An Open-Label, Long-Term Study of Oral Treprostinil in Subjects With Pulmonary Arterial Hypertension

• Sponsor: United Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01560637
• Collaborator: (none)
• Enrollment: 471
• Locations: 153
• Arm: 1
• Actual Duration (Months): 95
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study is an international, multi-center, open-label study designed to provide oral treprostinil (UT-15C) to eligible subjects with pulmonary arterial hypertension who have completed the TDE-PH-310 study. The purpose of this study is to assess the long-term safety of UT-15C and to assess the effects of long-term treatment with UT-15C on exercise capacity.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: UT-15C (treprostinil diolamine)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 471 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-Label Extension Study of UT-15C in Subjects With Pulmonary Arterial Hypertension- A Long-Term Follow-Up to Protocol TDE-PH-310
• Actual Study Start Date: Sep 11, 2013
• Actual Primary Completion Date: Aug 12, 2021
• Actual Study Completion Date: Aug 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: UT-15C Open label access	Drug: UT-15C (treprostinil diolamine); UT-15C extended release oral tablet three times daily

Outcome Measures

Primary Outcome Measures

1. Number of Adverse Events [Participants will be followed every 12 weeks, at minimum, until they discontinue the study or the study is discontinued by the sponsor or for a period up to 2.5 years]

   All subjects who received oral treprostinil in TDE-PH-311 were included in the Safety population. All AEs were captured from the time the ICF was signed. All AEs were followed until resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for up to 30 days if the AE extended beyond the final visit. All SAEs were followed until resolution, death, or the subject was lost to follow-up, even if they were ongoing more than 30 days after completion of the final visit. The overall summary of AEs includes the number of subjects with any AE, the number of subjects with any study drug-related AEs, the number of subjects with AEs leading to study drug withdrawal, the number of subjects with any serious AEs, the number of subjects with any severe AEs, and the number of subjects with any study drug-related severe/serious AEs. AEs were coded using the Medical Dictionary for Regulatory Activities.

Secondary Outcome Measures

1. Change in 6-Minute Walk Distance From Baseline [Baseline to Week 48]

   A summary of change from Baseline in 6MWD at Week 48 for the Safety Population is provided. The Safety Population is all subjects who received oral treprostinil in TDE-PH-311.

2. Change in Borg Dyspnea Score From Baseline to Week 48 [Baseline to Week 48]

   Change in Borg Dyspnea Score from at Week 48 is provided for the Safety Population (all subjects who received oral treprostinil in TDE-PH-311). The Borg Dyspnea Scale is a 0 to 10 rated numerical score used to measure dyspnea as reported by the patient during submaximal exercise and was administered during six-minute walk testing (6MWT), one of the most common and frequently used measures to assess disease severity in PAH. The numbers on the scale are as follows: 0 (no shortness of breath [SOB]), 0.5 (very very slight SOB), 1 (very slight SOB), 3 (moderate SOB), 4 (somewhat severe SOB), 5 (severe SOB), 7 (very severe SOB), 9 (very very severe SOB), 10 (maximal SOB).

3. Change From Baseline to Week 48 in WHO Functional Class [Baseline to Week 48]

   Change from Baseline at Week 48 in WHO FC in the Safety Population (all subjects who received oral treprostinil in TDE-PH-311). The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning. Class I (least severe): Patients are without limitation of physical activity. Class II: Patients are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III: Marked limitation of physical activity. They are comfortable at rest. Class IV (most severe): Inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure.

4. Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 48 [Baseline to Week 48]

   Change in N-terminal pro-brain natriuretic peptide from Baseline at Week 48 for the Safety Population (any subject who received oral treprostinil in TDE-PH-311)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participated in United Therapeutics Study TDE-PH-310

• All women of childbearing potential (WOCBP) must have practiced true abstinence from intercourse when it was in line with their preferred and usual lifestyle or used 2 different forms of highly effective contraception for the duration of the study and for at least 30 days after discontinuing study medication.

• Males who participated in the study must have used a condom during the length of the study and for at least 48 hours after their last dose of study medication.

Exclusion Criteria:

• The subject was pregnant or lactating.

• The subject had received infused or inhaled prostacyclin therapy for 29 days or more.

• The subject was prematurely discontinued from TDE-PH-310 for reasons other than a clinical worsening event.

