Pulmonary Hypertension
Conditions
Keywords
pulmonary hypertension
Brief summary
Acute secondary pulmonary hypertension (PH) often leads to dysfunction of the right ventricle (RV) and can be a significant cause of patient morbidity and mortality. Selective pulmonary vasodilation with inhaled nitric oxide (INO) has become the treatment of choice for this condition. The evidence supporting INO safety and efficacy under these circumstances is sparse, however, and is largely extrapolated from the use of INO in neonatal pulmonary hypertension. Moreover, the high cost and potential toxicity of INO makes the therapy far from ideal. Emerging evidence suggests that inhaled aerosolized prostacyclins such as iloprost may be a favorable alternative therapy.
Detailed description
Phase 1- In the original study, 3 doses of Iloprost were given. This was revised after 5 subjects were enrolled in order to study the effects of continuous delivery over a longer period of time. Phase 2 - All remaining subjects received Iloprost as a continuous treatment. The study was designed for an enrollment of 200 subjects and was ended early.
Interventions
DRUGInhaled Iloprost
A 20 mcg dose of Iloprost will be given initially.
Sponsors
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Clinical evidence of pulmonary hypertension (PH) requiring INO therapy as prescribed by the attending physician. 2. Indwelling arterial catheter. 3. Signed informed consent
Exclusion criteria
1. Clinically unstable circulatory condition requiring epinephrine \> 0.1 mcg/kg/min or levophed, or already meeting treatment failure criteria (see section 5.3 below) 2. Known hypersensitivity to prostacyclin compounds 3. Patients receiving sildenafil or bosentan 4. Refusal by the attending physician
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Oxygen Saturation (SpO2) From Baseline | 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours | Readings were taken from the medical record and the data may not have been present at the exact time frames. |
| Change in Mean Heart Rate From Baseline | 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours | — |
| Number of Treatment Failures | as long as subject was on drug up to approximately 24 hours | Treatment failure is defined as Central venous pressure (CVP) ≥ 20 mm Hg and any one of the following: 1. Cardiac Index (CI) \>/= 1.8 L/min/m2 2. Administration of \>/=0.1 ug/kg/min Epinephrine or Norepinephrine 3. MAP \</= 50 mmHg (or as appropriate for age in pediatrics). 4. SvO2\</= 55% (or \< 45% for patients with R to L intracardiac shunting and, thus, cyanosis at baseline.} |
| Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cardiac Output (CO) From Baseline | 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours | — |
| Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours | SvO2 represents an average of all the venous oxygen saturations of the various organs and tissues. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 2: Inhaled Iloprost Continuous Each subject will have a stable dose of INO therapy as established by the attending physicians for at least one hour. Initial baseline data collection will then be made.
A 20 mcg dose of Iloprost will be given initially. During this treatment there will be a nitric oxide titration to 0. Iloprost will be aerosolized continuously at a dose of 5-30mcg/hour for as long as the attending physician deems it necessary to deliver vasodilator therapy.
Inhaled Iloprost: A 20 mcg dose of Iloprost will be given initially. | 22 |
| Phase 1: Inhaled Iloprost 3 Doses Each subject will have a stable dose of INO therapy as established by the attending physicians for at least one hour. Initial baseline data collection will then be made.
A 20 mcg dose of Iloprost will be given initially. During this treatment there will be a nitric oxide titration to 0. Iloprost will be aerosolized three different times on hour apart. Thirty minutes after the last iloprost dose, INO will be added back at the previous (baseline) dose.
