Study to Evaluate the Efficacy and Safety of Reslizumab Treatment in Patients With Moderate to Severe Asthma

Comparateur placebo: Placebo

Placebo intravenous injection every 4 weeks for a total of 4 doses.

Médicament: Placebo

Matching placebo administered by intravenous (iv) infusion by qualified study personnel every 4 weeks for 16 weeks (for a total of 4 doses).

Expérimental: Reslizumab 3.0 mg/kg

Reslizumab intravenous injection at a dosage of 3.0 mg/kg every 4 weeks for a total of 4 doses.

Médicament: Reslizumab

Reslizumab administered at a dosage of 3.0 mg/kg by intravenous (iv) infusion by qualified study personnel every 4 weeks for 16 weeks (for a total of 4 doses).

Autres noms:

• Cinquil
• anticorps monoclonal humanisé
• CEP-38072

Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 16 in Full Analysis Set

FEV1 is a standard measurement of air movement in the lungs of patients with asthma. It is the volume of air expired in the first second of a forced expiration. Improvement in FEV1 is a measure in the reduction of bronchospasm, the reduction of airway inflammation, or both. FEV1 was measured using forced expiratory air spirometry.

Data represent the slope estimate of change from baseline in FEV1 (measured in liters) at Week 16 versus baseline eosinophil count (measured in 10^9/liter) by treatment group.

Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Over 16 Weeks Using Mixed Model for Repeated Measures

FEV1 is a standard measurement of air movement in the lungs of patients with asthma. It is the volume of air expired in the first second of a forced expiration. Improvement in FEV1 is a measure in the reduction of bronchospasm, the reduction of airway inflammation, or both. FEV1 was measured using forced expiratory air spirometry. Positive change from baseline scores indicate improvement in asthma control.

During study (Weeks 4, 8, 12 and 16) average value was calculated using a mixed effects model for repeated measures (MMRM) with treatment (reslizumab or placebo), blood eosinophil count at baseline, and the interaction of treatment and eosinophil count as a random effect.

Change From Baseline in Asthma Control Questionnaire (ACQ) Over 16 Weeks Using Mixed Model for Repeated Measures

The ACQ score was measured using the ACQ-7. Six questions are-self assessments; the seventh item is the result of the patient's % predicted 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 score of 0 indicates good asthma control; higher scores indicate increasingly poorer asthma control. Negative change from baseline scores indicate improvement in asthma control.

During study (Weeks 4, 8, 12 and 16) average value was calculated from mixed model repeated measures (MMRM) with treatment, visit, treatment by visit interaction, history of asthma exacerbation in the previous year, height, baseline value, and sex as fixed factors, and patient as a random effect.

Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 16 in FEV1 Subpopulation

FEV1 is a standard measurement of air movement in the lungs of patients with asthma. It is the volume of air expired in the first second of a forced expiration. Improvement in FEV1 is a measure in the reduction of bronchospasm, the reduction of airway inflammation, or both. FEV1 was measured using forced expiratory air spirometry.

As with the primary outcome, data represent the slope estimate of change from baseline in FEV1 (measured in liters) at Week 16 versus baseline eosinophil count (measured in 10^9/liter) by treatment group. However the FEV1 subpopulation includes participants with more impaired lung function (% predicted FEV1 <85% at baseline).

Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Weeks 4, 8, 12, and 16

FEV1 is a standard measurement of air movement in the lungs of patients with asthma. It is the volume of air expired in the first second of a forced expiration. Improvement in FEV1 is a measure in the reduction of bronchospasm, the reduction of airway inflammation, or both. FEV1 was measured using forced expiratory air spirometry. Positive change from baseline scores indicate improvement in asthma control.

Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (% Predicted FEV1) at Weeks 4, 8, 12, 16 and Endpoint

The percent predicted FEV1 is the ratio of the volume of air expired in the first second of a forced expiration to the patient's predicted FEV based on a similar population without asthma. Percent predicted lung function values were transcribed directly from the lung function report to the CRF, without any calculation by Teva. Positive change from baseline scores indicate improvement in asthma control.

Change From Baseline in Forced Vital Capacity (FVC) at Weeks 4, 8, 12, and 16

The FVC is the volume of air that can be forcibly blown out after full inspiration, measured in liters. FV was measured using forced expiratory air spirometry. Positive change from baseline scores indicate improvement in asthma control.

