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Clinical Trial Results:
A 24-week multi-center, double-blind, placebo controlled dose-range finding study to investigate the efficacy and safety of oral QBW251 in COPD patients on triple inhaled therapy (LABA / LAMA / ICS)

Summary
EudraCT number	2018-003197-28
Trial protocol	SK NL BE DK FR AT CZ GR HU IT ES GB
Global end of trial date	01 Feb 2022

Results information
Results version number	v1(current)
This version publication date	15 Feb 2023
First version publication date	15 Feb 2023
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CQBW251B2201

ISRCTN number

-

US NCT number

NCT04072887

WHO universal trial number (UTN)

-

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

01 Feb 2022

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

01 Feb 2022

Was the trial ended prematurely?

No

Main objective of the trial

To characterize the dose-response relationship of QBW251 administered orally over 12 Weeks on lung function, compared to placebo when added to inhaled triple combination therapy (long-acting β2 agonist/long-acting muscarinic receptor antagonist/inhaled corticosteroid; LABA/LAMA/ICS).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

COPD maintenance background therapy: Combination of fluticasone furoate, vilanterol and umeclidinium bromide

Evidence for comparator

-

Actual start date of recruitment

12 Sep 2019

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 17

Country: Number of subjects enrolled

Hong Kong: 2

Country: Number of subjects enrolled

Japan: 83

Country: Number of subjects enrolled

Philippines: 55

Country: Number of subjects enrolled

Thailand: 12

Country: Number of subjects enrolled

Czechia: 48

Country: Number of subjects enrolled

Greece: 20

Country: Number of subjects enrolled

Hungary: 64

Country: Number of subjects enrolled

Poland: 31

Country: Number of subjects enrolled

Slovakia: 50

Country: Number of subjects enrolled

Turkey: 18

Country: Number of subjects enrolled

Argentina: 95

Country: Number of subjects enrolled

Colombia: 2

Country: Number of subjects enrolled

Guatemala: 24

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

United States: 156

Country: Number of subjects enrolled

Austria: 28

Country: Number of subjects enrolled

Belgium: 15

Country: Number of subjects enrolled

Germany: 172

Country: Number of subjects enrolled

Denmark: 17

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

Korea, Republic of: 6

Worldwide total number of subjects

974

EEA total number of subjects

480

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

371

From 65 to 84 years

603

85 years and over

0

Subject disposition

Top of page

Recruitment details

Participants were recruited from 149 sites in 26 countries.

Screening details

Participants underwent a Screening period of up to 1 week. Then, participants entered the run-in period of up to 2 weeks to establish baseline values for symptom assessments, to standardize the COPD background therapy and to complete eligibility assessments.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer

Are arms mutually exclusive

Yes

QBW251 450 mg

Arm description

QBW251 was orally administered 450 mg b.i.d for 24 weeks

Arm type

Experimental

Investigational medicinal product name

QBW251

Investigational medicinal product code

QBW251

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

QBW251 was orally administered 450 mg b.i.d for 24 weeks

QBW251 300 mg

Arm description

QBW251 was orally administered 300 mg b.i.d for 24 weeks

Arm type

Experimental

Investigational medicinal product name

QBW251

Investigational medicinal product code

QBW251

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

QBW251 was orally administered 300 mg b.i.d for 24 weeks

QBW251 150 mg

Arm description

QBW251 was orally administered 150 mg b.i.d for 24 weeks

Arm type

Experimental

Investigational medicinal product name

QBW251

Investigational medicinal product code

QBW251

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

QBW251 was orally administered 150 mg b.i.d for 24 weeks

QBW251 75 mg

Arm description

QBW251 was orally administered 75 mg b.i.d for 24 weeks

Arm type

Experimental

Investigational medicinal product name

QBW251

Investigational medicinal product code

QBW251

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

QBW251 was orally administered 75 mg b.i.d for 24 weeks

QBW251 25 mg

Arm description

QBW251 was orally administered 25 mg b.i.d for 24 weeks

Arm type

Experimental

Investigational medicinal product name

QBW251

Investigational medicinal product code

QBW251

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

QBW251 was orally administered 25 mg b.i.d for 24 weeks

Placebo

Arm description

Placebo was orally administered b.i.d for 24 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo was orally administered b.i.d for 24 weeks

Number of subjects in period 1	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo
Started	99	250	124	126	124	251
Pharmacokinetic (PK) Set	99	250	123	126	124	0 ^[1]
Serial Pharmacokinetic (PK) Set	14 ^[2]	21 ^[3]	14 ^[4]	13 ^[5]	14 ^[6]	0 ^[7]
Completed	91	233	122	117	118	236
Not completed	8	17	2	9	6	15
Adverse event, serious fatal	-	2	-	2	3	-
Consent withdrawn by subject	3	8	1	3	3	13
Physician decision	2	-	-	-	-	1
Adverse event, non-fatal	2	4	1	4	-	1
Lost to follow-up	1	3	-	-	-	-

