Trial Outcomes & Findings for Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy (NCT NCT01560624)

NCT ID: NCT01560624

Last Updated: 2020-02-13

Results Overview

Clinical worsening was assessed continuously from randomization until the subject's last study visit. Clinical worsening events were defined as death (all causes), hospitalizations due to worsening pulmonary arterial hypertension (PAH), initiation of an inhaled or infused prostacyclin (PGI2) for the treatment of worsening PAH, disease progression, or unsatisfactory long-term clinical response. All clinical worsening events reported by the study sites were reviewed by the Sponsor Medical Monitors. Once a clinical worsening event occurred, it was entered in the eCRF and a narrative was submitted for review by the Sponsor's Medical Monitor within 48 hours after the event became known to the Investigator or designee. Subsequently, the narratives for subjects with the reported clinical worsening events were sent to an independent adjudication committee. The independent adjudication committee reviewed and adjudicated all clinical worsening events throughout the study.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 690 participants
• Primary outcome timeframe: From randomization to approximately 4 years
• Results posted on: 2020-02-13

Participant Flow

Participant milestones

Measure	UT-15C Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg three times daily (TID) Treprostinil Diolamine: Active	Placebo Matching placebo tablets (oral) Placebo: Placebo
Overall Study STARTED	346	344
Overall Study Clinical Worsening Event	91	133
Overall Study Early Discontinuation From Treatment	107	56
Overall Study COMPLETED	148	155
Overall Study NOT COMPLETED	198	189

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy

Baseline characteristics by cohort

Measure	UT-15C n=346 Participants Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID Treprostinil Diolamine: Active	Placebo n=344 Participants Matching placebo tablets (oral) Placebo: Placebo	Total n=690 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	292 Participants n=5 Participants	294 Participants n=7 Participants	586 Participants n=5 Participants
Age, Categorical >=65 years	54 Participants n=5 Participants	50 Participants n=7 Participants	104 Participants n=5 Participants
Age, Continuous	45.6 years STANDARD_DEVIATION 15.7 • n=5 Participants	44.8 years STANDARD_DEVIATION 15.4 • n=7 Participants	45.2 years STANDARD_DEVIATION 15.5 • n=5 Participants
Sex: Female, Male Female	275 Participants n=5 Participants	269 Participants n=7 Participants	544 Participants n=5 Participants
Sex: Female, Male Male	71 Participants n=5 Participants	75 Participants n=7 Participants	146 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	150 Participants n=5 Participants	156 Participants n=7 Participants	306 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	8 Participants n=5 Participants	13 Participants n=7 Participants	21 Participants n=5 Participants
Race (NIH/OMB) White	187 Participants n=5 Participants	173 Participants n=7 Participants	360 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment North America	39 Participants n=5 Participants	54 Participants n=7 Participants	93 Participants n=5 Participants
Region of Enrollment Southeast Asia	162 Participants n=5 Participants	160 Participants n=7 Participants	322 Participants n=5 Participants
Region of Enrollment Europe	55 Participants n=5 Participants	44 Participants n=7 Participants	99 Participants n=5 Participants
Region of Enrollment South America	90 Participants n=5 Participants	86 Participants n=7 Participants	176 Participants n=5 Participants
Time since Diagnosis	1.34 years STANDARD_DEVIATION 2.50 • n=5 Participants	1.37 years STANDARD_DEVIATION 2.58 • n=7 Participants	1.35 years STANDARD_DEVIATION 2.54 • n=5 Participants
6MWD at Baseline	392.9 meters STANDARD_DEVIATION 92.5 • n=5 Participants	398.5 meters STANDARD_DEVIATION 100.0 • n=7 Participants	395.7 meters STANDARD_DEVIATION 96.3 • n=5 Participants
Etiology of PAH Idiopathic or Heritable PAH	219 Participants n=5 Participants	216 Participants n=7 Participants	435 Participants n=5 Participants
Etiology of PAH Collagen Vascular Disease	94 Participants n=5 Participants	84 Participants n=7 Participants	178 Participants n=5 Participants
Etiology of PAH HIV Infection	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Etiology of PAH Congenital Heart Defect	20 Participants n=5 Participants	27 Participants n=7 Participants	47 Participants n=5 Participants
Etiology of PAH Other	11 Participants n=5 Participants	10 Participants n=7 Participants	21 Participants n=5 Participants
WHO Functional Class at Baseline I	9 Participants n=5 Participants	13 Participants n=7 Participants	22 Participants n=5 Participants
WHO Functional Class at Baseline II	205 Participants n=5 Participants	228 Participants n=7 Participants	433 Participants n=5 Participants
WHO Functional Class at Baseline III	131 Participants n=5 Participants	103 Participants n=7 Participants	234 Participants n=5 Participants
WHO Functional Class at Baseline IV	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to approximately 4 years

Clinical worsening was assessed continuously from randomization until the subject's last study visit. Clinical worsening events were defined as death (all causes), hospitalizations due to worsening pulmonary arterial hypertension (PAH), initiation of an inhaled or infused prostacyclin (PGI2) for the treatment of worsening PAH, disease progression, or unsatisfactory long-term clinical response. All clinical worsening events reported by the study sites were reviewed by the Sponsor Medical Monitors. Once a clinical worsening event occurred, it was entered in the eCRF and a narrative was submitted for review by the Sponsor's Medical Monitor within 48 hours after the event became known to the Investigator or designee. Subsequently, the narratives for subjects with the reported clinical worsening events were sent to an independent adjudication committee. The independent adjudication committee reviewed and adjudicated all clinical worsening events throughout the study.

Outcome measures

Measure	UT-15C n=346 Participants Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID Treprostinil Diolamine: Active	Placebo n=344 Participants Matching placebo tablets (oral) Placebo: Placebo
Time to First Clinical Worsening Event	60.58 weeks Standard Deviation 42.93	49.31 weeks Standard Deviation 46.28

SECONDARY outcome

Timeframe: From Baseline to Week 24

The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living. A baseline 6MWT was performed prior to initiation of study drug on the day of randomization. 6MWTs were conducted at Weeks 4, 8, 12, 24, and every 12 weeks thereafter. The change between Baseline and Week 24 is reported.

Outcome measures

Measure	UT-15C n=346 Participants Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID Treprostinil Diolamine: Active	Placebo n=344 Participants Matching placebo tablets (oral) Placebo: Placebo
Change in 6-Minute Walk Distance Baseline	392.9 meters Standard Deviation 92.5	398.5 meters Standard Deviation 100.00
Change in 6-Minute Walk Distance Week 24	395.4 meters Standard Deviation 120.0	372.3 meters Standard Deviation 163.0

SECONDARY outcome

Timeframe: From Baseline to Week 24

Population: Subjects who did not have a valid NT-proBNP measurement at Baseline or Week 24 were excluded from the analysis.

Plasma NT-proBNP concentration is a useful biomarker for the severity of PAH as it is associated with changes in right heart morphology and function. NT-proBNP sample collection occurred at Baseline (prior to starting study drug), Week 12, Week 24, the first Continued Visit, and every other Continued Visit thereafter (ie, Continued Visits 3, 5, 7, etc). NT-proBNP was also assessed at the Study Drug Termination Visit. The change between Baseline and Week 24 is reported.

Outcome measures

Measure	UT-15C n=346 Participants Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID Treprostinil Diolamine: Active	Placebo n=344 Participants Matching placebo tablets (oral) Placebo: Placebo
Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24	0.7859 Ratio to baseline Standard Error 1.05470	1.1230 Ratio to baseline Standard Error 1.05439

SECONDARY outcome

Timeframe: Baseline to Week 48

The WHO FC for PAH was assessed at Baseline prior to starting study drug, at all subsequent scheduled study visits, and every time the 6MWT was performed for purposes of assessing clinical worsening status.

