A Study to Assess the Safety and Efficacy of Treprostinil to Facilitate Liver Transplantation in Patients With Portopulmonary Hypertension

• Sponsor: United Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01028651
• Collaborator: University of California, Los Angeles (Other), Brigham and Women's Hospital (Other), University of Texas (Other), Emory University (Other)
• Enrollment: 13
• Locations: 4
• Duration (Months): 27
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a multicenter, prospective, observational, open-label study. Patients meeting inclusion/exclusion criteria received treatment with treprostinil as recommended by their treating physicians and were followed according to standard of care. This observational study collected clinical data and biologic specimens from patients who were treated for portopulmonary hypertension (PoPH), with a goal of achieving hemodynamic parameters appropriate for orthotopic liver transplantation candidacy, including mean pulmonary arterial pressure (mPAP) less than 35 mmHg and pulmonary vascular resistance (PVR) less than 3 Wood-units (WU) at Week 24 in patients with severe PoPH.

Condition or Disease	Intervention/Treatment	Phase
Portopulmonary Hypertension; Pulmonary Arterial Hypertension; Pulmonary Hypertension	Drug: Treprostinil

Detailed Description

Treprostinil is approved as a continuous subcutaneous (SC) or intravenous (IV) infusion by the FDA for the treatment of WHO group I PAH with New York Heart Association (NYHA) Functional Class II, III or IV symptomatology. To date, treprostinil has not been studied in the setting of PoPH; however, it is commonly prescribed in this setting. This was an observational, open-label, multicenter study which documented the safety and efficacy profile of this agent in PoPH to facilitate orthotopic liver transplantation (OLT).

Study Design

• Study Type: Observational
• Actual Enrollment: 13 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: An Open-Label Study to Assess the Safety and Efficacy of Treprostinil to Facilitate Liver Transplantation in Patients With Portopulmonary Hypertension
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Portopulmonary hypertension

Drug: Treprostinil; Remodulin is supplied in concentrations of 1, 2.5 , 5, and 10 mg/mL and can be administered as supplied or diluted for intravenous (IV) infusion prior to administration. Remodulin is indicated for subcutaneous (SC) or IV use only as a continuous infusion. Remodulin is preferably infused subcutaneously, but can be administered by a central IV line if the SC route is not tolerated. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, the infusion rate should be reduced to 0.625 ng/kg/min.; Other Names: Remodulin

Outcome Measures

Primary Outcome Measures

1. Number of Subjects Who Achieved Hemodynamic Parameters Appropriate for Orthotopic Liver Transplantation Candidacy at Week 24. [24 Weeks]

   The primary efficacy endpoint was the number of subjects who achieved a mean pulmonary arterial pressure (mPAP) less than 35 mmHg and a pulmonary vascular resistance (PVR) less than 3 Wood units (WU) at Week 24 in patients with severe portopulmonary hypertension (PoPH).

Secondary Outcome Measures

1. Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 [24 weeks]

   The change in hemodynamic parameters (including systolic pulmonary arterial pressure [PAPs], diastolic pulmonary arterial pressure [PAPd], mean pulmonary arterial pressure [mPAP], and transpulmonary gradient [TPG]) was evaluated at rest from Baseline to Week 24. The median change in hemodynamic parameters from Baseline to Week 24 via right-heart catheterization (RHC) is presented.

2. Change in Heart Rate at Rest From Baseline to Week 24 [24 weeks]

   The change in heart rate was evaluated at rest from Baseline to Week 24.

3. Change in Cardiac Output at Rest From Baseline to Week 24 [24 weeks]

   The change in cardiac output was evaluated at rest from Baseline to Week 24. The median change in cardiac output from Baseline to Week 24 is presented.

4. Change in Arterial and Venous Oxygen Saturation at Rest From Baseline to Week 24 [24 weeks]

   The change in arterial and venous oxygen saturation was evaluated at rest from Baseline to Week 24.

5. Change in Pulmonary Vascular Resistance (PVR) at Rest From Baseline to Week 24 [24 weeks]

   The change in pulmonary vascular resistance (PVR) was evaluated at rest from Baseline to Week 24.

