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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

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ClinicalTrials.gov Identifier: NCT01287039
Recruitment Status : Completed
First Posted : February 1, 2011
Results First Posted : June 27, 2016
Last Update Posted : June 27, 2016
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Eosinophilic Asthma
Interventions Drug: Reslizumab
Drug: Placebo
Enrollment 489
Recruitment Details A total of 1486 patients were screened at 121 centers. Of the 1486 patients screened, 489 patients with asthma and blood eosinophils ≥400/ μL at 102 centers in 17 countries were randomly assigned to double-blind treatment.
Pre-assignment Details 997 of 1486 screened patients were not randomized: 888 were excluded on the basis of not meeting inclusion criteria, 23 withdrew consent, 17 had an adverse event during the screening period, 12 met an exclusion criterion, 7 were lost to follow-up and 50 were excluded for other reasons. One placebo patient was randomized but not treated.
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Period Title: Overall Study
Started 244 245
Completed 215 218
Not Completed 29 27
Reason Not Completed
Noncompliance with study procedures             0             1
Change of location/residence             0             3
Elective surgery             0             1
Protocol Violation             2             3
Excluded medication taken             1             0
Noncompliance with study medication             0             1
Problem with travel             0             1
Death             1             0
Change of residence             1             0
Adverse Event             7             4
Withdrawal by Subject             14             11
Lost to Follow-up             3             2
Arm/Group Title Placebo Reslizumab 3.0 mg/kg Total
Hide Arm/Group Description Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. Total of all reporting groups
Overall Number of Baseline Participants 244 245 489
Hide Baseline Analysis Population Description
Randomized set
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 244 participants 245 participants 489 participants
46.7  (14.83) 46.6  (13.82) 46.6  (14.32)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 244 participants 245 participants 489 participants
Female
161
  66.0%
142
  58.0%
303
  62.0%
Male
83
  34.0%
103
  42.0%
186
  38.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 244 participants 245 participants 489 participants
White 182 173 355
Black 20 14 34
Asian 33 50 83
American Indian or Alaskan Native 0 0 0
Pacific Islander 0 1 1
Other 9 7 16
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 244 participants 245 participants 489 participants
Non-Hispanic and non-Latino 223 216 439
Hispanic or Latino 21 28 49
Unknown 0 1 1
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 244 participants 245 participants 489 participants
76.5  (18.71) 75.6  (19.05) 76.0  (18.87)
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 244 participants 245 participants 489 participants
165.0  (9.74) 164.9  (10.42) 164.9  (10.07)
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 244 participants 245 participants 489 participants
28.0  (6.16) 27.7  (6.26) 27.9  (6.20)
Oral Glucocorticosteroid (OCS) Use at Baseline   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 244 participants 245 participants 489 participants
OCS - Yes 46 46 92
OCS - No 198 199 397
[1]
Measure Description: Oral glucocorticosteroid (OCS) use at baseline was a stratification factor. Values input by the investigator into the interactive response technology (IRT) were used during randomization. However, 6 patients in the placebo group and 22 patients in the reslizumab group were misclassified in IRT as having used oral glucocorticosteroids at baseline according to the case report form.
Asthma Exacerbations In Previous 12 Months  
Mean (Standard Deviation)
Unit of measure:  Exacerbations
Number Analyzed 244 participants 245 participants 489 participants
2.1  (2.31) 1.9  (1.63) 2.0  (2.00)
Forced Expiratory Volume in 1 Second  
Mean (Standard Deviation)
Unit of measure:  Liters
Number Analyzed 244 participants 245 participants 489 participants
1.928  (0.7908) 1.894  (0.7258) 1.911  (0.7583)
Asthma Control Questionnaire (ACQ) Overall Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 244 participants 245 participants 489 participants
2.763  (0.8782) 2.657  (0.8541) 2.710  (0.867)
[1]
Measure Description: 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 overall score is the mean of all responses. A higher score is an indication of poorer asthma control.
Asthma Quality of Life Questionnaire (AQLQ)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 244 participants 245 participants 489 participants
4.159  (1.0883) 4.303  (1.1208) 4.231  (1.1059)
[1]
Measure Description: 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.
Asthma Symptom Utility Index (ASUI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 244 participants 245 participants 489 participants
0.613  (0.2029) 0.633  (0.1938) 0.623  (0.1984)
[1]
Measure Description: 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.
Number of Short-Acting Beta-Agonist Puffs (SABA) Daily   [1] 
Mean (Standard Deviation)
Unit of measure:  Puffs/day
Number Analyzed 244 participants 245 participants 489 participants
2.7  (3.18) 2.4  (2.82) 2.6  (3.01)
[1]
Measure Description: Based on patient-reported total number of SABA puffs over the past 3 days.
1.Primary Outcome
Title Frequency of Clinical Asthma Exacerbations (CAEs) During 12 Months of Treatment
Hide Description

