The "VISION" Trial: Ventavis Inhalation With Sildenafil to Improve and Optimize Pulmonary Arterial Hypertension

• Sponsor: Actelion (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00302211
• Collaborator: (none)
• Enrollment: 67
• Locations: 34
• Arms: 5
• Actual Duration (Months): 28.9
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this multi-center international trial is to evaluate the safety and effectiveness of adding iloprost or placebo (an inactive substance that contains no active study drug) to sildenafil therapy for pulmonary arterial hypertension (PAH). The study will also examine whether patients on sildenafil can reduce the number of iloprost inhalations from the approved 6 doses per day to 4 doses per day.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension	Drug: Inhaled Iloprost (5 μg); Drug: Inhaled Placebo; Drug: Sildenafil; Drug: Bosentan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of the Addition of Inhaled Iloprost in Patients With Pulmonary Arterial Hypertension Receiving Oral Sildenafil
• Actual Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Dec 1, 2007
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DB inhaled iloprost 6x/day inhaled iloprost (5 μg) 6 times per day (6×/day) plus sildenafil with or without bosentan during the double blind period	Drug: Inhaled Iloprost (5 μg); iloprost inhalation solution (Ventavis) (5 μg); Drug: Sildenafil; oral sildenafil (dosage between 60 and 300 mg/day); Drug: Bosentan; oral bosentan (dosage between 62.5 and 125 mg BID)
Experimental: DB inhaled iloprost 4x/day Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan during the double blind period	Drug: Inhaled Iloprost (5 μg); iloprost inhalation solution (Ventavis) (5 μg); Drug: Inhaled Placebo; inhaled placebo; Drug: Sildenafil; oral sildenafil (dosage between 60 and 300 mg/day); Drug: Bosentan; oral bosentan (dosage between 62.5 and 125 mg BID)
Placebo Comparator: DB inhaled placebo 6x/day Inhaled placebo 6×/day plus sildenafil with or without bosentan during the double blind period	Drug: Inhaled Placebo; inhaled placebo; Drug: Sildenafil; oral sildenafil (dosage between 60 and 300 mg/day); Drug: Bosentan; oral bosentan (dosage between 62.5 and 125 mg BID)
Experimental: OL inhaled iloprost 6x/day Inhaled iloprost (5 μg) 6 times per day (6×/day) plus sildenafil with or without bosentan during the Open-Label treatment period	Drug: Inhaled Iloprost (5 μg); iloprost inhalation solution (Ventavis) (5 μg)
Experimental: OL inhaled iloprost 4x/day Inhaled iloprost (5 μg) 4 times per day (4×/day) plus sildenafil with or without bosentan during the Open-Label treatment period	Drug: Inhaled Iloprost (5 μg); iloprost inhalation solution (Ventavis) (5 μg)

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline to Week 16 in 6-Minute Walk Distance (6MWD) During the Double-blind Treatment Period [Day 1 and Week 16]

   The 6MWD test is a non-encouraged test, performed in a 30-meter long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones during 6 minutes. They can slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline.

Secondary Outcome Measures

1. Number of Subjects With WHO Functional Class (WHO FC) Improvement at Week 16 [Day 1 and Week 16]

   This test is used to assess disease severity. Four fucntional classes (FC) are defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). Improvement is considered when a participant changes from a higher class to a lower class.

2. Time to Clinical Worsening [Week 16 and Week 48]

   Clinical worsening is defined as one of the following: death due to worsening PAH, receipt of lung or heart-lung transplantation, or atrial septostomy, hospitalization for worsening PAH, any early discontinuation from study during the blinded or open-label phase due to worsening PAH, initiation of additional PAH-specific treatment. Due to insufficient data, time could not be assessed accurately and only number of patients with clinical worsening could be reported.

Other Outcome Measures

1. Number of Participants With Any Adverse Events [From Day 1 to Week 16 and Week 48]

   This is the overall number of participants in each group who reported at least one adverse event (i.e., any untoward medical occurrence or unfavorable and unintended sign whether or not considered related to the study drug) with an onset from the first administration of study drug up to the last study visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Aged 12-85 years; of either gender.

• Confirmed PAH due to idiopathic pulmonary arterial hypertension (IPAH) or familial pulmonary arterial hypertension (FPAH).

