Trial Outcomes & Findings for An Open-Label Extension Trial of UT-15C Sustained-release (SR) in Subjects With Pulmonary Arterial Hypertension (NCT NCT01027949)

NCT ID: NCT01027949

Last Updated: 2021-05-10

Results Overview

Assess the effect of continued therapy with oral treprostinil on exercise capacity as assessed by the change from Baseline in 6-Minute Walk Test (6MWT) after 1 year of treatment. The 6MWT is the clinical standard for assessing subject functional status in the treatment of PAH and has been considered an objective measure of subject functional status by the American Thoracic Society. The distance a subject can walk in 6 minutes is recorded in meters.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 894 participants
• Primary outcome timeframe: From First Visit (Visit 1) to Month 12
• Results posted on: 2021-05-10

Participant Flow

Baseline values for demographic parameters were defined and collected in the same manner for subjects who received either placebo or oral treprostinil in the preceding studies. Note that Studies TDE-PH-202 (NCT01104870), TDE-PH-203 (NCT01477333), and TDE-PH-205 (NCT01588405) had an open-label design; therefore, all Baseline demographic parameters were based on values collected at the time of enrollment in the previous study.

Subjects eligible for TDE-PH-304 previously participated in Studies TDE-PH-202 (NCT01104870), TDE-PH-203 (NCT01477333), and TDE-PH-205 (NCT01588405), TDE-PH-301 (NCT00325442), TDE-PH-302 (NCT00325403), or TDE PH-308 (NCT00887978).

Participant milestones

Measure	Oral Treprostinil Subjects eligible for TDE-PH-304 previously participated in Studies TDE-PH-202 (NCT01104870), TDE-PH-203 (NCT01477333), and TDE-PH-205 (NCT01588405), TDE-PH-301 (NCT00325442), TDE-PH-302 (NCT00325403), or TDE PH-308 (NCT00887978)
Overall Study STARTED	894
Overall Study COMPLETED	208
Overall Study NOT COMPLETED	686

Reasons for withdrawal

Measure	Oral Treprostinil Subjects eligible for TDE-PH-304 previously participated in Studies TDE-PH-202 (NCT01104870), TDE-PH-203 (NCT01477333), and TDE-PH-205 (NCT01588405), TDE-PH-301 (NCT00325442), TDE-PH-302 (NCT00325403), or TDE PH-308 (NCT00887978)
Overall Study Death	174
Overall Study Progressive Disease	163
Overall Study Adverse Event	172
Overall Study Withdrawal by Subject	113
Overall Study Lost to Follow-up	17
Overall Study Protocol Violation	13
Overall Study PI Decision	8
Overall Study Limited Study Drug Effectiveness	7
Overall Study Non-compliance with Study Procedures	7
Overall Study Lung Transplant	5
Overall Study Unable to Tolerate Study Drug	2
Overall Study Use of Excluded Medication	2
Overall Study Patient Self-discontinuation	1
Overall Study Pregnancy	1
Overall Study Surgery	1

Baseline Characteristics

An Open-Label Extension Trial of UT-15C Sustained-release (SR) in Subjects With Pulmonary Arterial Hypertension

