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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01560624
Recruitment Status : Completed
First Posted : March 22, 2012
Results First Posted : February 13, 2020
Last Update Posted : February 13, 2020
Sponsor:
Information provided by (Responsible Party):
United Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Pulmonary Arterial Hypertension
Interventions Drug: Treprostinil Diolamine
Drug: Placebo
Enrollment 690
Recruitment Details  
Pre-assignment Details  
Arm/Group Title UT-15C Placebo
Hide Arm/Group Description

Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg three times daily (TID)

Treprostinil Diolamine: Active

Matching placebo tablets (oral)

Placebo: Placebo

Period Title: Overall Study
Started 346 344
Clinical Worsening Event [1] 91 133
Early Discontinuation From Treatment [2] 107 56
Completed [3] 148 155
Not Completed 198 189
[1]
Including death
[2]
Due to progressive disease, AE, withdrawal by subject, protocol violation, lost to follow-up
[3]
Completed the study without clinical worsening or early discontinuation
Arm/Group Title UT-15C Placebo Total
Hide Arm/Group Description

Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID

Treprostinil Diolamine: Active

Matching placebo tablets (oral)

Placebo: Placebo

Total of all reporting groups
Overall Number of Baseline Participants 346 344 690
Hide Baseline Analysis Population Description
The Intent-to-Treat (ITT) Population was defined as all subjects randomized into the study who received at least 1 dose of study drug. The Safety Population was defined as all subjects in the study that received study drug. ITT subjects with major protocol deviations were excluded from the Per-Protocol population.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 346 participants 344 participants 690 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
292
  84.4%
294
  85.5%
586
  84.9%
>=65 years
54
  15.6%
50
  14.5%
104
  15.1%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 346 participants 344 participants 690 participants
45.6  (15.7) 44.8  (15.4) 45.2  (15.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 346 participants 344 participants 690 participants
Female
275
  79.5%
269
  78.2%
544
  78.8%
Male
71
  20.5%
75
  21.8%
146
  21.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 346 participants 344 participants 690 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
150
  43.4%
156
  45.3%
306
  44.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
8
   2.3%
13
   3.8%
21
   3.0%
White
187
  54.0%
173
  50.3%
360
  52.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   0.3%
2
   0.6%
3
   0.4%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 346 participants 344 participants 690 participants
North America
39
  11.3%
54
  15.7%
93
  13.5%
Southeast Asia
162
  46.8%
160
  46.5%
322
  46.7%
Europe
55
  15.9%
44
  12.8%
99
  14.3%
South America
90
  26.0%
86
  25.0%
176
  25.5%
Time since Diagnosis  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 346 participants 344 participants 690 participants
1.34  (2.50) 1.37  (2.58) 1.35  (2.54)
6MWD at Baseline  
Mean (Standard Deviation)
Unit of measure:  Meters
Number Analyzed 346 participants 344 participants 690 participants
392.9  (92.5) 398.5  (100.0) 395.7  (96.3)
Etiology of PAH  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 346 participants 344 participants 690 participants
Idiopathic or Heritable PAH
219
  63.3%
216
  62.8%
435
  63.0%
Collagen Vascular Disease
94
  27.2%
84
  24.4%
178
  25.8%
HIV Infection
2
   0.6%
7
   2.0%
9
   1.3%
Congenital Heart Defect
20
   5.8%
27
   7.8%
47
   6.8%
Other
11
   3.2%
10
   2.9%
21
   3.0%
WHO Functional Class at Baseline   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 346 participants 344 participants 690 participants
I
9
   2.6%
13
   3.8%
22
   3.2%
II
205
  59.2%
228
  66.3%
433
  62.8%
III
131
  37.9%
103
  29.9%
234
  33.9%
IV
1
   0.3%
0
   0.0%
1
   0.1%
[1]
Measure Description: WHO FC I describes patients who do not experience symptoms with exercise or at rest. WHO FC II describes patients who experience symptoms with ordinary activities but not at rest. WHO FC III describes patients who are limited in normal activities but do not experience symptoms at rest. WHO FC IV describes patients who are symptomatic at rest and experience severe symptoms with any activity.
1.Primary Outcome
Title Time to First Clinical Worsening Event
Hide Description Clinical worsening was assessed continuously from randomization until the subject's last study visit. Clinical worsening events were defined as death (all causes), hospitalizations due to worsening pulmonary arterial hypertension (PAH), initiation of an inhaled or infused prostacyclin (PGI2) for the treatment of worsening PAH, disease progression, or unsatisfactory long-term clinical response. All clinical worsening events reported by the study sites were reviewed by the Sponsor Medical Monitors. Once a clinical worsening event occurred, it was entered in the eCRF and a narrative was submitted for review by the Sponsor's Medical Monitor within 48 hours after the event became known to the Investigator or designee. Subsequently, the narratives for subjects with the reported clinical worsening events were sent to an independent adjudication committee. The independent adjudication committee reviewed and adjudicated all clinical worsening events throughout the study.
Time Frame From randomization to approximately 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title UT-15C Placebo
Hide Arm/Group Description:

Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID

Treprostinil Diolamine: Active

Matching placebo tablets (oral)

Placebo: Placebo

Overall Number of Participants Analyzed 346 344
Mean (Standard Deviation)
Unit of Measure: weeks
60.58  (42.93) 49.31  (46.28)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UT-15C, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0275
Comments [Not Specified]
Method Cox proportion-hazard model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.56 to 0.97
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection UT-15C, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0391
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
2.Secondary Outcome
Title Change in 6-Minute Walk Distance
Hide Description The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living. A baseline 6MWT was performed prior to initiation of study drug on the day of randomization. 6MWTs were conducted at Weeks 4, 8, 12, 24, and every 12 weeks thereafter. The change between Baseline and Week 24 is reported.
Time Frame From Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title UT-15C Placebo
Hide Arm/Group Description:

Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID

Treprostinil Diolamine: Active

Matching placebo tablets (oral)

Placebo: Placebo

Overall Number of Participants Analyzed 346 344
Mean (Standard Deviation)
Unit of Measure: meters
Baseline 392.9  (92.5) 398.5  (100.00)
Week 24 395.4  (120.0) 372.3  (163.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UT-15C, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0913
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges Lehmann estimate location shift
Estimated Value 7.0
Confidence Interval (2-Sided) 95%
0 to 16.0
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24
Hide Description Plasma NT-proBNP concentration is a useful biomarker for the severity of PAH as it is associated with changes in right heart morphology and function. NT-proBNP sample collection occurred at Baseline (prior to starting study drug), Week 12, Week 24, the first Continued Visit, and every other Continued Visit thereafter (ie, Continued Visits 3, 5, 7, etc). NT-proBNP was also assessed at the Study Drug Termination Visit. The change between Baseline and Week 24 is reported.
Time Frame From Baseline to Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who did not have a valid NT-proBNP measurement at Baseline or Week 24 were excluded from the analysis.
Arm/Group Title UT-15C Placebo
Hide Arm/Group Description:

Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID

Treprostinil Diolamine: Active

Matching placebo tablets (oral)

Placebo: Placebo

Overall Number of Participants Analyzed 346 344
Least Squares Mean (Standard Error)
Unit of Measure: Ratio to baseline
0.7859  (1.05470) 1.1230  (1.05439)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UT-15C, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
4.Secondary Outcome
Title Change in World Health Organization Functional Class (WHO FC) From Baseline to Week 48
Hide Description The WHO FC for PAH was assessed at Baseline prior to starting study drug, at all subsequent scheduled study visits, and every time the 6MWT was performed for purposes of assessing clinical worsening status.
Time Frame Baseline to Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title UT-15C Placebo
Hide Arm/Group Description:

Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID

Treprostinil Diolamine: Active

Matching placebo tablets (oral)