• 6-minute walk distance (6-MWD) between 100-450 meters at screening.

• On a stable dose of sildenafil, with or without bosentan.

Exclusion Criteria:

• Any treatment for PAH with prostacyclins, prostacyclin analogues, endothelin-1 antagonists, or phosphodiesterase-5 (PDE-5) inhibitors other than sildenafil within the past 12 weeks.

• Pulmonary hypertension due to conditions other than those stated in inclusion criteria.

• Additional PAH medications added within the past 12 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pulmonary Associates, PA	Phoenix	Arizona	United States	85006
2	University of California San Diego Medical Center	La Jolla	California	United States	92037
3	GLVA Medical Center	Los Angeles	California	United States	90073
4	UCLA Medical Offices	Los Angeles	California	United States	90095
5	University of California Davis School of Medicine	Sacramento	California	United States	95817
6	University of California San Francisco Medical Center	San Francisco	California	United States	94143
7	Stanford University Medical Center	Stanford	California	United States	94305-5351
8	University of Colorado Health Services	Denver	Colorado	United States	80262
9	University of Connecticut Health Center	Farmington	Connecticut	United States	06030-1321
10	University of Miami	Miami	Florida	United States	33136
11	Midwest Heart Foundation	Lombard	Illinois	United States	60148
12	Midwest Heart Specialists, Edwards Hospital	Lombard	Illinois	United States	60148
13	University of Iowa Hospital	Iowa City	Iowa	United States	52242
14	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
15	LSU Health Sciences Center	New Orleans	Louisiana	United States	70112
16	University of Maryland Hospital	Baltimore	Maryland	United States	21201
17	Tufts New England Medical Center	Boston	Massachusetts	United States	02111
18	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
19	Spectrum Blodgett Hospital	Grand Rapids	Michigan	United States	49506
20	Minneapolis Heart Institute	Minneapolis	Minnesota	United States	55407
21	North Shore University Hospital	New Hyde Park	New York	United States	11040
22	Beth Israel Medical Center	New York	New York	United States	10003
23	Columbia University Medical Center	New York	New York	United States	10032
24	New York Presbyterian Hospital	New York	New York	United States	10032
25	Ohio State University	Columbus	Ohio	United States	43210
26	Alleghany General Hospital	Pittsburgh	Pennsylvania	United States	15212
27	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
28	Rhode Island Hospital	Providence	Rhode Island	United States	02903
29	University of SC School of Medicine	Columbia	South Carolina	United States	29203
30	Baylor College of Medicine	Houston	Texas	United States	77030
31	Diagnostic Research Group	San Antonio	Texas	United States	78229
32	LDS Hospital	Salt Lake City	Utah	United States	84143
33	University of Washington Medical Center	Seattle	Washington	United States	98195
34	Heart Care Associates, LLC	Milwaukee	Wisconsin	United States	53215

Sponsors and Collaborators

• Actelion

Investigators

• Principal Investigator: Nazzareno Galie, MD, Istituto Malattie Apparato Cardio Univ di Bologna

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CoTherix Clinical Development

Publications

None provided.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT00302211
• Other Study ID Numbers: C200-006
• First Posted: Mar 14, 2006
• Last Update Posted: Apr 16, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Actelion: PAH; Pulmonary Arterial Hypertension
• Additional relevant MeSH terms: Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Bosentan; Sildenafil Citrate; Iloprost

Study Results

Participant Flow

Recruitment Details	Due to slow participant enrollment, the study was prematurely terminated, and recruitment was stopped after 67 subjects had been recruited instead of 180 initially planned (37% of the originally-planned sample size)

Arm/Group Title	DB Iloprost 6×/Day	DB Iloprost 4×/Day	DB Placebo 6×/Day	OL Iloprost 6x/Day	OL Inhaled Iloprost 4x/Day
Arm/Group Description	Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan	Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan	Inhaled placebo 6×/day plus sildenafil with or without bosentan	The subjects received inhaled iloprost(5 μg) 6 times per day plus sildenafil with or without bosentan during the 32-week open-label period	Subjects in this group received inhaled iloprost (5μg) 4x/day plus sildenafil with or without bosentan during the open-label period
Period Title: Double Blind Period (New Patients)
STARTED	26	27	14	0	0
COMPLETED	23	25	10	0	0
NOT COMPLETED	3	2	4	0	0
Period Title: Double Blind Period (New Patients)
STARTED	0	0	0	26	32
COMPLETED	0	0	0	18	24
NOT COMPLETED	0	0	0	8	8