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the numbers for the analysis subset are displayed
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the numbers for the analysis subset are displayed
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the numbers for the analysis subset are displayed
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the numbers for the analysis subset are displayed
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the numbers for the analysis subset are displayed
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the numbers for the analysis subset are displayed
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the numbers for the analysis subset are displayed

Baseline characteristics

Top of page

Reporting group title

QBW251 450 mg

Reporting group description

QBW251 was orally administered 450 mg b.i.d for 24 weeks

Reporting group title

QBW251 300 mg

Reporting group description

QBW251 was orally administered 300 mg b.i.d for 24 weeks

Reporting group title

QBW251 150 mg

Reporting group description

QBW251 was orally administered 150 mg b.i.d for 24 weeks

Reporting group title

QBW251 75 mg

Reporting group description

QBW251 was orally administered 75 mg b.i.d for 24 weeks

Reporting group title

QBW251 25 mg

Reporting group description

QBW251 was orally administered 25 mg b.i.d for 24 weeks

Reporting group title

Placebo

Reporting group description

Placebo was orally administered b.i.d for 24 weeks

Reporting group values	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo	Total
Number of subjects	99	250	124	126	124	251	974
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	38	96	40	59	45	93	371
From 65-84 years	61	154	84	67	79	158	603
85 years and over	0	0	0	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	66.5 ± 7.28	66.6 ± 7.56	66.7 ± 6.58	65.7 ± 8.30	67.0 ± 7.83	66.7 ± 7.59	-
Sex: Female, Male
Units: Participants
Female	36	99	47	50	49	92	373
Male	63	151	77	76	75	159	601
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	2	10	1	4	4	5	26
Asian	9	42	27	20	25	43	166
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	1	5	2	6	2	5	21
White	87	193	94	96	93	198	761
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0

End points

Top of page

Reporting group title

QBW251 450 mg

Reporting group description

QBW251 was orally administered 450 mg b.i.d for 24 weeks

Reporting group title

QBW251 300 mg

Reporting group description

QBW251 was orally administered 300 mg b.i.d for 24 weeks

Reporting group title

QBW251 150 mg

Reporting group description

QBW251 was orally administered 150 mg b.i.d for 24 weeks

Reporting group title

QBW251 75 mg

Reporting group description

QBW251 was orally administered 75 mg b.i.d for 24 weeks

Reporting group title

QBW251 25 mg

Reporting group description

QBW251 was orally administered 25 mg b.i.d for 24 weeks

Reporting group title

Placebo

Reporting group description

Placebo was orally administered b.i.d for 24 weeks

Primary: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at week 12

Top of page

End point title

Change From Baseline in Forced Expiratory Volume in One Second (FEV1) at week 12

End point description

The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters on Week 12. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. Change from baseline in the FEV1 mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in FEV1 + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.

End point type

Primary

End point timeframe

Baseline and Week 12

End point values	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo
Number of subjects analysed	42	209	111	112	105	219
Units: Liter
least squares mean (standard error)	0.013 ± 0.021	0.013 ± 0.0103	0.014 ± 0.0142	0.021 ± 0.0141	0.006 ± 0.0144	0.001 ± 0.0101

ANCOVA

Comparison groups

QBW251 450 mg v Placebo

Number of subjects included in analysis

261

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.628

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

0.011

Confidence interval

level

90%

sides

2-sided

lower limit

-0.027

upper limit

0.05

Variability estimate

Standard error of the mean

Dispersion value

0.0235

ANCOVA

Comparison groups

QBW251 300 mg v Placebo

Number of subjects included in analysis

428

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.425

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

0.012

Confidence interval

level

90%

sides

2-sided

lower limit

-0.012

upper limit

0.035

Variability estimate

Standard error of the mean

Dispersion value

0.0144

ANCOVA

Comparison groups

QBW251 150 mg v Placebo

Number of subjects included in analysis

330

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.463

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

0.013

Confidence interval

level

90%

sides

2-sided

lower limit

-0.016

upper limit

0.041

Variability estimate

Standard error of the mean

Dispersion value

0.0174

ANCOVA

Comparison groups

QBW251 75 mg v Placebo

Number of subjects included in analysis

331

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.244

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

0.02

Confidence interval

level

90%

sides

2-sided

lower limit

-0.008

upper limit

0.049

Variability estimate

Standard error of the mean

Dispersion value

0.0173

ANCOVA

Comparison groups

QBW251 25 mg v Placebo

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.793

Method

ANCOVA

Parameter type

Least Squares Mean Difference

Point estimate

0.005

Confidence interval

level

90%

sides

2-sided

lower limit

-0.024

upper limit

0.034

Variability estimate

Standard error of the mean

Dispersion value

0.0176

Secondary: Change From Baseline in Forced Expiratory Volume in One Second (FEV1)

Top of page

End point title

Change From Baseline in Forced Expiratory Volume in One Second (FEV1)

End point description

The primary efficacy analysis assessed the effect of QBW251 on the absolute change from baseline in trough FEV1 in liters compared to placebo on Weeks 4, 8, 16, 20 and 24. Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline measurement was defined as the baseline visit pre-bronchodilator spirometry assessment. A positive trend for change from baseline in FEV1 across the dose range is considered a favorable outcome.