6. Change in 6-minute Walk Distance (6MWD) From Baseline to Weeks 12 and 24. [Baseline and Weeks 12 and 24]

   The 6-Minute Walk Test was conducted at Screening, Baseline prior to starting study drug and at least 24 hours after the Screening test, and during the Treatment Phase at Weeks 12 and 24.

7. Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24 [Baseline and Weeks 12 and 24]

   Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.

8. Change in Echocardiogram Parameters (Right Ventricle Diameter) From Baseline to Weeks 12 and 24 [Baseline and Weeks 12 and 24]

   Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.

9. Change in Echocardiogram Parameters (Right Ventricular Systolic Pressure) From Baseline to Weeks 12 and 24 [Baseline and Weeks 12 and 24]

   Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.

10. Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion) From Baseline to Weeks 12 and 24 [Baseline and Weeks 12 and 24]

    Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.

11. Change in Quality of Life From Baseline to Weeks 12 and 24 [Baseline and Weeks 12 and 24]

    The 36-item Short Form Survey (SF-36) is a health related quality of life instrument, which measures dimensions of physical and social roles and functioning, mental health, vitality, and pain. Items are scored on a 0 to 100 range so that the lowest scores represent the highest disability. The quality of life assessment was conducted at Baseline and Weeks 12 and 24 and the change from Baseline to Weeks 12 and 24 is presented.

12. Change in Plasma Brain N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Weeks 12 and 24 [Baseline to Weeks 12 and 24]

    NT-proBNP was assessed at Baseline, Weeks 12 and 24.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must:

1. Had portal hypertension.

2. Be otherwise suitable candidates for OLT.

3. Had severe pulmonary arterial hypertension (PAH) defined as a resting mean pulmonary arterial pressure (mPAP) >35 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood Units (WU) by right heart catheterization (RHC) performed as part of standard of care evaluation within 90 days of enrollment.

4. Treprostinil therapy must be recommended by the treating physician per standard of care.

5. Be NYHA Functional Class II, III, or IV.

6. Had pulmonary capillary wedge (PCW) pressure ≤18 mmHg and transpulmonary gradient (TPG) ≥15 mmHg.

Exclusion Criteria:

• Patients must not:

1. Had received any any investigational therapy as part of a clinical trial for any indication within 30 days prior to enrollment.

2. Had a change in dose of treatment for PAH (bosentan [Tracleer], ambrisentan [Letairis], tadalafil [Adcirca], or sildenafil [Revatio]), within 30 days prior to enrollment. That is, subjects may have been treated with any of these agents provided the dose was stable for at least 30 days prior to enrollment.

3. Had renal failure requiring hemodialysis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Los Angeles	Los Angeles	California	United States	90024
2	Emory Univeristy	Atlanta	Georgia	United States	30322
3	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
4	University of Texas, Southwestern Medical Center	Dallas	Texas	United States	75235

Sponsors and Collaborators

• United Therapeutics
• University of California, Los Angeles
• Brigham and Women's Hospital
• University of Texas
• Emory University

Investigators

• Study Director: Rajan Saggar, MD, University of California, Los Angeles
• Study Director: Micah Fisher, MD, Emory University
• Study Director: Aaron Waxman, MD, PhD, Brigham and Women's Hospital
• Study Director: Sonja Bartolome, MD, UT Southwestern Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: United Therapeutics
• ClinicalTrials.gov Identifier: NCT01028651
• Other Study ID Numbers: RIV-PH-414
• First Posted: Dec 9, 2009
• Last Update Posted: Feb 24, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by United Therapeutics: PAH; Pulmonary Hypertension; Remodulin; Treprostinil; Quality of Life
• Additional relevant MeSH terms: Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Treprostinil

Study Results

Participant Flow

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Period Title: Overall Study
STARTED	13
COMPLETED	10
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Overall Participants	13
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.8 (8.00)
Gender (Count of Participants)
Female	8 61.5%
Male	5 38.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 38.5%
Not Hispanic or Latino	8 61.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	13 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects Who Achieved Hemodynamic Parameters Appropriate for Orthotopic Liver Transplantation Candidacy at Week 24.
Description	The primary efficacy endpoint was the number of subjects who achieved a mean pulmonary arterial pressure (mPAP) less than 35 mmHg and a pulmonary vascular resistance (PVR) less than 3 Wood units (WU) at Week 24 in patients with severe portopulmonary hypertension (PoPH).
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

The total number of subjects enrolled and analyzed.