Baseline Characteristics

Arm/Group Title	DB Iloprost 6×/Day	DB Iloprost 4×/Day	DB Placebo 6×/Day	Total
Arm/Group Description	Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan	Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan	Inhaled placebo 6×/day plus sildenafil with or without bosentan	Total of all reporting groups
Overall Participants	26	27	14	67
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	23 88.5%	17 63%	9 64.3%	49 73.1%
>=65 years	3 11.5%	10 37%	5 35.7%	18 26.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.9 (11.95)	56.6 (16.27)	56.9 (11.90)	54.8 (13.85)
Sex: Female, Male (Count of Participants)
Female	20 76.9%	19 70.4%	13 92.9%	52 77.6%
Male	6 23.1%	8 29.6%	1 7.1%	15 22.4%
Region of Enrollment (Count of Participants)
United States	14 53.8%	15 55.6%	9 64.3%	38 56.7%
United Kingdom	4 15.4%	2 7.4%	1 7.1%	7 10.4%
Spain	0 0%	1 3.7%	1 7.1%	2 3%
Italy	0 0%	1 3.7%	0 0%	1 1.5%
Germany	7 26.9%	6 22.2%	3 21.4%	16 23.9%
Austria	1 3.8%	2 7.4%	0 0%	3 4.5%

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline to Week 16 in 6-Minute Walk Distance (6MWD) During the Double-blind Treatment Period
Description	The 6MWD test is a non-encouraged test, performed in a 30-meter long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones during 6 minutes. They can slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline.
Time Frame	Day 1 and Week 16

Outcome Measure Data

Analysis Population Description

Only Participants in the double-blind treatment period were included if they received at least one dose of study drug and had at least one post-baseline efficacy measure at Week 16. Due to early study termination (about 30% of the enrollment goal) the study was severely under-powered and no accurate statistical analyses could be performed.

Arm/Group Title	DB Iloprost 6×/Day	DB Iloprost 4×/Day	DB Placebo 6×/Day
Arm/Group Description	Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan	Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan	Inhaled placebo 6×/day plus sildenafil with or without bosentan
Measure Participants	26	27	13
Mean (Standard Deviation) [Meters]	10.1 (62.15)	29.6 (55.17)	-22.0 (124.7)

2. Secondary Outcome

Title	Number of Subjects With WHO Functional Class (WHO FC) Improvement at Week 16
Description	This test is used to assess disease severity. Four fucntional classes (FC) are defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). Improvement is considered when a participant changes from a higher class to a lower class.
Time Frame	Day 1 and Week 16

Outcome Measure Data

Analysis Population Description

Only Participants in the double-blind treatment period were included if they received at least one dose of study drug and had at least one post-baseline efficacy measure at Week 16. Due to early study termination (about 30% of the enrollment goal) the study was severely under-powered and no accurate statistical analyses could be performed.

Arm/Group Title	DB Iloprost 6×/Day	DB Iloprost 4×/Day	DB Placebo 6×/Day
Arm/Group Description	Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan	Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan	Inhaled placebo 6×/day plus sildenafil with or without bosentan
Measure Participants	26	27	13
Count of Participants [Participants]	4 15.4%	6 22.2%	0 0%

3. Secondary Outcome

Title	Time to Clinical Worsening
Description	Clinical worsening is defined as one of the following: death due to worsening PAH, receipt of lung or heart-lung transplantation, or atrial septostomy, hospitalization for worsening PAH, any early discontinuation from study during the blinded or open-label phase due to worsening PAH, initiation of additional PAH-specific treatment. Due to insufficient data, time could not be assessed accurately and only number of patients with clinical worsening could be reported.
Time Frame	Week 16 and Week 48

Outcome Measure Data

Analysis Population Description

Only participants who received at least one dose of study drug and with available data at Week 16 (for the double-blind period) and at Week 48 (for the open-label period) were included in the analysis

