Clinical Trial Results:
A Multicentre, Randomized, Double-blind, Parallel Group, Placebo-Controlled, 12-Week, Phase 2 Study to Evaluate the Effect of Tralokinumab on Airway Inflammation in Adults with Asthma Inadequately Controlled on Inhaled Corticosteroid (MESOS)
Summary
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EudraCT number |
2015-000857-19 |
Trial protocol |
GB DK |
Global end of trial date |
21 Jun 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
23 May 2018
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First version publication date |
23 May 2018
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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 |
D2210C00014
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02449473 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
AstraZeneca
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Sponsor organisation address |
200 Orchard Ridge Drive, Gaithersburg, United States, MD 20878
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Public contact |
Global Clinical Lead, AstraZeneca, 1 3013980582, ClinicalTrialTransparency@astrazeneca.com
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Scientific contact |
Global Clinical Lead, AstraZeneca, 1 3013980582, ClinicalTrialTransparency@astrazeneca.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 |
21 Jun 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Jun 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Jun 2017
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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 |
To evaluate the effect of tralokinumab on eosinophilic airway infiltration in adult patients with asthma inadequately controlled with inhaled corticosteroid (ICS).
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Protection of trial subjects |
This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
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Background therapy |
Patients were maintained on their currently prescribed ICS (≥250 micrograms fluticasone dry powder formulation equivalents total daily dose) + any additional maintenance asthma controller medication throughout the study. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Sep 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
United Kingdom: 45
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Country: Number of subjects enrolled |
Denmark: 23
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Country: Number of subjects enrolled |
Canada: 11
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Worldwide total number of subjects |
79
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EEA total number of subjects |
68
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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) |
0
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Adults (18-64 years) |
66
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From 65 to 84 years |
13
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85 years and over |
0
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Recruitment
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Recruitment details |
First patient enrolled: 29 Sep 2015; Last patient last visit: 21 Jun 2017. Study performed at 14 sites in 3 countries. | |||||||||
Pre-assignment
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Screening details |
224 patients signed informed consent, 172 entered screening/run-in period, 79 patients were randomised to receive investigational product (IP) and all those randomised received treatment. | |||||||||
Period 1
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Period 1 title |
Overall Study (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, Monitor, Data analyst, Assessor, Investigator | |||||||||
Blinding implementation details |
Neither the patient nor any of the investigator or sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the patients will be aware of the study treatment received. Since tralokinumab and placebo are visually distinct, IP will be handled by an unblinded IP manager at the site and will be administered by an unblinded investigational site study team member who will not be involved in the management of study patients.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Tralo 300 mg Q2W | |||||||||
Arm description |
Tralokinumab 300 milligrams (mg) administered subcutaneously every 2 weeks (Q2W) over a 12-week treatment period (up to 6 doses). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Tralokinumab
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Investigational medicinal product code |
CAT-354
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Other name |
Tralo
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
150 milligrams/millilitre (mg/mL) solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 subcutaneous injections of 150 mg tralokinumab at each dosing interval to receive a total dose of 300 mg.
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Arm title
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Placebo | |||||||||
Arm description |
Placebo administered subcutaneously Q2W over a 12-week treatment period (up to 6 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 injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 subcutaneous injections of placebo at each dosing interval.
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Baseline characteristics reporting groups
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Reporting group title |
Tralo 300 mg Q2W
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Reporting group description |
Tralokinumab 300 milligrams (mg) administered subcutaneously every 2 weeks (Q2W) over a 12-week treatment period (up to 6 doses). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo administered subcutaneously Q2W over a 12-week treatment period (up to 6 doses). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tralo 300 mg Q2W
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Reporting group description |
Tralokinumab 300 milligrams (mg) administered subcutaneously every 2 weeks (Q2W) over a 12-week treatment period (up to 6 doses). | ||
Reporting group title |
Placebo
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Reporting group description |
Placebo administered subcutaneously Q2W over a 12-week treatment period (up to 6 doses). |
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End point title |
Change from baseline to Week 12, expressed as a ratio, in number of airway submucosal eosinophils | ||||||||||||
End point description |
The number of airway submucosal eosinophils per millimetre squared (mm^2) was determined by microscopic evaluation of bronchoscopic biopsies. The ratio of post-randomisation value at Week 12 to baseline value was computed as (Week 12 value / baseline value). The change from baseline to Week 12 (ratio) in the number of airway submucosal eosinophils is presented as geometric mean (back-transformed to be original scale), with standard deviation (SD) values presented on the log scale. Results are presented for the FAS comprising all randomised patients who received any IP.