End point type

Secondary

End point timeframe

Baseline, weeks 4, 8, 16, 20 and 24

End point values	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo
Number of subjects analysed	99	250	124	126	124	251
Units: Liter
arithmetic mean (standard deviation)
Week 4	0.007 ± 0.14	0.007 ± 0.15	0.009 ± 0.13	0.000 ± 0.14	0.009 ± 0.14	0.005 ± 0.13
Week 8	0.028 ± 0.14	0.013 ± 0.16	-0.002 ± 0.13	0.002 ± 0.15	0.016 ± 0.16	0.009 ± 0.15
Week 16	0.013 ± 0.18	0.003 ± 0.16	0.005 ± 0.14	0.011 ± 0.15	0.007 ± 0.17	-0.011 ± 0.14
Week 20	-0.031 ± 0.20	0.005 ± 0.18	0.012 ± 0.13	0.001 ± 0.16	0.003 ± 0.16	-0.007 ± 0.15
Week 24	0.033 ± 0.13	0.023 ± 0.19	0.004 ± 0.16	0.003 ± 0.19	0.003 ± 0.17	-0.013 ± 0.16

No statistical analyses for this end point

Secondary: Change from baseline in Evaluating Respiratory Symptoms (E-RS); Total score

Top of page

End point title

Change from baseline in Evaluating Respiratory Symptoms (E-RS); Total score ^[1]

End point description

The E-RS assesses overall daily respiratory COPD symptoms (Total score) and it is derived as the sum of 11 severity items; a higher scores indicate more severe symptoms. E-RS total score has a range of 0 to 40. Change from baseline in the E-RS Total weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction. The mean baseline E-RS Total score was the average of the corresponding daily scores from the run-in period. A negative change from baseline corresponds to improvement in symptoms severity.

End point type

Secondary

End point timeframe

Baseline, weeks 12 and 24

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: only descriptive analyses performed

End point values	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo
Number of subjects analysed	250	124	126	124	251
Units: Score on a scale
least squares mean (standard error)
Week 12	-1.75 ± 0.234	-1.26 ± 0.323	-1.66 ± 0.317	-1.30 ± 0.324	-1.41 ± 0.228
Week 24	-2.16 ± 0.239	-1.37 ± 0.327	-1.36 ± 0.325	-1.36 ± 0.333	-1.31 ± 0.232

No statistical analyses for this end point

Secondary: Change from baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum score

Top of page

End point title

Change from baseline in Evaluating Respiratory Symptoms (E-RS); Cough and Sputum score ^[2]

End point description

The E-RS assesses both overall daily respiratory COPD symptoms (Total score) and specific respiratory symptoms using 3 subscales (Breathlessness, Cough & Sputum, and Chest Symptoms). The E-RS comprises 11 severity items and higher scores indicate more severe symptoms. The Cough and Sputum subscale score has a range of 0 to 11 and was derived as the sum of items 2 - 4. Change from baseline in the E-RS Cough and Sputum weekly mean scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction. The mean baseline E-RS Cough & Sputum subscale score was the average of the corresponding daily scores from the run-in period. Lower scores in the change from baseline correspond to lower symptom severity.

End point type

Secondary

End point timeframe

Baseline, weeks 12 and 24

Notes
[2] - 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: only descriptive analyses performed

End point values	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo
Number of subjects analysed	250	124	126	124	251
Units: Score on a scale
least squares mean (standard error)
Week 12	-0.78 ± 0.077	-0.63 ± 0.105	-0.52 ± 0.104	-0.22 ± 0.106	-0.44 ± 0.074
Week 24	-0.90 ± 0.078	-0.68 ± 0.107	-0.51 ± 0.106	-0.26 ± 0.109	-0.50 ± 0.076

No statistical analyses for this end point

Secondary: Number of Participants with a "Better" change in the Patient Global Impression of Severity (PGI-S) from baseline

Top of page

End point title

Number of Participants with a "Better" change in the Patient Global Impression of Severity (PGI-S) from baseline ^[3]

End point description

The PGI-S questionnaire is a patient-reported outcomes score that rates the severity of the respiratory symptoms and of cough and mucus. The change in severity scores (Better, No change and Worse) from baseline were reported at weeks 12 and 24. Thus, the number of participants with a Better change in the severity score are reported in the table below.

End point type

Secondary

End point timeframe

Baseline, weeks 12 and 24

Notes
[3] - 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: only descriptive analyses performed

End point values	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo
Number of subjects analysed	250	124	126	124	251
Units: Participants
Week 12 - Respiratory Symptoms	66	27	35	33	64
Week 24 - Respiratory Symptoms	72	28	40	31	79
Week 12 - Cough and mucus	85	55	54	41	78
Week 24 - Cough and mucus	104	57	50	37	96

No statistical analyses for this end point

Secondary: Change from baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q)

Top of page

End point title

Change from baseline in the Cough and Sputum Assessment Questionnaire (CASA-Q) ^[4]

End point description

The CASA-Q is a validated questionnaire instrument used to measure cough and sputum production, and their impact in patients COPD and/or chronic bronchitis. It contains a total of 20 items on a 5-step scale distributed in 4 domains: Cough symptoms, Cough impact, Sputum symptoms and Sputum impact. All items are rescored from 1-5 to 0-4 and then reverse scored such that better responses have higher scores. The four domains are ranged from 0-100 where higher scores associated with fewer symptoms/less impact due to cough or sputum. Change from baseline in the CASA-Q cough and symptoms scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + run-in E-RS + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.

