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Clinical Trial Results:
A Long-term, Randomized, Double-blind, Multicenter, Parallel-group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT007 Administered as Needed in Response to Symptoms in Symptomatic Adults and Children 4 Years of Age or Older with Asthma (MANDALA).

Summary
EudraCT number	2018-003673-10
Trial protocol	DE CZ GB SK ES IT
Global end of trial date	07 Feb 2022

Results information
Results version number	v1(current)
This version publication date	28 Jul 2022
First version publication date	28 Jul 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AV003

ISRCTN number

US NCT number

NCT03769090

WHO universal trial number (UTN)

Sponsor organisation name

Bond Avillion 2 Development LP

Sponsor organisation address

Sarnia House, Le Truchot, St Peter Port, Guernsey, GY1 1GR

Public contact

Clinical Operations, Global Project Manager, Avillion LLP, +44 (0)203 764 9530, avillion@avillionllp.com

Scientific contact

Chief Medical Officer, Avillion LLP, +44 (0)203 764 9530, avillion@avillionllp.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 Aug 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Aug 2021

Global end of trial reached?

Yes

Global end of trial date

07 Feb 2022

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of budesonide/albuterol sulfate (salbutamol) metered-dose inhaler 80/180 μg and 160/180 μg administered prn in response to symptoms compared to albuterol sulfate (salbutamol) metered-dose inhaler 180 μg.

Protection of trial subjects

The final protocol, informed consent form (ICF) and other written materials provided to patients were submitted to and approved by an Ethics Committee (EC). The investigator at each study centre ensured that the distribution of these documents to the applicable EC and to the study site staff. An Independent data monitoring committee (IDMC) was established to assess the ongoing safety of the study. The IDMC reviewed blinded data (open session) and unblinded safety data (closed session) quarterly to assess any safety related reasons why the study should continue, be modified, or stopped. The IDMC chair and all committee members were independent specialists separate from the study team or contract research organization. Electronic diary alerted patients, investigator site and the Sponsor’s medical monitoring team when the patient’s symptoms and/or study medication prn use had increased and/or PEF decreased over 2 days in order to initiate contact between the patient and the investigator site to determine the well-being of the patient. Patients were advised to contact the investigator if their symptoms necessitated more than 8 puffs in a day.

Background therapy

Patients enrolled onto the trial were allowed to continue to take their background asthma maintenance therapy following randomization to investigational product. Per eligibility criteria, acceptable background maintenance therapies included: Medium-to-high-dose inhaled corticosteroids (ICS) with or without 1 additional controller (leukotriene receptor agonist (LTRA), long-acting muscarinic antagonist (LAMA), or theophylline); Or Low-to-high-dose ICS in combination with long-acting ß2-agonist (LABA), with or without 1 additional controller (LTRA, LAMA, or theophylline).

Evidence for comparator

Actual start date of recruitment

13 Dec 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 842

Country: Number of subjects enrolled

Argentina: 564

Country: Number of subjects enrolled

Ukraine: 434

Country: Number of subjects enrolled

South Africa: 341

Country: Number of subjects enrolled

Germany: 330

Country: Number of subjects enrolled

Czechia: 211

Country: Number of subjects enrolled

Serbia: 176

Country: Number of subjects enrolled

Slovakia: 83

Country: Number of subjects enrolled

Spain: 75

Country: Number of subjects enrolled

Canada: 42

Country: Number of subjects enrolled

United Kingdom: 34

Worldwide total number of subjects

3132

EEA total number of subjects

699

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

100

Adults (18-64 years)

2383

From 65 to 84 years

566

85 years and over

Subject disposition

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Recruitment details

The first subject enrolled on 13DEC2018 and the last subject completed the study on 07FEB2022. Subjects were enrolled at 347 study centers worldwide (ARG, CAN, CZE, DEU, ESP, GBR, SRB, SVK, UKR, USA, ZAF).

Screening details

A total of 5620 patients were screened for this study, of which 2488 patients were not randomized to treatment; 2456 were ineligible for participation in the trial, the next most frequent reason was withdrawal by patient, of which 18 patients met this criteria.

Period 1 title

Overall (Study Period) (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

BDA MDI 160/180

Arm description

Combination product: Budesonide/albuterol sulfate (salbutamol) pressurized metered dose inhaler (BDA MDI) 160/180 micrograms (μg), given as 2 inhalations of BDA MDI 80/90 μg for as needed use (prn).

