Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary Arterial Hypertension, PAH, EPITOME-1
Brief summary
This is a prospective, multi-center, open-label, randomized, Phase IV exploratory study comparing safety, tolerability, pharmacokinetics, and effectiveness of ACT-385781A and Flolan (epoprostenol sodium) in patients with pulmonary arterial hypertension who are naïve to injectable prostanoid treatment and in need of such treatment. Approximately 30 patients from 8 U.S. clinical sites will be randomized to receive either ACT-385781A or Flolan (2:1 respectively) for 28 days of treatment.
Interventions
per Prescribing Information
DRUGFlolan®
Per Prescribing Information
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female subjects aged 18-65 years 2. Patients with the following types of pulmonary arterial hypertension (PAH) belonging to WHO Group I: * Idiopathic (IPAH) * Heritable (HPAH) * Associated (APAH) with * Connective tissue diseases * Drugs and toxins 3. Patients with PAH in modified NYHA functional class III or IV at the time of enrollment in need of injectable epoprostenol. 4. Patients must be injectable prostanoid treatment-naïve and either * newly diagnosed and not yet treated with specific PAH therapies or * currently treated with existing background PAH therapy with one or more of the following medications for 90 days prior to enrollment and on a stable dose for 30 days prior to enrollment: * Bosentan * Ambrisentan * Sildenafil * Tadalafil 5. Women of childbearing potential must use a reliable method of contraception.
Exclusion criteria
1. Patients with respiratory and/or cardiovascular distress in need of emergency care including i.v. epoprostenol administration or any vasopressive i.v. drugs 2. Known pulmonary veno-occlusive disease (PVOD) 3. Current use of i.v. inotropic agents 4. Tachycardia with heart rate \> 120 beats/min 5. Pulmonary arterial hypertension related to any condition other than those specified in the inclusion criteria 6. Known hypersensitivity to the formulations of ACT-385781A or any of its excipients, and Flolan or any of its excipients 7. Use of inhaled iloprost or treprostinil during the week prior to screening 8. Cerebrovascular events (e.g., transient ischemic attack or stroke) within 6 months of screening 9. History of myocardial infarction 10. History of left-sided heart disease, including any of the following: * hemodynamically significant aortic or mitral valve disease * restrictive or congestive cardiomyopathy * left ventricular ejection fraction \< 40% by multigated radionucleotide angiogram(MUGA),angiography, or echocardiography * unstable angina pectoris * life-threatening cardiac arrhythmias 11. Chronic bleeding disorder 12. Infection(s) within the past month that in the mind of the investigator would contraindicate the use of epoprostenol 13. Pregnancy or breast-feeding 14. Participation in another clinical trial, except observational (noninterventional), or receipt of an investigational product within 30 days prior to randomization 15. Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease 16. Known concomitant life-threatening disease other than PAH with a life expectancy \< 12 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 2 ng/kg/Min | Day 1 | The plasma concentration for the epoprostenol metabolite 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha was measured at 2 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. |
| Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 4 ng/kg/Min | Day 1 | The plasma concentration for the epoprostenol metabolite 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha was measured at 4 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. |
| Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 2 ng/kg/Min | Day 1 | The plasma concentration for the epoprostenol metabolite 6-keto-Prostacyclin F1alpha was measured at 2 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. |
| Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 4 ng/kg/Min | Day 1 | The plasma concentration for the epoprostenol metabolite 6-keto-Prostacyclin F1alpha was measured at 4 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. |