Placebo: Placebo

Overall Number of Participants Analyzed 315 311
Measure Type: Count of Participants
Unit of Measure: Participants
Improved
46
  14.6%
38
  12.2%
No change
203
  64.4%
170
  54.7%
Deteriorated
66
  21.0%
103
  33.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection UT-15C, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0028
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Time Frame The study lasted 6 years; however, subjects remained in the study for various durations. The longest subject duration in the study was 5.1 years.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title UT-15C Placebo
Hide Arm/Group Description

Treprostinil diolamine extended-release tablets (oral) 0.125 to 12 mg TID

Treprostinil Diolamine: Active

Matching placebo tablets (oral)

Placebo: Placebo

All-Cause Mortality
UT-15C Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   17/346 (4.91%)      18/344 (5.23%)    
Hide Serious Adverse Events
UT-15C Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   116/346 (33.53%)      110/344 (31.98%)    
Blood and lymphatic system disorders     
Anaemia   1/346 (0.29%)  1 2/344 (0.58%)  5
Duodenal ulcer haemorhage   1/346 (0.29%)  1 0/344 (0.00%)  0
Iron deficiency anaemia   1/346 (0.29%)  1 0/344 (0.00%)  0
Thrombocytopenia   1/346 (0.29%)  1 1/344 (0.29%)  1
Cardiac disorders     
Right ventricular failure   17/346 (4.91%)  18 12/344 (3.49%)  12
Cardiac failure   5/346 (1.45%)  5 3/344 (0.87%)  3
Atrial fibrillation   2/346 (0.58%)  2 1/344 (0.29%)  1
Atrial flutter   1/346 (0.29%)  1 0/344 (0.00%)  0
Cardiac arrest   1/346 (0.29%)  1 3/344 (0.87%)  3
Cardiac failure congestive   1/346 (0.29%)  1 2/344 (0.58%)  2
Cardiogenic shock   1/346 (0.29%)  1 4/344 (1.16%)  4
Cardiovascular insufficiency   1/346 (0.29%)  1 0/344 (0.00%)  0
Cor pulmonale   1/346 (0.29%)  1 0/344 (0.00%)  0
Coronary artery disease   1/346 (0.29%)  1 0/344 (0.00%)  0
Myocardial infarction   1/346 (0.29%)  1 0/344 (0.00%)  0
Sinus node dysfunction   1/346 (0.29%)  1 1/344 (0.29%)  1
Ascites   0/346 (0.00%)  0 1/344 (0.29%)  1
Bradycardia   0/346 (0.00%)  0 1/344 (0.29%)  1
Palpitations   0/346 (0.00%)  0 1/344 (0.29%)  1
Pericardial effusion   0/346 (0.00%)  0 1/344 (0.29%)  1
Supraventricular tachycardia   0/346 (0.00%)  0 1/344 (0.29%)  1
Ventricular tachycardia   0/346 (0.00%)  0 1/344 (0.29%)  1
Congenital, familial and genetic disorders     
Arteriovenous malformation   1/346 (0.29%)  1 0/344 (0.00%)  0
Endocrine disorders     
Hyperthyroidism   2/346 (0.58%)  2 0/344 (0.00%)  0
Inappropriate antidiuretic hormone secretion   0/346 (0.00%)  0 1/344 (0.29%)  1
Eye disorders     
Retinal vein occlusion   0/346 (0.00%)  0 1/344 (0.29%)  1