End point type

Secondary

End point timeframe

Baseline, weeks 12 and 24

Notes
[4] - 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: only descriptive analyses performed

End point values	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo
Number of subjects analysed	250	124	126	124	251
Units: Score on a scale
least squares mean (standard error)
Cough symptoms score, week 12	6.06 ± 1.082	8.82 ± 1.488	6.68 ± 1.498	6.73 ± 1.535	6.06 ± 1.077
Cough symptoms score, week 24	10.49 ± 1.148	10.59 ± 1.556	8.04 ± 1.575	5.84 ± 1.623	7.25 ± 1.118
Cough impact score, week 12	4.97 ± 0.983	5.94 ± 1.352	5.89 ± 1.359	5.03 ± 1.394	5.26 ± 0.978
Cough impact score, week 24	7.08 ± 0.983	8.29 ± 1.334	7.51 ± 1.349	4.02 ± 1.391	7.12 ± 0.958
Sputum symptoms score, week 12	7.74 ± 1.142	8.51 ± 1.571	7.01 ± 1.580	5.74 ± 1.620	6.96 ± 1.136
Sputum symptoms score, week 24	10.52 ± 1.242	11.34 ± 1.685	5.81 ± 1.704	4.64 ± 1.756	9.05 ± 1.211
Sputum impact score, week 12	5.88 ± 1.011	6.58 ± 1.391	6.98 ± 1.398	4.35 ± 1.433	4.72 ± 1.005
Sputum impact score, week 24	7.14 ± 1.032	7.66 ± 1.401	7.75 ± 1.417	4.40 ± 1.460	7.04 ± 1.007

No statistical analyses for this end point

Secondary: Change from baseline in St. George's Respiratory Questionnaire (SGRQ)

Top of page

End point title

Change from baseline in St. George's Respiratory Questionnaire (SGRQ)

End point description

SGRQ measures health impairment and contains 50 items divided into three components: Symptoms, Activity and Impacts. A score was calculated for each component and a "Total" score was also calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of quality of life. Change from baseline in the SGRQ scores were analyzed using a Mixed Model for Repeated Measures (MMRM): treatment + baseline score + smoking status at screening + baseline SGRQ score + airflow limitation severity + region + time interval + treatment*time interval interaction + baseline score*time interval interaction.

End point type

Secondary

End point timeframe

Baseline, weeks 12 and 24

End point values	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg	Placebo
Number of subjects analysed	99	250	124	126	124	251
Units: Score on a scale
least squares mean (standard error)
Week 12 - Total score	-0.34 ± 11.17	-5.84 ± 14.82	-3.14 ± 12.67	-6.78 ± 14.64	-3.85 ± 10.82	-3.36 ± 13.27
Week 24 - Total score	-2.93 ± 10.58	-6.48 ± 15.35	-3.69 ± 12.39	-6.06 ± 14.88	-1.70 ± 10.97	-4.37 ± 13.00
Week 12 - Symptoms score	-5.24 ± 21.16	-8.23 ± 18.73	-5.70 ± 18.39	-6.93 ± 19.29	-5.59 ± 16.52	-6.07 ± 17.14
Week 24 - Symptoms score	-7.90 ± 22.47	-10.59 ± 21.06	-7.09 ± 17.02	-8.42 ± 18.21	-5.16 ± 15.61	-6.97 ± 17.39
Week 12 - Activity score	-2.00 ± 10.83	-4.80 ± 17.67	-4.72 ± 17.35	-7.27 ± 17.48	-4.06 ± 14.68	-2.40 ± 15.21
Week 24 - Activity score	-1.25 ± 12.50	-5.12 ± 17.36	-3.69 ± 16.37	-5.80 ± 20.47	-1.20 ± 14.36	-4.27 ± 16.07
Week 12 - Impacts score	2.03 ± 14.28	-5.69 ± 17.06	-1.49 ± 13.88	-6.42 ± 16.63	-3.13 ± 13.11	-3.11 ± 15.90
Week 24 - Impacts score	-2.21 ± 8.24	-6.04 ± 17.455	-2.63 ± 14.18	-5.44 ± 16.05	-1.04 ± 13.95	-3.68 ± 14.95

No statistical analyses for this end point

Secondary: Minimum plasma concentration (Cmin) for QBW251

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End point title

Minimum plasma concentration (Cmin) for QBW251 ^[5]

End point description

Venous whole blood samples were collected for pharmacokinetics characterization. Cmin was measured pre dose at all visits and was summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.

End point type

Secondary

End point timeframe

Pre-dose on Days 15, 29, 57, 85, 113, 141 and 169

Notes
[5] - 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: only descriptive analyses performed

End point values	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg
Number of subjects analysed	99	250	123	126	124
Units: ng/mL
arithmetic mean (standard deviation)
Day 15	1280 ± 1700	619 ± 1230	143 ± 158	44.0 ± 49.0	12.7 ± 15.5
Day 29	951 ± 1050	571 ± 923	125 ± 123	47.8 ± 47.3	10.1 ± 10.1
Day 57	1040 ± 1330	572 ± 833	116 ± 103	47.7 ± 62.2	14.2 ± 25.5
Day 85	1080 ± 1360	587 ± 951	119 ± 147	49.7 ± 71.2	9.93 ± 10.3
Day 113	859 ± 1150	593 ± 1000	120 ± 130	52.7 ± 73.9	9.89 ± 9.20
Day 141	1150 ± 1150	552 ± 923	118 ± 103	66.8 ± 226	15.9 ± 45.7
Day 169	637 ± 349	465 ± 618	128 ± 147	44.9 ± 61.1	8.97 ± 8.08

No statistical analyses for this end point

Secondary: Maximum plasma concentration (Cmax) for QBW251

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End point title

Maximum plasma concentration (Cmax) for QBW251 ^[6]

End point description

Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. Cmax was measured in the samples taken at 3 hours post-dose with the exception of the participants included in the Serial PK set on Days 1 and 15 for whom all samples (1, 2, 4, 6, and 8 hours post-dose) were taken into consideration for the measurement of Cmax. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.

End point type

Secondary

End point timeframe

Days 1, 15 and 169

Notes
[6] - 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: only descriptive analyses performed

End point values	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg
Number of subjects analysed	99	250	123	126	124
Units: ng/mL
arithmetic mean (standard deviation)
Day 1	1280 ± 847	751 ± 598	251 ± 238	68.9 ± 64.5	14.4 ± 15.2
Day 15	2500 ± 1710	1320 ± 1030	411 ± 368	114 ± 101	26.1 ± 20.6
Day 169	2370 ± 1160	1210 ± 797	361 ± 303	104 ± 86.6	22.5 ± 16.4

No statistical analyses for this end point

Secondary: Maximum plasma concentration (Cmax) for QBW251 in Serial PK set

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End point title

Maximum plasma concentration (Cmax) for QBW251 in Serial PK set ^[7]

End point description

Venous whole blood samples were collected for pharmacokinetics characterization. Cmax was calculated from plasma concentration data using non-compartmental methods and summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.

End point type

Secondary

End point timeframe

1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15

Notes
[7] - 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: only descriptive analyses performed

End point values	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg
Number of subjects analysed	14	21	14	13	14
Units: ng/mL
arithmetic mean (standard deviation)
Day 1	1510 ± 928	1280 ± 622	478 ± 241	96.6 ± 72.7	25.3 ± 29.7
Day 15	2700 ± 1170	1870 ± 844	542 ± 523	175 ± 127	39.4 ± 27.0

No statistical analyses for this end point

Secondary: Area under the curve from time 0 to 24 hours (AUC0-24h) of QBW251 in Serial PK set

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End point title

Area under the curve from time 0 to 24 hours (AUC0-24h) of QBW251 in Serial PK set ^[8]

End point description

Venous whole blood samples were collected for pharmacokinetics characterization. AUC0-24h was calculated from plasma concentration-time data using non-compartmental methods and summarized using descriptive statistics. All concentrations below the lower limit of quantification (LLOQ) were treated as zero.

End point type

Secondary

End point timeframe

1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15

Notes
[8] - 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: only descriptive analyses performed

End point values	QBW251 450 mg	QBW251 300 mg	QBW251 150 mg	QBW251 75 mg	QBW251 25 mg
Number of subjects analysed	14	21	14	13	14
Units: ng*h/mL
arithmetic mean (standard deviation)
Day 1	10900 ± 3740	8480 ± 3660	2920 ± 1140	769 ± 330	185 ± 107
Day 15	30000 ± 22600	16500 ± 8380	4740 ± 2390	1390 ± 679	333 ± 209

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from the start of treatment to 30 days after end of treatment, assessed up to maximum duration of 199 days.

Adverse event reporting additional description

Any sign or symptom that occurs during the study treatment plus the 30 days post treatment

