A Study to Evaluate the Efficacy and Safety of Reslizumab (3.0 mg/kg) in the Reduction of Clinical Asthma Exacerbations in Patients (12-75 Years of Age) With Eosinophilic Asthma

Phase 3

Completed

Conditions: Eosinophilic Asthma

Interventions: Drug: Placebo
Drug: Reslizumab

Registration Number: NCT01287039

Lead Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

Brief Summary: This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and immunogenicity of treatment with reslizumab in patients with eosinophilic asthma.

Detailed Description: Demonstrate the efficacy of reslizumab, at a dose of 3 mg/kg administered iv every 4 weeks over 12 months, as assessed by the reduction in frequency of clinical asthma exacerbations (CAEs) during 12 months.

An exacerbation event will be considered a CAE if the patient meets either or both of the criteria listed below and this is 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

* asthma-related emergency treatment The above criteria must be corroborated with at least 1 other measurement to indicate worsening in the clinical signs and symptoms of asthma.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 489

Inclusion Criteria

The patient is male or female, 12 through 75 years of age, with a previous diagnosis of asthma.
The patient has had at least 1 asthma exacerbation requiring oral, intramuscular (im), or intravenous (iv) corticosteroid use for at least 3 days over the past 12 months before screening.
The patient has a current blood eosinophil level of at least 400/μl.
The patient has airway reversibility of at least 12% to beta-agonist administration.
The patient has an ACQ score of at least 1.5 at the screening and baseline (before the 1st dose of study drug) visits.
The patient is taking inhaled fluticasone at a dosage of at least 440 μg, or equivalent, daily. Chronic oral corticosteroid use (no more than 10 mg/day prednisone or equivalent) is allowed. If a patient is on a stable dose, eg, 2 weeks or more of oral corticosteroid treatment at the time of study enrollment, the patient must remain on this dose throughout the study. The patient's baseline asthma therapy regimen (including but not limited to inhaled corticosteroids, oral corticosteroids up to a maximum of 10 mg of prednisone daily or equivalent, leukotriene antagonists, 5-lipooxygenase inhibitors, or cromolyn) must be stable for 30 days prior to screening and baseline, and must continue without dosage changes throughout study.
All female patients must be surgically sterile, 2 years postmenopausal, or must have a negative pregnancy test ß-human chorionic gonadotropin [ß-HCG]) at screening (serum) and baseline (urine).
Female patients of childbearing potential (not surgically sterile or 2 years postmenopausal), must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study.
Written informed consent is obtained. Patients 12 through 17 years old must provide assent.
The patient is in reasonable health (except for diagnosis of asthma) as judged by the investigator, and as determined by a medical history, medical examination, ECG evaluation (at screening), serum chemistry, hematology, and urinalysis.
- Other criteria apply; please contact the investigator for more information.

Exclusion Criteria

The patient has a clinically meaningful co-morbidity that would interfere with the study schedule or procedures, or compromise the patient's safety.
The patient has known hypereosinophilic syndrome.
The patient has another confounding underlying lung disorder (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, or lung cancer). Patients with pulmonary conditions with symptoms of asthma and blood eosinophilia (eg, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis) will also be excluded.
The patient is a current smoker (ie, has smoked within the last 6 months prior to screening).
The patient is using systemic immunosuppressive or immunomodulating or other biologic agents (including, but not limited to, anti-IgE mAb, methotrexate, cyclosporin, interferon-α, or anti-tumor necrosis factor [anti TNF] mAb) within 6 months prior to screening.
The patient has previously received an anti-hIL-5 monoclonal antibody (eg, reslizumab, mepolizumab, or benralizumab).
The patient has any aggravating medical factors that are inadequately controlled (eg, rhinitis, gastroesophageal reflux disease, and uncontrolled diabetes).
The patient has participated in any investigative drug or device study within 30 days prior to screening.
The patient has participated in any investigative biologics study within 6 months prior to screening.
Female patients who are pregnant, nursing, or, if of childbearing potential, and not using a medically accepted, effective method of birth control (eg, barrier method with spermicide, abstinence, IUD, or steroidal contraceptive [oral, transdermal, implanted, and injected]) are excluded from this study. NOTE: Partner sterility alone is not considered an acceptable form of birth control.
- Other criteria apply; please contact the investigator for more information.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg	Reslizumab	Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.

