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

• Sponsor: United Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01027949
• Collaborator: (none)
• Enrollment: 894
• Locations: 135
• Arm: 1
• Actual Duration (Months): 156.9
• Patients Per Site: 6.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study provided/continued to provide oral treprostinil (UT-15C SR; treprostinil diethanolamine) to eligible subjects who participated in Studies TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, and TDE-PH-308. The study assessed the long term safety of oral treprostinil and the effect of continued treatment with oral treprostinil on exercise capacity after 1 year of treatment.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Oral Treprostinil	Phase 3

Detailed Description

This was an international, multicenter, open-label study designed to provide oral treprostinil for eligible subjects who participated in Studies TDE-PH-301, TDE-PH-302, TDE-PH-308, TDE-PH-202, TDE PH 203, and TDE-PH-205. Subjects randomly allocated to receive oral treprostinil in Studies TDE-PH-301, TDE-PH-302, or TDE-PH-308 and enrolled in this open-label study completed visits at Months 6, 12, 24, 36, and yearly visits thereafter. Subjects randomly allocated to receive placebo in Studies TDE-PH-301, TDE-PH-302, or TDE-PH-308 completed visits at Months 3, 6, 12, 24, 36, and yearly visits thereafter. Subjects that transitioned from Studies TDE-PH-202, TDE-PH-203, and TDE-PH-205 (that had an open-label study design) followed the regimen for subjects receiving oral treprostinil. A 6-Minute Walk Test (6MWT) and Borg dyspnea score were conducted at the visit which occurred 12 months after the subject's first exposure to oral treprostinil.

Adverse events (AEs) were reported continuously throughout the study; any AEs ongoing at the time of discharge from Studies TDE PH-301, TDE PH-302, TDE-PH-308, TDE-PH-202, TDE-PH-203, and TDE-PH-205 were recorded as AEs and marked as "ongoing from previous study" in the subject's electronic Case Report Form (eCRF). Study drug dosing and pulmonary arterial hypertension (PAH) concomitant medication usage were assessed at each scheduled study visit and recorded in the subject's eCRF.

Study Design

• Study Type: Interventional
• Actual Enrollment: 894 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Extension Trial of UT-15C SR in Subjects With Pulmonary Arterial Hypertension
• Actual Study Start Date: Jan 16, 2007
• Actual Primary Completion Date: Feb 12, 2020
• Actual Study Completion Date: Feb 12, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Oral Treprostinil Subjects from previous 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). Subjects were instructed to take the appropriate amount of 0.125, 0.25, 0.5, 1, and/or 2.5 mg tablets based upon their prescribed dose. Investigators were instructed to increase the dose of oral treprostinil in the absence of dose limiting drug-related AEs to ensure each subject received the optimal clinical dose throughout the study

Drug: Oral Treprostinil; Oral sustained release tablet, twice or thrice daily. Open label study with active drug, no other intervention arms.; Other Names: Treprostinil diethanolamine, treprostinil diolamine UT-15C

Outcome Measures

Primary Outcome Measures

1. Change in Exercise Capacity at Month 12 [From First Visit (Visit 1) to Month 12]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. The subject remained on study drug and completed all assessments during the Treatment Phase of the previous study (TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE PH-302, or TDE-PH-308) OR the subject permanently discontinued study drug during the Treatment Phase of the previous study due to clinical worsening (as defined in the protocol of the previous study), completed premature termination assessments prior to discontinuing study drug, completed all remaining scheduled study visits, AND received placebo during the Treatment Phase of the previous studies OR the subject was randomized into Group 1 or Group 2 in Study TDE PH 202, permanently discontinued study drug during the 12-week Treatment Phase due to clinical worsening, completed all premature termination assessments prior to discontinuing study drug, and completed all remaining scheduled study visits and assessments (with the exception of the hemodynamic measurements) through Week 12. Such subjects should have started treatment with oral treprostinil in the open-label study at 0.25 mg twice daily (BID).

2. The subject voluntarily gave informed consent to participate in the study.

3. Women of childbearing potential includes any female who had experienced menarche and who had not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or was not postmenopausal (defined as amenorrhea for at least 12 consecutive months). Sexually active women of childbearing potential must have used 2 effective forms of contraception during the length of the study. Medically acceptable forms of effective contraception included: (1) approved hormonal contraceptives (such as birth control pills), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, (3) an intrauterine device, (4) partner vasectomy, or (5) abstinence. Males participating in the study must have used a condom during the length of the study, and for at least 48 hours after discontinuing study medication. Protocol Amendment A.1AU included the required assessment for Austrian subjects to perform urine pregnancy tests every 4 weeks during the study.

Exclusion Criteria:

1. The subject permanently discontinued study drug during the previous study (TDE PH 202, TDE-PH-203, TDE PH 205, TDE-PH-301, TDE-PH-302, or TDE PH 308) due to treatment-related adverse events (AEs).

2. The subject permanently discontinued study drug during the Treatment Phase of the previous study (TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE-PH-308) due to clinical worsening (as defined in those study protocols) and did not undergo premature termination assessments prior to discontinuing study drug, and/or did not complete all remaining study visits through the final scheduled visit.

3. The subject prematurely discontinued study drug during the Treatment Phase of the previous study due to clinical worsening (as defined in those study protocols), completed premature termination assessments prior to discontinuing study drug, completed all remaining scheduled study visits AND received oral treprostinil during the Treatment Phase of the previous study (TDE PH-202, TDE-PH-203, TDE-PH-301, TDE-PH-302, or TDE PH-308). Subjects enrolled in Study TDE-PH-202 who were randomized into the individual maximum tolerated dose (iMTD) group who clinically worsened could not participate. Subjects who permanently discontinued study drug during the 12-week Treatment Phase due to treatment-related AEs were not eligible even if they completed all remaining scheduled study visits. Subjects who permanently discontinued study drug during the 12 week Treatment Phase and did not undergo premature termination assessments prior to discontinuing study drug and/or who did not complete all remaining study visits through the Week 12 visit were also not eligible.