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.

Time Frame Day 1 to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 244 245
Mean (95% Confidence Interval)
Unit of Measure: CAEs in 52 weeks
1.804
(1.372 to 2.372)
0.904
(0.678 to 1.205)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter CAE rate ratio (reslizumab vs placebo)
Estimated Value 0.5010
Confidence Interval (2-Sided) 95%
0.3726 to 0.6737
Estimation Comments [Not Specified]
2.Primary Outcome
Title Frequency of Each of the Two Criteria for Clinical Asthma Exacerbations (CAEs)
Hide Description

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.

Time Frame Day 1 to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 244 245
Mean (95% Confidence Interval)
Unit of Measure: CAEs in 52 weeks
Requiring systemic corticosterioids >3 days
1.604
(1.195 to 2.152)
0.722
(0.528 to 0.986)
Requiring hospitalization or ER visit
0.207
(0.107 to 0.400)
0.137
(0.068 to 0.274)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments CAE Due to Requiring Systemic Corticosteroids The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter CAE rate ratio (reslizumab vs placebo)
Estimated Value 0.4499
Confidence Interval (2-Sided) 95%
0.3255 to 0.6220
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments CAE Due to Hospitalization or ER visit The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2572
Comments The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter CAE rate ratio (reslizumab vs placebo)
Estimated Value 0.6595
Confidence Interval (2-Sided) 95%
0.3210 to 1.3550
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Over 16 Weeks Using Mixed Model for Repeated Measures
Hide Description

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.

Time Frame Day 1 (baseline, pre-dose), Weeks 4, 8, 12 and 16
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set, including participants who contributed at least once to the analysis.
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 241 243
Least Squares Mean (Standard Error)
Unit of Measure: liters
0.110  (0.031) 0.248  (0.030)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments For each week and overall change, inferential statistics were from mixed model repeated measures (MMRM) with treatment, visit, treatment by visit interaction, region, oral glucocorticosteroids use at enrollment and sex as fixed factors, and covariates for height and baseline value and patient as a random effect. Unstructured covariance structure was assumed for the repeated measures.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.137
Confidence Interval (2-Sided) 95%
0.076 to 0.198
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0311
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) to Week 16
Hide Description

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.

Time Frame Day 1 (baseline, pre-dose), Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set of patients with assessments at both timepoints
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 229 228
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.695  (0.088) 0.933  (0.088)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments For each week and overall change, inferential statistics were from mixed model repeated measures (MMRM) with treatment, visit, treatment by visit interaction, region, oral glucocorticosteroids use at enrollment and sex as fixed factors, and covariates for height and baseline value and patient as a random effect. Unstructured covariance structure was assumed for the repeated measures.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0143
Comments [Not Specified]
Method Mixed model repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.238
Confidence Interval (2-Sided) 95%
0.048 to 0.428
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0967
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline in Asthma Control Questionnaire (ACQ) Over 16 Weeks Using Mixed Model for Repeated Measures
Hide Description

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.