Gastrointestinal disorders     
Gastritis erosive   2/346 (0.58%)  2 0/344 (0.00%)  0
Gastrointestinal haemorrhage   2/346 (0.58%)  2 1/344 (0.29%)  1
Abdominal distension   1/346 (0.29%)  1 0/344 (0.00%)  0
Abdominal pain   1/346 (0.29%)  1 1/344 (0.29%)  1
Abdominal pain upper   1/346 (0.29%)  1 0/344 (0.00%)  0
Abdominal pain lower   1/346 (0.29%)  1 0/344 (0.00%)  0
Colitis   1/346 (0.29%)  1 0/344 (0.00%)  0
Constipation   1/346 (0.29%)  1 1/344 (0.29%)  1
Diarrhoea   1/346 (0.29%)  1 0/344 (0.00%)  0
Diverticulum   1/346 (0.29%)  1 0/344 (0.00%)  0
Erosive duodenitis   1/346 (0.29%)  1 0/344 (0.00%)  0
Gastritis   1/346 (0.29%)  1 0/344 (0.00%)  0
Gastrointestinal disorder   1/346 (0.29%)  1 0/344 (0.00%)  0
Haemorrhoids   1/346 (0.29%)  1 0/344 (0.00%)  0
Lower gastrointestinal haemorrhage   1/346 (0.29%)  1 0/344 (0.00%)  0
Palatal disorder   1/346 (0.29%)  1 0/344 (0.00%)  0
Upper gastrointestinal haemorrhage   1/346 (0.29%)  1 0/344 (0.00%)  0
Chronic gastritis   0/346 (0.00%)  0 1/344 (0.29%)  1
Gastrointestinal angiodysplasia   0/346 (0.00%)  0 1/344 (0.29%)  1
Incarcerated umbilical hernia   0/346 (0.00%)  0 1/344 (0.29%)  1
Inguinal hernia strangulated   0/346 (0.00%)  0 1/344 (0.29%)  1
Large intestine polyp   0/346 (0.00%)  0 1/344 (0.29%)  1
Nausea   0/346 (0.00%)  0 1/344 (0.29%)  1
Vomiting   0/346 (0.00%)  0 1/344 (0.29%)  1
General disorders     
Chest discomfort   2/346 (0.58%)  2 0/344 (0.00%)  0
Chest pain   2/346 (0.58%)  2 5/344 (1.45%)  5
Sudden death   2/346 (0.58%)  2 0/344 (0.00%)  0
Asthenia   1/346 (0.29%)  1 2/344 (0.58%)  2
Death   1/346 (0.29%)  1 0/344 (0.00%)  0
Malaise   1/346 (0.29%)  1 0/344 (0.00%)  0
Pain   1/346 (0.29%)  1 0/344 (0.00%)  0
Implant site irritation   0/346 (0.00%)  0 1/344 (0.29%)  1
Influenza like illness   0/346 (0.00%)  0 1/344 (0.29%)  1
Pyrexia   0/346 (0.00%)  0 2/344 (0.58%)  2
Hepatobiliary disorders     
Cholecystitis acute   1/346 (0.29%)  1 0/344 (0.00%)  0
Cholelithiasis   1/346 (0.29%)  1 0/344 (0.00%)  0
Hepatic cyst   1/346 (0.29%)  1 0/344 (0.00%)  0
Hepatic function abnormal   1/346 (0.29%)  1 0/344 (0.00%)  0
Autoimmune hepatitis   0/346 (0.00%)  0 1/344 (0.29%)  1
Hepatic mass   0/346 (0.00%)  0 1/344 (0.29%)  1
Infections and infestations     
Pneumonia   10/346 (2.89%)  11 10/344 (2.91%)  11
Gastroenteritis   5/346 (1.45%)  5 0/344 (0.00%)  0
Upper respiratory tract infection   5/346 (1.45%)  5 3/344 (0.87%)  3
Bronchitis   4/346 (1.16%)  4 3/344 (0.87%)  3
Lung infection   4/346 (1.16%)  4 1/344 (0.29%)  1
Septic shock   3/346 (0.87%)  3 1/344 (0.29%)  1
Appendicitis   2/346 (0.58%)  2 0/344 (0.00%)  0
Lower respiratory tract infection   2/346 (0.58%)  2 2/344 (0.58%)  2
Urinary tract infection   2/346 (0.58%)  2 2/344 (0.58%)  2
