Clinical Trial Results:
A 12-Month, Double-Blind, Placebo-Controlled, Parallel-Group 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
Summary
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EudraCT number |
2010-024006-35 |
Trial protocol |
SK DE GR |
Global end of trial date |
03 Apr 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Jul 2016
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First version publication date |
09 Jul 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
C38072/3083
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01285323 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Teva Branded Pharmaceutical Products, R&D Inc.
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Sponsor organisation address |
41 Moores Road, Frazer, Pennsylvania, United States, 19355
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 Mar 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Apr 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to determine whether reslizumab, at a dose of 3 mg/kg administered intravenously (iv) every 4 weeks over 12 months, is more effective than placebo in reducing the number of clinical asthma exacerbations (CAEs) in patients with eosinophilic asthma as assessed by the frequency of CAEs.
A CAE is defined by 1 of the following:
1) a hospitalization because of asthma,
2) emergency treatment because of asthma,
3) a decrease in forced expiratory volume in 1 second (FEV1) by 20% or more from baseline, or
4) If the peak expiratory flow rate (PEFR) drops below 30% from baseline on 2 consecutive days worsening of asthma will be assessed. If there is a prescribed increase in baseline oral corticosteroid (OCS) or inhaled corticosteroid (ICS) or if the symptoms warrant additional asthma treatment (OCS) this would be considered a CAE.
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Protection of trial subjects |
This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; European Union (EU) Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). Information regarding any investigational study centers participating in this study that could not comply with these standards was documented.
Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. For patients aged 12 through 17, a signed and dated informed consent form (ICF) was obtained from each parent/guardian and a signed and dated assent form was obtained from each patient before any study specific procedures or assessments are done and after the aims, methods, anticipated benefits, and potential hazards were explained, according to local IEC/IRB requirements.
The patient’s willingness to participate in the study was documented in the assent form, which was signed by the patient with the date of that signature indicated. Each investigator kept the original consent/assent forms and copies were given to the patients. It was also explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Feb 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Romania: 18
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Country: Number of subjects enrolled |
Slovakia: 30
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Country: Number of subjects enrolled |
France: 11
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Country: Number of subjects enrolled |
Germany: 64
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Country: Number of subjects enrolled |
Greece: 7
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Country: Number of subjects enrolled |
Argentina: 14
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Country: Number of subjects enrolled |
Brazil: 21
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Country: Number of subjects enrolled |
Canada: 4
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Country: Number of subjects enrolled |
Korea, Republic of: 34
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Country: Number of subjects enrolled |
Mexico: 12
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Country: Number of subjects enrolled |
Peru: 68
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Country: Number of subjects enrolled |
Russian Federation: 40
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Country: Number of subjects enrolled |
Taiwan: 3
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Country: Number of subjects enrolled |
Ukraine: 107
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Country: Number of subjects enrolled |
United States: 31
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Worldwide total number of subjects |
464
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EEA total number of subjects |
130
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
12
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Adults (18-64 years) |
415
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From 65 to 84 years |
37
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 1111 patients were screened for this study. Of the 1111 patients screened, 464 patients at 82 centers in 15 countries were randomly assigned to double-blind treatment. | |||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Patients who continued to meet inclusion/exclusion criteria and who enrolled in the study were randomly assigned in a blinded fashion (1:1) to 1 of the following 2 treatment groups: reslizumab at 3 mg/kg or placebo, stratified by OCS use (yes or no) at study enrollment and by region (US or other). | |||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Patients were randomly assigned to treatment through an Interactive Response Technology (IRT). Using this system ensured a balance across treatment groups; no effort was made to maintain a balance among treatment groups, within a study center. To maintain the blinding to study drug in this 2 treatment group study, the volume of study drug (including active or placebo treatment) to be taken from each vial was assigned by IRT on the basis of the patient’s body weight and assigned treatment group.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||||||||
Arm description |
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. | |||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Matching placebo (acetate sucrose buffer), administered intravenously (iv) once every 4 weeks for a total of 13 doses.