Baseline characteristics by cohort

Measure	Oral Treprostinil n=894 Participants Subjects eligible for TDE-PH-304 previously participated in Studies TDE PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE PH-308.
Age, Continuous	47.7 years n=5 Participants
Sex: Female, Male Female	696 Participants n=5 Participants
Sex: Female, Male Male	198 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	83 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	809 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	34 Participants n=5 Participants
Race (NIH/OMB) Asian	219 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants n=5 Participants
Race (NIH/OMB) Black or African American	46 Participants n=5 Participants
Race (NIH/OMB) White	589 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants
Region of Enrollment Puerto Rico	1 participants n=5 Participants
Region of Enrollment United States	436 participants n=5 Participants
Region of Enrollment United Kingdom	27 participants n=5 Participants
Region of Enrollment Portugal	1 participants n=5 Participants
Region of Enrollment India	79 participants n=5 Participants
Region of Enrollment Spain	6 participants n=5 Participants
Region of Enrollment Canada	19 participants n=5 Participants
Region of Enrollment Austria	7 participants n=5 Participants
Region of Enrollment Netherlands	15 participants n=5 Participants
Region of Enrollment Sweden	2 participants n=5 Participants
Region of Enrollment Belgium	6 participants n=5 Participants
Region of Enrollment Ireland	2 participants n=5 Participants
Region of Enrollment Poland	16 participants n=5 Participants
Region of Enrollment Italy	13 participants n=5 Participants
Region of Enrollment Mexico	38 participants n=5 Participants
Region of Enrollment Israel	22 participants n=5 Participants
Region of Enrollment Australia	44 participants n=5 Participants
Region of Enrollment France	22 participants n=5 Participants
Region of Enrollment Germany	14 participants n=5 Participants
Region of Enrollment China	124 participants n=5 Participants
PAH Etiology Idiopathic Pulmonary Arterial Hypertension/ Heritable Pulmonary Arterial Hypertension	608 Participants n=5 Participants
PAH Etiology Collagen Vascular Disease	224 Participants n=5 Participants
PAH Etiology Other	60 Participants n=5 Participants
PAH Etiology Missing	2 Participants n=5 Participants
World Health Organization (WHO) Functional Class I	18 Participants n=5 Participants
World Health Organization (WHO) Functional Class II	298 Participants n=5 Participants
World Health Organization (WHO) Functional Class III	527 Participants n=5 Participants
World Health Organization (WHO) Functional Class IV	11 Participants n=5 Participants
World Health Organization (WHO) Functional Class Missing	40 Participants n=5 Participants

PRIMARY outcome

Timeframe: From First Visit (Visit 1) to Month 12

Population: All subjects enrolled in the study with Baseline and matched follow-up 6MWTs.

Assess the effect of continued therapy with oral treprostinil on exercise capacity as assessed by the change from Baseline in 6-Minute Walk Test (6MWT) after 1 year of treatment. The 6MWT is the clinical standard for assessing subject functional status in the treatment of PAH and has been considered an objective measure of subject functional status by the American Thoracic Society. The distance a subject can walk in 6 minutes is recorded in meters.

Outcome measures

Measure	Oral Treprostinil n=572 Participants Subjects eligible for TDE-PH-304 previously participated in Studies TDE PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE PH-308.
Change in Exercise Capacity at Month 12	22.0 meters Interval -345.0 to 282.0