Primary Outcome Measures

Name	Time	Method
Frequency of Clinical Asthma Exacerbations (CAEs) During 12 Months of Treatment	Day 1 to Week 52	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. Adjusted CAE rate and confidence intervals were based on Negative Binomial regression model adjusted for stratification factors. Results are offered as adjusted means.
Frequency of Each of the Two Criteria for Clinical Asthma Exacerbations (CAEs)	Day 1 to Week 52	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. Adjusted CAE rate and confidence intervals for the two criteria were based on Negative Binomial regression model adjusted for stratification factors. Results are offered as adjusted means.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Blood Eosinophil Count Over 16 Weeks and 52 Weeks Using Mixed Model for Repeated Measures	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 or early withdrawal	Blood eosinophil counts were measured using a standard complete blood count (CBC) with differential blood test at each scheduled visit, and from all patients experiencing a serious adverse event, an adverse event leading to withdrawal, or an exacerbation of asthma symptoms. The during treatment average eosinophil counts were 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 values correlate to reduced asthma severity.
Participants With a Positive Anti-Reslizumab Antibody Status During Study	Weeks 16, 32, 48 and 52	The immunogenicity of reslizumab was assessed by measuring for the presence of anti-reslizumab antibodies at baseline, weeks 16, 32, 48, and 52 or early withdrawal. Blood samples for anti-reslizumab antibodies assessment were also obtained from all patients (inside or outside of the US) experiencing a serious adverse event, an adverse event leading to withdrawal, or an exacerbation of asthma symptoms.
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Over 16 Weeks Using Mixed Model for Repeated Measures	Day 1 (baseline, pre-dose), Weeks 4, 8, 12 and 16	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. The during treatment (Weeks 4, 8, 12 and 16) average FEV1 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.
Change From Baseline in Asthma Control Questionnaire (ACQ) Over 16 Weeks Using Mixed Model for Repeated Measures	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16	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.
Participants With Treatment-Emergent Adverse Events	Day 1 (post-dose) to Week 65. The last postbaseline value for approximately 20 patients in each	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.
Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) to Week 16	Day 1 (baseline, pre-dose), Week 16	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.
Kaplan-Meier Estimates for Time to First Clinical Asthma Exacerbation (CAE)	Day 1 to Day 478 (longest treatment time plus 2 weeks)	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).
Change From Baseline in Asthma Symptom Utility Index (ASUI) Over 16 Weeks Using Mixed Model for Repeated Measures	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16	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.
Change From Baseline in Short-Acting Beta-Agonist (SABA) Use Over 16 Weeks Using Mixed Model for Repeated Measures	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16	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) 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.
Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Abnormal Lab Values	Week 4 to Week 65. The last postbaseline value for approximately 20 patients in each	Data represents participants with potentially clinically significant (PCS) abnormal serum chemistry, hematology, and urinalysis values. Significance criteria: * Blood urea nitrogen: \>=10.71 mmol/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 5-49 U/L. Bilirubin: \>=34.2 μmol/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 * Neutrophils: \<=1.0 10\^9/L * Eosinophils: \>10.0 % * Platelets: \<75 or \>=700 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	Week 4 to Week 65. The last postbaseline value for approximately 20 patients in each	Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria * Sitting pulse - high 12-17 yr: \>100 and increase of \>= 30 beats/minute (bpm) * Sitting pulse - low \>=18 yr: \<50 and decrease of \>=30 bpm * Sitting pulse - high \>=18 yr: \>100 and increase of \>=30 bpm * Sitting systolic blood pressure - low \>=18 yr: \<90 and decrease of \>=30 mmHg * Sitting systolic blood pressure - high \>=18 yr: \>160 and increase of \>=30 mmHg * Sitting diastolic blood pressure - low 12-17 yr: \<55 and decrease of \>=12 mmHg * Sitting diastolic blood pressure - low \>=18 yr: \<50 and decrease of \>=12 mmHg * Sitting diastolic blood pressure - high \>=18 yr: \>100 and increase of \>=12 mmHg * Respiratory rate \>=18 yr: \>24 and increase of \>=10 breaths/minute * Body temperature - low 12-17 yr: \<96.5° Fahrenheit or \<35.8° Celsius * Body temp - low \>=18 yr: \<96.5° F or \<35.8° C * Body temp - high \>=18 yr: \>100.5° Fahrenheit