• The subject developed a concurrent illness or condition during the conduct of TDE-PH-310 which, in the opinion of the Investigator, would represent a risk to their overall health if they enrolled in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Pulmonary Specialists, Ltd.	Phoenix	Arizona	United States	85012
2	University of Arizona	Tucson	Arizona	United States	85724
3	University of California, San Francisco-Fresno	Fresno	California	United States	93701
4	Cedars-Sinai Medical Center	Los Angeles	California	United States	90211
5	University of California-Davis Medical Group, Advanced Lung Disease/Transplant Program	Sacramento	California	United States	95817
6	David Geffen School of Medicine	Torrance	California	United States	90502
7	University of Colorado Hospital	Aurora	Colorado	United States	80045
8	University of Florida	Gainesville	Florida	United States	32610
9	University of Florida College of Medicine Jacksonville- Division of Pulmonary & Critical Medicine	Jacksonville	Florida	United States	32209
10	Cleveland Clinic Florida	Weston	Florida	United States	33331
11	Emory University Hospital	Atlanta	Georgia	United States	30322
12	Augusta University	Augusta	Georgia	United States	30912
13	Piedmont - Georgia Lung Associates	Austell	Georgia	United States	30106
14	HeartCare Midwest	Peoria	Illinois	United States	61614
15	Indiana University Hospital	Carmel	Indiana	United States	46032
16	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	55242
17	Kentuckiana Pulmonary Associates	Louisville	Kentucky	United States	40202
18	University of Maryland	Baltimore	Maryland	United States	21201
19	Tufts Medical Center	Boston	Massachusetts	United States	02111
20	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
21	Henry Ford Health System	Detroit	Michigan	United States	48202
22	Beaumont Health	Troy	Michigan	United States	48085
23	Nebraska Medical Center	Omaha	Nebraska	United States	68198-5990
24	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
25	University of Rochester	Rochester	New York	United States	14642
26	Asheville Cardiology Associates	Asheville	North Carolina	United States	28803
27	University of Cincinnati	Cincinnati	Ohio	United States	45267
28	University Hospital	Cleveland	Ohio	United States	44106
29	Ohio State University	Columbus	Ohio	United States	43321
30	Oregon Health and Science University	Portland	Oregon	United States	97201-3098
31	Legacy Research Institute	Portland	Oregon	United States	97210
32	Perelman Center for Advanced Medicine, University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
33	University of Pittsburgh Medical Center - Presbyterian Cardiovascular Institute	Pittsburgh	Pennsylvania	United States	15213
34	Rhode Island Hospital	Providence	Rhode Island	United States	02903
35	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
36	Sentara Cardiovascular Research Institute	Norfolk	Virginia	United States	23507
37	Virginia Commonwealth University	Richmond	Virginia	United States	23298
38	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
39	Sanatorio San José	Caba	Buenos Aires	Argentina	C1425DUH
40	Hospital Italiano de Buenos Aires	Ciudad Autónoma de Buenos Aires	Distrito Federal	Argentina	C1181ACH
41	Hospital Italiano Garibaldi	Rosario	Santa Fe	Argentina	S2001OAD
42	Sanatorio de la Trinidad Mitre	Buenos Aires		Argentina
43	Hospital Dr. José María Cullen	Santa Fe		Argentina	S3000EOY
44	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
45	Nepean Hospital	Kingswood	New South Wales	Australia	2751
46	Saint Vincents Hospital	Sydney	New South Wales	Australia	2010
47	Macquarie University	Sydney	New South Wales	Australia	2109
48	Prince Charles Hospital	Chermside	Queensland	Australia	4032
49	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
50	The Alfred Hospital	Melbourne	Victoria	Australia	3004
51	Royal Melbourne Hospital	Parkville	Victoria	Australia	3050
52	Krankenhaus Elisabethinen Linz	Linz	Upper Austria	Austria	4020
53	Medizinische Universität Wien	Wien		Austria	1090
54	Hospital das Clinicas da Universidade Federal de Goias	Goiania	Goias	Brazil	74605-050
55	Hospital das Clínicas da Universidade Federal de Minas Gerais	Belo Horizonte	Minas Gerais	Brazil	30130-100
56	Hospital Madre Teresa	Belo Horizonte	Minas Gerais	Brazil	30380-090
57	Complexo Hospitalar Santa Casa de Porto Alegre	Porto Alegre	RIO Grande DO SUL	Brazil	90020-090
58	Hospital das Clínicas da Faculdade de Medicina de Botucatu- UNESP	Botucatu	SAO Paulo	Brazil	18618-970
59	Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo	SAO Paulo	Brazil	05403-000
60	Escola Paulista de Medicina, Universidade Federal de São Paulo	São Paulo	SAO Paulo	Brazil
61	Hospital Alemão Oswaldo Cruz	São Paulo		Brazil	01323-020
62	Respiratory Research Foundation	Calgary	Alberta	Canada	T1Y 6J4
63	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
64	Vancouver Coastal Health	Vancouver	British Columbia	Canada	V5Z 1M9
65	Lawson Health Research Institute	London	Ontario	Canada	N6A 5A5
66	Centro de Investigaciones TASOL	Santiago	Region Metropolitana	Chile	7500710
67	Clínica Tabancura	Vitacura	Santiago	Chile	7650018
68	Beijing Chao-Yang Hospital	Beijing	Beijing	China	100020
69	Guangdong General Hospital	Guangzhou	Guangdong	China	510080
70	Wuhan Asia Heart Hospital	Wuhan	Hubei	China	430022
71	Xiangya Hospital	Changsha	Hunan	China	410008
72	The First Affiliated Hospital of Nanjing Medical University	Nanjing	Jiangsu	China	210029
73	The Second Affiliated Hospital of Nanchang Medical University	Nanchang	Jiangxi	China	330006
74	Zhongshan Hospital Fudan University	Shanghai	Shanghai	China	200032
75	Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai	Shanghai	China	200120
76	West China Hospital	Chengdu	Sichuan	China	610047
77	Peking Union Medical College Hospital	Beijing		China	100005
78	Beijing Shijitan Hospital	Beijing		China	100038
79	Chinese PLA General Hospital	Beijing		China	100853
80	The Affiliated Hospital of Qingdao University	Qingdao		China	26603
81	Renji Hospital of Shanghai Jiaotong University	Shanghai		China	200001
82	Shanghai Pulmonary Hospital of Tongji University	Shanghai		China	200433
83	Shenyang General Hospital of Shenyang Military Command	Shenyang		China	110015
84	Aarhus Universitetshospital, Skejby	Aarhus		Denmark	8200
85	Rigshospitalet-Copenhagen University Hospital	Copenhagen		Denmark	2100
86	Hopital Haut-Leveque, CHU Bordeaux	Pessac	Aquitaine	France	33064
87	Hopital Jean Minjoz Centre Hospitalier Universitaire Besancon	Besancon	Franche-comte	France	25030
88	CHU de Montpellier	Montpellier cedex 5	Languedoc-roussillon	France	34295
89	Hopital Brabois	Vandoeuvre-Les-Nancy	Limousin, Lorraine	France	54500
90	Centre Hospitalier Régional Universitaire de Lille - Hôpital Claude Huriez	Lille	NORD Pas-de-calais	France	59037
91	Centre Hospitalier Universitaire Hopital Nord	Marseille	Provence Alpes COTE D'azur	France	13015
92	Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg	Baden-wuerttemberg	Germany	69126
93	Ludwig-Maximilians-Universitat Munchen	Munchen	Bayern	Germany	81377
94	Universitätsklinikum Regensburg	Regensburg	Bayern	Germany	93053
95	Missionsarztliche Klinik Wurzburg gGmbH	Wurzburg	Bayern	Germany	97074
96	Universitätsmedizin Greifswald	Greifswald	Mecklenburg-vorpommern	Germany	17475
97	Bergmannsheil Berufsgenossenschaftliche Universitätsklinik GmbH	Bochum	Nordrhein-westfalen	Germany	44789
98	Herzzentrum Duisburg	Duisburg	Nordrhein-westfalen	Germany	47137
99	Universitätsklinikum Köln	Köln	Nordrhein-westfalen	Germany	50937
100	Universitätsmedizin der Johannes Gutenberg Universität	Mainz	Rheinland-pfalz	Germany	55131
101	Universitätsklinikum des Saarlandes	Homburg	Saarland	Germany	66424
102	Technische Universität Dresden	Dresden	Sachsen	Germany	01307
103	Universitätsklinikum Leipzig	Leipzig	Sachsen	Germany	04103
104	Universitätskrankenhaus Hamburg-Eppendorf	Hamburg		Germany	20246
105	University General Hospital of Attikon	Athens	Attica	Greece	12462
106	General Hospital of Thessaloniki, "G.Papanikolaou"	Thessaloniki	Macedoni	Greece	57010
107	CARE Hospital	Hyderabad	Andhra Pradesh	India	500 001
108	Mediciti Hospital	Hyderabad	Andhra Pradesh	India	500 063
109	Sir Ganga Ram Hospital	New Delhi	Delhi	India	110060
110	Indraprastha Apollo Hospital	New Delhi	Delhi	India	110076
111	Care Institute Medical Sciences	Ahmedabad	Gujarat	India	38006
112	Apollo Hospitals International, Ltd.	Gandhinagar	Gujarat	India	382428
113	Medanta - The Medicity	Gurgaon	Haryana	India	122 001
114	Narayana Institute of Cardiac Sciences	Bangalore	Karnataka	India	560 099
115	KEM Hospital	Mumbai	Maharashtra	India	400012
116	King Edward Memorial Hospital & Seth Gordhandas Sunderdas Medical College	Mumbai	Maharashtra	India	400012
117	Ruby Hall Clinic	Pune	Maharashtra	India	411 001
118	Apollo Hospital	Chennai	Tamil NADU	India	600006
119	G. Kuppuswamy Naidu Memorial Hospital	Coimbatore	Tamil NADU	India	641037
120	Rabin Medical Center	Petach Tikvah	Petah Tiqwa	Israel	49100
121	The Chaim Sheba Medical Center at Tel Hashomer	Tel Hashomer	Tel Aviv	Israel	52621
122	Rambam Health Corp.	Haifa		Israel	31096
123	Carmel Medical Center	Haifa		Israel	34362
124	Hadassah Medical Center	Jerusalem		Israel	91120
125	Azienda Ospedaliera Universitaria	Napoli		Italy
126	Istituto Mediterraneo Trapianti e Terapia Alta Specializzazione (ISMETT)	Palermo		Italy	90127
127	Fondazione IRCCS Policlinico S. Matteo	Pavia		Italy	27100
128	Azienda Policlinico Umberto I di Roma	Roma		Italy	00161
129	Gachon University Gil Medical Center	Incheon		Korea, Republic of	405-760
130	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
131	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	120-752
132	Samsung Medical Center	Seoul		Korea, Republic of	135-710
133	Asan Medical Center	Seoul		Korea, Republic of	138-736
134	Instituto Nacional de Cardiologia Ignacio Chavez	Tlalpan	Distrito Federal	Mexico	14080
135	Unidad de Investigacion Clinica en Medicina S.C.	Monterrey	Nuevo LEON	Mexico	64718
136	Universitair Medisch Centrum Sint Radboud	Nijmegen	Gelderland	Netherlands	6525 GA
137	Vrije Universiteit Medisch Centrum	Amsterdam	Noord-holland	Netherlands	1081 HV
138	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok		Poland	15276
139	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K. Marcinkowskiego w Poznaniu	Krakow		Poland	61848
140	Krakowski Szpital Specjalistyczny im. Jana Pawla II	Malogoskie		Poland	31202
141	Europejskie Centrum Zdrowia Otwock, Szpital im. Fryderyka Chopina	Otwock		Poland
142	National University Hospital	Singapore		Singapore	119228
143	National Heart Centre Singapore	Singapore		Singapore	168 752
144	Sahlgrenska University Hospital	Göteborg	Vastra Gotaland	Sweden	413 45
145	Karolinska University Hospital Solna	Stockholm		Sweden	171 76
146	National Cheng Kung University Hospital	Tainan	Tainan CITY	Taiwan	70403
147	Veterans General Hospital-Kaohsiung	Kaohsiung		Taiwan	81362
148	Taichung Veterans General Hospital	Taichung		Taiwan	40705
149	National Taiwan University Hospital	Taipei		Taiwan	10002
150	Papworth Hospital	Papworth Everard	Cambridgshire	United Kingdom	CB3 8RE
151	Royal Free Hospital	London	England	United Kingdom	NW3 2QG
152	Freeman Hospital	Newcastle upon Tyne	England	United Kingdom	NE7 7DN
153	Royal Hallamshire Hospital	Sheffield	England	United Kingdom	S10 2JF

Sponsors and Collaborators

• United Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 13, 2018
• Statistical Analysis Plan - Jan 15, 2019
• Informed Consent Form - Jul 13, 2018

More Information

Publications

None provided.

• Responsible Party: United Therapeutics
• ClinicalTrials.gov Identifier: NCT01560637
• Other Study ID Numbers: TDE-PH-311
• First Posted: Mar 22, 2012
• Last Update Posted: Jun 2, 2022
• Last Verified: May 1, 2022

• Keywords provided by United Therapeutics: PAH; PH; FREEDOM; 6 minute walk test; treprostinil; open label
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Treprostinil

Study Results

Participant Flow

Arm/Group Title	UT-15C
Arm/Group Description	Open label access UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration
Period Title: Overall Study
STARTED	470
COMPLETED	272
NOT COMPLETED	198

Baseline Characteristics

Arm/Group Title	UT-15C
Arm/Group Description	Open label access UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration
Overall Participants	470
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	398 84.7%
>=65 years	72 15.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.2 (15.1)
Sex: Female, Male (Count of Participants)
Female	374 79.6%
Male	96 20.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	135 28.7%
Not Hispanic or Latino	334 71.1%
Unknown or Not Reported	1 0.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	213 45.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	10 2.1%
White	245 52.1%
More than one race	0 0%
Unknown or Not Reported	2 0.4%
Etiology of Pulmonary Arterial Hypertension (PAH) (Count of Participants)
Idiopathic of Heritable PAH	299 63.6%
Collagen Vascular Disease	114 24.3%
HIV Infection	8 1.7%
Congenital Heart Defect	38 8.1%
Other	11 2.3%
Background PAH Therapy at Randomization in Parent Study (Count of Participants)
Phosphodiesterase Type 5 Inhibitor (PDE5-I) Alone/Soluble Guanylate Cyclase (sGC) Stimulator Alone	348 74%
Endothelin Receptor Antagonist (ERA) alone	122 26%
Time since Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.16 (2.69)
6-Minute Walk Distance (6MWD) at Baseline (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	392.0 (128.1)
WHO Functional Class at Baseline (Count of Participants)
I	41 8.7%
II	226 48.1%
III	182 38.7%
IV	21 4.5%

Outcome Measures

1. Primary Outcome

Title	Number of Adverse Events
Description	All subjects who received oral treprostinil in TDE-PH-311 were included in the Safety population. All AEs were captured from the time the ICF was signed. All AEs were followed until resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for up to 30 days if the AE extended beyond the final visit. All SAEs were followed until resolution, death, or the subject was lost to follow-up, even if they were ongoing more than 30 days after completion of the final visit. The overall summary of AEs includes the number of subjects with any AE, the number of subjects with any study drug-related AEs, the number of subjects with AEs leading to study drug withdrawal, the number of subjects with any serious AEs, the number of subjects with any severe AEs, and the number of subjects with any study drug-related severe/serious AEs. AEs were coded using the Medical Dictionary for Regulatory Activities.
Time Frame	Participants will be followed every 12 weeks, at minimum, until they discontinue the study or the study is discontinued by the sponsor or for a period up to 2.5 years

Outcome Measure Data

Analysis Population Description

All subjects who received oral treprostinil in TDE-PH-311 were included in the Safety population.

