Arthritis, Rheumatoid
Conditions
Brief summary
This is a study to compare the effect of infliximab versus placebo on synovial inflammation as measured by dynamic contrast enhanced (DCE)-MRI of one wrist. The primary hypothesis is that over 14 weeks of therapy, the change from baseline in the volume transfer rate in enhancing synovium is larger due to treatment with infliximab than with placebo.
Interventions
DRUGInfliximab
3 mg/kg of Infliximab at Weeks 0, 2, 6, 14 via intravenous infusion
DRUGPlacebo
250 mL of 0.9% sodium chloride at Weeks 0, 2, 6, 14 via intravenous infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must have a clinical diagnosis of rheumatoid arthritis for at least 6 months * Must have at least 6 tender joints AND 6 swollen joints * Has a C-reactive protein ≥ 1.0 mg/L OR Erythrocyte Sedimentation Rate (ESR) ≥ 28 mm/hr * Baseline MRI must show evidence of synovitis in the wrist * Must have screening laboratory tests within acceptable levels * Women of childbearing potential and all men must agree to use a medically accepted method of contraception prior to entering the study and continue throughout study up to 6 weeks after study completion * Must meet tuberculosis (TB) screening criteria * Have received methotrexate therapy for ≥ 3 months; dose must be stable for at least 8 weeks * If taking the a disease modifying anti-rheumatic drug (DMARD) in combination with methotrexate must be on a stable dose * Must have a clinically acceptable 12 lead electrocardiogram (ECG) * If taking oral corticosteroids must be on a stable dose equivalent to ≤10 mg of prednisone (or prednisolone) per day for ≥2 weeks * If taking daily non-steroidal anti-inflammatory drug (NSAID) must be on a stable dose for ≥2 weeks; if taking NSAID on an as-needed basis must agree to discontinue use for at least 3 days and use only acetaminophen for breakthrough pain for 3 days before each MRI and clinic visit * If received biological therapies, the last dose of these drugs was to be received ≥ 3 months prior to the baseline visit AND the reason for discontinuations was not for safety considerations OR lack of efficacy
Exclusion criteria
* Are pregnant, intend to become pregnant, or are breastfeeding * Has inflammatory arthritis other than RA * Has uncontrolled hypertension * Has moderate or severe congestive heart failure * Has a history of or current signs and/or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, cerebral, or psychiatric disease * Has a history of demyelinating disease or symptoms suggestive of multiple sclerosis or optic neuritis * Is currently participating in another clinical study or have participated in a clinical study (e.g., laboratory or clinical evaluation) within 4 weeks * Has history of any tumor with the exception of adequately treated basal cell carcinoma or carcinoma in situ of the cervix * Has a history of any latent or active granulomatous infection including histoplasmosis, or coccidiomycosis * Had a non-tuberculous mycobacterial infection or opportunistic infection (e.g. cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months * Has a history of an infected joint prosthesis which has not been removed or replaced * Has a known hypersensitivity to human immunoglobulin proteins or other components of infliximab * Has received rituximab or natalizumab * Has known claustrophobia or other contraindication to MRI * Does not meet washout period guidelines for previous treatments/injections/vaccinations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Volume Transfer Rate From the Blood Plasma to the Enhancing Synovium (Ktrans) | Baseline and week 14 | Dynamic Contrast Enhanced (DCE) Magnetic Resonance Imaging (MRI) was performed on one hand at baseline, and then at treatment week 14 to measure the rate constant of transfer of contrast (Ktrans). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders With a 50% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR50). | Baseline and week 14 | ACR50 requires that both tender and swollen joint counts improve by at least 50% from baseline, as well as a 50% improvement in at least 3 other core measures from the following: pain, patient's and physician's global assessment, physical disability and CRP. |
| Percentage of Responders With a 20% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR20). | Baseline and week 14 | ACR20 requires that both tender and swollen joint counts improve by at least 20% from baseline, as well as a 20% improvement in at least 3 other core measures from the following: pain, patient's and physician's global assessment, physical disability and C-reactive protein (CRP). |
| Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Ktrans. | Baseline and Week 14 | Clinical disease activity score (DAS28 CRP) is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), Patient Global Assessment of Disease Status (GADP) on a 100 mm visual analog scale (VAS) and concentration of CRP. Ktrans is the volume transfer rate from the blood plasma to the enhancing synovium. The individual endpoints are standardized using z-scores, then the z-scores are averaged to create a composite endpoint by use of O'Brien's global statistic. |
| Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Rheumatoid Arthritis MRI Score (RAMRIS) Synovitis + RAMRIS Osteitis. | Baseline and Week 14 | DAS28 CRP is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), GADP on a 100 mm VAS and concentration of CRP. RAMRIS Synovitis is an ordinal scoring system of hand synovitis that is scored from 0 to 3 in 8 locations, ranging from 0 to 24 total. RAMRIS Osteitis is an ordinal scoring system of hand osteitis that is scored from 0 to 3 in 25 locations, ranging from 0 to 75 total. The individual endpoints are standardized using z-scores, then the z-scores are averaged to create a composite endpoint by use of O'Brien's global statistic. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in RAMRIS Osteitis. | Baseline and Week 14 | RAMRIS Osteitis is an ordinal scoring system of hand osteitis that is scored from 0 to 3 in 25 locations. The scores can range from 0 to 75, with higher values corresponding to higher disease activity, and lower values to better outcomes. |
| Change From Baseline in RAMRIS Synovitis. | Baseline and Week 14 | RAMRIS Synovitis is an ordinal scoring system of hand synovitis that is scored from 0 to 3 in 8 locations. The scores can range from 0 to 24, with higher values corresponding to higher disease activity, and lower values to better outcomes. |
| Change From Baseline in DAS28 CRP. | Baseline and Week 14 | DAS28 CRP is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), GADP on a 100 mm VAS and concentration of serum CRP. Scores can range from 2-10; with higher values corresponding to higher disease activity, and lower values to better outcomes. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Infliximab 3 mg/kg of Infliximab intravenous infusion | 30 |
| Placebo saline via intravenous infusion | 31 |
| Total | 61 |
Baseline characteristics
| Characteristic | Infliximab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50.3 years STANDARD_DEVIATION 9.5 | 50.1 years STANDARD_DEVIATION 10.7 | 50.2 years STANDARD_DEVIATION 10.04 |
| Sex: Female, Male Female | 28 Participants | 28 Participants | 56 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 30 | 8 / 31 |
| serious Total, serious adverse events | 0 / 30 | 0 / 31 |
Outcome results
Primary
Change From Baseline in the Volume Transfer Rate From the Blood Plasma to the Enhancing Synovium (Ktrans)
Dynamic Contrast Enhanced (DCE) Magnetic Resonance Imaging (MRI) was performed on one hand at baseline, and then at treatment week 14 to measure the rate constant of transfer of contrast (Ktrans).
Time frame: Baseline and week 14
Population: Participants treated with infliximab or placebo
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Infliximab | Change From Baseline in the Volume Transfer Rate From the Blood Plasma to the Enhancing Synovium (Ktrans) | -0.2 min ^-1 |
| Placebo | Change From Baseline in the Volume Transfer Rate From the Blood Plasma to the Enhancing Synovium (Ktrans) | 0.1 min ^-1 |
p-value: <0.00195% CI: [-0.4, -0.1]Constrained Longitudinal Data Analysis
Secondary
Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Ktrans.
Clinical disease activity score (DAS28 CRP) is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), Patient Global Assessment of Disease Status (GADP) on a 100 mm visual analog scale (VAS) and concentration of CRP. Ktrans is the volume transfer rate from the blood plasma to the enhancing synovium. The individual endpoints are standardized using z-scores, then the z-scores are averaged to create a composite endpoint by use of O'Brien's global statistic.
Time frame: Baseline and Week 14
Population: Participants treated with Infliximab or placebo
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Ktrans. | -0.8 Z-score | 95% Confidence Interval 0.3 |
| Placebo | Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Ktrans. | 0.8 Z-score | 95% Confidence Interval 0.2 |
90% CI: [0.92, 1.87]
Secondary
Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Rheumatoid Arthritis MRI Score (RAMRIS) Synovitis + RAMRIS Osteitis.
DAS28 CRP is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), GADP on a 100 mm VAS and concentration of CRP. RAMRIS Synovitis is an ordinal scoring system of hand synovitis that is scored from 0 to 3 in 8 locations, ranging from 0 to 24 total. RAMRIS Osteitis is an ordinal scoring system of hand osteitis that is scored from 0 to 3 in 25 locations, ranging from 0 to 75 total. The individual endpoints are standardized using z-scores, then the z-scores are averaged to create a composite endpoint by use of O'Brien's global statistic.
Time frame: Baseline and Week 14
Population: Participants treated with Infliximab or placebo
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Rheumatoid Arthritis MRI Score (RAMRIS) Synovitis + RAMRIS Osteitis. | -0.7 Z-score | 95% Confidence Interval 0.3 |
| Placebo | Change From Baseline in Standardized Z-scores of Composite Endpoint Consisting of Clinical Disease Activity Measure DAS28 CRP + Rheumatoid Arthritis MRI Score (RAMRIS) Synovitis + RAMRIS Osteitis. | 0.8 Z-score | 95% Confidence Interval 0.2 |
90% CI: [0.64, 1.55]
Secondary
Percentage of Responders With a 20% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR20).
ACR20 requires that both tender and swollen joint counts improve by at least 20% from baseline, as well as a 20% improvement in at least 3 other core measures from the following: pain, patient's and physician's global assessment, physical disability and C-reactive protein (CRP).
Time frame: Baseline and week 14
Population: Participants treated with Infliximab or Placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab | Percentage of Responders With a 20% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR20). | 56.7 percentage of responders |
| Placebo | Percentage of Responders With a 20% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR20). | 32.3 percentage of responders |
p-value: 0.048Fisher Exact
Secondary
Percentage of Responders With a 50% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR50).
ACR50 requires that both tender and swollen joint counts improve by at least 50% from baseline, as well as a 50% improvement in at least 3 other core measures from the following: pain, patient's and physician's global assessment, physical disability and CRP.
Time frame: Baseline and week 14
Population: Participants treated with Infliximab or placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab | Percentage of Responders With a 50% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR50). | 20.0 percentage of responders |
| Placebo | Percentage of Responders With a 50% Improvement From Baseline in American College of Rheumatology (ACR) Responder Criteria for Tender and Swollen Joints (ACR50). | 0 percentage of responders |
p-value: 0.011Fisher Exact
Other Pre-specified
Change From Baseline in DAS28 CRP.
DAS28 CRP is a composite index of the following: number of tender joints (28 joint count), number of swollen joints (28 joint count), GADP on a 100 mm VAS and concentration of serum CRP. Scores can range from 2-10; with higher values corresponding to higher disease activity, and lower values to better outcomes.
Time frame: Baseline and Week 14
Population: Participants treated with infliximab or placebo
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change From Baseline in DAS28 CRP. | -1.8 units on a scale | 95% Confidence Interval 0.18 |
| Placebo | Change From Baseline in DAS28 CRP. | -0.8 units on a scale | 95% Confidence Interval 0.18 |
p-value: <0.0001Constrained longitudinal data analysis
Other Pre-specified
Change From Baseline in RAMRIS Osteitis.
RAMRIS Osteitis is an ordinal scoring system of hand osteitis that is scored from 0 to 3 in 25 locations. The scores can range from 0 to 75, with higher values corresponding to higher disease activity, and lower values to better outcomes.
Time frame: Baseline and Week 14
Population: Participants treated with infliximab or placebo. One participant in the placebo group missing a baseline value was not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change From Baseline in RAMRIS Osteitis. | -3.10 units on a scale | Standard Deviation 5.04 |
| Placebo | Change From Baseline in RAMRIS Osteitis. | 0.48 units on a scale | Standard Deviation 3.22 |
p-value: 0.0005van Elteren test
Other Pre-specified
Change From Baseline in RAMRIS Synovitis.
RAMRIS Synovitis is an ordinal scoring system of hand synovitis that is scored from 0 to 3 in 8 locations. The scores can range from 0 to 24, with higher values corresponding to higher disease activity, and lower values to better outcomes.
Time frame: Baseline and Week 14
Population: Participants treated with infliximab or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change From Baseline in RAMRIS Synovitis. | -2.30 units on a scale | Standard Deviation 4.25 |
| Placebo | Change From Baseline in RAMRIS Synovitis. | 0.24 units on a scale | Standard Deviation 1.98 |
p-value: 0.001van Elteren test