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Clinical Trial Results:
A randomized, blinded, parallel group, multi-center dose-finding study, to assess the efficacy, safety and tolerability of different doses of tobramycin inhalation powder in patients with Non Cystic Fibrosis Bronchiectasis and pulmonary P. aeruginosa infection

Summary
EudraCT number	2015-003040-39
Trial protocol	ES BE DE IE NL GB FR IT
Global end of trial date	20 Mar 2019

Results information
Results version number	v3(current)
This version publication date	26 Sep 2020
First version publication date	03 Apr 2020
Other versions	v1 , v2
Version creation reason

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

CTBM100G2202

ISRCTN number

US NCT number

NCT02712983

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, 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)

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

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

Analysis stage

Final

Date of interim/final analysis

20 Mar 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Mar 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objectives were to: • Evaluate the change in colony forming units (CFUs) in P. aeruginosa bacterial load in sputum, from baseline to Day 29 of treatment, for different doses of tobramycin inhalation powder (TIP) administered once daily (o.d.) and twice daily (b.i.d.), each compared to placebo. • Assess safety and tolerability during the treatment epoch (112 days) and during the follow-up epoch (56 days) for each of the different doses of TIP, as compared to placebo. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

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

Evidence for comparator

Actual start date of recruitment

28 Feb 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Germany: 16

Country: Number of subjects enrolled

United Kingdom: 26

Country: Number of subjects enrolled

Italy: 17

Country: Number of subjects enrolled

Spain: 26

Worldwide total number of subjects

107

EEA total number of subjects

107

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 107 subjects were enrolled in the trial from 6 countries (Belgium [2 sites], France [4 sites], Germany [5 sites], Italy [6 sites], Spain [8 sites] and United Kingdom [9 sites]).

Screening details

This study planned to recruit approximately 180 subjects to one of the 3 cohorts in a ratio of 1:1:1. The subjects within each cohort were randomized to blinded TIP or placebo with the following randomization scheme: TIP:TIP/Placebo cyclical:Placebo, in a 2:2:1 ratio.

Period 1 title

Treatment Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Cohort A (3 capsules o.d.): TIP

Arm description

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)

Arm type

Experimental

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Three capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, for 112 days (on treatment). The total daily dose and each treatment therefore consisted of 84 mg tobramycin (3 capsules of 28 mg each).

Cohort A (3 capsules o.d.): TIP/PBO

Arm description

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Arm type

Experimental

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Three capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Three capsules of matching placebo to blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Cohort A (3 capsules o.d.): PBO

Arm description

Cohort A (3 capsules o.d.): Inhaled placebo (PBO)

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

The reference product consisted of placebo capsules (1,2 distearoyl-sn-glycero-3-phosphocholine /CaCl2). The dose regimen for the reference product was 3 capsules blinded, inhaled o.d. via the T 326 inhaler, for 112 days (on treatment).

Cohort B (5 capsules o.d.): TIP

Arm description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)

Arm type

Experimental

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Five capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, for 112 days (on treatment). The total daily dose and each treatment therefore consisted of 140 mg tobramycin (5 capsules of 28 mg each).

Cohort B (5 capsules o.d.): TIP/PBO

Arm description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Five capsules of matching placebo to blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Five capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Cohort B (5 capsules o.d.): PBO

Arm description

Cohort B (5 capsules o.d.): inhaled placebo (PBO)

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

The reference product consisted of placebo capsules. The dose regimen for the reference product was 5 capsules blinded, inhaled o.d. via the T-326 inhaler, for 112 days (on treatment).

Cohort C (4 capsules b.i.d.): TIP

Arm description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)

Arm type

Experimental

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Four capsules of blinded TIP at 28 mg dosage strength, inhaled b.i.d. in the morning and in the evening via the T-326 inhaler, for 112 days of treatment. Each dose therefore consisted of 112 mg tobramycin (4 capsules of 28 mg each), the total daily dose corresponds to 224 mg tobramycin (112 mg b.i.d.).

Cohort C (4 capsules b.i.d.): TIP/PBO

Arm description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Four capsules of matching placebo to blinded TIP at 28 mg dosage strength, inhaled b.i.d. in the morning and in the evening via the T-326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Four capsules of blinded TIP at 28 mg dosage strength, inhaled b.i.d. in the morning and in the evening via the T-326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Cohort C (4 capsules b.i.d.): PBO

Arm description

Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

The reference product consisted of placebo capsules. The dose regimen for the reference product was four capsules blinded, inhaled b.i.d. via the T-326 inhaler, for 112 days (on treatment).

Number of subjects in period 1	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort A (3 capsules o.d.): PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): PBO
Started	14	13	7	15	14	7	15	15	7
Pharmacokinetic Analysis Set	14	13	0 ^[1]	15	14	0 ^[2]	15	14	0 ^[3]
Completed	9	12	6	7	10	7	6	6	5
Not completed	5	1	1	8	4	0	9	9	2
Physician decision	-	-	-	-	-	-	-	1	1
Subject Decision	2	-	-	2	1	-	1	2	-
Adverse event, non-fatal	3	1	1	4	3	-	6	6	1
Protocol Deviation	-	-	-	2	-	-	1	-	-
Technical Problems	-	-	-	-	-	-	1	-	-

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: PK assessments were done for placebo groups per protocol but they might have not considered in Analysis set for placebo group
[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: PK assessments were done for placebo groups per protocol but they might have not considered in Analysis set for placebo group
[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: PK assessments were done for placebo groups per protocol but they might have not considered in Analysis set for placebo group

Period 2 title

Post-Treatment Efficacy Follow-Up Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Cohort A (3 capsules o.d.): TIP/PBO

Arm description

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Arm type

Experimental

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Three capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Three capsules of matching placebo to blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Cohort B (5 capsules o.d.): TIP

Arm description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)

Arm type

Experimental

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Cohort B (5 capsules o.d.): TIP/PBO

Arm description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Arm type

Experimental

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Five capsules of blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Five capsules of matching placebo to blinded TIP at 28 mg dosage strength, inhaled o.d. via the T 326 inhaler, by alternating TIP 28-days with placebo 28-days for two cycles for a total of 112 days.

Cohort B (5 capsules o.d.): PBO

Arm description

Cohort B (5 capsules o.d.): inhaled placebo (PBO)

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

The reference product consisted of placebo capsules. The dose regimen for the reference product was 5 capsules blinded, inhaled o.d. via the T-326 inhaler, for 112 days (on treatment).

Cohort C (4 capsules b.i.d.): TIP

Arm description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)

Arm type

Experimental

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Cohort C (4 capsules b.i.d.): TIP/PBO

Arm description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Investigational medicinal product name

tobramycin dry powder

Investigational medicinal product code

TBM100

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Number of subjects in period 2	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO
Started	1	1	2	1	2	3
Completed	0	0	0	0	0	0
Not completed	1	1	2	1	2	3
Subject Decision	-	-	2	1	1	2
Adverse event, non-fatal	1	-	-	-	1	1
Lost to follow-up	-	1	-	-	-	-

Baseline characteristics

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Reporting group title

Cohort A (3 capsules o.d.): TIP

Reporting group description

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)

Reporting group title

Cohort A (3 capsules o.d.): TIP/PBO

Reporting group description

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Reporting group title

Cohort A (3 capsules o.d.): PBO

Reporting group description

Cohort A (3 capsules o.d.): Inhaled placebo (PBO)

Reporting group title

Cohort B (5 capsules o.d.): TIP

Reporting group description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)

Reporting group title

Cohort B (5 capsules o.d.): TIP/PBO

Reporting group description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Reporting group title

Cohort B (5 capsules o.d.): PBO

Reporting group description

Cohort B (5 capsules o.d.): inhaled placebo (PBO)

Reporting group title

Cohort C (4 capsules b.i.d.): TIP

Reporting group description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)

Reporting group title

Cohort C (4 capsules b.i.d.): TIP/PBO

Reporting group description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Reporting group title

Cohort C (4 capsules b.i.d.): PBO

Reporting group description

Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)

Reporting group values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort A (3 capsules o.d.): PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): PBO	Total
Number of subjects	14	13	7	15	14	7	15	15	7	107
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	6	10	4	6	6	1	5	6	1	45
From 65-84 years	8	3	3	9	8	6	9	9	6	61
85 years and over	0	0	0	0	0	0	1	0	0	1
Age Continuous
Units: Years
arithmetic mean (standard deviation)	63.4 ( 12.66 )	57.5 ( 11.83 )	61.3 ( 7.45 )	64.3 ( 17.86 )	62.4 ( 16.71 )	69.1 ( 13.21 )	66.1 ( 12.23 )	60.8 ( 12.94 )	71.3 ( 10.39 )	-
Sex: Female, Male
Units: Participants
Female	9	10	3	10	7	6	9	8	4	66
Male	5	3	4	5	7	1	6	7	3	41
Race/Ethnicity, Customized
Units: Subjects
Caucasian	12	11	7	13	11	5	15	15	7	96
Asian	1	0	0	0	0	1	0	0	0	2
Pacific Islander	0	0	0	1	0	0	0	0	0	1
Other	1	2	0	1	3	1	0	0	0	8

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP/PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled inhaled placebo (PBO): For efficacy analysis, subjects assigned to Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments.