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Arm title
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Reslizumab 3.0 mg/kg | |||||||||||||||||||||||||||||||||||||||
Arm description |
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. | |||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Reslizumab
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Investigational medicinal product code |
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Other name |
Cinquil, humanized monoclonal antibody, CEP-38072
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients were administered intravenously over 15 to 30 minutes reslizumab at a dosage of 3.0 mg/kg at baseline and once every 4 weeks relative to baseline over 48 weeks for a total of 13 doses.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Reslizumab 3.0 mg/kg
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Reporting group description |
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. | ||
Reporting group title |
Reslizumab 3.0 mg/kg
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Reporting group description |
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. |
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End point title |
Frequency of Clinical Asthma Exacerbations (CAEs) During 12 Months of Treatment | ||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
Day 1 to Month 12
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Notes [1] - Randomized set - patients assigned to a treatment group, regardless if they took study drug [2] - Randomized set - patients assigned to a treatment group, regardless if they took study drug |
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Statistical analysis title |
CAEs During 12 Months | ||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
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Number of subjects included in analysis |
464
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [3] | ||||||||||||
Method |
Chi-squared | ||||||||||||
Parameter type |
CAE rate ratio (reslizumab vs placebo | ||||||||||||
Point estimate |
0.4063
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2819 | ||||||||||||
upper limit |
0.5855 | ||||||||||||
Notes [3] - The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level. |
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End point title |
Frequency of Each of the Two Criteria for Clinical Asthma Exacerbations (CAEs) | ||||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
Day 1 to Month 12
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Notes [4] - Randomized set - patients assigned to a treatment group, regardless if they took study drug [5] - Randomized set - patients assigned to a treatment group, regardless if they took study drug |
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Statistical analysis title |
CAEs requiring systemic corticosteroids >3 days | ||||||||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
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Number of subjects included in analysis |
464
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
< 0.0001 [6] | ||||||||||||||||||
Method |
Chi-squared | ||||||||||||||||||
Parameter type |
CAE rate ratio (reslizumab vs placebo) | ||||||||||||||||||
Point estimate |
0.3893
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.2621 | ||||||||||||||||||
upper limit |
0.5782 | ||||||||||||||||||
Notes [6] - The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level. |
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Statistical analysis title |
CAEs requiring hospitalization or ER visit | ||||||||||||||||||
Statistical analysis description |
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.
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Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
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Number of subjects included in analysis |
464
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.402 [7] | ||||||||||||||||||
Method |
Chi-squared | ||||||||||||||||||
Parameter type |
CAE rate ratio (reslizumab vs placebo) | ||||||||||||||||||
Point estimate |
0.6686
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.2878 | ||||||||||||||||||
upper limit |
1.6479 | ||||||||||||||||||
Notes [7] - The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level. |
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End point title |
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) At Week 16 | ||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline, pre-dose), Week 16
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Notes [8] - Randomized set Number analyzed reflects participants with both baseline and Week 16 assessments. [9] - Randomized set Number analyzed reflects participants with both baseline and Week 16 assessments. |
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Statistical analysis title |
Change From Baseline FEV1 to Week 16 | ||||||||||||
Statistical analysis description |
A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially
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Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
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Number of subjects included in analysis |
428
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0109 [10] | ||||||||||||
Method |
Mixed model repeated measures (MMRM) | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.101
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.023 | ||||||||||||
upper limit |
0.179 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.0397
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Notes [10] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient |
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End point title |
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Over 16 Weeks | ||||||||||||
End point 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. During study values 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.
