no) and prior exposure to non-anti-tumor necrosis factor (TNF) biologics or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for less than 3 months and terminated not due to lack of efficacy or intolerance (yes/no).
Participants by arm
| Arm | Count |
|---|---|
| Adalimumab Participants were administered placebo to ABBV-3373 by IV infusion and 80 mg adalimumab by subcutaneous injection EOW for 12 weeks. After 12 weeks, participants received 80 mg adalimumab subcutaneously EOW until Week 22. | 17 |
| ABBV-3373 Followed by Placebo Participants were administered 100 mg ABBV-3373 by IV infusion and placebo to adalimumab by subcutaneous injection EOW for 12 weeks. After 12 weeks, participants received placebo to adalimumab EOW until Week 22. | 31 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2: Weeks 12 to Week 24 | Adverse Event | 1 | 1 |
| Period 2: Weeks 12 to Week 24 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Adalimumab | ABBV-3373 Followed by Placebo | Total |
|---|---|---|---|
| Age, Continuous | 54.0 years STANDARD_DEVIATION 10.21 | 52.8 years STANDARD_DEVIATION 13.14 | 53.2 years STANDARD_DEVIATION 12.08 |
| Age, Customized 40 to 65 years | 13 Participants | 21 Participants | 34 Participants |
| Age, Customized < 40 years | 0 Participants | 5 Participants | 5 Participants |
| Age, Customized ≥ 65 years | 4 Participants | 5 Participants | 9 Participants |
| Baseline Use of Systemic Glucocorticoids No | 12 Participants | 20 Participants | 32 Participants |
| Baseline Use of Systemic Glucocorticoids Yes | 5 Participants | 11 Participants | 16 Participants |
| Disease Activity Score 28 C-reactive protein (DAS28[CRP]) | 5.6 units on a scale STANDARD_DEVIATION 0.71 | 5.6 units on a scale STANDARD_DEVIATION 0.92 | 5.6 units on a scale STANDARD_DEVIATION 0.84 |
| Duration of RA Diagnosis | 3.5 years STANDARD_DEVIATION 3.09 | 5.0 years STANDARD_DEVIATION 6.02 | 4.5 years STANDARD_DEVIATION 5.19 |
| Duration of RA Symptoms | 5.9 years STANDARD_DEVIATION 3.22 | 8.0 years STANDARD_DEVIATION 8.73 | 7.2 years STANDARD_DEVIATION 7.29 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 8 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 23 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Prior Exposure to Non-anti-TNF or Targeted Synthetic DMARDs No | 17 Participants | 31 Participants | 48 Participants |
| Prior Exposure to Non-anti-TNF or Targeted Synthetic DMARDs Yes | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 28 Participants | 44 Participants |
| Sex: Female, Male Female | 14 Participants | 24 Participants | 38 Participants |
| Sex: Female, Male Male | 3 Participants | 7 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 17 | 0 / 30 | 0 / 16 |
| other Total, other adverse events | 4 / 31 | 12 / 17 | 7 / 30 | 12 / 16 |
| serious Total, serious adverse events | 4 / 31 | 0 / 17 | 0 / 30 | 2 / 16 |
Outcome results
Primary
Change From Baseline to Week 12 in Disease Activity Score (DAS) 28 (C-reactive Protein [CRP])
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 (measured on a visual analog scale \[VAS\] from 0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 (CRP) range from 0.96 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.