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

QBW251 450 mg

Reporting group description

QBW251 was orally administered 450 mg b.i.d for 24 weeks

Reporting group title

QBW251 150 mg

Reporting group description

QBW251 was orally administered 150 mg b.i.d for 24 weeks

Reporting group title

QBW251 300 mg

Reporting group description

QBW251 was orally administered 300 mg b.i.d for 24 weeks

Reporting group title

QBW251 75 mg

Reporting group description

QBW251 was orally administered 75 mg b.i.d for 24 weeks

Reporting group title

QBW251 25 mg

Reporting group description

QBW251 was orally administered 25 mg b.i.d for 24 weeks

Reporting group title

Placebo

Reporting group description

Placebo was orally administered b.i.d for 24 weeks

Reporting group title

Total

Reporting group description

Total

Serious adverse events	QBW251 450 mg	QBW251 150 mg	QBW251 300 mg	QBW251 75 mg	QBW251 25 mg	Placebo	Total
Total subjects affected by serious adverse events
subjects affected / exposed	10 / 99 (10.10%)	6 / 124 (4.84%)	33 / 250 (13.20%)	14 / 126 (11.11%)	12 / 124 (9.68%)	15 / 251 (5.98%)	90 / 974 (9.24%)
number of deaths (all causes)	0	0	2	2	3	0	7
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Abdominal neoplasm
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	1 / 124 (0.81%)	0 / 251 (0.00%)	2 / 974 (0.21%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder adenocarcinoma
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Lung neoplasm malignant
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	3 / 250 (1.20%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	4 / 974 (0.41%)
occurrences causally related to treatment / all	1 / 1	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lymph nodes
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer stage IIIA
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal adenocarcinoma
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	1 / 124 (0.81%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	1 / 124 (0.81%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Pyrexia
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular stent thrombosis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	2 / 974 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Bronchospasm
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	5 / 99 (5.05%)	1 / 124 (0.81%)	9 / 250 (3.60%)	5 / 126 (3.97%)	2 / 124 (1.61%)	5 / 251 (1.99%)	27 / 974 (2.77%)
occurrences causally related to treatment / all	5 / 5	1 / 1	10 / 10	5 / 5	2 / 2	5 / 5	28 / 28
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung consolidation
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	1 / 124 (0.81%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood potassium increased
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone graft lysis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural intestinal perforation
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Aortic valve stenosis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bundle branch block left
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Cardiac failure congestive
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cor pulmonale
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Coronary artery stenosis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolic stroke
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vitreous haemorrhage
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	1 / 251 (0.40%)	2 / 974 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute abdomen
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	1 / 124 (0.81%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erosive oesophagitis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	1 / 124 (0.81%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	2 / 974 (0.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Plantar fasciitis
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	3 / 250 (1.20%)	1 / 126 (0.79%)	2 / 124 (1.61%)	0 / 251 (0.00%)	6 / 974 (0.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	1 / 1	2 / 2	0 / 0	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
COVID-19 pneumonia
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	1 / 124 (0.81%)	0 / 251 (0.00%)	2 / 974 (0.21%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 2
Diverticulitis
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis bacterial
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	1 / 126 (0.79%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal abscess