Arm/Group Title	UT-15C
Arm/Group Description	Open label access UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration
Measure Participants	470
Adverse Event	450
Study Drug Related AE	362
AE Leading to Study Drug Withdrawal	126
Serious AE	206
Severe AE	182
Study Drug Related Severe AE	67
Study Drug Related Serious AE	37

2. Secondary Outcome

Title	Change in 6-Minute Walk Distance From Baseline
Description	A summary of change from Baseline in 6MWD at Week 48 for the Safety Population is provided. The Safety Population is all subjects who received oral treprostinil in TDE-PH-311.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

All participants are subjects who received oral treprostinil in TDE-PH-311. For post-Baseline visits, only subjects with measurements at Baseline and the corresponding visit are included. Baseline is defined as the last measurement prior to the first dose of oral treprostinil in TDE-PH-311.

Arm/Group Title	UT-15C
Arm/Group Description	Open label access UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration
Measure Participants	341
Mean (Standard Deviation) [meters]	20.1 (79.6)

3. Secondary Outcome

Title	Change in Borg Dyspnea Score From Baseline to Week 48
Description	Change in Borg Dyspnea Score from at Week 48 is provided for the Safety Population (all subjects who received oral treprostinil in TDE-PH-311). The Borg Dyspnea Scale is a 0 to 10 rated numerical score used to measure dyspnea as reported by the patient during submaximal exercise and was administered during six-minute walk testing (6MWT), one of the most common and frequently used measures to assess disease severity in PAH. The numbers on the scale are as follows: 0 (no shortness of breath [SOB]), 0.5 (very very slight SOB), 1 (very slight SOB), 3 (moderate SOB), 4 (somewhat severe SOB), 5 (severe SOB), 7 (very severe SOB), 9 (very very severe SOB), 10 (maximal SOB).
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Safety Population (all subjects who received oral treprostinil in TDE-PH-311). For post-Baseline visits, only subjects with measurements at Baseline and the corresponding visit are included. Baseline is defined as the last measurement prior to the first dose of oral treprostinil in TDE-PH-311.

Arm/Group Title	UT-15C
Arm/Group Description	Open label access UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration
Measure Participants	341
Mean (Standard Deviation) [score on a scale]	-0.49 (1.92)

4. Secondary Outcome

Title	Change From Baseline to Week 48 in WHO Functional Class
Description	Change from Baseline at Week 48 in WHO FC in the Safety Population (all subjects who received oral treprostinil in TDE-PH-311). The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning. Class I (least severe): Patients are without limitation of physical activity. Class II: Patients are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III: Marked limitation of physical activity. They are comfortable at rest. Class IV (most severe): Inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Safety Population was analyzed. Baseline is defined as the last measurement prior to the first dose of oral treprostinil in TDE PH 311.

Arm/Group Title	UT-15C
Arm/Group Description	Open label access UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration
Measure Participants	362
Mean (Standard Deviation) [score on a scale]	-0.2 (0.6)

5. Secondary Outcome

Title	Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 48
Description	Change in N-terminal pro-brain natriuretic peptide from Baseline at Week 48 for the Safety Population (any subject who received oral treprostinil in TDE-PH-311)
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Subjects in the Safety Population were analyzed. For post-Baseline visits, only subjects with measurements at Baseline and the corresponding visit are included. Baseline is defined as the last measurement prior to the first dose of oral treprostinil in TDE-PH-311.

Arm/Group Title	UT-15C
Arm/Group Description	Open label access UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration
Measure Participants	322
Mean (Standard Deviation) [pg/mL]	-179.23 (1968.99)

Adverse Events

Time Frame	AEs were recorded for each subject throughout the course of the study from Baseline to 30 days following the final study visit (up to 356 weeks).
Adverse Event Reporting Description	All AEs were captured from the time the ICF was signed. All AEs were followed until resolution (or return to baseline values), until they were judged by the Investigator to no longer be clinically significant, or for up to 30 days if the AE extended beyond the final visit. All SAEs were followed until resolution, death, or the subject was lost to follow-up, even if they were ongoing more than 30 days after completion of the final visit.
Arm/Group Title	UT-15C
Arm/Group Description	Open label access UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration
All Cause Mortality
	UT-15C
	Affected / at Risk (%)	# Events
Total	74/470 (15.7%)
Serious Adverse Events
	UT-15C
	Affected / at Risk (%)	# Events
Total	206/470 (43.8%)
Blood and lymphatic system disorders
Anaemia	5/470 (1.1%)	5
Thrombocytopenia	2/470 (0.4%)	2
Anaemia of malignant disease	1/470 (0.2%)	1
Erythropenia	1/470 (0.2%)	1
Haemolytic anaemia	1/470 (0.2%)	1
Iron deficiency anaemia	1/470 (0.2%)	1
Pancytopenia	1/470 (0.2%)	1
Cardiac disorders
Right ventricular failure	22/470 (4.7%)	27
Cardiac failure	19/470 (4%)	25
Cardiac arrest	4/470 (0.9%)	4
Cardiogenic shock	4/470 (0.9%)	4
Atrial fibrillation	3/470 (0.6%)	3
Atrial flutter	3/470 (0.6%)	3
Cardiac failure congestive	3/470 (0.6%)	3
Cor pulmonale	3/470 (0.6%)	3
Myocardial infarction	3/470 (0.6%)	3
Atrioventricular block complete	2/470 (0.4%)	2
Cardiac failure acute	2/470 (0.4%)	2
Cardiopulmonary failure	2/470 (0.4%)	2
Pericardial effusion	2/470 (0.4%)	2
Pulmonary oedema	2/470 (0.4%)	2
Right ventricular dysfunction	2/470 (0.4%)	2
Supraventricular tachycardia	2/470 (0.4%)	2
Acute myocardial infarction	1/470 (0.2%)	1
Acute pulmonary oedema	1/470 (0.2%)	1
Acute right ventricular failure	1/470 (0.2%)	1
Aortic valve incompetence	1/470 (0.2%)	1
Arrhythmia	1/470 (0.2%)	1
Atrioventricular block	1/470 (0.2%)	1
Atrioventricular block second degree	1/470 (0.2%)	1
Cardiac failure chronic	1/470 (0.2%)	2
Cardio-respiratory arrest	1/470 (0.2%)	1
Cor pulmonale acute	1/470 (0.2%)	2
Coronary artery disease	1/470 (0.2%)	1
Pericarditis	1/470 (0.2%)	1
Pulseless electrical activity	1/470 (0.2%)	1
Sinus tachycardia	1/470 (0.2%)	1
Sudden cardiac death	1/470 (0.2%)	1
Tricuspid valve incompetence	1/470 (0.2%)	1
Ear and labyrinth disorders
Vertigo	1/470 (0.2%)	1
Endocrine disorders
Hyperthyroidism	4/470 (0.9%)	4
Adrenocortical insufficiency acute	1/470 (0.2%)	1
Eye disorders
Amaurosis	1/470 (0.2%)	1
Endocrine ophthalmopathy	1/470 (0.2%)	1
Gastrointestinal disorders
Diarrhoea	6/470 (1.3%)	6
Upper gastrointestinal haemorrhage	3/470 (0.6%)	5
Vomiting	3/470 (0.6%)	3
Abdominal pain	2/470 (0.4%)	2
Melaena	2/470 (0.4%)	2
Abdominal distension	1/470 (0.2%)	1
Acute abdomen	1/470 (0.2%)	1
Ascites	1/470 (0.2%)	1
Colitis	1/470 (0.2%)	1
Diverticulum	1/470 (0.2%)	1
Enteritis	1/470 (0.2%)	1
Gastric polyps	1/470 (0.2%)	1
Gastric varices haemorrhage	1/470 (0.2%)	1
Gastritis	1/470 (0.2%)	1
Gastritis haemorrhagic	1/470 (0.2%)	1
Gastrointestinal disorder	1/470 (0.2%)	1
Gastrointestinal haemorrhage	1/470 (0.2%)	1
Gastrointestinal polyp haemorrhage	1/470 (0.2%)	1
Gastrointestinal vascular malformation haemorrhagic	1/470 (0.2%)	2
Gastrooesophageal reflux disease	1/470 (0.2%)	1
Ileus	1/470 (0.2%)	1
Inguinal hernia	1/470 (0.2%)	1
Intestinal obstruction	1/470 (0.2%)	1
Large intestine polyp	1/470 (0.2%)	2
Mechanical ileus	1/470 (0.2%)	1
Portal hypertensive gastropathy	1/470 (0.2%)	1
Rectal haemorrhage	1/470 (0.2%)	1
General disorders
Multiple organ dysfunction syndrome	3/470 (0.6%)	3
Chest pain	2/470 (0.4%)	3
Oedema	2/470 (0.4%)	2
Sudden death	2/470 (0.4%)	2
Asthenia	1/470 (0.2%)	1
Chest discomfort	1/470 (0.2%)	1
Disease progression	1/470 (0.2%)	1
Generalised oedema	1/470 (0.2%)	1
Oedema peripheral	1/470 (0.2%)	1
Pyrexia	1/470 (0.2%)	1
Hepatobiliary disorders
Cholecystitis acute	5/470 (1.1%)	5
Hepatic function abnormal	2/470 (0.4%)	2
Acute hepatic failure	1/470 (0.2%)	1
Biliary tract disorder	1/470 (0.2%)	2
Cholestasis	1/470 (0.2%)	1
Congestive hepatopathy	1/470 (0.2%)	1
Hepatic cirrhosis	1/470 (0.2%)	1
Hepatic encephalopathy	1/470 (0.2%)	1
Hepatic failure	1/470 (0.2%)	1
Hepatitis	1/470 (0.2%)	1
Liver injury	1/470 (0.2%)	1
Subcapsular hepatic haematoma	1/470 (0.2%)	1
Infections and infestations
Pneumonia	32/470 (6.8%)	39
Septic shock	9/470 (1.9%)	9
Gastroenteritis	6/470 (1.3%)	6
Respiratory tract infection	5/470 (1.1%)	5
Sepsis	5/470 (1.1%)	5
Urinary tract infection	5/470 (1.1%)	5
Appendicitis	3/470 (0.6%)	5
COVID-19	3/470 (0.6%)	3
COVID-19 pneumonia	3/470 (0.6%)	3
Bronchitis	2/470 (0.4%)	2
Cellulitis	2/470 (0.4%)	2
Clostridium difficile colitis	2/470 (0.4%)	2
Peritonitis	2/470 (0.4%)	2
Upper respiratory tract infection	2/470 (0.4%)	2
Bacteraemia	1/470 (0.2%)	1
Bacterial translocation	1/470 (0.2%)	1
Cholecystitis infective	1/470 (0.2%)	1
Diarrhoea infectious	1/470 (0.2%)	1
Diverticulitis	1/470 (0.2%)	2
Enteritis infectious	1/470 (0.2%)	1
Gangrene	1/470 (0.2%)	1
Infective exacerbation of bronchiectasis	1/470 (0.2%)	1
Influenza	1/470 (0.2%)	1
Lower respiratory tract infection	1/470 (0.2%)	1
Meningitis listeria	1/470 (0.2%)	1
Ophthalmic herpes zoster	1/470 (0.2%)	1
Pneumonia aspiration	1/470 (0.2%)	1
Pneumonia influenzal	1/470 (0.2%)	1
Sialoadenitis	1/470 (0.2%)	1
Staphylococcal sepsis	1/470 (0.2%)	1
Urosepsis	1/470 (0.2%)	1
Injury, poisoning and procedural complications
Hand fracture	2/470 (0.4%)	2
Accidental overdose	1/470 (0.2%)	1
Arteriovenous fistula site haemorrhage	1/470 (0.2%)	1
Fall	1/470 (0.2%)	2
Intentional overdose	1/470 (0.2%)	1
Pelvic fracture	1/470 (0.2%)	1
Post procedural haemorrhage	1/470 (0.2%)	1
Road traffic accident	1/470 (0.2%)	1
Splenic rupture	1/470 (0.2%)	1
Subdural haematoma	1/470 (0.2%)	1
Investigations
Catheterisation cardiac	2/470 (0.4%)	2
Blood creatinine increased	1/470 (0.2%)	1
Coagulation time prolonged	1/470 (0.2%)	1
Transaminases increased	1/470 (0.2%)	1
Metabolism and nutrition disorders
Fluid overload	3/470 (0.6%)	5
Dehydration	2/470 (0.4%)	2
Electrolyte imbalance	2/470 (0.4%)	3
Hypokalaemia	2/470 (0.4%)	2
Gout	1/470 (0.2%)	1
Hyperglycaemia	1/470 (0.2%)	1
Hyperuricaemia	1/470 (0.2%)	1
Hypervolaemia	1/470 (0.2%)	1
Metabolic acidosis	1/470 (0.2%)	1
Metabolic encephalopathy	1/470 (0.2%)	1
Musculoskeletal and connective tissue disorders
Systemic lupus erythematosus	3/470 (0.6%)	3
Osteonecrosis	2/470 (0.4%)	2
Sjogren's syndrome	2/470 (0.4%)	2
Muscle atrophy	1/470 (0.2%)	1
Osteoarthritis	1/470 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	1/470 (0.2%)	1
Breast cancer	1/470 (0.2%)	1
Chronic myeloid leukaemia	1/470 (0.2%)	1
Diffuse large B-cell lymphoma	1/470 (0.2%)	1
Hepatic cancer recurrent	1/470 (0.2%)	1
Hepatocellular carcinoma	1/470 (0.2%)	3
Lung neoplasm malignant	1/470 (0.2%)	1
Malignant pleural effusion	1/470 (0.2%)	1
Ovarian adenoma	1/470 (0.2%)	1
POEMS syndrome	1/470 (0.2%)	1
Nervous system disorders
Syncope	4/470 (0.9%)	4
Cerebrovascular accident	2/470 (0.4%)	2
Brain injury	1/470 (0.2%)	1
Coma	1/470 (0.2%)	1
Headache	1/470 (0.2%)	1
Ischaemic stroke	1/470 (0.2%)	1
Loss of consciousness	1/470 (0.2%)	1
Presyncope	1/470 (0.2%)	1
