Rheumatoid Arthritis
Conditions
Keywords
anti-inflammatory agents, Joint Diseases, Arthritis, Musculoskeletal Disease, antirheumatic agents
Brief summary
The primary objective is to compare the safety and efficacy of multiple doses of ABT-494 versus placebo in moderately to severely active RA subjects on stable background MTX therapy with inadequate response or intolerance to anti-TNF biologic therapy.
Interventions
DRUGABT-494
ABT-494 capsule administered orally twice daily (BID).
DRUGPlacebo
Placebo for ABT-494 capsule administered orally twice daily (BID).
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with rheumatoid arthritis (RA) based on either the 1987-revised American College of Rheumatology (ACR) classification criteria or the 2010 American College of Rheumatology/European League against Rheumatism (ACR/EULAR) criteria for ≥ 3 months. * Subjects must have been receiving oral or parenteral methotrexate (MTX) therapy ≥ 3 months and on a stable prescription of 7.5 to 25 mg/week for at least 4 weeks prior to initiating the study drug. Subjects should also be on a stable dose of folic acid (or equivalent) for at least 4 weeks prior to initiating the study drug. Subjects should continue with their stable doses of MTX and folic acid throughout the study * Subjects have been treated with 1 or more anti-tumor necrosis factor (TNF) biologics (no maximum cap) for ≥ 3 months but continue to exhibit active RA, or had to discontinue due to intolerability or toxicity. In addition, subjects with prior exposure to non-anti-TNF biologic(s) (no maximum cap) (e.g., abatacept, rituximab, anakinra, or tocilizumab) are allowed. * Have active RA as defined by the following minimum disease activity criteria: ≥ 6 swollen joints (based on 66 joint counts) at Screening and Baseline, ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline, high sensitivity C reactive protein (hs-CRP) \> Upper Limit of Normal (ULN) OR positive for both rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibody.
Exclusion criteria
* Prior exposure to Janus Activated Kinase (JAK) inhibitor (e.g. tofacitinib, baricitinib) * Pregnant or breastfeeding female * Ongoing or active infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | Baseline (Week 0) and Week 12 | Response defined as at least 20% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, patient's global assessment of disease activity (PtGA); physician's global assessment of disease activity (PGA), Health Assessment Questionnaire - Disability Index (HAQ-DI), and high-sensitivity C-reactive protein (hs CRP). Last observation carried forward (LOCF) was used for missing data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | Baseline (Week 0) and Week 12 | Response defined as at least 50% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, PtGA; PGA, HAQ-DI, and hs CRP. LOCF was used. |
| Number of Subjects Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | Baseline (Week 0) and Week 12 | Response defined as at least 70% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, PtGA; PGA, HAQ-DI, and hs CRP. LOCF was used. |
| Number of Subjects Achieving Low Disease Activity (LDA) Based on Disease Activity Score (DAS28) or Clinical Remission (CR) Based on (DAS28) at Week 12 | Baseline (Week 0) and Week 12 | LDA is defined as DAS28 from 2.6 to \< 3.2 at Week 12. CR is defined as DAS28 (CRP) \< 2.6 at Week 12. The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, hs CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score \>5.1 indicates high disease activity, a DAS28 score \<3.2 indicates low disease activity, and a DAS28 score \<2.6 indicates clinical remission. LOCF was used. |
| Number of Subjects Achieving CR Based on DAS28 at Week 12 | Baseline (Week 0) and Week 12 | The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, hs CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score \>5.1 indicates high disease activity, a DAS28 score \<3.2 indicates low disease activity, and a DAS28 score \<2.6 indicates clinical remission. LOCF was used. |
Participant flow
Pre-assignment details
The study included a screening period of 30 days.
Participants by arm
| Arm | Count |
|---|---|
| Placebo BID Placebo twice daily (BID) for 12 weeks. | 56 |
| ABT-494 3 mg BID ABT-494 3 mg twice daily (BID) for 12 weeks. | 55 |
| ABT-494 6 mg BID ABT-494 6 mg twice daily (BID) for 12 weeks. | 55 |
| ABT-494 12 mg BID ABT-494 12 mg twice daily (BID) for 12 weeks. | 55 |
| ABT-494 18 mg BID ABT-494 18 mg twice daily (BID) for 12 weeks. | 55 |
| Total | 276 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 6 | 2 | 2 |
| Overall Study | Consent withdrawn by subject | 3 | 1 | 2 | 1 | 1 |
| Overall Study | Lack of Efficacy | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 | 0 | 2 |
| Overall Study | Other | 2 | 1 | 1 | 1 | 0 |
| Overall Study | Subject noncompliant | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo BID | ABT-494 3 mg BID | ABT-494 6 mg BID | ABT-494 12 mg BID | ABT-494 18 mg BID | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 12.04 | 57 years STANDARD_DEVIATION 13.06 | 56.3 years STANDARD_DEVIATION 11.71 | 59.1 years STANDARD_DEVIATION 11.4 | 56.7 years STANDARD_DEVIATION 12.39 | 57.3 years STANDARD_DEVIATION 12.12 |
| Sex: Female, Male Female | 48 Participants | 43 Participants | 43 Participants | 45 Participants | 42 Participants | 221 Participants |
| Sex: Female, Male Male | 8 Participants | 12 Participants | 12 Participants | 10 Participants | 13 Participants | 55 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 55 | 0 / 55 | 0 / 55 | 0 / 55 |
| other Total, other adverse events | 9 / 56 | 13 / 55 | 9 / 55 | 14 / 55 | 27 / 55 |
| serious Total, serious adverse events | 1 / 56 | 2 / 55 | 2 / 55 | 0 / 55 | 1 / 55 |
Outcome results
Primary
Number of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12
Response defined as at least 20% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, patient's global assessment of disease activity (PtGA); physician's global assessment of disease activity (PGA), Health Assessment Questionnaire - Disability Index (HAQ-DI), and high-sensitivity C-reactive protein (hs CRP). Last observation carried forward (LOCF) was used for missing data.