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	6 / 250 (2.40%)	3 / 126 (2.38%)	2 / 124 (1.61%)	3 / 251 (1.20%)	15 / 974 (1.54%)
occurrences causally related to treatment / all	1 / 1	0 / 0	6 / 6	3 / 3	2 / 2	3 / 3	15 / 15
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Respiratory tract infection
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	1 / 124 (0.81%)	0 / 251 (0.00%)	1 / 974 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	QBW251 450 mg	QBW251 150 mg	QBW251 300 mg	QBW251 75 mg	QBW251 25 mg	Placebo	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	48 / 99 (48.48%)	59 / 124 (47.58%)	117 / 250 (46.80%)	55 / 126 (43.65%)	60 / 124 (48.39%)	107 / 251 (42.63%)	446 / 974 (45.79%)
Investigations
C-reactive protein increased
subjects affected / exposed	1 / 99 (1.01%)	4 / 124 (3.23%)	8 / 250 (3.20%)	0 / 126 (0.00%)	0 / 124 (0.00%)	2 / 251 (0.80%)	15 / 974 (1.54%)
occurrences all number	1	4	8	0	0	2	15
Gamma-glutamyltransferase increased
subjects affected / exposed	4 / 99 (4.04%)	4 / 124 (3.23%)	6 / 250 (2.40%)	2 / 126 (1.59%)	0 / 124 (0.00%)	3 / 251 (1.20%)	19 / 974 (1.95%)
occurrences all number	4	5	6	2	0	3	20
Haemoglobin decreased
subjects affected / exposed	2 / 99 (2.02%)	0 / 124 (0.00%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	3 / 974 (0.31%)
occurrences all number	2	0	0	0	0	1	3
Hepatic enzyme increased
subjects affected / exposed	2 / 99 (2.02%)	0 / 124 (0.00%)	2 / 250 (0.80%)	0 / 126 (0.00%)	0 / 124 (0.00%)	2 / 251 (0.80%)	6 / 974 (0.62%)
occurrences all number	2	0	2	0	0	3	7
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 99 (0.00%)	0 / 124 (0.00%)	2 / 250 (0.80%)	0 / 126 (0.00%)	3 / 124 (2.42%)	1 / 251 (0.40%)	6 / 974 (0.62%)
occurrences all number	0	0	2	0	3	1	6
Vascular disorders
Hypertension
subjects affected / exposed	4 / 99 (4.04%)	3 / 124 (2.42%)	8 / 250 (3.20%)	3 / 126 (2.38%)	3 / 124 (2.42%)	4 / 251 (1.59%)	25 / 974 (2.57%)
occurrences all number	4	3	8	3	3	4	25
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 99 (2.02%)	2 / 124 (1.61%)	1 / 250 (0.40%)	0 / 126 (0.00%)	1 / 124 (0.81%)	3 / 251 (1.20%)	9 / 974 (0.92%)
occurrences all number	2	2	1	0	1	3	9
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 99 (4.04%)	0 / 124 (0.00%)	5 / 250 (2.00%)	1 / 126 (0.79%)	1 / 124 (0.81%)	1 / 251 (0.40%)	12 / 974 (1.23%)
occurrences all number	5	0	5	1	1	1	13
Headache
subjects affected / exposed	4 / 99 (4.04%)	4 / 124 (3.23%)	11 / 250 (4.40%)	4 / 126 (3.17%)	4 / 124 (3.23%)	6 / 251 (2.39%)	33 / 974 (3.39%)
occurrences all number	5	5	11	4	4	6	35
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 99 (0.00%)	3 / 124 (2.42%)	2 / 250 (0.80%)	0 / 126 (0.00%)	1 / 124 (0.81%)	1 / 251 (0.40%)	7 / 974 (0.72%)
occurrences all number	0	3	3	0	1	1	8
Fatigue
subjects affected / exposed	2 / 99 (2.02%)	2 / 124 (1.61%)	3 / 250 (1.20%)	1 / 126 (0.79%)	0 / 124 (0.00%)	3 / 251 (1.20%)	11 / 974 (1.13%)
occurrences all number	2	2	3	1	0	3	11
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	6 / 99 (6.06%)	1 / 124 (0.81%)	7 / 250 (2.80%)	2 / 126 (1.59%)	3 / 124 (2.42%)	6 / 251 (2.39%)	25 / 974 (2.57%)
occurrences all number	6	2	9	2	3	6	28
Nausea
subjects affected / exposed	5 / 99 (5.05%)	2 / 124 (1.61%)	4 / 250 (1.60%)	3 / 126 (2.38%)	1 / 124 (0.81%)	5 / 251 (1.99%)	20 / 974 (2.05%)
occurrences all number	5	2	4	3	1	5	20
Vomiting
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	2 / 250 (0.80%)	3 / 126 (2.38%)	1 / 124 (0.81%)	4 / 251 (1.59%)	11 / 974 (1.13%)
occurrences all number	1	0	2	3	1	4	11
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	16 / 99 (16.16%)	32 / 124 (25.81%)	51 / 250 (20.40%)	24 / 126 (19.05%)	34 / 124 (27.42%)	56 / 251 (22.31%)	213 / 974 (21.87%)
occurrences all number	22	46	69	37	44	73	291
Cough
subjects affected / exposed	1 / 99 (1.01%)	0 / 124 (0.00%)	4 / 250 (1.60%)	1 / 126 (0.79%)	1 / 124 (0.81%)	6 / 251 (2.39%)	13 / 974 (1.33%)
occurrences all number	1	0	4	1	1	6	13
Rhinitis allergic
subjects affected / exposed	2 / 99 (2.02%)	0 / 124 (0.00%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	3 / 974 (0.31%)
occurrences all number	2	0	1	0	0	0	3
Skin and subcutaneous tissue disorders
Photosensitivity reaction
subjects affected / exposed	2 / 99 (2.02%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	3 / 974 (0.31%)
occurrences all number	3	1	0	0	0	0	4
Rash
subjects affected / exposed	3 / 99 (3.03%)	2 / 124 (1.61%)	2 / 250 (0.80%)	0 / 126 (0.00%)	0 / 124 (0.00%)	0 / 251 (0.00%)	7 / 974 (0.72%)
occurrences all number	3	2	2	0	0	0	7