Gastrointestinal bacterial   1/346 (0.29%)  1 0/344 (0.00%)  0
Influenza   1/346 (0.29%)  1 2/344 (0.58%)  2
Peritonitis   1/346 (0.29%)  1 0/344 (0.00%)  0
Respiratory tract infection   1/346 (0.29%)  1 4/344 (1.16%)  4
Sepsis   1/346 (0.29%)  1 4/344 (1.16%)  4
Sinusitis   1/346 (0.29%)  1 0/344 (0.00%)  0
Tracheobronchitis   1/346 (0.29%)  1 0/344 (0.00%)  0
Appendiceal abscess   0/346 (0.00%)  0 1/344 (0.29%)  1
Atypical pneumonia   0/346 (0.00%)  0 1/344 (0.29%)  2
Cellulitis   0/346 (0.00%)  0 1/344 (0.29%)  1
Chronic sinusitis   0/346 (0.00%)  0 1/344 (0.29%)  1
Clostridium difficile infection   0/346 (0.00%)  0 1/344 (0.29%)  1
Dengue fever   0/346 (0.00%)  0 1/344 (0.29%)  1
Organising pneumonia   0/346 (0.00%)  0 1/344 (0.29%)  1
Pyelonephritis acute   0/346 (0.00%)  0 1/344 (0.29%)  1
Injury, poisoning and procedural complications     
Ankle fracture   1/346 (0.29%)  1 0/344 (0.00%)  0
Joint injury   1/346 (0.29%)  1 0/344 (0.00%)  0
Limb injury   1/346 (0.29%)  1 0/344 (0.00%)  0
Road traffic accident   1/346 (0.29%)  1 0/344 (0.00%)  0
Arteriovenous fistula site complication   0/346 (0.00%)  0 1/344 (0.29%)  1
Femoral neck fracture   0/346 (0.00%)  0 1/344 (0.29%)  1
Foot fracture   0/346 (0.00%)  0 1/344 (0.29%)  1
Muscle strain   0/346 (0.00%)  0 1/344 (0.29%)  1
Spinal compression fracture   0/346 (0.00%)  0 1/344 (0.29%)  1
Subarachnoid haemorrhage   0/346 (0.00%)  0 1/344 (0.29%)  1
Toxicity to various agents   0/346 (0.00%)  0 1/344 (0.29%)  1
Investigations     
Alanine aminotransferase increased   1/346 (0.29%)  1 0/344 (0.00%)  0
Aspartate aminotransferase increased   1/346 (0.29%)  1 0/344 (0.00%)  0
Blood creatinine increased   1/346 (0.29%)  1 0/344 (0.00%)  0
Catheterisation cardiac   1/346 (0.29%)  1 0/344 (0.00%)  0
Oxygen saturation decreased   1/346 (0.29%)  1 0/344 (0.00%)  0
Interleukin level increased   0/346 (0.00%)  0 1/344 (0.29%)  1
Metabolism and nutrition disorders     
Dehydration   1/346 (0.29%)  1 0/344 (0.00%)  0
Fluid overload   1/346 (0.29%)  1 0/344 (0.00%)  0
Hypokalaemia   1/346 (0.29%)  1 0/344 (0.00%)  0
Electrolyte imbalance   0/346 (0.00%)  0 1/344 (0.29%)  1
Hyperuricaemia   0/346 (0.00%)  0 1/344 (0.29%)  1
Hyponatraemia   0/346 (0.00%)  0 2/344 (0.58%)  2
Musculoskeletal and connective tissue disorders     
Systemic lupus erythematosus   2/346 (0.58%)  2 2/344 (0.58%)  2
Arthritis   1/346 (0.29%)  1 0/344 (0.00%)  0
Osteonecrosis   1/346 (0.29%)  1 0/344 (0.00%)  0
Bursitis   0/346 (0.00%)  0 1/344 (0.29%)  1
Exostosis   0/346 (0.00%)  0 1/344 (0.29%)  1
Myalgia   0/346 (0.00%)  0 1/344 (0.29%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenocarcinoma of colon   1/346 (0.29%)  1 0/344 (0.00%)  0
