Clinical Trial Results:
A Randomized, Double-Blind, Parallel Group, Multicenter 12 Week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler in Participants with Inadequately Controlled Asthma (LITHOS)
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Summary
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EudraCT number |
2021-003334-36 |
Trial protocol |
DE CZ |
Global end of trial date |
19 Nov 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
31 May 2025
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First version publication date |
31 May 2025
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Other versions |
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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 |
D5982C00005
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05755906 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AstraZeneca
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Sponsor organisation address |
Forskargatan 18, Södertälje, Sweden,
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Public contact |
Global Clinical Lead, AstraZeneca, +1 18772409479, information.center@astrazeneca.com
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Scientific contact |
Global Clinical Lead, AstraZeneca, +1 18772409479, information.center@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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Jan 2025
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 Nov 2024
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Nov 2024
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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 efficacy and safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler (BFF MDI) 160/9.6 μg BID compared with Budesonide MDI 160 μg, over 12 weeks.
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Protection of trial subjects |
The conduct of this study met all the local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and was consistent with the ICH guidelines on GCP. Participating participants signed the informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Feb 2023
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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 |
Canada: 32
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Country: Number of subjects enrolled |
Czechia: 82
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Country: Number of subjects enrolled |
Malaysia: 9
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Country: Number of subjects enrolled |
Philippines: 22
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Country: Number of subjects enrolled |
South Africa: 26
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Country: Number of subjects enrolled |
Korea, Republic of: 6
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Country: Number of subjects enrolled |
United States: 176
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Worldwide total number of subjects |
353
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EEA total number of subjects |
82
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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) |
11
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Adults (18-64 years) |
276
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From 65 to 84 years |
66
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects with inadequately controlled asthma (ACQ-7 total score ≥ 1.5) despite treatment with low dose ICS or ICS/LABA were recruited at 106 sites across 7 countries. Participants were randomized in a 1:1 scheme to BFF MDI 160/9.6 μg or BD MDI 160 μg. The treatment period was 12 weeks in duration. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
All participants had to be taking a stable daily low dose ICS or ICS/LABA for at least 8 weeks prior to Visit 1. Of the 374 randomized participants, all populations exclude 17 participants from 4 sites due GCP violation and 4 participants due to not receiving therapy. | ||||||||||||||||||||||||
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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, Investigator, Monitor, Carer, Data analyst, Assessor | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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BFF MDI 160/9.6 μg | ||||||||||||||||||||||||
Arm description |
Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg BID (320/19.2μg/day) | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Budesonide/formoterol fumarate pressurized inhalation suspension, desiccated flow path device
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Pressurised inhalation
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Routes of administration |
Inhalation use
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Dosage and administration details |
Two inhalations BID of 80/4.8 μg per actuation. Total daily dose: 320/19.2 μg.
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Arm title
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BD MDI 160 μg | ||||||||||||||||||||||||
Arm description |
Budesonide (BD) metered-dose inhaler (MDI), 160 μg BID (320 μg/day) | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Budesonide pressurized inhalation suspension, desiccated flow path device
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Pressurised inhalation
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Routes of administration |
Inhalation use
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Dosage and administration details |
Two inhalations BID of 80 μg per actuation. Total daily dose: 320 μg.
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Baseline characteristics reporting groups
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Reporting group title |
BFF MDI 160/9.6 μg
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Reporting group description |
Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg BID (320/19.2μg/day) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BD MDI 160 μg
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Reporting group description |
Budesonide (BD) metered-dose inhaler (MDI), 160 μg BID (320 μg/day) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BFF MDI 160/9.6 μg
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Reporting group description |
Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg BID (320/19.2μg/day) | ||
Reporting group title |
BD MDI 160 μg
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Reporting group description |
Budesonide (BD) metered-dose inhaler (MDI), 160 μg BID (320 μg/day) | ||
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End point title |
Change from baseline in morning pre-dose trough FEV1 over 12 Weeks | ||||||||||||
End point description |
Change from baseline in morning pre-dose trough FEV1 over 12 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
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End point type |
Primary
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End point timeframe |
Over 12 Weeks
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
The ANCOVA model includes treatment, visit, prior maintenance medication, treatment-by-visit interaction, baseline trough FEV1, and percent Albuterol reversibility.
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Comparison groups |
BFF MDI 160/9.6 μg v BD MDI 160 μg
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Number of subjects included in analysis |
346
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.0133 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.062
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.013 | ||||||||||||
upper limit |
0.111 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.025
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| Notes [1] - An increase in estimate favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 7 participants who were randomized multiple times at sites or studies. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis. |
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End point title |
Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) over 12 Weeks | ||||||||||||
End point description |
Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) over 12 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
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End point type |
Secondary
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End point timeframe |
Over 12 Weeks
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
The ANCOVA model includes treatment, visit, prior maintenance medication, treatment-by-visit interaction, baseline trough FEV1, and percent Albuterol reversibility.
