Trial Outcomes & Findings for Safety and Efficacy of Inhaled Treprostinil in Adult PH With ILD Including CPFE (NCT NCT02630316)

Last Updated: 2022-07-27

Results Overview

The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 16, correlates with the current clinical standard for assessing patient functional status in the treatment of PH and is considered an objective measure of patient functional status. Subjects will be instructed to walk down a corridor at a comfortable speed as far as they can manage for six minutes. Peak exposure 6MWD will occur by conducting 6-minute walk test (6MWT) within 10 to 60 minutes after the most recent dose of study drug dose.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

326 participants

Primary outcome timeframe

Baseline and Week 16

Results posted on

2022-07-27

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Inhaled Treprostinil Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily
Overall Study STARTED	163	163
Overall Study COMPLETED	128	130
Overall Study NOT COMPLETED	35	33

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Height was not collected for 1 subject in the Placebo group and 1 subject in the Inhaled Treprostinil group.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=163 Participants Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Inhaled Treprostinil n=163 Participants Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily	Total n=326 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=163 Participants	0 Participants n=163 Participants	0 Participants n=326 Participants
Age, Categorical Between 18 and 65 years	48 Participants n=163 Participants	64 Participants n=163 Participants	112 Participants n=326 Participants
Age, Categorical >=65 years	115 Participants n=163 Participants	99 Participants n=163 Participants	214 Participants n=326 Participants
Age, Continuous	67.4 years STANDARD_DEVIATION 11.2 • n=163 Participants	65.6 years STANDARD_DEVIATION 12.7 • n=163 Participants	66.5 years STANDARD_DEVIATION 12.0 • n=326 Participants
Sex: Female, Male Female	68 Participants n=163 Participants	85 Participants n=163 Participants	153 Participants n=326 Participants
Sex: Female, Male Male	95 Participants n=163 Participants	78 Participants n=163 Participants	173 Participants n=326 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=163 Participants	2 Participants n=163 Participants	3 Participants n=326 Participants
Race (NIH/OMB) Asian	5 Participants n=163 Participants	7 Participants n=163 Participants	12 Participants n=326 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=163 Participants	0 Participants n=163 Participants	0 Participants n=326 Participants
Race (NIH/OMB) Black or African American	30 Participants n=163 Participants	41 Participants n=163 Participants	71 Participants n=326 Participants
Race (NIH/OMB) White	126 Participants n=163 Participants	112 Participants n=163 Participants	238 Participants n=326 Participants
Race (NIH/OMB) More than one race	1 Participants n=163 Participants	0 Participants n=163 Participants	1 Participants n=326 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=163 Participants	1 Participants n=163 Participants	1 Participants n=326 Participants
Region of Enrollment Puerto Rico	2 participants n=163 Participants	0 participants n=163 Participants	2 participants n=326 Participants
Region of Enrollment United States	161 participants n=163 Participants	163 participants n=163 Participants	324 participants n=326 Participants
Weight	83.5 kg STANDARD_DEVIATION 20.6 • n=163 Participants	83.9 kg STANDARD_DEVIATION 20.5 • n=163 Participants	83.7 kg STANDARD_DEVIATION 20.5 • n=326 Participants
Height	169.0 cm STANDARD_DEVIATION 9.4 • n=162 Participants • Height was not collected for 1 subject in the Placebo group and 1 subject in the Inhaled Treprostinil group.	167.5 cm STANDARD_DEVIATION 10.3 • n=162 Participants • Height was not collected for 1 subject in the Placebo group and 1 subject in the Inhaled Treprostinil group.	168.2 cm STANDARD_DEVIATION 9.9 • n=324 Participants • Height was not collected for 1 subject in the Placebo group and 1 subject in the Inhaled Treprostinil group.
