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Study of ACT-293987 (NS-304) in Pulmonary Arterial Hypertension (PAH)

Primary Purpose

Pulmonary Arterial Hypertension

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ACT-293987 (NS-304)
Sponsored by
Actelion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Pulmonary Arterial Hypertension

Eligibility Criteria

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

Inclusion Criteria:

  1. Male and female subjects 18 years of age or older with symptomatic PAH despite treatment with anticoagulants, calcium channel blockers, diuretics, cardiac glycosides, supplemental oxygen, endothelin-receptor antagonists and/or phosphodiesterase inhibitors. Endothelin receptor antagonists and phosphodiesterase inhibitors must have been used at a stable dose for more than 12 weeks before screening.
  2. Subjects with idiopathic PAH, familial pulmonary arterial hypertension and PAH associated with collagen vascular disease, corrected congenital vitium (congenital systemic to pulmonary shunts surgically repaired at least five years before) or anorexigen use.
  3. Diagnosis of PAH established according to the standard criteria:

    1. Resting mean pulmonary arterial pressure > 25 mmHg.
    2. PVR > 240 dynes s/cm5.
    3. Pulmonary capillary wedge pressure or left ventricular end diastolic pressure < 15 mmHg.
  4. PVR > 400 dynes s/cm5.
  5. Two 6MWTs between 150 and 500 m (inclusive) with the variation in 6MWT within ± 15% between the two tests despite other treatments for PAH.

    - Two 6MWT values are needed. Only one 6MWT should be performed at screening for confirmation of eligibility if 6MWT has been previously conducted within six weeks of the screening visit unless the subject was taking another investigational drug or participating in a specific training and exercise programme at the time of the previous test.

  6. Subjects who are able and willing to refrain from sunbathing, prolonged sun exposure, and solarium use, and to limit skin and eye exposure to sunlight using appropriate precautions (protective clothing, sunscreen and sunglasses) from the first dose until 14 days after study drug discontinuation.

Exclusion Criteria:

Subjects will not be entered in the study for any of the following reasons:

  1. Subjects with clinically unstable right heart failure within the last three months (NYHA Class IV).
  2. Subjects who have received or have been scheduled to receive long-term treatment with epoprostenol within three months before screening.
  3. Hypotensive subjects (systemic systolic blood pressure < 85 mmHg).
  4. Subjects with PAH associated with portal hypertension, Human Immunodeficiency Virus infection or unrepaired congenital systemic to pulmonary shunts.
  5. Subjects with ventilation-perfusion lung scan or pulmonary angiography indicative of thromboembolic disease.
  6. Subjects with significant obstructive (forced expiratory volume in one second [FEV1]/forced vital capacity [FVC] < 70% predicted) or restrictive (total lung capacity < 70% predicted) lung disease.
  7. In collagen vascular diseases, subjects with significant interstitial disease (FVC < 70% predicted).
  8. Subjects with evidence of left sided heart disease.
  9. Subjects with moderate or severe hepatic impairment (Child-Pugh B and C).
  10. Subjects with clinically significant chronic renal insufficiency (estimated creatinine clearance < 30 mL/minute, or serum creatinine > 2.5 mg/dL).
  11. Subjects who are receiving or have been receiving any investigational drugs within 30 days before screening.
  12. Subjects with musculoskeletal disorder limiting ambulation.
  13. Females who are breast-feeding, pregnant or plan to become pregnant during the study and females who are not using a highly effective method of birth control (failure rate less than 1% per year) such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner.

Sites / Locations

  • Medizinische Universitat Wien, Universitatsklinik fur Innere Medizin II, Kardiologie
  • Gasthuisberg University Hospital, Pneumology
  • Hopital Antoine Beclere, Pneumologie
  • Department of Respiratory Medicine, Hannover Medical School
  • Semmelweis University, Clinic of Pulmonology
  • Hospital Sant'Orsola Malpighi, Cardiology's Department
  • Instytut Gruzilcy i Chorob Pluc, Klinika Chorob Wewnetrznych Klatki Piersiowej
  • Hammersmith Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ACT-293987 (NS-304) and matching placebo

Arm Description

Subjects will be randomized to the study following screening. Each subject will then undergo an acute hemodynamic study with right heart catheterization after a single oral administration of ACT-293987 (NS-304)on Day 0. The objectives are to collect data about the drug effect on the right heart hemodynamic parameters (PVR, calculated SVR and PVR/SVR) measured by right heart catheterization after single oral dose administration of NS-304 and to assess the safety and tolerability of a single oral dose of NS-304.