Inhaled Iloprost: A 20 mcg dose of Iloprost will be given initially. | 5 |
| Total | 27 |
Baseline characteristics
| Characteristic | Phase 2: Inhaled Iloprost Continuous | Phase 1: Inhaled Iloprost 3 Doses | Total |
|---|---|---|---|
| Age, Customized <=18 years | 1 participants | 0 participants | 1 participants |
| Age, Customized >18 years | 21 participants | 5 participants | 26 participants |
| Region of Enrollment United States | 22 participants | 5 participants | 27 participants |
| Sex: Female, Male Female | 14 Participants | 1 Participants | 15 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 22 | 0 / 5 |
| serious Total, serious adverse events | 0 / 22 | 0 / 5 |
Outcome results
Primary
Change in Mean Heart Rate From Baseline
Time frame: dose 1 (1 hour), dose 2 (2 hour), dose 3 (3 hour), combined therapy (4.5 - 5 hour), end INO (6 - 7 hour)
Population: Phase 1 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | dose 1 | 0.9 percent change | Standard Deviation 4.8 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | dose 2 | 2.5 percent change | Standard Deviation 4.5 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | dose 3 | 0.7 percent change | Standard Deviation 6.7 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | combined therapy | 0.9 percent change | Standard Deviation 7.8 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | end INO | -0.2 percent change | Standard Deviation 8.9 |
Primary
Change in Mean Heart Rate From Baseline
Time frame: 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours
Population: Phase 2 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 10 hours | 2.2 percent change | Standard Deviation 14.3 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 30 mins after initial dose | -1.8 percent change | Standard Deviation 4.4 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 2 hours | -1.1 percent change | Standard Deviation 6.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 4 hours | 4.2 percent change | Standard Deviation 18.7 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 6 hours | 0.8 percent change | Standard Deviation 12.5 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 8 hours | -1.0 percent change | Standard Deviation 13.7 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 12 hours | -2.9 percent change | Standard Deviation 12 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 18 hours | -4.0 percent change | Standard Deviation 12.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Heart Rate From Baseline | 24 hours | -9.9 percent change | Standard Deviation 16.1 |
Primary
Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline
Time frame: 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours
Population: Phase 2 subjects: Measurement completed on subjects having a Swan Ganz catheter. 4 subjects did not have a swan ganz catheter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 30 mins after initial dose | 1.9 percent change | Standard Deviation 9.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 2 hours | -1.1 percent change | Standard Deviation 19.1 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 4 hours | 3.1 percent change | Standard Deviation 17.2 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 6 hours | -1.9 percent change | Standard Deviation 16.9 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 8 hours | -3.2 percent change | Standard Deviation 20.4 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 10 hours | 1.6 percent change | Standard Deviation 12.7 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 12 hours | 1.3 percent change | Standard Deviation 15.7 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 18 hours | 6.5 percent change | Standard Deviation 17.1 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | 24 hours | 7.0 percent change | Standard Deviation 23.5 |
Primary
Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline
Time frame: dose 1 (1 hour), dose 2 (2 hour), dose 3 (3 hour), combined therapy (4.5 - 5 hour), end INO (6 - 7 hour)
Population: Phase 1 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | dose 1 | -0.9 percent change | Standard Deviation 10 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | dose 2 | -6.5 percent change | Standard Deviation 10.9 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | dose 3 | -10.2 percent change | Standard Deviation 8.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | combined therapy | -13.0 percent change | Standard Deviation 9.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Pulmonary Artery Pressure (mPAP) From Baseline | end INO | -9.3 percent change | Standard Deviation 12.9 |
Primary
Number of Treatment Failures
Treatment failure is defined as Central venous pressure (CVP) ≥ 20 mm Hg and any one of the following: 1. Cardiac Index (CI) \>/= 1.8 L/min/m2 2. Administration of \>/=0.1 ug/kg/min Epinephrine or Norepinephrine 3. MAP \</= 50 mmHg (or as appropriate for age in pediatrics). 4. SvO2\</= 55% (or \< 45% for patients with R to L intracardiac shunting and, thus, cyanosis at baseline.}
Time frame: as long as subject was on drug up to approximately 24 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Number of Treatment Failures | 0 participants |
| Phase 1: Inhaled Iloprost 3 Doses | Number of Treatment Failures | 0 participants |
Primary
Percent Change in Oxygen Saturation (SpO2) From Baseline
Time frame: dose 1 (1 hour), dose 2 (2 hour), dose 3 (3 hour), combined therapy (4.5 - 5 hour), end INO (6 - 7 hour)
Population: Phase 1 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | dose 1 | -0.4 percent change | Standard Deviation 0.6 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | dose 2 | -0.4 percent change | Standard Deviation 1.6 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | dose 3 | 0.0 percent change | Standard Deviation 2.9 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | combined therapy | 0.2 percent change | Standard Deviation 2.4 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | end INO | 0.4 percent change | Standard Deviation 1.6 |
Primary
Percent Change in Oxygen Saturation (SpO2) From Baseline
Readings were taken from the medical record and the data may not have been present at the exact time frames.