4. The subject developed any concurrent illness or condition during the conduct of the previous study, including but not restricted to: sleep apnea, chronic renal insufficiency, anemia, uncontrolled systemic hypertension, or left sided heart disease, unless their physician felt that entry into this study would not be detrimental to their overall health.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Kirklin Clinic	Birmingham	Alabama	United States	35233
2	Arizona Pulmonary Specialists, Ltd.	Phoenix	Arizona	United States	85013
3	Mayo Clinic Phoenix	Phoenix	Arizona	United States	85054
4	St. Joseph's Hospital and Medical Center	Phoenix	Arizona	United States
5	University Medical Center	Tucson	Arizona	United States	85724
6	University of Arizona Clinical and Translational Science (CATS) Research Center	Tucson	Arizona	United States	85724
7	University of California, San Francisco-Fresno	Fresno	California	United States	93701
8	West Los Angeles VA Healthcare Center	Los Angeles	California	United States	90073
9	David Geffen School of Medicine at UCLA	Los Angeles	California	United States	90095
10	UC Davis Medical Center	Sacramento	California	United States	95817
11	UCSD Medical Center	San Diego	California	United States	30322
12	University of California San Francisco Medical Center	San Francisco	California	United States	94118
13	Stanford University, Pulmonary and Critical Care Medicine	Stanford	California	United States	94305-5351
14	Harbor-UCLA Medical Center	Torrance	California	United States	90502
15	The Children's Hospital	Aurora	Colorado	United States	80045
16	University of Colorado Health Science Center	Aurora	Colorado	United States	80045
17	University of Florida College of Medicine Jacksonville	Jacksonville	Florida	United States	32209
18	Cleveland Clinic Florida	Weston	Florida	United States	33331
19	The Emory Clinic	Atlanta	Georgia	United States	30322
20	The University of Chicago Hospitals	Chicago	Illinois	United States	60637
21	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
22	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
23	Kentuckiana Pulmonary Associates	Louisville	Kentucky	United States	40202
24	Alexandria Cardiology Clinic	Alexandria	Louisiana	United States	71301
25	Maine Medical Center	Portland	Maine	United States	04102
26	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
27	Johns Hopkins Outpatient Center	Baltimore	Maryland	United States	21287
28	Tufts Medical Center	Boston	Massachusetts	United States	02111
29	Brigham and Woman's Hospital	Boston	Massachusetts	United States	02114
30	University of Michigan Health System	Ann Arbor	Michigan	United States	48103
31	University of Minnesota Medical Center, Fairview	Minneapolis	Minnesota	United States	55455
32	Mayo Clinic	Rochester	Minnesota	United States	55902
33	Washington University School of Medicine	Saint Louis	Missouri	United States	63110-1093
34	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-5300
35	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
36	Winthrop University Hospital	Mineola	New York	United States	11501
37	Columbia University Medical Center	New York	New York	United States	10032
38	Mary Parkes Center	Rochester	New York	United States	14643
39	University of North Carolina Hospitals	Chapel Hill	North Carolina	United States	27599
40	Duke University Medical Center	Durham	North Carolina	United States	27710
41	The Carl and Ethyl Linder Center for Research and Education at the Christ Church	Cincinnati	Ohio	United States	45219
42	University of Cincinnati	Cincinnati	Ohio	United States	45267-0564
43	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
44	Cleveland Clinic	Cleveland	Ohio	United States	44195
45	Ohio State University	Columbus	Ohio	United States	43210
46	The University of Toledo Medical Center	Toledo	Ohio	United States	43614
47	Legacy Pulmonary Clinic	Portland	Oregon	United States	97210
48	Oregon Health and Sciences University	Portland	Oregon	United States	97239
49	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
50	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
51	UPMC Presbyterian Hospital	Pittsburgh	Pennsylvania	United States	15213
52	Medical University of South Carolina	Charleston	South Carolina	United States	29425
53	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232-2650
54	UT Southwestern Medical Center	Dallas	Texas	United States	75390
55	Baylor College of Medicine	Houston	Texas	United States	77030
56	University of Texas Medical School	Houston	Texas	United States	77030
57	The University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
58	Intermountain Medical Center	Murray	Utah	United States	84157-7000
59	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
60	University of Washington Medical Center	Seattle	Washington	United States	98195
61	Aurora Cardiovascular Services	Milwaukee	Wisconsin	United States	53215
62	The Prince Charles Hospital	Chermside West		Australia	4032