Time Frame Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set, including participants who contributed at least once to the analysis.
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 241 242
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-0.676  (0.066) -0.941  (0.065)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments For each week and overall change, inferential statistics were from mixed model repeated measures (MMRM) with treatment, visit, treatment by visit interaction, region, oral glucocorticosteroids use at enrollment and sex as fixed factors, and covariates for height and baseline value and patient as a random effect. Unstructured covariance structure was assumed for the repeated measures.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Mixed model repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.266
Confidence Interval (2-Sided) 95%
-0.399 to -0.132
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0681
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Kaplan-Meier Estimates for Time to First Clinical Asthma Exacerbation (CAE)
Hide Description

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).

Time Frame Day 1 to Day 478 (longest treatment time plus 2 weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 244 245
Median (95% Confidence Interval)
Unit of Measure: weeks
34.9 [1] 
(23.3 to NA)
NA [1] 
(NA to NA)
[1]
Insufficient data to estimate time
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments Kaplan-Meier estimate of probability (5) of not experiencing a CAE by week 52. The first CAEs for each patient occurring after randomization and up to 2 weeks after the end of treatment period were analyzed. Patients without a CAE within this time frame were censored at two weeks after the treatment completion date or study discontinuation, whichever came first.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Regression, Cox
Comments Stratified by baseline usage of oral corticosteroid (yes or no) and geographical region (US or other).
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.575
Confidence Interval (2-Sided) 95%
0.440 to 0.750
Estimation Comments Reslizumab vs placebo
7.Secondary Outcome
Title Change From Baseline in Asthma Symptom Utility Index (ASUI) Over 16 Weeks Using Mixed Model for Repeated Measures
Hide Description

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.

Time Frame Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set, including participants who contributed at least once to the analysis.
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 238 238
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
0.109  (0.012) 0.167  (0.188)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments For each week, inferential statistics were from mixed model repeated measures (MMRM) with treatment, visit, treatment by visit interaction, region, oral glucocorticosteroids use at enrollment as fixed factor, and covariate baseline value and patient as a random effect. Unstructured covariance structure was assumed for the repeated measures.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed model repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 0.058
Confidence Interval (2-Sided) 95%
0.034 to 0.083
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0125
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in Short-Acting Beta-Agonist (SABA) Use Over 16 Weeks Using Mixed Model for Repeated Measures
Hide Description

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.

Time Frame Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set of participants with assessments within the timeframe
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 238 240
Least Squares Mean (Standard Error)
Unit of Measure: puffs/day
-0.36  (0.158) -0.64  (0.156)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments Inferential statistics were from mixed model repeated measures (MMRM) with treatment, visit, treatment by visit interaction, region, OCS use at enrollment as fixed factors, and covariate for baseline value and patient as a random effect. Unstructured covariance structure was assumed for the repeated measures.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0919
Comments [Not Specified]
Method Mixed model repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.276
Confidence Interval (2-Sided) 95%
-0.597 to 0.045
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.1632
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Change From Baseline in Blood Eosinophil Count Over 16 Weeks and 52 Weeks Using Mixed Model for Repeated Measures
Hide Description

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.

Time Frame Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 or early withdrawal
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized set of participants with assessments within timeframe
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 241 243
Least Squares Mean (Standard Error)
Unit of Measure: 10^9 blood eosinophil/L
Over first 16 weeks -0.118  (0.0232) -0.584  (0.0230)
Over 52 weeks -0.127  (0.0168) -0.582  (0.0167)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments

Eosinophil Count Over 16 Weeks

Inferential statistics were from mixed model repeated measures (MMRM) with treatment, visit, treatment by visit interaction, region, oral glucocorticosteroids use at enrollment as fixed factor, and covariate baseline value and patient as a random effect. Unstructured covariance structure was assumed for the repeated measures.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed model repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.466
Confidence Interval (2-Sided) 95%
-0.514 to -0.418
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0244
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Reslizumab 3.0 mg/kg
Comments

