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Clinical Trial Results:
A 12-week, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel Group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT008 and PT007 Administered QID in Adults and Children 4 Years of Age or Older with Asthma (DENALI)

Summary
EudraCT number	2018-003674-27
Trial protocol	DE CZ SK
Global end of trial date	20 Jul 2021

Results information
Results version number	v1(current)
This version publication date	16 Mar 2022
First version publication date	16 Mar 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

AV004

ISRCTN number

US NCT number

NCT03847896

WHO universal trial number (UTN)

Sponsor organisation name

Bond Avillion 2 Development LLP

Sponsor organisation address

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

Public contact

Clinical Operations, Global Project Manager, Avillion LLP, +44 (0)2037649530, avillion@avillionllp.com

Scientific contact

Chief Medical Officer, Avillion LLP, +44 (0)2037649530, 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

20 Jul 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

20 Jul 2021

Global end of trial reached?

Yes

Global end of trial date

20 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

This is a randomized, double-blind, placebo-controlled, multicenter, parallel group study to compare 2 dose levels of budesonide/albuterol BDA MDI (PT027) to its components budesonide BD MDI (PT008) and albuterol AS MDI (PT007) on improvement in lung function and asthma symptoms after 12 weeks of treatment in adult, adolescent, and child subjects with symptomatic asthma currently being treated with a short/rapid-acting β2-adrenoreceptor agonist (SABA) as needed alone or with low-dose inhaled corticosteroid (ICS) maintenance therapy plus SABA as needed.

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 investigators/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 Ventolin 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

Evidence for comparator

Actual start date of recruitment

20 Mar 2019

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: 522

Country: Number of subjects enrolled

Ukraine: 203

Country: Number of subjects enrolled

Germany: 138

Country: Number of subjects enrolled

Czechia: 71

Country: Number of subjects enrolled

Argentina: 54

Country: Number of subjects enrolled

Serbia: 12

Country: Number of subjects enrolled

Slovakia: 1

Worldwide total number of subjects

1001

EEA total number of subjects

210

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)

Adults (18-64 years)

790

From 65 to 84 years

174

85 years and over

Subject disposition

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Recruitment details

The first subject enrolled on 20 March 2019 and the last subjected completed the study on 20 July 2021. Subjects were enrolled at 126 study centers worldwide (Argentina, Czechia, Germany, Serbia, Slovakia, Ukraine and the United States).

Screening details

A total of 1876 patients were screened for this study, of which 875 patients were not randomized to treatment; 851 were ineligible, 3 were lost to follow up, 1 was excluded due to a protocol deviation, 18 withdrew by subject decision, and 2 withdrew by parent/guardian decision.

Period 1 title

Overall Study (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 pressurized metered dose inhaler (BDA MDI) 160/180 micrograms (μg), given as 2 inhalations of BDA MDI 80/90 μg, four times a day (QID).

Arm type

Experimental

Investigational medicinal product name

Budesonide/albuterol 160/180 milligrams (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

4 doses (8 inhalations of BDA MDI 80/90) per day.

BDA MDI 80/180

Arm 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, four times a day (QID).

Arm type

Experimental

Investigational medicinal product name

Budesonide/albuterol 80/180 milligrams (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

4 doses (8 inhalations of BDA MDI 40/90) per day.

BD MDI 160

Arm description

Budesonide pressurized metered dose inhaler (BD MDI) 160 micrograms (μg), given as 2 inhalations of BD MDI 80 μg, four times a day (QID).

Arm type

Active comparator

Investigational medicinal product name

Budesonide 160 milligrams (µg) pressurized metered dose inhaler (MDI)

Investigational medicinal product code

Other name

PT008

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

4 doses (8 inhalations of BD MDI 80) per day.

AS MDI 180

Arm description

Albuterol pressurized metered dose inhaler (AS MDI) 180 micrograms (μg), given as 2 inhalations of AS MDI 90 μg, four times a day (QID)

Arm type

Active comparator

Investigational medicinal product name

Albuterol 180 milligrams (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

4 doses (8 inhalations of AS MDI 90) per day.