Time frame: 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours
Population: Phase 2 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 30 mins after initial dose | -0.4 percent change | Standard Deviation 1.7 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 2 hours | -0.8 percent change | Standard Deviation 2.8 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 4 hours | -1.2 percent change | Standard Deviation 2.9 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 6 hours | -0.2 percent change | Standard Deviation 3.6 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 8 hours | -0.7 percent change | Standard Deviation 3.1 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 10 hours | -0.9 percent change | Standard Deviation 3 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 12 hours | -0.9 percent change | Standard Deviation 3.7 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 18 hours | -1.5 percent change | Standard Deviation 5.6 |
| Phase 2: Inhaled Iloprost Continuous | Percent Change in Oxygen Saturation (SpO2) From Baseline | 24 hours | 1.7 percent change | Standard Deviation 6.4 |
Secondary
Change in Cardiac Output (CO) From Baseline
Time frame: dose 1 (1 hour), dose 2 (2 hour), dose 3 (3 hour), combined therapy (4.5 - 5 hour), end INO (6 - 7 hour)
Population: Phase 1 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | dose 1 | 8.4 percent change | Standard Deviation 33.7 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | dose 2 | -0.9 percent change | Standard Deviation 36.3 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | dose 3 | 8.7 percent change | Standard Deviation 18.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | combined therapy | 2.5 percent change | Standard Deviation 9.3 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | end INO | -8.7 percent change | Standard Deviation 20.9 |
Secondary
Change in Cardiac Output (CO) From Baseline
Time frame: 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours
Population: Phase 2 subjects: 4 subjects did not have a swan ganz catheter. 1 subject had a swan ganz catheter, but measurement was unattainable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 30 mins after initial dose | 16.2 percent change | Standard Deviation 25.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 2 hours | 3.4 percent change | Standard Deviation 20.5 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 4 hours | 21.2 percent change | Standard Deviation 31.1 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 6 hours | 14.3 percent change | Standard Deviation 43.1 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 8 hours | 12.5 percent change | Standard Deviation 55.1 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 10 hours | 9.3 percent change | Standard Deviation 43.3 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 12 hours | 8.9 percent change | Standard Deviation 38.8 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 18 hours | 36.6 percent change | Standard Deviation 68.9 |
| Phase 2: Inhaled Iloprost Continuous | Change in Cardiac Output (CO) From Baseline | 24 hours | 4.4 percent change | Standard Deviation 27.9 |
Secondary
Change in Mean Venous Oxygen Saturation (SvO2) From Baseline
SvO2 represents an average of all the venous oxygen saturations of the various organs and tissues.
Time frame: 30 mins after initial dose, every 2 hours as long as subject was on drug up to approximately 24 hours
Population: Phase 2 subjects: 4 subjects did not have a swan ganz catheter. 1 subject had a swan ganz catheter, but measurement was unattainable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 12 hours | -1.6 percent change | Standard Deviation 6.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 30 mins after initial dose | 1.5 percent change | Standard Deviation 8.5 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 2 hours | 1.5 percent change | Standard Deviation 9.6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 4 hours | 1.3 percent change | Standard Deviation 5.1 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 6 hours | 1.1 percent change | Standard Deviation 7.4 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 8 hours | 1.4 percent change | Standard Deviation 4.8 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 10 hours | -3.4 percent change | Standard Deviation 7.4 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 18 hours | -0.5 percent change | Standard Deviation 10.3 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | 24 hours | -3.0 percent change | Standard Deviation 13.9 |
Secondary
Change in Mean Venous Oxygen Saturation (SvO2) From Baseline
Time frame: dose 1 (1 hour), dose 2 (2 hour), dose 3 (3 hour), combined therapy (4.5 - 5 hour), end INO (6 - 7 hour)
Population: Phase 1 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | dose 1 | -2.3 percent change | Standard Deviation 2.3 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | dose 2 | -2.6 percent change | Standard Deviation 5.5 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | dose 3 | -1.7 percent change | Standard Deviation 7.5 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | combined therapy | 0.3 percent change | Standard Deviation 6 |
| Phase 2: Inhaled Iloprost Continuous | Change in Mean Venous Oxygen Saturation (SvO2) From Baseline | end INO | 1.4 percent change | Standard Deviation 2 |