Trial Locations

Locations (128): Teva Investigational Site 61
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Los Angeles, California, United States
Teva Investigational Site 51
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Boston, Massachusetts, United States
Teva Investigational Site 500
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Ostrow Wielkopolski, Poland
Teva Investigational Site 781
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Muang, Thailand
Teva Investigational Site 509
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Bydgoszcz, Poland
Teva Investigational Site 260
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Gent, Belgium
Teva Investigational Site 602
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Göteborg, Sweden
Teva Investigational Site 280
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Olomouc, Czechia
Teva Investigational Site 405
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Törökbálint, Hungary
Teva Investigational Site 700
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Kuala Lumpur, Malaysia
Teva Investigational Site 430
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Beer-Sheva, Israel
Teva Investigational Site 433
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Ramat Gan, Israel
Teva Investigational Site 56
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San Diego, California, United States
Teva Investigational Site 427
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Ramat Gan, Israel
Teva Investigational Site 286
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Liberec, Czechia
Teva Investigational Site 507
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Bialystok, Poland
Teva Investigational Site 504
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Tarnow, Poland
Teva Investigational Site 284
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Breclav, Czechia
Teva Investigational Site 403
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Sopron, Hungary
Teva Investigational Site 553
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Novosibirsk, Russian Federation
Teva Investigational Site 30
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Winston-Salem, North Carolina, United States
Teva Investigational Site 182
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Cali, Colombia
Teva Investigational Site 180
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Floridablanca, Colombia
Teva Investigational Site 404
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Mosonmagyaróvár, Hungary
Teva Investigational Site 425
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Jerusalem, Israel
Teva Investigational Site 642
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Frankston, Australia
Teva Investigational Site 287
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Brno, Czechia
Teva Investigational Site 63
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Boerne, Texas, United States
Teva Investigational Site 501
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Bystra, Poland
Teva Investigational Site 580
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Johannesburg, South Africa
Teva Investigational Site 542
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St. Petersburg, Russian Federation
Teva Investigational Site 281
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Olomouc, Czechia
Teva Investigational Site 401
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Balassagyarmat, Hungary
Teva Investigational Site 400
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Miskolc, Hungary
Teva Investigational Site 721
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Wellington, New Zealand
Teva Investigational Site 603
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Linköping, Sweden
Teva Investigational Site 702
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Kuala Lumpur, Malaysia
Teva Investigational Site 601
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Malmö, Sweden
Teva Investigational Site 585
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Durban, South Africa
Teva Investigational Site 545
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Barnaul, Russian Federation
Teva Investigational Site 549
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Kemerovo, Russian Federation
Teva Investigational Site 502
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Sopot, Poland
Teva Investigational Site 722
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Christchurch, New Zealand
Teva Investigational Site 584
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Cape Town, South Africa
Teva Investigational Site 589
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Johannesburg, South Africa
Teva Investigational Site 586
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Cape Town, South Africa
Teva Investigational Site 780
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Bangkok, Thailand
Teva Investigational Site 783
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Bangkok, Thailand
Teva Investigational Site 588
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Pretoria, South Africa
Teva Investigational Site 301
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Hvidovre, Denmark
Teva Investigational Site 300
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Odense, Denmark
Teva Investigational Site 604
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Göteborg, Sweden
Teva Investigational Site 160
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Rancagua, Chile
Teva Investigational Site 162
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Valdivia, Chile
Teva Investigational Site 705
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Batu Caves, Malaysia
Teva Investigational Site 161
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Temuco, Chile
Teva Investigational Site 743
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Quezon City, Philippines
Teva Investigational Site 784
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Nakhon Ratchasima, Thailand
Teva Investigational Site 35
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Missoula, Montana, United States
Teva Investigational Site 164
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Santiago, Chile
Teva Investigational Site 744
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Governor Mangubat Drive, Dasma, Philippines
Teva Investigational Site 741
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Quezon City, Philippines
Teva Investigational Site 166
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Valparaiso, Chile
Teva Investigational Site 163
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Santiago, Chile
Teva Investigational Site 782
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Bangkok, Thailand