Eosinophil Count Over 52 Weeks

Inferential statistics were from mixed model repeated measures (MMRM) with treatment, visit, treatment by visit interaction, region, oral glucocorticosteroids use at enrollment as fixed factor, and covariate baseline value and patient as a random effect. Unstructured covariance structure was assumed for the repeated measures.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed model repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.455
Confidence Interval (2-Sided) 95%
-0.491 to -0.419
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.0182
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Participants With Treatment-Emergent Adverse Events
Hide Description 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.
Time Frame Day 1 (post-dose) to Week 65. The last postbaseline value for approximately 20 patients in each
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Hide Analysis Population Description
Safety analysis set
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 243 245
Measure Type: Number
Unit of Measure: participants
At least 1 AE 206 197
Mild severity AE 41 68
Moderate severity AE 133 107
Severe AE 32 22
Treatment-related AE 36 36
Treatment-related mild AE 23 24
Treatment-related moderate AE 13 9
Treatment-related severe AE 0 3
AE causing patient discontinuation 8 4
Serious AE 34 24
Deaths 1 0
11.Secondary Outcome
Title Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Abnormal Lab Values
Hide Description

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
Time Frame Week 4 to Week 65. The last postbaseline value for approximately 20 patients in each
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 243 245
Measure Type: Number
Unit of Measure: participants
Blood urea nitrogen 9 8
Uric acid 9 6
Aspartate aminotransferase 1 1
Alanine aminotransferase 3 5
Gamma-glutamyl transpeptidase 12 12
Bilirubin 2 1
White blood cells - low 6 6
White blood cells - high 5 3
Hemoglobin 7 4
Hematocrit 9 6
Neutrophils 8 6
Eosinophils 135 3
Platelets - low 1 2
Platelets - high 2 0
Urinalysis - Blood (hemoglobin) 32 21
Urinalysis - Ketones 4 5
Urinalysis - Glucose 11 14
Urinalysis - Protein 32 34
12.Secondary Outcome
Title Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Vital Signs Values
Hide Description