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP/PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP/PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis sets values	Pooled TIP	Pooled TIP/PBO	Pooled PBO	Pooled TIP	Pooled TIP	Pooled TIP	Pooled TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects	44	42	21	43	42	38	33	7	6	2
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Units: Years
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )	( )	16.2 ( 7.05 )	15.2 ( 6.44 )	10.5 ( 0.71 )
Sex: Female, Male
Units: Participants
Female
Male
Race/Ethnicity, Customized
Units: Subjects
Caucasian
Asian
Pacific Islander
Other

End points

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Reporting group title

Cohort A (3 capsules o.d.): TIP

Reporting group description

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP)

Reporting group title

Cohort A (3 capsules o.d.): TIP/PBO

Reporting group description

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Reporting group title

Cohort A (3 capsules o.d.): PBO

Reporting group description

Cohort A (3 capsules o.d.): Inhaled placebo (PBO)

Reporting group title

Cohort B (5 capsules o.d.): TIP

Reporting group description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)

Reporting group title

Cohort B (5 capsules o.d.): TIP/PBO

Reporting group description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Reporting group title

Cohort B (5 capsules o.d.): PBO

Reporting group description

Cohort B (5 capsules o.d.): inhaled placebo (PBO)

Reporting group title

Cohort C (4 capsules b.i.d.): TIP

Reporting group description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)

Reporting group title

Cohort C (4 capsules b.i.d.): TIP/PBO

Reporting group description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Reporting group title

Cohort C (4 capsules b.i.d.): PBO

Reporting group description

Cohort C (4 capsules b.i.d.): inhaled placebo (PBO)

Reporting group title

Cohort A (3 capsules o.d.): TIP/PBO

Reporting group description

Cohort A (3 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Reporting group title

Cohort B (5 capsules o.d.): TIP

Reporting group description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP)

Reporting group title

Cohort B (5 capsules o.d.): TIP/PBO

Reporting group description

Cohort B (5 capsules o.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Reporting group title

Cohort B (5 capsules o.d.): PBO

Reporting group description

Cohort B (5 capsules o.d.): inhaled placebo (PBO)

Reporting group title

Cohort C (4 capsules b.i.d.): TIP

Reporting group description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP)

Reporting group title

Cohort C (4 capsules b.i.d.): TIP/PBO

Reporting group description

Cohort C (4 capsules b.i.d.): Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP/PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP/PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP): For efficacy analysis, subjects assigned to TIP groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled TIP/PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Pooled Tobramycin inhalation powder (TIP) and inhaled placebo (PBO) cyclical: For efficacy analysis, subjects assigned to TIP/PBO groups were pooled across the 3 cohorts.

Subject analysis set title

Pooled PBO

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. aeruginosa) density in sputum (log10 CFUs)

Top of page

End point title

Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. aeruginosa) density in sputum (log10 CFUs) ^[1]

End point description

Microbiological data was collected to understand the direct impact of the drug on the pathogens. Sputum samples were cultured for the presence of three Pseudomonas aeruginosa (P. aeruginosa) biotypes measured were mucoid, dry and small colony variant. Change was determined using the formula = (Post-baseline value - baseline value). If no P. aeruginosa was isolated for a visit, log10 colony forming units (CFU) was imputed with log10 (19) for all biotypes. Only values for all morphotypes presented.

End point type

Primary

End point timeframe

Baseline (Visit 101/Day 1), Visit 102 (Day 8), Visit 103 (Day 29)

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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: log10 CFUs
arithmetic mean (standard deviation)
Baseline	6.80 ( 1.202 )	7.67 ( 1.507 )	6.10 ( 2.419 )	6.98 ( 1.804 )	6.79 ( 0.908 )	5.73 ( 1.885 )	6.57 ( 1.625 )	6.74 ( 1.892 )	7.09 ( 2.012 )
Change from BL at Day 8	-2.82 ( 1.440 )	-3.23 ( 2.204 )	-2.04 ( 2.274 )	-3.98 ( 1.865 )	-4.54 ( 1.283 )	-3.47 ( 1.583 )	-3.30 ( 1.937 )	-3.58 ( 1.878 )	-0.72 ( 1.765 )
Change from BL at Day 29	-2.61 ( 2.600 )	-2.80 ( 2.823 )	-1.56 ( 2.885 )	-3.57 ( 2.218 )	-4.36 ( 1.101 )	-2.58 ( 2.871 )	-2.98 ( 2.474 )	-2.96 ( 2.618 )	0.05 ( 1.518 )

Day 8 Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.62

upper limit

-1.22

Variability estimate

Standard error of the mean

Dispersion value

0.6

Day 8 Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

-0.98

Variability estimate

Standard error of the mean

Dispersion value

0.58

Day 8 Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

-0.68

Variability estimate

Standard error of the mean

Dispersion value

0.63

Day 8 Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.38

upper limit

-2.15

Variability estimate

Standard error of the mean

Dispersion value

0.56

Day 8 Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-4

Confidence interval

level

95%

sides

2-sided

lower limit

-5.06

upper limit

-2.88

Variability estimate

Standard error of the mean

Dispersion value

0.55

Day 8 Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.57

upper limit

-2.14

Variability estimate

Standard error of the mean

Dispersion value

0.61

Day 8: Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-3.66

upper limit

-1.89

Variability estimate

Standard error of the mean

Dispersion value

0.44

Day 8: Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.79

upper limit

-2.05

Variability estimate

Standard error of the mean

Dispersion value

0.43

Day 29 Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.28

upper limit

-1.31

Variability estimate

Standard error of the mean

Dispersion value

0.75

Day 29 Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.03

upper limit

-0.67

Variability estimate

Standard error of the mean

Dispersion value

0.84

Day 29 Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.04

upper limit

-0.52

Variability estimate

Standard error of the mean

Dispersion value

0.88

Day 29 Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-5.16

upper limit

-1.85

Variability estimate

Standard error of the mean

Dispersion value

0.83

Day 29 Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-4.6

Confidence interval

level

95%

sides

2-sided

lower limit

-6.13

upper limit

-3.09

Variability estimate

Standard error of the mean

Dispersion value

0.76

Day 29 Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.68

upper limit

-1.52

Variability estimate

Standard error of the mean

Dispersion value

0.79

Day 29: Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-4.43

upper limit

-2.02

Variability estimate

Standard error of the mean

Dispersion value

0.61

Day 29: Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.19

upper limit

-1.78

Variability estimate

Standard error of the mean

Dispersion value

0.61

Secondary: Change From Baseline to each post-baseline visit in Pseudomonas aeruginosa (P. aeruginosa) density in sputum (log10 CFUs)

Top of page

End point title

Change From Baseline to each post-baseline visit in Pseudomonas aeruginosa (P. aeruginosa) density in sputum (log10 CFUs) ^[2]

End point description

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1), Visit 104 (Day 57), Visit 105 (Day 85), Visit 106 (Day 113), End of Treatment (EOT), Visit 201 (Day 141), Visit 202 (Day 169)

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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: log10 CFUs
arithmetic mean (standard deviation)
Baseline (BL)	6.80 ( 1.202 )	7.67 ( 1.507 )	6.10 ( 2.419 )	6.98 ( 1.804 )	6.79 ( 0.908 )	5.73 ( 1.885 )	6.57 ( 1.625 )	6.74 ( 1.892 )	7.09 ( 2.012 )
Change from BL at Day 57	-1.72 ( 3.066 )	-0.72 ( 2.677 )	-0.90 ( 1.894 )	-1.62 ( 2.804 )	-3.53 ( 2.220 )	-0.49 ( 2.305 )	-2.25 ( 2.646 )	-0.96 ( 2.576 )	0.20 ( 1.408 )
Change from BL at Day 85	-2.47 ( 2.446 )	-2.94 ( 2.492 )	-2.81 ( 3.653 )	-3.88 ( 2.470 )	-3.08 ( 1.624 )	-2.00 ( 2.951 )	-2.76 ( 2.446 )	-3.01 ( 2.641 )	-0.36 ( 2.238 )
Change from BL at Day 113	-2.94 ( 1.977 )	-1.03 ( 2.002 )	-1.82 ( 2.331 )	-1.99 ( 3.020 )	-3.17 ( 2.378 )	-1.54 ( 3.534 )	-2.79 ( 2.141 )	-1.50 ( 2.707 )	-0.20 ( 1.513 )
Change from BL at EOT	-2.49 ( 1.896 )	-1.08 ( 1.907 )	-0.84 ( 1.766 )	-1.86 ( 2.607 )	-2.60 ( 2.531 )	-1.29 ( 3.300 )	-2.01 ( 2.192 )	-1.42 ( 2.650 )	-0.34 ( 1.445 )
Change from BL at Day 141	-0.90 ( 2.113 )	-0.82 ( 2.117 )	0.10 ( 1.551 )	-2.17 ( 2.863 )	-0.92 ( 2.385 )	-0.87 ( 3.640 )	-0.68 ( 2.067 )	-1.34 ( 2.793 )	-0.06 ( 2.191 )
Change from BL at Day 169	-0.62 ( 2.324 )	-1.19 ( 1.885 )	0.46 ( 1.651 )	-1.27 ( 2.684 )	0.62 ( 1.038 )	1.33 ( 4.219 )	0.03 ( 1.882 )	-0.51 ( 3.036 )	0.62 ( 2.694 )

