Trial Outcomes & Findings for Clinical Investigation Into Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension (PAH) (NCT NCT00147199)
NCT ID: NCT00147199
Last Updated: 2024-01-02
Results Overview
Change in peak 6-minute walk distance from baseline to Week 12. Peak 6MWD was defined as a 6-minute walk test (6MWT) within 10 to 60 minutes after study drug inhalation
COMPLETED
PHASE3
235 participants
12 weeks
2024-01-02
Participant Flow
The first subject was enrolled on 7 June 2005 and the last subject exited the study on 12 Oct 2007.
Participant milestones
| Measure |
Inhaled Treprostinil
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
Identical placebo inhalation solution
|
|---|---|---|
|
Overall Study
STARTED
|
115
|
120
|
|
Overall Study
COMPLETED
|
102
|
110
|
|
Overall Study
NOT COMPLETED
|
13
|
10
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Clinical Investigation Into Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension (PAH)
Baseline characteristics by cohort
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 Participants
Identical placebo inhalation solution
|
Total
n=235 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
55 years
FULL_RANGE 13.1 • n=5 Participants
|
52 years
n=7 Participants
|
54 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
93 Participants
n=5 Participants
|
98 Participants
n=7 Participants
|
191 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
22 Participants
n=5 Participants
|
22 Participants
n=7 Participants
|
44 Participants
n=5 Participants
|
|
Pulmonary Arterial Hypertension (PAH) Etiology
Idiopathic PAH (IPAH)
|
64 participants
n=5 Participants
|
67 participants
n=7 Participants
|
131 participants
n=5 Participants
|
|
Pulmonary Arterial Hypertension (PAH) Etiology
Connective Tissue Disease (CTD)
|
40 participants
n=5 Participants
|
37 participants
n=7 Participants
|
77 participants
n=5 Participants
|
|
Pulmonary Arterial Hypertension (PAH) Etiology
Other
|
11 participants
n=5 Participants
|
16 participants
n=7 Participants
|
27 participants
n=5 Participants
|
|
Background PAH Therapy
Bosentan
|
77 participants
n=5 Participants
|
88 participants
n=7 Participants
|
165 participants
n=5 Participants
|
|
Background PAH Therapy
Sildenafil
|
38 participants
n=5 Participants
|
32 participants
n=7 Participants
|
70 participants
n=5 Participants
|
|
Time on Background Therapy
Bosentan
|
98 weeks
STANDARD_DEVIATION 79 • n=5 Participants
|
90 weeks
STANDARD_DEVIATION 75 • n=7 Participants
|
94 weeks
STANDARD_DEVIATION 77 • n=5 Participants
|
|
Time on Background Therapy
Sildenafil
|
65 weeks
STANDARD_DEVIATION 60 • n=5 Participants
|
77 weeks
STANDARD_DEVIATION 69 • n=7 Participants
|
70 weeks
STANDARD_DEVIATION 64 • n=5 Participants
|
|
Baseline NYHA Class
Class III
|
112 participants
n=5 Participants
|
118 participants
n=7 Participants
|
230 participants
n=5 Participants
|
|
Baseline NYHA Class
Class IV
|
3 participants
n=5 Participants
|
2 participants
n=7 Participants
|
5 participants
n=5 Participants
|
|
Baseline Six-Minute Walk Distance (6MWD)
|
346 meters
STANDARD_DEVIATION 63 • n=5 Participants
|
351 meters
STANDARD_DEVIATION 69 • n=7 Participants
|
348 meters
STANDARD_DEVIATION 66 • n=5 Participants
|
PRIMARY outcome
Timeframe: 12 weeksPopulation: Intention to treat analysis
Change in peak 6-minute walk distance from baseline to Week 12. Peak 6MWD was defined as a 6-minute walk test (6MWT) within 10 to 60 minutes after study drug inhalation
Outcome measures
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
Peak 6-minute Walk Distance
Week 12
|
366.0 meters
Interval 300.0 to 423.0
|
360.0 meters
Interval 296.0 to 414.9
|
|
Peak 6-minute Walk Distance
Change from Baseline
|
21.6 meters
Interval -8.0 to 54.0
|
3.0 meters
Interval -26.0 to 31.5
|
SECONDARY outcome
Timeframe: 12 weeksPopulation: Intention to treat population
Clinical worsening was defined as the first incidence of clinical worsening from randomization to the first occurrence of death, transplantation, hospitalization for PAH, or initiation of additional approved PAH therapy.