| Six-minute Walk Distance (6MWD) - Baseline and Day 28 | Baseline and 28 days (+3 days) | The 6-minute walk test (6MWT) was to be performed prior to initiating study treatment either during the screening visit or on Day 1 prior to drug initiation, and Day 28 (End of treatment (EOT)). This assessment is a non-encouraged test that measures the distance walked for a duration of 6 minutes. The 6MWD was recorded in the Case Report Form (CRF). |
| Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28 | From baseline to 28 days (+3 days) | Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. |
| Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28 | Baseline and 28 days | Central venous blood oxygen saturation assessment was performed only in specific centers. Measurements for ScVO2 were performed during the inpatient hospitalization period on Day 1 (prior to drug initiation) and on Day 28 (EOT). Samples for ScVO2 were obtained by aspirating blood from the indwelling central venous catheter. After the sample had been drawn, the catheter was primed with study drug in order to refill the lumen to avoid interruption in treatment and sudden decompensation. |
| Blood Pressure - Baseline and Day 28 | Baseline and 28 days | Blood pressure (systolic and diastolic) were measured indirectly using an automatic oscillometric device, on the same arm for each measurement. The Blood Pressure was assessed at baseline and at Day 28 (End of Study Treatment visit). |
| Heart Rate - Baseline and Day 28 | Baseline and 28 days | Heart rate was measured indirectly using an automatic oscillometric device, on the same arm for each measurement. The Heart Rate was assessed at Baseline and at Day 28 (End of Study Treatment visit). |
| Body Weight - Baseline and Day 28 | Baseline and 28 days | Body weight was measured both at baseline and day 28. |
Participant flow
Recruitment details
The study was conducted at seven Pulmonary Hypertension centers in the U.S. Patients were recruited from these Pulmonary Hypertension medical clinics. Recruitment period was March 2010 through March 2011.
Pre-assignment details
Up to 14 days screening period.
Participants by arm
| Arm | Count |
|---|---|
| ACT-385781A (Epoprostenol for Injection) The prepared solution was administered by continuous intravenous (i.v.) infusion via a central venous catheter using an ambulatory infusion pump. Administration was to be initiated at an infusion rate of 2 ng/kg/min, with up titration according to therapeutic need and tolerability. | 20 |
| Flolan® (Epoprostenol Sodium) for Injection The prepared solution was administered by continuous i.v. infusion via a central venous catheter using an ambulatory infusion pump. Administration was to be initiated at an infusion rate of 2 ng/kg/min, with up titration according to therapeutic need and tolerability | 10 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
Baseline characteristics
| Characteristic | ACT-385781A (Epoprostenol for Injection) | Flolan® (Epoprostenol Sodium) for Injection | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 10 Participants | 28 Participants |
| Age, Continuous | 45.0 years STANDARD_DEVIATION 17 | 44.1 years STANDARD_DEVIATION 12.6 | 44.7 years STANDARD_DEVIATION 15.4 |
| New York Heart Association (NYHA) Functional Class Class I | 0 participants | 0 participants | 0 participants |
| New York Heart Association (NYHA) Functional Class Class II | 0 participants | 0 participants | 0 participants |
| New York Heart Association (NYHA) Functional Class Class III | 17 participants | 8 participants | 25 participants |
| New York Heart Association (NYHA) Functional Class Class IV | 3 participants | 2 participants | 5 participants |
| Region of Enrollment United States | 20 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 14 Participants | 10 Participants | 24 Participants |
| Sex: Female, Male Male | 6 Participants | 0 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 20 | 10 / 10 |
| serious Total, serious adverse events | 6 / 20 | 2 / 10 |
Outcome results
Primary
Blood Pressure - Baseline and Day 28
Blood pressure (systolic and diastolic) were measured indirectly using an automatic oscillometric device, on the same arm for each measurement. The Blood Pressure was assessed at baseline and at Day 28 (End of Study Treatment visit).
Time frame: Baseline and 28 days
Population: Patients who had both baseline and Day 28 assessments were included in the analysis. The analysis was conducted without replacement of missing values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Blood Pressure - Baseline and Day 28 | Systolic Blood Pressure (Baseline) | 106.5 mm Hg |
| ACT-385781A (Epoprostenol for Injection) | Blood Pressure - Baseline and Day 28 | Systolic Blood Pressure (Day 28) | 117.5 mm Hg |
| ACT-385781A (Epoprostenol for Injection) | Blood Pressure - Baseline and Day 28 | Diastolic Blood Pressure (Baseline) | 62.0 mm Hg |
| ACT-385781A (Epoprostenol for Injection) | Blood Pressure - Baseline and Day 28 | Diastolic Blood Pressure (Day 28)) | 71.0 mm Hg |
| Flolan® (Epoprostenol Sodium) for Injection | Blood Pressure - Baseline and Day 28 | Diastolic Blood Pressure (Day 28)) | 73.0 mm Hg |
| Flolan® (Epoprostenol Sodium) for Injection | Blood Pressure - Baseline and Day 28 | Systolic Blood Pressure (Baseline) | 106.5 mm Hg |
| Flolan® (Epoprostenol Sodium) for Injection | Blood Pressure - Baseline and Day 28 | Diastolic Blood Pressure (Baseline) | 68.0 mm Hg |
| Flolan® (Epoprostenol Sodium) for Injection | Blood Pressure - Baseline and Day 28 | Systolic Blood Pressure (Day 28) | 116.0 mm Hg |
Primary
Body Weight - Baseline and Day 28
Body weight was measured both at baseline and day 28.
Time frame: Baseline and 28 days
Population: Patients who had both baseline and Day 28 assessments were included in the analysis. The analysis was conducted without replacement of missing values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Body Weight - Baseline and Day 28 | Baseline | 74.1 kg |
| ACT-385781A (Epoprostenol for Injection) | Body Weight - Baseline and Day 28 | Day 28 | 73.6 kg |
| Flolan® (Epoprostenol Sodium) for Injection | Body Weight - Baseline and Day 28 | Baseline | 74.2 kg |
| Flolan® (Epoprostenol Sodium) for Injection | Body Weight - Baseline and Day 28 | Day 28 | 73.3 kg |
Primary
Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 2 ng/kg/Min
The plasma concentration for the epoprostenol metabolite 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha was measured at 2 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results.
Time frame: Day 1
Population: A per-protocol analysis set that included all patients in the treated set who did not violate the protocol in a way that might affect the evaluation of the effect of the study drug(s) on the pharmacokinetic endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 2 ng/kg/Min | 98.0 (pg/ml)/(ng/kg/min) |
| Flolan® (Epoprostenol Sodium) for Injection | Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 2 ng/kg/Min | 83.1 (pg/ml)/(ng/kg/min) |
Primary
Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 4 ng/kg/Min
The plasma concentration for the epoprostenol metabolite 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha was measured at 4 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results.
Time frame: Day 1
Population: A per-protocol analysis set that included all patients in the treated set who did not violate the protocol in a way that might affect the evaluation of the effect of the study drug(s) on the pharmacokinetic endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 4 ng/kg/Min | 90.9 (pg/ml)/(ng/kg/min) |
| Flolan® (Epoprostenol Sodium) for Injection | Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 4 ng/kg/Min | 59.6 (pg/ml)/(ng/kg/min) |
Primary
Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 2 ng/kg/Min
The plasma concentration for the epoprostenol metabolite 6-keto-Prostacyclin F1alpha was measured at 2 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results.
Time frame: Day 1
Population: A per-protocol analysis set that included all patients in the treated set who did not violate the protocol in a way that might affect the evaluation of the effect of the study drug(s) on the pharmacokinetic endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 2 ng/kg/Min | 85.5 (pg/ml)/(ng/kg/min) |
| Flolan® (Epoprostenol Sodium) for Injection | Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 2 ng/kg/Min | 109.2 (pg/ml)/(ng/kg/min) |
Primary
Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 4 ng/kg/Min
The plasma concentration for the epoprostenol metabolite 6-keto-Prostacyclin F1alpha was measured at 4 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results.