BMI	29.0 kg/m^2 STANDARD_DEVIATION 5.9 • n=162 Participants • Height was not collected for 1 subject in the Placebo group and 1 subject in the Inhaled Treprostinil group.	30.0 kg/m^2 STANDARD_DEVIATION 6.6 • n=162 Participants • Height was not collected for 1 subject in the Placebo group and 1 subject in the Inhaled Treprostinil group.	29.5 kg/m^2 STANDARD_DEVIATION 6.3 • n=324 Participants • Height was not collected for 1 subject in the Placebo group and 1 subject in the Inhaled Treprostinil group.
6 Minute Walk Distance	265.1 meters STANDARD_DEVIATION 93.1 • n=163 Participants	254.1 meters STANDARD_DEVIATION 102.4 • n=163 Participants	259.6 meters STANDARD_DEVIATION 97.9 • n=326 Participants
N-terminal prohormone brain natriuretic peptide (NT-proBNP)	210.9 pg/mL STANDARD_DEVIATION 370.7 • n=158 Participants • NT-proBNP was not collected for 10 subjects from the Inhaled Treprostinil group and 5 subjects from the Placebo group.	223.5 pg/mL STANDARD_DEVIATION 378.5 • n=153 Participants • NT-proBNP was not collected for 10 subjects from the Inhaled Treprostinil group and 5 subjects from the Placebo group.	217.1 pg/mL STANDARD_DEVIATION 374.0 • n=311 Participants • NT-proBNP was not collected for 10 subjects from the Inhaled Treprostinil group and 5 subjects from the Placebo group.
Pulmonary Vascular Resistance (PVR)	6.0 Wood Units (WU) STANDARD_DEVIATION 2.7 • n=163 Participants	6.4 Wood Units (WU) STANDARD_DEVIATION 2.9 • n=163 Participants	6.2 Wood Units (WU) STANDARD_DEVIATION 2.8 • n=326 Participants
Mean pulmonary arterial pressure (PAPm)	36.0 mmHg STANDARD_DEVIATION 8.4 • n=163 Participants	37.2 mmHg STANDARD_DEVIATION 8.6 • n=163 Participants	36.6 mmHg STANDARD_DEVIATION 8.5 • n=326 Participants
Pulmonary Capillary Wedge Pressure (PCWP)	9.6 mmHg STANDARD_DEVIATION 3.5 • n=163 Participants	10.1 mmHg STANDARD_DEVIATION 3.4 • n=163 Participants	9.8 mmHg STANDARD_DEVIATION 3.5 • n=326 Participants
Vasodilator testing during confirmatory right heart catheterization (RHC)? Yes	45 Participants n=163 Participants	42 Participants n=163 Participants	87 Participants n=326 Participants
Vasodilator testing during confirmatory right heart catheterization (RHC)? No	118 Participants n=163 Participants	121 Participants n=163 Participants	239 Participants n=326 Participants
10 mmHg decrease in PAPm during Confirmatory RHC? Yes	8 Participants n=163 Participants	6 Participants n=163 Participants	14 Participants n=326 Participants
10 mmHg decrease in PAPm during Confirmatory RHC? No	35 Participants n=163 Participants	37 Participants n=163 Participants	72 Participants n=326 Participants
10 mmHg decrease in PAPm during Confirmatory RHC? Not tested	120 Participants n=163 Participants	120 Participants n=163 Participants	240 Participants n=326 Participants
Vasodilator medications used during Confirmatory RHC? Inhaled Nitrous Oxide	43 Participants n=163 Participants	39 Participants n=163 Participants	82 Participants n=326 Participants
Vasodilator medications used during Confirmatory RHC? Adenosine	2 Participants n=163 Participants	1 Participants n=163 Participants	3 Participants n=326 Participants
Vasodilator medications used during Confirmatory RHC? Other	0 Participants n=163 Participants	2 Participants n=163 Participants	2 Participants n=326 Participants
Vasodilator medications used during Confirmatory RHC? No medication	118 Participants n=163 Participants	121 Participants n=163 Participants	239 Participants n=326 Participants

PRIMARY outcome

Timeframe: Baseline and Week 16

Population: All Subjects Dosed

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Inhaled Treprostinil n=163 Participants Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily
Change in 6-minute Walk Distance (6MWD) Measured at Peak Exposure From Baseline to Week 16	-9.0 meters Interval -426.0 to 179.0	6.0 meters Interval -396.0 to 183.0

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Only subjects with Baseline NT-proBNP are included. For subjects who do not have Week 16 measure, the last observation carried forward imputation is used.