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline, pre-dose), Weeks 4, 8, 12 and 16
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Notes [11] - Randomized set. Includes participants who contributed at least once to the analysis. [12] - Randomized set. Includes participants who contributed at least once to the analysis. |
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Statistical analysis title |
Change From Baseline FEV1 over 16 Weeks | ||||||||||||
Statistical analysis description |
A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
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Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
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Number of subjects included in analysis |
457
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0037 [13] | ||||||||||||
Method |
Mixed model repeated measures (MMRM | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.093
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.03 | ||||||||||||
upper limit |
0.155 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.0317
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Notes [13] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient |
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End point title |
Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) to Week 16 | ||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Day 1 (baseline, pre-dose), Week 16
|
||||||||||||
|
|||||||||||||
Notes [14] - Randomized set of participants with assessments at each timepoint. [15] - Randomized set of participants with assessments at each timepoint. |
|||||||||||||
Statistical analysis title |
Change From Baseline in AQLQ to Week 16 | ||||||||||||
Statistical analysis description |
A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
|
||||||||||||
Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
|
||||||||||||
Number of subjects included in analysis |
429
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0259 [16] | ||||||||||||
Method |
Mixed model repeated measures (MMRM) | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.209
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.025 | ||||||||||||
upper limit |
0.393 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.937
|
||||||||||||
Notes [16] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient. |
|
|||||||||||||
End point title |
Change From Baseline in Asthma Control Questionnaire (ACQ) Over 16 Weeks | ||||||||||||
End point 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 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
|
||||||||||||
|
|||||||||||||
Notes [17] - Randomized set, including participants who contributed at least once to the analysis. [18] - Randomized set, including participants who contributed at least once to the analysis. |
|||||||||||||
Statistical analysis title |
Change From Baseline in ACQ Over 16 Weeks | ||||||||||||
Statistical analysis description |
A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
|
||||||||||||
Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
|
||||||||||||
Number of subjects included in analysis |
458
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0032 [19] | ||||||||||||
Method |
Mixed model repeated measures (MMRM) | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.196
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.327 | ||||||||||||
upper limit |
-0.066 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.0664
|
||||||||||||
Notes [19] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient |
|
|||||||||||||
End point title |
Kaplan-Meier Estimates for Time to First Clinical Asthma Exacerbation (CAE) | ||||||||||||
End point 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 (U.S. or other).
Values of 9999 = Insufficient data to estimate time.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 1 to Day 526 (longest treatment time plus 2 weeks)
|
||||||||||||
|
|||||||||||||
Notes [20] - Randomized set [21] - Randomized set |
|||||||||||||
Statistical analysis title |
Time to First CAE | ||||||||||||
Statistical analysis description |
Kaplan-Meier estimate of probability (%) 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.
|
||||||||||||
Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
|
||||||||||||
Number of subjects included in analysis |
464
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [22] | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.486
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.353 | ||||||||||||
upper limit |
0.67 | ||||||||||||
Notes [22] - Stratified by baseline usage of oral corticosteroid (yes or no) and geographical region (U.S. or other). |
|
|||||||||||||
End point title |
Change From Baseline in Asthma Symptom Utility Index (ASUI) Over 16 Weeks | ||||||||||||
End point 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 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
|
||||||||||||
|
|||||||||||||
Notes [23] - Randomized set, including participants who contributed at least once to the analysis. [24] - Randomized set, including participants who contributed at least once to the analysis. |
|||||||||||||
Statistical analysis title |
Change from Baseline in ASUI Over 16 Weeks | ||||||||||||
Statistical analysis description |
A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
|
||||||||||||
Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
|
||||||||||||
Number of subjects included in analysis |
451
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0037 [25] | ||||||||||||
Method |
Mixed model repeated measures (MMRM) | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.035
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.011 | ||||||||||||
upper limit |
0.059 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.012
|
||||||||||||
Notes [25] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient |
|
|||||||||||||
End point title |
Change From Baseline in Short-Acting Beta-Agonist (SABA) Use Over 16 Weeks | ||||||||||||
End point 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 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
|
||||||||||||
|
|||||||||||||
Notes [26] - Randomized set including patients who contributed at least once to the analysis. [27] - Randomized set including patients who contributed at least once to the analysis. |
|||||||||||||
Statistical analysis title |
Change from Baseline in SABA use | ||||||||||||
Statistical analysis description |
A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
|
||||||||||||
Comparison groups |
Reslizumab 3.0 mg/kg v Placebo
|
||||||||||||
Number of subjects included in analysis |
368
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.7263 [28] | ||||||||||||
Method |
Mixed model repeated measures (MMRM) | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.062
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.411 | ||||||||||||
upper limit |
0.287 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.1775
|
||||||||||||
Notes [28] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient |
|
|||||||||||||||||||
End point title |
Change From Baseline in Blood Eosinophil Count Over 16 Weeks and 52 Weeks | ||||||||||||||||||
End point description |
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.