Arm type

Experimental

Investigational medicinal product name

Budesonide/albuterol 160/180 micrograms (µg) pressurized metered dose inhaler (MDI)

Investigational medicinal product code

Other name

PT027 high dose

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Taken as needed (prn) in response to asthma symptoms.

BDA MDI 80/180

Arm description

Combination product: Budesonide/albuterol sulfate (salbutamol) pressurized metered dose inhaler (BDA MDI) 80/180 micrograms (μg), given as 2 inhalations of BDA MDI 40/90 μg, for as needed use (prn).

Arm type

Experimental

Investigational medicinal product name

Budesonide/albuterol 80/180 micrograms (µg) pressurized metered dose inhaler (MDI)

Investigational medicinal product code

Other name

PT027 low dose

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Taken as needed (prn) in response to asthma symptoms.

AS MDI 180

Arm description

Albuterol sulfate (salbutamol) pressurized metered dose inhaler (AS MDI) 180 micrograms (μg), given as 2 inhalations of AS MDI 90 μg, for as needed use (prn)

Arm type

Active comparator

Investigational medicinal product name

Albuterol 180 micrograms (µg) pressurized metered dose inhaler (MDI)

Investigational medicinal product code

Other name

PT007

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

Taken as needed (prn) in response to asthma symptoms.

Number of subjects in period 1 ^[1]	BDA MDI 160/180	BDA MDI 80/180	AS MDI 180
Started	1015	1055	1057
Completed	909	919	898
Not completed	106	136	159
Adverse event, serious fatal	4	2	1
On-going at the primary database lock	6	14	18
Condition under investigation worsened	2	-	1
>=3 severe exacerbations within a 3-month period	1	4	4
Consent withdrawn by subject	52	62	74
>=5 total severe exacerbation events	-	1	1
Adverse event, non-fatal	7	7	8
Other	8	12	16
Pregnancy	1	-	3
A single severe exacerbation lasting >20 days	-	1	2
Lost to follow-up	19	25	21
Protocol deviation	5	6	8
Lack of efficacy	1	2	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Four patients were randomized in error and immediately discontinued without receiving any amount of randomly assigned treatment. One patient was randomized but never exposed to randomized study drug. These subjects are excluded from summaries of baseline characteristics, efficacy, and safety. A further four randomized subjects were excluded from the summaries of baseline characteristics and efficacy in the full analysis set due to being determined to be duplicate patients.

Baseline characteristics

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Reporting group title

BDA MDI 160/180

Reporting group description

Reporting group title

BDA MDI 80/180

Reporting group description

Reporting group title

AS MDI 180

Reporting group description

Albuterol sulfate (salbutamol) pressurized metered dose inhaler (AS MDI) 180 micrograms (μg), given as 2 inhalations of AS MDI 90 μg, for as needed use (prn)

Reporting group values	BDA MDI 160/180	BDA MDI 80/180	AS MDI 180	Total
Number of subjects	1015	1055	1057	3127
Age categorical
Units: Subjects
Children (>=4 to <12 years)	0	41	42	83
Adolescents (>=12 to <18 years)	34	32	34	100
Adults (>=18 to <65 years)	789	805	784	2378
Elderly (>=65 years)	192	177	197	566
Age continuous
Units: years
arithmetic mean (standard deviation)	50.6 ( 15.05 )	48.5 ( 16.71 )	49.1 ( 17.22 )	-
Gender categorical
Units: Subjects
Female	647	686	695	2028
Male	368	369	362	1099
Race
Units: Subjects
White	820	848	869	2537
Black or African American	139	141	137	417
Asian	29	33	23	85
American Indian or Alaska Native	1	1	0	2
Other	26	32	28	86
Ethnicity
Units: Subjects
Hispanic or Latino	235	261	316	812
Not Hispanic or Latino	780	794	741	2315
Height
Units: centimetre
arithmetic mean (standard deviation)	166.8 ( 9.92 )	165.1 ( 11.45 )	164.4 ( 11.67 )	-
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	80.5 ( 16.88 )	78.2 ( 18.93 )	78.8 ( 18.47 )	-
Body mass index
Units: kilogram(s)/square metre
arithmetic mean (standard deviation)	28.887 ( 5.4002 )	28.496 ( 5.5886 )	28.948 ( 5.6271 )	-