Outcome measures

Measure	UT-15C n=315 Participants Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID Treprostinil Diolamine: Active	Placebo n=311 Participants Matching placebo tablets (oral) Placebo: Placebo
Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48 No change	203 Participants	170 Participants
Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48 Improved	46 Participants	38 Participants
Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48 Deteriorated	66 Participants	103 Participants

Adverse Events

UT-15C

Serious events: 116 serious events

Other events: 342 other events

Deaths: 17 deaths

Placebo

Serious events: 110 serious events

Other events: 328 other events

Deaths: 18 deaths

Serious adverse events

Measure	UT-15C n=346 participants at risk Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID Treprostinil Diolamine: Active	Placebo n=344 participants at risk Matching placebo tablets (oral) Placebo: Placebo
Gastrointestinal disorders Vomiting	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Surgical and medical procedures Spinal decompression	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Reproductive system and breast disorders Vaginal haemorrhage	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Ventricular tachycardia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Vocal cord paresis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Subarachnoid haemorrhage	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Supraventricular tachycardia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	7.5% 26/346 • Number of events 27 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	10.5% 36/344 • Number of events 40 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Right ventricular failure	4.9% 17/346 • Number of events 18 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	3.5% 12/344 • Number of events 12 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Pneumonia	2.9% 10/346 • Number of events 11 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	2.9% 10/344 • Number of events 11 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.0% 7/346 • Number of events 8 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	2.3% 8/344 • Number of events 9 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Cardiac failure	1.4% 5/346 • Number of events 5 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.87% 3/344 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Gastroenteritis	1.4% 5/346 • Number of events 5 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Upper respiratory tract infection	1.4% 5/346 • Number of events 5 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.87% 3/344 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Bronchitis	1.2% 4/346 • Number of events 4 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.87% 3/344 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Headache	1.2% 4/346 • Number of events 4 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Lung infection	1.2% 4/346 • Number of events 4 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.87% 3/346 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.87% 3/346 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Septic shock	0.87% 3/346 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Acute kidney injury	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Appendicitis	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Atrial fibrillation	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Chest discomfort	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Chest pain	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	1.5% 5/344 • Number of events 5 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.58% 2/346 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Vascular disorders Circulatory collapse	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Gastritis erosive	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Endocrine disorders Hyperthyroidism	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Vascular disorders Hypotension	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	1.2% 4/344 • Number of events 5 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Lower respiratory tract infection	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Sudden death	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Syncope	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	1.2% 4/344 • Number of events 4 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Systemic lupus erythematosus	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Urinary tract infection	0.58% 2/346 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Abdominal distension	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Abdominal pain	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Abdominal pain upper	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Abdominal pain lower	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Acute lung injury	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Investigations Alanine aminotransferase increased	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Blood and lymphatic system disorders Anaemia	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 5 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Ankle fracture	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Congenital, familial and genetic disorders Arteriovenous malformation	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Arthritis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Investigations Aspartate aminotransferase increased	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Asthenia	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Atrial flutter	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Investigations Blood creatinine increased	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Brain injury	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Cardiac arrest	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.87% 3/344 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Cardiac failure congestive	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Cardio-respiratory arrest	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.87% 3/344 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Cardiogenic shock	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	1.2% 4/344 • Number of events 4 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Cardiovascular insufficiency	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Carotid artery stenosis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Investigations Catheterisation cardiac	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Cerebral infarction	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Hepatobiliary disorders Cholecystitis acute	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Hepatobiliary disorders Cholelithiasis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Colitis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer metastatic	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Constipation	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Cor pulmonale	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Coronary artery disease	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Death	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Metabolism and nutrition disorders Dehydration	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Diarrhoea	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Diverticulum	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Blood and lymphatic system disorders Duodenal ulcer haemorhage	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Psychiatric disorders Emotional distress	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Erosive duodenitis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Vascular disorders Femoral vein perforation	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Metabolism and nutrition disorders Fluid overload	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Pregnancy, puerperium and perinatal conditions Foetal death	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Gastritis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Gastrointestinal bacterial	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Gastrointestinal disorder	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Glomerulonephritis rapidly progressive	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.87% 3/344 • Number of events 4 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Haemorrhoids	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Hepatobiliary disorders Hepatic cyst	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Hepatobiliary disorders Hepatic function abnormal	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatocellular carcinoma	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Metabolism and nutrition disorders Hypokalaemia	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Vascular disorders Hypovolaemic shock	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Influenza	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Blood and lymphatic system disorders Iron deficiency anaemia	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Joint injury	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Limb injury	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Malaise	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Reproductive system and breast disorders Menorrhagia	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Myocardial infarction	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Nephrotic syndrome	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Reproductive system and breast disorders Ovarian cyst	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Reproductive system and breast disorders Ovarian rupture	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Investigations Oxygen saturation decreased	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Pain	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Palatal disorder	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Peritonitis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Productive cough	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Proteinuria	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Pulmonary arterial hypertension	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Renal failure	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Respiratory tract infection	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	1.2% 4/344 • Number of events 4 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Road traffic accident	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Sepsis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	1.2% 4/344 • Number of events 4 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Vascular disorders Shock haemorrhagic	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Sinus node dysfunction	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Sinusitis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Blood and lymphatic system disorders Thrombocytopenia	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Tracheobronchitis	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Reproductive system and breast disorders Uterine cyst	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Surgical and medical procedures Uterine tumour excision	0.29% 1/346 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.00% 0/344 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Psychiatric disorders Adjustment disorder with depressed mood	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Psychiatric disorders Altered state of consciousness	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Appendiceal abscess	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Arteriovenous fistula site complication	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Ascites	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Atypical pneumonia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Hepatobiliary disorders Autoimmune hepatitis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Bradycardia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Bursitis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Cellulitis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Chronic gastritis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Chronic kidney disease	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Chronic sinusitis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Clostridium difficile infection	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Vascular disorders Deep vein thrombosis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Dengue fever	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Dizziness	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Reproductive system and breast disorders Dysfunctional uterine bleeding	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Metabolism and nutrition disorders Electrolyte imbalance	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Encephalopathy	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Exostosis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Foot fracture	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Gastrointestinal angiodysplasia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic cancer	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic cancer recurrent	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 3 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Hepatobiliary disorders Hepatic mass	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Hydronephrosis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Metabolism and nutrition disorders Hyperuricaemia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Implant site irritation	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Endocrine disorders Inappropriate antidiuretic hormone secretion	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Incarcerated umbilical hernia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Toxicity to various agents	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Influenza like illness	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Inguinal hernia strangulated	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Investigations Interleukin level increased	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Large intestine polyp	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Meningioma	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Injury, poisoning and procedural complications Muscle strain	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Nausea	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Nephrolithiasis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Oedema	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Oedema peripheral	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Optic neuritis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Organising pneumonia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Palpitations	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Skin and subcutaneous tissue disorders Panniculitis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Pericardial effusion	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasmacytoma	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Pregnancy, puerperium and perinatal conditions Pregnancy	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Pyelonephritis acute	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Pyrexia	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Surgical and medical procedures Renal transplant	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Respiratory acidosis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.58% 2/344 • Number of events 2 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Eye disorders Retinal vein occlusion	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Renal and urinary disorders Scleroderma renal crisis	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Somnolence	0.00% 0/346 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	0.29% 1/344 • Number of events 1 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.