Teva Investigational Site 583
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Pretoria, South Africa
Teva Investigational Site 550
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Nizhniy Novgorod, Russian Federation
Teva Investigational Site 428
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Jerusalem, Israel
Teva Investigational Site 421
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Rehovot, Israel
Teva Investigational Site 429
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Jerusalem, Israel
Teva Investigational Site 285
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Olomouc, Czechia
Teva Investigational Site 546
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Yaroslavl, Russian Federation
Teva Investigational Site 551
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Kazan, Russian Federation
Teva Investigational Site 552
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Tomsk, Russian Federation
Teva Investigational Site 432
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Haifa, Israel
Teva Investigational Site 426
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Kfar Saba, Israel
Teva Investigational Site 420
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Tel-Aviv, Israel
Teva Investigational Site 555
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Novosibirsk, Russian Federation
Teva Investigational Site 581
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Cape Town, South Africa
Teva Investigational Site 582
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Durban, South Africa
Teva Investigational Site 58
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Scottsdale, Arizona, United States
Teva Investigational Site 37
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Orange, California, United States
Teva Investigational Site 34
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Colorado Springs, Colorado, United States
Teva Investigational Site 52
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DeBary, Florida, United States
Teva Investigational Site 55
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Miami, Florida, United States
Teva Investigational Site 18
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Valrico, Florida, United States
Teva Investigational Site 49
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Lexington, Kentucky, United States
Teva Investigational Site 65
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Louisville, Kentucky, United States
Teva Investigational Site 74
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Saint Louis, Missouri, United States
Teva Investigational Site 68
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Rochester, New York, United States
Teva Investigational Site 64
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Boys Town, Nebraska, United States
Teva Investigational Site 62
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Columbus, Ohio, United States
Teva Investigational Site 60
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Bronx, New York, United States
Teva Investigational Site 31
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Cincinnati, Ohio, United States
Teva Investigational Site 50
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Oklahoma City, Oklahoma, United States
Teva Investigational Site 38
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Richmond, Virginia, United States
Teva Investigational Site 32
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Nashville, Tennessee, United States
Teva Investigational Site 72
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Houston, Texas, United States
Teva Investigational Site 66
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Altoona, Pennsylvania, United States
Teva Investigational Site 644
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Daw Park, Australia
Teva Investigational Site 33
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Madison, Wisconsin, United States
Teva Investigational Site 643
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Nedlands, Western Australia, Australia
Teva Investigational Site 641
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Clayton, Australia
Teva Investigational Site 645
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Liverpool, Australia
Teva Investigational Site 261
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Bruxelles, Belgium
Teva Investigational Site 264
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Bruxelles, Belgium
Teva Investigational Site 262
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Jambes, Belgium
Teva Investigational Site 263
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Liège, Belgium
Teva Investigational Site 165
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Santiago, Chile
Teva Investigational Site 185
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Bogota, Colombia
Teva Investigational Site 181
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Bogotá, Colombia
Teva Investigational Site 283
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Tabor, Czechia
Teva Investigational Site 423
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Ashkelon, Israel
Teva Investigational Site 431
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Haifa, Israel
Teva Investigational Site 422
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Petach Tikva, Israel
Teva Investigational Site 703
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Kuantan, Malaysia
Teva Investigational Site 701
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Penang, Malaysia
Teva Investigational Site 704
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Taiping, Malaysia
Teva Investigational Site 726
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Christchurch, New Zealand
Teva Investigational Site 724
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Dunedin, New Zealand
Teva Investigational Site 723
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Auckland, New Zealand
Teva Investigational Site 727
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Hamilton, New Zealand
Teva Investigational Site 742
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Manila, Philippines
Teva Investigational Site 740
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Quezon City, Philippines
Teva Investigational Site 720
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Tauranga, New Zealand
Teva Investigational Site 745
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Quezon City, Philippines
Teva Investigational Site 511
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Poznan, Poland
Teva Investigational Site 587
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Centurion, South Africa