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	13
Primary endpoint achieved	1 7.7%
Primary endpoint not achieved	12 92.3%

2. Secondary Outcome

Title	Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24
Description	The change in hemodynamic parameters (including systolic pulmonary arterial pressure [PAPs], diastolic pulmonary arterial pressure [PAPd], mean pulmonary arterial pressure [mPAP], and transpulmonary gradient [TPG]) was evaluated at rest from Baseline to Week 24. The median change in hemodynamic parameters from Baseline to Week 24 via right-heart catheterization (RHC) is presented.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Week 24

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	13
Mean pulmonary arterial pressure (mmHg)	-3.8
Systolic pulmonary arterial pressure (mmHg)	-2.0
Diastolic pulmonary arterial pressure (mmHg)	-4.0
Mean right arterial pressure (mmHg)	-2.0
Mean systemic arterial pressure (mmHg)	-0.7
Systolic systemic arterial pressure (mmHg)	7.0
Diastolic systemic arterial pressure	0
Mean pulmonary capillary wedge pressure (mmHg)	0
Transpulmonary gradient (mmHg)	-6.8

3. Secondary Outcome

Title	Change in Heart Rate at Rest From Baseline to Week 24
Description	The change in heart rate was evaluated at rest from Baseline to Week 24.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Week 24

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	13
Median (Full Range) [beats/min]	0.5

4. Secondary Outcome

Title	Change in Cardiac Output at Rest From Baseline to Week 24
Description	The change in cardiac output was evaluated at rest from Baseline to Week 24. The median change in cardiac output from Baseline to Week 24 is presented.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Week 24

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	13
Median (Full Range) [L/min]	0.3

5. Secondary Outcome

Title	Change in Arterial and Venous Oxygen Saturation at Rest From Baseline to Week 24
Description	The change in arterial and venous oxygen saturation was evaluated at rest from Baseline to Week 24.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Week 24

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	13
Mixed venous oxygen saturation (%)	-2.0
Arterial oxygen saturation (%)	0.5

6. Secondary Outcome

Title	Change in Pulmonary Vascular Resistance (PVR) at Rest From Baseline to Week 24
Description	The change in pulmonary vascular resistance (PVR) was evaluated at rest from Baseline to Week 24.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Week 24

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	13
Median (Full Range) [Wood Units]	-0.3

7. Secondary Outcome

Title	Change in 6-minute Walk Distance (6MWD) From Baseline to Weeks 12 and 24.
Description	The 6-Minute Walk Test was conducted at Screening, Baseline prior to starting study drug and at least 24 hours after the Screening test, and during the Treatment Phase at Weeks 12 and 24.
Time Frame	Baseline and Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Weeks 12 and 24

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	11
Change from Baseline to Week 12	54.5
Change from Baseline to Week 24	12.0

8. Secondary Outcome

Title	Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24
Description	Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.
Time Frame	Baseline and Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Weeks 12 and 24.

Arm/Group Title	Treprostinil Injection-Baseline to Week 12	Treprostinil Injection-Baseline to Week 24
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	8	7
Right atrium area (cm2)	-0.1	-1.7
Right ventricle area (cm2)	-1.0	-7.4

9. Secondary Outcome

Title	Change in Echocardiogram Parameters (Right Ventricle Diameter) From Baseline to Weeks 12 and 24
Description	Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.
Time Frame	Baseline and Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Weeks 12 and 24.