Seizure	1/470 (0.2%)	1
Psychiatric disorders
Delirium	1/470 (0.2%)	1
Mental status changes	1/470 (0.2%)	1
Renal and urinary disorders
Acute kidney injury	7/470 (1.5%)	8
Renal failure	2/470 (0.4%)	2
Chronic kidney disease	1/470 (0.2%)	1
Glomerulonephritis acute	1/470 (0.2%)	1
Haematuria	1/470 (0.2%)	1
Lupus nephritis	1/470 (0.2%)	1
Renal vasculitis	1/470 (0.2%)	1
Scleroderma renal crisis	1/470 (0.2%)	1
Tubulointerstitial nephritis	1/470 (0.2%)	1
Urinary bladder polyp	1/470 (0.2%)	1
Reproductive system and breast disorders
Breast mass	1/470 (0.2%)	1
Fibrocystic breast disease	1/470 (0.2%)	1
Intermenstrual bleeding	1/470 (0.2%)	1
Ovarian cyst	1/470 (0.2%)	1
Pelvic fluid collection	1/470 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertension	57/470 (12.1%)	79
Respiratory failure	8/470 (1.7%)	8
Dyspnoea	7/470 (1.5%)	7
Hypoxia	5/470 (1.1%)	5
Acute respiratory failure	3/470 (0.6%)	3
Dyspnoea exertional	2/470 (0.4%)	2
Haemoptysis	2/470 (0.4%)	2
Acute respiratory distress syndrome	1/470 (0.2%)	1
Interstitial lung disease	1/470 (0.2%)	1
Pulmonary arterial hypertension	1/470 (0.2%)	2
Pulmonary embolism	1/470 (0.2%)	1
Skin and subcutaneous tissue disorders
Rash	2/470 (0.4%)	2
Purpura	1/470 (0.2%)	1
Surgical and medical procedures
Abortion induced	2/470 (0.4%)	2
Vascular disorders
Hypotension	6/470 (1.3%)	6
Shock	3/470 (0.6%)	3
Peripheral arterial occlusive disease	1/470 (0.2%)	1
Other (Not Including Serious) Adverse Events
	UT-15C
	Affected / at Risk (%)	# Events
Total	467/470 (99.4%)
Blood and lymphatic system disorders
Anaemia	51/470 (10.9%)	55
Thrombocytopenia	17/470 (3.6%)	19
Iron deficiency anaemia	9/470 (1.9%)	11
Leukopenia	8/470 (1.7%)	10
Splenomegaly	4/470 (0.9%)	4
Coagulopathy	2/470 (0.4%)	2
Pancytopenia	2/470 (0.4%)	2
Anaemia of malignant disease	1/470 (0.2%)	1
Antiphospholipid syndrome	1/470 (0.2%)	1
Erythropenia	1/470 (0.2%)	1
Haemolytic anaemia	1/470 (0.2%)	1
Hyperglobulinaemia	1/470 (0.2%)	1
Leukocytosis	1/470 (0.2%)	1
Lymphadenopathy	1/470 (0.2%)	1
Microcytic anaemia	1/470 (0.2%)	1
Neutropenia	1/470 (0.2%)	2
Neutrophilia	1/470 (0.2%)	1
Normochromic normocytic anaemia	1/470 (0.2%)	1
Splenic calcification	1/470 (0.2%)	1
Splenic cyst	1/470 (0.2%)	1
White blood cell disorder	1/470 (0.2%)	1
Cardiac disorders
Palpitations	74/470 (15.7%)	81
Right ventricular failure	39/470 (8.3%)	54
Cardiac failure	26/470 (5.5%)	34
Tachycardia	11/470 (2.3%)	16
Atrial fibrillation	10/470 (2.1%)	11
Atrial flutter	7/470 (1.5%)	7
Supraventricular tachycardia	5/470 (1.1%)	5
Cardiac arrest	4/470 (0.9%)	4
Cardiogenic shock	4/470 (0.9%)	4
Cor pulmonale	4/470 (0.9%)	4
Pericardial effusion	4/470 (0.9%)	4
Angina pectoris	3/470 (0.6%)	3
Cardiac failure congestive	3/470 (0.6%)	4
Extrasystoles	3/470 (0.6%)	3
Myocardial infarction	3/470 (0.6%)	3
Right ventricular dysfunction	3/470 (0.6%)	4
Supraventricular extrasystoles	3/470 (0.6%)	3
Aortic valve incompetence	2/470 (0.4%)	2
Arteriosclerosis coronary artery	2/470 (0.4%)	2
Atrioventricular block	2/470 (0.4%)	2
Atrioventricular block complete	2/470 (0.4%)	2
Atrioventricular block second degree	2/470 (0.4%)	2
Bradycardia	2/470 (0.4%)	2
Bundle branch block right	2/470 (0.4%)	2
Cardiac failure acute	2/470 (0.4%)	2
Cardiopulmonary failure	2/470 (0.4%)	2
Coronary artery disease	2/470 (0.4%)	2
Right ventricular hypertrophy	2/470 (0.4%)	2
Sinus tachycardia	2/470 (0.4%)	2
Acute myocardial infarction	1/470 (0.2%)	1
Acute right ventricular failure	1/470 (0.2%)	1
Arrhythmia	1/470 (0.2%)	1
Atrial tachycardia	1/470 (0.2%)	1
Atrioventricular block first degree	1/470 (0.2%)	1
Cardiac discomfort	1/470 (0.2%)	1
Cardiac failure chronic	1/470 (0.2%)	3
Cardio-respiratory arrest	1/470 (0.2%)	1
Cardiomegaly	1/470 (0.2%)	1
Cor pulmonale acute	1/470 (0.2%)	2
Pericarditis	1/470 (0.2%)	1
Pulseless electrical activity	1/470 (0.2%)	1
Sinus arrhythmia	1/470 (0.2%)	1
Sinus bradycardia	1/470 (0.2%)	1
Sinus node dysfunction	1/470 (0.2%)	1
Tricuspid valve incompetence	1/470 (0.2%)	1
Tricuspid valve stenosis	1/470 (0.2%)	1
Ventricular extrasystoles	1/470 (0.2%)	1
Ventricular tachycardia	1/470 (0.2%)	1
Congenital, familial and genetic disorders
Atrial septal defect	2/470 (0.4%)	2
Ear and labyrinth disorders
Tinnitus	9/470 (1.9%)	9
Vertigo	9/470 (1.9%)	9
Deafness	5/470 (1.1%)	5
Ear congestion	2/470 (0.4%)	2
Ear haemorrhage	1/470 (0.2%)	1
Ear pain	1/470 (0.2%)	1
Hypoacusis	1/470 (0.2%)	1
Meniere's disease	1/470 (0.2%)	1
Middle ear inflammation	1/470 (0.2%)	1
Vertigo positional	1/470 (0.2%)	1
Endocrine disorders
Hypothyroidism	18/470 (3.8%)	18
Hyperthyroidism	13/470 (2.8%)	15
Adrenocortical insufficiency acute	1/470 (0.2%)	1
Cushingoid	1/470 (0.2%)	1
Eye disorders
Eyelid oedema	7/470 (1.5%)	7
Conjunctival hyperaemia	4/470 (0.9%)	4
Vision blurred	4/470 (0.9%)	4
Visual impairment	4/470 (0.9%)	4
Cataract	3/470 (0.6%)	4
Amaurosis	2/470 (0.4%)	2
Dry eye	2/470 (0.4%)	2
Eye pruritus	2/470 (0.4%)	2
Blepharitis	1/470 (0.2%)	1
Conjunctival haemorrhage	1/470 (0.2%)	1
Conjunctivitis allergic	1/470 (0.2%)	1
Corneal bleeding	1/470 (0.2%)	1
Corneal erosion	1/470 (0.2%)	1
Diplopia	1/470 (0.2%)	1
Endocrine ophthalmopathy	1/470 (0.2%)	1
Exophthalmos	1/470 (0.2%)	1
Eye discharge	1/470 (0.2%)	1
Eye haemorrhage	1/470 (0.2%)	1
Eye pain	1/470 (0.2%)	1
Keratitis	1/470 (0.2%)	1
Lacrimation increased	1/470 (0.2%)	1
Macular degeneration	1/470 (0.2%)	1
Ocular hyperaemia	1/470 (0.2%)	1
Periorbital oedema	1/470 (0.2%)	1
Periorbital pain	1/470 (0.2%)	1
Photophobia	1/470 (0.2%)	1
Pterygium	1/470 (0.2%)	1
Retinal haemorrhage	1/470 (0.2%)	1
Scleritis	1/470 (0.2%)	1
Ulcerative keratitis	1/470 (0.2%)	1
Vitreous floaters	1/470 (0.2%)	1
Gastrointestinal disorders
Diarrhoea	311/470 (66.2%)	354
Nausea	188/470 (40%)	197
Vomiting	147/470 (31.3%)	161
Abdominal pain	40/470 (8.5%)	43
Abdominal pain upper	38/470 (8.1%)	40
Gastrooesophageal reflux disease	36/470 (7.7%)	37
Abdominal distension	35/470 (7.4%)	38
Abdominal discomfort	30/470 (6.4%)	30
Dyspepsia	28/470 (6%)	30
Colitis	25/470 (5.3%)	29
Constipation	22/470 (4.7%)	23
Gastritis	22/470 (4.7%)	23
Ascites	14/470 (3%)	14
Dry mouth	10/470 (2.1%)	10
Haemorrhoids	10/470 (2.1%)	10
Irritable bowel syndrome	9/470 (1.9%)	9
Toothache	9/470 (1.9%)	10
Frequent bowel movements	8/470 (1.7%)	8
Dysphagia	7/470 (1.5%)	7
Diverticulum	6/470 (1.3%)	6
Flatulence	5/470 (1.1%)	5
Haematemesis	5/470 (1.1%)	5
Melaena	5/470 (1.1%)	5
Abdominal pain lower	4/470 (0.9%)	4
Gingival bleeding	4/470 (0.9%)	4
Haematochezia	4/470 (0.9%)	4
Hiatus hernia	4/470 (0.9%)	4
Oesophagitis	4/470 (0.9%)	4
Chronic gastritis	3/470 (0.6%)	3
Epigastric discomfort	3/470 (0.6%)	3
Gastric polyps	3/470 (0.6%)	3
Gastrointestinal haemorrhage	3/470 (0.6%)	3
Large intestine polyp	3/470 (0.6%)	4
Mouth ulceration	3/470 (0.6%)	3
Portal hypertensive gastropathy	3/470 (0.6%)	3
Upper gastrointestinal haemorrhage	3/470 (0.6%)	5
Anal incontinence	2/470 (0.4%)	2
Dental caries	2/470 (0.4%)	2
Enteritis	2/470 (0.4%)	2
Faeces soft	2/470 (0.4%)	2
Food poisoning	2/470 (0.4%)	2
Functional gastrointestinal disorder	2/470 (0.4%)	2
Ileus	2/470 (0.4%)	2
Inguinal hernia	2/470 (0.4%)	2
Lower gastrointestinal haemorrhage	2/470 (0.4%)	2
Rectal haemorrhage	2/470 (0.4%)	2
Acute abdomen	1/470 (0.2%)	1
Appendicitis noninfective	1/470 (0.2%)	1
Defaecation urgency	1/470 (0.2%)	1
Eructation	1/470 (0.2%)	1