Subject analysis set title

BDA MDI 160/180 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All patients who are randomized, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

BDA MDI 80/180 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All patients who are randomized, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

AS MDI 180 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All patients who are randomized, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

Total (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All patients who are randomized, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

BDA MDI 160/180 (Full analysis set; >=12 years)

Subject analysis set type

Full analysis

Subject analysis set description

All patients aged >=12 years at randomization, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

BDA MDI 80/180 (Full analysis set; >=12 years)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

AS MDI 180 (full analysis set; >=12 years)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Total (Full analysis set; >= 12 years)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis sets values	BDA MDI 160/180 (Full analysis set)	BDA MDI 80/180 (Full analysis set)	AS MDI 180 (Full analysis set)	Total (Full analysis set)	BDA MDI 160/180 (Full analysis set; >=12 years)	BDA MDI 80/180 (Full analysis set; >=12 years)	AS MDI 180 (full analysis set; >=12 years)	Total (Full analysis set; >= 12 years)
Number of subjects	1013	1054	1056	3123	1013	1013	1014	3040
Age categorical
Units: Subjects
Children (>=4 to <12 years)	0	41	42	83	0	0	0	0
Adolescents (>=12 to <18 years)	34	32	34	100	34	32	34	100
Adults (>=18 to <65 years)	787	804	783	2374	787	804	783	2374
Elderly (>=65 years)	192	177	197	566	192	177	197	566
Age continuous
Units: years
arithmetic mean (standard deviation)	50.6 ( 15.06 )	48.5 ( 16.71 )	49.1 ( 17.23 )	49.4 ( 16.40 )	50.6 ( 15.06 )	50.1 ( 15.02 )	50.7 ( 15.49 )	50.5 ( 15.19 )
Gender categorical
Units: Subjects
Female	645	685	694	2024	645	671	681	1997
Male	368	369	362	1099	368	342	333	1043
Race
Units: Subjects
White	818	847	868	2533	818	819	843	2480
Black or African American	139	141	137	417	139	131	125	395
Asian	29	33	23	85	29	32	21	82
American Indian or Alaska Native	1	1	0	2	1	1	0	2
Other	26	32	28	86	26	30	25	81
Ethnicity
Units: Subjects
Hispanic or Latino	233	260	315	808	233	241	293	767
Not Hispanic or Latino	780	794	741	2315	780	772	721	2273
Height
Units: centimetre
arithmetic mean (standard deviation)	166.8 ( 9.93 )	165.1 ( 11.46 )	164.4 ( 11.67 )	165.4 ( 11.10 )	166.8 ( 9.93 )	166.2 ( 9.99 )	165.6 ( 10.02 )	166.2 ( 9.99 )
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	80.4 ( 16.86 )	78.2 ( 18.92 )	78.8 ( 18.48 )	79.1 ( 18.14 )	80.4 ( 16.86 )	79.8 ( 17.4 )	80.5 ( 16.61 )	80.2 ( 16.96 )
Body mass index
Units: kilogram(s)/square metre
arithmetic mean (standard deviation)	28.869 ( 5.3903 )	28.487 ( 5.5832 )	28.950 ( 5.6296 )	28.767 ( 5.5392 )	28.869 ( 5.3903 )	28.817 ( 5.3706 )	29.328 ( 5.3341 )	29.005 ( 5.3682 )

End points

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Reporting group title

BDA MDI 160/180

Reporting group description

Reporting group title

BDA MDI 80/180

Reporting group description

Reporting group title

AS MDI 180

Reporting group description

Albuterol sulfate (salbutamol) pressurized metered dose inhaler (AS MDI) 180 micrograms (μg), given as 2 inhalations of AS MDI 90 μg, for as needed use (prn)

Subject analysis set title

BDA MDI 160/180 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All patients who are randomized, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

BDA MDI 80/180 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All patients who are randomized, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

AS MDI 180 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All patients who are randomized, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

Total (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All patients who are randomized, take at least 1 puff of randomized treatment and have at least one efficacy assessment, excluding patients who have been identified as confirmed duplicates.

