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Epoprostenol for Injection in Pulmonary Arterial Hypertension (EPITOME-1)

Primary Purpose

Pulmonary Arterial Hypertension

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
ACT-385781A (Actelion Epoprostenol)
Flolan®
Sponsored by
Actelion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring Pulmonary Arterial Hypertension, PAH, EPITOME-1

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California - San Diego
  • University of Colorado - Denver
  • Duke University Medical Center
  • University of Pennsylvania
  • Vanderbilt Medical Center
  • University of Texas Southwestern Medical Center
  • Baylor College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

1

2

Arm Description

ACT-385781A (Actelion Epoprostenol)

Flolan®

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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).
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.
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.
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).
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).
Body Weight - Baseline and Day 28
Body weight was measured both at baseline and day 28.

Secondary Outcome Measures

Full Information

First Posted
April 15, 2010
Last Updated
November 29, 2012
Sponsor
Actelion
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1. Study Identification

Unique Protocol Identification Number
NCT01105091
Brief Title
Epoprostenol for Injection in Pulmonary Arterial Hypertension
Acronym
EPITOME-1
Official Title
A Phase IV, Open-label, Randomized, Multicenter Study of the Safety, Tolerability,and Pharmacokinetics of ACT- 385781A Compared to Flolan® in Injectable Prostanoid Treatment-naïve Patients With Pulmonary Arterial Hypertension (PAH)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2012
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
May 2011 (Actual)
Study Completion Date
July 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Actelion

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
Keywords
Pulmonary Arterial Hypertension, PAH, EPITOME-1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
ACT-385781A (Actelion Epoprostenol)
Arm Title
2
Arm Type
Active Comparator
Arm Description
Flolan®
Intervention Type
Drug
Intervention Name(s)
ACT-385781A (Actelion Epoprostenol)
Intervention Description
per Prescribing Information
Intervention Type
Drug
Intervention Name(s)
Flolan®
Intervention Description
Per Prescribing Information
Primary Outcome Measure Information:
Title
Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 2 ng/kg/Min
Description
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
Title
Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 4 ng/kg/Min
Description
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
Title
Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 2 ng/kg/Min
Description
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
Title
Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 4 ng/kg/Min
Description
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
Title
Six-minute Walk Distance (6MWD) - Baseline and Day 28
Description
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)
Title
Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28
Description
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)
Title
Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28
Description
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
Title
Blood Pressure - Baseline and Day 28
Description
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
Title
Heart Rate - Baseline and Day 28
Description
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
Title
Body Weight - Baseline and Day 28
Description
Body weight was measured both at baseline and day 28.
Time Frame
Baseline and 28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female subjects aged 18-65 years 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 Patients with PAH in modified NYHA functional class III or IV at the time of enrollment in need of injectable epoprostenol. 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 Women of childbearing potential must use a reliable method of contraception. Exclusion Criteria: Patients with respiratory and/or cardiovascular distress in need of emergency care including i.v. epoprostenol administration or any vasopressive i.v. drugs Known pulmonary veno-occlusive disease (PVOD) Current use of i.v. inotropic agents Tachycardia with heart rate > 120 beats/min Pulmonary arterial hypertension related to any condition other than those specified in the inclusion criteria Known hypersensitivity to the formulations of ACT-385781A or any of its excipients, and Flolan or any of its excipients Use of inhaled iloprost or treprostinil during the week prior to screening Cerebrovascular events (e.g., transient ischemic attack or stroke) within 6 months of screening History of myocardial infarction 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 Chronic bleeding disorder Infection(s) within the past month that in the mind of the investigator would contraindicate the use of epoprostenol Pregnancy or breast-feeding Participation in another clinical trial, except observational (noninterventional), or receipt of an investigational product within 30 days prior to randomization 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 Known concomitant life-threatening disease other than PAH with a life expectancy < 12 months
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wade Benton, PharmD
Organizational Affiliation
Actelion
Official's Role
Study Director
Facility Information:
Facility Name
University of California - San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Facility Name
University of Colorado - Denver
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Vanderbilt Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

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Epoprostenol for Injection in Pulmonary Arterial Hypertension

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