Colon cancer metastatic   1/346 (0.29%)  1 0/344 (0.00%)  0
Hepatocellular carcinoma   1/346 (0.29%)  1 1/344 (0.29%)  1
Hepatic cancer   0/346 (0.00%)  0 1/344 (0.29%)  1
Hepatic cancer recurrent   0/346 (0.00%)  0 1/344 (0.29%)  3
Meningioma   0/346 (0.00%)  0 1/344 (0.29%)  1
Plasmacytoma   0/346 (0.00%)  0 1/344 (0.29%)  1
Renal cell carcinoma   0/346 (0.00%)  0 1/344 (0.29%)  1
Nervous system disorders     
Headache   4/346 (1.16%)  4 2/344 (0.58%)  2
Syncope   2/346 (0.58%)  2 4/344 (1.16%)  4
Brain injury   1/346 (0.29%)  1 0/344 (0.00%)  0
Carotid artery stenosis   1/346 (0.29%)  1 0/344 (0.00%)  0
Cerebral infarction   1/346 (0.29%)  1 0/344 (0.00%)  0
Dizziness   0/346 (0.00%)  0 1/344 (0.29%)  1
Encephalopathy   0/346 (0.00%)  0 1/344 (0.29%)  1
Optic neuritis   0/346 (0.00%)  0 1/344 (0.29%)  1
Somnolence   0/346 (0.00%)  0 1/344 (0.29%)  1
Vocal cord paresis   0/346 (0.00%)  0 1/344 (0.29%)  1
Pregnancy, puerperium and perinatal conditions     
Foetal death   1/346 (0.29%)  1 0/344 (0.00%)  0
Pregnancy   0/346 (0.00%)  0 1/344 (0.29%)  1
Psychiatric disorders     
Emotional distress   1/346 (0.29%)  1 0/344 (0.00%)  0
Adjustment disorder with depressed mood   0/346 (0.00%)  0 1/344 (0.29%)  1
Altered state of consciousness   0/346 (0.00%)  0 1/344 (0.29%)  1
Renal and urinary disorders     
Acute kidney injury   2/346 (0.58%)  2 2/344 (0.58%)  2
Glomerulonephritis rapidly progressive   1/346 (0.29%)  1 0/344 (0.00%)  0
Nephrotic syndrome   1/346 (0.29%)  1 0/344 (0.00%)  0
Proteinuria   1/346 (0.29%)  1 0/344 (0.00%)  0
Renal failure   1/346 (0.29%)  1 0/344 (0.00%)  0
Chronic kidney disease   0/346 (0.00%)  0 1/344 (0.29%)  1
Hydronephrosis   0/346 (0.00%)  0 1/344 (0.29%)  1
Nephrolithiasis   0/346 (0.00%)  0 1/344 (0.29%)  1
Scleroderma renal crisis   0/346 (0.00%)  0 1/344 (0.29%)  1
Reproductive system and breast disorders     
Menorrhagia   1/346 (0.29%)  1 0/344 (0.00%)  0
Ovarian cyst   1/346 (0.29%)  1 0/344 (0.00%)  0
Ovarian rupture   1/346 (0.29%)  1 0/344 (0.00%)  0
Uterine cyst   1/346 (0.29%)  1 0/344 (0.00%)  0
Dysfunctional uterine bleeding   0/346 (0.00%)  0 1/344 (0.29%)  1
Vaginal haemorrhage   0/346 (0.00%)  0 2/344 (0.58%)  2
Respiratory, thoracic and mediastinal disorders     
Pulmonary hypertension   26/346 (7.51%)  27 36/344 (10.47%)  40
Dyspnoea   7/346 (2.02%)  8 8/344 (2.33%)  9
Hypoxia   3/346 (0.87%)  3 0/344 (0.00%)  0
Respiratory failure   3/346 (0.87%)  3 0/344 (0.00%)  0
Chronic obstructive pulmonary disease   2/346 (0.58%)  3 0/344 (0.00%)  0
Dyspnoea exertional   2/346 (0.58%)  2 1/344 (0.29%)  1
Acute lung injury   1/346 (0.29%)  1 0/344 (0.00%)  0
Acute respiratory failure   1/346 (0.29%)  1 0/344 (0.00%)  0