Arm/Group Title	DB Iloprost 6×/Day	DB Iloprost 4×/Day	DB Placebo 6×/Day	OL Iloprost 6x/Day	OL Iloprost 4x/Day
Arm/Group Description	Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan	Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan	Inhaled placebo 6×/day plus sildenafil with or without bosentan	The subjects received inhaled iloprost(5 μg) 6 times per day plus sildenafil with or without bosentan during the 32-week open-label period	The subjects received inhaled iloprost (5μg) 4 times per day plus sildenafil with or without bosentan during the 32-week open-label period
Measure Participants	26	27	14	22	28
Count of Participants [Participants]	0 0%	1 3.7%	1 7.1%	2 3%	3 NaN

4. Other Pre-specified Outcome

Title	Number of Participants With Any Adverse Events
Description	This is the overall number of participants in each group who reported at least one adverse event (i.e., any untoward medical occurrence or unfavorable and unintended sign whether or not considered related to the study drug) with an onset from the first administration of study drug up to the last study visit.
Time Frame	From Day 1 to Week 16 and Week 48

Outcome Measure Data

Analysis Population Description

Safety population: All randomiized subjects who received at least one dose of the study drug

Arm/Group Title	DB Iloprost 6×/Day	DB Iloprost 4×/Day	DB Placebo 6×/Day	OL Iloprost 6x/Day	OL Iloprost 4x/Day
Arm/Group Description	Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan	Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan	Inhaled placebo 6×/day plus sildenafil with or without bosentan	The subjects received inhaled iloprost(5 μg) 6 times per day plus sildenafil with or without bosentan during the 32-week open-label period	The subjects received inhaled iloprost (5μg) 4 times per day plus sildenafil with or without bosentan during the 32-week open-label period
Measure Participants	26	27	14	26	32
Count of Participants [Participants]	24 92.3%	22 81.5%	14 100%	23 34.3%	30 NaN

5. Post-Hoc Outcome

Title	Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period
Description	The number of participants in the double-blind treatment period who showed improvement or worsening in the 6-MWT - from baseline distance between 100-450 meters - was assessed for each treatment group. The 6-minute walks were measured in meters. Any increase in walk distance at Week 16 was considered improvement from baseline, any decrease was considered as deterioration from baseline.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Only Participants in the double-blind treatment period were included if they received at least one dose of study drug and had a post-baseline efficacy measure at Week 16.

Arm/Group Title	DB Iloprost 6×/Day	DB Iloprost 4×/Day	DB Placebo 6×/Day
Arm/Group Description	Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan	Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan	Inhaled placebo 6×/day plus sildenafil with or without bosentan
Measure Participants	26	27	13
6-MWT improvement	13 50%	18 66.7%	9 64.3%
6-MWT deterioration	12 46.2%	8 29.6%	4 28.6%
No change	1 3.8%	1 3.7%	0 0%

