A Study of Mavrilimumab in Subjects With Moderate-to-Severe Rheumatoid Arthritis

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.

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.

Vital sign assessments included blood pressure, pulse rate, temperature, weight and respiration rate. Vital signs abnormalities reported as TEAEs were reported.

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%.

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.

Oxygen saturation measured by pulse oximetry which measures the concentration of oxygen in the blood.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Immunogenicity assessment included determination of anti-drug (mavrilimumab) antibodies in serum samples. ADA detection measured by using electrochemiluminescence assays.