Adverse Events

Oral Treprostinil

Serious events: 547 serious events

Other events: 890 other events

Deaths: 174 deaths

Serious adverse events

Measure	Oral Treprostinil n=894 participants at risk Subjects eligible for TDE-PH-304 previously participated in Studies TDE PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE PH-308.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast mass	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations Blood sodium decreased	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Bone pain	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Arrhythmia supraventricular	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Aspiration	0.11% 1/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Bacteraemia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Borderline ovarian tumour	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Bile duct stone	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary Hypertension	14.4% 129/894 • Number of events 147 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Right ventricular failure	14.4% 129/894 • Number of events 188 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pneumonia	7.0% 63/894 • Number of events 76 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.6% 41/894 • Number of events 51 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Acute kidney injury	4.1% 37/894 • Number of events 48 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac failure	4.0% 36/894 • Number of events 43 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Syncope	3.4% 30/894 • Number of events 33 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Anaemia	3.1% 28/894 • Number of events 32 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Chest pain	3.1% 28/894 • Number of events 33 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Hypotension	2.6% 23/894 • Number of events 26 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Fluid overload	2.3% 21/894 • Number of events 27 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac failure congestive	2.1% 19/894 • Number of events 26 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Atrial fibrillation	1.7% 15/894 • Number of events 18 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.7% 15/894 • Number of events 17 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Sudden death	1.7% 15/894 • Number of events 15 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Atrial flutter	1.6% 14/894 • Number of events 14 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Diarrhoea	1.5% 13/894 • Number of events 15 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Hypoxia	1.5% 13/894 • Number of events 14 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Gastrointestinal haemorrhage	1.3% 12/894 • Number of events 16 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hypokalaemia	1.3% 12/894 • Number of events 13 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Bronchitis	1.2% 11/894 • Number of events 13 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.2% 11/894 • Number of events 17 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Lower respiratory tract infection	1.2% 11/894 • Number of events 12 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Nausea	1.2% 11/894 • Number of events 11 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Gastritis	1.1% 10/894 • Number of events 11 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Gastroenteritis	1.1% 10/894 • Number of events 10 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.1% 10/894 • Number of events 10 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Sepsis	1.1% 10/894 • Number of events 11 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Vomiting	1.1% 10/894 • Number of events 10 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Sudden cardiac death	1.1% 10/894 • Number of events 10 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiogenic shock	1.0% 9/894 • Number of events 10 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Dehydration	1.0% 9/894 • Number of events 13 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Supraventricular tachycardia	1.0% 9/894 • Number of events 13 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Ascites	0.89% 8/894 • Number of events 9 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Cellulitis	0.89% 8/894 • Number of events 9 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Upper respiratory tract infection	0.89% 8/894 • Number of events 8 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac arrest	0.78% 7/894 • Number of events 7 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Death	0.78% 7/894 • Number of events 7 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Headache	0.78% 7/894 • Number of events 7 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Urinary tract infection	0.78% 7/894 • Number of events 7 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Abdominal pain	0.67% 6/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Surgical and medical procedures Abortion induced	0.67% 6/894 • Number of events 7 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Asthma	0.67% 6/894 • Number of events 12 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Back pain	0.67% 6/894 • Number of events 8 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Iron deficiency anaemia	0.67% 6/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Pericardial effusion	0.67% 6/894 • Number of events 7 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Pyrexia	0.67% 6/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Renal failure	0.67% 6/894 • Number of events 7 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Subdural haematoma	0.67% 6/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.67% 6/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Deep vein thrombosis	0.67% 6/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Cholecystitis	0.56% 5/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Dizziness	0.56% 5/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hypoglycaemia	0.56% 5/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Oedema peripheral	0.56% 5/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Palpitations	0.56% 5/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Pancytopenia	0.56% 5/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Presyncope	0.56% 5/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.56% 5/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Mental status changes	0.56% 5/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Non-cardiac chest pain	0.56% 5/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder transitional cell carcinoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardio-respiratory arrest	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Dysphagia	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Fall	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Fluid retention	0.45% 4/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Pain in extremity	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Systemic lupus erythematosus	0.45% 4/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Ventricular extrasystoles	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Large intestine polyp	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Disease progression	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Respiratory tract infection	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Multiple organ dysfunction syndrome	0.45% 4/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Abdominal pain upper	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Asthenia	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Atrial tachycardia	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Coronary artery disease	0.34% 3/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Epistaxis	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Fatigue	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Generalised oedema	0.34% 3/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Haematuria	0.34% 3/894 • Number of events 5 • From the time of subject enrollment until exit from the study (up to 13 years).
Endocrine disorders Hyperthyroidism	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hyponatraemia	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations International normalised ratio increased	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Melaena	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Portal hypertension	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Rectal haemorrhage	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Viral infection	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Urosepsis	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Post procedural haemorrhage	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Clostridium difficile infection	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations Hepatic enzyme increased	0.34% 3/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary arterial hypertension	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Drug-induced liver injury	0.34% 3/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Accidental overdose	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Acute myocardial infarction	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Appendicitis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Arrhythmia	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations Blood glucose decreased	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Bradycardia	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac tamponade	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Cerebrovascular accident	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Chest discomfort	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Cholelithiasis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Clostridium difficile colitis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Coagulopathy	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cor pulmonale	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Costochondritis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Diverticulitis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Flushing	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Gout	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Haemarthrosis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Haematemesis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Herpes zoster	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hypercalcaemia	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hyperglycaemia	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Immune system disorders Hypersensitivity	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Endocrine disorders Hypopituitarism	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Intestinal obstruction	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Lupus nephritis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Metabolic acidosis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Oesophagitis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Osteoarthritis	0.22% 2/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Osteomyelitis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Pancreatitis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pyelonephritis	0.22% 2/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Rectal ulcer	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Seizure	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Septic shock	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Shock	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Skin and subcutaneous tissue disorders Skin ulcer	0.22% 2/894 • Number of events 3 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Suicidal ideation	0.22% 2/894 • Number of events 4 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Tachycardia	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Thrombocytopenia	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Thrombosis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Tibia fracture	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Typhoid fever	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Ventricular tachycardia	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Eye disorders Visual impairment	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders General physical health deterioration	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Left ventricular dysfunction	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Staphylococcal sepsis	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pneumonia bacterial	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Upper limb fracture	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Chronic kidney disease	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Toxicity to various agents	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic cancer	0.22% 2/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Abdominal distension	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Altered state of consciousness	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Anaemia macrocytic	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Skin and subcutaneous tissue disorders Angioedema	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Angiosarcoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Ankle fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Antiphospholipid syndrome	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Blood pressure fluctuation	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Anxiety	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Aortic dissection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast neoplasm	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Bronchiolitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Cachexia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Campylobacter gastroenteritis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac failure acute	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac failure chronic	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac failure high output	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiomegaly	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Carotid body tumour	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Cerebral haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations Chest X-ray abnormal	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Cholecystitis acute	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Chronic respiratory failure	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Chronic sinusitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Circulatory collapse	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Colitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Coma hepatic	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Completed suicide	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Confusional state	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Corneal abrasion	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Cough	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Cyanosis central	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Cytomegalovirus infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Dengue fever	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Depressed level of consciousness	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Depression	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Diabetes mellitus	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Diarrhoea haemorrhagic	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Duodenal ulcer haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Duodenitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Dysarthria	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Pregnancy, puerperium and perinatal conditions Ectopic pregnancy	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Electrolyte imbalance	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Encephalopathy	0.11% 1/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Enteritis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Enterocolitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Eosinophilic pneumonia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Epilepsy	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Escherichia sepsis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Facial bones fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Facial paralysis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Febrile neutropenia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Femur fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Fibula fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Flank pain	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Food poisoning	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Fracture malunion	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Gastric ulcer	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Gastric ulcer haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Gastritis erosive	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Gastroenteritis viral	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Gastrointestinal disorder	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Gastrointestinal infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Gun shot wound	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Haematoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Haemolytic anaemia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Haemorrhoids	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Haemothorax	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Congenital, familial and genetic disorders Heart disease congenital	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Hepatic encephalopathy	0.11% 1/894 • Number of events 6 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Hepatic function abnormal	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Hepatitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Hiatus hernia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Hip fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Hydronephrosis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hyperkalaemia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Hypersplenism	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Hypertensive crisis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Hypertensive heart disease	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hypocalcaemia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hypovolaemia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Ileus	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Impaired gastric emptying	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Impaired healing	0.11% 1/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Incisional hernia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Infected skin ulcer	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Influenza	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Inguinal hernia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Intentional overdose	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations International normalised ratio abnormal	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.11% 1/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Jaw fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Left ventricular failure	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma stage IV	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung carcinoma cell type unspecified stage IV	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Lung consolidation	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Lymphadenopathy	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm of renal pelvis	0.11% 1/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm of spinal cord	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Mallory-Weiss syndrome	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Mass	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Meningitis bacterial	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lung	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Mouth haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Myalgia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Myocardial infarction	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Myositis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Nasal turbinate hypertrophy	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Neck pain	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Normocytic anaemia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Oedema	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Oesophageal haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Oliguria	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Orthopnoea	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Orthostatic hypotension	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Osteoporosis	0.11% 1/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Reproductive system and breast disorders Ovarian cyst	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Reproductive system and breast disorders Ovarian cyst ruptured	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Reproductive system and breast disorders Ovarian rupture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Overdose	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Pancreatitis acute	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Papillary thyroid cancer	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Peptic ulcer	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Pericardial haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Pericarditis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Peripheral ischaemia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pleurisy	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pleuritic pain	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pneumonia cytomegaloviral	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pneumonia klebsiella	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pneumonia legionella	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pneumonia pseudomonal	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pneumonia streptococcal	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Post-traumatic stress disorder	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Skin and subcutaneous tissue disorders Psoriasis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary artery aneurysm	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pulmonary tuberculosis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Raynaud's phenomenon	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Rectal ulcer haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cancer	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Renal failure acute	0.11% 1/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Rib fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Road traffic accident	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Scleroderma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Sialoadenitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Sinusitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer limited stage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Small intestinal obstruction	0.11% 1/894 • Number of events 2 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Spinal fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Skin and subcutaneous tissue disorders Stasis dermatitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Synovial cyst	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Tracheobronchitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Transient ischaemic attack	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Reproductive system and breast disorders Vaginal haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Ear and labyrinth disorders Vertigo	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Viral upper respiratory tract infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations Weight decreased	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Vascular pseudoaneurysm	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Urinary tract infection fungal	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Streptococcal bacteraemia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Incision site haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Eye disorders Ocular discomfort	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Catheter site inflammation	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Acquired oesophageal web	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Evans syndrome	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Sepsis syndrome	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Central line infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer metastatic	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary mass	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Intra-abdominal haematoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Hydrocholecystis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Post procedural bile leak	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Staphylococcal infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Pulseless electrical activity	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Retroperitoneal haematoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Right ventricular dysfunction	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Skin laceration	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Reproductive system and breast disorders Adnexa uteri mass	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Surgical and medical procedures Palliative care	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Surgical and medical procedures Cardiac ablation	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Reproductive system and breast disorders Haemorrhagic ovarian cyst	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Bacterial infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain neoplasm	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac disorder	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Pelvic fracture	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Congenital, familial and genetic disorders Hamartoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Intra-abdominal haemorrhage	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Ischaemic stroke	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Mediastinal disorder	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic neoplasm	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Decreased appetite	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Polyp	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Angiodysplasia	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations Paracentesis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Parainfluenzae virus infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Renal mass	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastasis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Renal impairment	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Cholecystitis infective	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Hepatobiliary disorders Cryptogenic cirrhosis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Surgical and medical procedures Balloon atrial septostomy	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Eosinophilic oesophagitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Lower respiratory tract infection viral	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Aortic arteriosclerosis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Metapneumovirus infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pseudomonas bronchitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Post procedural infection	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Infective exacerbation of bronchiectasis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Chemical peritonitis	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Vascular compression	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brenner tumour	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Intensive care unit acquired weakness	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).
Injury, poisoning and procedural complications Post procedural fever	0.11% 1/894 • Number of events 1 • From the time of subject enrollment until exit from the study (up to 13 years).