Outcomes

Primary Outcome Measures

Assessment of hemodynamic parameters after single oral dose of ACT-293987.
Proof-of-concept assessment of the efficacy of ACT-293987 in subjects with PAH by measuring the change from baseline in the PVR at Week 17 compared to placebo.

Secondary Outcome Measures

Safety and tolerability of a single oral dose of ACT-293987.
Assessments of preliminary efficacy of ACT-293987 regarding 6 minute walk test (6MWT), proportion of subjects with aggravation of PAH, hemodynamic parameters other than PVR

Full Information

First Posted
October 9, 2009
Last Updated
August 11, 2023
Sponsor
Actelion
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1. Study Identification

Unique Protocol Identification Number
NCT00993408
Brief Title
Study of ACT-293987 (NS-304) in Pulmonary Arterial Hypertension (PAH)
Official Title
A Multi-centre, Multinational, Open-label, Single-dose Acute Hemodynamic Study Followed by Multi-centre, Multinational, Randomized, Double-blind, Parallel-group, Placebo Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy (Proof-of-concept) of ACT-293987 (NS-304) in the Treatment of Pulmonary Arterial Hypertension in Subjects Aged 18 Years and Over
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
April 30, 2008 (Actual)
Primary Completion Date
June 30, 2009 (Actual)
Study Completion Date
June 30, 2009 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a multi-centre, multinational, open-label, single-dose acute hemodynamic study followed by randomized, double-blind, parallel-group, placebo controlled study. Eligible subjects will undergo an open-label, single-dose acute hemodynamic study with ACT-293987(NS-304) and 21 weeks of double-blind treatment during which subjects will receive either ACT-293987 (NS-304) or placebo b.i.d. Subjects who have completed the double-blind study can enter the open extension study (separate protocol) and receive administration of ACT-293987 (NS-304) if the subject wishes and the Investigator considers it appropriate.
Detailed Description
This is a multi-centre, multinational, open-label, single-dose acute hemodynamic study followed by a randomized, double-blind, parallel-group, placebo controlled study. Eligible subjects will undergo screening followed by randomized allocation to treatment group for the double-blind study, followed in turn by immediate enrollment in an open-label, single-dose acute hemodynamic study with ACT-293987 (NS-304) and 21 weeks of double-blind treatment during which subjects will receive either ACT-293987 (NS-304)or placebo twice daily (b.i.d.). Subjects who have completed the double-blind study can enter the open extension study and receive administration of ACT-293987 (NS-304) (separate protocol)if the subject wishes and the investigator considers it appropriate. Unblinding will occur on a subject-by-subject basis when the Week 17 data for the subject have been fixed. Approximately 44 subjects are to be randomized in a ratio of 3:1 to the two treatment groups, ACT-293987 (NS-304) and placebo (33 subjects to ACT-293987 (NS-304) and 11 subjects to placebo). Subjects will be randomized to the study following screening.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Allocation
Randomized
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ACT-293987 (NS-304) and matching placebo
Arm Type
Experimental
Arm Description
Subjects will be randomized to the study following screening. Each subject will then undergo an acute hemodynamic study with right heart catheterization after a single oral administration of ACT-293987 (NS-304)on Day 0. The objectives are to collect data about the drug effect on the right heart hemodynamic parameters (PVR, calculated SVR and PVR/SVR) measured by right heart catheterization after single oral dose administration of NS-304 and to assess the safety and tolerability of a single oral dose of NS-304.
Intervention Type
Device
Intervention Name(s)
ACT-293987 (NS-304)
Primary Outcome Measure Information:
Title
Assessment of hemodynamic parameters after single oral dose of ACT-293987.
Time Frame
17 weeks
Title
Proof-of-concept assessment of the efficacy of ACT-293987 in subjects with PAH by measuring the change from baseline in the PVR at Week 17 compared to placebo.
Time Frame
17 weeks
Secondary Outcome Measure Information:
Title
Safety and tolerability of a single oral dose of ACT-293987.
Time Frame
17 weeks
Title
Assessments of preliminary efficacy of ACT-293987 regarding 6 minute walk test (6MWT), proportion of subjects with aggravation of PAH, hemodynamic parameters other than PVR
Time Frame
17 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female subjects 18 years of age or older with symptomatic PAH despite treatment with anticoagulants, calcium channel blockers, diuretics, cardiac glycosides, supplemental oxygen, endothelin-receptor antagonists and/or phosphodiesterase inhibitors. Endothelin receptor antagonists and phosphodiesterase inhibitors must have been used at a stable dose for more than 12 weeks before screening. Subjects with idiopathic PAH, familial pulmonary arterial hypertension and PAH associated with collagen vascular disease, corrected congenital vitium (congenital systemic to pulmonary shunts surgically repaired at least five years before) or anorexigen use. Diagnosis of PAH established according to the standard criteria: Resting mean pulmonary arterial pressure > 25 mmHg. PVR > 240 dynes s/cm5. Pulmonary capillary wedge pressure or left ventricular end diastolic pressure < 15 mmHg. PVR > 400 dynes s/cm5. Two 6MWTs between 150 and 500 m (inclusive) with the variation in 6MWT within ± 15% between the two tests despite other treatments for PAH. - Two 6MWT values are needed. Only one 6MWT should be performed at screening for confirmation of eligibility if 6MWT has been previously conducted within six weeks of the screening visit unless the subject was taking another investigational drug or participating in a specific training and exercise programme at the time of the previous test. Subjects who are able and willing to refrain from sunbathing, prolonged sun exposure, and solarium use, and to limit skin and eye exposure to sunlight using appropriate precautions (protective clothing, sunscreen and sunglasses) from the first dose until 14 days after study drug discontinuation. Exclusion Criteria: Subjects will not be entered in the study for any of the following reasons: Subjects with clinically unstable right heart failure within the last three months (NYHA Class IV). Subjects who have received or have been scheduled to receive long-term treatment with epoprostenol within three months before screening. Hypotensive subjects (systemic systolic blood pressure < 85 mmHg). Subjects with PAH associated with portal hypertension, Human Immunodeficiency Virus infection or unrepaired congenital systemic to pulmonary shunts. Subjects with ventilation-perfusion lung scan or pulmonary angiography indicative of thromboembolic disease. Subjects with significant obstructive (forced expiratory volume in one second [FEV1]/forced vital capacity [FVC] < 70% predicted) or restrictive (total lung capacity < 70% predicted) lung disease. In collagen vascular diseases, subjects with significant interstitial disease (FVC < 70% predicted). Subjects with evidence of left sided heart disease. Subjects with moderate or severe hepatic impairment (Child-Pugh B and C). Subjects with clinically significant chronic renal insufficiency (estimated creatinine clearance < 30 mL/minute, or serum creatinine > 2.5 mg/dL). Subjects who are receiving or have been receiving any investigational drugs within 30 days before screening. Subjects with musculoskeletal disorder limiting ambulation. Females who are breast-feeding, pregnant or plan to become pregnant during the study and females who are not using a highly effective method of birth control (failure rate less than 1% per year) such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner.
Facility Information:
Facility Name
Medizinische Universitat Wien, Universitatsklinik fur Innere Medizin II, Kardiologie
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
Gasthuisberg University Hospital, Pneumology
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Hopital Antoine Beclere, Pneumologie
City
Paris
Country
France
Facility Name
Department of Respiratory Medicine, Hannover Medical School
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Semmelweis University, Clinic of Pulmonology
City
Budapest
ZIP/Postal Code
H-1125
Country
Hungary
Facility Name
Hospital Sant'Orsola Malpighi, Cardiology's Department
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
Instytut Gruzilcy i Chorob Pluc, Klinika Chorob Wewnetrznych Klatki Piersiowej
City
Warsaw
ZIP/Postal Code
01-138
Country
Poland
Facility Name
Hammersmith Hospital
City
London
ZIP/Postal Code
W12 0HS
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
22362844
Citation
Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N, Degano B, Bonderman D, Kurzyna M, Efficace M, Giorgino R, Lang IM. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012 Oct;40(4):874-80. doi: 10.1183/09031936.00137511. Epub 2012 Feb 23.
Results Reference
derived

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Study of ACT-293987 (NS-304) in Pulmonary Arterial Hypertension (PAH)

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