Subject analysis set title

BDA MDI 160/180 (Full analysis set; >=12 years)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

BDA MDI 80/180 (Full analysis set; >=12 years)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

AS MDI 180 (full analysis set; >=12 years)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Total (Full analysis set; >= 12 years)

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Time to first severe exacerbation

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End point title

Time to first severe exacerbation

End point description

The descriptive summary shows the number of patients with a severe exacerbaton event, occurring between the date of randomization up to the date of randomized treatment discontinuation or a change in maintenance therapy.

End point type

Primary

End point timeframe

From randomization up to discontinuation of randomized treatment or a change in maintenance therapy.

End point values	BDA MDI 80/180 (Full analysis set)	AS MDI 180 (Full analysis set)	BDA MDI 160/180 (Full analysis set; >=12 years)	AS MDI 180 (full analysis set; >=12 years)
Number of subjects analysed	1054	1056	1013	1014
Units: Number of patients
Patients with a severe exacerbation event	241	276	207	266

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

H0 = Null hypothesis. Hazard ratios, 95% CIs for hazard ratios and p-values are estimated using a Cox regression model with treatment group, age group, region and number of severe exacerbations in the last 12 months prior to randomization as factors. A hazard ratio less than 1 favours BDA MDI treatment.

Comparison groups

BDA MDI 160/180 (Full analysis set; >=12 years) v AS MDI 180 (full analysis set; >=12 years)

Number of subjects included in analysis

2027

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.733

Confidence interval

level

95%

sides

2-sided

lower limit

0.611

upper limit

0.879

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Comparison groups

BDA MDI 80/180 (Full analysis set) v AS MDI 180 (Full analysis set)

Number of subjects included in analysis

2110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.041

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.835

Confidence interval

level

95%

sides

2-sided

lower limit

0.702

upper limit

0.992

Secondary: Annualized severe exacerbation rate.

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End point title

Annualized severe exacerbation rate.

End point description

The annualized severe exacerbation rate (severe exacerbation per year) is estmated from a negative binomial model with treatment, age group, region, and number of severe exacerbations in the last 12 months prior to randomization as categorical covariates. The logarithm of the time at risk is included as an offset variable.

End point type

Secondary

End point timeframe

From randomization up to discontinuation of randomized treatment or a change in maintenance therapy.

End point values	BDA MDI 80/180 (Full analysis set)	AS MDI 180 (Full analysis set)	BDA MDI 160/180 (Full analysis set; >=12 years)	AS MDI 180 (full analysis set; >=12 years)
Number of subjects analysed	1054	1056	1013	1014
Units: Severe exacerbations per year
least squares mean (confidence interval 95%)	0.49 (0.37 to 0.64)	0.61 (0.46 to 0.80)	0.45 (0.34 to 0.60)	0.59 (0.44 to 0.78)

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

Estimated from a negative binomial model with treatment, age group, region, and number of severe exacerbations in the last 12 months prior to randomization as categorical covariates. The logarithm of the time at risk is included as an offset variable. A sequential testing strategy is used for secondary endpoints. A null hypothesis can only be rejected if all preceding null hypotheses are also rejected.

Comparison groups

BDA MDI 160/180 (Full analysis set; >=12 years) v AS MDI 180 (full analysis set; >=12 years)

Number of subjects included in analysis

2027

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008

Method

Negative binomial model

Parameter type

Rate ratio

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

0.93

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Comparison groups

BDA MDI 80/180 (Full analysis set) v AS MDI 180 (Full analysis set)

Number of subjects included in analysis

2110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.028

Method

Negative binomial model

Parameter type

Rate ratio

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

0.98

Secondary: Total annualized dose of systemic corticosteroid

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End point title

Total annualized dose of systemic corticosteroid

End point description

This endpoint includes all systemic corticosteroids (SCS) taken in response to a severe exacerbation event from randomization up to randomized treatment discontinuation or a change in maintenance therapy. All SCS are standardized to equipotent doses of prednisone before deriving the total dose. The total annualized dose is calculated as the total dose of SCS divided by the duration of the randomized treatment period.

End point type

Secondary

End point timeframe

From randomization up to discontinuation of randomized treatment or a change in maintenance therapy.