Change From Baseline in the Forced Expiratory Flow at 25% to 75% of the Forced Vital Capacity (FEF25%-75%) at Weeks 4, 8, 12, and 16

The FEF25%-75% is the forced expiratory flow at 25% to 75% of the forced vital capacity. FEF25%-75% was measured using forced expiratory air spirometry. Positive change from baseline scores indicate improvement in asthma control.

Change From Baseline in Average Daily Use of Short-Acting Beta-Agonist Therapy (SABA) at Weeks 4, 8, 12, and 16

SABA are used for quick relief of asthma symptoms. The number of times SABA therapy was used was assessed using 3 day recall at scheduled visits. Participants were asked to recall whether SABAs were used within 3 days of the scheduled visit and, if so, how many puffs were used. Daily use was the average of those 3 days. Negative change from baseline scores indicate improvement in asthma control.

Change From Baseline in Blood Eosinophil Counts at Weeks 4, 8, 12, 16, Follow-up (Week 28) and Endpoint

Blood eosinophil counts were measured using a standard complete blood count with differential blood test at each scheduled visit. Follow-up was performed approximately 12 weeks after the 16 week treatment period. Endpoint is the last post-baseline assessment.

Change From Baseline in Asthma Control Questionnaire (ACQ) at Weeks 4, 8, 12 and 16

The ACQ score was measured using the ACQ-7. Six questions are self-assessments; the seventh item is the result of the patient's % predicted 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 score of 0 indicates good asthma control; higher scores indicate increasingly poorer asthma control. Negative change from baseline scores indicate improvement in asthma control.

Participants With Treatment-Emergent Adverse Events

An adverse event 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.

Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Abnormal Lab Values

Data represents participants with potentially clinically significant (PCS) abnormal serum chemistry, hematology, and urinalysis values during any of the lab tests conducted during the treatment period.

Significance criteria:

• Blood urea nitrogen: >=10.71 mmol/L
• Creatinine: >=177 μmol/L
• Uric acid: M>=625, F>=506 μmol/L
• Aspartate aminotransferase: >=3*upper limit of normal (ULN). Normal range is 10-43 U/L
• Alanine aminotransferase: >=3*ULN. Normal range is 10-40 U/L
• GGT = gamma-glutamyl transpeptidase: >= 3*ULN. Normal range is 4-49 U/L.
• Total bilirubin: >=34.2 μmol/L
• Creatinine phosphokinase: >5*ULN. Normal range is 24-207 U/L.
• White blood cells: <=3.0 or >20 10^9/L
• Hemoglobin: M<=115, F<=95 g/dL
• Hematocrit: M<0.37, F<0.32 L/L
• Platelets: <=75 10^9/L
• Absolute neutrophil count: <=1.0 10^9/L
• Urinalysis: blood, glucose, ketones and total protein: >=2 unit increase from baseline

Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Vital Signs Values

Data represents participants with potentially clinically significant (PCS) vital sign values during any of the treatment period exams.

Significance criteria

• Heart rate - high: >100 and increase of >= 30 beats/minute (bpm)
• Sitting systolic blood pressure - high: >160 and increase of >=30 mmHg
• Sitting systolic blood pressure - low: <90 and decrease of >=30 mmHg
• Sitting diastolic blood pressure - high: >100 and increase of >=12 mmHg
• Sitting diastolic blood pressure - low: <50 and decrease of >=12 mmHg
• Body temperature - high: >100.5° Fahrenheit or 38.1° Celsius and increase of >2°
• Body temperature - low: <96.5° Fahrenheit or <35.8° Celsius

Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Electrocardiogram (ECG) Abnormalities

Counts represent the number of participants with potentially clinically significant ECG abnormalities as assessed by the investigator.

Participants With a Positive Anti-Reslizumab Antibody Status During Study

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 at screening, weeks 8 and 16 or early withdrawal. Serum samples from patients who were treated with reslizumab were analyzed for ADA by Teva (Teva Biopharmaceuticals USA, Rockville, MD) using a validated homogeneous solution-based bridging enzyme-linked immunosorbent assay (ELISA).

Endpoint =week 16 or early withdrawal.

Counts represent the total number of participants at each time point with a positive immunogenicity test, and not 'new' participants with a positive test. An overall status of positive includes participants who had a positive ADA at any time point.