Arm/Group Title	Treprostinil Injection-Baseline to Week 12	Treprostinil Injection-Baseline to Week 24
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	8	7
Median (Full Range) [mm]	-5.0	3.0

10. Secondary Outcome

Title	Change in Echocardiogram Parameters (Right Ventricular Systolic Pressure) From Baseline to Weeks 12 and 24
Description	Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.
Time Frame	Baseline and Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Weeks 12 and 24.

Arm/Group Title	Treprostinil Injection-Baseline to Week 12	Treprostinil Injection-Baseline to Week 24
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	8	7
Median (Full Range) [mmHg]	-12	-5.0

11. Secondary Outcome

Title	Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion) From Baseline to Weeks 12 and 24
Description	Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.
Time Frame	Baseline and Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Weeks 12 and 24.

Arm/Group Title	Treprostinil Injection-Baseline to Week 12	Treprostinil Injection-Baseline to Week 24
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	8	7
Median (Full Range) [cm]	0.5	0.1

12. Secondary Outcome

Title	Change in Quality of Life From Baseline to Weeks 12 and 24
Description	The 36-item Short Form Survey (SF-36) is a health related quality of life instrument, which measures dimensions of physical and social roles and functioning, mental health, vitality, and pain. Items are scored on a 0 to 100 range so that the lowest scores represent the highest disability. The quality of life assessment was conducted at Baseline and Weeks 12 and 24 and the change from Baseline to Weeks 12 and 24 is presented.
Time Frame	Baseline and Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Weeks 12 and 24.

Arm/Group Title	Treprostinil Injection-Baseline to Week 12	Treprostinil Injection-Baseline to Week 24
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	11	9
Physical functioning	5.7	10.5
Role-Physical	7.9	9.0
Bodily pain	3.6	6.0
General health	4.5	3.6
Vitality	5.9	7.4
Social functioning	7.5	0
Role-Emotional	13.9	10.4
Mental health	2.6	0
Physical component summary	9.8	8.2
Mental component summary	7.0	2.6

13. Secondary Outcome

Title	Change in Plasma Brain N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Weeks 12 and 24
Description	NT-proBNP was assessed at Baseline, Weeks 12 and 24.
Time Frame	Baseline to Weeks 12 and 24

Outcome Measure Data

Analysis Population Description

All subjects with data available at Baseline and Weeks 12 and 24.

Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
Measure Participants	9
Change from Baseline to Week 12	-628
Change from Baseline to Week 24	-478