Gastric antral vascular ectasia	1/470 (0.2%)	1
Gastric disorder	1/470 (0.2%)	1
Gastric mucosal lesion	1/470 (0.2%)	1
Gastric varices haemorrhage	1/470 (0.2%)	1
Gastritis erosive	1/470 (0.2%)	1
Gastritis haemorrhagic	1/470 (0.2%)	1
Gastrointestinal disorder	1/470 (0.2%)	2
Gastrointestinal motility disorder	1/470 (0.2%)	1
Gastrointestinal polyp haemorrhage	1/470 (0.2%)	1
Gastrointestinal sounds abnormal	1/470 (0.2%)	1
Gastrointestinal vascular malformation haemorrhagic	1/470 (0.2%)	2
Gingival swelling	1/470 (0.2%)	1
Glossodynia	1/470 (0.2%)	1
Hypoaesthesia oral	1/470 (0.2%)	1
Intestinal obstruction	1/470 (0.2%)	1
Mechanical ileus	1/470 (0.2%)	1
Mouth haemorrhage	1/470 (0.2%)	1
Pancreatic cyst	1/470 (0.2%)	1
Peptic ulcer	1/470 (0.2%)	1
Periodontal disease	1/470 (0.2%)	1
Reflux gastritis	1/470 (0.2%)	1
Retching	1/470 (0.2%)	1
Salivary hypersecretion	1/470 (0.2%)	1
Umbilical hernia	1/470 (0.2%)	1
General disorders
Oedema peripheral	85/470 (18.1%)	98
Fatigue	64/470 (13.6%)	68
Chest pain	45/470 (9.6%)	54
Chest discomfort	44/470 (9.4%)	48
Asthenia	34/470 (7.2%)	38
Pyrexia	24/470 (5.1%)	24
Oedema	22/470 (4.7%)	23
Pain	17/470 (3.6%)	17
Malaise	9/470 (1.9%)	9
Chills	6/470 (1.3%)	7
Face oedema	6/470 (1.3%)	6
Disease progression	5/470 (1.1%)	5
Feeling hot	4/470 (0.9%)	4
Peripheral swelling	4/470 (0.9%)	4
Effusion	3/470 (0.6%)	3
Exercise tolerance decreased	3/470 (0.6%)	3
Feeling cold	3/470 (0.6%)	3
Multiple organ dysfunction syndrome	3/470 (0.6%)	3
Non-cardiac chest pain	3/470 (0.6%)	3
Calcinosis	2/470 (0.4%)	2
Generalised oedema	2/470 (0.4%)	2
Sudden death	2/470 (0.4%)	2
Swelling	2/470 (0.4%)	2
Swelling face	2/470 (0.4%)	2
Adverse drug reaction	1/470 (0.2%)	1
Axillary pain	1/470 (0.2%)	1
Early satiety	1/470 (0.2%)	1
Hypothermia	1/470 (0.2%)	1
Inflammation	1/470 (0.2%)	1
Influenza like illness	1/470 (0.2%)	1
Injection site pain	1/470 (0.2%)	1
Polyp	1/470 (0.2%)	1
Sudden cardiac death	1/470 (0.2%)	1
Ulcer	1/470 (0.2%)	1
Hepatobiliary disorders
Hepatic function abnormal	14/470 (3%)	15
Cholelithiasis	6/470 (1.3%)	6
Cholecystitis acute	5/470 (1.1%)	5
Hepatic cirrhosis	5/470 (1.1%)	5
Hepatic steatosis	4/470 (0.9%)	4
Cholecystitis chronic	3/470 (0.6%)	3
Congestive hepatopathy	3/470 (0.6%)	3
Hepatic failure	3/470 (0.6%)	3
Hyperbilirubinaemia	3/470 (0.6%)	3
Cholestasis	2/470 (0.4%)	2
Hepatic cyst	2/470 (0.4%)	2
Hepatic mass	2/470 (0.4%)	2
Acute hepatic failure	1/470 (0.2%)	1
Bile duct stone	1/470 (0.2%)	1
Biliary tract disorder	1/470 (0.2%)	2
Cholecystitis	1/470 (0.2%)	1
Hepatic calcification	1/470 (0.2%)	1
Hepatitis	1/470 (0.2%)	1
Hepatomegaly	1/470 (0.2%)	1
Liver injury	1/470 (0.2%)	1
Nonalcoholic fatty liver disease	1/470 (0.2%)	1
Portal hypertension	1/470 (0.2%)	1
Portal vein thrombosis	1/470 (0.2%)	1
Steatohepatitis	1/470 (0.2%)	1
Subcapsular hepatic haematoma	1/470 (0.2%)	1
Immune system disorders
Hypersensitivity	5/470 (1.1%)	6
Seasonal allergy	5/470 (1.1%)	5
Atopy	1/470 (0.2%)	1
Drug hypersensitivity	1/470 (0.2%)	2
Immune system disorder	1/470 (0.2%)	1
Infections and infestations
Upper respiratory tract infection	116/470 (24.7%)	160
Nasopharyngitis	61/470 (13%)	85
Pneumonia	50/470 (10.6%)	59
Bronchitis	31/470 (6.6%)	41
Urinary tract infection	30/470 (6.4%)	37
Gastroenteritis	20/470 (4.3%)	23
Pharyngitis	19/470 (4%)	27
Respiratory tract infection	17/470 (3.6%)	23
Influenza	16/470 (3.4%)	18
Sinusitis	14/470 (3%)	17
COVID-19	12/470 (2.6%)	12
Cellulitis	9/470 (1.9%)	9
Rhinitis	9/470 (1.9%)	9
Septic shock	9/470 (1.9%)	9
Lower respiratory tract infection	7/470 (1.5%)	7
Vaginal infection	7/470 (1.5%)	7
Herpes zoster	6/470 (1.3%)	6
Gastrointestinal infection	5/470 (1.1%)	5
Pharyngitis bacterial	5/470 (1.1%)	5
Sepsis	5/470 (1.1%)	5
Appendicitis	4/470 (0.9%)	6
Cystitis	4/470 (0.9%)	4
Gingivitis	4/470 (0.9%)	4
COVID-19 pneumonia	3/470 (0.6%)	3
Laryngitis	3/470 (0.6%)	3
Tonsillitis	3/470 (0.6%)	3
Clostridium difficile colitis	2/470 (0.4%)	2
Clostridium difficile infection	2/470 (0.4%)	2
Conjunctivitis	2/470 (0.4%)	2
Helicobacter infection	2/470 (0.4%)	2
Herpes simplex	2/470 (0.4%)	2
Localised infection	2/470 (0.4%)	2
Oral candidiasis	2/470 (0.4%)	2
Otitis media	2/470 (0.4%)	3
Pericoronitis	2/470 (0.4%)	2
Peritonitis	2/470 (0.4%)	2
Pharyngitis streptococcal	2/470 (0.4%)	2
Tooth abscess	2/470 (0.4%)	2
Urinary tract infection bacterial	2/470 (0.4%)	2
Viral upper respiratory tract infection	2/470 (0.4%)	2
Bacteraemia	1/470 (0.2%)	1
Bacterial translocation	1/470 (0.2%)	1
Bed bug infestation	1/470 (0.2%)	1
Body tinea	1/470 (0.2%)	1
Bronchiolitis	1/470 (0.2%)	1
Campylobacter infection	1/470 (0.2%)	1
Candida infection	1/470 (0.2%)	2
Cat scratch disease	1/470 (0.2%)	1
Cholecystitis infective	1/470 (0.2%)	1
Chronic sinusitis	1/470 (0.2%)	1
Conjunctivitis bacterial	1/470 (0.2%)	1
Diarrhoea infectious	1/470 (0.2%)	1
Diverticulitis	1/470 (0.2%)	7
Ear infection	1/470 (0.2%)	1
Enteritis infectious	1/470 (0.2%)	1
Erysipelas	1/470 (0.2%)	1
Eye infection	1/470 (0.2%)	1
Folliculitis	1/470 (0.2%)	1
Gangrene	1/470 (0.2%)	1
Gastroenteritis bacterial	1/470 (0.2%)	1
Gastroenteritis viral	1/470 (0.2%)	1
Hepatitis A	1/470 (0.2%)	1
Hepatitis B	1/470 (0.2%)	1
Hepatitis C	1/470 (0.2%)	1
Hordeolum	1/470 (0.2%)	1
Impetigo	1/470 (0.2%)	1
Infected cyst	1/470 (0.2%)	1
Infected skin ulcer	1/470 (0.2%)	1
Infective exacerbation of bronchiectasis	1/470 (0.2%)	1
Lymphadenitis bacterial	1/470 (0.2%)	1
Meningitis listeria	1/470 (0.2%)	1
Metapneumovirus infection	1/470 (0.2%)	1
Onychomycosis	1/470 (0.2%)	1
Ophthalmic herpes zoster	1/470 (0.2%)	1
Pelvic inflammatory disease	1/470 (0.2%)	1
Periodontitis	1/470 (0.2%)	1
Pharyngotonsillitis	1/470 (0.2%)	1
Pneumonia influenzal	1/470 (0.2%)	1
Postoperative wound infection	1/470 (0.2%)	1
Pulpitis dental	1/470 (0.2%)	1
Pyelonephritis	1/470 (0.2%)	1
Sialoadenitis	1/470 (0.2%)	1
Sinusitis bacterial	1/470 (0.2%)	1
Skin infection	1/470 (0.2%)	1
Staphylococcal infection	1/470 (0.2%)	2
Staphylococcal sepsis	1/470 (0.2%)	1
Tonsillitis bacterial	1/470 (0.2%)	1
Tooth infection	1/470 (0.2%)	1
Urethritis	1/470 (0.2%)	1
Urosepsis	1/470 (0.2%)	1
Viral pharyngitis	1/470 (0.2%)	1
Injury, poisoning and procedural complications
Ligament sprain	11/470 (2.3%)	11
Contusion	9/470 (1.9%)	10
Fall	5/470 (1.1%)	6
Hand fracture	4/470 (0.9%)	4
Skin laceration	4/470 (0.9%)	4
Tooth fracture	3/470 (0.6%)	3
Animal bite	2/470 (0.4%)	2
Foot fracture	2/470 (0.4%)	2
Joint injury	2/470 (0.4%)	2
Skin injury	2/470 (0.4%)	2
Soft tissue injury	2/470 (0.4%)	2
Spinal fracture	2/470 (0.4%)	2
Upper limb fracture	2/470 (0.4%)	2
Wound	2/470 (0.4%)	3
Accidental overdose	1/470 (0.2%)	1
Arteriovenous fistula site haemorrhage	1/470 (0.2%)	1
Bone contusion	1/470 (0.2%)	1
Buttock injury	1/470 (0.2%)	1
Concussion	1/470 (0.2%)	1
Face injury	1/470 (0.2%)	1
Injury	1/470 (0.2%)	1
Intentional overdose	1/470 (0.2%)	1
Joint dislocation	1/470 (0.2%)	1
Pelvic fracture	1/470 (0.2%)	1
Post procedural haemorrhage	1/470 (0.2%)	1
Radius fracture	1/470 (0.2%)	1
Road traffic accident	1/470 (0.2%)	1
Spinal column injury	1/470 (0.2%)	1
Splenic rupture	1/470 (0.2%)	1
Subdural haematoma	1/470 (0.2%)	1
Sunburn	1/470 (0.2%)	1
Thermal burn	1/470 (0.2%)	1
Vascular pseudoaneurysm	1/470 (0.2%)	1
Wound complication	1/470 (0.2%)	1
Wrist fracture	1/470 (0.2%)	1
Investigations
Weight decreased	25/470 (5.3%)	25
N-terminal prohormone brain natriuretic peptide increased	15/470 (3.2%)	15