Placebo MDI

Arm description

Placebo pressurized metered dose inhaler (Placebo MDI), given as 2 inhalations of Placebo MDI four times a day (QID)

Arm type

Placebo

Investigational medicinal product name

Placebo pressurized metered dose inhaler (MDI)

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation, suspension

Routes of administration

Inhalation use

Dosage and administration details

4 doses (8 inhalations) of Placebo MDI per day.

Number of subjects in period 1 ^[1]	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI
Started	197	204	199	201	199
Completed	190	188	188	184	178
Not completed	7	16	11	17	21
Consent withdrawn by subject	2	10	6	9	8
A severe exacerbation event	-	-	-	-	3
Adverse event, non-fatal	2	1	3	2	4
Other	3	3	1	2	1
Condition under investigation worsened	-	-	-	1	1
Lost to follow-up	-	-	-	1	-
Protocol deviation	-	2	1	-	2
Lack of efficacy	-	-	-	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: One subject was randomised in error and immediately discontinued without receiving any amount of randomly assigned treatment. This subject was excluded from summaries of baseline characteristics, efficacy, and safety. One subject was randomised and received randomly assigned treatment before being determined to be a duplicate patient. This subject was excluded from summaries of baseline characteristics and efficacy but included in analyses of safety.

Baseline characteristics

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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, four times a day (QID).

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, four times a day (QID).

Reporting group title

BD MDI 160

Reporting group description

Budesonide pressurized metered dose inhaler (BD MDI) 160 micrograms (μg), given as 2 inhalations of BD MDI 80 μg, four times a day (QID).

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, four times a day (QID)

Reporting group title

Placebo MDI

Reporting group description

Placebo pressurized metered dose inhaler (Placebo MDI), given as 2 inhalations of Placebo MDI four times a day (QID)

Reporting group values	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI	Total
Number of subjects	197	204	199	201	199	1000
Age categorical
Units: Subjects
Children (>=4 to <12 years)	0	3	0	4	3	10
Adolescents (>=12 to <18 years)	4	7	5	5	4	25
Adults (>=18 to <65 years)	154	155	161	159	161	790
Elderly (>=65 years)	39	39	33	33	31	175
Age continuous
Units: years
arithmetic mean (standard deviation)	50.0 ( 15.80 )	48.7 ( 16.79 )	48.3 ( 15.80 )	47.0 ( 16.75 )	48.6 ( 15.82 )	-
Gender categorical
Units: Subjects
Female	125	128	120	121	127	621
Male	72	76	79	80	72	379
Race
Units: Subjects
White	179	185	180	167	174	885
Black or African American	14	15	18	30	19	96
Asian	1	0	0	0	1	2
American Indian or Alaska Native	1	0	0	1	1	3
Other	2	4	1	3	4	14
Ethnicity
Units: Subjects
Hispanic or Latino	61	62	50	46	63	282
Not Hispanic or Latino	136	142	149	155	136	718
Height
Units: centimetre
arithmetic mean (standard deviation)	167.8 ( 8.61 )	166.8 ( 9.71 )	167.7 ( 9.92 )	168.5 ( 9.86 )	168.0 ( 10.85 )	-
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	80.4 ( 16.43 )	80.0 ( 16.06 )	80.0 ( 14.52 )	82.3 ( 15.09 )	81.6 ( 17.79 )	-
Body mass index
Units: kilogram(s)/square metre
arithmetic mean (standard deviation)	28.537 ( 5.2488 )	28.635 ( 4.8491 )	28.477 ( 4.9140 )	29.016 ( 4.8513 )	28.793 ( 5.2534 )	-

Subject analysis set title

BDA MDI 160/180 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects 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 subjects 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

BD MDI 160 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects 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 subjects 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

Placebo MDI (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects 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 subjects 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 sets values	BDA MDI 160/180 (Full analysis set)	BDA MDI 80/180 (Full analysis set)	BD MDI 160 (Full analysis set)	AS MDI 180 (full analysis set)	Placebo MDI (Full analysis set)	Total (Full analysis set)
Number of subjects	197	204	199	200	199	999
Age categorical
Units: Subjects
Children (>=4 to <12 years)	0	3	0	4	3	10
Adolescents (>=12 to <18 years)	4	7	5	5	4	25
Adults (>=18 to <65 years)	154	155	161	158	161	789
Elderly (>=65 years)	39	39	33	33	31	175
Age continuous
Units: years
arithmetic mean (standard deviation)	50.0 ( 15.8 )	48.7 ( 16.79 )	48.3 ( 15.8 )	47.0 ( 16.79 )	48.6 ( 15.82 )	48.5 ( 16.21 )
Gender categorical
Units: Subjects
Female	125	128	120	120	127	620
Male	72	76	79	80	72	379
Race
Units: Subjects
White	179	185	180	166	174	884
Black or African American	14	15	18	30	19	96
Asian	1	0	0	0	1	2
American Indian or Alaska Native	1	0	0	1	1	3
Other	2	4	1	3	4	14
Ethnicity
Units: Subjects
Hispanic or Latino	61	62	50	45	63	281
Not Hispanic or Latino	136	142	149	155	136	718
Height
Units: centimetre
arithmetic mean (standard deviation)	167.8 ( 8.61 )	166.8 ( 9.71 )	167.7 ( 9.92 )	168.6 ( 9.86 )	168.0 ( 10.85 )	167.8 ( 9.81 )
Weight
Units: kilogram(s)
arithmetic mean (standard deviation)	80.4 ( 16.43 )	80.0 ( 16.06 )	80.0 ( 14.52 )	82.4 ( 15.12 )	81.6 ( 17.79 )	80.9 ( 16.02 )
Body mass index
Units: kilogram(s)/square metre
arithmetic mean (standard deviation)	28.537 ( 5.2488 )	28.635 ( 4.8491 )	28.477 ( 4.9140 )	29.011 ( 4.8629 )	28.793 ( 5.2534 )	28.691 ( 5.0211 )

End points

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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, four times a day (QID).

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, four times a day (QID).

Reporting group title

BD MDI 160

Reporting group description

Budesonide pressurized metered dose inhaler (BD MDI) 160 micrograms (μg), given as 2 inhalations of BD MDI 80 μg, four times a day (QID).

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, four times a day (QID)

Reporting group title

Placebo MDI

Reporting group description

Placebo pressurized metered dose inhaler (Placebo MDI), given as 2 inhalations of Placebo MDI four times a day (QID)

Subject analysis set title

BDA MDI 160/180 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects 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 subjects 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

BD MDI 160 (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects 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 subjects 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

Placebo MDI (Full analysis set)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects 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 subjects 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.

Primary: Change from baseline FEV1 AUC0-6 hours over 12 weeks

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End point title

Change from baseline FEV1 AUC0-6 hours over 12 weeks

End point description

FEV1 = Forced expiratory volume in 1 second. AUC0-6hours = Area under the curve from 0 to 6 hours. The dual-primary endpoint of change from baseline FEV1 AUC0-6 hours is calculated from the changes from baseline in serial spirometry measures following dosing of randomized treatment at each clinical visit. The area under the curve is calculated using the trapezoidal rule and is normalized by dividing through by the time from dosing to the last measurement included in the serial spirometry profile in order to present the result in millilitres. Baseline FEV1 is defined as the average of the 30- and 60-minute pre-dose measures collected on the day of randomization.

End point type

Primary

End point timeframe

Estimated over the 12 week period.

End point values	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI
Number of subjects analysed	197	200	199	195	196
Units: millilitre(s)
least squares mean (standard error)	258.6 ( 18.87 )	242.2 ( 18.80 )	178.0 ( 18.79 )	157.2 ( 19.08 )	96.7 ( 19.02 )

AS MDI 180 versus Placebo MDI

Statistical analysis description

Only includes data from date of first dose up to date of last dose of randomized treatment. A sequential testing strategy is used such that the primary hypothesis tests are listed in ascending order of sequence. A null hypothesis can only be rejected if all preceding null hypotheses are also rejected. Tests are each conducted at the 5% level of significance.

Comparison groups

AS MDI 180 v Placebo MDI

Number of subjects included in analysis

391

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

60.5

Confidence interval

level

95%

sides

2-sided

lower limit

7.7

upper limit

113.4

BDA MDI 160/180 versus Placebo MDI

Statistical analysis description

Comparison groups

Placebo MDI v BDA MDI 160/180

Number of subjects included in analysis

393

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

161.9

Confidence interval

level

95%

sides

2-sided

lower limit

109.4

upper limit

214.5

BDA MDI 160/180 versus BD MDI 160

Statistical analysis description

Comparison groups

BDA MDI 160/180 v BD MDI 160

Number of subjects included in analysis

396

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

80.7

Confidence interval

level

95%

sides

2-sided

lower limit

28.4

upper limit

132.9

Primary: Change from baseline in trough FEV1 at Week 12

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End point title

Change from baseline in trough FEV1 at Week 12

End point description

FEV1 = Forced expiratory volume in 1 second. Trough FEV1 is calculated at each clinic visit as the average of the 30- and 60-minute pre-dose FEV1 measurements. Baseline FEV1 is defined as the average of the 30- and 60-minute pre-dose measures collected on the day of randomization.

End point type

Primary

End point timeframe

At the Week 12 timepoint.

End point values	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI
Number of subjects analysed	197	198	198	192	192
Units: millilitre(s)
least squares mean (standard error)	135.5 ( 24.58 )	123.5 ( 24.65 )	108.9 ( 24.51 )	2.7 ( 25.24 )	35.6 ( 25.12 )

BD MDI 160 versus Placebo MDI

Statistical analysis description

Comparison groups

BD MDI 160 v Placebo MDI

Number of subjects included in analysis

390

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.037

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

73.3

Confidence interval

level

95%

sides

2-sided

lower limit

4.4

upper limit

142.2

BDA MDI 160/180 versus Placebo MDI

Statistical analysis description

Comparison groups

BDA MDI 160/180 v Placebo MDI

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

99.9

Confidence interval

level

95%

sides

2-sided

lower limit

30.9

upper limit

168.8

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

Comparison groups

BDA MDI 160/180 v AS MDI 180

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

132.8

Confidence interval

level

95%

sides

2-sided

lower limit

63.6

upper limit

201.9

BDA MDI 80/180 versus Placebo MDI

Statistical analysis description

Comparison groups

BDA MDI 80/180 v Placebo MDI

Number of subjects included in analysis

390

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

87.9

Confidence interval

level

95%

sides

2-sided

lower limit

18.8

upper limit

156.9

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Comparison groups

BDA MDI 80/180 v AS MDI 180

Number of subjects included in analysis

390

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

120.8

Confidence interval

level

95%

sides

2-sided

lower limit

51.5

upper limit

190.1

Secondary: Time to 15% increase in FEV1 over the pre-treatment value on Day 1

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End point title

Time to 15% increase in FEV1 over the pre-treatment value on Day 1

End point description

FEV1 = Forced expiratory volume in 1 second. CI = Confidence interval. The time to onset is defined as the time (minutes) from the first inhalation of randomized treatment (Day 1) to the first instance where a percentage change from baseline in FEV1 of at least 15% is observed. Patients were only be included in the analyses if a percent change from baseline of at least 15% is observed within 30 minutes post dose assessment time point. Baseline FEV1 is defined as the average of the 60- and 30-minute pre-dose spirometry measures taken at randomization.

End point type

Secondary

End point timeframe

The 30 minute post-treatment spirometry assessment period on Day 1.

End point values	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI
Number of subjects analysed	98	88	27	84	26
Units: minute
median (full range (min-max))	7.5 (3 to 33)	7.0 (3 to 35)	17.0 (4 to 37)	9.5 (4 to 37)	14.0 (4 to 34)