Adverse Events

Time Frame	Adverse events were recorded throughout the 24-week study as well as for 4 weeks after completion of the final visit.
Arm/Group Title	Treprostinil Injection
Arm/Group Description	Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH).
All Cause Mortality
	Treprostinil Injection
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treprostinil Injection
	Affected / at Risk (%)	# Events
Total	8/13 (61.5%)
Blood and lymphatic system disorders
Anaemia macrocytic	1/13 (7.7%)	1
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/13 (7.7%)	1
General disorders
Death	1/13 (7.7%)	1
Infusion site pain	1/13 (7.7%)	1
Multi-organ failure	1/13 (7.7%)	1
Pyrexia	1/13 (7.7%)	1
Hepatobiliary disorders
Chronic hepatic failure	2/13 (15.4%)	2
Hepatorenal syndrome	1/13 (7.7%)	1
Infections and infestations
Pneumonia	2/13 (15.4%)	2
Infusion site cellulitis	1/13 (7.7%)	1
Urinary tract infection	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Hip fracture	1/13 (7.7%)	1
Procedural pain	1/13 (7.7%)	1
Nervous system disorders
Hepatic encephalopathy	1/13 (7.7%)	3
Renal and urinary disorders
Renal failure acute	2/13 (15.4%)	2
Renal failure	1/13 (7.7%)	1
Vascular disorders
Hypotension	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Treprostinil Injection
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Anaemia	1/13 (7.7%)	1
Thrombocytopenia	1/13 (7.7%)	1
Cardiac disorders
Cardiac failure congestive	1/13 (7.7%)	1
Eye disorders
Conjunctival haemorrhage	1/13 (7.7%)	1
Gastrointestinal disorders
Nausea	10/13 (76.9%)	10
Vomiting	7/13 (53.8%)	9
Diarrhoea	4/13 (30.8%)	6
Ascites	2/13 (15.4%)	2
Constipation	2/13 (15.4%)	2
Abdominal distention	1/13 (7.7%)	1
Gastrooesophageal reflux disease	1/13 (7.7%)	1
Gingival bleeding	1/13 (7.7%)	1
Lower gastrointestinal haemorrhage	1/13 (7.7%)	1
Rectal haemorrhage	1/13 (7.7%)	1
Toothache	1/13 (7.7%)	1
General disorders
Infusion site pain	5/13 (38.5%)	7
Oedema peripheral	2/13 (15.4%)	4
Asthenia	1/13 (7.7%)	1
Device leakage	1/13 (7.7%)	1
Dyspepsia	1/13 (7.7%)	1
Infusion site erythema	1/13 (7.7%)	1
Infusion site vesicles	1/13 (7.7%)	1
Oedema	1/13 (7.7%)	1
Pain	1/13 (7.7%)	1
Hepatobiliary disorders
Hepatic lesion	1/13 (7.7%)	1
Infections and infestations
Urinary tract infection	3/13 (23.1%)	8
Infusion site infection	3/13 (23.1%)	4
Pneumonia	1/13 (7.7%)	1
Bronchitis	1/13 (7.7%)	1
Conjunctivitis	1/13 (7.7%)	1
Oral herpes	1/13 (7.7%)	1
Upper respiratory tract infection	1/13 (7.7%)	1
Vulvovaginal mycotic infection	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Procedural haemorrhage	1/13 (7.7%)	1
Subcutaneous haematoma	1/13 (7.7%)	1
Investigations
Blood creatinine increased	1/13 (7.7%)	1
Blood uric acide increased	1/13 (7.7%)	1
Oxygen saturation decreased	1/13 (7.7%)	1
Metabolism and nutrition disorders
Decreased appetite	4/13 (30.8%)	5
Hypomagnesaemia	2/13 (15.4%)	2
Diabetes mellitus	1/13 (7.7%)	1
Electrolyte imbalance	1/13 (7.7%)	1
Hyperglycaemia	1/13 (7.7%)	1
Hyperkalaemia	1/13 (7.7%)	1
Hyperuricaemia	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	7/13 (53.8%)	7
Pain in jaw	6/13 (46.2%)	6
Arthralgia	2/13 (15.4%)	3
Bursitis	1/13 (7.7%)	1
Myalgia	1/13 (7.7%)	1
Neck pain	1/13 (7.7%)	1
Nervous system disorders
Headache	8/13 (61.5%)	10
Dizziness	2/13 (15.4%)	2
Lethargy	1/13 (7.7%)	1
Migraine	1/13 (7.7%)	1
Peripheral sensory neuropathy	1/13 (7.7%)	1
Psychiatric disorders
Insomnia	1/13 (7.7%)	1
Mental status changes	1/13 (7.7%)	1
Renal and urinary disorders
Renal failure acute	1/13 (7.7%)	1
Renal tubular necrosis	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/13 (15.4%)	2
Pleural effusion	2/13 (15.4%)	2
Asthma	1/13 (7.7%)	1
Epistaxis	1/13 (7.7%)	1
Hypoxia	1/13 (7.7%)	1
Oropharyngeal pain	1/13 (7.7%)	1
Pulmonary mass	1/13 (7.7%)	1
Pulmonary oedema	1/13 (7.7%)	1
Respiratory tract congestion	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Erythema	1/13 (7.7%)	1
Rash	1/13 (7.7%)	1
Surgical and medical procedures
Cataract operation	1/13 (7.7%)	1
Tooth extraction	1/13 (7.7%)	1
Vascular disorders
Hypotension	1/13 (7.7%)	1
Flushing	1/13 (7.7%)	1

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 interim results of the Study without the prior written consent of Sponsor, not to be unreasonably withheld or delayed, except as provided below. 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.