63	Heart/Lung Transplant Unit - St. Vincent's Hospital	Darlinghurst		Australia	2010
64	The Alfred Hospital	Melbourne		Australia	3004
65	Royal Perth Hospital	Perth		Australia
66	Medical University Graz	Wein		Austria
67	Medizininische Universitaet Wien	Wien		Austria
68	Universitaetsklinik für Innere Medizin Innsbruck	Wien		Austria
69	Department of Cardiology Erasme University Hospital	Brussels		Belgium
70	University Hospital Gasthuisberg	Leuven		Belgium
71	Peter Lougheed Centre	Calgary	Alberta	Canada	T1Y 6J4
72	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
73	Vancouver Coastal Health Authority Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
74	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2N2
75	London Health Sciences Center Victoria Hospital	Toronto	Ontario	Canada	N6A 4G5
76	Sir Mortimer B. Davis Jewish General Hospital	Montréal	Quebec	Canada	H3T 1E2
77	Beijing Shijitan Hospital, Cadres Respiratory Department	Beijing		China
78	Peking Union Medical College Hospital, Respiratory Medicine Department	Beijing		China
79	Shanghai Pulmonary Hospital, Respiratory Medicine Department	Shanghai		China
80	Service Chirurgie Thoracique, Hôpital Haut Levêque	Pessac	Pessac Cedex	France	33604
81	PMAC, Clinique de Pneumologie	Bernin		France
82	Centre d'Investigation Clinique Hôpital La Cavale Blanche - CHU Brest	Brest		France
83	Hospital Antoine Beclere	Clamart		France
84	Hospital Claude Huriez	Lille Cedex		France
85	Hôpital Louis Pradel	Lyon		France
86	CHU Arnaud de Villeneuve - Service maladies respiratoires	Montpellier cedex 5		France	34295
87	Service de Pneumologie Centre de Competence pour l'HTAP- Pole des Voies Respiratoires Hôpital Larrey	Toulouse		France
88	Universitätsklinikum Dresden Abtl. Pneumologie	Dresden		Germany	01307
89	University Hospital Greifswald	Greifswald		Germany	17475
90	DRK Kliniken Berlin Köpenick	Hamburg		Germany
91	Universitatsklinikum Hamburg Eppendorf	Hamburg		Germany
92	Universitätsklinkium Köln Klinik III für Innere Medizin	Hamburg		Germany
93	Zentrum für Lungenhochdruck Thoraxklinik am Universitätsklinikum Heidelberg	Hamburg		Germany
94	Medizinische Hochschule Hannover (MHH)	Hannover		Germany
95	Dept. of Internal Medicine III University Heidelberg	Heidelberg		Germany	69120
96	Care Institute of Medical Sciences	Ahmedabad	Gujarat	India	380054
97	Narayana Hrudayalaya Hospitals	Bangalore	Karnataka	India	560034
98	Asian Heart Institute & Research Centre Pvt. Ltd.	Mumbai	Maharashtra	India	400012
99	Poona Hospital and Research Centre	Pune	Maharashtra	India	411030
100	Life Care Institute of Medical Sciences & Research	Ahmedabad		India	380054
101	Sri Ramachandra Medical College & Research Institute	Chennai		India
102	G. Kuppuswamy Naidu Memorial Hospital	Coimbatore		India
103	PRIME Hospitals	Hyderabad		India	500038
104	Sir Ganga Ram Hospital	New Delhi		India	110060
105	Ruby Hall Clinic	Pune		India
106	Queen's NRI Hospital	Visakhapatnam		India
107	Pulmonary Hypertension Unit Centre for Lung Health Mater Misericordiae University Hospital	Dublin		Ireland
108	Rambam Medical Center	Haifa		Israel	31096
109	The Lady Davis Carmel Medical Center	Haifa		Israel
110	Hadassah Hebrew University Medical Center	Jerusalem		Israel
111	Pulmonary Institute Rabin Medical Center (Belinson Kampus)	Petah Tiqva		Israel
112	Pulmonary Institute Chaim Sheba Medical Center	Ramat Gan		Israel
113	Policlinico S. Orsola Malpighi - Università degli studi di Bologna	Bologna		Italy
114	Azienda Ospedaliera di Rilievo Nazionale Monaldi - Cotugno-CTO Cardiologia S.U.N.	Naples		Italy
115	Azienda Ospedaliera di Rilievo Nazionale Monaldi - Cotugno-CTO Cardiologia S.U.N.	Napoli		Italy
116	Dipartimento di Scienze Cardiovascolari, Respiratorie e Morfologiche	Rome		Italy
117	Instituto Nacional de Cardiologia	Mexico City		Mexico	14080
118	Hospital Universitario de la UANL	Monterrey		Mexico	64460
119	Unidad de Investigacion Clinica en Medicina S.C.	Monterrey		Mexico	64718
120	Radboud University Nijmegen Medical Center	Amsterdam		Netherlands
121	VU Medish Centrum	Amsterdam		Netherlands
122	Klinika Chorób Serca i Naczyń, Krakowski Szpital Specjalistyczny im. Jana Pawla II	Kraków		Poland	31-202
123	Europejskie Centrum Zdrowia Otwock	Warsaw		Poland
124	Oddzial Kardiologiczny	Wroclaw		Poland	51-124
125	Servico de Cardiologia Hospital de Santa Marta	Lisbon		Portugal
126	Auxilio Mutuo Hospital CardioPulmonary Research Center	Guaynabo		Puerto Rico	00968
127	Hospital Clínic I Provincial	Barcelona		Spain
128	Hospital Vall d'Hebron	Barcelona		Spain
129	Hospital 12 de Octubre	Madrid		Spain
130	Skane University Hospital	Lund		Sweden	SE 22185
131	Papworth Hospital	Cambridge		United Kingdom
132	Papworth Hospital NHS Foundation Trust	Glasgow		United Kingdom
133	Royal Free Hospital	London		United Kingdom
134	Freeman Hospital	Newcastle		United Kingdom
135	Royal Hallamshire Hospital	Sheffield		United Kingdom	S10 2JF

