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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00660179




Registration number
NCT00660179
Ethics application status
Date submitted
14/04/2008
Date registered
17/04/2008
Date last updated
28/09/2015

Titles & IDs
Public title
Study of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension
Scientific title
A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group, Event-driven, Phase III Study to Assess the Effects of Macitentan (ACT-064992) on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension
Secondary ID [1] 0 0
AC-055-302
Universal Trial Number (UTN)
Trial acronym
SERAPHIN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - macitentan (ACT-064992)
Treatment: Drugs - macitentan (ACT-064992)
Treatment: Drugs - placebo

Experimental: 1 - Macitentan (ACT-064992) tablet, 3 mg, once daily

Experimental: 2 - Macitentan (ACT-064992) tablet, 10 mg, once daily

Placebo Comparator: 3 - Matching placebo, once daily


Treatment: Drugs: macitentan (ACT-064992)
Tablet, 3 mg dosage, once daily

Treatment: Drugs: macitentan (ACT-064992)
Tablet, 10 mg dosage, once daily

Treatment: Drugs: placebo
Matching placebo, once daily

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Time to First Confirmed Morbidity or Mortality Event up to the End of Treatment (Kaplan-Meier Estimate of Patients Without a Morbidity or Mortality Event) - Morbidity or mortality events were defined as: a) Death; b) Atrial septostomy; c) Lung transplantation; d) Initiation of intravenous (i.v.) or subcutaneous prostanoids, or; e) Other worsening of pulmonary arterial hypertension (PAH).
Other worsening of PAH was defined by the combined occurrence of all the following 3 events:
At least 15% decrease in the 6 minute walk distance from baseline, confirmed by 2 tests performed on separate days, within 2 weeks.
AND worsening of PAH symptoms including at least one of the following:
a) Increase in WHO Functional Class (WHO FC), or no change in patients in WHO FC IV at baseline; b) Appearance or worsening of signs of right heart failure that did not respond to optimized oral diuretic therapy
AND need for new treatment(s) for PAH that included the following: a) Oral or inhaled prostanoids; b) Oral phosphodiesterase inhibitors; c) Endothelin receptor antagonists (only after discontinuation of study treatment; d) i.v. diuretics
Timepoint [1] 0 0
Up to end of treatment (data presented up to month 36)
Secondary outcome [1] 0 0
Time to Death Due to PAH or Hospitalisation for PAH up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) - Events of PAH or hospitalization for PAH up to the end of treatment included: death due to PAH, or onset of a treatment-emergent adverse event with a fatal outcome due to PAH occurring up to 4 weeks after the end of treatment, or hospitalisation for PAH up to the end of treatment.
Timepoint [1] 0 0
Up to end of treatment (data presented up to month 36)
Secondary outcome [2] 0 0
Time to Death Due to Any Cause up to the End of Treatment (Kaplan-Meier Estimate of Patients Without an Event) - Events of death due to any cause up to the end of treatment (plus 7 days)
Timepoint [2] 0 0
Up to end of treatment (data presented up to month 36)
Secondary outcome [3] 0 0
Time to Death Due to Any Cause up to the End of Study (Kaplan-Meier Estimate of Patients Without an Event) - Events of death due to any cause up to the end of study (EOS). The initiation of EOS procedure occurred when the target of 285 events was expected to have been achieved (30 January 2012).
Timepoint [3] 0 0
Up to end of study (data presented up to month 36)
Secondary outcome [4] 0 0
Change From Baseline to Month 6 in 6-minute Walk Distance - The 6-minute walk test (6MWT) is a non-encouraged test, performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. These guidelines were provided to all sites. For patients who had never performed a 6MWT previously, a training test was required before the qualifying tests for inclusion were performed.
Timepoint [4] 0 0
Baseline to month 6
Secondary outcome [5] 0 0
Number of Patients With Improvements in World Health Organization Functional Class From Baseline to Month 6 - Class I: no limitation of usual physical activity (PA) which does not increase dyspnea, fatigue, chest pain, or presyncope.
Class II: mild limitation of PA. No discomfort at rest. Normal PA increases dyspnea, fatigue, chest pain, or presyncope.
Class III: marked limitation of PA. No discomfort at rest. Less than ordinary activity increases dyspnea, fatigue, chest pain, or presyncope.
Class IV: unable to perform any PA and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any PA.
Timepoint [5] 0 0
Baseline to month 6
Secondary outcome [6] 0 0
Pulmonary Vascular Resistance at Baseline and Month 6 - In a sub-study, hemodynamic variables were assessed at baseline and Month 6. If the patient had undergone a right heart catheterization during the 3 months prior to randomization, these results were to be used as baseline values, if the background therapy had not changed during the intervening period.
Timepoint [6] 0 0
Baseline to month 6
Secondary outcome [7] 0 0
Cardiac Index at Baseline and Month 6 - In a sub-study, hemodynamic variables were assessed at baseline and Month 6. If the patient had undergone a right heart catheterization during the 3 months prior to randomization, these results were to be used as baseline values, if the background therapy had not changed during the intervening period.
Timepoint [7] 0 0
Baseline to month 6