End point values	BDA MDI 80/180 (Full analysis set)	AS MDI 180 (Full analysis set)	BDA MDI 160/180 (Full analysis set; >=12 years)	AS MDI 180 (full analysis set; >=12 years)
Number of subjects analysed	1052	1052	1012	1011
Units: milligram(s)
arithmetic mean (full range (min-max))	95.5 (0 to 4974)	127.1 (0 to 18941)	86.2 (0 to 3678)	129.3 (0 to 18941)

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

P-values are calculated via a Wilcoxon rank sum test. A sequential testing strategy is used for secondary endpoints. A null hypothesis can only be rejected if all preceding null hypotheses are also rejected.

Comparison groups

BDA MDI 160/180 (Full analysis set; >=12 years) v AS MDI 180 (full analysis set; >=12 years)

Number of subjects included in analysis

2023

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Wilcoxon rank sum test

Confidence interval

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Comparison groups

BDA MDI 80/180 (Full analysis set) v AS MDI 180 (Full analysis set)

Number of subjects included in analysis

2104

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.06

Method

Wilcoxon rank sum test

Confidence interval

Secondary: Asthma Control Questionnaire 5-item version (ACQ-5) minimal important difference at Week 24

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End point title

Asthma Control Questionnaire 5-item version (ACQ-5) minimal important difference at Week 24

End point description

A responder is defined as a patient with a change from baseline to Week 24 overall ACQ-5 score of -0.5 or less. ACQ-5 is not validated for children less than 6 years old, data for subjects who are 4 or 5 years of age were excluded from the analyses of ACQ-5.

End point type

Secondary

End point timeframe

From randomization up to discontinuation of randomized treatment or a change in maintenance therapy.

End point values	BDA MDI 80/180 (Full analysis set)	AS MDI 180 (Full analysis set)	BDA MDI 160/180 (Full analysis set; >=12 years)	AS MDI 180 (full analysis set; >=12 years)
Number of subjects analysed	1052	1055	1013	1014
Units: Number of patients	681	650	677	630

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

Logistic regression model with baseline ACQ-5 as a continuous covariate and age group, region and number of severe exacerbations in the past 12 months prior to randomization (Visit 2) as categorical covariates. A sequential testing strategy is used for secondary endpoints. A null hypothesis can only be rejected if all preceding null hypotheses are also rejected.

Comparison groups

BDA MDI 160/180 (Full analysis set; >=12 years) v AS MDI 180 (full analysis set; >=12 years)

Number of subjects included in analysis

2027

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.033 ^[1]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.221

Confidence interval

level

95%

sides

2-sided

lower limit

1.016

upper limit

1.467

Notes
[1] - Nominal p-value following type-I error control on secondary endpoints.

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Comparison groups

BDA MDI 80/180 (Full analysis set) v AS MDI 180 (Full analysis set)

Number of subjects included in analysis

2107

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.175

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.132

Confidence interval

level

95%

sides

2-sided

lower limit

0.946

upper limit

1.353

Secondary: Asthma Quality of Life Questionnaire for patients aged 12 years and older (AQLQ+12) minimal important difference at Week 24

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End point title

Asthma Quality of Life Questionnaire for patients aged 12 years and older (AQLQ+12) minimal important difference at Week 24

End point description

A responder is defined as a patient with an increase from baseline to week 24 AQLQ+12 score of at least 0.5.

End point type

Secondary

End point timeframe

From randomization up to discontinuation of randomized treatment or a change in maintenance therapy.

End point values	BDA MDI 160/180 (Full analysis set; >=12 years)	BDA MDI 80/180 (Full analysis set; >=12 years)	AS MDI 180 (full analysis set; >=12 years)
Number of subjects analysed	994	987	993
Units: Number of patients	508	489	461

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

Logistic regression model with baseline AQLQ+12 as a continuous covariate and age group, region and number of severe exacerbations in the past 12 months prior to randomization (Visit 2) as categorical covariates. A sequential testing strategy is used for secondary endpoints. A null hypothesis can only be rejected if all preceding null hypotheses are also rejected.

Comparison groups

BDA MDI 160/180 (Full analysis set; >=12 years) v AS MDI 180 (full analysis set; >=12 years)

Number of subjects included in analysis

1987

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.028 ^[2]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.228

Confidence interval

level

95%

sides

2-sided

lower limit

1.022

upper limit

1.475

Notes
[2] - Nominal p-value following type-I error control on secondary endpoints.