Adverse Events

Time Frame	from Day 1 (Baseline) up to Week 48 (or up to 30 days after the last dose of study drug for serious adverse events)
Adverse Event Reporting Description	Safety was assessed on the basis of adverse events, laboratory tests, physical examination and vital signs during both the double-blind and open-label phases of the study.
Arm/Group Title	DB Iloprost 6×/Day		DB Iloprost 4×/Day		DB Placebo 6×/Day		OL Iloprost 6x/Day		OL Iloprost 4x/Day
Arm/Group Description	Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan		Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan		Inhaled placebo 6×/day plus sildenafil with or without bosentan		The subjects received inhaled iloprost(5 μg) 6 times per day plus sildenafil with or without bosentan during the 32-week open-label period		The subjects received inhaled iloprost (5μg) 4 times per day plus sildenafil with or without bosentan during the 32-week open-label period
All Cause Mortality
	DB Iloprost 6×/Day		DB Iloprost 4×/Day		DB Placebo 6×/Day		OL Iloprost 6x/Day		OL Iloprost 4x/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	DB Iloprost 6×/Day		DB Iloprost 4×/Day		DB Placebo 6×/Day		OL Iloprost 6x/Day		OL Iloprost 4x/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/26 (11.5%)		5/27 (18.5%)		3/14 (21.4%)		4/26 (15.4%)		13/32 (40.6%)
Blood and lymphatic system disorders
Anemia	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Cardiac disorders
Atrial fibrillation	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Right ventricular failure	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Atrial flutter	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Cardiac failure	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Sick sinus syndrome	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Gastrointestinal disorders
Inguinal hernia	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
General disorders
Chest pain	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Infections and infestations
Cellulitis	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Gastroenteritis viral	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Pneumonia	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		1/26 (3.8%)		1/32 (3.1%)
Herpes zoster	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Pneumococcal sepsis	0/26 (0%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Sepsis	0/26 (0%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Injury, poisoning and procedural complications
Subdural hematoma	0/26 (0%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Wrist fracture	0/26 (0%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Metabolism and nutrition disorders
Fluid overload	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		2/32 (6.3%)
Dehydration	0/26 (0%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Multiple myeloma	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Nervous system disorders
Presyncope	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Syncope	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Pulmonary hypertension	0/26 (0%)		1/27 (3.7%)		2/14 (14.3%)		1/26 (3.8%)		3/32 (9.4%)
Vascular disorders
Lupus vasculitis	0/26 (0%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	DB Iloprost 6×/Day		DB Iloprost 4×/Day		DB Placebo 6×/Day		OL Iloprost 6x/Day		OL Iloprost 4x/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/26 (92.3%)		22/27 (81.5%)		14/14 (100%)		23/26 (88.5%)		30/32 (93.8%)
Cardiac disorders
Arrhythmia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Atrial Fibrillation	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Atrial flutter	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Cardiac failure	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Palpitations	3/26 (11.5%)		0/27 (0%)		0/14 (0%)		2/26 (7.7%)		0/32 (0%)
Right ventricular failure	1/26 (3.8%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Supraventricular extrasystoles	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Tachycardia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Ventricular arrhythmia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Ventricular extrasystoles	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Ear and labyrinth disorders
Ear pain	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Middle ear effusion	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Vertigo	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Eye disorders
Conjunctivitis	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Gastrointestinal disorders
Abdominal pain	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Abdominal pain upper	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Constipation	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Diarrhoea	2/26 (7.7%)		1/27 (3.7%)		1/14 (7.1%)		0/26 (0%)		2/32 (6.3%)
Dry mouth	2/26 (7.7%)		1/27 (3.7%)		0/14 (0%)		3/26 (11.5%)		1/32 (3.1%)
Dysphagia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Glossodynia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Inguinal hernia	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Mouth ulceration	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Nausea	2/26 (7.7%)		2/27 (7.4%)		1/14 (7.1%)		1/26 (3.8%)		0/32 (0%)
Oesophagitis	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Abdominal distension	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Vomiting	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
General disorders
Asthenia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Chest discomfort	4/26 (15.4%)		1/27 (3.7%)		1/14 (7.1%)		2/26 (7.7%)		1/32 (3.1%)
Chest pain	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Chills	2/26 (7.7%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Fatigue	2/26 (7.7%)		1/27 (3.7%)		1/14 (7.1%)		1/26 (3.8%)		1/32 (3.1%)
Oedema	1/26 (3.8%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Oedema peripheral	1/26 (3.8%)		3/27 (11.1%)		0/14 (0%)		1/26 (3.8%)		1/32 (3.1%)
Swelling	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Infections and infestations