Cardio-respiratory arrest   1/346 (0.29%)  1 3/344 (0.87%)  3
Haemoptysis   1/346 (0.29%)  1 3/344 (0.87%)  4
Productive cough   1/346 (0.29%)  1 0/344 (0.00%)  0
Pulmonary arterial hypertension   1/346 (0.29%)  1 0/344 (0.00%)  0
Pulmonary oedema   1/346 (0.29%)  1 2/344 (0.58%)  2
Pulmonary embolism   1/346 (0.29%)  1 2/344 (0.58%)  2
Acute pulmonary oedema   0/346 (0.00%)  0 1/344 (0.29%)  1
Cough   0/346 (0.00%)  0 2/344 (0.58%)  2
Oedema   0/346 (0.00%)  0 2/344 (0.58%)  2
Oedema peripheral   0/346 (0.00%)  0 1/344 (0.29%)  1
Pleural effusion   0/346 (0.00%)  0 2/344 (0.58%)  2
Respiratory acidosis   0/346 (0.00%)  0 2/344 (0.58%)  2
Skin and subcutaneous tissue disorders     
Panniculitis   0/346 (0.00%)  0 1/344 (0.29%)  1
Surgical and medical procedures     
Uterine tumour excision   1/346 (0.29%)  1 0/344 (0.00%)  0
Renal transplant   0/346 (0.00%)  0 1/344 (0.29%)  1
Spinal decompression   0/346 (0.00%)  0 1/344 (0.29%)  1
Vascular disorders     
Circulatory collapse   2/346 (0.58%)  2 0/344 (0.00%)  0
Hypotension   2/346 (0.58%)  2 4/344 (1.16%)  5
Femoral vein perforation   1/346 (0.29%)  1 0/344 (0.00%)  0
Hypovolaemic shock   1/346 (0.29%)  1 0/344 (0.00%)  0
Shock haemorrhagic   1/346 (0.29%)  1 0/344 (0.00%)  0
Deep vein thrombosis   0/346 (0.00%)  0 1/344 (0.29%)  1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
UT-15C Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   342/346 (98.84%)      328/344 (95.35%)    
Blood and lymphatic system disorders     
Anaemia   17/346 (4.91%)  17 12/344 (3.49%)  17
Cardiac disorders     
Palpitations   47/346 (13.58%)  48 31/344 (9.01%)  35
Right ventricular failure   22/346 (6.36%)  23 19/344 (5.52%)  19
Gastrointestinal disorders     
Diarrhoea   240/346 (69.36%)  277 98/344 (28.49%)  106
Nausea   139/346 (40.17%)  146 78/344 (22.67%)  90
Vomiting   123/346 (35.55%)  135 35/344 (10.17%)  37
Abdominal pain upper   40/346 (11.56%)  41 17/344 (4.94%)  20
Abdominal discomfort   29/346 (8.38%)  30 12/344 (3.49%)  14
Abdominal pain   28/346 (8.09%)  30 13/344 (3.78%)  13
Gastrooesophageal reflux disease   24/346 (6.94%)  25 12/344 (3.49%)  12
Abdominal distension   27/346 (7.80%)  28 16/344 (4.65%)  16
Dyspepsia   18/346 (5.20%)  19 20/344 (5.81%)  20
Constipation   16/346 (4.62%)  18 9/344 (2.62%)  10
Gastritis   16/346 (4.62%)  16 7/344 (2.03%)  8
Chest discomfort   29/346 (8.38%)  32 30/344 (8.72%)  32
General disorders     
Oedema peripheral   46/346 (13.29%)  50 81/344 (23.55%)  89
Fatigue   37/346 (10.69%)  43 46/344 (13.37%)  48
Chest pain   26/346 (7.51%)  34 45/344 (13.08%)  48
Pyrexia   25/346 (7.23%)  26 26/344 (7.56%)  28
Aesthenia   23/346 (6.65%)  23 17/344 (4.94%)  18
Oedema   17/346 (4.91%)  17 12/344 (3.49%)  12