Eligibility
Key inclusion criteria
1. Signed informed consent prior to initiation of any study mandated procedure.

2. Patients with symptomatic pulmonary arterial hypertension (PAH) in modified World
Health Organization (WHO) functional class II to IV.

3. Patients with the following types of pulmonary arterial hypertension (PAH) belonging
to groups 1.1 to 1.3 of the Venice classification:

- Idiopathic (IPAH);

- Familial (FPAH); or

- Related to:

- Collagen vascular disease;

- Simple, congenital systemic-to-pulmonary shunts at least 1 year post
surgical repair;

- Human immunodeficiency virus (HIV) infection; or

- Drugs and toxins.

4. PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization and
showing all of the following:

- Mean pulmonary artery pressure (mPAP) > 25 mmHg at rest;

- Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic
pressure (LVEDP) < 15 mmHg; and

- Pulmonary vascular resistance (PVR) at rest >= 320 dyn×sec/cm^5.

5. 6-minute walk distance (6MWD) >= 50 m.

6. Men or women > 12 years of age (women of childbearing potential must have a negative
pre-treatment serum pregnancy test and must use a reliable method of contraception).
Minimum age
12 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. PAH associated with portal hypertension, thyroid disorders, glycogen storage disease,
Gaucher''s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies,
myeloproliferative disorders or splenectomy.

2. PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and
combined and complex systemic-to-pulmonary shunts, corrected or non corrected.

3. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg),
known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.

4. Persistent pulmonary hypertension of the newborn.

5. Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.

6. Moderate to severe obstructive lung disease: forced expiratory volume in 1
second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value after
bronchodilator administration.

7. Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of
predicted value.

8. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.

9. Estimated creatinine clearance < 30 mL/min

10. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5
times the upper limit of normal.

11. Hemoglobin < 75% of the lower limit of the normal range.

12. Systolic blood pressure < 100 mmHg.

13. Acute or chronic physical impairment (other than dyspnea), limiting the ability to
comply with study requirements.

14. Pregnant or breast-feeding.

15. Known concomitant life-threatening disease with a life expectancy < 12 months.

16. Body weight < 40 kg.

17. Any condition that prevents compliance with the protocol or adherence to therapy.

18. Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary
rehabilitation program based on exercise.

19. Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to
randomization.

20. Systemic treatment within 4 week prior to randomization with cyclosporine A or
tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR)
inhibitors).

21. Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization

22. Known hypersensitivity to drugs of the same class as the study drug, or any of their
excipients.

23. Planned treatment, or treatment, with another investigational drug within 1 month
prior to randomization.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
St. Vincent's Hospital - Darlinghurst, NSW
Recruitment hospital [2] 0 0
The Alfred Hospital - Melbourne, VIC
Recruitment hospital [3] 0 0
Royal Brisbane Hospital - Sunshine Coast
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst, NSW
Recruitment postcode(s) [2] 0 0
3181 - Melbourne, VIC
Recruitment postcode(s) [3] 0 0
4558 - Sunshine Coast
Recruitment outside Australia
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Actelion
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The AC-055-302/SERAPHIN study will be an event-driven Phase III study, comparing two
different doses of macitentan (ACT-064992) (3 and 10 mg) vs placebo in patients with
symptomatic PAH. The main study objective is to demonstrate that macitentan (ACT-064992)
prolongs time to the first morbidity or mortality event, and to evaluate the benefit/risk
profile of macitentan (ACT-064992) in the treatment of patients with symptomatic PAH.
Trial website
https://clinicaltrials.gov/show/NCT00660179
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Loic Perchenet, PhD
Address 0 0
Actelion
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications