The primary objective of this study is to evaluate the efficacy of 3 subcutaneous doses of mavrilimumab compared with placebo in combination with methotrexate (MTX) in subjects with moderate-to-severe adult onset Rheumatoid Arthritis (RA).
Despite the therapeutic improvements with recent biologic agents approved for rheumatoid arthritis, there is still significant unmet medical need for the treatment of subjects with this chronic disease to achieve a faster, more complete response, and higher rates of remission. The aim of the study is to explore the optimum dose of mavrilimumab for further clinical development and more fully investigate the efficacy and safety profile of mavrilimumab after longer drug exposure (that is, 24 weeks). The results of this study will form the basis for future clinical studies with mavrilimumab.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
420
Mavrilimumab (CAM-3001) 30 mg injection subcutaneously every 2 weeks for 24 weeks
Mavrilimumab (CAM-3001) 100 mg injection subcutaneously every 2 weeks for 24 weeks.
Mavrilimumab (CAM-3001) 150 mg injection subcutaneously every 2 weeks for 24 weeks.
Change From Baseline in Disease Activity Score of 28 Joints Using C-Reactive Protein (DAS28 [CRP]) Score at Day 85
DAS28 (CRP) calculated swollen joint count (SJC) and tender joint count (TJC) using the 28 joints, general health (GH) using participant assessment of disease activity (participant rated arthritis activity using the numerical rating scale with 0 = best, 10 = worst), and CRP (milligram per liter \[mg/L\]). Total score range: 0-9.4, higher score= more disease activity. DAS28 (CRP) less than (\<) 3.2 = low disease activity, greater than or equal to (\>=) 3.2 to 5.1 = moderate to high disease activity and \<2.6= remission. A Day 85 responder was defined as a participant who experienced more than 1.2 decrease from baseline in DAS28 (CRP) score at Day 85.
Time frame: Baseline and Day 85
Percentage of Participants Who Achieved American College of Rheumatology 20 (ACR20) Responses at Day 169
ACR20 was defined as \>=20 percent (%) improvement, in: SJC and TJC and \>=20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and CRP.
Time frame: Day 169
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and Day 169 that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Baseline up to Day 169
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Placebo matched to mavrilimumab (CAM-3001) injection subcutaneously every 2 weeks for 24 weeks.
Research Site
Ciudad Autonoma de Buenos Aire, Argentina
Research Site
Rosario, Argentina
Research Site
San Miguel de Tucumán, Argentina
Research Site
Plovdiv, Bulgaria
Research Site
Sofia, Bulgaria
Research Site
Santiago, Chile
Research Site
Viña del Mar, Chile
Research Site
Barranquilla, Colombia
Research Site
Bogotá, Colombia
Research Site
Bruntál, Czechia
...and 32 more locations
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Treatment-Emergent Adverse Events (TEAEs)
Any medically significant change in laboratory evaluations were recorded as adverse events. Following parameters were analyzed for laboratory examination: hematology (haemoglobin, absolute neutrophil count, leukocyte count, platelet count), serum chemistry (alanine transaminase, aspartate transaminase, bilirubin, gamma-glutamyl transferase), other serum chemistry (low-density lipoprotein cholesterol, triglycerides), and urinalysis.
Time frame: Baseline up to Day 169
Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs)
Vital sign assessments included blood pressure, pulse rate, temperature, weight and respiration rate. Vital signs abnormalities reported as TEAEs were reported.
Time frame: Baseline up to Day 169
Percentage of Pulmonary Function Test Values Below Threshold Values at Day 169
Pulmonary function testing were performed by spirometry to assess forced expiratory volume in 1 second (FEV1), forced expiratory volume in 6 second (FEV6), and forced vital capacity (FVC). FEV1 was the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. FEV6 was the maximal volume of air exhaled in the six second of a forced expiration from a position of full inspiration. FVC was the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. The percentage of predicted values of these pulmonary function tests were calculated based on decreases from baseline and categorized as less than or equal to (=\<) 15 percent (%), more than (\>) 15 to =\<20%, and \>20%.
Time frame: Day 169
Dyspnea Score at Day 169
Borg dyspnea scale is a validated participant reported outcome assessing participant's perceived difficulty in breathing (dyspnea). The scale ranges from 0 (nothing at all) to 10 (maximal difficulty). Higher scores indicate greater difficulty in breathing.
Time frame: Day 169
Oxygen Saturation Level at Day 169
Oxygen saturation measured by pulse oximetry which measures the concentration of oxygen in the blood.
Time frame: Day 169
Percentage of Participants Who Achieved American College of Rheumatology 50 (ACR50) Responses at Day 169
ACR50 was defined as \>=50% improvement, in: SJC and TJC and \>=50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP.
Time frame: Day 169
Percentage of Participants Who Achieved American College of Rheumatology 70 (ACR70) Responses at Day 169
ACR70 was defined as \>=70% improvement, in: SJC and TJC and \>=70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP.
Time frame: Day 169
Change From Baseline in Continuous American College of Rheumatology (ACRn) Score at Day 169
ACR score - continuous (ACRn) was defined as the minimum of the percentage improvement in TJC, SJC and the median of the percentage improvements in the other five components of the ACR criteria (participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; disability index of the HAQ; and CRP). Total score range was -100 to 100, where negative numbers indicated worsening and positive numbers indicated improvement.
Time frame: Baseline up to Day 169
Percentage of Participants Who Achieved DAS28 (CRP) Response by European League Against Rheumatism (EULAR) Category at Day 169
DAS28 (CRP) response by EULAR category were used to measure individual response as none, moderate, and good, depending on the extent of change from baseline and the level of disease activity reached. Good response: change from baseline \>1.2 with baseline DAS28 (CRP) \<3.2; moderate response: change from baseline \>1.2 with baseline DAS28 (CRP) \>=3.2 to less than or equal to (=\<) 5.1 or change from baseline \>=0.6 to =\< 1.2 with baseline DAS28 (CRP) \>=3.2 to =\<5.1; no response: change from baseline \<0.6 or change from baseline \>=0.6 and =\<1.2 with baseline DAS28 (CRP) \>5.1.
Time frame: Day 169
Percentage of Participants With DAS28 (CRP) Remission and Low Disease Activity at Day 169
DAS28 (CRP) calculated SJC and TJC using the 28 joints, GH using participant assessment of disease activity (participant rated arthritis activity using the numerical rating scale with 0 = best, 10 = worst), and CRP (mg/L). Total score range: 0-9.4, higher score= more disease activity. Remission was defined as less than 2.6 DAS28 (CRP) score. Low disease activity was defined as less than 3.2 DAS28 (CRP) score.
Time frame: Day 169
Mean Change From Baseline in Swollen and Tender Joint Count at Day 169
Number of swollen joints was determined by examination of 66 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form, no swelling = 0, swelling =1. Number of tender joints was determined by examining 68 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form, no tenderness = 0, tenderness = 1.
Time frame: Baseline and Day 169
Mean Change From Baseline in Patient Assessment of Pain at Day 169
Participants rated the severity of arthritis pain on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS), where 0 mm = no pain and 100 mm = most severe pain.
Time frame: Baseline and Day 169
Mean Change From Baseline in Patient Global Assessment (PGA) of Disease Activity at Day 169
Participants responded to a question, "Considering all the ways your arthritis affects you, how are you feeling today?" by using a 0 - 100 millimeter (mm) VAS, where 0 = very well and 100 = very poorly.
Time frame: Baseline and Day 169
Mean Change From Baseline in Physician Global Assessment of Disease Activity (MDGA) at Day 169
Physician Global Assessment of Arthritis was measured by asking the physician to assess the participant's current arthritis disease activity by placing a vertical line on a 0 to 10 centimeter (cm) VAS, where 0 cm = very good and 10 cm = very bad.
Time frame: Baseline and Day 169
Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Day 169
HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item was scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range from 0 to 3; where 0 = least difficulty and 3 = extreme difficulty.
Time frame: Baseline and Day 169
Ratio of Change From Baseline in C-Reactive Protein (CRP) at Day 169
CRP is a substance produced by the liver that increases in the presence of inflammation in the body. The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement in underlying disease.
Time frame: Baseline, Day 169
Ratio of Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 169
ESR is a laboratory test that provides a non-specific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. The farther the red blood cells have descended, the greater the inflammatory response.
Time frame: Baseline, Day 169
Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission at Day 169
The SDAI was the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, patient global assessment and physician global assessment assessed on 0 - 10 cm VAS; and C-reactive protein (CRP) (milligram per deciliter \[mg/dL\]). The SDAI total score ranges from 0 to 86, where higher scores indicates greater affection due to disease activity. SDAI remission was defined as a score less than or equal to 3.3.
Time frame: Day 169
Percentage of Participants With Clinical Disease Activity Index (CDAI) Remission at Day 169
The CDAI was the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, patient global assessment and physician global assessment assessed on 0 - 10 cm VAS. The CDAI total score ranges from 0 to 76 where higher scores indicates greater affection due to disease activity. CDAI remission was defined as a score less than or equal to 2.8.
Time frame: Day 169
Percentage of Participants With American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Remission at Day 169
ACR/EULAR remission was defined as swollen joint count (0-66), tender joint count (0-68), CRP (mg/dL) and participant global assessment (0-10) all less than or equal to one.
Time frame: Day 169
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-fatigue) at Day 169
FACIT-F is a 13-item questionnaire questionnaire to measure the degree of fatigue experiences by participants in the previous 7 days. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). Larger the participant's response to the questions (with the exception of 2 negatively stated), greater was the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score) where higher sore represent less fatigue.
Time frame: Baseline and Day 169
Serum Concentrations of Mavrilimumab
Serum concentrations after multiple subcutaneous doses of mavrilimumab were calculated for each cohort (30mg, 100mg and 150mg). Geometric coefficient of variation at Baseline for cohorts 30mg and 150mg were calculated as the negligible mean value was observed.
Time frame: Baseline, Day 8, 15, 29, 85, 141, and 169
Percentage of Participants Exhibiting Anti-Drug Antibodies (ADAs) to Mavrilimumab at Any Visit
Immunogenicity assessment included determination of anti-drug (mavrilimumab) antibodies in serum samples. ADA detection measured by using electrochemiluminescence assays.
Time frame: Day 1 to Day 169