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End point type |
Primary
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End point timeframe |
Baseline (Week 0) and Week 12
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Statistical analysis title |
Change from baseline; airway submucosal eosinophil | ||||||||||||
Statistical analysis description |
Comparison of change from baseline, expressed as a ratio, in airway submucosal eosinophils; Tralo 300 mg Q2W vs placebo. The null hypothesis was that the change in airway submucosal eosinophils at Week 12 on tralokinumab was equal to the corresponding change on placebo.
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Comparison groups |
Tralo 300 mg Q2W v Placebo
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Number of subjects included in analysis |
74
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.3862 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least square (LS) geometric mean ratio | ||||||||||||
Point estimate |
1.43
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.63 | ||||||||||||
upper limit |
3.27 | ||||||||||||
Notes [1] - The model included treatment group as fixed effect and baseline log-transformed airway submucosal eosinophils as a continuous covariate. No interaction terms were included in the model. The analysis was performed using log-transformed data. All group comparisons from analysis of covariance (ANCOVA) model were based on Type III sums of squares. |
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End point title |
Change from baseline to Week 12, expressed as a ratio, in number of blood eosinophils | ||||||||||||
End point description |
The blood eosinophil count was obtained from the total and differential white blood cell counts. The ratio of post-randomisation value at Week 12 to baseline value was computed as (Week 12 value / baseline value). The change from baseline to Week 12 (ratio) in the number of blood eosinophils is presented as geometric mean (back-transformed to be original scale), with SD values presented on the log scale. Results are presented for the FAS comprising all randomised patients who received any IP.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 0) and Week 12
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Statistical analysis title |
Change from baseline; blood eosinophils | ||||||||||||
Statistical analysis description |
Comparison of change from baseline, expressed as a ratio, in blood eosinophil count; Tralo 300 mg Q2W vs placebo.
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Comparison groups |
Tralo 300 mg Q2W v Placebo
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Number of subjects included in analysis |
70
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
= 0.0546 | ||||||||||||
Method |
Repeated measures analysis | ||||||||||||
Parameter type |
LS geometric mean ratio | ||||||||||||
Point estimate |
1.21
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1 | ||||||||||||
upper limit |
1.48 | ||||||||||||
Notes [2] - The repeated measures analysis included treatment group, baseline log-transformed eosinophils and visit as fixed effects. Treatment-by-visit interaction was also included. The analysis was performed using log-transformed data. A restricted maximum likelihood (REML) approach was used. An unstructured variance-covariance matrix was used to model the within-subject errors. |
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End point title |
Change from baseline to Week 12, expressed as a ratio, in number of differential sputum eosinophils | ||||||||||||
End point description |
Sputum induction was performed to obtain satisfactory samples of sputum originating from the airways. The ratio of post-randomisation value at Week 12 to baseline value was computed as (Week 12 value / baseline value). The change from baseline to Week 12 (ratio) in the number of eosinophils in induced sputum is presented as geometric mean (back-transformed to be original scale), with SD values presented on the log scale. Results are presented for the FAS comprising all randomised patients who received any IP.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 0) and Week 12
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Statistical analysis title |
Change from baseline; induced sputum eosinophils | ||||||||||||
Statistical analysis description |
Comparison of change from baseline, expressed as a ratio, in differential sputum eosinophils; Tralo 300 mg Q2W vs placebo.
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Comparison groups |
Tralo 300 mg Q2W v Placebo
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Number of subjects included in analysis |
33
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.6334 | ||||||||||||
Method |
Repeated measures analysis | ||||||||||||
Parameter type |
LS geometric mean ratio | ||||||||||||
Point estimate |
0.57
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.06 | ||||||||||||
upper limit |
6 | ||||||||||||
Notes [3] - The repeated measures analysis included treatment group, baseline log-transformed differential sputum eosinophils and visit as fixed effects. Treatment-by-visit interaction was also included. The analysis was performed using log-transformed data. A REML approach was used. An unstructured variance-covariance matrix was used to model the within-subject errors. |
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End point title |
Change from baseline to Week 12, expressed as a ratio, in blood free eosinophil cationic protein (ECP) concentrations | ||||||||||||
End point description |
ECP concentrations were determined to assess evidence of activation of eosinophils in blood. The ratio of post-randomisation value at Week 12 to baseline value was computed as (Week 12 value / baseline value). The change from baseline to Week 12 (ratio) in blood free ECP concentrations is presented as geometric mean (back-transformed to be original scale), with SD values presented on the log scale. Results are presented for the FAS comprising all randomised patients who received any IP.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 0) and Week 12
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Statistical analysis title |
Change from baseline; blood free ECP | ||||||||||||
Statistical analysis description |
Comparison of change from baseline, expressed as a ratio, in blood free ECP concentration; Tralo 300 mg Q2W vs placebo.