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Comparison groups

BDA MDI 80/180 (Full analysis set; >=12 years) v AS MDI 180 (full analysis set; >=12 years)

Number of subjects included in analysis

1980

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.26

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.111

Confidence interval

level

95%

sides

2-sided

lower limit

0.925

upper limit

1.335

Adverse events

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Timeframe for reporting adverse events

Adverse events (AEs) were collected from the time of signed informed consent/assent and up to the safety follow up period. Reported AEs are those that occurred from the date of first dose of randomized treatment up to date of treatment discontinuation.

Adverse event reporting additional description

Adverse events reported include the AEs accrued between the primary database lock and up to the final database lock, treatment completion and safety follow-up for the patients who were still on-going at the time of the primary database lock.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

BDA MDI 160/180

Reporting group description

Combination product: Budesonide/albuterol pressurized metered dose inhaler (BDA MDI) 160/180 micrograms (μg), given as 2 inhalations of BDA MDI 80/90 μg for as needed use (prn).

Reporting group title

BDA MDI 80/180

Reporting group description

Combination product: Budesonide/albuterol pressurized metered dose inhaler (BDA MDI) 80/180 micrograms (μg), given as 2 inhalations of BDA MDI 40/90 μg, for as needed use (prn).

Reporting group title

AS MDI 180

Reporting group description

Albuterol pressurized metered dose inhaler (AS MDI) 180 micrograms (μg), given as 2 inhalations of AS MDI 90 μg, for as needed use (prn)

Serious adverse events	BDA MDI 160/180	BDA MDI 80/180	AS MDI 180
Total subjects affected by serious adverse events
subjects affected / exposed	53 / 1015 (5.22%)	40 / 1055 (3.79%)	48 / 1057 (4.54%)
number of deaths (all causes)	4	2	2
number of deaths resulting from adverse events	4	2	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute promyelocytic leukaemia
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholesteatoma
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemangioma
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Neoplasm skin
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal adenoma
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Accelerated hypertension
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergy to arthropod sting
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaphylactic shock
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Food allergy
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colpocele
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	7 / 1015 (0.69%)	8 / 1055 (0.76%)	20 / 1057 (1.89%)
occurrences causally related to treatment / all	0 / 7	0 / 9	0 / 20
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Psychiatric disorders
Adjustment disorder with depressed mood
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mixed anxiety and depressive disorder
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post-traumatic stress disorder
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Blood glucose increased
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Troponin I increased
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Animal bite
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention postoperative
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 1015 (0.00%)	2 / 1055 (0.19%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervicobrachial syndrome
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intensive care unit acquired weakness
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Duodenal ulcer
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	3 / 1015 (0.30%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cirrhosis alcoholic
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Foot deformity
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 1015 (0.10%)	1 / 1055 (0.09%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	11 / 1015 (1.08%)	5 / 1055 (0.47%)	8 / 1057 (0.76%)
occurrences causally related to treatment / all	0 / 12	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 1
COVID-19 pneumonia
subjects affected / exposed	3 / 1015 (0.30%)	4 / 1055 (0.38%)	5 / 1057 (0.47%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 1015 (0.00%)	3 / 1055 (0.28%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 1015 (0.00%)	1 / 1055 (0.09%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	5 / 1015 (0.49%)	4 / 1055 (0.38%)	2 / 1057 (0.19%)
occurrences causally related to treatment / all	0 / 5	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pneumonia viral
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suspected COVID-19
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	3 / 1057 (0.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 1015 (0.10%)	0 / 1055 (0.00%)	0 / 1057 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vitamin D deficiency
subjects affected / exposed	0 / 1015 (0.00%)	0 / 1055 (0.00%)	1 / 1057 (0.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	BDA MDI 160/180	BDA MDI 80/180	AS MDI 180
Total subjects affected by non serious adverse events
subjects affected / exposed	244 / 1015 (24.04%)	253 / 1055 (23.98%)	243 / 1057 (22.99%)
Vascular disorders
Hypertension
subjects affected / exposed	22 / 1015 (2.17%)	27 / 1055 (2.56%)	26 / 1057 (2.46%)
occurrences all number	23	27	27
Nervous system disorders
Headache
subjects affected / exposed	44 / 1015 (4.33%)	50 / 1055 (4.74%)	49 / 1057 (4.64%)
occurrences all number	71	77	76
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	27 / 1015 (2.66%)	23 / 1055 (2.18%)	20 / 1057 (1.89%)
occurrences all number	29	23	20
Infections and infestations
Nasopharyngitis
subjects affected / exposed	76 / 1015 (7.49%)	61 / 1055 (5.78%)	54 / 1057 (5.11%)
occurrences all number	95	68	67
COVID-19
subjects affected / exposed	33 / 1015 (3.25%)	47 / 1055 (4.45%)	38 / 1057 (3.60%)
occurrences all number	33	47	38
Upper respiratory tract infection
subjects affected / exposed	26 / 1015 (2.56%)	31 / 1055 (2.94%)	26 / 1057 (2.46%)
occurrences all number	31	35	28
Bronchitis
subjects affected / exposed	25 / 1015 (2.46%)	27 / 1055 (2.56%)	28 / 1057 (2.65%)
occurrences all number	30	30	32
Sinusitis
subjects affected / exposed	15 / 1015 (1.48%)	17 / 1055 (1.61%)	25 / 1057 (2.37%)
occurrences all number	16	17	28
Influenza
subjects affected / exposed	21 / 1015 (2.07%)	20 / 1055 (1.90%)	14 / 1057 (1.32%)
occurrences all number	23	22	16