Infections and infestations     
Upper respiratory tract infection   73/346 (21.10%)  105 82/344 (23.84%)  109
Viral upper respiratory tract infection   56/346 (16.18%)  69 46/344 (13.37%)  63
Bronchitis   24/346 (6.94%)  27 19/344 (5.52%)  25
Pneumonia   16/346 (4.62%)  18 17/344 (4.94%)  18
Urinary tract infection   16/346 (4.62%)  20 17/344 (4.94%)  20
Influenza   13/346 (3.76%)  13 17/344 (4.94%)  18
Metabolism and nutrition disorders     
Decreased appetite   32/346 (9.25%)  33 16/344 (4.65%)  16
Musculoskeletal and connective tissue disorders     
Pain in jaw   62/346 (17.92%)  64 10/344 (2.91%)  11
Pain in extremity   61/346 (17.63%)  78 30/344 (8.72%)  32
Myalgia   49/346 (14.16%)  53 37/344 (10.76%)  42
Arthralgia   41/346 (11.85%)  51 31/344 (9.01%)  39
Back pain   31/346 (8.96%)  32 27/344 (7.85%)  27
Muscle spasms   10/346 (2.89%)  12 22/344 (6.40%)  23
Nervous system disorders     
Headache   259/346 (74.86%)  283 120/344 (34.88%)  134
Dizziness   81/346 (23.41%)  86 75/344 (21.80%)  83
Syncope   20/346 (5.78%)  23 20/344 (5.81%)  24
Psychiatric disorders     
Insomnia   22/346 (6.36%)  22 16/344 (4.65%)  17
Respiratory, thoracic and mediastinal disorders     
Dyspnoea   56/346 (16.18%)  61 77/344 (22.38%)  88
Cough   46/346 (13.29%)  48 63/344 (18.31%)  72
Pulmonary hypertension   38/346 (10.98%)  39 64/344 (18.60%)  70
Epistaxis   21/346 (6.07%)  25 31/344 (9.01%)  33
Nasal congestion   20/346 (5.78%)  21 17/344 (4.94%)  19
Oropharyngeal pain   11/346 (3.18%)  11 18/344 (5.23%)  19
Skin and subcutaneous tissue disorders     
Rash   19/346 (5.49%)  19 15/344 (4.36%)  17
Vascular disorders     
Flushing   154/346 (44.51%)  158 27/344 (7.85%)  28
Hypotension   24/346 (6.94%)  24 14/344 (4.07%)  17
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Institution and/or Principal Investigator agree not to publish or publicly present any interim results of the Study without the prior written consent of Sponsor, not to be unreasonably withheld or delayed. Institution and/or Principal Investigator further agree to provide Sponsor with drafts of any such publication or presentation for review and approval no less than 30 days prior to submission for publication or the date of public presentation.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Louis Holdstock
Organization: United Therapeutics
Phone: 919-425-8866
EMail: lholdstock@unither.com
Layout table for additonal information
Responsible Party: United Therapeutics
ClinicalTrials.gov Identifier: NCT01560624    
Other Study ID Numbers: TDE-PH-310
First Submitted: March 9, 2012
First Posted: March 22, 2012
Results First Submitted: November 20, 2019
Results First Posted: February 13, 2020
Last Update Posted: February 13, 2020