A Study to Evaluate the Efficacy and Safety of Reslizumab in Patients With Eosinophilic Asthma

FEV1 is a standard measurement of air movement in the lungs of patients with asthma obtained from pulmonary function tests. It is the volume of air expired in the first second of a forced expiration using a spirometer.

Positive change from baseline scores indicate improvement in asthma control.

FEV1 is a standard measurement of air movement in the lungs of patients with asthma obtained from pulmonary function tests. It is the volume of air expired in the first second of a forced expiration using a spirometer. During study (Weeks 4, 8, 12 and 16) average value used a mixed effect model for repeated measures (MMRM) with treatment group, visit, treatment and visit interaction, and stratification factors as fixed effects and participant as a random effect. Covariates for baseline values were also included in the model; for pulmonary function test analyses, covariates for height and sex were included as well.

Positive change from baseline scores indicate improvement in asthma control.

The AQLQ is a 32-item instrument administered as a self-assessment (Juniper et al 1992). The questionnaire is divided into 4 domains: activity limitation, symptoms, emotional function, and environmental stimuli. Patients were asked to recall their experiences during the last 2 weeks and to respond to each question on a 7-point scale (1=severe impairment, 7=no impairment). The overall AQLQ score is the mean of all 32 responses. Five of the activity questions were "patient-specific," which means that each patient identified and scored 5 activities in which the patient was limited by asthma; these 5 activities were identified at the first visit and retained for all subsequent follow-up visits.

Positive change from baseline scores indicate improvement in quality of life.

The ACQ is a 7-item instrument that measures asthma control (Juniper et al 1999). Six questions are self-assessments; the seventh item, completed by a member of the study staff, is the result of the patient's FEV1 measurement. Each item has 7 possible answers on a scale of 0 to 6, and the total score is the mean of all responses (the total scale is therefore 0-6). A higher score is an indication of poorer asthma control. The during treatment (Weeks 4, 8, 12 and 16) average ACQ was estimated using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.

Negative change from baseline scores indicate improvement in asthma control.

An exacerbation event was considered a CAE if the patient met either or both of the criteria listed below and this was corroborated with at least 1 other measurement to indicate the worsening of clinical signs and symptoms of asthma:

• use of systemic, or an increase in the use of inhaled, corticosteroid treatment for 3 or more days; or an increased 2 or more fold for at least 3 or more days for patient's already on corticosteroids.
• asthma-related emergency treatment, such as an unscheduled visit to the physician's office or emergency room for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms, or an asthma-related hospitalization.

CAEs were adjudicated by committee to assure consistency. The distributions were compared by a log rank test stratified by baseline usage of oral corticosteroid (yes or no) and geographical region (US or other).

The ASUI is an 11-item instrument designed to assess the frequency and severity of asthma symptoms and side effects, weighted by patient preferences (Revicki et al 1998). ASUI is a utility score that ranges from 0 to 1, with higher values indicating better asthma control; info obtained from questionnaire about asthma symptoms.

The during treatment (Weeks 4, 8, 12 and 16) average ASUI was estimated using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.

Positive change from baseline values indicate improvement in asthma symptoms. Information was obtained from questionnaire about asthma symptoms.

SABA are used for quick relief of asthma symptoms. To measure SABA use, at each clinical visit patients were asked to recall their usage of SABA therapy within the last 3 days of the scheduled visit. If usage was confirmed, the number of puffs used was recorded. For the purpose of summaries, an average daily usage was evaluated by dividing the total number of puffs recorded over 3 days by 3.

The during treatment (Weeks 4, 8, 12 and 16) average SABA use was estimated using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.

Negative change from baseline scores indicate improvement in asthma control.

The blood eosinophil counts were measured using a standard complete blood count (CBC) with differential blood test. Results of all differential blood tests conducted after randomization were blinded.

The during treatment average eosinophil count was estimated using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements. The 'over 16 weeks' value used data from Weeks 4, 8, 12 and 16. The 'over 52 weeks' value used all the during study time points listed in the Time Frame field.

Negative change from baseline values correlate to reduced asthma severity.

An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Data represents participants with potentially clinically significant (PCS) abnormal serum chemistry, hematology (except for eosinophil values), and urinalysis values.

Significance criteria:

• Blood urea nitrogen: >=10.71 mmol/L
• Creatinine: >=177 μmol/L
• Urate: M>=625, F>=506 μmol/L
• Aspartate aminotransferase (AST): >=3*upper limit of normal (ULN)
• Alanine aminotransferase (ALT): >=3*ULN
• GGT = gamma-glutamyl transpeptidase: >= 3*ULN
• Total bilirubin: >=34.2 μmol/L
• White blood cells (low): <=3.0*10^9/L
• White blood cells (high): >=20*10^9/L
• Hemoglobin (age >=18 years): M<=115, F<=95 g/dL
• Hematocrit (age >=18 years): M<0.37, F<0.32 L/L
• Eosinophils/leukocytes: >=10.0%
• Platelets: <=75*10^9/L
• Neutrophils: <=1.0*10^9/L
• Urinalysis: blood, ketones, glucose, and protein: >=2 unit increase from baseline

Data represents participants with potentially clinically significant (PCS) vital sign values.

Significance criteria

• Sitting pulse (high): >100 and increase of >= 30 beats/minute
• Sitting systolic blood pressure (low): <90 and decrease of >= 30 mmHg
• Sitting systolic blood pressure (high): >160 and increase of >= 30 mmHg
• Sitting diastolic blood pressure (low): <50 and decrease of >=12 mmHg (if 12-17 years old: <55 and decrease of >=12 mmHg 0
• Sitting diastolic blood pressure (high): >100 and increase of >=12 mmHg
• Respiratory rate (low): <6 breaths/minute
• Respiratory rate (high): >24 and increase of >=10 breaths/minute
• Body temperature (low): <35.8° Celsius
• Body temperature (high): >=38.1 and increase of >=1.1° Celsius

Counts of participants with a positive anti-drug antibody (ADA) response during treatment is offered for the experimental treatment arm. Blood samples were collected for determination of ADAs before study drug infusion.