Negative change from baseline values correlate to reduced asthma severity.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 or early withdrawal
|
||||||||||||||||||
|
|||||||||||||||||||
Notes [29] - Randomized set including patients who contributed at least once to the analysis. [30] - Randomized set including patients who contributed at least once to the analysis. |
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||
End point title |
Participants With Treatment-Emergent Adverse Events TEAE) | ||||||||||||||||||||||||||||||||||||||||||
End point description |
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.
|
||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1 (post-dose) to Week 65. The endpoint for adverse events was the last postbaseline observation, which included the 90 day follow-up visit.
|
||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
Notes [31] - Safety analysis set [32] - Safety analysis set |
|||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Abnormal Lab Values | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 4 to Week 52
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [33] - Safety analysis set, including participants who contributed to the analysis [34] - Safety analysis set, including participants who contributed to the analysis |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Vital Signs Values | |||||||||||||||||||||||||||||||||||||||
End point description |
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
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point timeframe |
Week 4 to Week 52
|
|||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
Notes [35] - Safety analysis set including participants who contributed data to the analysis [36] - Safety analysis set including participants who contributed data to the analysis |
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Participants With a Positive Anti-Reslizumab Antibody Status During Study | |||||||||||||||||||||||||||
End point description |
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.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline visit (prior to reslizumab exposure), Weeks 16, 32, 48 and 52
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Notes [37] - Test not reported for placebo arm [38] - Safety Set |
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Day 1 (post-dose) to Week 65. The endpoint for adverse events was the last postbaseline observation, which included the 90 day follow-up visit.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
|
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Reslizumab 3.0 mg/kg
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Reporting group description |
Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 Apr 2011 |
Amendment 1 (dated 14 April 2011) to the protocol was issued when 1 patient had been enrolled into the study.
The following major procedural changes (not all-inclusive) were made to the protocol:
• change in sponsor’s medical expert and pharmacovigilance representative
• text was added to the study objectives to clarify the definition of emergency treatment for asthma
• inclusion criterion (f) was revised to clearly state that baseline asthma therapy must be stable for 30 days prior to screening and continue without dosage changes throughout the study
• exclusion criterion (c) was revised to clearly state that patients with pulmonary conditions with symptoms of asthma and blood eosinophilia (eg, Churg Strauss syndrome, allergic bronchopulmonary aspergillosis) were also to be excluded
• exclusion criterion (n) was added to exclude patients who had the presence of or suspected parasitic infestation/infection
• exclusion criterion (o) was added to exclude patients who have received any live attenuated vaccine within the 12 week period prior to screening
• a 90-day follow-up evaluation was added for assessment of adverse events, blood eosinophils, and vital signs for patients who did not enroll in the available open-label extension study
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19 Apr 2011 |
Amendment 2 (dated 19 April 2011) to the protocol was issued after 1 patient was enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study.
The following major procedural changes (not all-inclusive) were made to the protocol:
• a change was made to stipulate that blood samples were to be collected for pharmacokinetics evaluation, blood eosinophil determination, and anti reslizumab antibody assessment each time a patient experienced a serious adverse event, an adverse event leading to withdrawal, or an exacerbation of asthma symptoms
• inclusion criterion (h) was revised to clarify acceptable contraceptive methods to be used during the study
• exclusion criterion (e) was revised to include other prohibited biologics (ie, interferon-α and anti-TNF)
• exclusion criterion (f) was revised to specifically exclude patients who had previously received anti IL 5 mAbs, whether within or outside of a clinical study
• exclusion criterion (i) was revised to clarify that patients may not have participated in any investigative biologics study within 90 days prior to screening
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11 Aug 2011 |
Amendment 3 (dated 11 August 2011) to the protocol was issued after 8 patients had been enrolled into the study.