Blood creatinine increased	10/470 (2.1%)	10
Platelet count decreased	10/470 (2.1%)	10
Weight increased	9/470 (1.9%)	9
Alanine aminotransferase increased	8/470 (1.7%)	8
Blood bilirubin increased	8/470 (1.7%)	8
Oxygen saturation decreased	8/470 (1.7%)	8
Aspartate aminotransferase increased	7/470 (1.5%)	7
Gamma-glutamyltransferase increased	7/470 (1.5%)	7
Haemoglobin decreased	7/470 (1.5%)	7
Blood potassium decreased	6/470 (1.3%)	7
Hepatic enzyme increased	6/470 (1.3%)	6
International normalised ratio increased	5/470 (1.1%)	5
Blood urea increased	4/470 (0.9%)	4
Brain natriuretic peptide increased	4/470 (0.9%)	4
Blood uric acid increased	3/470 (0.6%)	3
Electrocardiogram QT prolonged	3/470 (0.6%)	3
White blood cell count decreased	3/470 (0.6%)	3
Blood alkaline phosphatase increased	2/470 (0.4%)	2
Catheterisation cardiac	2/470 (0.4%)	2
Haemoglobin increased	2/470 (0.4%)	2
Heart rate increased	2/470 (0.4%)	4
Protein urine	2/470 (0.4%)	2
Protein urine present	2/470 (0.4%)	2
Vitamin D decreased	2/470 (0.4%)	2
Anticoagulation drug level above therapeutic	1/470 (0.2%)	1
Blood albumin increased	1/470 (0.2%)	1
Blood bicarbonate decreased	1/470 (0.2%)	1
Blood bilirubin unconjugated increased	1/470 (0.2%)	1
Blood immunoglobulin G increased	1/470 (0.2%)	1
Blood pressure decreased	1/470 (0.2%)	1
Blood pressure increased	1/470 (0.2%)	1
Blood thyroid stimulating hormone decreased	1/470 (0.2%)	1
Blood thyroid stimulating hormone increased	1/470 (0.2%)	1
Blood triglycerides increased	1/470 (0.2%)	1
Blood urine	1/470 (0.2%)	1
C-reactive protein increased	1/470 (0.2%)	1
Cardiac output increased	1/470 (0.2%)	1
Coagulation time prolonged	1/470 (0.2%)	1
Ejection fraction decreased	1/470 (0.2%)	1
Electrocardiogram P wave abnormal	1/470 (0.2%)	1
Electrocardiogram ST-T change	1/470 (0.2%)	1
Electrocardiogram abnormal	1/470 (0.2%)	1
Fibrin D dimer increased	1/470 (0.2%)	1
Haematocrit decreased	1/470 (0.2%)	1
Heart rate decreased	1/470 (0.2%)	1
Heart sounds abnormal	1/470 (0.2%)	1
Liver function test abnormal	1/470 (0.2%)	1
Lymphocyte morphology abnormal	1/470 (0.2%)	1
Myocardial necrosis marker increased	1/470 (0.2%)	1
Occult blood	1/470 (0.2%)	1
Platelet count increased	1/470 (0.2%)	1
QRS axis abnormal	1/470 (0.2%)	1
Red blood cells urine	1/470 (0.2%)	1
Serum ferritin decreased	1/470 (0.2%)	1
Thyroxine free decreased	1/470 (0.2%)	1
Transaminases increased	1/470 (0.2%)	2
Troponin T increased	1/470 (0.2%)	1
Urine output decreased	1/470 (0.2%)	1
Vitamin B12 decreased	1/470 (0.2%)	1
White blood cell count increased	1/470 (0.2%)	1
Metabolism and nutrition disorders
Hypokalaemia	50/470 (10.6%)	56
Decreased appetite	41/470 (8.7%)	43
Hyperuricaemia	17/470 (3.6%)	17
Gout	15/470 (3.2%)	15
Iron deficiency	12/470 (2.6%)	13
Fluid retention	11/470 (2.3%)	12
Hyponatraemia	7/470 (1.5%)	7
Dehydration	5/470 (1.1%)	6
Dyslipidaemia	5/470 (1.1%)	5
Electrolyte imbalance	5/470 (1.1%)	6
Fluid overload	4/470 (0.9%)	7
Hyperlipidaemia	4/470 (0.9%)	4
Diabetes mellitus	3/470 (0.6%)	3
Folate deficiency	3/470 (0.6%)	4
Hypocalcaemia	3/470 (0.6%)	3
Overweight	3/470 (0.6%)	3
Cachexia	2/470 (0.4%)	2
Hyperkalaemia	2/470 (0.4%)	2
Hypomagnesaemia	2/470 (0.4%)	3
Hypoproteinaemia	2/470 (0.4%)	2
Insulin resistance	2/470 (0.4%)	2
Malnutrition	2/470 (0.4%)	2
Metabolic acidosis	2/470 (0.4%)	2
Obesity	2/470 (0.4%)	2
Vitamin D deficiency	2/470 (0.4%)	2
Calciphylaxis	1/470 (0.2%)	1
Fructose intolerance	1/470 (0.2%)	1
Hypercalcaemia	1/470 (0.2%)	1
Hypercholesterolaemia	1/470 (0.2%)	1
Hyperglycaemia	1/470 (0.2%)	1
Hypernatraemia	1/470 (0.2%)	1
Hypertriglyceridaemia	1/470 (0.2%)	1
Hypervolaemia	1/470 (0.2%)	1
Hypoalbuminaemia	1/470 (0.2%)	1
Hypoglycaemia	1/470 (0.2%)	1
Hypovolaemia	1/470 (0.2%)	1
Lactose intolerance	1/470 (0.2%)	1
Metabolic alkalosis	1/470 (0.2%)	1
Steroid diabetes	1/470 (0.2%)	1
Type 2 diabetes mellitus	1/470 (0.2%)	1
Vitamin B complex deficiency	1/470 (0.2%)	1
Musculoskeletal and connective tissue disorders
Pain in jaw	103/470 (21.9%)	106
Myalgia	78/470 (16.6%)	82
Pain in extremity	78/470 (16.6%)	90
Arthralgia	57/470 (12.1%)	69
Back pain	41/470 (8.7%)	45
Muscle spasms	7/470 (1.5%)	7
Neck pain	7/470 (1.5%)	7
Arthritis	5/470 (1.1%)	6
Bone pain	5/470 (1.1%)	5
Muscular weakness	5/470 (1.1%)	5
Osteoarthritis	5/470 (1.1%)	5
Systemic lupus erythematosus	5/470 (1.1%)	6
Tendonitis	5/470 (1.1%)	5
Joint swelling	4/470 (0.9%)	4
Limb discomfort	4/470 (0.9%)	4
Musculoskeletal chest pain	4/470 (0.9%)	4
Osteoporosis	4/470 (0.9%)	4
Musculoskeletal pain	3/470 (0.6%)	3
Plantar fasciitis	3/470 (0.6%)	3
Rheumatoid arthritis	3/470 (0.6%)	3
Costochondritis	2/470 (0.4%)	2
Flank pain	2/470 (0.4%)	2
Intervertebral disc protrusion	2/470 (0.4%)	2
Mixed connective tissue disease	2/470 (0.4%)	2
Muscle contracture	2/470 (0.4%)	2
Muscle tightness	2/470 (0.4%)	2
Muscle twitching	2/470 (0.4%)	2
Musculoskeletal stiffness	2/470 (0.4%)	2
Osteonecrosis	2/470 (0.4%)	2
Sjogren's syndrome	2/470 (0.4%)	2
Spinal osteoarthritis	2/470 (0.4%)	2
Ankylosing spondylitis	1/470 (0.2%)	1
Clubbing	1/470 (0.2%)	1
Enthesopathy	1/470 (0.2%)	1
Exostosis	1/470 (0.2%)	1
Fracture malunion	1/470 (0.2%)	1
Groin pain	1/470 (0.2%)	1
Joint effusion	1/470 (0.2%)	1
Muscle atrophy	1/470 (0.2%)	1
Musculoskeletal discomfort	1/470 (0.2%)	1
Myopathy	1/470 (0.2%)	1
Osteopenia	1/470 (0.2%)	1
Periarthritis	1/470 (0.2%)	1
Psoriatic arthropathy	1/470 (0.2%)	1
Synovial cyst	1/470 (0.2%)	1
Trigger finger	1/470 (0.2%)	1
Undifferentiated connective tissue disease	1/470 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	3/470 (0.6%)	3
Bladder cancer	2/470 (0.4%)	2
Colon adenoma	2/470 (0.4%)	3
Haemangioma of liver	2/470 (0.4%)	2
Lipoma	2/470 (0.4%)	2
Skin papilloma	2/470 (0.4%)	2
Acrochordon	1/470 (0.2%)	1
Adenocarcinoma	1/470 (0.2%)	1
Basal cell carcinoma	1/470 (0.2%)	1
Benign neoplasm of thyroid gland	1/470 (0.2%)	1
Bladder transitional cell carcinoma recurrent	1/470 (0.2%)	1
Breast cancer	1/470 (0.2%)	1
Chronic myeloid leukaemia	1/470 (0.2%)	1
Diffuse large B-cell lymphoma	1/470 (0.2%)	1
Haemangioma	1/470 (0.2%)	1
Hepatic cancer recurrent	1/470 (0.2%)	2
Hepatic neoplasm	1/470 (0.2%)	1
Hepatocellular carcinoma	1/470 (0.2%)	4
Lung carcinoma cell type unspecified recurrent	1/470 (0.2%)	1
Lung neoplasm	1/470 (0.2%)	1
Lung neoplasm malignant	1/470 (0.2%)	1
Malignant pleural effusion	1/470 (0.2%)	1
Melanocytic naevus	1/470 (0.2%)	1
Myelofibrosis	1/470 (0.2%)	1
Neurofibroma	1/470 (0.2%)	1
Ovarian adenoma	1/470 (0.2%)	1
POEMS syndrome	1/470 (0.2%)	1
Plasma cell myeloma	1/470 (0.2%)	1
Renal cell carcinoma	1/470 (0.2%)	1
Teratoma	1/470 (0.2%)	1
Nervous system disorders
Headache	328/470 (69.8%)	348
Dizziness	120/470 (25.5%)	131
Syncope	18/470 (3.8%)	19
Hypoaesthesia	14/470 (3%)	15
Paraesthesia	11/470 (2.3%)	12
Presyncope	11/470 (2.3%)	11
Somnolence	6/470 (1.3%)	6
Head discomfort	5/470 (1.1%)	5
Memory impairment	4/470 (0.9%)	4
Restless legs syndrome	4/470 (0.9%)	4
Amnesia	3/470 (0.6%)	3
Migraine	3/470 (0.6%)	4
Cerebrovascular accident	2/470 (0.4%)	2
Neuralgia	2/470 (0.4%)	2
Neuropathy peripheral	2/470 (0.4%)	2
Sciatica	2/470 (0.4%)	2
Tremor	2/470 (0.4%)	2
Aphasia	1/470 (0.2%)	1
Brain injury	1/470 (0.2%)	1
Coma	1/470 (0.2%)	1
Disturbance in attention	1/470 (0.2%)	1
Dizziness exertional	1/470 (0.2%)	1
Dizziness postural	1/470 (0.2%)	2