Day 57 Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.82

upper limit

-0.36

Variability estimate

Standard error of the mean

Dispersion value

0.87

Day 57 Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.21

upper limit

1.29

Variability estimate

Standard error of the mean

Dispersion value

0.88

Day 57 Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.87

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.99

Day 57 Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.34

upper limit

0.16

Variability estimate

Standard error of the mean

Dispersion value

0.88

Day 57 Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-5.5

upper limit

-2.22

Variability estimate

Standard error of the mean

Dispersion value

0.82

Day 57 Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.26

upper limit

0.41

Variability estimate

Standard error of the mean

Dispersion value

0.92

Day 57: Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.98

upper limit

-1.25

Variability estimate

Standard error of the mean

Dispersion value

0.68

Day 57: Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

0.19

Variability estimate

Standard error of the mean

Dispersion value

0.67

Day 85 Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-4

upper limit

-0.38

Variability estimate

Standard error of the mean

Dispersion value

0.9

Day 85 Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-3.81

upper limit

0.13

Variability estimate

Standard error of the mean

Dispersion value

0.99

Day 85 Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-4.96

upper limit

-0.53

Variability estimate

Standard error of the mean

Dispersion value

1.11

Day 85 Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-5.44

upper limit

-1.73

Variability estimate

Standard error of the mean

Dispersion value

0.93

Day 85 Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-4.9

upper limit

-1.07

Variability estimate

Standard error of the mean

Dispersion value

0.96

Day 85 Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.66

upper limit

-0.53

Variability estimate

Standard error of the mean

Dispersion value

1.03

Day 85: Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.11

upper limit

-1.17

Variability estimate

Standard error of the mean

Dispersion value

0.74

Day 85: Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-4.12

upper limit

-1.23

Variability estimate

Standard error of the mean

Dispersion value

0.72

Day 113 Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.55

upper limit

-1.08

Variability estimate

Standard error of the mean

Dispersion value

0.87

Day 113 Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.61

upper limit

1.71

Variability estimate

Standard error of the mean

Dispersion value

0.83

Day 113 Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.93

upper limit

-0.29

Variability estimate

Standard error of the mean

Dispersion value

1.16

Day 113 Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.62

upper limit

-0.25

Variability estimate

Standard error of the mean

Dispersion value

0.84

Day 113 Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.94

upper limit

-1.3

Variability estimate

Standard error of the mean

Dispersion value

0.91

Day 113 Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.37

upper limit

-0.43

Variability estimate

Standard error of the mean

Dispersion value

0.98

Day 113: Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.24

upper limit

-1.45

Variability estimate

Standard error of the mean

Dispersion value

0.7

Day 113: Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.73

upper limit

-0.13

Variability estimate

Standard error of the mean

Dispersion value

0.65

EoT Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.64

upper limit

-0.73

Variability estimate

Standard error of the mean

Dispersion value

0.73

EoT Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.61

upper limit

1.43

Variability estimate

Standard error of the mean

Dispersion value

0.76

EoT Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.81

upper limit

0.25

Variability estimate

Standard error of the mean

Dispersion value

0.77

EoT Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3.14

upper limit

-0.22

Variability estimate

Standard error of the mean

Dispersion value

0.73

EoT Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.89

upper limit

-0.98

Variability estimate

Standard error of the mean

Dispersion value

0.73

EoT Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-3.12

upper limit

-0.22

Variability estimate

Standard error of the mean

Dispersion value

0.73

EOT_Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.08

upper limit

-0.85

Variability estimate

Standard error of the mean

Dispersion value

0.56

EoT: Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.25

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.56

Day 141 Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.63

upper limit

0.99

Variability estimate

Standard error of the mean

Dispersion value

0.91

Day 141 Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.83

upper limit

1.98

Variability estimate

Standard error of the mean

Dispersion value

0.95

Day 141 Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.03

upper limit

2.41

Variability estimate

Standard error of the mean

Dispersion value

1.11

Day 141 Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-3.68

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.92

Day 141 Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.78

upper limit

1.07

Variability estimate

Standard error of the mean

Dispersion value

0.96

Day 141 Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.36

upper limit

0.89

Variability estimate

Standard error of the mean

Dispersion value

1.06

Day 141: Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.97

upper limit

0.98

Variability estimate

Standard error of the mean

Dispersion value

0.74

Day 141: Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.45

upper limit

0.45

Variability estimate

Standard error of the mean

Dispersion value

0.73

Day 169 Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-3.24

upper limit

0.61

Variability estimate

Standard error of the mean

Dispersion value

0.96

Day 169 Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.05

upper limit

0.91

Variability estimate

Standard error of the mean

Dispersion value

0.99

Day 169 Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.73

upper limit

1.62

Variability estimate

Standard error of the mean

Dispersion value

1.09

Day 169 Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.22

upper limit

-0.08

Variability estimate

Standard error of the mean

Dispersion value

1.03

Day 169 Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.48

upper limit

2.1

Variability estimate

Standard error of the mean

Dispersion value

1.14

Day 169 Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.33

upper limit

2.13

Variability estimate

Standard error of the mean

Dispersion value

1.12

Day 169: Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.24

upper limit

0.86

Variability estimate

Standard error of the mean

Dispersion value

0.77

Day 169: Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.61

upper limit

0.4

Variability estimate

Standard error of the mean

Dispersion value

0.75

Secondary: Time to first onset of pulmonary exacerbation by exacerbation category

Top of page

End point title

Time to first onset of pulmonary exacerbation by exacerbation category ^[3]

End point description

The time to first onset of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization. Participants were censored at the time of completion of study or early discontinuation if they did not have a pulmonary exacerbation during the study period.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Days
median (full range (min-max))
Overall	999 (39.00 to 999)	999 (48.00 to 999)	999 (15.00 to 999)	999 (85.00 to 999)	999 (127.00 to 999)	999 (24.00 to 999)	999 (127.00 to 999)	999 (85.00 to 999)	173.00 (77.00 to 999)
Oral	999 (999 to 999)	999 (48.00 to 999)	999 (22.00 to 999)	999 (85.00 to 999)	999 (999 to 999)	999 (84.00 to 999)	999 (999 to 999)	999 (999 to 999)	173.00 (106.00 to 999)
Parenteral	999 (110.00 to 999)	999 (999 to 999)	999 (60.00 to 999)	999 (154.00 to 999)	999 (999 to 999)	999 (33.00 to 999)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)

Overall Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.14

upper limit

3.18

Overall Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.57

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

1.85

Overall Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.42

upper limit

3.77

Overall Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

1.83

Overall Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.21

upper limit

2.17

Overall Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

3.62

Overall Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

2.23

Overall Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.34

upper limit

1.71

Oral Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.08

upper limit

1.83

Oral Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

2.89

Oral Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

3.93

Oral Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

2.36

Oral Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

1.57

Oral Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

2.41

Oral Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.42

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

1.31

Oral Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

1.8

Parenteral Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

10.71

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

104.19

Parenteral Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

4.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

52.29

Parenteral Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

3.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

37.06

Parenteral Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.61

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

25.94

Parenteral Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

11.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.09

upper limit

117.34

Parenteral Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

37.32

Secondary: Duration of pulmonary exacerbation by exacerbation category

Top of page

End point title

Duration of pulmonary exacerbation by exacerbation category ^[4]

End point description

The duration of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Days
arithmetic mean (standard deviation)
Overall	15.7 ( 6.22 )	18.0 ( 8.26 )	20.2 ( 6.37 )	10.3 ( 5.12 )	25.5 ( 27.09 )	14.8 ( 6.73 )	19.0 ( 12.64 )	15.2 ( 7.39 )	14.5 ( 5.61 )
Oral	19.5 ( 12.02 )	15.4 ( 4.24 )	19.3 ( 3.20 )	8.3 ( 4.16 )	14.0 ( 999 )	16.3 ( 5.51 )	18.6 ( 5.77 )	14.0 ( 5.24 )	15.6 ( 5.75 )
Parenteral	15.0 ( 5.52 )	999 ( 999 )	22.0 ( 12.73 )	16.0 ( 999 )	66.0 ( 999 )	16.8 ( 4.86 )	23.1 ( 18.73 )	16.6 ( 4.22 )	10.0 ( 999 )

Overall Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

9.8

Confidence interval

level

95%

sides

2-sided

lower limit

-27.15

upper limit

46.81

Variability estimate

Standard error of the mean

Dispersion value

18.15

Overall Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

19.8

Confidence interval

level

95%

sides

2-sided

lower limit

-22.63

upper limit

62.14

Variability estimate

Standard error of the mean

Dispersion value

20.81

Overall Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-31.32

upper limit

47.26

Variability estimate

Standard error of the mean

Dispersion value

19.29

Overall Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

12.7

Confidence interval

level

95%

sides

2-sided

lower limit

-26.49

upper limit

51.89

Variability estimate

Standard error of the mean

Dispersion value

19.24

Overall Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

46.5

Confidence interval

level

95%

sides

2-sided

lower limit

3.37

upper limit

89.61

Variability estimate

Standard error of the mean

Dispersion value

21.17

Overall Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-34.21

upper limit

40.64

Variability estimate

Standard error of the mean

Dispersion value

18.37

Overall Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

21.4

Confidence interval

level

95%

sides

2-sided

lower limit

-8.03

upper limit

50.89

Variability estimate

Standard error of the mean

Dispersion value

14.46

Overall Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

LS Mean Diff (SE) vs pooled placebo

Point estimate

11.9

Confidence interval

level

95%

sides

2-sided

lower limit

-17.52

upper limit

41.29

Variability estimate

Standard error of the mean

Dispersion value

14.44

Secondary: Exposure adjusted rate of pulmonary exacerbations (PE) over the entire study period

Top of page

End point title

Exposure adjusted rate of pulmonary exacerbations (PE) over the entire study period ^[5]

End point description

The exposure adjusted rate of pulmonary exacerbation compared to placebo was analyzed. Participants with pulmonary exacerbation were categorized as: a) Overall, b) Category 1 (Oral): treated with oral antibiotics only and c) Category 2 (Parenteral): treated with parenteral Antibiotics and/or requiring hospitalization. The Exposure adjusted rate = (Number of pulmonary exacerbations reported during the study period) / (sum of study duration in days for all participants/ 365.25). Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: pulmonary exacerbation per study years
number (confidence interval 95%)
Overall	1.71 (0.92 to 3.17)	1.39 (0.70 to 2.78)	1.29 (0.58 to 2.87)	1.20 (0.57 to 2.51)	0.66 (0.25 to 1.76)	1.46 (0.73 to 2.93)	1.21 (0.78 to 1.87)	1.35 (0.90 to 2.03)	1.41 (0.82 to 2.42)
Oral	0.34 (0.09 to 1.37)	1.22 (0.58 to 2.56)	0.86 (0.32 to 2.29)	0.85 (0.36 to 2.05)	0.16 (0.02 to 1.17)	0.55 (0.18 to 1.70)	0.42 (0.20 to 0.89)	0.88 (0.53 to 1.46)	1.19 (0.66 to 2.15)
Parenteral	0.85 (0.36 to 2.05)	999 (999 to 999)	0.43 (0.11 to 1.72)	0.34 (0.09 to 1.37)	0.16 (0.02 to 1.17)	0.73 (0.27 to 1.95)	0.48 (0.24 to 0.96)	0.35 (0.16 to 0.78)	0.11 (0.02 to 0.77)

No statistical analyses for this end point

Secondary: Time to permanent study drug discontinuation due to Pulmonary exacerbation

Top of page

End point title

Time to permanent study drug discontinuation due to Pulmonary exacerbation ^[6]

End point description

The time to permanent study drug discontinuation due to Pulmonary exacerbation. Participants were censored at the time of last contact if they did not permanently discontinue study drug due to pulmonary exacerbation requiring during the study period. Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Days
median (confidence interval 95%)	999 (94.00 to 999)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)	999 (84.00 to 999)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Time to first use (overall, oral, and parenteral) of anti-pseudomonal antibiotics usage

Top of page

End point title

Time to first use (overall, oral, and parenteral) of anti-pseudomonal antibiotics usage ^[7]

End point description

The time to first use of anti-pseudomonal antibiotics administered compared to placebo was analyzed. Participants were censored at the time of last contact if they did not have anti-pseudomonal antibiotics over the entire study period.