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 99 (2.02%)	2 / 124 (1.61%)	2 / 250 (0.80%)	1 / 126 (0.79%)	3 / 124 (2.42%)	6 / 251 (2.39%)	16 / 974 (1.64%)
occurrences all number	2	2	2	1	3	6	16
Back pain
subjects affected / exposed	2 / 99 (2.02%)	3 / 124 (2.42%)	7 / 250 (2.80%)	3 / 126 (2.38%)	2 / 124 (1.61%)	7 / 251 (2.79%)	24 / 974 (2.46%)
occurrences all number	2	3	7	3	2	7	24
Myalgia
subjects affected / exposed	1 / 99 (1.01%)	4 / 124 (3.23%)	1 / 250 (0.40%)	1 / 126 (0.79%)	0 / 124 (0.00%)	3 / 251 (1.20%)	10 / 974 (1.03%)
occurrences all number	1	4	1	1	0	3	10
Infections and infestations
Bronchitis
subjects affected / exposed	4 / 99 (4.04%)	2 / 124 (1.61%)	6 / 250 (2.40%)	0 / 126 (0.00%)	3 / 124 (2.42%)	2 / 251 (0.80%)	17 / 974 (1.75%)
occurrences all number	4	2	7	0	4	2	19
COVID-19
subjects affected / exposed	0 / 99 (0.00%)	1 / 124 (0.81%)	4 / 250 (1.60%)	1 / 126 (0.79%)	6 / 124 (4.84%)	5 / 251 (1.99%)	17 / 974 (1.75%)
occurrences all number	0	1	4	1	6	5	17
Cystitis
subjects affected / exposed	0 / 99 (0.00%)	2 / 124 (1.61%)	2 / 250 (0.80%)	3 / 126 (2.38%)	1 / 124 (0.81%)	1 / 251 (0.40%)	9 / 974 (0.92%)
occurrences all number	0	2	2	3	1	2	10
Gastroenteritis
subjects affected / exposed	4 / 99 (4.04%)	0 / 124 (0.00%)	2 / 250 (0.80%)	1 / 126 (0.79%)	1 / 124 (0.81%)	1 / 251 (0.40%)	9 / 974 (0.92%)
occurrences all number	4	0	2	1	1	1	9
Influenza
subjects affected / exposed	2 / 99 (2.02%)	0 / 124 (0.00%)	4 / 250 (1.60%)	1 / 126 (0.79%)	1 / 124 (0.81%)	2 / 251 (0.80%)	10 / 974 (1.03%)
occurrences all number	2	0	4	1	1	2	10
Lower respiratory tract infection
subjects affected / exposed	3 / 99 (3.03%)	3 / 124 (2.42%)	3 / 250 (1.20%)	2 / 126 (1.59%)	4 / 124 (3.23%)	5 / 251 (1.99%)	20 / 974 (2.05%)
occurrences all number	3	4	3	2	4	7	23
Nasopharyngitis
subjects affected / exposed	4 / 99 (4.04%)	5 / 124 (4.03%)	12 / 250 (4.80%)	10 / 126 (7.94%)	6 / 124 (4.84%)	10 / 251 (3.98%)	47 / 974 (4.83%)
occurrences all number	5	8	14	15	7	12	61
Pharyngitis
subjects affected / exposed	2 / 99 (2.02%)	1 / 124 (0.81%)	0 / 250 (0.00%)	0 / 126 (0.00%)	2 / 124 (1.61%)	3 / 251 (1.20%)	8 / 974 (0.82%)
occurrences all number	2	1	0	0	2	3	8
Pneumonia
subjects affected / exposed	3 / 99 (3.03%)	1 / 124 (0.81%)	5 / 250 (2.00%)	1 / 126 (0.79%)	2 / 124 (1.61%)	2 / 251 (0.80%)	14 / 974 (1.44%)
occurrences all number	4	1	5	1	2	3	16
Sinusitis
subjects affected / exposed	0 / 99 (0.00%)	3 / 124 (2.42%)	1 / 250 (0.40%)	1 / 126 (0.79%)	0 / 124 (0.00%)	2 / 251 (0.80%)	7 / 974 (0.72%)
occurrences all number	0	3	1	1	0	2	7
Upper respiratory tract infection
subjects affected / exposed	3 / 99 (3.03%)	5 / 124 (4.03%)	4 / 250 (1.60%)	0 / 126 (0.00%)	0 / 124 (0.00%)	5 / 251 (1.99%)	17 / 974 (1.75%)
occurrences all number	3	5	5	0	0	5	18
Upper respiratory tract infection bacterial
subjects affected / exposed	3 / 99 (3.03%)	4 / 124 (3.23%)	12 / 250 (4.80%)	4 / 126 (3.17%)	4 / 124 (3.23%)	9 / 251 (3.59%)	36 / 974 (3.70%)
occurrences all number	3	5	13	4	4	12	41
Urinary tract infection
subjects affected / exposed	3 / 99 (3.03%)	3 / 124 (2.42%)	8 / 250 (3.20%)	5 / 126 (3.97%)	2 / 124 (1.61%)	5 / 251 (1.99%)	26 / 974 (2.67%)
occurrences all number	5	3	8	6	3	5	30
Viral upper respiratory tract infection
subjects affected / exposed	3 / 99 (3.03%)	3 / 124 (2.42%)	8 / 250 (3.20%)	3 / 126 (2.38%)	3 / 124 (2.42%)	7 / 251 (2.79%)	27 / 974 (2.77%)
occurrences all number	3	3	11	4	3	9	33
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	2 / 99 (2.02%)	1 / 124 (0.81%)	1 / 250 (0.40%)	0 / 126 (0.00%)	0 / 124 (0.00%)	1 / 251 (0.40%)	5 / 974 (0.51%)
occurrences all number	2	1	1	0	0	1	5

More information

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Were there any global substantial amendments to the protocol? Yes

18 Jun 2019

The protocol is being amended to implement requested protocol changes and in response to considerations received from health authorities in some countries where the study is planned to be conducted.

24 Oct 2019

The protocol is being amended to implement requested protocol changes and in response to considerations received from health authorities and ethics committees in countries where the study is planned to be conducted.

10 Jun 2020

The protocol is being amended in response to both the discontinuation of the 450 mg b.i.d. treatment arm and the impact of the COVID-19 pandemic.

Were there any global interruptions to the trial? No

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

None reported

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