Bronchitis	0/26 (0%)		2/27 (7.4%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Cellulitis	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Gastroenteritis rotavirus	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Gastroenteritis viral	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Herpes zoster	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Infection	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Influenza	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Lymph gland infection	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Mastitis	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Nasopharyngitis	4/26 (15.4%)		2/27 (7.4%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Oral candidiasis	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Oral herpes	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Pharyngitis	1/26 (3.8%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Pneumonia	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Rash pustular	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Rhinitis	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Sinusitis	3/26 (11.5%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Staphylococcal infection	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Tooth abscess	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Upper respiratory tract infection	2/26 (7.7%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Viral infection	1/26 (3.8%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Ear infection	0/26 (0%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Injury, poisoning and procedural complications
Contusion	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Head injury	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Laceration	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Fluid overload	1/26 (3.8%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Fluid retention	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Gout	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Hyperkalaemia	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Back pain	3/26 (11.5%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Intervertebral disc protrusion	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Limb discomfort	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Musculoskeletal pain	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		1/32 (3.1%)
Myalgia	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Osteoarthritis	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Pain in extremity	0/26 (0%)		1/27 (3.7%)		1/14 (7.1%)		0/26 (0%)		1/32 (3.1%)
Pain in jaw	2/26 (7.7%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Sensation of heaviness	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Multiple myeloma	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Nasal sinus cancer	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Nervous system disorders
Burning sensation	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Dizziness	4/26 (15.4%)		0/27 (0%)		3/14 (21.4%)		5/26 (19.2%)		1/32 (3.1%)
Headache	10/26 (38.5%)		7/27 (25.9%)		2/14 (14.3%)		10/26 (38.5%)		6/32 (18.8%)
Hypogeusia	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Presyncope	1/26 (3.8%)		2/27 (7.4%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Somnolence	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Syncope	2/26 (7.7%)		3/27 (11.1%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Psychiatric disorders
Anxiety	2/26 (7.7%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Depression	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Dyssomnia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Insomnia	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Nervousness	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Dysuria	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Reproductive system and breast disorders
Erectile dysfunction	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Gynaecomastia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Penile oedema	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	6/26 (23.1%)		8/27 (29.6%)		2/14 (14.3%)		4/26 (15.4%)		2/32 (6.3%)
Dry throat	3/26 (11.5%)		0/27 (0%)		0/14 (0%)		2/26 (7.7%)		0/32 (0%)
Dysphonia	2/26 (7.7%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Dyspnoea	2/26 (7.7%)		0/27 (0%)		1/14 (7.1%)		1/26 (3.8%)		0/32 (0%)
Epistaxis	2/26 (7.7%)		2/27 (7.4%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Hypoxia	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Nasal congestion	2/26 (7.7%)		1/27 (3.7%)		1/14 (7.1%)		0/26 (0%)		1/32 (3.1%)
Nasal dryness	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Paranasal sinus hypersecretion	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Pharyngolaryngeal pain	1/26 (3.8%)		1/27 (3.7%)		0/14 (0%)		4/26 (15.4%)		1/32 (3.1%)
Productive cough	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		1/26 (3.8%)		0/32 (0%)
Pulmonary hypertension	0/26 (0%)		1/27 (3.7%)		3/14 (21.4%)		0/26 (0%)		0/32 (0%)
Sleep apnoea syndrome	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Throat irritation	4/26 (15.4%)		0/27 (0%)		1/14 (7.1%)		1/26 (3.8%)		1/32 (3.1%)
Throat tightness	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Wheezing	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Skin and subcutaneous tissue disorders
Hyperkeratosis	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Periorbital oedema	0/26 (0%)		0/27 (0%)		1/14 (7.1%)		0/26 (0%)		0/32 (0%)
Pruritus	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Rash	0/26 (0%)		2/27 (7.4%)		0/14 (0%)		0/26 (0%)		1/32 (3.1%)
Swelling face	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Surgical and medical procedures
Inguinal hernia	0/26 (0%)		1/27 (3.7%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Medical device implantation	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Vascular disorders
Cardiovascular insufficiency	1/26 (3.8%)		0/27 (0%)		0/14 (0%)		0/26 (0%)		0/32 (0%)
Flushing	6/26 (23.1%)		3/27 (11.1%)		1/14 (7.1%)		6/26 (23.1%)		4/32 (12.5%)
Hypotension	3/26 (11.5%)		4/27 (14.8%)		1/14 (7.1%)		0/26 (0%)		2/32 (6.3%)

Limitations/Caveats

Primary purpose was to evaluate the efficacy of iloprost in PAH patients. Due to slow recruitment only 67 of the 180 participants planned were enrolled. Consequently efficacy results are not meaningful and no statistical analyses could be performed.

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Certain Agreements

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

Written permission to publish results must be obtained in advance from Actelion (formerly CoTherix). Manuscript of any proposed publication must be sent to Actelion at least 30 days in advance of the submission date. Actelion will inform in writing of any objection of specific content in the proposed publication.In addition, the institution shall either delete disclosure of all potentially patentable inventions or delay submission of the proposed publication for up to 90 days.