Other adverse events

Measure	Oral Treprostinil n=894 participants at risk Subjects eligible for TDE-PH-304 previously participated in Studies TDE PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE PH-308.
Vascular disorders Flushing	46.5% 416/894 • Number of events 499 • From the time of subject enrollment until exit from the study (up to 13 years).
Vascular disorders Hypotension	8.8% 79/894 • Number of events 91 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Fatigue	22.5% 201/894 • Number of events 228 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Oedema peripheral	21.5% 192/894 • Number of events 240 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Chest pain	15.1% 135/894 • Number of events 180 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Pain	10.9% 97/894 • Number of events 102 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Pyrexia	9.3% 83/894 • Number of events 100 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Chest discomfort	6.4% 57/894 • Number of events 70 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Asthenia	5.7% 51/894 • Number of events 64 • From the time of subject enrollment until exit from the study (up to 13 years).
General disorders Oedema	4.8% 43/894 • Number of events 44 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Insomnia	10.6% 95/894 • Number of events 98 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Anxiety	6.4% 57/894 • Number of events 60 • From the time of subject enrollment until exit from the study (up to 13 years).
Psychiatric disorders Depression	6.3% 56/894 • Number of events 59 • From the time of subject enrollment until exit from the study (up to 13 years).
Investigations Weight decreased	5.3% 47/894 • Number of events 49 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Dizziness	27.7% 248/894 • Number of events 320 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Palpitations	16.2% 145/894 • Number of events 175 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Right ventricular failure	15.2% 136/894 • Number of events 202 • From the time of subject enrollment until exit from the study (up to 13 years).
Cardiac disorders Cardiac failure	4.7% 42/894 • Number of events 54 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Dyspnoea	23.2% 207/894 • Number of events 294 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	21.3% 190/894 • Number of events 215 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Cough	17.8% 159/894 • Number of events 202 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Nasal congestion	11.0% 98/894 • Number of events 103 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Epistais	8.6% 77/894 • Number of events 88 • From the time of subject enrollment until exit from the study (up to 13 years).
Respiratory, thoracic and mediastinal disorders Haemoptysis	5.0% 45/894 • Number of events 57 • From the time of subject enrollment until exit from the study (up to 13 years).
Blood and lymphatic system disorders Anaemia	9.4% 84/894 • Number of events 112 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Headache	78.1% 698/894 • Number of events 994 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Syncope	11.3% 101/894 • Number of events 141 • From the time of subject enrollment until exit from the study (up to 13 years).
Nervous system disorders Presyncope	5.7% 51/894 • Number of events 55 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Diarrhoea	66.2% 592/894 • Number of events 808 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Nausea	56.5% 505/894 • Number of events 673 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Vomiting	39.0% 349/894 • Number of events 485 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Abdominal pain	13.5% 121/894 • Number of events 144 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Abdominal pain upper	10.9% 97/894 • Number of events 111 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Abdominal distension	10.3% 92/894 • Number of events 102 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Dyspepsia	10.3% 92/894 • Number of events 95 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Constipation	7.3% 65/894 • Number of events 74 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Gastrooesophageal reflux disease	5.1% 46/894 • Number of events 48 • From the time of subject enrollment until exit from the study (up to 13 years).
Gastrointestinal disorders Abdominal discomfort	5.0% 45/894 • Number of events 48 • From the time of subject enrollment until exit from the study (up to 13 years).
Renal and urinary disorders Acute kidney injury	5.8% 52/894 • Number of events 69 • From the time of subject enrollment until exit from the study (up to 13 years).
Skin and subcutaneous tissue disorders Rash	8.8% 79/894 • Number of events 87 • From the time of subject enrollment until exit from the study (up to 13 years).
Skin and subcutaneous tissue disorders Pruritus	4.8% 43/894 • Number of events 50 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Pain in jaw	35.0% 313/894 • Number of events 360 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Pain in extremity	28.5% 255/894 • Number of events 337 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Arthralgia	15.7% 140/894 • Number of events 163 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Myalgia	13.8% 123/894 • Number of events 143 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Back pain	11.7% 105/894 • Number of events 127 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Muscle spasms	7.2% 64/894 • Number of events 71 • From the time of subject enrollment until exit from the study (up to 13 years).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.7% 42/894 • Number of events 44 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Decreased appetite	14.4% 129/894 • Number of events 142 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Hypokalaemia	10.5% 94/894 • Number of events 119 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Fluid overload	4.9% 44/894 • Number of events 58 • From the time of subject enrollment until exit from the study (up to 13 years).
Metabolism and nutrition disorders Fluid retention	4.8% 43/894 • Number of events 54 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Upper respiratory tract infection	24.8% 222/894 • Number of events 334 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Nasopharyngitis	20.7% 185/894 • Number of events 316 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Bronchitis	11.5% 103/894 • Number of events 153 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Pneumonia	10.5% 94/894 • Number of events 118 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Urinary tract infection	10.0% 89/894 • Number of events 115 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Sinusitis	8.9% 80/894 • Number of events 108 • From the time of subject enrollment until exit from the study (up to 13 years).
Infections and infestations Influenza	6.0% 54/894 • Number of events 64 • From the time of subject enrollment until exit from the study (up to 13 years).

Additional Information

Louis Holdstock, PhD

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 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