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
Time Frame Week 4 to Week 65. The last postbaseline value for approximately 20 patients in each
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 243 245
Measure Type: Number
Unit of Measure: participants
Sitting pulse - high 12-17 yr 1 1
Sitting pulse - low >=18 yr 1 0
Sitting pulse - high >=18 yr 5 7
Sitting systolic blood pressure - low >=18 yr 2 5
Sitting systolic blood pressure - high >=18 yr 7 7
Sitting diastolic blood pressure - low 12-17 yr 1 0
Sitting diastolic blood pressure - low >=18 yr 0 1
Sitting diastolic blood pressure - high >=18 yr 10 5
Respiratory rate >=18 yr 3 2
Body temperature - low 12-17 yr 1 1
Body temperature - low >=18 yr 54 49
Body temperature - high >=18 yr 0 1
13.Secondary Outcome
Title Participants With a Positive Anti-Reslizumab Antibody Status During Study
Hide Description 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.
Time Frame Weeks 16, 32, 48 and 52
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set. Immunogenicity for anti-reslizumab antibodies not reported for the placebo treatment arm.
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description:
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
Overall Number of Participants Analyzed 0 245
Measure Type: Number
Unit of Measure: participants
8
Time Frame Day 1 to Day 464
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Reslizumab 3.0 mg/kg
Hide Arm/Group Description Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.
All-Cause Mortality
Placebo Reslizumab 3.0 mg/kg
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Reslizumab 3.0 mg/kg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   34/243 (13.99%)      24/245 (9.80%)    
Cardiac disorders     
Right ventricular failure  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Sinus tachycardia  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Gastrointestinal disorders     
Diaphragmatic hernia  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Diarrhoea  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Oesophagitis  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Small intestinal obstruction  1  0/243 (0.00%)  0 1/245 (0.41%)  1
General disorders     
Chest pain  1  0/243 (0.00%)  0 2/245 (0.82%)  2
Infections and infestations     
Bronchitis  1  2/243 (0.82%)  3 0/245 (0.00%)  0
Diverticulitis  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Gastroenteritis  1  1/243 (0.41%)  1 1/245 (0.41%)  1
Influenza  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Lower respiratory tract infection  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Otitis media  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Periorbital cellulitis  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Pneumonia  1  0/243 (0.00%)  0 2/245 (0.82%)  2
Sinusitis  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Urinary tract infection  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Viral infection  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Injury, poisoning and procedural complications     
Concussion  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Face injury  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Procedural nausea  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Procedural vomiting  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Radius fracture  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Rib fracture  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Thermal burn  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Tibia fracture  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Toxicity to various agents  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Ulna fracture  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Metabolism and nutrition disorders     
Diabetes mellitus inadequate control  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Musculoskeletal and connective tissue disorders     
Osteonecrosis  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bladder transitional cell carcinoma  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Colon cancer  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Lung adenocarcinoma  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Lung neoplasm malignant  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Metastases to liver  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Metastases to lung  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Prostate cancer  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Uterine leiomyoma  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Nervous system disorders     
Meningism  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Nerve compression  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Neurological symptom  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Status migrainosus  1  1/243 (0.41%)  2 0/245 (0.00%)  0
Renal and urinary disorders     
Ureteric obstruction  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Asthma  1  13/243 (5.35%)  28 11/245 (4.49%)  12
Nasal polyps  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Pneumothorax  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Pulmonary hypertension  1  1/243 (0.41%)  1 0/245 (0.00%)  0
Vascular disorders     
Deep vein thrombosis  1  0/243 (0.00%)  0 1/245 (0.41%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Reslizumab 3.0 mg/kg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   184/243 (75.72%)      165/245 (67.35%)    
Infections and infestations     
Bronchitis  1  22/243 (9.05%)  31 13/245 (5.31%)  14
Influenza  1  23/243 (9.47%)  32 17/245 (6.94%)  25
Nasopharyngitis  1  33/243 (13.58%)  44 28/245 (11.43%)  45
Pharyngitis  1  13/243 (5.35%)  13 10/245 (4.08%)  11
Sinusitis  1  28/243 (11.52%)  48 21/245 (8.57%)  31
Upper respiratory tract infection  1  32/243 (13.17%)  49 39/245 (15.92%)  50
Urinary tract infection  1  10/243 (4.12%)  13 13/245 (5.31%)  15
Musculoskeletal and connective tissue disorders     
Back pain  1  13/243 (5.35%)  13 13/245 (5.31%)  15
Nervous system disorders     
Dizziness  1  13/243 (5.35%)  13 5/245 (2.04%)  7
Headache  1  30/243 (12.35%)  50 19/245 (7.76%)  31
Respiratory, thoracic and mediastinal disorders     
Asthma  1  123/243 (50.62%)  364 92/245 (37.55%)  192
Cough  1  13/243 (5.35%)  14 11/245 (4.49%)  13
Oropharyngeal pain  1  8/243 (3.29%)  9 13/245 (5.31%)  17
Rhinitis allergic  1  6/243 (2.47%)  7 13/245 (5.31%)  16
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (15.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor’s review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor’s designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc
Phone: 215-591-3000
EMail: ustevatrials@tevapharm.com
Layout table for additonal information
Responsible Party: Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )
ClinicalTrials.gov Identifier: NCT01287039     History of Changes
Other Study ID Numbers: C38072/3082
First Submitted: January 28, 2011
First Posted: February 1, 2011
Results First Submitted: March 23, 2016
Results First Posted: June 27, 2016
Last Update Posted: June 27, 2016