Time frame: Baseline and Week 12
Population: Participants in the full analysis set with non-missing Baseline and at least one post-baseline value are included in the analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Adalimumab | Change From Baseline to Week 12 in Disease Activity Score (DAS) 28 (C-reactive Protein [CRP]) | -2.51 score on a scale | Standard Error 0.293 |
| ABBV-3373 | Change From Baseline to Week 12 in Disease Activity Score (DAS) 28 (C-reactive Protein [CRP]) | -2.65 score on a scale | Standard Error 0.215 |
Comparison: Two primary comparisons were performed between ABBV-3373 and adalimumab. The first was the comparison of ABBV-3373 to historical adalimumab reference value -2.13 based on a meta-analysis consisting of 242 subjects from 3 historical adalimumab studies in which the success criterion was 2-sided P value ≤ 0.1.p-value: 0.02290% CI: [-0.89, -0.15]Mixed-effect model repeated measurement
Comparison: The second comparison was ABBV-3373 to adalimumab with combined in-trial and borrowed historical adalimumab data using a Bayesian historical borrowing approach in which the success criterion was posterior probability of ABBV-3373 being better than adalimumab \> 95%. When borrowing 30 historical adalimumab subjects, the combined least squares mean change from Baseline was -2.29.p-value: 0.899Historical data borrowing
Comparison: The mean difference in change from Baseline in DAS28 (CRP) at Week 12 between ABBV-3373 and adalimumab was also estimated only based on in-study data.p-value: 0.68390% CI: [-0.74, 0.45]Mixed Effect Model Repeated Measurement
Secondary
Change From Baseline in Simplified Disease Activity Index (SDAI)
The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), Patient Global Assessment of Disease Activity and Physician Global Assessment of Disease Activity both measured on a VAS from 0-10 cm and level of CRP (in mg/dL; normal \< 1 mg/dL). The SDAI has a range from 0 to 86, with higher scores indicating higher disease activity. A negative change from Baseline indicates improvement in disease activity.
Time frame: Baseline and Week 12
Population: Participants in the full analysis set with non-missing Baseline and at least one post-baseline value were included in the analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Adalimumab | Change From Baseline in Simplified Disease Activity Index (SDAI) | -27.42 score on a scale | Standard Error 2.659 |
| ABBV-3373 | Change From Baseline in Simplified Disease Activity Index (SDAI) | -28.50 score on a scale | Standard Error 1.961 |
p-value: 0.73790% CI: [-6.47, 4.3]Mixed Effect Model Repeated Measurement
Secondary
Change From Baseline to Week 12 in Clinical Disease Activity Index (CDAI)
The clinical disease activity index (CDAI) is a composite index for assessing disease activity based on the summation of the counts of tender joint count (out of 28 evaluated joints) and swollen joint count (out of 28 evaluated joints), Patient Global Assessment of Disease Activity and Physician Global Assessment of Disease Activity both measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 76 with higher scores indicating higher disease activity. A negative change from Baseline indicates improvement in disease activity.
Time frame: Baseline and Week 12
Population: Participants in the full analysis set with non-missing Baseline and at least one post-baseline value were included in the analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Adalimumab | Change From Baseline to Week 12 in Clinical Disease Activity Index (CDAI) | -26.30 score on a scale | Standard Error 2.656 |
| ABBV-3373 | Change From Baseline to Week 12 in Clinical Disease Activity Index (CDAI) | -27.99 score on a scale | Standard Error 1.955 |
p-value: 0.60190% CI: [-7.08, 3.7]Mixed Effect Model Repeated Measurement
Secondary
Change From Baseline to Week 12 in DAS28 (Erythrocyte Sedimentation Rate [ESR])
The DAS28 (ESR) 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 (measured on a VAS from 0-100 mm), and ESR (in mm/hr). Scores on the DAS28 (ESR) range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline indicates improvement in disease activity.
Time frame: Baseline and Week 12
Population: Participants in the full analysis set with non-missing Baseline and at least one post-baseline value were included in the analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Adalimumab | Change From Baseline to Week 12 in DAS28 (Erythrocyte Sedimentation Rate [ESR]) | -2.55 score on a scale | Standard Error 0.344 |
| ABBV-3373 | Change From Baseline to Week 12 in DAS28 (Erythrocyte Sedimentation Rate [ESR]) | -2.76 score on a scale | Standard Error 0.254 |
p-value: 0.61290% CI: [-0.92, 0.49]Mixed Effect Model Repeated Measurement
Secondary
Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28 (CRP) at Week 12
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 (measured on a VAS from 0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 (CRP) range from 0.96 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.
Time frame: Week 12
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adalimumab | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28 (CRP) at Week 12 | 58.8 percentage of participants |
| ABBV-3373 | Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28 (CRP) at Week 12 | 54.8 percentage of participants |
p-value: 0.87790% CI: [-28.5, 20.5]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response 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).
Time frame: Baseline and Week 12
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adalimumab | Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 | 64.7 percentage of participants |
| ABBV-3373 | Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 | 51.6 percentage of participants |
p-value: 0.42690% CI: [-37.2, 11]Cochran-Mantel-Haenszel