The following major procedural changes (not all-inclusive) were made to the protocol:
• change in sponsor’s authorized representative and therapeutic area head
• the definition of CAE was changed: the criterion capturing a fall in peak expiratory flow was modified to mandate associated asthma symptomatology
• the assessment of CAEs was changed to only the treatment period of the study
• inclusion criterion (b) requiring use of corticosteroids for the treatmeant of a CAE within the previous 12 months was changed to include use of intramuscular corticosteroids
• exclusion criterion (p) was added and stated: The patient has a history of allergic reactions to or hypersensitivity to any component of the study drug
• the procedures for diagnosing a CAE were changed to agree with the new definition of a CAE
• the exclusion of a patient using OCSs greater than 10 mg/day was removed as part of an administrative letter dated 26 July 2011 and was presented in revised exclusion criterion (e2). As a result of this revision, inclusion criterion (f2) was amended so that a patient’s baseline asthma therapy regimen could now include OCSs up to a maximum dose of prednisone daily, or equivalent, and that they would be allowed into the study as long as they were stable for 30 days prior to screening and continued without dosage changes throughout the study.
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16 Aug 2012 |
Amendment 4 (dated 16 August 2012) to the protocol was issued after 328 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study.
The following major procedural changes (not all-inclusive) were made to the protocol:
• change in sponsor, medical expert, pharmacovigilance representative, and contact information
• assessments at the time of 1st CAE was removed based on United States Food and Drug Administration (FDA) input
• revisions were made to include language regarding withholding of SABAs before lung function testing because of their impact on spirometry
• additional assessments performed at screening were added (12 lead ECG, physical examination, urinalysis, vital signs measurements, β-HCG serum pregnancy test for all females of childbearing potential)
• independent DSMB information was added
• revision was made to ensure that the study blind was maintained when pharmacokinetic analysis was performed during the study
• the study sample size was increased and the expected study completion date, study duration, and number of study centers were revised because of the change in sample size
• 2 ACQ scores required prior to randomization, both had to be 1.5 or greater
• patients with recent infections requiring hospitalization or oral/iv antibiotic were excluded from entering the study
• benralizumab was added as an excluded prior medication
• the use of an adjudication committee to assess CAEs was added
• a 48-hour window was added for evaluating patients with a CAE
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19 Apr 2013 |
Amendment 5 (dated 19 April 2013) to the protocol was issued after 464 patients were enrolled into the study.
The following major procedural changes (not all-inclusive) were made to the protocol:
• change in sponsor’s authorized representative, medical expert, pharmacovigilance representative, and contact information for serious adverse event reporting
• pharmacokinetic and immunogenicity information was updated
• the sample size was revised using an annualized exacerbation rate of 1.2, from more current global data
• additional ECG assessments incorporated into the study
• clarification of sampling times and assessments
• clarification of exploratory endpoints and secondary endpoints
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24 Jan 2014 |
Amendment 6 (dated 24 January 2014) to the protocol was issued after 464 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study.
The following major procedural changes (not all-inclusive) were made to the protocol:
• change in sponsor’s authorized representative and medical expert
• the definition of a CAE was changed to the current, more stringent definition such that a decease in lung function (ie, a CRF decrease in FEV1 or PEFR) was now designated as supportive of a medical intervention for worsening asthma, and not definitive in an of itself.
• secondary objectives were revised to more clearly define the variables to be analyzed and OCS use was deleted as a secondary variable because this is a subset of the primary objective
• evaluation of sputum eosinophils and potential asthma biomarkers in sputum supernatants were added as exploratory objective
• the filter size was changed to 0.20-micron size
• statistical analyses were changed to agree with the new efficacy variables
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |