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Clinical Trial Results:
A Randomized, Double-Blind, Double Dummy, Parallel Group, Multicenter 24 to 52 Week Variable Length Study to Assess the Efficacy and Safety of Budesonide, Glycopyrronium, and Formoterol Fumarate Metered Dose Inhaler (MDI) Relative to Budesonide and Formoterol Fumarate MDI and Symbicort® Pressurized MDI in Adult and Adolescent Participants with Inadequately Controlled Asthma (KALOS)

Summary
EudraCT number	2020-001520-34
Trial protocol	DK NL BG BE PL HU IT RO
Global end of trial date	21 Mar 2025

Results information
Results version number	v1(current)
This version publication date	23 Oct 2025
First version publication date	23 Oct 2025
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

D5982C00007

ISRCTN number

US NCT number

NCT04609878

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

1800 Concorde Pike, Wilmington, United States, DE 19803

Public contact

Global Clinical Head, AstraZeneca, +1 8772409479, information.center@astrazeneca.com

Scientific contact

Global Clinical Head, AstraZeneca, +1 8772409479, information.center@astrazeneca.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-002063-PIP01-16

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?

Yes

Analysis stage

Final

Date of interim/final analysis

12 Jun 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

21 Mar 2025

Global end of trial reached?

Yes

Global end of trial date

21 Mar 2025

Was the trial ended prematurely?

Main objective of the trial

This was a randomised, double-blind, double dummy, parallel group, multicenter 24 to 52 week variable length study to assess the efficacy and safety of budesonide, glycopyrronium, and formoterol fumarate metered dose inhaler (MDI) relative to budesonide and formoterol fumarate MDI and Symbicort® pressurized MDI in adult and adolescent participants with inadequately controlled asthma.

Protection of trial subjects

The protocol, protocol amendments, informed consent form (ICF), and other relevant documents (e.g., advertisements) were submitted to an Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the Investigator and reviewed and approved by the IRB/IEC before the study was initiated. The Investigator or their representative explained the nature of the study to the participant or their legally authorised representative and answered all questions regarding the study. Participants were informed that their participation was voluntary. Participants or their legally authorised representative were required to sign a statement of informed consent that met the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. The authorised person obtaining the informed consent must have also signed the ICF. Participants must have been re-consented to the most current version of the ICF(s) during their participation in the study.

Background therapy

Participants eligible for this study were required to be on a stable regimen of an inhaled asthma maintenance therapy defined as an Inhaled Corticosteroid (ICS)/Long-Acting β2-Agonist (LABA) for at least 4 weeks prior to Visit 1. After meeting all eligibility criteria, participants discontinued their medium or high dose ICS/LABA at Visit 1 and initiated run-in BFF MDI 320/9.6 μg taken BID until the evening prior to Visit 5 (randomisation) when the run-in BFF MDI was discontinued. All participants received albuterol sulfate inhalation aerosol or salbutamol sulfate inhalation aerosol, hereinafter referred to as albuterol, at Visit 1 for rescue use during the study.

Evidence for comparator

Actual start date of recruitment

15 Dec 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

India: 140

Country: Number of subjects enrolled

Japan: 52

Country: Number of subjects enrolled

Philippines: 111

Country: Number of subjects enrolled

Korea, Republic of: 40

Country: Number of subjects enrolled

Taiwan: 34

Country: Number of subjects enrolled

Thailand: 50

Country: Number of subjects enrolled

Viet Nam: 75

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Bulgaria: 298

Country: Number of subjects enrolled

Hungary: 130

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

New Zealand: 2

Country: Number of subjects enrolled

Poland: 199

Country: Number of subjects enrolled

Romania: 71

Country: Number of subjects enrolled

Spain: 33

Country: Number of subjects enrolled

Argentina: 361

Country: Number of subjects enrolled

Chile: 84

Country: Number of subjects enrolled

Peru: 164

Country: Number of subjects enrolled

Canada: 53

Country: Number of subjects enrolled

United States: 224

Worldwide total number of subjects

2144

EEA total number of subjects

754

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)

1566

From 65 to 84 years

508

85 years and over

Subject disposition

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Recruitment details

A total of 2274 subjects were randomised at 378 study centers in 20 countries from 15 December 2020. The last subject completed their last study visit on 21 March 2025. Of the 2274 randomised subjects, all populations excluded 125 subjects due to GCP violations and 5 subjects due to not receiving study therapy.

Screening details

Adult and adolescent subjects with inadequately controlled moderate to severe asthma were randomised to 1 of 4 treatment groups: BGF MDI 320/14.4/9.6 μg, BGF MDI 320/28.8/9.6 μg, BFF MDI, or Symbicort. Those who were eligible discontinued their medium or high dose ICS/LABA at Visit 1 and initiated run-in BFF MDI until randomisation.

Period 1 title

24 to 52-Wk Treatment Period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Blinding implementation details

All participants were centrally assigned to 1 of 4 randomised study interventions using a Randomisation and Trial Supply Management (RTSM). Before the study was initiated, the log-in information and directions for the RTSM were provided to each site.

Are arms mutually exclusive

Yes

BGF MDI 320/14.4/9.6 μg BID

Arm description

Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered-dose inhaler (MDI), 320/14.4/9.6 μg BID

Arm type

Experimental

Investigational medicinal product name

Budesonide, glycopyrronium, and formoterol fumarate pressurised inhalation suspension, desiccated flow path device

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation

Routes of administration

Inhalation use

Dosage and administration details

Two inhalations BID of 160/7.2/4.8 μg per actuation. Total daily dose: 640/28.8/19.2 μg.

BGF MDI 320/28.8/9.6 μg BID

Arm description

Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered-dose inhaler (MDI), 320/28.8/9.6 μg BID

Arm type

Experimental

Investigational medicinal product name

Budesonide, glycopyrronium, and formoterol fumarate pressurised inhalation suspension, desiccated flow path device

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation

Routes of administration

Inhalation use

Dosage and administration details

Two inhalations BID of 160/14.4/4.8 μg per actuation. Total daily dose: 640/57.6/19.2 μg.

BFF MDI 320/9.6 μg BID

Arm description

Budesonide/Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg BID

Arm type

Active comparator

Investigational medicinal product name

Budesonide/formoterol fumarate pressurised inhalation suspension, desiccated flow path device

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation

Routes of administration

Inhalation use

Dosage and administration details

Two inhalations BID of 160/4.8 μg per actuation. Total daily dose: 640/19.2 μg.

Symbicort® pMDI 320/9 μg BID

Arm description

Budesonide/Formoterol Fumarate pMDI 320/9 μg BID

Arm type

Active comparator

Investigational medicinal product name

Symbicort®

Investigational medicinal product code

Other name

Pharmaceutical forms

Pressurised inhalation

Routes of administration

Inhalation use

Dosage and administration details

Two inhalations BID of 160/4.5 μg per actuation. Total daily dose: 640/18 μg.

Number of subjects in period 1	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID	Symbicort® pMDI 320/9 μg BID
Started	342	594	606	602
Completed	316	541	560	551
Not completed	26	53	46	51
Consent withdrawn by subject	12	30	29	28
Physician decision	3	3	8	4
Adverse event, non-fatal	4	2	2	3
Death	1	1	1	2
Not specified	2	6	1	3
Failure to meet randomisation criteria	1	-	1	1
Non-compliance with study drug	-	2	-	-
Lost to follow-up	2	5	2	6
Withdrawal by parent/guardian	-	2	1	1
Development of study-specific withdrawal criteria	-	1	-	-
Lack of efficacy	1	1	1	3

Baseline characteristics

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Reporting group title

BGF MDI 320/14.4/9.6 μg BID

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered-dose inhaler (MDI), 320/14.4/9.6 μg BID

Reporting group title

BGF MDI 320/28.8/9.6 μg BID

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered-dose inhaler (MDI), 320/28.8/9.6 μg BID

Reporting group title

BFF MDI 320/9.6 μg BID

Reporting group description

Budesonide/Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg BID

Reporting group title

Symbicort® pMDI 320/9 μg BID

Reporting group description

Budesonide/Formoterol Fumarate pMDI 320/9 μg BID

Reporting group values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID	Symbicort® pMDI 320/9 μg BID	Total
Number of subjects	342	594	606	602	2144
Age Categorical
Units: Participants
Adolescents (12-17 years)	10	16	22	22	70
Adults (18-64 years)	247	437	450	432	1566
From 65-84 years	85	141	134	148	508
Age Continuous
Units: years
arithmetic mean (standard deviation)	51.6 ( 16.0 )	52.7 ( 14.8 )	51.9 ( 15.3 )	53.1 ( 14.7 )	-
Gender Categorical
Units: Participants
Female	228	384	376	403	1391
Male	114	210	230	199	753
Race
Units: Subjects
White	216	384	397	378	1375
Asian	72	147	142	157	518
Black or African American	9	12	15	9	45
American Indian or Alaska Native	4	2	5	4	15
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Other	41	49	47	54	191
Ethnicity
Units: Subjects
Hispanic or Latino	112	184	178	190	664
Not Hispanic or Latino	230	410	428	412	1480
Prior Inhaled Corticosteroid (ICS) Dose
Classification of the prior inhaled corticosteroid (ICS) total daily dose (defined as a stable dose for at least 4 weeks prior to Visit 1).
Units: Subjects
Low	9	4	3	3	19
Medium	176	351	341	344	1212
High	156	239	261	255	911
Missing	1	0	1	0	2
Baseline Severe Asthma Exacerbation History Within the Prior Year
Units: Subjects
0 exacerbations	74	204	216	204	698
1 exacerbation	186	275	261	272	994
≥2 exacerbations	82	115	129	126	452
Baseline Pre-bronchodilator Percent Predicted FEV1 (%)
Units: Percentage
arithmetic mean (standard deviation)	58.6 ( 12.5 )	58.3 ( 12.1 )	59.2 ( 12.0 )	58.4 ( 12.4 )	-
Baseline Reversibility (%)
Reversibility (%) was calculated as (Post-Albuterol FEV1 - Pre-Albuterol FEV1)/Pre-Albuterol FEV1 x100
Units: Percentage
arithmetic mean (standard deviation)	24.5 ( 19.8 )	23.6 ( 19.9 )	22.5 ( 17.4 )	22.0 ( 16.9 )	-

End points

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Reporting group title

BGF MDI 320/14.4/9.6 μg BID

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered-dose inhaler (MDI), 320/14.4/9.6 μg BID

Reporting group title

BGF MDI 320/28.8/9.6 μg BID

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) metered-dose inhaler (MDI), 320/28.8/9.6 μg BID

Reporting group title

BFF MDI 320/9.6 μg BID

Reporting group description

Budesonide/Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg BID

Reporting group title

Symbicort® pMDI 320/9 μg BID

Reporting group description

Budesonide/Formoterol Fumarate pMDI 320/9 μg BID

Subject analysis set title

BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This reporting arm combines the 2 treatment groups BFF MDI 320/9.6 μg and Symbicort pMDI 320/9 μg from protocol D5982C00007 (2020-001520-34). In the EU regional multiple testing approach, BGF MDI was compared to these combined treatment groups (with a total of 1208 subjects in the Efficacy Set; 606 in the BFF treatment group and 602 in the Symbicort treatment group).

Subject analysis set title

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This reporting arm contains the pooled population of subjects from protocol D5982C00007 (2020-001520-34) and protocol D5982C00008 (2020-001521-31) who received BGF MDI 320/14.4/9.6 μg study intervention. A total of 725 subjects were included in this pooled analysis Efficacy Set comprising 342 subjects from D5982C00007 (KALOS) and 383 subjects from D5982C00008 (LOGOS).

Subject analysis set title

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This reporting arm contains the pooled population of subjects from protocol D5982C00007 (2020-001520-34) and protocol D5982C00008 (2020-001521-31) who received BGF MDI 320/28.8/9.6 μg study intervention. A total of 1179 subjects were included in this pooled analysis Efficacy Set comprising 594 subjects from D5982C00007 (KALOS) and 585 subjects from D5982C00008 (LOGOS).

Subject analysis set title

Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This reporting arm contains the pooled population of subjects from protocol D5982C00007 (2020-001520-34) and protocol D5982C00008 (2020-001521-31) who received BFF MDI 320/9.6 μg or Symbicort pMDI 320/9 μg BID study intervention. In the EU regional approach of both studies, BGF MDI was compared to subjects who received BFF MDI or Symbicort pMDI. A total of 2400 subjects were included in this pooled analysis Efficacy Set comprising 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS).

Primary: Change from baseline in morning pre-dose trough FEV1 (L) over 24 weeks

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End point title

Change from baseline in morning pre-dose trough FEV1 (L) over 24 weeks ^[1]

End point description

Change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) over 24 weeks. Treatment policy was implemented to handle all intercurrent events (ICEs) with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Primary

End point timeframe

Over 24 weeks

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: In the EU regional multiple testing approach, BGF MDI was compared to the combined BFF MDI 320/9.6 µg and Symbicort 320/9 µg reporting groups. Therefore, data for these two reporting groups were presented combined, and not individually for the BFF MDI and Symbicort reporting groups

End point values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID
Number of subjects analysed	339	593	1204
Units: Litres
least squares mean (standard error)
Estimate (SE)	0.124 ( 0.014 )	0.155 ( 0.011 )	0.099 ( 0.008 )

Change from BL in Pre-dose Trough FEV1 (L)

Statistical analysis description

The repeated measures ANCOVA model included treatment, visit, prior ICS dose (medium vs. high), and treatment-by-visit interaction as categorical covariates and baseline trough FEV1 and percent reversibility as continuous covariates.

Comparison groups

BGF MDI 320/14.4/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1543

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.126

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.025

Confidence interval

level

95%

sides

2-sided

lower limit

-0.007

upper limit

0.056

Variability estimate

Standard error of the mean

Dispersion value

0.016

Notes
[2] - An increase in estimate for comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.

Change from BL in Pre-dose Trough FEV1 (L)

Statistical analysis description

Comparison groups

BGF MDI 320/28.8/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1797

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.001 ^[4]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.056

Confidence interval

level

95%

sides

2-sided

lower limit

0.031

upper limit

0.082

Variability estimate

Standard error of the mean

Dispersion value

0.013

Notes
[3] - An increase in estimate for comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.
[4] - Statistically significant per the Type I error control procedure.

Primary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations

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End point title

Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations

End point description

Rate of severe asthma exacerbations was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (2020-001521-31). An asthma exacerbation was severe if it resulted in at least 1 of the following: a course of systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required treatment with systemic corticosteroids, an inpatient hospitalisation, or death related to asthma. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Primary

End point timeframe

Up to 52 weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	725	1179	2400 ^[5]
Units: Exacerbations/Subject Years
number (not applicable)
Number of subjects with exacerbations	257	398	914
Percentage of subjects with exacerbations	35.4	33.8	38.1
Number of exacerbations	422	612	1444
Total time at risk (subject-years)	723.6	1077.9	2188.7
Adjusted exacerbation rate per year	0.533	0.541	0.633

Notes
[5] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Rate of Severe Asthma Exacerbations

Statistical analysis description

The analysis for rate ratio used a negative binomial regression. Treatments were compared adjusting for baseline trough FEV1, percent reversibility, baseline severe asthma exacerbation history (0, 1, ≥2), prior ICS dose (medium vs. high), region, and study.

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3579

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.012 ^[7]

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.855

Confidence interval

level

95%

sides

2-sided

lower limit

0.757

upper limit

0.966

Notes
[6] - A rate ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[7] - Statistically significant per the Type I error control procedure.

Rate of Severe Asthma Exacerbations

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3125

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.017 ^[9]

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.842

Confidence interval

level

95%

sides

2-sided

lower limit

0.731

upper limit

0.97

Notes
[8] - A rate ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[9] - Statistically significant per the Type I error control procedure.

Secondary: Change from baseline in FEV1 AUC0-3 (L) over 24 weeks

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End point title

Change from baseline in FEV1 AUC0-3 (L) over 24 weeks ^[10]

End point description

Change from baseline in FEV1 AUC0-3 (L) over 24 weeks. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Over 24 weeks

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: In the EU regional multiple testing approach, BGF MDI was compared to the combined BFF MDI 320/9.6 µg and Symbicort 320/9 µg reporting groups. Therefore, data for these two reporting groups were presented combined, and not individually for the BFF MDI and Symbicort reporting groups

End point values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID
Number of subjects analysed	341	593	1205
Units: Litres
least squares mean (standard error)
Estimate (SE)	0.284 ( 0.014 )	0.308 ( 0.010 )	0.239 ( 0.007 )

Change from Baseline in FEV1 AUC0-3 (L)

Statistical analysis description

Comparison groups

BGF MDI 320/14.4/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1546

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.003 ^[12]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.045

Confidence interval

level

95%

sides

2-sided

lower limit

0.015

upper limit

0.076

Variability estimate

Standard error of the mean

Dispersion value

0.015

Notes
[11] - An increase in estimate for comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.
[12] - Nominally significant due to placement in Type I error control for EU submission.

Change from Baseline in FEV1 AUC0-3 (L)

Statistical analysis description

Comparison groups

BGF MDI 320/28.8/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1798

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.001 ^[14]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.069

Confidence interval

level

95%

sides

2-sided

lower limit

0.044

upper limit

0.094

Variability estimate

Standard error of the mean

Dispersion value

0.013

Notes
[13] - An increase in estimate for comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.
[14] - Statistically significant per the Type I error control procedure.

Secondary: Onset of action on Day 1: Absolute change in FEV1 (L) at 5 minutes on Day 1

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End point title

Onset of action on Day 1: Absolute change in FEV1 (L) at 5 minutes on Day 1

End point description

Onset of action (L) on Day 1: Absolute change in FEV1 at 5 minutes on Day 1. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

On Day 1

End point values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID	Symbicort® pMDI 320/9 μg BID
Number of subjects analysed	329	561	579	573
Units: Litres
number (standard deviation)
Mean change from baseline (SD)	0.129	0.161	0.143	0.122

Absolute Change in FEV1 (L) at 5 Min on Day 1

Statistical analysis description

The analysis was performed using a within-active-treatment group T-test to demonstrate that the mean change from baseline in FEV1 at 5 minutes post-dose was statistically greater than 0.1 L.

Comparison groups

BGF MDI 320/28.8/9.6 μg BID v BFF MDI 320/9.6 μg BID v Symbicort® pMDI 320/9 μg BID

Number of subjects included in analysis

1713

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.001 ^[16]

Method

t-test, 1-sided

Parameter type

Within BGF MDI group T-test estimate

Point estimate

0.161

Confidence interval

level

95%

sides

2-sided

lower limit

0.145

upper limit

0.177

Notes
[15] - Analysis was within the BGF MDI 320/28.8/9.6 μg group. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing value at the visit were included in the analysis.
[16] - Statistically significant per the Type I error control procedure.

Absolute Change in FEV1 (L) at 5 Min on Day 1

Statistical analysis description

The analysis was performed using a within-active-treatment group T-test to demonstrate that the mean change from baseline in FEV1 at 5 minutes post-dose was statistically greater than 0.1 L.

Comparison groups

BGF MDI 320/14.4/9.6 μg BID v BFF MDI 320/9.6 μg BID v Symbicort® pMDI 320/9 μg BID

Number of subjects included in analysis

1481

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.003 ^[18]

Method

t-test, 1-sided

Parameter type

Within BGF MDI group T-test estimate

Point estimate

0.129

Confidence interval

level

95%

sides

2-sided

lower limit

0.108

upper limit

0.15

Notes
[17] - Analysis was within the BGF MDI 320/14.4/9.6 μg group. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing value at the visit were included in the analysis.
[18] - Nominally significant due to placement in Type I error control for EU submission.

Secondary: Rate of severe asthma exacerbations

Top of page

End point title

Rate of severe asthma exacerbations ^[19]

End point description

Rate of severe asthma exacerbations. An asthma exacerbation was severe if it resulted in at least 1 of the following: a course of systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required treatment with systemic corticosteroids, an inpatient hospitalisation, or death related to asthma. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Up to 52 weeks

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: In the EU regional multiple testing approach, BGF MDI was compared to the combined BFF MDI 320/9.6 µg and Symbicort 320/9 µg reporting groups. Therefore, data for these two reporting groups were presented combined, and not individually for the BFF MDI and Symbicort reporting groups

End point values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID
Number of subjects analysed	342	594	1208
Units: Exacerbations/Subject years
number (not applicable)
Number of subjects with exacerbations	143	218	528
Percentage of subjects with exacerbations	41.8	36.7	43.7
Number of exacerbations	242	353	877
Total time at risk (subject-years)	336.6	540.5	1097.5
Adjusted exacerbation rate per year	0.64	0.62	0.77

Rate of Severe Asthma Exacerbations

Statistical analysis description

The analysis for rate ratio used a negative binomial regression (applying a bootstrap approach for multiple imputation). Treatments were compared adjusting for baseline trough FEV1, percent reversibility, baseline severe asthma exacerbation history (0, 1, ≥2), prior ICS dose (medium vs. high), and region.

Comparison groups

BGF MDI 320/28.8/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1802

Analysis specification

Pre-specified

Analysis type

superiority ^[20]

P-value

= 0.007 ^[21]

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.804

Confidence interval

level

95%

sides

2-sided

lower limit

0.685

upper limit

0.943

Notes
[20] - A rate ratio below 1 favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates were included in the analysis.
[21] - Nominally significant due to placement in Type I error control for EU submission.

Rate of Severe Asthma Exacerbations

Statistical analysis description

Comparison groups

BGF MDI 320/14.4/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1550

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

P-value

= 0.041 ^[23]

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.821

Confidence interval

level

95%

sides

2-sided

lower limit

0.679

upper limit

0.992

Notes
[22] - A rate ratio below 1 favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates were included in the analysis.
[23] - Nominally significant due to placement in Type I error control for EU submission.

Secondary: Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks

Top of page

End point title

Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks ^[24]

End point description

Percentage of responders in the Asthma Control Questionnaire (ACQ)-7 (≥0.5 decrease equals response) over 24 weeks. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Over 24 weeks

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: In the EU regional multiple testing approach, BGF MDI was compared to the combined BFF MDI 320/9.6 µg and Symbicort 320/9 µg reporting groups. Therefore, data for these two reporting groups were presented combined, and not individually for the BFF MDI and Symbicort reporting groups

End point values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID
Number of subjects analysed	339	592	1203
Units: Responders
number (not applicable)
Number of responders	222	418	799
Percentage (%)	65.5	70.6	66.4

Percentage of Responders in ACQ-7

Statistical analysis description

The logistic regression model included treatment and prior ICS dose (medium vs. high) as categorical covariates and baseline ACQ-7 score, baseline trough FEV1, and percent reversibility as continuous covariates.

Comparison groups

BGF MDI 320/28.8/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1795

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.099

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.49

Notes
[25] - An odds ratio >1 for the comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.

Percentage of Responders in ACQ-7

Statistical analysis description

Comparison groups

BGF MDI 320/14.4/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1542

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.862

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.27

Notes
[26] - An odds ratio >1 for the comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.

Secondary: Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks

Top of page

End point title

Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks ^[27]

End point description

Percentage of responders in the ACQ-5 (≥0.5 decrease equals response) over 24 weeks. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Over 24 weeks

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: In the EU regional multiple testing approach, BGF MDI was compared to the combined BFF MDI 320/9.6 µg and Symbicort 320/9 µg reporting groups. Therefore, data for these two reporting groups were presented combined, and not individually for the BFF MDI and Symbicort reporting groups

End point values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID
Number of subjects analysed	340	592	1203
Units: Responders
number (not applicable)
Number of responders	237	428	840
Percentage (%)	69.7	72.3	69.8

Percentage of Responders in ACQ-5

Statistical analysis description

The logistic regression model included treatment and prior ICS dose (medium vs. high) as categorical covariates and baseline ACQ-5 score, baseline trough FEV1, and percent reversibility as continuous covariates.

Comparison groups

BGF MDI 320/28.8/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1795

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.33

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.4

Notes
[28] - An odds ratio >1 for the comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.

Percentage of Responders in ACQ-5

Statistical analysis description

Comparison groups

BGF MDI 320/14.4/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1543

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.877

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

1.33

Notes
[29] - An odds ratio >1 for the comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.

Secondary: Percentage of responders in the AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks

Top of page

End point title

Percentage of responders in the AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks ^[30]

End point description

Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s)+12) (≥0.5 increase equals response) over 24 weeks. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Over 24 weeks

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: In the EU regional multiple testing approach, BGF MDI was compared to the combined BFF MDI 320/9.6 µg and Symbicort 320/9 µg reporting groups. Therefore, data for these two reporting groups were presented combined, and not individually for the BFF MDI and Symbicort reporting groups

End point values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID
Number of subjects analysed	323	566	1153
Units: Responders
number (not applicable)
Number of responders	187	333	645
Percentage (%)	57.9	58.8	55.9

Percentage of Responders in AQLQ(s)+12

Statistical analysis description

The logistic regression model included treatment and prior ICS dose (medium vs. high) as categorical covariates and baseline AQLQ(s)+12 score, baseline trough FEV1, and percent reversibility as continuous covariates.

Comparison groups

BGF MDI 320/28.8/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1719

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

= 0.439

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.35

Notes
[31] - An odds ratio >1 for the comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.

Percentage of Responders in AQLQ(s)+12

Statistical analysis description

Comparison groups

BGF MDI 320/14.4/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1476

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.948

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.29

Notes
[32] - An odds ratio >1 for the comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.

Secondary: Percentage of responders in SGRQ (≥4.0 decrease equals response) over 24 weeks

Top of page

End point title

Percentage of responders in SGRQ (≥4.0 decrease equals response) over 24 weeks ^[33]

End point description

Percentage of responders in the St. George’s Respiratory Questionnaire (SGRQ) (≥4.0 unit decrease equals response) over 24 weeks. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Over 24 weeks

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: In the EU regional multiple testing approach, BGF MDI was compared to the combined BFF MDI 320/9.6 µg and Symbicort 320/9 µg reporting groups. Therefore, data for these two reporting groups were presented combined, and not individually for the BFF MDI and Symbicort reporting groups

End point values	BGF MDI 320/14.4/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID	BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID
Number of subjects analysed	331	581	1158
Units: Responders
number (not applicable)
Number of responders	215	426	771
Percentage (%)	65.0	73.3	66.6

Percentage of Responders in SGRQ

Statistical analysis description

The logistic regression included treatment and prior ICS dose (medium vs. high) as categorical covariates and baseline SGRQ score, baseline trough FEV1, and percent reversibility as continuous covariates.

Comparison groups

BGF MDI 320/28.8/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1739

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.021 ^[35]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

1.64

Notes
[34] - An odds ratio >1 for the comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.
[35] - Nominally significant due to placement in Type I error control for EU submission.

Percentage of Responders in SGRQ

Statistical analysis description

The logistic regression model included treatment and prior ICS dose (medium vs. high) as categorical covariates and baseline SGRQ score, baseline trough FEV1, and percent reversibility as continuous covariates.

Comparison groups

BGF MDI 320/14.4/9.6 μg BID v BFF MDI 320/9.6 μg BID or Symbicort pMDI 320/9 μg BID

Number of subjects included in analysis

1489

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

P-value

= 0.593

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.21

Notes
[36] - An odds ratio greater than 1 for the comparison favors study drug. The number of subjects analysed is based on the Efficacy Set. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.

Secondary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations for participants with percent predicted FEV1 ≤55% at baseline

Top of page

End point title

Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations for participants with percent predicted FEV1 ≤55% at baseline

End point description

Rate of severe asthma exacerbations for subjects with percent predicted FEV1 ≤55% at baseline was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (2020-001521-31). An asthma exacerbation was severe if it resulted in at least 1 of the following: a course of systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required treatment with systemic corticosteroids, an inpatient hospitalisation, or death related to asthma. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Up to 52 Weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	251	417	814 ^[37]
Units: Exacerbations/Subject Years
number (not applicable)
Number of subjects with exacerbations	106	162	363
Percentage of subjects with exacerbations	42.2	38.8	44.6
Number of exacerbations	194	264	605
Total time at risk (subject-years)	249.1	377.4	739.2
Adjusted exacerbation rate per year	0.733	0.663	0.797

Notes
[37] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Rate of Severe Asthma Exacerbations

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

1231

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

P-value

= 0.058

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.831

Confidence interval

level

95%

sides

2-sided

lower limit

0.686

upper limit

1.006

Notes
[38] - A rate ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.

Rate of Severe Asthma Exacerbations

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

1065

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

= 0.455

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.738

upper limit

1.146

Notes
[39] - A rate ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.

Secondary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations for participants with ≥1 severe exacerbation in the 12 months prior to Visit 1

Top of page

End point title

Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations for participants with ≥1 severe exacerbation in the 12 months prior to Visit 1

End point description

Rate of severe asthma exacerbations for subjects with ≥1 severe exacerbation in the 12 months prior to Visit 1 was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (2020-001521-31). An asthma exacerbation was severe if it resulted in at least 1 of the following: a course of systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required treatment with systemic corticosteroids, an inpatient hospitalisation, or death related to asthma. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Up to 52 weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	481	665	1367 ^[40]
Units: Exacerbations/Subject Years
number (not applicable)
Number of subjects with exacerbations	200	255	590
Percentage of subjects with exacerbations	41.6	38.3	43.2
Number of exacerbations	341	419	976
Total time at risk (subject-years)	478.7	626.3	1279.2
Adjusted exacerbation rate per year	0.707	0.653	0.757

Notes
[40] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Rate of Severe Asthma Exacerbations

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

2032

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.055

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.863

Confidence interval

level

95%

sides

2-sided

lower limit

0.741

upper limit

1.003

Notes
[41] - A rate ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.