Time frame: Day 1
Population: A per-protocol analysis set that included all patients in the treated set who did not violate the protocol in a way that might affect the evaluation of the effect of the study drug(s) on the pharmacokinetic endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 4 ng/kg/Min | 93.1 (pg/ml)/(ng/kg/min) |
| Flolan® (Epoprostenol Sodium) for Injection | Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 4 ng/kg/Min | 95.0 (pg/ml)/(ng/kg/min) |
Primary
Heart Rate - Baseline and Day 28
Heart rate was measured indirectly using an automatic oscillometric device, on the same arm for each measurement. The Heart Rate was assessed at Baseline and at Day 28 (End of Study Treatment visit).
Time frame: Baseline and 28 days
Population: Patients who had both baseline and Day 28 assessments were included in the analysis. The analysis was conducted without replacement of missing values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Heart Rate - Baseline and Day 28 | Baseline | 83.0 Beats per minute |
| ACT-385781A (Epoprostenol for Injection) | Heart Rate - Baseline and Day 28 | Day 28 | 85.0 Beats per minute |
| Flolan® (Epoprostenol Sodium) for Injection | Heart Rate - Baseline and Day 28 | Baseline | 77.5 Beats per minute |
| Flolan® (Epoprostenol Sodium) for Injection | Heart Rate - Baseline and Day 28 | Day 28 | 88.0 Beats per minute |
Primary
Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28
Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA.
Time frame: From baseline to 28 days (+3 days)
Population: Patients who had both baseline and Day 28 assessments were included in the analysis. The analysis was conducted without replacement of missing values.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28 | Improved Patients | 6 participants |
| ACT-385781A (Epoprostenol for Injection) | Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28 | Worsened Patients | 0 participants |
| Flolan® (Epoprostenol Sodium) for Injection | Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28 | Improved Patients | 3 participants |
| Flolan® (Epoprostenol Sodium) for Injection | Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28 | Worsened Patients | 0 participants |
Primary
Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28
Central venous blood oxygen saturation assessment was performed only in specific centers. Measurements for ScVO2 were performed during the inpatient hospitalization period on Day 1 (prior to drug initiation) and on Day 28 (EOT). Samples for ScVO2 were obtained by aspirating blood from the indwelling central venous catheter. After the sample had been drawn, the catheter was primed with study drug in order to refill the lumen to avoid interruption in treatment and sudden decompensation.
Time frame: Baseline and 28 days
Population: Patients who had both baseline and Day 28 assessments were included in the analysis. The analysis was conducted without replacement of missing values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28 | Baseline | 63.0 percentage oxygen saturation |
| ACT-385781A (Epoprostenol for Injection) | Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28 | Day 28 | 58.0 percentage oxygen saturation |
| Flolan® (Epoprostenol Sodium) for Injection | Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28 | Baseline | 61.5 percentage oxygen saturation |
| Flolan® (Epoprostenol Sodium) for Injection | Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28 | Day 28 | 56.0 percentage oxygen saturation |
Primary
Six-minute Walk Distance (6MWD) - Baseline and Day 28
The 6-minute walk test (6MWT) was to be performed prior to initiating study treatment either during the screening visit or on Day 1 prior to drug initiation, and Day 28 (End of treatment (EOT)). This assessment is a non-encouraged test that measures the distance walked for a duration of 6 minutes. The 6MWD was recorded in the Case Report Form (CRF).
Time frame: Baseline and 28 days (+3 days)
Population: Patients who had both baseline and Day 28 assessments were included in the analysis. The analysis was conducted without replacement of missing values.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| ACT-385781A (Epoprostenol for Injection) | Six-minute Walk Distance (6MWD) - Baseline and Day 28 | Baseline | 339.0 meters | Full Range 84 |
| ACT-385781A (Epoprostenol for Injection) | Six-minute Walk Distance (6MWD) - Baseline and Day 28 | Day 28 | 288.0 meters | — |
| Flolan® (Epoprostenol Sodium) for Injection | Six-minute Walk Distance (6MWD) - Baseline and Day 28 | Baseline | 302.5 meters | Full Range 58.8 |
| Flolan® (Epoprostenol Sodium) for Injection | Six-minute Walk Distance (6MWD) - Baseline and Day 28 | Day 28 | 323.5 meters | — |