Facial paralysis	1/470 (0.2%)	1
Hand-arm vibration syndrome	1/470 (0.2%)	1
Hepatic encephalopathy	1/470 (0.2%)	1
Hyperaesthesia	1/470 (0.2%)	1
Intention tremor	1/470 (0.2%)	1
Ischaemic stroke	1/470 (0.2%)	1
Loss of consciousness	1/470 (0.2%)	1
Mental impairment	1/470 (0.2%)	1
Metabolic encephalopathy	1/470 (0.2%)	1
Muscle contractions involuntary	1/470 (0.2%)	1
Nerve compression	1/470 (0.2%)	1
Post herpetic neuralgia	1/470 (0.2%)	1
Sedation	1/470 (0.2%)	1
Seizure	1/470 (0.2%)	1
Spinal cord compression	1/470 (0.2%)	1
Vocal cord paralysis	1/470 (0.2%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/470 (0.2%)	1
Psychiatric disorders
Insomnia	40/470 (8.5%)	41
Depression	22/470 (4.7%)	22
Anxiety	10/470 (2.1%)	10
Poor quality sleep	8/470 (1.7%)	8
Sleep disorder	4/470 (0.9%)	4
Agitation	3/470 (0.6%)	3
Confusional state	2/470 (0.4%)	2
Restlessness	2/470 (0.4%)	2
Alcoholism	1/470 (0.2%)	1
Anxiety disorder	1/470 (0.2%)	1
Bipolar II disorder	1/470 (0.2%)	1
Borderline personality disorder	1/470 (0.2%)	1
Delirium	1/470 (0.2%)	1
Emotional distress	1/470 (0.2%)	1
Major depression	1/470 (0.2%)	1
Mental status changes	1/470 (0.2%)	1
Neurosis	1/470 (0.2%)	1
Panic attack	1/470 (0.2%)	1
Stress	1/470 (0.2%)	1
Renal and urinary disorders
Acute kidney injury	14/470 (3%)	16
Proteinuria	12/470 (2.6%)	12
Renal failure	10/470 (2.1%)	10
Haematuria	6/470 (1.3%)	7
Chronic kidney disease	5/470 (1.1%)	5
Nephrolithiasis	5/470 (1.1%)	5
Dysuria	3/470 (0.6%)	4
Renal impairment	3/470 (0.6%)	3
Diabetic nephropathy	2/470 (0.4%)	2
Lupus nephritis	2/470 (0.4%)	3
Oliguria	2/470 (0.4%)	2
Pollakiuria	2/470 (0.4%)	2
Bladder spasm	1/470 (0.2%)	1
Focal segmental glomerulosclerosis	1/470 (0.2%)	1
Glomerulonephritis acute	1/470 (0.2%)	2
Hydronephrosis	1/470 (0.2%)	1
Micturition urgency	1/470 (0.2%)	1
Nephropathy	1/470 (0.2%)	1
Nephrotic syndrome	1/470 (0.2%)	1
Renal cyst	1/470 (0.2%)	1
Renal pain	1/470 (0.2%)	1
Renal vasculitis	1/470 (0.2%)	1
Scleroderma renal crisis	1/470 (0.2%)	1
Tubulointerstitial nephritis	1/470 (0.2%)	1
Urinary bladder polyp	1/470 (0.2%)	1
Urinary incontinence	1/470 (0.2%)	1
Urinary tract pain	1/470 (0.2%)	1
Urine abnormality	1/470 (0.2%)	1
Urine flow decreased	1/470 (0.2%)	1
Reproductive system and breast disorders
Menstrual disorder	8/470 (1.7%)	8
Menstruation irregular	6/470 (1.3%)	6
Breast mass	4/470 (0.9%)	5
Ovarian cyst	3/470 (0.6%)	3
Pelvic fluid collection	3/470 (0.6%)	3
Benign prostatic hyperplasia	2/470 (0.4%)	2
Breast pain	2/470 (0.4%)	2
Fibrocystic breast disease	2/470 (0.4%)	2
Heavy menstrual bleeding	2/470 (0.4%)	2
Adnexa uteri mass	1/470 (0.2%)	1
Amenorrhoea	1/470 (0.2%)	1
Breast calcifications	1/470 (0.2%)	1
Breast cyst	1/470 (0.2%)	1
Breast hyperplasia	1/470 (0.2%)	1
Breast swelling	1/470 (0.2%)	1
Dysmenorrhoea	1/470 (0.2%)	1
Gynaecomastia	1/470 (0.2%)	1
Haemorrhagic ovarian cyst	1/470 (0.2%)	1
Hypomenorrhoea	1/470 (0.2%)	1
Intermenstrual bleeding	1/470 (0.2%)	2
Nipple pain	1/470 (0.2%)	1
Pelvic pain	1/470 (0.2%)	1
Polycystic ovaries	1/470 (0.2%)	1
Prostatic calcification	1/470 (0.2%)	1
Prostatomegaly	1/470 (0.2%)	1
Vaginal haemorrhage	1/470 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	113/470 (24%)	131
Pulmonary hypertension	103/470 (21.9%)	147
Cough	72/470 (15.3%)	76
Epistaxis	24/470 (5.1%)	26
Nasal congestion	19/470 (4%)	19
Hypoxia	17/470 (3.6%)	17
Oropharyngeal pain	17/470 (3.6%)	20
Haemoptysis	16/470 (3.4%)	17
Productive cough	15/470 (3.2%)	16
Dyspnoea exertional	10/470 (2.1%)	10
Respiratory failure	9/470 (1.9%)	10
Rhinitis allergic	9/470 (1.9%)	9
Rhinorrhoea	8/470 (1.7%)	8
Asthma	6/470 (1.3%)	10
Dysphonia	5/470 (1.1%)	5
Nasal obstruction	5/470 (1.1%)	5
Sleep apnoea syndrome	4/470 (0.9%)	4
Acute respiratory failure	3/470 (0.6%)	3
Dyspnoea paroxysmal nocturnal	3/470 (0.6%)	3
Interstitial lung disease	3/470 (0.6%)	3
Orthopnoea	3/470 (0.6%)	3
Pulmonary arterial hypertension	3/470 (0.6%)	4
Pulmonary mass	3/470 (0.6%)	3
Pulmonary oedema	3/470 (0.6%)	3
Wheezing	3/470 (0.6%)	3
Bronchial hyperreactivity	2/470 (0.4%)	2
Chronic obstructive pulmonary disease	2/470 (0.4%)	2
Emphysema	2/470 (0.4%)	2
Pleural effusion	2/470 (0.4%)	2
Acute pulmonary oedema	1/470 (0.2%)	1
Acute respiratory distress syndrome	1/470 (0.2%)	1
Bronchial obstruction	1/470 (0.2%)	1
Bronchospasm	1/470 (0.2%)	1
Choking	1/470 (0.2%)	1
Dyspnoea at rest	1/470 (0.2%)	1
Hiccups	1/470 (0.2%)	1
Increased upper airway secretion	1/470 (0.2%)	1
Lung disorder	1/470 (0.2%)	1
Lung infiltration	1/470 (0.2%)	1
Nasal polyps	1/470 (0.2%)	1
Nasal septum deviation	1/470 (0.2%)	1
Nasal turbinate hypertrophy	1/470 (0.2%)	1
Oropharyngeal discomfort	1/470 (0.2%)	1
Paranasal sinus discomfort	1/470 (0.2%)	1
Pharyngeal cyst	1/470 (0.2%)	1
Pneumonia aspiration	1/470 (0.2%)	1
Pulmonary congestion	1/470 (0.2%)	1
Pulmonary embolism	1/470 (0.2%)	1
Pulmonary fibrosis	1/470 (0.2%)	1
Respiratory symptom	1/470 (0.2%)	1
Sinus congestion	1/470 (0.2%)	1
Ventilation perfusion mismatch	1/470 (0.2%)	1
Vocal cord dysfunction	1/470 (0.2%)	1
Skin and subcutaneous tissue disorders
Rash	20/470 (4.3%)	20
Pruritus	13/470 (2.8%)	13
Erythema	12/470 (2.6%)	13
Alopecia	11/470 (2.3%)	11
Urticaria	5/470 (1.1%)	5
Ecchymosis	4/470 (0.9%)	4
Eczema	4/470 (0.9%)	5
Skin lesion	4/470 (0.9%)	4
Acne	3/470 (0.6%)	3
Dermatitis	3/470 (0.6%)	3
Dry skin	3/470 (0.6%)	3
Hyperhidrosis	3/470 (0.6%)	3
Skin ulcer	3/470 (0.6%)	3
Actinic keratosis	2/470 (0.4%)	2
Dermatitis contact	2/470 (0.4%)	2
Night sweats	2/470 (0.4%)	2
Rash pruritic	2/470 (0.4%)	3
Alopecia areata	1/470 (0.2%)	1
Angioedema	1/470 (0.2%)	1
Blister	1/470 (0.2%)	1
Chloasma	1/470 (0.2%)	1
Cold sweat	1/470 (0.2%)	1
Decubitus ulcer	1/470 (0.2%)	1
Dermal cyst	1/470 (0.2%)	1
Dermatitis atopic	1/470 (0.2%)	1
Dermatomyositis	1/470 (0.2%)	1
Dermatosis	1/470 (0.2%)	1
Drug eruption	1/470 (0.2%)	1
Hyperkeratosis	1/470 (0.2%)	1
Intertrigo	1/470 (0.2%)	1
Lichen planus	1/470 (0.2%)	1
Nail discolouration	1/470 (0.2%)	1
Pigmentation disorder	1/470 (0.2%)	1
Pityriasis rosea	1/470 (0.2%)	1
Psoriasis	1/470 (0.2%)	1
Purpura	1/470 (0.2%)	1
Rosacea	1/470 (0.2%)	1
Seborrhoeic dermatitis	1/470 (0.2%)	1
Skin discolouration	1/470 (0.2%)	1
Skin fissures	1/470 (0.2%)	1
Skin mass	1/470 (0.2%)	1
Stasis dermatitis	1/470 (0.2%)	1
Social circumstances
Cardiac assistance device user	1/470 (0.2%)	1
Surgical and medical procedures
Tooth extraction	4/470 (0.9%)	4
Abortion induced	2/470 (0.4%)	2
Abdominal hernia repair	1/470 (0.2%)	1
Dacryocystorhinostomy	1/470 (0.2%)	1
Endodontic procedure	1/470 (0.2%)	1
Hernia repair	1/470 (0.2%)	1
Knee arthroplasty	1/470 (0.2%)	1
Oxygen therapy	1/470 (0.2%)	1
Vascular disorders
Flushing	201/470 (42.8%)	204
Hypotension	36/470 (7.7%)	42
Hypertension	12/470 (2.6%)	12
Hyperaemia	8/470 (1.7%)	8
Haematoma	7/470 (1.5%)	8
Hot flush	6/470 (1.3%)	7
Peripheral venous disease	5/470 (1.1%)	5
Cyanosis	4/470 (0.9%)	4
Shock	3/470 (0.6%)	3
Raynaud's phenomenon	2/470 (0.4%)	2
Varicose vein	2/470 (0.4%)	2
Angiodysplasia	1/470 (0.2%)	1
Aortic stenosis	1/470 (0.2%)	1
Claudication of jaw muscles	1/470 (0.2%)	1
Orthostatic hypotension	1/470 (0.2%)	1
Pallor	1/470 (0.2%)	1
Peripheral arterial occlusive disease	1/470 (0.2%)	1
Peripheral coldness	1/470 (0.2%)	1
Phlebitis	1/470 (0.2%)	1
Thrombophlebitis superficial	1/470 (0.2%)	1
Vena cava thrombosis	1/470 (0.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.