AS MDI 180 versus Placebo MDI

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

AS MDI 180 v Placebo MDI

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

BD MDI 160 versus Placebo MDI

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

BD MDI 160 v Placebo MDI

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

BDA MDI 80/180 versus Placebo MDI

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

Placebo MDI v BDA MDI 80/180

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

-4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-9

upper limit

BDA MDI 160/180 versus Placebo MDI

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

Placebo MDI v BDA MDI 160/180

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

-4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-9

upper limit

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

BDA MDI 80/180 v AS MDI 180

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

-1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-3

upper limit

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

BDA MDI 160/180 v AS MDI 180

Number of subjects included in analysis

182

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

BDA MDI 80/180 versus BD MDI 160

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

BDA MDI 80/180 v BD MDI 160

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

-6.5

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

-2

BDA MDI 160/180 versus BD MDI 160

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

BD MDI 160 v BDA MDI 160/180

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

-6.5

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

-2

BDA MDI 160/180 versus BDA MDI 80/180

Statistical analysis description

Not Type-I error controlled. The estimated median difference and 95% CIs are calculated using the Hodges-Lehmann method.

Comparison groups

BDA MDI 160/180 v BDA MDI 80/180

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Median difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

Secondary: Asthma Control Questionnaire 7-item version (ACQ-7) clinically meaningful difference at Week 12

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End point title

Asthma Control Questionnaire 7-item version (ACQ-7) clinically meaningful difference at Week 12

End point description

ACQ-7 = Asthma control questionnaire (7-item). A responder is defined as a patient who achieves a change from baseline in overall ACQ-7 score of at least 0.5. The overall ACQ-7 score is defined as the averaged score across the 7 questions. All patients who discontinue treatment prior to Week 12 are classified as non-responders. The analysis only includes patients who are uncontrolled at baseline, i.e. baseline ACQ-7 >= 1.5.

End point type

Secondary

End point timeframe

At the Week 12 visit.

End point values	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI
Number of subjects analysed	161	165	162	163	159
Units: Number of patients	107	108	100	77	88

AS MDI 180 versus Placebo MDI

Statistical analysis description

Comparisons are not type-I error controlled.

Comparison groups

AS MDI 180 v Placebo MDI

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.118

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.699

Confidence interval

level

95%

sides

2-sided

lower limit

0.445

upper limit

1.096

BD MDI 160 versus Placebo MDI

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BD MDI 160 v Placebo MDI

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.161

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.386

Confidence interval

level

95%

sides

2-sided

lower limit

0.878

upper limit

2.187

BDA MDI 80/180 versus Placebo MDI

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 80/180 v Placebo MDI

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.605

Confidence interval

level

95%

sides

2-sided

lower limit

1.013

upper limit

2.541

BDA MDI 160/180 versus Placebo MDI

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 160/180 v Placebo MDI

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.039

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.626

Confidence interval

level

95%

sides

2-sided

lower limit

1.024

upper limit

2.584

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 80/180 v AS MDI 180

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.297

Confidence interval

level

95%

sides

2-sided

lower limit

1.456

upper limit

3.626

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 160/180 v AS MDI 180

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.328

Confidence interval

level

95%

sides

2-sided

lower limit

1.471

upper limit

3.687

BDA MDI 80/180 versus BD MDI 160

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 80/180 v BD MDI 160

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.532

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.158

Confidence interval

level

95%

sides

2-sided

lower limit

0.731

upper limit

1.835

BDA MDI 160/180 versus BD MDI 160

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 160/180 v BD MDI 160

Number of subjects included in analysis

323

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.499

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.174

Confidence interval

level

95%

sides

2-sided

lower limit

0.737

upper limit

1.868

BDA MDI 160/180 versus BDA MDI 80/180

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 160/180 v BDA MDI 80/180

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.955

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.014

Confidence interval

level

95%

sides

2-sided

lower limit

0.635

upper limit

1.618

Secondary: Change from baseline in trough FEV1 at Week 1

Top of page

End point title

Change from baseline in trough FEV1 at Week 1

End point description

End point type

Secondary

End point timeframe

Week 1 visit.

