Epoprostenol for Injection in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension Clinical Trial

— 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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01105091
• Other study ID #: AC-066A401
• Status: Completed
• Phase: Phase 4
• First received: April 15, 2010
• Last updated: November 29, 2012
• Start date: March 2010
• Est. completion date: July 2011

Study information

• Verified date: November 2012
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• ACT-385781A (Actelion Epoprostenol)
per Prescribing Information
• Flolan®
Per Prescribing Information

Locations

Country	Name	City	State
United States	University of Colorado - Denver	Aurora	Colorado
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Baylor College of Medicine	Houston	Texas
United States	University of California - San Diego	La Jolla	California
United States	Vanderbilt Medical Center	Nashville	Tennessee
United States	University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Day 1	No
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.	Day 1	No
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.	Day 1	No
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.	Day 1	No
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).	Baseline and 28 days (+3 days)	No
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.	From baseline to 28 days (+3 days)	No
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.	Baseline and 28 days	No
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).	Baseline and 28 days	Yes
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).	Baseline and 28 days	Yes
Primary	Body Weight - Baseline and Day 28	Body weight was measured both at baseline and day 28.	Baseline and 28 days	No