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Were there any global substantial amendments to the protocol? Yes

29 Jul 2019

Incorporated country-specific changes. Added the de facto estimand as a treatment policy strategy defined in the draft International Conference on Harmonization E9 addendum. Updated the current versions of the AQLQ+12, PAQLQ, and ACQ-5 and ACQ-7.

21 Jul 2020

Incorporated country-specific changes. Updated a secondary endpoint to “systemic corticosteroids”. Added additional exploratory endpoints. Provided clarifications for statistical analyses. Adjusted inclusion criterion for subjects aged < 18 years. Incorporated temporary measures to protect subjects and site staff safety during the COVID 19 pandemic.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Long-term, Randomized, Double-blind, Multicenter, Parallel-group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT007 Administered as Needed in Response to Symptoms in Symptomatic Adults and Children 4 Years of Age or Older with Asthma (MANDALA).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to first severe exacerbation

Primary: Time to first severe exacerbation

Secondary: Annualized severe exacerbation rate.

Secondary: Annualized severe exacerbation rate.

Secondary: Total annualized dose of systemic corticosteroid

Secondary: Total annualized dose of systemic corticosteroid

Secondary: Asthma Control Questionnaire 5-item version (ACQ-5) minimal important difference at Week 24

Secondary: Asthma Control Questionnaire 5-item version (ACQ-5) minimal important difference at Week 24

Secondary: Asthma Quality of Life Questionnaire for patients aged 12 years and older (AQLQ+12) minimal important difference at Week 24

Secondary: Asthma Quality of Life Questionnaire for patients aged 12 years and older (AQLQ+12) minimal important difference at Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
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Luxembourg
Malta
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Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Long-term, Randomized, Double-blind, Multicenter, Parallel-group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT007 Administered as Needed in Response to Symptoms in Symptomatic Adults and Children 4 Years of Age or Older with Asthma (MANDALA).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to first severe exacerbation

Primary: Time to first severe exacerbation

Secondary: Annualized severe exacerbation rate.

Secondary: Annualized severe exacerbation rate.

Secondary: Total annualized dose of systemic corticosteroid

Secondary: Total annualized dose of systemic corticosteroid

Secondary: Asthma Control Questionnaire 5-item version (ACQ-5) minimal important difference at Week 24

Secondary: Asthma Control Questionnaire 5-item version (ACQ-5) minimal important difference at Week 24

Secondary: Asthma Quality of Life Questionnaire for patients aged 12 years and older (AQLQ+12) minimal important difference at Week 24

Secondary: Asthma Quality of Life Questionnaire for patients aged 12 years and older (AQLQ+12) minimal important difference at Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Long-term, Randomized, Double-blind, Multicenter, Parallel-group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT007 Administered as Needed in Response to Symptoms in Symptomatic Adults and Children 4 Years of Age or Older with Asthma (MANDALA).