Time frame: Baseline (Week 0) and Week 12
Population: Subjects in the modified intent-to-treat (mITT) population with a baseline value and at least 1 post-baseline value
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo BID | Number of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 19 Participants |
| ABT-494 3 mg BID | Number of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 30 Participants |
| ABT-494 6 mg BID | Number of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 33 Participants |
| ABT-494 12 mg BID | Number of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 40 Participants |
| ABT-494 18 mg BID | Number of Subjects Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 39 Participants |
p-value: =0.033Chi-squared
p-value: =0.004Chi-squared
p-value: <0.001Chi-squared
p-value: <0.001Chi-squared
Secondary
Number of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 12
Response defined as at least 50% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, PtGA; PGA, HAQ-DI, and hs CRP. LOCF was used.
Time frame: Baseline (Week 0) and Week 12
Population: Subjects in the mITT population with a baseline value and at least 1 post-baseline value.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo BID | Number of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 9 Participants |
| ABT-494 3 mg BID | Number of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 13 Participants |
| ABT-494 6 mg BID | Number of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 20 Participants |
| ABT-494 12 mg BID | Number of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 24 Participants |
| ABT-494 18 mg BID | Number of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 22 Participants |
p-value: =0.364Chi-squared
p-value: =0.014Chi-squared
p-value: =0.003Chi-squared
p-value: =0.008Chi-squared
Secondary
Number of Subjects Achieving American College of Rheumatology 70% (ACR70) Response at Week 12
Response defined as at least 70% reduction (improvement) compared with baseline in tender joint count (TJC68), swollen joint count (SJC66), and at least 3 of the 5 remaining ACR core set measures: patient's assessment of pain, PtGA; PGA, HAQ-DI, and hs CRP. LOCF was used.
Time frame: Baseline (Week 0) and Week 12
Population: Subjects in the mITT population with a baseline value and at least 1 post-baseline value.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo BID | Number of Subjects Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 2 Participants |
| ABT-494 3 mg BID | Number of Subjects Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 7 Participants |
| ABT-494 6 mg BID | Number of Subjects Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 14 Participants |
| ABT-494 12 mg BID | Number of Subjects Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 12 Participants |
| ABT-494 18 mg BID | Number of Subjects Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 12 Participants |
p-value: =0.093Chi-squared
p-value: <0.001Chi-squared
p-value: =0.004Chi-squared
p-value: =0.004Chi-squared
Secondary
Number of Subjects Achieving CR Based on DAS28 at Week 12
The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, hs CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score \>5.1 indicates high disease activity, a DAS28 score \<3.2 indicates low disease activity, and a DAS28 score \<2.6 indicates clinical remission. LOCF was used.
Time frame: Baseline (Week 0) and Week 12
Population: Subjects in the mITT population with a baseline value and at least 1 post-baseline value.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo BID | Number of Subjects Achieving CR Based on DAS28 at Week 12 | 7 Participants |
| ABT-494 3 mg BID | Number of Subjects Achieving CR Based on DAS28 at Week 12 | 13 Participants |
| ABT-494 6 mg BID | Number of Subjects Achieving CR Based on DAS28 at Week 12 | 14 Participants |
| ABT-494 12 mg BID | Number of Subjects Achieving CR Based on DAS28 at Week 12 | 18 Participants |
| ABT-494 18 mg BID | Number of Subjects Achieving CR Based on DAS28 at Week 12 | 17 Participants |
p-value: =0.126Chi-squared
p-value: =0.072Chi-squared
p-value: =0.012Chi-squared
p-value: =0.021Chi-squared
Secondary
Number of Subjects Achieving Low Disease Activity (LDA) Based on Disease Activity Score (DAS28) or Clinical Remission (CR) Based on (DAS28) at Week 12
LDA is defined as DAS28 from 2.6 to \< 3.2 at Week 12. CR is defined as DAS28 (CRP) \< 2.6 at Week 12. The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, hs CRP, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score \>5.1 indicates high disease activity, a DAS28 score \<3.2 indicates low disease activity, and a DAS28 score \<2.6 indicates clinical remission. LOCF was used.
Time frame: Baseline (Week 0) and Week 12
Population: Subjects in the mITT population with a baseline value and at least 1 post-baseline value.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo BID | Number of Subjects Achieving Low Disease Activity (LDA) Based on Disease Activity Score (DAS28) or Clinical Remission (CR) Based on (DAS28) at Week 12 | 14 Participants |
| ABT-494 3 mg BID | Number of Subjects Achieving Low Disease Activity (LDA) Based on Disease Activity Score (DAS28) or Clinical Remission (CR) Based on (DAS28) at Week 12 | 18 Participants |
| ABT-494 6 mg BID | Number of Subjects Achieving Low Disease Activity (LDA) Based on Disease Activity Score (DAS28) or Clinical Remission (CR) Based on (DAS28) at Week 12 | 20 Participants |
| ABT-494 12 mg BID | Number of Subjects Achieving Low Disease Activity (LDA) Based on Disease Activity Score (DAS28) or Clinical Remission (CR) Based on (DAS28) at Week 12 | 29 Participants |
| ABT-494 18 mg BID | Number of Subjects Achieving Low Disease Activity (LDA) Based on Disease Activity Score (DAS28) or Clinical Remission (CR) Based on (DAS28) at Week 12 | 25 Participants |
p-value: =0.366Chi-squared
p-value: =0.17Chi-squared
p-value: =0.003Chi-squared
p-value: =0.028Chi-squared