End point type

Secondary

End point timeframe

From Baseline (Visit 101/Day 1) up to approximately Day 173

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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Days
median (full range (min-max))
Overall	122.00 (29.00 to 999)	999 (50.00 to 999)	116.00 (17.00 to 999)	161.00 (58.00 to 999)	999 (127.00 to 999)	999 (11.00 to 999)	999 (110.00 to 999)	999 (84.00 to 999)	141.00 (57.00 to 999)
Oral	999 (43.00 to 999)	999 (50.00 to 999)	999 (17.00 to 999)	999 (85.00 to 999)	999 (999 to 999)	999 (11.00 to 999)	999 (999 to 999)	999 (85.00 to 999)	173.00 (106.00 to 999)
Parenteral	999 (105.0 to 999)	999 (999 to 999)	999 (63.00 to 999)	999 (95.00 to 999)	999 (999 to 999)	999 (37.00 to 999)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)

Overall Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

3.13

Overall Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.15

upper limit

1.46

Overall Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

3.21

Overall Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.32

upper limit

2.18

Overall Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

1.27

Overall Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

2.99

Overall Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

1.76

Overall Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

1.61

Oral Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

2.55

Oral Cohort A: TIP/PBO, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

2.03

Oral Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

3.6

Oral Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

2.55

Oral Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.06

upper limit

1.27

Oral Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

3.73

Oral Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.66

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

1.6

Oral Pooled TIP/PBO, Pooled PBO

Comparison groups

Pooled TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

2.02

Parenteral Cohort A: TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

3.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

16.52

Parenteral Cohort B: TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

8.16

Parenteral Cohort B: TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

2.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

10.05

Parenteral Cohort C: TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

4.87

Parenteral Cohort C: TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

2.56

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

12.49

Paremteral Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

5.68

Secondary: Duration of anti-pseudomonal antibiotics usage

Top of page

End point title

Duration of anti-pseudomonal antibiotics usage ^[8]

End point description

The total number of days of new anti-pseudomonal antibiotic use compared to placebo was analyzed. Only descriptive analysis

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Days
arithmetic mean (standard deviation)
Overall	18.4 ( 10.39 )	20.0 ( 12.03 )	19.2 ( 14.84 )	25.7 ( 13.21 )	15.3 ( 10.07 )	15.7 ( 10.90 )	18.1 ( 11.43 )	20.6 ( 12.24 )	14.6 ( 8.27 )
Oral	14.2 ( 7.79 )	19.8 ( 12.34 )	15.0 ( 7.42 )	14.0 ( 10.92 )	20.0 ( 8.49 )	10.8 ( 6.24 )	15.5 ( 7.29 )	14.3 ( 9.79 )	13.7 ( 7.41 )
Parenteral	15.0 ( 10.02 )	999 ( 999 )	20.0 ( 14.14 )	23.8 ( 15.20 )	6.0 ( 999 )	11.3 ( 2.75 )	15.1 ( 10.23 )	17.5 ( 12.12 )	12.7 ( 7.64 )

No statistical analyses for this end point

Secondary: Duration of hospitalization due to serious respiratory-related adverse events

Top of page

End point title

Duration of hospitalization due to serious respiratory-related adverse events ^[9]

End point description

The duration of hospitalization due to serious respiratory-related adverse events (other than those regularly scheduled hospitalization that were planned prior to study start) was analyzed to define severity of pulmonary exacerbations compared to placebo. Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Notes
[9] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	4	0 ^[10]	2	2	1	4	7	6	2
Units: Days
arithmetic mean (standard deviation)	15.2 ( 5.19 )	( )	22.0 ( 12.73 )	12.2 ( 6.06 )	11.0 ( 999 )	19.0 ( 5.23 )	16.2 ( 7.05 )	15.2 ( 6.44 )	10.5 ( 0.71 )

Notes
[10] - No participants with at least one hospitalization

No statistical analyses for this end point

Secondary: Number of hospitalization due to serious respiratory-related adverse events

Top of page

End point title

Number of hospitalization due to serious respiratory-related adverse events ^[11]

End point description

The number of hospitalization due to serious respiratory-related AEs was analyzed to define severity of pulmonary exacerbations compared to placebo. Respiratory related adverse events were identified using the AEs captured under system organ class 'Respiratory, thoracic and mediastinal disorders' and 'Infections and infestations'.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Notes
[11] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Hospitalization	6	0	2	5	2	4	10	9	2

Cohort A (3 capsules o.d.): TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Log odds ratio

Point estimate

5.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

38.18

Cohort B (5 capsules o.d.): TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Log odds ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.21

upper limit

19.16

Cohort B (5 capsules o.d.): TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Log odds ratio

Point estimate

3.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

21.8

Cohort C (4 capsules b.i.d.): TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Log odds ratio

Point estimate

1.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

17.42

Cohort C (4 capsules b.i.d.): TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Log odds ratio

Point estimate

3.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

25.03

Pooled TIP/Pooled TIP/PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Log odds ratio

Point estimate

2.74

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

16.07

Secondary: Time to first hospitalization due to serious respiratory-related adverse events

Top of page

End point title

Time to first hospitalization due to serious respiratory-related adverse events ^[12]

End point description

Time to first hospitalization due to serious respiratory-related AEs was analyzed to define severity of pulmonary exacerbations compared to placebo. Participants were censored at the time of last contact if they did not have a hospitalization due to serious respiratory-related adverse events over the entire study period.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Notes
[12] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Day
median (confidence interval 95%)	999 (93.00 to 999)	999 (999 to 999)	999 (60.00 to 999)	999 (999 to 999)	999 (999 to 999)	999 (65.00 to 999)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)

Cohort A (3 capsules o.d.): TIP, Pooled PBO

Comparison groups

Cohort A (3 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

4.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

26.42

Cohort B (5 capsules o.d.): TIP, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

14.47

Cohort B (5 capsules o.d.): TIP/PBO, Pooled PBO

Comparison groups

Cohort B (5 capsules o.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

11.6

Cohort C (4 capsules b.i.d.): TIP, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.06

upper limit

7.49

Cohort C (4 capsules b.i.d.): TIP/PBO, Pooled PBO

Comparison groups

Cohort C (4 capsules b.i.d.): TIP/PBO v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

3.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

23.29

Pooled TIP, Pooled PBO

Comparison groups

Pooled TIP v Pooled PBO

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.35

upper limit

9.45

Secondary: Serum tobramycin concentration

Top of page

End point title

Serum tobramycin concentration ^[13]

End point description

The serum pharmacokinetic (PK) properties of tobramycin were assessed by evaluating tobramycin concentrations in serum collected from the non-cystic fibrosis bronchiectasis population post administration of o.d. or b.i.d. doses of TIP. Serum specimens for PK tobramycin concentration were assessed at Visit 101 (Day 1/start of treatment) 0 to 1 and 1 to 2 hours post-dose and Visit 102 (Day 8) 0 to 1 and 1 to 2 hours post-dose. Prior to protocol amendment #2, PK samples were assessed on Visits 103 (Day 29) rather than Visit 102. Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1), Visit 102 (Day 8) and Visits 103 (Day 29): 0-1 hours and 1-2 hours post-dose.

Notes
[13] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO
Number of subjects analysed	14	13	15	14	15	15
Units: microgram/milliliter
arithmetic mean (standard deviation)
Visit 101 (Day 1)/0-1 hr post dose	0.256 ( 0.144 )	0.479 ( 0.47 )	0.4 ( 0.259 )	0.441 ( 0.273 )	0.59 ( 0.37 )	0.321 ( 0.21 )
Visit 101 (Day 1)/1-2 hr post dose	0.481 ( 0.287 )	0.571 ( 0.349 )	0.517 ( 0.392 )	0.624 ( 0.322 )	0.64 ( 0.338 )	0.476 ( 0.295 )
Visit 102 (Day 8)/0-1 hr post dose	999 ( 999 )	0 ( 999 )	1.81 ( 999 )	0.258 ( 999 )	1.4 ( 999 )	0.489 ( 0.257 )
Visit 102 (Day 8)/1-2 hr post dose	999 ( 999 )	0.18 ( 999 )	1.67 ( 999 )	0.588 ( 999 )	1.48 ( 999 )	0.447 ( 999 )
Visit 103 (Day 29)/0-1 hr post dose	0.607 ( 0.455 )	0.0718 ( 0.0498 )	1.23 ( 1.08 )	0.103 ( 0.0983 )	1.05 ( 0.603 )	0.339 ( 0.274 )
Visit 103 (Day 29)/1-2 hr post dose	0.768 ( 0.477 )	0.0818 ( 0.0972 )	1.37 ( 0.647 )	0.104 ( 0.096 )	1.05 ( 0.622 )	0.307 ( 0.24 )

No statistical analyses for this end point

Secondary: Sputum tobramycin concentration

Top of page

End point title

Sputum tobramycin concentration ^[14]

End point description

The sputum pharmacokinetic (PK) properties of tobramycin were assessed by evaluating tobramycin concentrations in sputum collected from the non-cystic fibrosis bronchiectasis population post administration of o.d. or b.i.d. doses of TIP. Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1): 0-1 hours and 1-2 hours post-dose; Visit 102 (Day 8):0-2 hours and 5-6 hours post-dose; Visits 103 (Day 29): 5 to 6 hours post-dose, Visit 104 (Day 57) and Visit 105 (Day 85): 3-4 hours post-dose.

Notes
[14] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO
Number of subjects analysed	14	13	15	14	15	15
Units: microgram/milliliter
arithmetic mean (standard deviation)
Visit 101 (Day 1)/0-1 hr post dose	1750 ( 2160 )	637 ( 608 )	2640 ( 2680 )	2020 ( 2360 )	2820 ( 2250 )	2060 ( 1840 )
Visit 101 (Day 1)/1-2 hr post dose	1100 ( 2480 )	204 ( 445 )	1650 ( 2340 )	1100 ( 2310 )	631 ( 441 )	610 ( 463 )
Visit 102 (Day 8)/0-2 hr post dose	1440 ( 1470 )	2390 ( 2730 )	2460 ( 761 )	4290 ( 3730 )	1980 ( 2060 )	2290 ( 1560 )
Visit 102 (Day 8)/5-6 hr post dose	999 ( 999 )	32.4 ( 999 )	999 ( 999 )	4460 ( 999 )	999 ( 999 )	1200 ( 51.6 )
Visit 103 (Day 29)/5-6 hr post dose	389 ( 554 )	136 ( 258 )	915 ( 1450 )	16.3 ( 28.6 )	620 ( 513 )	134 ( 175 )
Visit 104 (Day 57)/3-4 hr post dose	198 ( 138 )	0 ( 999 )	96.4 ( 999 )	4540 ( 999 )	999 ( 999 )	0 ( 0 )
Visit 105 (Day 85)/3-4 hr post dose	791 ( 883 )	45.7 ( 75.8 )	101 ( 100 )	61 ( 108 )	2810 ( 2200 )	121 ( 166 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning

Top of page

End point title

Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning ^[15]

End point description

The QoL-B consists of 37 items across 8 domains: Physical Functioning (PF), Role Functioning (RF), Vitality, Emotional Function (EF), Social Functioning (SF), Treatment Burden (TB), Health Perception (HP) and Respiratory Symptoms (RS). Each of the 37 items is scored from 1 to 4, and each of the 8 scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HRQoL. A total score is not calculated since functioning can vary greatly from one domain to another. Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Notes
[15] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP/PBO	Pooled PBO	Pooled TIP
Number of subjects analysed	14	13	15	14	15	15	42	21	43
Units: Score on Scale
arithmetic mean (standard deviation)
Baseline (BL)	51.33 ( 38.33 )	60.5 ( 28.60 )	45.8 ( 19.98 )	50.5 ( 33.04 )	46.2 ( 30.29 )	53.8 ( 26.72 )	54.8 ( 29.10 )	49.8 ( 27.97 )	47.6 ( 29.41 )
Change from BL at Day 8	5.6 ( 18.83 )	-2.8 ( 14.35 )	-6.7 ( 22.02 )	-2.9 ( 18.06 )	0.9 ( 11.51 )	3.1 ( 14.44 )	-0.7 ( 15.62 )	-7.4 ( 17.76 )	0.2 ( 17.83 )
Change from BL at Day 29	-2.1 ( 24.40 )	-7.2 ( 16.44 )	-5.3 ( 27.90 )	-2.6 ( 8.41 )	-0.4 ( 16.23 )	-6.2 ( 27.48 )	-5.3 ( 19.05 )	-1.1 ( 17.68 )	-2.3 ( 22.04 )
Change from BL at EoT	-6.7 ( 18.66 )	-6.1 ( 18.53 )	-19.4 ( 23.00 )	-6.7 ( 23.39 )	-5.8 ( 31.36 )	-9.8 ( 30.43 )	-7.6 ( 24.47 )	0.4 ( 20.30 )	-10.2 ( 25.44 )
Change from BL at Day 169	5.5 ( 25.27 )	-3.3 ( 18.09 )	0.0 ( 22.44 )	-1.3 ( 16.27 )	-3.9 ( 26.43 )	7.3 ( 22.54 )	0.6 ( 19.04 )	-4.8 ( 16.77 )	0.4 ( 24.43 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning

Top of page

End point title

Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning ^[16]

End point description

End point type

Secondary

End point timeframe

Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Notes
[16] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP/PBO	Pooled PBO	Pooled TIP
Number of subjects analysed	14	13	15	14	15	15	42	21	43
Units: Score on Scale
arithmetic mean (standard deviation)
Baseline (BL)	63.1 ( 24.28 )	67.2 ( 14.26 )	53.3 ( 21.68 )	64.3 ( 29.77 )	57.8 ( 26.86 )	67.6 ( 24.67 )	66.3 ( 23.46 )	63.9 ( 19.79 )	57.8 ( 24.11 )
Change from BL at Day 8	5.6 ( 14.36 )	-2.2 ( 19.76 )	2.2 ( 20.17 )	-1.4 ( 13.88 )	3.6 ( 17.43 )	-4.2 ( 20.95 )	-2.7 ( 18.03 )	-1.4 ( 14.67 )	3.8 ( 17.01 )
Change from BL at Day 29	1.5 ( 19.66 )	-1.1 ( 18.17 )	2.0 ( 21.33 )	-1.0 ( 14.87 )	-0.9 ( 19.82 )	-4.5 ( 23.88 )	-2.3 ( 19.06 )	1.8 ( 16.00 )	0.7 ( 19.65 )
Change from BL at EoT	-0.5 ( 23.95 )	-5.0 ( 24.47 )	-0.4 ( 23.79 )	-9.0 ( 25.30 )	0.9 ( 20.30 )	-4.0 ( 24.27 )	-6.0 ( 24.17 )	1.0 ( 19.70 )	0.0 ( 22.01 )
Change from BL at Day 169	10.3 ( 16.96 )	-7.2 ( 17.17 )	10.7 ( 13.41 )	-2.7 ( 21.82 )	-6.1 ( 15.94 )	6.7 ( 16.92 )	-1.5 ( 18.99 )	-4.4 ( 15.51 )	4.4 ( 17.13 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality

Top of page

End point title

Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality ^[17]

End point description

End point type

Secondary

End point timeframe

Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Notes
[17] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP/PBO	Pooled PBO	Pooled TIP
Number of subjects analysed	14	13	15	14	15	15	42	21	42
Units: Score on Scale
arithmetic mean (standard deviation)
Baseline (BL)	56.4 ( 22.89 )	47.9 ( 17.21 )	52.4 ( 21.54 )	44.4 ( 26.51 )	47.4 ( 25.36 )	51.9 ( 18.63 )	48.1 ( 20.92 )	46.2 ( 25.46 )	51.9 ( 23.11 )
Change from BL at Day 8	6.8 ( 18.45 )	1.9 ( 24.54 )	-6.1 ( 31.18 )	4.8 ( 17.27 )	5.2 ( 20.52 )	2.2 ( 11.27 )	3.0 ( 17.57 )	-2.9 ( 16.08 )	2.6 ( 23.43 )
Change from BL at Day 29	-4.3 ( 30.95 )	4.6 ( 15.23 )	-9.9 ( 28.57 )	3.4 ( 18.36 )	-0.7 ( 24.66 )	-5.6 ( 23.77 )	80.6 ( 19.74 )	1.8 ( 19.69 )	-4.2 ( 27.39 )
Change from BL at EoT	-5.6 ( 25.26 )	2.8 ( 24.22 )	-12.1 ( 26.04 )	3.2 ( 28.05 )	-0.7 ( 29.24 )	2.2 ( 30.35 )	2.7 ( 27.19 )	-1.2 ( 23.97 )	-5.6 ( 26.77 )
Change from BL at Day 169	8.1 ( 20.55 )	3.7 ( 22.89 )	3.7 ( 24.22 )	2.2 ( 21.47 )	-2.8 ( 22.78 )	1.1 ( 19.21 )	2.4 ( 20.69 )	-2.5 ( 20.36 )	2.8 ( 22.22 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning

Top of page

End point title

Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning ^[18]

End point description

End point type

Secondary

End point timeframe

Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Notes
[18] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP/PBO	Pooled PBO	Pooled TIP
Number of subjects analysed	14	13	15	14	15	15	42	21	42
Units: Score on Scale
arithmetic mean (standard deviation)
Baseline (BL)	79.5 ( 14.28 )	71.2 ( 18.51 )	77.4 ( 17.73 )	74.4 ( 29.50 )	71.1 ( 18.86 )	76.1 ( 23.54 )	74.0 ( 23.87 )	79.6 ( 16.96 )	75.8 ( 17.15 )
Change from BL at Day 8	2.6 ( 11.48 )	-4.2 ( 12.05 )	-0.8 ( 13.67 )	2.4 ( 11.52 )	4.4 ( 18.33 )	4.4 ( 6.19 )	1.2 ( 10.47 )	-1.4 ( 11.87 )	2.4 ( 14.80 )
Change from BL at Day 29	1.9 ( 11.36 )	-4.9 ( 12.03 )	2.8 ( 13.18 )	3.8 ( 16.53 )	5.6 ( 13.24 )	-1.2 ( 14.93 )	-0.6 ( 14.73 )	-1.9 ( 12.31 )	3.6 ( 12.35 )
Change from BL at EoT	1.3 ( 17.63 )	-8.3 ( 22.19 )	-9.1 ( 18.43 )	2.4 ( 32.26 )	1.1 ( 15.06 )	-3.3 ( 14.36 )	-2.8 ( 23.76 )	-2.3 ( 15.60 )	-1.7 ( 17.12 )
Change from BL at Day 169	6.1 ( 21.44 )	-6.9 ( 15.00 )	7.4 ( 17.40 )	5.0 ( 18.51 )	0.0 ( 7.11 )	6.7 ( 21.45 )	1.0 ( 18.78 )	3.9 ( 13.85 )	4.2 ( 15.98 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning

Top of page

End point title

Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning ^[19]

End point description

End point type

Secondary

End point timeframe

Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP/PBO	Pooled PBO	Pooled TIP
Number of subjects analysed	14	13	15	14	15	15	42	21	43
Units: Score on Scale
arithmetic mean (standard deviation)
Baseline (BL)	66.2 ( 19.21 )	51.3 ( 22.53 )	36.5 ( 21.18 )	63.5 ( 26.17 )	48.5 ( 19.95 )	55.7 ( 26.80 )	56.9 ( 25.22 )	51.9 ( 25.24 )	49.7 ( 23.13 )
Change from BL at Day 8	3.0 ( 13.49 )	2.1 ( 23.61 )	29.6 ( 23.67 )	-2.6 ( 12.49 )	-0.7 ( 21.91 )	8.5 ( 15.66 )	2.8 ( 17.67 )	5.0 ( 14.18 )	9.6 ( 23.78 )
Change from BL at Day 29	4.9 ( 15.51 )	-2.5 ( 26.05 )	22.8 ( 18.14 )	-1.5 ( 24.50 )	2.6 ( 23.95 )	4.8 ( 19.89 )	0.4 ( 23.07 )	-1.2 ( 15.72 )	8.7 ( 21.19 )
Change from BL at EoT	3.0 ( 21.71 )	2.1 ( 26.14 )	17.8 ( 27.89 )	-5.6 ( 26.73 )	1.5 ( 30.10 )	5.7 ( 15.38 )	0.8 ( 22.95 )	-0.6 ( 18.04 )	6.9 ( 27.25 )
Change from BL at Day 169	3.3 ( 24.27 )	-5.1 ( 20.41 )	25.3 ( 21.73 )	-4.2 ( 28.43 )	-4.2 ( 25.42 )	11.9 ( 21.91 )	0.5 ( 24.15 )	-0.5 ( 19.37 )	7.2 ( 26.36 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden

Top of page

End point title

Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden ^[20]

End point description

End point type

Secondary

End point timeframe

Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Notes
[20] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled PBO	Pooled TIP	Pooled TIP/PBO
Number of subjects analysed	14	13	15	14	15	15	21	38	33
Units: Score on Scale
arithmetic mean (standard deviation)
Baseline (BL)	67.7 ( 25.56 )	68.9 ( 26.09 )	64.3 ( 29.29 )	73.1 ( 18.63 )	56.4 ( 27.76 )	54.5 ( 27.42 )	64.6 ( 30.69 )	62.6 ( 27.39 )	65.7 ( 24.75 )
Change from BL at Day 8	-2.2 ( 19.46 )	-8.6 ( 29.28 )	0.0 ( 15.71 )	-9.3 ( 17.62 )	4.3 ( 14.01 )	4.0 ( 7.49 )	-2.6 ( 19.33 )	1.0 ( 16.04 )	-4.5 ( 19.73 )
Change from BL at Day 29	-9.1 ( 28.03 )	-8.3 ( 27.70 )	8.3 ( 30.14 )	-10.0 ( 22.50 )	1.9 ( 13.26 )	-3.7 ( 25.46 )	-5.1 ( 25.91 )	-0.4 ( 24.26 )	-7.4 ( 24.27 )
Change from BL at EoT	-7.1 ( 21.81 )	-8.6 ( 31.32 )	-10.1 ( 16.07 )	-14.8 ( 23.37 )	6.8 ( 26.66 )	1.0 ( 9.23 )	-3.0 ( 30.13 )	-2.9 ( 22.92 )	-7.6 ( 22.83 )
Change from BL at Day 169	1.4 ( 26.19 )	-3.7 ( 31.92 )	0.0 ( 13.28 )	-4.2 ( 24.44 )	0.0 ( 17.37 )	12.7 ( 11.88 )	-5.1 ( 18.16 )	0.4 ( 18.72 )	0.9 ( 25.15 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions

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End point title

Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions ^[21]

End point description

End point type

Secondary

End point timeframe

Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Notes
[21] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP/PBO	Pooled PBO	Pooled TIP
Number of subjects analysed	14	13	15	14	15	15	42	21	43
Units: Score on Scale
arithmetic mean (standard deviation)
Baseline (BL)	41.0 ( 17.83 )	35.3 ( 19.29 )	33.1 ( 20.26 )	41.1 ( 27.83 )	39.4 ( 21.70 )	40.0 ( 20.70 )	38.9 ( 22.52 )	41.7 ( 16.67 )	37.7 ( 19.91 )
Change from BL at Day 8	7.1 ( 23.28 )	4.9 ( 20.24 )	10.0 ( 11.87 )	-2.4 ( 13.25 )	5.6 ( 13.24 )	5.6 ( 15.96 )	2.6 ( 16.50 )	0.0 ( 16.43 )	7.4 ( 16.52 )
Change from BL at Day 29	7.1 ( 26.54 )	4.9 ( 20.24 )	12.8 ( 16.26 )	3.8 ( 19.73 )	-1.1 ( 18.06 )	-1.8 ( 26.19 )	2.1 ( 22.02 )	3.1 ( 14.49 )	5.3 ( 21.19 )
Change from BL at EoT	-3.2 ( 25.35 )	0.7 ( 17.93 )	-2.5 ( 15.28 )	-3.6 ( 23.51 )	1.1 ( 23.12 )	-0.6 ( 23.46 )	-1.2 ( 21.53 )	1.6 ( 16.67 )	-1.4 ( 21.43 )
Change from BL at Day 169	10.6 ( 13.99 )	0.0 ( 21.32 )	14.4 ( 19.72 )	6.7 ( 17.91 )	-1.4 ( 11.70 )	9.2 ( 14.93 )	4.9 ( 18.31 )	0.9 ( 19.57 )	7.4 ( 16.30 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms

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End point title

Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms ^[22]

End point description

End point type

Secondary

End point timeframe

Baseline, Visit 102 (Day 8), Visit 103 (Day 29), End of Treatment (Day 113) and Visit 202 (Day 169)

Notes
[22] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP/PBO	Pooled PBO	Pooled TIP
Number of subjects analysed	14	13	15	14	15	15	42	21	43
Units: Score on Scale
arithmetic mean (standard deviation)
Baseline (BL)	56.0 ( 13.05 )	53.8 ( 18.12 )	56.8 ( 17.63 )	55.9 ( 21.69 )	52.3 ( 22.39 )	61.9 ( 13.31 )	57.4 ( 17.83 )	53.8 ( 14.42 )	55.0 ( 17.98 )
Change from BL at Day 8	10.3 ( 6.83 )	6.5 ( 14.66 )	13.9 ( 16.12 )	3.3 ( 9.99 )	9.8 ( 12.30 )	-0.6 ( 16.20 )	2.8 ( 13.85 )	1.0 ( 12.09 )	11.2 ( 12.05 )
Change from BL at Day 29	7.0 ( 11.94 )	0.6 ( 19.97 )	6.3 ( 24.57 )	3.6 ( 14.69 )	6.9 ( 22.57 )	-5.7 ( 25.58 )	-0.7 ( 20.58 )	2.3 ( 13.48 )	6.8 ( 19.65 )
Change from BL at EoT	-0.4 ( 11.21 )	4.1 ( 15.65 )	1.9 ( 18.52 )	-0.6 ( 20.73 )	6.7 ( 16.52 )	-6.5 ( 26.18 )	-1.4 ( 21.59 )	4.0 ( 12.12 )	2.9 ( 15.58 )
Change from BL at Day 169	7.1 ( 11.76 )	0.9 ( 16.42 )	10.7 ( 8.63 )	-2.7 ( 24.33 )	5.6 ( 16.53 )	10.7 ( 12.52 )	2.8 ( 18.57 )	1.6 ( 19.98 )	7.6 ( 12.76 )

No statistical analyses for this end point

Secondary: Percentage of participants with at least one pulmonary exacerbation by exacerbation category

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End point title

Percentage of participants with at least one pulmonary exacerbation by exacerbation category ^[23]

End point description

Pulmonary exacerbations are defined as events requiring antibiotic therapy AND for which at least 3 of the following 6 symptoms, signs, or findings were present outside of normal variation: 1. Increased sputum volume, or change in viscosity/consistency or purulence for more than 24 hours; 2. Increased shortness of breath at rest or on exercise for more than 24 hours; 3. Increased cough for more than 24 hours; 4. Fever of ≥38° Celsius within the last 24 hours; 5. Increased malaise/fatigue/lethargy for more than 24 hours; 6. A reduction in forced expiratory volume in the first second of expiration (FEV1) or forced vital capacity (FVC) of least 10% from screening. Participants were categorized as: a) Overall, b) Category 1: treated with oral antibiotics only and c) Category 2: treated with parenteral Antibiotics and/or requiring hospitalization. Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Notes
[23] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Participants
Overall\|No of participants with no events	8	9	10	9	11	9	29	27	11
Oral\|No of participants with no events	12	9	12	10	14	12	38	31	13
Parenteral\|No of participants with no events	10	13	13	12	14	11	37	36	20
Overall\|No. of participants with 1 event	3	1	4	3	4	4	11	8	7
Oral\|No. of participants with 1 event	2	2	2	3	1	3	5	8	5
Parenteral\|No. of participants with 1 event	3	0	2	2	1	4	6	6	1
Overall\|No. of participants with 2 events	2	2	1	2	0	2	3	6	3
Oral\|No. of participants with 2 events	0	1	1	1	0	0	1	2	3
Parenteral\|No. of participants with 2 events	1	0	0	0	0	0	1	0	0
Overall\|No. of participants with 3 events	1	1	0	0	0	0	1	1	0
Oral\|No. of participants with 3 events	0	1	0	0	0	0	0	1	0
Parenteral\|No. of participants with 3 events	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of participants who permanently discontinued study drug due to pulmonary exacerbation

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End point title

Percentage of participants who permanently discontinued study drug due to pulmonary exacerbation ^[24]

End point description

The percentage of participants who permanently discontinued study drug due to pulmonary exacerbation compared to placebo was analyzed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Participants	2	0	1	0	0	2	41	40	0

No statistical analyses for this end point

Secondary: Percentage of participants requiring anti-pseudomonal antibiotics

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End point title

Percentage of participants requiring anti-pseudomonal antibiotics ^[25]

End point description

The percentage of participants requiring anti-pseudomonal antibiotics compared to placebo was analyzed. Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Notes
[25] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Participants
Overall\|Any antipseudomonal antibiotic use?=Yes	8	4	6	7	3	7	17	18	12
Oral\|Any antipseudomonal antibiotic use?=Yes	5	4	5	6	2	6	12	16	10
Parenteral\|Any antipseudomonal antibiotic use?=Yes	5	0	2	4	1	4	8	8	3
Overall\|Any antipseudomonal antibiotic use?=No	6	9	9	7	12	8	27	24	9
Oral\|Any antipseudomonal antibiotic use?=No	9	9	10	8	13	9	32	26	11
Parenteral\|Any antipseudomonal antibiotic use?=No	9	13	13	10	14	11	36	34	18

No statistical analyses for this end point

Secondary: Percentage of participants requiring hospitalization due to serious respiratory-related adverse events

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End point title

Percentage of participants requiring hospitalization due to serious respiratory-related adverse events ^[26]

End point description

The percentage of participants requiring hospitalization due to serious respiratory-related adverse events (other than those regularly scheduled hospitalization that were planned prior to study start) was analyzed to define severity of pulmonary exacerbations compared to placebo. Only descriptive analysis performed.

End point type

Secondary

End point timeframe

Baseline (Visit 101/Day 1) to Visit 202 (Day 169)

Notes
[26] - 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: For efficacy analysis, subjects assigned to: Placebo groups were pooled across the 3 cohorts, as the number of placebo capsules was not expected to impact the efficacy assessments (Pooled inhaled placebo (PBO)); TIP groups were pooled across the 3 cohorts (Pooled TIP) and TIP/PBO groups were pooled across the 3 cohorts (Pooled TIP/PBO).

End point values	Cohort A (3 capsules o.d.): TIP	Cohort A (3 capsules o.d.): TIP/PBO	Cohort B (5 capsules o.d.): TIP	Cohort B (5 capsules o.d.): TIP/PBO	Cohort C (4 capsules b.i.d.): TIP	Cohort C (4 capsules b.i.d.): TIP/PBO	Pooled TIP	Pooled TIP/PBO	Pooled PBO
Number of subjects analysed	14	13	15	14	15	15	44	42	21
Units: Participants
No of participants with 0 event	10	13	13	12	14	11	37	36	19
No. of participants with 1 event	3	0	2	1	0	4	5	5	2
No. of participants with 2 events	0	0	0	0	1	0	1	0	0
No. of participants with > 2 events	1	0	0	1	0	0	1	1	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from first dose of study drug treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 134 days.

Adverse event reporting additional description

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

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Cohort A:3 capsules o.d. TIP

Reporting group description

Cohort A:3 capsules o.d. TIP

Reporting group title

Cohort A:3 capsules o.d. TIP/PBO

Reporting group description

Cohort A:3 capsules o.d. TIP/PBO

Reporting group title

Cohort A:3 capsules o.d. PBO

Reporting group description

Cohort A:3 capsules o.d. PBO

Reporting group title

Cohort B:5 capsules o.d. TIP

Reporting group description

Cohort B:5 capsules o.d. TIP

Reporting group title

Cohort B:5 capsules o.d. TIP/PBO

Reporting group description

Cohort B:5 capsules o.d. TIP/PBO

Reporting group title

Cohort B:5 capsules o.d. PBO

Reporting group description

Cohort B:5 capsules o.d. PBO

Reporting group title

Cohort C:4 capsules b.i.d. TIP

Reporting group description

Cohort C:4 capsules b.i.d. TIP

Reporting group title

Cohort C:4 capsules b.i.d. TIP/PBO

Reporting group description

Cohort C:4 capsules b.i.d. TIP/PBO

Reporting group title

Cohort C:4 capsules b.i.d. PBO

Reporting group description

Cohort C:4 capsules b.i.d. PBO

Serious adverse events	Cohort A:3 capsules o.d. TIP	Cohort A:3 capsules o.d. TIP/PBO	Cohort A:3 capsules o.d. PBO	Cohort B:5 capsules o.d. TIP	Cohort B:5 capsules o.d. TIP/PBO	Cohort B:5 capsules o.d. PBO	Cohort C:4 capsules b.i.d. TIP	Cohort C:4 capsules b.i.d. TIP/PBO	Cohort C:4 capsules b.i.d. PBO
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 14 (28.57%)	2 / 13 (15.38%)	0 / 7 (0.00%)	4 / 15 (26.67%)	3 / 14 (21.43%)	2 / 7 (28.57%)	2 / 15 (13.33%)	4 / 15 (26.67%)	1 / 7 (14.29%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0
Investigations
Blood creatinine abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glomerular filtration rate decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Orthostatic hypotension
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Intestinal obstruction
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacterial disease carrier
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of bronchiectasis
subjects affected / exposed	3 / 14 (21.43%)	0 / 13 (0.00%)	0 / 7 (0.00%)	2 / 15 (13.33%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	3 / 15 (20.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 2	1 / 1	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort A:3 capsules o.d. TIP	Cohort A:3 capsules o.d. TIP/PBO	Cohort A:3 capsules o.d. PBO	Cohort B:5 capsules o.d. TIP	Cohort B:5 capsules o.d. TIP/PBO	Cohort B:5 capsules o.d. PBO	Cohort C:4 capsules b.i.d. TIP	Cohort C:4 capsules b.i.d. TIP/PBO	Cohort C:4 capsules b.i.d. PBO
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 14 (85.71%)	12 / 13 (92.31%)	6 / 7 (85.71%)	10 / 15 (66.67%)	10 / 14 (71.43%)	7 / 7 (100.00%)	13 / 15 (86.67%)	14 / 15 (93.33%)	5 / 7 (71.43%)
Vascular disorders
Hot flush
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0
Hypertension
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Chest discomfort
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	1 / 14 (7.14%)	1 / 7 (14.29%)	2 / 15 (13.33%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	1	3	2	0	0
Chest pain
subjects affected / exposed	1 / 14 (7.14%)	2 / 13 (15.38%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	2 / 15 (13.33%)	0 / 7 (0.00%)
occurrences all number	1	2	0	0	0	0	0	2	0
Discomfort
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	2 / 15 (13.33%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	2	0	0	0	0	0
Exercise tolerance decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Fatigue
subjects affected / exposed	1 / 14 (7.14%)	2 / 13 (15.38%)	0 / 7 (0.00%)	1 / 15 (6.67%)	3 / 14 (21.43%)	2 / 7 (28.57%)	2 / 15 (13.33%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	1	2	0	1	5	3	2	0	1
Influenza like illness
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0
Pyrexia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	2 / 15 (13.33%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	2	0	0
Immune system disorders
Food allergy
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	1
Prostatitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Bronchiectasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Bronchospasm
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	3 / 15 (20.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	1	3	0
Cough
subjects affected / exposed	2 / 14 (14.29%)	3 / 13 (23.08%)	1 / 7 (14.29%)	4 / 15 (26.67%)	2 / 14 (14.29%)	1 / 7 (14.29%)	2 / 15 (13.33%)	2 / 15 (13.33%)	3 / 7 (42.86%)
occurrences all number	8	4	1	10	3	1	2	2	3
Dry throat
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	3 / 15 (20.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	3	0	0
Dysphonia
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	2 / 15 (13.33%)	0 / 7 (0.00%)
occurrences all number	0	1	0	1	0	0	1	2	0
Dyspnoea
subjects affected / exposed	2 / 14 (14.29%)	2 / 13 (15.38%)	1 / 7 (14.29%)	3 / 15 (20.00%)	2 / 14 (14.29%)	2 / 7 (28.57%)	4 / 15 (26.67%)	2 / 15 (13.33%)	0 / 7 (0.00%)
occurrences all number	2	2	1	4	2	2	4	2	0
Dyspnoea exertional
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	1	0	0	0	1
Dyspnoea paroxysmal nocturnal
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Epistaxis
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0
Haemoptysis
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	2 / 14 (14.29%)	3 / 7 (42.86%)	0 / 15 (0.00%)	2 / 15 (13.33%)	1 / 7 (14.29%)
occurrences all number	1	3	0	0	2	8	0	2	1
Increased bronchial secretion
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	1	0	0	1	0	0
Increased viscosity of bronchial secretion
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0
Nasal discomfort
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	2 / 14 (14.29%)	1 / 7 (14.29%)	2 / 15 (13.33%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	2	1	2	0	1
Pulmonary pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Rales
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Respiratory symptom
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Sputum discoloured
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0	0
Sputum increased
subjects affected / exposed	3 / 14 (21.43%)	1 / 13 (7.69%)	1 / 7 (14.29%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	3 / 15 (20.00%)	1 / 7 (14.29%)
occurrences all number	3	1	1	0	2	0	0	3	1
Throat irritation
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Wheezing
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	1 / 7 (14.29%)	1 / 15 (6.67%)	2 / 15 (13.33%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0	1	1	2	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	0	1	0	0	1
Investigations
Blood cholesterol increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0
Blood creatinine increased
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	1 / 15 (6.67%)	1 / 14 (7.14%)	0 / 7 (0.00%)	6 / 15 (40.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	1	1	0	1	1	0	6	1	0
Blood electrolytes decreased
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Blood urea increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
C-reactive protein increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	1 / 7 (14.29%)	2 / 15 (13.33%)	0 / 14 (0.00%)	0 / 7 (0.00%)	2 / 15 (13.33%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	1	2	0	0	2	0	0
Eosinophil count abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Forced expiratory volume decreased
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	3	0	1	0	0
Forced vital capacity decreased
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Glomerular filtration rate decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	1 / 14 (7.14%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	1	0	1	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Liver function test abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Neutrophil count increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Protein urine present
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0
Sputum abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Urine albumin/creatinine ratio increased
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	1	0	0	0	0	1	0	0
Urine protein/creatinine ratio increased
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	2 / 15 (13.33%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	0	2	0	0
Weight decreased
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	0	0	0	0	1
White blood cell count increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Injury, poisoning and procedural complications
Airway complication of anaesthesia
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Arthropod bite
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Fall
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Hypobarism
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Ligament sprain
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Procedural pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Road traffic accident
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Nervous system disorders
Ageusia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Anosmia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Dizziness
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Headache
subjects affected / exposed	2 / 14 (14.29%)	4 / 13 (30.77%)	0 / 7 (0.00%)	1 / 15 (6.67%)	2 / 14 (14.29%)	1 / 7 (14.29%)	2 / 15 (13.33%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	4	5	0	1	3	1	3	0	0
Hypoaesthesia
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Muscle spasticity
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Tremor
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Eosinophilia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Iron deficiency anaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	1
Thrombocytopenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Deafness
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	1
Eustachian tube dysfunction
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Middle ear effusion
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Tinnitus
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	1	1	0	0
Eye disorders
Eye pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	1	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	1	0	0	1
Aerophagia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Cheilitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Constipation
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Dental caries
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Diarrhoea
subjects affected / exposed	0 / 14 (0.00%)	3 / 13 (23.08%)	2 / 7 (28.57%)	1 / 15 (6.67%)	1 / 14 (7.14%)	0 / 7 (0.00%)	2 / 15 (13.33%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	3	3	1	1	0	3	0	0
Dry mouth
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	2 / 14 (14.29%)	1 / 7 (14.29%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	3	1	1	0	1
Dyspepsia
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0
Gastric polyps
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Gastrointestinal disorder
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Glossodynia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Inguinal hernia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Lip swelling
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Nausea
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	1	1	0	0
Oral pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Paraesthesia oral
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0
Vomiting
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	1	0	0	0	0	0	0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Hepatotoxicity
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Dermatitis allergic
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Night sweats
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0
Rash
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0
Rash papular
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Skin exfoliation
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Swelling face
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Urticaria
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Glycosuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	1
Haematuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	1
Proteinuria
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	2	1	0	0	0	0	0	0	1
Renal cyst
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Renal failure
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Renal impairment
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0
Urinary incontinence
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	0	0	0	1
Joint contracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Joint swelling
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Limb discomfort
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Muscle contracture
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	2 / 15 (13.33%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	2	0	1
Muscle tightness
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	1 / 15 (6.67%)	1 / 15 (6.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	0	1	1	1
Myalgia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	0	1
Pain in extremity
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	2 / 7 (28.57%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	2	0	0	0
Periarthritis
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0	0	0	1	0
Candida infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Cystitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	1	0	0	0	0	0	0	0	1
Ear infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Herpes simplex
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Hordeolum
subjects affected / exposed	1 / 14 (7.14%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Infective exacerbation of bronchiectasis
subjects affected / exposed	4 / 14 (28.57%)	4 / 13 (30.77%)	6 / 7 (85.71%)	3 / 15 (20.00%)	5 / 14 (35.71%)	2 / 7 (28.57%)	4 / 15 (26.67%)	5 / 15 (33.33%)	2 / 7 (28.57%)
occurrences all number	6	8	6	4	6	4	4	5	3
Influenza
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1	0	1
Joint abscess
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Labyrinthitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Lower respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	1 / 15 (6.67%)	2 / 14 (14.29%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	1	0	1	2	1	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	1 / 7 (14.29%)	0 / 15 (0.00%)	1 / 15 (6.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	2	1	0	1	1
Oral fungal infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Oral herpes
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Respiratory tract infection viral
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Rhinitis
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	0	0	1	0
Sinusitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	2	0	0	0	0	0	0
Sputum purulent
subjects affected / exposed	1 / 14 (7.14%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	1	0	0	1	0
Tooth infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Urinary tract infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	2 / 15 (13.33%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	2	0
Viral infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 14 (0.00%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Decreased appetite
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 14 (7.14%)	1 / 7 (14.29%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	1	1	0	0	0
Hyperglycaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	1 / 15 (6.67%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Hyponatraemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 15 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	0 / 14 (0.00%)	0 / 7 (0.00%)	0 / 15 (0.00%)	1 / 15 (6.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

26 Sep 2017

Amendment 1: The purpose of this protocol amendment was to clarify specific elements in the protocol. First, the timing of the Data Monitoring Committee (DMC) interim review wasremoved, as this was detailed in the DMC charter. Furthermore, the amendment clarified that for the signs and symptoms characterizing the pulmonary exacerbations and which were required to last for more than 24 hours, additional information regarding duration were collected to document if the reported signs and symptoms were present for more than 48 hours. The additional information was collected in line with the recently published consensus definition of pulmonary exacerbations for clinical research (Hill et al 2017). In addition, thresholds and criteria for renal event monitoring were revised in accordance with the updated Novartis renal safety guideline and the safety profile of Tobramycin Inhalation Powder (TIP) obtained from clinical and post-marketing experience in cystic fibrosis (CF) patients. Based on the review of the most recent data cumulatively (until 30-June-2017), there was no evidence to suggest a causal relationship between use of TIP and the potential risk of nephrotoxicity. The risk for nephrotoxicity was expected to be very low considering the systemic levels of tobramycin after TIP administration (Cmax is 1.02 ± 0.53 μg/mL) compared to the maximum systemic levels recommended for avoidance of the toxicity associated with intravenous tobramycin therapy (Cmax greater than 12 μg/mL) (Sweetman 2011). The revised renal safety alert criteria were designed to facilitate the early detection of a renal event. Moreover, corrections on minor inconsistencies or clarifications were incorporated in this protocol amendment.

09 Feb 2018

Amendment 2: The purpose of this protocol amendment is to revise the following enrolment criteria (9a, 10a, 18a, 21a and 33a). Furthermore, the renal alert criteria and follow-up actions and the discontinuation criteria were amended in order to focus on the relevant renal function markers. To improve the renal function monitoring distinction was made between renal findings and confirmed renal events. Instructions for study treatment interruption/discontinuation were clarified to distinguish events that mandate permanent study drug discontinuation as per protocol from those that are at investigators’ discretion. The pharmacokinetics (PK) sampling scheme was revised in order to maximize the number of samples for tobramycin exposure in particular in patients who are on alternating TIP/placebo treatment. Changing PK sampling from Day 29 to Day 8 is acceptable to assess the exposure. This is based on the short estimated terminal half-life of tobramycin in serum after inhalation of a single 112 mg dose of TIP which was approximately 3 hours (Ting 2014).

21 Jun 2018

Amendment 3: The purpose of this protocol amendment was to revise: a) Exclusion criterion 33b: To clarify the assessment of total abstinence as highly effective contraception method. Total abstinence was to be in line with the preferred and usual lifestyle of the subject. For consistency with the “Recommendations related to contraception and pregnancy testing” of the Clinical Trials Facilitation Group the wording was reverted to the initial protocol wording. In addition, this amendment included the definition of personal data and modified withdrawal of study consent definition in accordance with the European Economic Area General Data Protection Regulation requirements. This amendment also included the following changes in planned statistical analysis: • removing the cohort from the models due to confounding with treatment, • including the multiple imputation technique as a sensitivity analysis and, • dropping some exploratory analyses due to small sample size as outlined below.

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.

Novartis decided to close the recruitment of new subjects into this study earlier than scheduled. The early recruitment halt of the study was not due to safety or lack of efficacy.

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Clinical trials

Clinical Trial Results: A randomized, blinded, parallel group, multi-center dose-finding study, to assess the efficacy, safety and tolerability of different doses of tobramycin inhalation powder in patients with Non Cystic Fibrosis Bronchiectasis and pulmonary P. aeruginosa infection

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. aeruginosa) density in sputum (log10 CFUs)

Primary: Change From Baseline to Day 29 in Pseudomonas Aeruginosa (P. aeruginosa) density in sputum (log10 CFUs)

Secondary: Change From Baseline to each post-baseline visit in Pseudomonas aeruginosa (P. aeruginosa) density in sputum (log10 CFUs)

Secondary: Change From Baseline to each post-baseline visit in Pseudomonas aeruginosa (P. aeruginosa) density in sputum (log10 CFUs)

Secondary: Time to first onset of pulmonary exacerbation by exacerbation category

Secondary: Time to first onset of pulmonary exacerbation by exacerbation category

Secondary: Duration of pulmonary exacerbation by exacerbation category

Secondary: Duration of pulmonary exacerbation by exacerbation category

Secondary: Exposure adjusted rate of pulmonary exacerbations (PE) over the entire study period

Secondary: Exposure adjusted rate of pulmonary exacerbations (PE) over the entire study period

Secondary: Time to permanent study drug discontinuation due to Pulmonary exacerbation

Secondary: Time to permanent study drug discontinuation due to Pulmonary exacerbation

Secondary: Time to first use (overall, oral, and parenteral) of anti-pseudomonal antibiotics usage

Secondary: Time to first use (overall, oral, and parenteral) of anti-pseudomonal antibiotics usage

Secondary: Duration of anti-pseudomonal antibiotics usage

Secondary: Duration of anti-pseudomonal antibiotics usage

Secondary: Duration of hospitalization due to serious respiratory-related adverse events

Secondary: Duration of hospitalization due to serious respiratory-related adverse events

Secondary: Number of hospitalization due to serious respiratory-related adverse events

Secondary: Number of hospitalization due to serious respiratory-related adverse events

Secondary: Time to first hospitalization due to serious respiratory-related adverse events

Secondary: Time to first hospitalization due to serious respiratory-related adverse events

Secondary: Serum tobramycin concentration

Secondary: Serum tobramycin concentration

Secondary: Sputum tobramycin concentration

Secondary: Sputum tobramycin concentration

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Physical Functioning

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Role Functioning

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Vitality

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Emotional Functioning

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Social Functioning

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Treatment Burden

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Health Perceptions

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms

Secondary: Change from Baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B)-Respiratory Symptoms

Secondary: Percentage of participants with at least one pulmonary exacerbation by exacerbation category

Secondary: Percentage of participants with at least one pulmonary exacerbation by exacerbation category

Secondary: Percentage of participants who permanently discontinued study drug due to pulmonary exacerbation

Secondary: Percentage of participants who permanently discontinued study drug due to pulmonary exacerbation

Secondary: Percentage of participants requiring anti-pseudomonal antibiotics

Secondary: Percentage of participants requiring anti-pseudomonal antibiotics

Secondary: Percentage of participants requiring hospitalization due to serious respiratory-related adverse events

Secondary: Percentage of participants requiring hospitalization due to serious respiratory-related adverse events

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A randomized, blinded, parallel group, multi-center dose-finding study, to assess the efficacy, safety and tolerability of different doses of tobramycin inhalation powder in patients with Non Cystic Fibrosis Bronchiectasis and pulmonary P. aeruginosa infection