End point values	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI
Number of subjects analysed	197	198	198	192	192
Units: millilitre(s)
least squares mean (standard error)	107.2 ( 21.46 )	72.0 ( 21.31 )	93.4 ( 21.35 )	-0.8 ( 21.69 )	41.3 ( 21.47 )

AS MDI 180 versus Placebo MDI

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

Placebo MDI v AS MDI 180

Number of subjects included in analysis

384

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.169

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-42.1

Confidence interval

level

95%

sides

2-sided

lower limit

-101.9

upper limit

17.8

BD MDI 160 versus Placebo MDI

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BD MDI 160 v Placebo MDI

Number of subjects included in analysis

390

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.086

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

52.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.4

upper limit

111.5

BDA MDI 80/180 versus Placebo MDI

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 80/180 v Placebo MDI

Number of subjects included in analysis

390

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.31

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

30.7

Confidence interval

level

95%

sides

2-sided

lower limit

-28.6

upper limit

90.1

BDA MDI 160/180 versus Placebo MDI

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 160/180 v Placebo MDI

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.03

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

65.9

Confidence interval

level

95%

sides

2-sided

lower limit

6.3

upper limit

125.4

BDA MDI 80/180 versus AS MDI 180

Statistical analysis description

Comparisons are not type-I error controlled.

Comparison groups

BDA MDI 80/180 v AS MDI 180

Number of subjects included in analysis

390

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

72.8

Confidence interval

level

95%

sides

2-sided

lower limit

13.1

upper limit

132.5

BDA MDI 160/180 versus AS MDI 180

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 160/180 v AS MDI 180

Number of subjects included in analysis

389

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

107.9

Confidence interval

level

95%

sides

2-sided

lower limit

48.1

upper limit

167.8

BDA MDI 80/180 versus BD MDI 160

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 80/180 v BD MDI 160

Number of subjects included in analysis

396

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.48

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-21.3

Confidence interval

level

95%

sides

2-sided

lower limit

-80.5

upper limit

37.9

BDA MDI 160/180 versus BD MDI 160

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 160/180 v BD MDI 160

Number of subjects included in analysis

395

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.648

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

13.8

Confidence interval

level

95%

sides

2-sided

lower limit

-45.6

upper limit

73.2

BDA MDI 160/180 versus BDA MDI 80/180

Statistical analysis description

Comparison is not type-I error controlled.

Comparison groups

BDA MDI 160/180 v BDA MDI 80/180

Number of subjects included in analysis

395

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.246

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

35.1

Confidence interval

level

95%

sides

2-sided

lower limit

-24.2

upper limit

94.5

Secondary: Duration of 15% increase in FEV1 over the pre-treatment value on Day 1

Top of page

End point title

Duration of 15% increase in FEV1 over the pre-treatment value on Day 1

End point description

FEV1 = Forced expiratory volume in 1 second. The duration of onset is defined as the time (minutes) of the continual period in which a percentage change from baseline in FEV1 of at least 15% is observed. Patients will only be included in the analyses if a percent change from baseline of at least 15% is observed within 30 minutes post dose assesment. If a patient has multiple periods of onset, only the first will contribute to the summary. Baseline FEV1 is defined as the average of the 60- and 30-minute pre-dose spirometry taken at randomization.

End point type

Secondary

End point timeframe

The 30 minute post-treatment spirometry assessment period on Day 1.

End point values	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI
Number of subjects analysed	98	88	27	84	26
Units: minute
median (full range (min-max))	185.5 (4 to 363)	174 (10 to 362)	98 (14 to 354)	158.5 (9 to 363)	229.5 (8 to 356)

No statistical analyses for this end point

Adverse events

Top of page

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.

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, four times a day (QID).

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, four times a day (QID).

Reporting group title

BD MDI 160

Reporting group description

Budesonide pressurized metered dose inhaler (BD MDI) 160 micrograms (μg), given as 2 inhalations of BD MDI 80 μg, four times a day (QID).