Sponsors and Collaborators

• United Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 20, 2013
• Statistical Analysis Plan - Mar 2, 2016

More Information

Publications

None provided.

• Responsible Party: United Therapeutics
• ClinicalTrials.gov Identifier: NCT01027949
• Other Study ID Numbers: TDE-PH-304
• First Posted: Dec 9, 2009
• Last Update Posted: May 10, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Treprostinil

Study Results

Participant Flow

Recruitment Details

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.

Pre-assignment Detail

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).

Arm/Group Title	Oral Treprostinil
Arm/Group Description	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)
Period Title: Overall Study
STARTED	894
COMPLETED	208
NOT COMPLETED	686

Baseline Characteristics

Arm/Group Title	Oral Treprostinil
Arm/Group Description	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.
Overall Participants	894
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	47.7
Sex: Female, Male (Count of Participants)
Female	696 77.9%
Male	198 22.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	83 9.3%
Not Hispanic or Latino	809 90.5%
Unknown or Not Reported	2 0.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	34 3.8%
Asian	219 24.5%
Native Hawaiian or Other Pacific Islander	2 0.2%
Black or African American	46 5.1%
White	589 65.9%
More than one race	0 0%
Unknown or Not Reported	4 0.4%
Region of Enrollment (participants) [Number]
Puerto Rico	1 0.1%
United States	436 48.8%
United Kingdom	27 3%
Portugal	1 0.1%
India	79 8.8%
Spain	6 0.7%
Canada	19 2.1%
Austria	7 0.8%
Netherlands	15 1.7%
Sweden	2 0.2%
Belgium	6 0.7%
Ireland	2 0.2%
Poland	16 1.8%
Italy	13 1.5%
Mexico	38 4.3%
Israel	22 2.5%
Australia	44 4.9%
France	22 2.5%
Germany	14 1.6%
China	124 13.9%
PAH Etiology (Count of Participants)
Idiopathic Pulmonary Arterial Hypertension/ Heritable Pulmonary Arterial Hypertension	608 68%
Collagen Vascular Disease	224 25.1%
Other	60 6.7%
Missing	2 0.2%
World Health Organization (WHO) Functional Class (Count of Participants)
I	18 2%
II	298 33.3%
III	527 58.9%
IV	11 1.2%
Missing	40 4.5%

Outcome Measures

1. Primary Outcome

Title	Change in Exercise Capacity at Month 12
Description	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.
Time Frame	From First Visit (Visit 1) to Month 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Oral Treprostinil
Arm/Group Description	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.
Measure Participants	572
Median (Full Range) [meters]	22.0