Rate of Severe Asthma Exacerbations

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

1848

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

= 0.417

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.934

Confidence interval

level

95%

sides

2-sided

lower limit

0.791

upper limit

1.102

Notes
[42] - A rate ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.

Secondary: Pooled (KALOS/LOGOS): Time to first severe asthma exacerbation

Top of page

End point title

Pooled (KALOS/LOGOS): Time to first severe asthma exacerbation

End point description

Time to first severe asthma exacerbation was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (2020-001521-31). Time to first severe asthma exacerbation was the time from the first dose of study medication to the time of onset of the first severe asthma exacerbation. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Up to 52 weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	723	1175	2392 ^[43]
Units: Weeks
number (not applicable)
Number of subjects with exacerbations	257	398	914
Percentage of subjects with exacerbations	35.5	33.9	38.2
Kaplan-Meier estimate at 24 weeks (%)	18.9	18.6	21.6
Kaplan-Meier estimate at 52 weeks (%)	36.0	35.5	40.3

Notes
[43] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Time to First Severe Asthma Exacerbation

Statistical analysis description

The Cox regression model adjusted for baseline severe asthma exacerbation history (0, 1, ≥2), prior ICS dose (medium vs. high), region, study, baseline trough FEV1, and percent reversibility.

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3567

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.005 ^[45]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.845

Confidence interval

level

95%

sides

2-sided

lower limit

0.751

upper limit

0.951

Notes
[44] - A hazard ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[45] - Endpoint not included in the Type I error control procedure.

Time to First Severe Asthma Exacerbation

Statistical analysis description

The Cox regression model adjusted for baseline severe asthma exacerbation history (0, 1, ≥2), prior ICS dose (medium vs. high), region, study, baseline trough FEV1, and percent reversibility.

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3115

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

= 0.03 ^[47]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.858

Confidence interval

level

95%

sides

2-sided

lower limit

0.747

upper limit

0.986

Notes
[46] - A hazard ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[47] - Endpoint not included in the Type I error control procedure.

Secondary: Pooled (KALOS/LOGOS): Rate of moderate or severe asthma exacerbations

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End point title

Pooled (KALOS/LOGOS): Rate of moderate or severe asthma exacerbations

End point description

Rate of moderate or severe asthma exacerbations was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (2020-001521-31). An asthma exacerbation was severe if it resulted in at least 1 of the following: systemic corticosteroids for 3 days to treat symptoms of asthma worsening, an ER/urgent care visit that required treatment with systemic corticosteroids, an inpatient hospitalisation, or death related to asthma. A moderate asthma exacerbation was defined as worsening of asthma that resulted in an additional ICS for 3 days. Consecutive exacerbations with start/stop days ≤7 days apart were considered the same event of the highest severity. Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Up to 52 weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	725	1179	2400 ^[48]
Units: Exacerbations/Subject Years
number (not applicable)
Number of subjects with exacerbations	259	406	933
Percentage of subjects with exacerbations	35.7	34.4	38.9
Number of exacerbations	429	625	1483
Total time at risk (subject-years)	723.3	1077.3	2187.0
Adjusted exacerbation rate per year	0.545	0.555	0.653

Notes
[48] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Rate of Moderate or Severe Asthma Exacerbations

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3579

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

P-value

= 0.008 ^[50]

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.754

upper limit

0.959

Notes
[49] - A rate ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[50] - Endpoint not included in the Type I error control procedure.

Rate of Moderate or Severe Asthma Exacerbations

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3125

Analysis specification

Pre-specified

Analysis type

superiority ^[51]

P-value

= 0.011 ^[52]

Method

Negative binomial regression

Parameter type

Rate ratio

Point estimate

0.834

Confidence interval

level

95%

sides

2-sided

lower limit

0.725

upper limit

0.96

Notes
[51] - A rate ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[52] - Endpoint not included in the Type I error control procedure.

Secondary: Pooled (KALOS/LOGOS): Time to first moderate or severe asthma exacerbation

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End point title

Pooled (KALOS/LOGOS): Time to first moderate or severe asthma exacerbation

End point description

End point type

Secondary

End point timeframe

Up to 52 weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	723	1175	2392 ^[53]
Units: Weeks
number (not applicable)
Number of subjects with exacerbations	259	406	933
Percentage of subjects with exacerbations	35.8	34.6	39.0
Kaplan-Meier estimate at 24 weeks (%)	19.1	19.1	22.1
Kaplan-Meier estimate at 52 weeks (%)	36.3	36.2	41.1

Notes
[53] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Time to First Moderate/Severe Asthma Exacerbation

Statistical analysis description

The Cox regression model adjusted for baseline severe asthma exacerbation history (0, 1, ≥2), prior ICS dose (medium vs. high), region, study, baseline trough FEV1, and percent reversibility.

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3567

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.004 ^[55]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.843

Confidence interval

level

95%

sides

2-sided

lower limit

0.751

upper limit

0.948

Notes
[54] - A hazard ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[55] - Endpoint not included in the Type I error control procedure.

Time to First Severe Asthma Exacerbation

Statistical analysis description

The Cox regression model adjusted for baseline severe asthma exacerbation history (0, 1, ≥2), prior ICS dose (medium vs. high), region, study, baseline trough FEV1, and percent reversibility.

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3115

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.017 ^[57]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.845

Confidence interval

level

95%

sides

2-sided

lower limit

0.736

upper limit

0.97

Notes
[56] - A hazard ratio below 1 favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[57] - Endpoint not included in the Type I error control procedure.