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Comparison groups |
BFF MDI 160/9.6 μg v BD MDI 160 μg
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Number of subjects included in analysis |
346
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.179
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.13 | ||||||||||||
upper limit |
0.227 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.0248
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| Notes [2] - An increase in estimate favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 7 participants who were randomized multiple times at sites or studies. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis. |
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End point title |
Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1 | ||||||||||||
End point description |
Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
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End point type |
Secondary
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End point timeframe |
On Day 1
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
The ANCOVA model includes treatment, timepoint, prior maintenance medication, treatment-by-timepoints interaction, baseline tFEV1, and % Albuterol reversibility.
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Comparison groups |
BFF MDI 160/9.6 μg v BD MDI 160 μg
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Number of subjects included in analysis |
325
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.153
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.114 | ||||||||||||
upper limit |
0.192 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.0198
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| Notes [3] - An increase in estimate favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 7 participants who were randomized multiple times at sites or studies. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis. |
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End point title |
Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 12 Weeks | ||||||||||||
End point description |
Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 12 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
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End point type |
Secondary
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End point timeframe |
Over 12 Weeks
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Statistical analysis title |
Primary analysis | ||||||||||||
Statistical analysis description |
The ANCOVA model includes treatment, 4-week interval, their interaction, prior maintenance medication, severe asthma exacerbation history, baseline daily rescue use, baseline tFEV1, and % Albuterol reversibility.
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Comparison groups |
BFF MDI 160/9.6 μg v BD MDI 160 μg
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Number of subjects included in analysis |
338
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
= 0.0058 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.28
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.478 | ||||||||||||
upper limit |
-0.082 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.1008
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| Notes [4] - A decrease in estimate favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 7 participants who were randomized multiple times at sites or studies. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis. |
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End point title |
Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) over 12 Weeks | |||||||||
End point description |
Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) over 12 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
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End point type |
Secondary
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End point timeframe |
Over 12 Weeks
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
The logistic regression model includes treatment, prior maintenance medication, baseline instrument score, baseline tFEV1, and % Albuterol reversibility.
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Comparison groups |
BFF MDI 160/9.6 μg v BD MDI 160 μg
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Number of subjects included in analysis |
346
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | |||||||||
P-value |
= 0.0768 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.512
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.956 | |||||||||
upper limit |
2.391 | |||||||||
| Notes [5] - An odds ratio greater than 1 favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 7 participants who were randomized multiple times at sites or studies. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis. |
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End point title |
Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) over 12 Weeks | |||||||||
End point description |
Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) over 12 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
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End point type |
Secondary
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End point timeframe |
Over 12 Weeks
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
The logistic regression model includes treatment, prior maintenance medication, baseline instrument score, baseline tFEV1, and % Albuterol reversibility.
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Comparison groups |
BFF MDI 160/9.6 μg v BD MDI 160 μg
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Number of subjects included in analysis |
346
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Analysis specification |
Pre-specified
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Analysis type |
superiority [6] | |||||||||
P-value |
= 0.119 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.465
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.906 | |||||||||
upper limit |
2.367 | |||||||||
| Notes [6] - An odds ratio greater than 1 favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 7 participants who were randomized multiple times at sites or studies. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis. |
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End point title |
Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s) +12) (≥ 0.5 increase equals response) over 12 Weeks | |||||||||
End point description |
Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s) +12) (≥ 0.5 increase equals response) over 12 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
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End point type |
Secondary
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End point timeframe |
Over 12 Weeks
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Statistical analysis title |
Primary analysis | |||||||||
Statistical analysis description |
The logistic regression model includes treatment, prior maintenance medication, baseline instrument score, baseline tFEV1, and % Albuterol reversibility.
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Comparison groups |
BFF MDI 160/9.6 μg v BD MDI 160 μg
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Number of subjects included in analysis |
337
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | |||||||||
P-value |
= 0.0951 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.488
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.933 | |||||||||
upper limit |
2.374 | |||||||||
| Notes [7] - An odds ratio greater than 1 favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 7 participants who were randomized multiple times at sites or studies. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis. |
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Adverse events information
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Timeframe for reporting adverse events |
From the date of first dose of IP up to and including 1 day following the date of last IP dose.
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Adverse event reporting additional description |
Adverse events were reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). The Investigator and any designees were responsible for detecting, documenting, and recording events that meet the definition of an AE.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||
Dictionary version |
27.1
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Reporting groups
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Reporting group title |
BD MDI 160 μg
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Reporting group description |
Budesonide (BD) metered-dose inhaler (MDI), 160 μg BID (320 μg/day) | ||||||||||||||||||||||||||||||
Reporting group title |
BFF MDI 160/9.6 μg
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Reporting group description |
Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), BDI (320/19.2μg/day) | ||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||
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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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13 Oct 2022 |
Home-coached spirometry removed from study to reduce participant and clinical study site burden as well as reduce the study operational complexity; clarifications/additions to the statistical analysis; and required wording from the updated AstraZeneca protocol standard template added. |
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05 Dec 2023 |
An amendment was required to update statistical methodology, including changes to estimands, the Type 1 error control procedure, covariates in the analysis models, and analysis sets and to add updated wording from the new AstraZeneca protocol standard template. |
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15 Oct 2024 |
An amendment was required to update the statistical methodological approaches to handling intercurrent events and the Type 1 error control procedure for EU/RoW health authorities. |
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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 | |||