Adverse Events

Time Frame	From the time of subject enrollment until exit from the study (up to 13 years).
Arm/Group Title	Oral Treprostinil
Arm/Group Description	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.
All Cause Mortality
	Oral Treprostinil
	Affected / at Risk (%)	# Events
Total	174/894 (19.5%)
Serious Adverse Events
	Oral Treprostinil
	Affected / at Risk (%)	# Events
Total	547/894 (61.2%)
Blood and lymphatic system disorders
Anaemia	28/894 (3.1%)	32
Iron deficiency anaemia	6/894 (0.7%)	6
Pancytopenia	5/894 (0.6%)	5
Coagulopathy	2/894 (0.2%)	2
Thrombocytopenia	2/894 (0.2%)	2
Anaemia macrocytic	1/894 (0.1%)	1
Antiphospholipid syndrome	1/894 (0.1%)	1
Disseminated intravascular coagulation	1/894 (0.1%)	1
Febrile neutropenia	1/894 (0.1%)	1
Haemolytic anaemia	1/894 (0.1%)	1
Hypersplenism	1/894 (0.1%)	1
Lymphadenopathy	1/894 (0.1%)	1
Normocytic anaemia	1/894 (0.1%)	1
Evans syndrome	1/894 (0.1%)	1
Cardiac disorders
Right ventricular failure	129/894 (14.4%)	188
Cardiac failure	36/894 (4%)	43
Cardiac failure congestive	19/894 (2.1%)	26
Atrial fibrillation	15/894 (1.7%)	18
Atrial flutter	14/894 (1.6%)	14
Cardiogenic shock	9/894 (1%)	10
Supraventricular tachycardia	9/894 (1%)	13
Cardiac arrest	7/894 (0.8%)	7
Pericardial effusion	6/894 (0.7%)	7
Palpitations	5/894 (0.6%)	5
Cardio-respiratory arrest	4/894 (0.4%)	4
Ventricular extrasystoles	4/894 (0.4%)	4
Atrial tachycardia	3/894 (0.3%)	3
Coronary artery disease	3/894 (0.3%)	4
Acute myocardial infarction	2/894 (0.2%)	2
Arrhythmia	2/894 (0.2%)	2
Bradycardia	2/894 (0.2%)	2
Cardiac tamponade	2/894 (0.2%)	2
Cor pulmonale	2/894 (0.2%)	2
Tachycardia	2/894 (0.2%)	2
Ventricular tachycardia	2/894 (0.2%)	2
Left ventricular dysfunction	2/894 (0.2%)	2
Arrhythmia supraventricular	1/894 (0.1%)	1
Cardiac failure acute	1/894 (0.1%)	1
Cardiac failure chronic	1/894 (0.1%)	1
Cardiac failure high output	1/894 (0.1%)	1
Cardiomegaly	1/894 (0.1%)	1
Hypertensive heart disease	1/894 (0.1%)	1
Left ventricular failure	1/894 (0.1%)	1
Myocardial infarction	1/894 (0.1%)	1
Pericardial haemorrhage	1/894 (0.1%)	1
Pericarditis	1/894 (0.1%)	1
Pulseless electrical activity	1/894 (0.1%)	1
Right ventricular dysfunction	1/894 (0.1%)	1
Cardiac disorder	1/894 (0.1%)	1
Congenital, familial and genetic disorders
Heart disease congenital	1/894 (0.1%)	1
Hamartoma	1/894 (0.1%)	1
Ear and labyrinth disorders
Vertigo	1/894 (0.1%)	1
Endocrine disorders
Hyperthyroidism	3/894 (0.3%)	3
Hypopituitarism	2/894 (0.2%)	2
Eye disorders
Visual impairment	2/894 (0.2%)	2
Ocular discomfort	1/894 (0.1%)	1
Gastrointestinal disorders
Diarrhoea	13/894 (1.5%)	15
Gastrointestinal haemorrhage	12/894 (1.3%)	16
Nausea	11/894 (1.2%)	11
Gastritis	10/894 (1.1%)	11
Gastroenteritis	10/894 (1.1%)	10
Vomiting	10/894 (1.1%)	10
Ascites	8/894 (0.9%)	9
Abdominal pain	6/894 (0.7%)	6
Upper gastrointestinal haemorrhage	6/894 (0.7%)	6
Dysphagia	4/894 (0.4%)	4
Large intestine polyp	4/894 (0.4%)	4
Abdominal pain upper	3/894 (0.3%)	3
Melaena	3/894 (0.3%)	3
Rectal haemorrhage	3/894 (0.3%)	3
Haematemesis	2/894 (0.2%)	2
Intestinal obstruction	2/894 (0.2%)	2
Oesophagitis	2/894 (0.2%)	2
Pancreatitis	2/894 (0.2%)	2
Rectal ulcer	2/894 (0.2%)	2
Abdominal distension	1/894 (0.1%)	1
Colitis	1/894 (0.1%)	1
Diarrhoea haemorrhagic	1/894 (0.1%)	1
Duodenal ulcer haemorrhage	1/894 (0.1%)	1
Duodenitis	1/894 (0.1%)	1
Enteritis	1/894 (0.1%)	1
Enterocolitis	1/894 (0.1%)	1
Food poisoning	1/894 (0.1%)	1
Gastric ulcer	1/894 (0.1%)	1
Gastric ulcer haemorrhage	1/894 (0.1%)	1
Gastritis erosive	1/894 (0.1%)	1
Gastrointestinal disorder	1/894 (0.1%)	1
Haemorrhoids	1/894 (0.1%)	1
Hiatus hernia	1/894 (0.1%)	1
Ileus	1/894 (0.1%)	1
Impaired gastric emptying	1/894 (0.1%)	1
Inguinal hernia	1/894 (0.1%)	1
Mallory-Weiss syndrome	1/894 (0.1%)	1
Mouth haemorrhage	1/894 (0.1%)	1
Oesophageal haemorrhage	1/894 (0.1%)	1
Pancreatitis acute	1/894 (0.1%)	1
Peptic ulcer	1/894 (0.1%)	1
Rectal ulcer haemorrhage	1/894 (0.1%)	1
Small intestinal obstruction	1/894 (0.1%)	2
Lower gastrointestinal haemorrhage	1/894 (0.1%)	1
Acquired oesophageal web	1/894 (0.1%)	1
Intra-abdominal haematoma	1/894 (0.1%)	1
Retroperitoneal haematoma	1/894 (0.1%)	1
Intra-abdominal haemorrhage	1/894 (0.1%)	1
Eosinophilic oesophagitis	1/894 (0.1%)	1
General disorders
Chest pain	28/894 (3.1%)	33
Sudden death	15/894 (1.7%)	15
Sudden cardiac death	10/894 (1.1%)	10