Outcome measures
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
Clinical Worsening Events
|
4 clinical worsening events
|
6 clinical worsening events
|
SECONDARY outcome
Timeframe: 12 weeksPopulation: Intention to treat population. A Week 12 observation was not present for one subject and that data point is not included in the analysis.
The Borg dyspnea score is a patient reported number between 0 (no perceived shortness of breath) and 10 (maximum perceived shortness of breath), obtained at the completion of each 6MWT.
Outcome measures
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=119 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
Borg Dyspnea Score
Week 12
|
3.68 score
Standard Deviation 2.26
|
3.91 score
Standard Deviation 2.33
|
|
Borg Dyspnea Score
Change from Baseline
|
0.0 score
Standard Deviation 2.07
|
0.0 score
Standard Deviation 1.72
|
SECONDARY outcome
Timeframe: 12 weeksPopulation: Intention to treat population
Change in NYHA functional class at Week 12. NYHA classifications: Class I - Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II - Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III - Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope. Class IV - Patients with pulmonary hypertension in the inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
Outcome measures
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
New York Heart Association (NYHA) Functional Classification
NYHA Class II
|
22 participants
Interval 0.0 to 0.0
|
22 participants
|
|
New York Heart Association (NYHA) Functional Classification
NYHA Class IV
|
5 participants
|
5 participants
|
|
New York Heart Association (NYHA) Functional Classification
NYHA Class III
|
88 participants
|
93 participants
|
SECONDARY outcome
Timeframe: 12 WeeksPopulation: Intention to treat population
Change in 6MWD from Baseline to trough 6MWD at Week 12. Trough was defined as a 6MWT conducted at least 4 hours following study drug inhalation.
Outcome measures
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
Trough 6MWD at Week 12
Week 12 trough
|
364.0 meters
Interval 313.0 to 420.0
|
365.0 meters
Interval 289.0 to 422.0
|
|
Trough 6MWD at Week 12
Change from Baseline
|
12.4 meters
Interval -10.0 to 51.3
|
0.8 meters
Interval -17.9 to 25.0
|
SECONDARY outcome
Timeframe: 6 weeksPopulation: Intention to treat
Change in peak 6MWD between Baseline and Week 6.
Outcome measures
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
Peak 6MWD at Week 6
Change from Baseline
|
21.6 meters
Interval -4.0 to 51.8
|
3.0 meters
Interval -16.5 to 22.0
|
|
Peak 6MWD at Week 6
Week 6 Values
|
375 meters
Interval 305.0 to 421.0
|
367 meters
Interval 292.0 to 419.0
|
SECONDARY outcome
Timeframe: 12 weeksPopulation: Intention to treat population.
Quality of life as measured by the Minnesota Living With Heart Failure (MLWHF) questionnaire was evaluated at baseline and at Week 12. The MLWHF questionnaire consists of 21 questions assessing how the patient's heart failure has prevented them from living the way they wanted during the defined time period. Each question was graded by the patient with a numeric value between 0 (No/none) and 5 (very much). These scores were then summed across the 21 questions for a Global Score. Global scores ranged from 0 to 105. These questions were further grouped into Physical (8 of the questions) and Emotional (5 of the questions) dimensions to further characterize the effect of heart failure on the patient's life. Physical scores ranged from 0 to 40, and emotional scores ranged from 0 to 25. For all 3 categories, the lower the score, the better the outcome. Values presented as change from Baseline.
Outcome measures
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
Quality of Life (Minnesota Living With Heart Failure)
Emotional Dimension
|
0.0 units on a scale
Inter-Quartile Range 5.7 • Interval -4.0 to 1.0
|
0.0 units on a scale
Inter-Quartile Range 5.7 • Interval -3.0 to 3.0
|
|
Quality of Life (Minnesota Living With Heart Failure)
Global Score
|
-3.0 units on a scale
Inter-Quartile Range 18.7 • Interval -14.0 to 2.0
|
0.0 units on a scale
Inter-Quartile Range 16.2 • Interval -9.0 to 6.0
|
|
Quality of Life (Minnesota Living With Heart Failure)
Physical Dimension
|
-1.4 units on a scale
Inter-Quartile Range 8.9 • Interval -6.0 to 2.0
|
0.0 units on a scale
Inter-Quartile Range 7.1 • Interval -4.0 to 3.0
|
SECONDARY outcome
Timeframe: 12 weeksPopulation: Intention to treat population.
Signs and symptoms of PAH (Loud P2 sound, Ascites, Right ventricular S3 sound, Dyspnea, Right ventricular S4 sound, Orthopnea, Right ventricular heave, Dizziness, Murmur of tricuspid insufficiency, Syncope, Murmur of pulmonic insufficiency, Chest pain, Hepatomegaly, Palpitations, Jugular venous distension at 45 degrees, Fatigue, Edema) were assessed at Baseline and Week 12. The status of each sign and symptom ("absent" or "present") was assessed at each visit. To assess overall change from baseline in signs and symptoms, a "1" was assigned for each sign and symptom that was "present" at the Week 12 but was "absent" at baseline, a "-1" was assigned for each sign and symptom that was "absent" at Week 12 but was "present" at baseline, and a "0" was assigned for no change. An overall change score at each post-baseline assessment was then calculated by summing these values for all signs and symptoms. The overall change score had the potential to range from -17 to 17.
Outcome measures
| Measure |
Inhaled Treprostinil
n=115 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
Change in Signs and Symptoms of PAH
|
0 units on a scale
Full Range 3.5 • Interval -6.0 to 5.0
|
0 units on a scale
Full Range 2.5 • Interval -6.0 to 16.0
|
SECONDARY outcome
Timeframe: 12 weeksPopulation: Per protocol
Change in NT pro-BNP from Baseline to Week 12. Plasma samples were collected from patients at Baseline and Week 12 in order to measure any change over time in circulating plasma levels of this biomarker.
Outcome measures
| Measure |
Inhaled Treprostinil
n=73 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=82 Participants
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
|---|---|---|
|
N-terminal Pro-B-Type Natriuretic Peptide (NT Pro-BNP)
Week 12
|
377 pg/mL
Interval 124.0 to 1091.0
|
756 pg/mL
Interval 177.0 to 2213.0
|
|
N-terminal Pro-B-Type Natriuretic Peptide (NT Pro-BNP)
Change from Baseline
|
-57 pg/mL
Interval -396.0 to 34.0
|
40 pg/mL
Interval -93.0 to 288.0
|
Adverse Events
Inhaled Treprostinil
Placebo
Serious adverse events
| Measure |
Inhaled Treprostinil
n=115 participants at risk
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 participants at risk
Identical placebo inhalation solution
|
|---|---|---|
|
Respiratory, thoracic and mediastinal disorders
Worsening PAH
|
2.6%
3/115 • 12 Weeks
|
1.7%
2/120 • 12 Weeks
|
|
Nervous system disorders
Syncope
|
1.7%
2/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Blood and lymphatic system disorders
Anemia
|
0.87%
1/115 • 12 Weeks
|
0.00%
0/120 • 12 Weeks
|
|
Gastrointestinal disorders
Abdominal pain
|
0.87%
1/115 • 12 Weeks
|
0.00%
0/120 • 12 Weeks
|
|
Endocrine disorders
Diabetes mellitus
|
0.87%
1/115 • 12 Weeks
|
0.00%
0/120 • 12 Weeks
|
|
Gastrointestinal disorders
Diarrhea
|
0.87%
1/115 • 12 Weeks
|
0.00%
0/120 • 12 Weeks
|
|
Gastrointestinal disorders
Gastric ulcer
|
0.87%
1/115 • 12 Weeks
|
0.00%
0/120 • 12 Weeks
|
|
Cardiac disorders
right ventricular failure
|
0.87%
1/115 • 12 Weeks
|