The NT-proBNP serum concentration is a useful biomarker associated with changes in right heart morphology and function. NT-proBNP serum concentration will be assessed to compare the severity of heart failure at Baseline and Week 16. Blood for NT-proBNP assessment must be drawn prior to conducting the 6MWT.

Outcome measures

Outcome measures
Measure	Placebo n=160 Participants Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Inhaled Treprostinil n=156 Participants Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily
Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 16	20.65 pg/mL Interval -5483.3 to 87148.3	-22.65 pg/mL Interval -11433.0 to 5373.1

SECONDARY outcome

Timeframe: Baseline to Week 16

Population: All Subjects with Clinical Worsening Events

Subjects were monitored for clinical worsening from the time of randomization until 1 of the following criteria were met: hospitalization due to a cardiopulmonary indication; decrease in 6MWD \>15% from Baseline directly related to the disease under study, at 2 consecutive visits and at least 24 hours apart; death (all causes); or lung transplantation.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Inhaled Treprostinil n=163 Participants Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily
Incidence of Clinical Worsening	54 Participants	37 Participants

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: For those subjects who withdrew early due to death, were too ill to walk, or had no 6MWD measure due to clinical worsening event, the 6MWD is set to 0, for all other withdrawals without Week 12 measurement, last observation carried forward (LOCF) is used for imputation.

The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 12, correlates with the current clinical standard for assessing patient functional status in the treatment of PH and is considered an objective measure of patient functional status. Subjects will be instructed to walk down a corridor at a comfortable speed as far as they can manage for six minutes. Peak exposure 6MWD will occur by conducting 6MWT within 10 to 60 minutes after the most recent dose of study drug dose.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Inhaled Treprostinil n=163 Participants Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily
Change in Peak 6-minute Walk Distance (6MWD) From Baseline to Week 12	-3.0 meters Interval -369.0 to 152.0	8.0 meters Interval -360.0 to 192.0

SECONDARY outcome

Timeframe: Baseline and Week 15

Population: For those subjects who withdrew early due to death, were too ill to walk, or had no 6MWD measure due to clinical worsening event, the 6MWD is set to 0, for all other withdrawals without Week 15 measurement, baseline observation carried forward is used for imputation.

The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 15, correlates with the current clinical standard for assessing patient functional status in the treatment of PH and is considered an objective measure of patient functional status. Subjects will be instructed to walk down a corridor at a comfortable speed as far as they can manage for six minutes. Distance \<500 meters suggests considerable exercise limitation; Distance 500-800 meters suggests moderate limitation; Distance \>800 meters (with no rests) suggests mild or no limitation. Trough exposure 6MWD will occur by conducting 6-minute walk test (6MWT) at least four hours after the most recent study drug dose.

Outcome measures

Outcome measures
Measure	Placebo n=163 Participants Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Inhaled Treprostinil n=163 Participants Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily
Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15	-9.0 meter Interval -369.0 to 180.0	0.0 meter Interval -396.0 to 144.0