Death	7/894 (0.8%)	7
Pyrexia	6/894 (0.7%)	6
Oedema peripheral	5/894 (0.6%)	6
Non-cardiac chest pain	5/894 (0.6%)	6
Multiple organ dysfunction syndrome	4/894 (0.4%)	4
Asthenia	3/894 (0.3%)	3
Fatigue	3/894 (0.3%)	3
Generalised oedema	3/894 (0.3%)	4
Chest discomfort	2/894 (0.2%)	2
General physical health deterioration	2/894 (0.2%)	2
Impaired healing	1/894 (0.1%)	2
Mass	1/894 (0.1%)	1
Oedema	1/894 (0.1%)	1
Catheter site inflammation	1/894 (0.1%)	1
Hepatobiliary disorders
Cholecystitis	5/894 (0.6%)	5
Portal hypertension	3/894 (0.3%)	3
Drug-induced liver injury	3/894 (0.3%)	3
Cholelithiasis	2/894 (0.2%)	2
Bile duct stone	1/894 (0.1%)	1
Cholecystitis acute	1/894 (0.1%)	1
Hepatic function abnormal	1/894 (0.1%)	1
Hepatitis	1/894 (0.1%)	1
Hydrocholecystis	1/894 (0.1%)	1
Cryptogenic cirrhosis	1/894 (0.1%)	1
Immune system disorders
Hypersensitivity	2/894 (0.2%)	2
Infections and infestations
Pneumonia	63/894 (7%)	76
Bronchitis	11/894 (1.2%)	13
Lower respiratory tract infection	11/894 (1.2%)	12
Sepsis	10/894 (1.1%)	11
Cellulitis	8/894 (0.9%)	9
Upper respiratory tract infection	8/894 (0.9%)	8
Urinary tract infection	7/894 (0.8%)	7
Respiratory tract infection	4/894 (0.4%)	4
Viral infection	3/894 (0.3%)	3
Urosepsis	3/894 (0.3%)	3
Clostridium difficile infection	3/894 (0.3%)	3
Appendicitis	2/894 (0.2%)	2
Clostridium difficile colitis	2/894 (0.2%)	2
Diverticulitis	2/894 (0.2%)	2
Herpes zoster	2/894 (0.2%)	2
Osteomyelitis	2/894 (0.2%)	2
Pyelonephritis	2/894 (0.2%)	3
Septic shock	2/894 (0.2%)	2
Typhoid fever	2/894 (0.2%)	2
Staphylococcal sepsis	2/894 (0.2%)	2
Pneumonia bacterial	2/894 (0.2%)	2
Bacteraemia	1/894 (0.1%)	1
Bronchiolitis	1/894 (0.1%)	1
Campylobacter gastroenteritis	1/894 (0.1%)	1
Chronic sinusitis	1/894 (0.1%)	1
Cytomegalovirus infection	1/894 (0.1%)	1
Dengue fever	1/894 (0.1%)	1
Escherichia sepsis	1/894 (0.1%)	1
Gastroenteritis viral	1/894 (0.1%)	1
Gastrointestinal infection	1/894 (0.1%)	1
Infected skin ulcer	1/894 (0.1%)	1
Influenza	1/894 (0.1%)	1
Meningitis bacterial	1/894 (0.1%)	1
Pneumonia cytomegaloviral	1/894 (0.1%)	1
Pneumonia klebsiella	1/894 (0.1%)	1
Pneumonia legionella	1/894 (0.1%)	1
Pneumonia pseudomonal	1/894 (0.1%)	1
Pneumonia streptococcal	1/894 (0.1%)	1
Pulmonary tuberculosis	1/894 (0.1%)	1
Sialoadenitis	1/894 (0.1%)	1
Sinusitis	1/894 (0.1%)	1
Tracheobronchitis	1/894 (0.1%)	1
Viral upper respiratory tract infection	1/894 (0.1%)	1
Urinary tract infection fungal	1/894 (0.1%)	1
Streptococcal bacteraemia	1/894 (0.1%)	1
Sepsis syndrome	1/894 (0.1%)	1
Central line infection	1/894 (0.1%)	1
Staphylococcal infection	1/894 (0.1%)	1
Bacterial infection	1/894 (0.1%)	1
Parainfluenzae virus infection	1/894 (0.1%)	1
Cholecystitis infective	1/894 (0.1%)	1
Lower respiratory tract infection viral	1/894 (0.1%)	1
Metapneumovirus infection	1/894 (0.1%)	1
Pseudomonas bronchitis	1/894 (0.1%)	1
Post procedural infection	1/894 (0.1%)	1
Infective exacerbation of bronchiectasis	1/894 (0.1%)	1
Injury, poisoning and procedural complications
Subdural haematoma	6/894 (0.7%)	6
Fall	4/894 (0.4%)	4
Post procedural haemorrhage	3/894 (0.3%)	3
Accidental overdose	2/894 (0.2%)	2
Tibia fracture	2/894 (0.2%)	2
Upper limb fracture	2/894 (0.2%)	2
Toxicity to various agents	2/894 (0.2%)	2
Ankle fracture	1/894 (0.1%)	1
Corneal abrasion	1/894 (0.1%)	1
Facial bones fracture	1/894 (0.1%)	1
Femur fracture	1/894 (0.1%)	1
Fibula fracture	1/894 (0.1%)	1
Gun shot wound	1/894 (0.1%)	1
Hip fracture	1/894 (0.1%)	1
Incisional hernia	1/894 (0.1%)	1
Intentional overdose	1/894 (0.1%)	1
Jaw fracture	1/894 (0.1%)	1
Overdose	1/894 (0.1%)	1
Rib fracture	1/894 (0.1%)	1
Road traffic accident	1/894 (0.1%)	1
Spinal fracture	1/894 (0.1%)	1
Vascular pseudoaneurysm	1/894 (0.1%)	1
Incision site haemorrhage	1/894 (0.1%)	1
Post procedural bile leak	1/894 (0.1%)	1
Skin laceration	1/894 (0.1%)	1
Pelvic fracture	1/894 (0.1%)	1
Chemical peritonitis	1/894 (0.1%)	1
Post procedural fever	1/894 (0.1%)	1
Investigations
International normalised ratio increased	3/894 (0.3%)	3
Hepatic enzyme increased	3/894 (0.3%)	4
Blood glucose decreased	2/894 (0.2%)	2
Blood sodium decreased	1/894 (0.1%)	1
Chest X-ray abnormal	1/894 (0.1%)	1
International normalised ratio abnormal	1/894 (0.1%)	1
Weight decreased	1/894 (0.1%)	1
Paracentesis	1/894 (0.1%)	1
Metabolism and nutrition disorders
Fluid overload	21/894 (2.3%)	27
Hypokalaemia	12/894 (1.3%)	13
Dehydration	9/894 (1%)	13
Hypoglycaemia	5/894 (0.6%)	5
Fluid retention	4/894 (0.4%)	6
Hyponatraemia	3/894 (0.3%)	3
Gout	2/894 (0.2%)	2
Hypercalcaemia	2/894 (0.2%)	2
Hyperglycaemia	2/894 (0.2%)	2
Metabolic acidosis	2/894 (0.2%)	2
Cachexia	1/894 (0.1%)	1
Diabetes mellitus	1/894 (0.1%)	1
Electrolyte imbalance	1/894 (0.1%)	1
Hyperkalaemia	1/894 (0.1%)	1
Hypocalcaemia	1/894 (0.1%)	1
Hypovolaemia	1/894 (0.1%)	1
Decreased appetite	1/894 (0.1%)	1
Musculoskeletal and connective tissue disorders
Back pain	6/894 (0.7%)	8
Pain in extremity	4/894 (0.4%)	4
Systemic lupus erythematosus	4/894 (0.4%)	5
Musculoskeletal pain	3/894 (0.3%)	3
Costochondritis	2/894 (0.2%)	2
Haemarthrosis	2/894 (0.2%)	2
Osteoarthritis	2/894 (0.2%)	3
Bone pain	1/894 (0.1%)	1
Flank pain	1/894 (0.1%)	1
Fracture malunion	1/894 (0.1%)	1
Myalgia	1/894 (0.1%)	1
Myositis	1/894 (0.1%)	1
Neck pain	1/894 (0.1%)	1
Osteoporosis	1/894 (0.1%)	2
Rheumatoid arthritis	1/894 (0.1%)	1
Rotator cuff syndrome	1/894 (0.1%)	1
Scleroderma	1/894 (0.1%)	1
Synovial cyst	1/894 (0.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma	3/894 (0.3%)	3
Colon cancer	2/894 (0.2%)	2
Lung neoplasm malignant	2/894 (0.2%)	2
Hepatic cancer	2/894 (0.2%)	2
Adenocarcinoma of colon	1/894 (0.1%)	1
Angiosarcoma	1/894 (0.1%)	1
Bladder transitional cell carcinoma	1/894 (0.1%)	1
Borderline ovarian tumour	1/894 (0.1%)	1
Breast cancer	1/894 (0.1%)	1
Breast mass	1/894 (0.1%)	1
Breast neoplasm	1/894 (0.1%)	1
Bronchial carcinoma	1/894 (0.1%)	1
Carotid body tumour	1/894 (0.1%)	1
Diffuse large B-cell lymphoma	1/894 (0.1%)	1
Lung adenocarcinoma stage IV	1/894 (0.1%)	1
Lung carcinoma cell type unspecified stage IV	1/894 (0.1%)	1
Malignant neoplasm of renal pelvis	1/894 (0.1%)	2
Malignant neoplasm of spinal cord	1/894 (0.1%)	1
Metastases to bone	1/894 (0.1%)	1
Metastases to lung	1/894 (0.1%)	1
Myelodysplastic syndrome	1/894 (0.1%)	1
Neoplasm malignant	1/894 (0.1%)	1
Papillary thyroid cancer	1/894 (0.1%)	1
Rectal cancer	1/894 (0.1%)	1
Renal cancer	1/894 (0.1%)	1
Small cell lung cancer limited stage	1/894 (0.1%)	1
Colon cancer metastatic	1/894 (0.1%)	1
Brain neoplasm	1/894 (0.1%)	1
Metastatic neoplasm	1/894 (0.1%)	1
Polyp	1/894 (0.1%)	1
Non-small cell lung cancer	1/894 (0.1%)	1
Metastasis	1/894 (0.1%)	1
Renal cell carcinoma	1/894 (0.1%)	1
Brenner tumour	1/894 (0.1%)	1
Nervous system disorders
Syncope	30/894 (3.4%)	33
Headache	7/894 (0.8%)	7
Dizziness	5/894 (0.6%)	5
Presyncope	5/894 (0.6%)	5
Cerebrovascular accident	2/894 (0.2%)	2
Seizure	2/894 (0.2%)	2
Altered state of consciousness	1/894 (0.1%)	1
Cerebral haemorrhage	1/894 (0.1%)	1
Coma hepatic	1/894 (0.1%)	1
Depressed level of consciousness	1/894 (0.1%)	1
Dysarthria	1/894 (0.1%)	1
Encephalopathy	1/894 (0.1%)	2
Epilepsy	1/894 (0.1%)	1
Facial paralysis	1/894 (0.1%)	1
Hepatic encephalopathy	1/894 (0.1%)	6
Transient ischaemic attack	1/894 (0.1%)	1
Ischaemic stroke	1/894 (0.1%)	1
Intensive care unit acquired weakness	1/894 (0.1%)	1
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy	1/894 (0.1%)	1
Psychiatric disorders
Mental status changes	5/894 (0.6%)	5
Suicidal ideation	2/894 (0.2%)	4
Anxiety	1/894 (0.1%)	1
Completed suicide	1/894 (0.1%)	1
Confusional state	1/894 (0.1%)	1
Depression	1/894 (0.1%)	1
Post-traumatic stress disorder	1/894 (0.1%)	1
Renal and urinary disorders
Acute kidney injury	37/894 (4.1%)	48
Renal failure	6/894 (0.7%)	7
Haematuria	3/894 (0.3%)	5
Lupus nephritis	2/894 (0.2%)	2
Chronic kidney disease	2/894 (0.2%)	2
Hydronephrosis	1/894 (0.1%)	1
Oliguria	1/894 (0.1%)	1
Renal failure acute	1/894 (0.1%)	2
Renal mass	1/894 (0.1%)	1
Renal impairment	1/894 (0.1%)	1
Reproductive system and breast disorders
Ovarian cyst	1/894 (0.1%)	1
Ovarian cyst ruptured	1/894 (0.1%)	1
Ovarian rupture	1/894 (0.1%)	1
Vaginal haemorrhage	1/894 (0.1%)	1
Adnexa uteri mass	1/894 (0.1%)	1
Haemorrhagic ovarian cyst	1/894 (0.1%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary Hypertension	129/894 (14.4%)	147
Dyspnoea	41/894 (4.6%)	51
Respiratory failure	15/894 (1.7%)	17
Hypoxia	13/894 (1.5%)	14
Chronic obstructive pulmonary disease	11/894 (1.2%)	17
Haemoptysis	10/894 (1.1%)	10
Asthma	6/894 (0.7%)	12
Pulmonary embolism	5/894 (0.6%)	5
Acute respiratory failure	4/894 (0.4%)	4
Pulmonary haemorrhage	4/894 (0.4%)	4
Disease progression	4/894 (0.4%)	4
Epistaxis	3/894 (0.3%)	3