0.00%
0/120 • 12 Weeks
|
|
Nervous system disorders
Anxiety
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Cardiac disorders
Atrial flutter
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Metabolism and nutrition disorders
blood potassium increased
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Infections and infestations
Bronchitis
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Cardiac disorders
Congestive cardiac failure
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Skin and subcutaneous tissue disorders
Cellulitis
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Gastrointestinal disorders
Cholelithiasis
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Cardiac disorders
Cor pulmonale
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Metabolism and nutrition disorders
Fluid overload
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Gastrointestinal disorders
Gastrointestinal hemorrhage
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Blood and lymphatic system disorders
Hematuria
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Nervous system disorders
Headache
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Cardiac disorders
Hypotension
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Metabolism and nutrition disorders
iron deficiency anemia
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
General disorders
Sudden death
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Musculoskeletal and connective tissue disorders
musculoskeletal chest pain
|
0.00%
0/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
Other adverse events
| Measure |
Inhaled Treprostinil
n=115 participants at risk
Initial dose: 3 breaths. Titrated to 9 breaths, four times daily.
|
Placebo
n=120 participants at risk
Identical placebo inhalation solution
|
|---|---|---|
|
Respiratory, thoracic and mediastinal disorders
cough
|
53.9%
62/115 • 12 Weeks
|
29.2%
35/120 • 12 Weeks
|
|
Nervous system disorders
headache
|
40.9%
47/115 • 12 Weeks
|
22.5%
27/120 • 12 Weeks
|
|
Nervous system disorders
dizziness
|
17.4%
20/115 • 12 Weeks
|
15.0%
18/120 • 12 Weeks
|
|
Gastrointestinal disorders
nausea
|
19.1%
22/115 • 12 Weeks
|
10.8%
13/120 • 12 Weeks
|
|
Respiratory, thoracic and mediastinal disorders
throat irritation
|
13.9%
16/115 • 12 Weeks
|
8.3%
10/120 • 12 Weeks
|
|
Infections and infestations
Upper respiratory tract infection
|
8.7%
10/115 • 12 Weeks
|
11.7%
14/120 • 12 Weeks
|
|
General disorders
fatigue
|
8.7%
10/115 • 12 Weeks
|
10.0%
12/120 • 12 Weeks
|
|
Gastrointestinal disorders
diarrhea
|
9.6%
11/115 • 12 Weeks
|
7.5%
9/120 • 12 Weeks
|
|
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain
|
11.3%
13/115 • 12 Weeks
|
5.8%
7/120 • 12 Weeks
|
|
Vascular disorders
flushing
|
14.8%
17/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
|
Respiratory, thoracic and mediastinal disorders
dyspnea
|
5.2%
6/115 • 12 Weeks
|
5.0%
6/120 • 12 Weeks
|
|
General disorders
chest discomfort
|
6.1%
7/115 • 12 Weeks
|
3.3%
4/120 • 12 Weeks
|
|
Musculoskeletal and connective tissue disorders
pain in jaw
|
5.2%
6/115 • 12 Weeks
|
4.2%
5/120 • 12 Weeks
|
|
Infections and infestations
nasopharyngitis
|
1.7%
2/115 • 12 Weeks
|
5.8%
7/120 • 12 Weeks
|
|
Cardiac disorders
palpitations
|
1.7%
2/115 • 12 Weeks
|
5.8%
7/120 • 12 Weeks
|
|
Respiratory, thoracic and mediastinal disorders
epistaxis
|
5.2%
6/115 • 12 Weeks
|
1.7%
2/120 • 12 Weeks
|
|
Nervous system disorders
syncope
|
6.1%
7/115 • 12 Weeks
|
0.83%
1/120 • 12 Weeks
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the United Therapeutics publication policy. The rights of the investigator and of the sponsor with regard to publication of the results are described in the investigator contract.
- Publication restrictions are in place
Restriction type: OTHER