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, four times a day (QID)

Reporting group title

Placebo MDI

Reporting group description

Placebo pressurized metered dose inhaler (Placebo MDI), given as 2 inhalations of Placebo MDI four times a day (QID)

Serious adverse events	BDA MDI 160/180	BDA MDI 80/180	BD MDI 160	AS MDI 180	Placebo MDI
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 197 (1.02%)	4 / 204 (1.96%)	3 / 199 (1.51%)	1 / 201 (0.50%)	3 / 199 (1.51%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Investigations
Influenza A virus test positive
subjects affected / exposed	0 / 197 (0.00%)	0 / 204 (0.00%)	0 / 199 (0.00%)	0 / 201 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Subdural haematoma
subjects affected / exposed	0 / 197 (0.00%)	1 / 204 (0.49%)	0 / 199 (0.00%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic dissection
subjects affected / exposed	0 / 197 (0.00%)	0 / 204 (0.00%)	0 / 199 (0.00%)	1 / 201 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	0 / 197 (0.00%)	0 / 204 (0.00%)	1 / 199 (0.50%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 197 (0.00%)	1 / 204 (0.49%)	0 / 199 (0.00%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 197 (0.51%)	0 / 204 (0.00%)	0 / 199 (0.00%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis
subjects affected / exposed	1 / 197 (0.51%)	0 / 204 (0.00%)	0 / 199 (0.00%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
Additional description: Asthma AE occurring over the randomized treatment period correspond to patients who had a severe exacerbation event.
subjects affected / exposed	0 / 197 (0.00%)	1 / 204 (0.49%)	0 / 199 (0.00%)	0 / 201 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Foot deformity
subjects affected / exposed	0 / 197 (0.00%)	0 / 204 (0.00%)	1 / 199 (0.50%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metatarsalgia
subjects affected / exposed	0 / 197 (0.00%)	0 / 204 (0.00%)	1 / 199 (0.50%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 197 (0.00%)	0 / 204 (0.00%)	1 / 199 (0.50%)	0 / 201 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 197 (0.00%)	1 / 204 (0.49%)	0 / 199 (0.00%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 197 (0.00%)	0 / 204 (0.00%)	0 / 199 (0.00%)	1 / 201 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	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	BD MDI 160	AS MDI 180	Placebo MDI
Total subjects affected by non serious adverse events
subjects affected / exposed	37 / 197 (18.78%)	31 / 204 (15.20%)	31 / 199 (15.58%)	29 / 201 (14.43%)	38 / 199 (19.10%)
Vascular disorders
Hypertension
subjects affected / exposed	4 / 197 (2.03%)	2 / 204 (0.98%)	0 / 199 (0.00%)	2 / 201 (1.00%)	2 / 199 (1.01%)
occurrences all number	4	2	0	2	2
Nervous system disorders
Headache
subjects affected / exposed	10 / 197 (5.08%)	10 / 204 (4.90%)	7 / 199 (3.52%)	11 / 201 (5.47%)	14 / 199 (7.04%)
occurrences all number	10	10	8	14	18
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 197 (1.02%)	2 / 204 (0.98%)	2 / 199 (1.01%)	4 / 201 (1.99%)	4 / 199 (2.01%)
occurrences all number	2	2	2	4	4
Nausea
subjects affected / exposed	1 / 197 (0.51%)	2 / 204 (0.98%)	5 / 199 (2.51%)	0 / 201 (0.00%)	5 / 199 (2.51%)
occurrences all number	1	2	5	0	5
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	2 / 197 (1.02%)	2 / 204 (0.98%)	5 / 199 (2.51%)	2 / 201 (1.00%)	0 / 199 (0.00%)
occurrences all number	2	2	5	2	0
Asthma
subjects affected / exposed	0 / 197 (0.00%)	2 / 204 (0.98%)	0 / 199 (0.00%)	3 / 201 (1.49%)	4 / 199 (2.01%)
occurrences all number	0	2	0	3	4
Dysphonia
subjects affected / exposed	4 / 197 (2.03%)	1 / 204 (0.49%)	2 / 199 (1.01%)	0 / 201 (0.00%)	0 / 199 (0.00%)
occurrences all number	5	1	2	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	15 / 197 (7.61%)	13 / 204 (6.37%)	10 / 199 (5.03%)	9 / 201 (4.48%)	11 / 199 (5.53%)
occurrences all number	16	13	10	9	12
Upper respiratory tract infection
subjects affected / exposed	2 / 197 (1.02%)	3 / 204 (1.47%)	4 / 199 (2.01%)	1 / 201 (0.50%)	2 / 199 (1.01%)
occurrences all number	2	3	4	1	2
COVID-19
subjects affected / exposed	2 / 197 (1.02%)	1 / 204 (0.49%)	1 / 199 (0.50%)	0 / 201 (0.00%)	4 / 199 (2.01%)
occurrences all number	2	1	1	0	5

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

11 Feb 2019

Clarified that sponsor provided IP dose frequency was QID; Confirmed that new IP was to be dispensed and used for in clinic FEV1 measurements at each visit; Clarified instructions regarding proper IP preparation, dispensing, and dosing for postdose assessments at each in clinic dosing visit; Clarified that IP was to be dosed before 10:00am at all in clinic dosing visits; Clarified that pre-dose and post-dose FEV1 measurements for the bronchodilator responsiveness test were in relation to sponsor provided Ventolin; Removed supine as position for measuring blood pressure.

06 Jul 2020

Updated the number of adult and adolescent subjects randomized from 600 to 1000, the number of subjects within each treatment arm from 120 to 200, and the number of subjects screened from 1000 to 2000, following the protocol specified blinded sample size reassessment that was conducted. Text was added to describe and justify a second blinded sample size re-estimation. Clarified the timepoints for some of the exploratory objectives and endpoints as “at Week 12”. Added justification to continue study enrolment and treatment during the COVID-19 pandemic. Added methodology that will be used to evaluate the impact of the COVID-19 pandemic on efficacy and safety variables. Introduced unified language for the country specific protocols, which included age limits in various countries. Minor clarifications to the inclusion and exclusion criteria, and to the study procedures. Added pregnancy testing to Visit 3 and Visit 5. Clarified that primary analysis treatment comparisons will exclude the children (ages 4-11 years) and specified that the analysis will be repeated to include children, but will be considered a supportive analysis of the dual-primary endpoint.

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 12-week, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel Group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT008 and PT007 Administered QID in Adults and Children 4 Years of Age or Older with Asthma (DENALI)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline FEV1 AUC0-6 hours over 12 weeks

Primary: Change from baseline FEV1 AUC0-6 hours over 12 weeks

Primary: Change from baseline in trough FEV1 at Week 12

Primary: Change from baseline in trough FEV1 at Week 12

Secondary: Time to 15% increase in FEV1 over the pre-treatment value on Day 1

Secondary: Time to 15% increase in FEV1 over the pre-treatment value on Day 1

Secondary: Asthma Control Questionnaire 7-item version (ACQ-7) clinically meaningful difference at Week 12

Secondary: Asthma Control Questionnaire 7-item version (ACQ-7) clinically meaningful difference at Week 12

Secondary: Change from baseline in trough FEV1 at Week 1

Secondary: Change from baseline in trough FEV1 at Week 1

Secondary: Duration of 15% increase in FEV1 over the pre-treatment value on Day 1

Secondary: Duration of 15% increase in FEV1 over the pre-treatment value on Day 1

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
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Clinical trials

Clinical Trial Results: A 12-week, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel Group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT008 and PT007 Administered QID in Adults and Children 4 Years of Age or Older with Asthma (DENALI)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline FEV1 AUC0-6 hours over 12 weeks

Primary: Change from baseline FEV1 AUC0-6 hours over 12 weeks

Primary: Change from baseline in trough FEV1 at Week 12

Primary: Change from baseline in trough FEV1 at Week 12

Secondary: Time to 15% increase in FEV1 over the pre-treatment value on Day 1

Secondary: Time to 15% increase in FEV1 over the pre-treatment value on Day 1

Secondary: Asthma Control Questionnaire 7-item version (ACQ-7) clinically meaningful difference at Week 12

Secondary: Asthma Control Questionnaire 7-item version (ACQ-7) clinically meaningful difference at Week 12

Secondary: Change from baseline in trough FEV1 at Week 1

Secondary: Change from baseline in trough FEV1 at Week 1

Secondary: Duration of 15% increase in FEV1 over the pre-treatment value on Day 1

Secondary: Duration of 15% increase in FEV1 over the pre-treatment value on Day 1

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A 12-week, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel Group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT008 and PT007 Administered QID in Adults and Children 4 Years of Age or Older with Asthma (DENALI)