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Comparison groups |
Tralo 300 mg Q2W v Placebo
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Number of subjects included in analysis |
52
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
= 0.3769 | ||||||||||||
Method |
Repeated measures analysis | ||||||||||||
Parameter type |
LS geometric mean ratio | ||||||||||||
Point estimate |
1.11
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.88 | ||||||||||||
upper limit |
1.4 | ||||||||||||
Notes [4] - The repeated measures analysis included treatment group, baseline log-transformed blood free ECP and visit as fixed effects. Treatment-by-visit interaction was also included. The analysis was performed using log-transformed data. A REML approach was used. An unstructured variance-covariance matrix was used to model the within-subject errors. |
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End point title |
Change from baseline to Week 12, expressed as a ratio, in sputum free ECP concentrations | ||||||||||||
End point description |
ECP concentrations were determined to assess evidence of activation of eosinophils in sputum. The ratio of post-randomisation value at Week 12 to baseline value was computed as (Week 12 value / baseline value). The change from baseline to Week 12 (ratio) in sputum free ECP concentrations is presented as geometric mean (back-transformed to be original scale), with SD values presented on the log scale. Results are presented for the FAS comprising all randomised patients who received any IP.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 0) and Week 12
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Statistical analysis title |
Change from baseline; sputum free ECP | ||||||||||||
Statistical analysis description |
Comparison of change from baseline, expressed as a ratio, in sputum free ECP concentration; Tralo 300 mg Q2W vs placebo.
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Comparison groups |
Tralo 300 mg Q2W v Placebo
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Number of subjects included in analysis |
33
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | ||||||||||||
P-value |
= 0.1126 | ||||||||||||
Method |
Repeated measures analysis | ||||||||||||
Parameter type |
LS geometric mean ratio | ||||||||||||
Point estimate |
0.49
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.2 | ||||||||||||
upper limit |
1.2 | ||||||||||||
Notes [5] - The repeated measures analysis included treatment group, baseline log-transformed sputum free ECP and visit as fixed effects. Treatment-by-visit interaction was also included. The analysis was performed using log-transformed data. A REML approach was used. An unstructured variance-covariance matrix was used to model the within-subject errors. |
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Adverse events information
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Timeframe for reporting adverse events |
12 weeks
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Adverse event reporting additional description |
Data is reported for adverse events during the treatment period (onset date ≥ the first day of IP and ≤ the last day of IP + 2 weeks). Patient population was the safety analysis set which included all patients who received any IP, classified according to the treatment they actually received.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Tralo 300 mg Q2W
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Reporting group description |
Tralokinumab 300 mg administered subcutaneously Q2W over a 12-week treatment period (up to 6 doses). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo administered subcutaneously Q2W over a 12-week treatment period (up to 6 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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26 Feb 2015 |
- Text was revised to state that all patients would be followed up for a period of 14 weeks and that women of child bearing potential only would have an on-site follow-up visit at Week 26 to ascertain their pregnancy status. This revision was implemented following a request by the Medicines and Healthcare products Regulatory Agency. |
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15 Jan 2016 |
- For completion of the eosinophil evaluation, secondary objectives were updated to include assessment of sputum eosinophil levels. Submucosal eosinophil staining was removed as an outcome variable since this was included in the primary outcome variable.
- To clarify that functional respiratory imaging analysis was optional and may be performed later pending other results from the study as well as the outcome of the pivotal studies, exploratory objectives relating to airway volume and resistance for entire airway tree were updated.
- Revisions were applied to other exploratory objectives for the following reasons: to build flexibility to perform additional exploratory analysis; to clarify that both pre-bronchodilator (BD); and post-BD spirometry could be included; to allow the acceptance of both ‘PC20’ (provocative concentration required to achieve a 20% reduction in forced expiratory volume in 1 second [FEV1]) and ‘PD20’ (provocative dose required to achieve a 20% reduction in FEV1) in the airway hyper-responsiveness exploratory objective outcome variable; to make the RNA exploratory objective more specific; to remove sputum eosinophils from the exploratory variables since this was included as a secondary outcome measure; to provide flexibility for spirometry assessments; to clarify that whole body plethysmography was to be performed post-BD.
- Discontinuation criteria were revised to allow subjects with an asthma-related event requiring non-invasive ventilation to continue with IP. |
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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. | |||
The results for differential sputum eosinophils and sputum free ECP levels should be viewed cautiously due to the small sample size and wide variability in results for sputum analyses. |