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks

Top of page

End point title

Pooled (KALOS/LOGOS): Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks

End point description

Percentage responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (2020-001521-31). Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Over 24 weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	721	1173	2383 ^[58]
Units: Responders
number (not applicable)
Number of responders	486	821	1556
Percentage (%)	67.4	70.0	65.3

Notes
[58] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Pooled Percentage of Responders in ACQ-7

Statistical analysis description

The logistic regression model included treatment, study, and prior ICS dose (medium vs. high) as categorical covariates and baseline ACQ-7 score, baseline trough FEV1, and percent reversibility as continuous covariates.

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3556

Analysis specification

Pre-specified

Analysis type

superiority ^[59]

P-value

= 0.003 ^[60]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

1.47

Notes
[59] - An odds ratio >1 for the comparison favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[60] - Endpoint not included in the Type I error control procedure.

Pooled Percentage of Responders in ACQ-7

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3104

Analysis specification

Pre-specified

Analysis type

superiority ^[61]

P-value

= 0.217 ^[62]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.34

Notes
[61] - An odds ratio >1 for the comparison favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[62] - Endpoint not included in the Type I error control procedure.

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks

Top of page

End point title

Pooled (KALOS/LOGOS): Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks

End point description

Percentage responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (2020-001521-31). Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Over 24 weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	722	1173	2383 ^[63]
Units: Responders
number (not applicable)
Number of responders	520	853	1666
Percentage (%)	72.0	72.7	69.9

Notes
[63] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Pooled Percentage of Responders in ACQ-5

Statistical analysis description

The logistic regression model included treatment, study, and prior ICS dose (medium vs. high) as categorical covariates and baseline ACQ-5 score, baseline trough FEV1, and percent reversibility as continuous covariates.

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3556

Analysis specification

Pre-specified

Analysis type

superiority ^[64]

P-value

= 0.057 ^[65]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

1.37

Notes
[64] - An odds ratio >1 for the comparison favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[65] - Endpoint not included in the Type I error control procedure.

Pooled Percentage of Responders in ACQ-5

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3105

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

P-value

= 0.173 ^[67]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.38

Notes
[66] - An odds ratio >1 for the comparison favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates used in the analysis model were included in the analysis.
[67] - Endpoint not included in the Type I error control procedure.

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks

Top of page

End point title

Pooled (KALOS/LOGOS): Percentage of responders in AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks

End point description

Percentage responders in the AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks was assessed in a pre-specified pooled analysis across replicate studies D5982C00007 and D5982C00008 (2020-001521-31). Treatment policy was implemented to handle all ICEs with the exception of initiation of new asthma therapy or use of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of study intervention, for which the composite strategy was implemented.

End point type

Secondary

End point timeframe

Over 24 weeks

End point values	Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID	Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID	Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID
Number of subjects analysed	695	1124	2290 ^[68]
Units: Responders
number (not applicable)
Number of responders	415	654	1293
Percentage (%)	59.7	58.2	56.5

Notes
[68] - N=2400; 1208 subjects from D5982C00007 (KALOS) and 1192 subjects from D5982C00008 (LOGOS)

Pooled Percentage of Responders in AQLQ(s)+12

Statistical analysis description

The logistic regression model included treatment, study, and prior ICS dose (medium vs. high) as categorical covariates and baseline AQLQ(s)+12 score, baseline trough FEV1, and percent reversibility as continuous covariates.

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/28.8/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

3414

Analysis specification

Pre-specified

Analysis type

superiority ^[69]

P-value

= 0.215 ^[70]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.29

Notes
[69] - An odds ratio greater than 1 for the comparison favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[70] - Endpoint not included in the Type I error control procedure.

Pooled Percentage of Responders in AQLQ(s)+12

Statistical analysis description

Comparison groups

Pooled (KALOS/LOGOS) BGF MDI 320/14.4/9.6 µg BID v Pooled (KALOS/LOGOS) BFF MDI or Symbicort pMDI BID

Number of subjects included in analysis

2985

Analysis specification

Pre-specified

Analysis type

superiority ^[71]

P-value

= 0.275 ^[72]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

1.33

Notes
[71] - An odds ratio >1 for the comparison favors study drug. Number of subjects analysed is based on the Efficacy Set, which excluded 7 subjects in D5982C00008 who were randomised multiple times. Only subjects with nonmissing covariates were included in the analysis.
[72] - Endpoint not included in the Type I error control procedure.

Adverse events

Top of page

Timeframe for reporting adverse events

From first intake of study intervention after Visit 1, during screening, and throughout the Treatment Period and including the follow-up period. Serious adverse events were recorded from the time of signing of the informed consent form.

Adverse event reporting additional description

Adverse events were reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally authorised representative). The Investigator and any designees were responsible for detecting, documenting, and recording events that meet the definition of an AE.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.1

Reporting group title

BGF MDI 320/14.4/9.6 μg BID

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate MDI, 320/14.4/9.6 μg BID

Reporting group title

Symbicort pMDI 320/9 μg BID

Reporting group description

Symbicort pMDI 320/9 μg BID

Reporting group title

BFF MDI 320/9.6 μg BID

Reporting group description

Budesonide/Formoterol Fumarate MDI, 320/9.6 μg

Reporting group title

BGF MDI 320/28.8/9.6 μg BID

Reporting group description

Budesonide, Glycopyrronium, and Formoterol Fumarate MDI, 320/28.8/9.6 μg BID

Serious adverse events	BGF MDI 320/14.4/9.6 μg BID	Symbicort pMDI 320/9 μg BID	BFF MDI 320/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID
Total subjects affected by serious adverse events
subjects affected / exposed	18 / 342 (5.26%)	32 / 602 (5.32%)	34 / 606 (5.61%)	32 / 594 (5.39%)
number of deaths (all causes)	1	2	1	1
number of deaths resulting from adverse events	1	2	1	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Ovarian cancer
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngeal cancer
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mucinous breast carcinoma
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer stage II
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Varicose vein
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Sudden death
subjects affected / exposed	1 / 342 (0.29%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Acquired hydrocele
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenomyosis
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	3 / 342 (0.88%)	8 / 602 (1.33%)	11 / 606 (1.82%)	11 / 594 (1.85%)
occurrences causally related to treatment / all	0 / 3	0 / 8	0 / 11	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paranasal sinus inflammation
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillar hypertrophy
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Panic attack
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Craniofacial fracture
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lip injury
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	2 / 594 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	3 / 606 (0.50%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	2 / 606 (0.33%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Atrial flutter
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervicogenic vertigo
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	2 / 342 (0.58%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Middle ear inflammation
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ileus
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary obstruction
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Goitre
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint instability
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	4 / 606 (0.66%)	4 / 594 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 342 (0.29%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carbuncle
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 342 (0.29%)	1 / 602 (0.17%)	2 / 606 (0.33%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of asthma
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye abscess
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dengue haemorrhagic fever
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media chronic
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	0 / 606 (0.00%)	1 / 594 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral pericarditis
subjects affected / exposed	0 / 342 (0.00%)	0 / 602 (0.00%)	1 / 606 (0.17%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tubo-ovarian abscess
subjects affected / exposed	1 / 342 (0.29%)	0 / 602 (0.00%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 342 (0.00%)	1 / 602 (0.17%)	0 / 606 (0.00%)	0 / 594 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	BGF MDI 320/14.4/9.6 μg BID	Symbicort pMDI 320/9 μg BID	BFF MDI 320/9.6 μg BID	BGF MDI 320/28.8/9.6 μg BID
Total subjects affected by non serious adverse events
subjects affected / exposed	81 / 342 (23.68%)	119 / 602 (19.77%)	123 / 606 (20.30%)	109 / 594 (18.35%)
Infections and infestations
Nasopharyngitis
subjects affected / exposed	37 / 342 (10.82%)	52 / 602 (8.64%)	51 / 606 (8.42%)	49 / 594 (8.25%)
occurrences all number	40	60	57	55
COVID-19
subjects affected / exposed	28 / 342 (8.19%)	33 / 602 (5.48%)	30 / 606 (4.95%)	30 / 594 (5.05%)
occurrences all number	28	34	30	31
Upper respiratory tract infection
subjects affected / exposed	21 / 342 (6.14%)	39 / 602 (6.48%)	52 / 606 (8.58%)	43 / 594 (7.24%)
occurrences all number	36	56	73	65

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Were there any global substantial amendments to the protocol? Yes

27 Oct 2020

Clarity was required for the Type 1 Error Control for each region, an equivalence table was added for oral corticosteroids in the treatment of asthma exacerbations, and contraceptive language was updated to address Europe’s (EU) recommendation for contraception and pregnancy testing in clinical trials.

07 Jan 2022

An amendment was required due to recruitment challenges, and to make 1) updates to the inclusion and exclusion criteria, 2) adjustment to the multiple testing procedures, 3) a reduction in sample size, and 4) an update to the primary estimand for the US approach to address FDA recommendations.

21 Feb 2023

An amendment was required due to recruitment challenges, to make 1) an update to stop recruitment to the BGF MDI 320/14.4/9.6 μg treatment arm, 2) an update to the Type I error control procedure and power estimates, and 3) updates to statistical methodology, including changes to estimands, covariates in the analysis models, and populations for analyses.

19 Nov 2024

An amendment was required to update the statistical methodological approaches to handling intercurrent events and the Type I error control procedure for US, EU, China, and Japan health authorities.

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.

Protocol amendments were instituted during the SARS-CoV-2 pandemic to facilitate recruitment, including removal of the history of exacerbation criterion and terminating recruitment to the BGF 320/14.4/9.6 μg treatment group.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline in morning pre-dose trough FEV1 (L) over 24 weeks

Primary: Change from baseline in morning pre-dose trough FEV1 (L) over 24 weeks

Primary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations

Primary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations

Secondary: Change from baseline in FEV1 AUC0-3 (L) over 24 weeks

Secondary: Change from baseline in FEV1 AUC0-3 (L) over 24 weeks

Secondary: Onset of action on Day 1: Absolute change in FEV1 (L) at 5 minutes on Day 1

Secondary: Onset of action on Day 1: Absolute change in FEV1 (L) at 5 minutes on Day 1

Secondary: Rate of severe asthma exacerbations

Secondary: Rate of severe asthma exacerbations

Secondary: Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks

Secondary: Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks

Secondary: Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks

Secondary: Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks

Secondary: Percentage of responders in the AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks

Secondary: Percentage of responders in the AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks

Secondary: Percentage of responders in SGRQ (≥4.0 decrease equals response) over 24 weeks

Secondary: Percentage of responders in SGRQ (≥4.0 decrease equals response) over 24 weeks

Secondary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations for participants with percent predicted FEV1 ≤55% at baseline

Secondary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations for participants with percent predicted FEV1 ≤55% at baseline

Secondary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations for participants with ≥1 severe exacerbation in the 12 months prior to Visit 1

Secondary: Pooled (KALOS/LOGOS): Rate of severe asthma exacerbations for participants with ≥1 severe exacerbation in the 12 months prior to Visit 1

Secondary: Pooled (KALOS/LOGOS): Time to first severe asthma exacerbation

Secondary: Pooled (KALOS/LOGOS): Time to first severe asthma exacerbation

Secondary: Pooled (KALOS/LOGOS): Rate of moderate or severe asthma exacerbations

Secondary: Pooled (KALOS/LOGOS): Rate of moderate or severe asthma exacerbations

Secondary: Pooled (KALOS/LOGOS): Time to first moderate or severe asthma exacerbation

Secondary: Pooled (KALOS/LOGOS): Time to first moderate or severe asthma exacerbation

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in ACQ-7 (≥0.5 decrease equals response) over 24 weeks

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in ACQ-5 (≥0.5 decrease equals response) over 24 weeks

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks

Secondary: Pooled (KALOS/LOGOS): Percentage of responders in AQLQ(s)+12 (≥0.5 increase equals response) over 24 weeks

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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