Pleural effusion	3/894 (0.3%)	3
Respiratory distress	3/894 (0.3%)	3
Pulmonary arterial hypertension	3/894 (0.3%)	3
Lung infiltration	2/894 (0.2%)	2
Pneumonia aspiration	2/894 (0.2%)	2
Pulmonary fibrosis	2/894 (0.2%)	2
Pulmonary oedema	2/894 (0.2%)	2
Respiratory arrest	2/894 (0.2%)	2
Acute pulmonary oedema	1/894 (0.1%)	1
Acute respiratory distress syndrome	1/894 (0.1%)	1
Aspiration	1/894 (0.1%)	2
Chronic respiratory failure	1/894 (0.1%)	1
Cough	1/894 (0.1%)	1
Cyanosis central	1/894 (0.1%)	1
Eosinophilic pneumonia	1/894 (0.1%)	1
Haemothorax	1/894 (0.1%)	1
Interstitial lung disease	1/894 (0.1%)	2
Lung consolidation	1/894 (0.1%)	1
Nasal congestion	1/894 (0.1%)	1
Nasal turbinate hypertrophy	1/894 (0.1%)	1
Orthopnoea	1/894 (0.1%)	1
Pleurisy	1/894 (0.1%)	1
Pleuritic pain	1/894 (0.1%)	1
Pneumonitis	1/894 (0.1%)	1
Pneumothorax	1/894 (0.1%)	1
Pulmonary artery aneurysm	1/894 (0.1%)	1
Sleep apnoea syndrome	1/894 (0.1%)	1
Pulmonary mass	1/894 (0.1%)	1
Mediastinal disorder	1/894 (0.1%)	1
Skin and subcutaneous tissue disorders
Skin ulcer	2/894 (0.2%)	3
Angioedema	1/894 (0.1%)	1
Psoriasis	1/894 (0.1%)	1
Stasis dermatitis	1/894 (0.1%)	1
Surgical and medical procedures
Abortion induced	6/894 (0.7%)	7
Palliative care	1/894 (0.1%)	1
Cardiac ablation	1/894 (0.1%)	1
Balloon atrial septostomy	1/894 (0.1%)	1
Vascular disorders
Hypotension	23/894 (2.6%)	26
Deep vein thrombosis	6/894 (0.7%)	6
Flushing	2/894 (0.2%)	2
Shock	2/894 (0.2%)	2
Thrombosis	2/894 (0.2%)	2
Aortic dissection	1/894 (0.1%)	1
Blood pressure fluctuation	1/894 (0.1%)	1
Circulatory collapse	1/894 (0.1%)	1
Haematoma	1/894 (0.1%)	1
Hypertensive crisis	1/894 (0.1%)	1
Orthostatic hypotension	1/894 (0.1%)	1
Peripheral ischaemia	1/894 (0.1%)	1
Raynaud's phenomenon	1/894 (0.1%)	1
Angiodysplasia	1/894 (0.1%)	1
Aortic arteriosclerosis	1/894 (0.1%)	1
Vascular compression	1/894 (0.1%)	1
Other (Not Including Serious) Adverse Events
	Oral Treprostinil
	Affected / at Risk (%)	# Events
Total	890/894 (99.6%)
Blood and lymphatic system disorders
Anaemia	84/894 (9.4%)	112
Cardiac disorders
Dizziness	248/894 (27.7%)	320
Palpitations	145/894 (16.2%)	175
Right ventricular failure	136/894 (15.2%)	202
Cardiac failure	42/894 (4.7%)	54
Gastrointestinal disorders
Diarrhoea	592/894 (66.2%)	808
Nausea	505/894 (56.5%)	673
Vomiting	349/894 (39%)	485
Abdominal pain	121/894 (13.5%)	144
Abdominal pain upper	97/894 (10.9%)	111
Abdominal distension	92/894 (10.3%)	102
Dyspepsia	92/894 (10.3%)	95
Constipation	65/894 (7.3%)	74
Gastrooesophageal reflux disease	46/894 (5.1%)	48
Abdominal discomfort	45/894 (5%)	48
General disorders
Fatigue	201/894 (22.5%)	228
Oedema peripheral	192/894 (21.5%)	240
Chest pain	135/894 (15.1%)	180
Pain	97/894 (10.9%)	102
Pyrexia	83/894 (9.3%)	100
Chest discomfort	57/894 (6.4%)	70
Asthenia	51/894 (5.7%)	64
Oedema	43/894 (4.8%)	44
Infections and infestations
Upper respiratory tract infection	222/894 (24.8%)	334
Nasopharyngitis	185/894 (20.7%)	316
Bronchitis	103/894 (11.5%)	153
Pneumonia	94/894 (10.5%)	118
Urinary tract infection	89/894 (10%)	115
Sinusitis	80/894 (8.9%)	108
Influenza	54/894 (6%)	64
Investigations
Weight decreased	47/894 (5.3%)	49
Metabolism and nutrition disorders
Decreased appetite	129/894 (14.4%)	142
Hypokalaemia	94/894 (10.5%)	119
Fluid overload	44/894 (4.9%)	58
Fluid retention	43/894 (4.8%)	54
Musculoskeletal and connective tissue disorders
Pain in jaw	313/894 (35%)	360
Pain in extremity	255/894 (28.5%)	337
Arthralgia	140/894 (15.7%)	163
Myalgia	123/894 (13.8%)	143
Back pain	105/894 (11.7%)	127
Muscle spasms	64/894 (7.2%)	71
Musculoskeletal pain	42/894 (4.7%)	44
Nervous system disorders
Headache	698/894 (78.1%)	994
Syncope	101/894 (11.3%)	141
Presyncope	51/894 (5.7%)	55
Psychiatric disorders
Insomnia	95/894 (10.6%)	98
Anxiety	57/894 (6.4%)	60
Depression	56/894 (6.3%)	59
Renal and urinary disorders
Acute kidney injury	52/894 (5.8%)	69
Respiratory, thoracic and mediastinal disorders
Dyspnoea	207/894 (23.2%)	294
Pulmonary hypertension	190/894 (21.3%)	215
Cough	159/894 (17.8%)	202
Nasal congestion	98/894 (11%)	103
Epistais	77/894 (8.6%)	88
Haemoptysis	45/894 (5%)	57
Skin and subcutaneous tissue disorders
Rash	79/894 (8.8%)	87
Pruritus	43/894 (4.8%)	50
Vascular disorders
Flushing	416/894 (46.5%)	499
Hypotension	79/894 (8.8%)	91

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.