Other adverse events

Measure	UT-15C n=346 participants at risk Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID Treprostinil Diolamine: Active	Placebo n=344 participants at risk Matching placebo tablets (oral) Placebo: Placebo
Blood and lymphatic system disorders Anaemia	4.9% 17/346 • Number of events 17 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	3.5% 12/344 • Number of events 17 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Palpitations	13.6% 47/346 • Number of events 48 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	9.0% 31/344 • Number of events 35 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Cardiac disorders Right ventricular failure	6.4% 22/346 • Number of events 23 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	5.5% 19/344 • Number of events 19 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Diarrhoea	69.4% 240/346 • Number of events 277 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	28.5% 98/344 • Number of events 106 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Nausea	40.2% 139/346 • Number of events 146 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	22.7% 78/344 • Number of events 90 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Vomiting	35.5% 123/346 • Number of events 135 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	10.2% 35/344 • Number of events 37 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Abdominal pain upper	11.6% 40/346 • Number of events 41 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.9% 17/344 • Number of events 20 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Abdominal discomfort	8.4% 29/346 • Number of events 30 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	3.5% 12/344 • Number of events 14 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Abdominal pain	8.1% 28/346 • Number of events 30 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	3.8% 13/344 • Number of events 13 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Gastrooesophageal reflux disease	6.9% 24/346 • Number of events 25 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	3.5% 12/344 • Number of events 12 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Abdominal distension	7.8% 27/346 • Number of events 28 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.7% 16/344 • Number of events 16 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Dyspepsia	5.2% 18/346 • Number of events 19 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	5.8% 20/344 • Number of events 20 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Constipation	4.6% 16/346 • Number of events 18 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	2.6% 9/344 • Number of events 10 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Gastritis	4.6% 16/346 • Number of events 16 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	2.0% 7/344 • Number of events 8 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Oedema peripheral	13.3% 46/346 • Number of events 50 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	23.5% 81/344 • Number of events 89 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Fatigue	10.7% 37/346 • Number of events 43 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	13.4% 46/344 • Number of events 48 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Gastrointestinal disorders Chest discomfort	8.4% 29/346 • Number of events 32 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	8.7% 30/344 • Number of events 32 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Chest pain	7.5% 26/346 • Number of events 34 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	13.1% 45/344 • Number of events 48 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Pyrexia	7.2% 25/346 • Number of events 26 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	7.6% 26/344 • Number of events 28 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Aesthenia	6.6% 23/346 • Number of events 23 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.9% 17/344 • Number of events 18 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
General disorders Oedema	4.9% 17/346 • Number of events 17 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	3.5% 12/344 • Number of events 12 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Upper respiratory tract infection	21.1% 73/346 • Number of events 105 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	23.8% 82/344 • Number of events 109 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Viral upper respiratory tract infection	16.2% 56/346 • Number of events 69 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	13.4% 46/344 • Number of events 63 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Bronchitis	6.9% 24/346 • Number of events 27 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	5.5% 19/344 • Number of events 25 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Pneumonia	4.6% 16/346 • Number of events 18 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.9% 17/344 • Number of events 18 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Urinary tract infection	4.6% 16/346 • Number of events 20 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.9% 17/344 • Number of events 20 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Infections and infestations Influenza	3.8% 13/346 • Number of events 13 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.9% 17/344 • Number of events 18 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Metabolism and nutrition disorders Decreased appetite	9.2% 32/346 • Number of events 33 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.7% 16/344 • Number of events 16 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Pain in jaw	17.9% 62/346 • Number of events 64 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	2.9% 10/344 • Number of events 11 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Pain in extremity	17.6% 61/346 • Number of events 78 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	8.7% 30/344 • Number of events 32 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Myalgia	14.2% 49/346 • Number of events 53 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	10.8% 37/344 • Number of events 42 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Arthralgia	11.8% 41/346 • Number of events 51 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	9.0% 31/344 • Number of events 39 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Back pain	9.0% 31/346 • Number of events 32 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	7.8% 27/344 • Number of events 27 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Musculoskeletal and connective tissue disorders Muscle spasms	2.9% 10/346 • Number of events 12 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	6.4% 22/344 • Number of events 23 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Headache	74.9% 259/346 • Number of events 283 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	34.9% 120/344 • Number of events 134 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Dizziness	23.4% 81/346 • Number of events 86 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	21.8% 75/344 • Number of events 83 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Nervous system disorders Syncope	5.8% 20/346 • Number of events 23 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	5.8% 20/344 • Number of events 24 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Psychiatric disorders Insomnia	6.4% 22/346 • Number of events 22 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.7% 16/344 • Number of events 17 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Dyspnoea	16.2% 56/346 • Number of events 61 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	22.4% 77/344 • Number of events 88 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Cough	13.3% 46/346 • Number of events 48 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	18.3% 63/344 • Number of events 72 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	11.0% 38/346 • Number of events 39 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	18.6% 64/344 • Number of events 70 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Epistaxis	6.1% 21/346 • Number of events 25 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	9.0% 31/344 • Number of events 33 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Nasal congestion	5.8% 20/346 • Number of events 21 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.9% 17/344 • Number of events 19 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	3.2% 11/346 • Number of events 11 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	5.2% 18/344 • Number of events 19 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Skin and subcutaneous tissue disorders Rash	5.5% 19/346 • Number of events 19 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.4% 15/344 • Number of events 17 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Vascular disorders Flushing	44.5% 154/346 • Number of events 158 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	7.8% 27/344 • Number of events 28 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Vascular disorders Hypotension	6.9% 24/346 • Number of events 24 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.	4.1% 14/344 • Number of events 17 • The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.

Additional Information

Louis Holdstock

United Therapeutics

Phone: 919-425-8866

Email: lholdstock@unither.com

Results disclosure agreements

• Principal investigator is a sponsor employee Institution and/or Principal Investigator agree not to publish or publicly present any interim 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