Adverse Events

Placebo

Serious events: 42 serious events

Other events: 149 other events

Deaths: 12 deaths

Active Inhaled Treprostinil

Serious events: 38 serious events

Other events: 152 other events

Deaths: 10 deaths

Serious adverse events

Other adverse events

Additional Information

United Therapeutics Global Medical Information

United Therapeutics

Phone: 919-485-8350

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Institution and/or Principal Investigator agree not to publish or publicly present any results of the Study without the prior written consent of Sponsor, not to be unreasonably withheld or delayed. Institution and/or Principal Investigator further agree to provide Sponsor with drafts of any such publication or presentation for review and approval no less than 30 days prior to submission for publication or the date of public presentation.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Placebo n=163 participants at risk Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Active Inhaled Treprostinil n=163 participants at risk Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily
Blood and lymphatic system disorders Coagulopathy	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Acute myocardial infarction	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Acute right ventricular failure	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Arrythmia	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Cardiac arrest	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Cardiac failure congestive	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Cardiopulmonary failure	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Cor pulmonale	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Left ventricular failure	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Right ventricular failure	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Tachycardia	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Atrial fibrillation	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Bradycardia	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Cardiac failure	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Cardiac failure acute	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Cardiogenic shock	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Chronic right ventricular failure	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Cor pulmonale acute	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Cardiac disorders Coronary artery disease	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Gastrointestinal disorders Abdominal pain	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Gastrointestinal disorders Haematochezia	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
General disorders Death	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	1.8% 3/163 • Number of events 3 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
General disorders Chest pain	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
General disorders Disease progression	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
General disorders Pain	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Bronchitis	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Upper respiratory tract infection	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Bronchopulmonary aspergillosis	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Cellulitis	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Influenza	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Pneumonia	5.5% 9/163 • Number of events 9 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Rhinovirus infetion	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Pneumonia influenzal	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Post procedural infection	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Sepsis	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Urosepsis	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Injury, poisoning and procedural complications Transplant dysfunction	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Metabolism and nutrition disorders Hypervolaemia	0.00% 0/163 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	0.61% 1/163 • Number of events 1 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).

Other adverse events
Measure	Placebo n=163 participants at risk Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily	Active Inhaled Treprostinil n=163 participants at risk Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily
Respiratory, thoracic and mediastinal disorders Cough	33.1% 54/163 • Number of events 56 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	43.6% 71/163 • Number of events 76 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Nervous system disorders Headache	19.6% 32/163 • Number of events 34 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	27.6% 45/163 • Number of events 49 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Gastrointestinal disorders Nausea	16.0% 26/163 • Number of events 27 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	15.3% 25/163 • Number of events 26 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Gastrointestinal disorders Diarrhea	11.7% 19/163 • Number of events 19 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	13.5% 22/163 • Number of events 24 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
General disorders Fatigue	14.1% 23/163 • Number of events 24 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	14.1% 23/163 • Number of events 24 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
General disorders Chest pain	3.1% 5/163 • Number of events 5 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	8.6% 14/163 • Number of events 14 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
General disorders Oedema peripheral	6.1% 10/163 • Number of events 11 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	8.0% 13/163 • Number of events 13 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
General disorders Chest discomfort	2.5% 4/163 • Number of events 4 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	4.9% 8/163 • Number of events 9 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Upper respiratory tract infection	6.7% 11/163 • Number of events 11 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	6.7% 11/163 • Number of events 12 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Infections and infestations Pneumonia	6.7% 11/163 • Number of events 12 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	1.2% 2/163 • Number of events 2 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Injury, poisoning and procedural complications Fall	1.8% 3/163 • Number of events 3 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	4.9% 8/163 • Number of events 8 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Investigations N-terminal prohormone brain natriuretic peptide increased	15.3% 25/163 • Number of events 25 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	5.5% 9/163 • Number of events 9 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Metabolism and nutrition disorders Decreased appetite	4.9% 8/163 • Number of events 8 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	4.3% 7/163 • Number of events 7 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Nervous system disorders Dizziness	14.1% 23/163 • Number of events 23 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	18.4% 30/163 • Number of events 31 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Respiratory, thoracic and mediastinal disorders Dyspnoea	31.3% 51/163 • Number of events 56 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	25.2% 41/163 • Number of events 46 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Respiratory, thoracic and mediastinal disorders Throat irritation	3.7% 6/163 • Number of events 6 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	12.3% 20/163 • Number of events 20 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.5% 4/163 • Number of events 4 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	11.0% 18/163 • Number of events 18 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Respiratory, thoracic and mediastinal disorders Epistaxis	4.3% 7/163 • Number of events 7 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	5.5% 9/163 • Number of events 9 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	2.5% 4/163 • Number of events 4 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).	4.9% 8/163 • Number of events 8 • AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit).