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A Pulmonary Arterial Hypertension Study With Macitentan to Validate the PAH-SYMPACT™ in France, Italy and Spain (ORCHESTRA)

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ClinicalTrials.gov Identifier: NCT02081690
Recruitment Status : Terminated (Slow recruitment)
First Posted : March 7, 2014
Results First Posted : February 5, 2018
Last Update Posted : February 5, 2018
Sponsor:
Information provided by (Responsible Party):
Actelion

Brief Summary:

Prospective, multi-center, open-label, single-arm, Phase 3b psychometric validation study.

Primary objectives: To evaluate the psychometric characteristics of reliability and construct validity of the French, Italian and Spanish versions of the PAH-SYMPACT™.

To evaluate the ability of the French, Italian and Spanish versions of the PAH SYMPACT™ to detect change.

Secondary objective: To assess the safety of macitentan in patients with pulmonary arterial hypertension (PAH).

Exploratory objective: To explore the effects of macitentan on PAH symptoms and their impact (as measured by the PAH-SYMPACT™) in patients with PAH in France, Italy and Spain.


Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Macitentan Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 160 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-center, Open-label, Single-arm, Phase 3b Study of Macitentan in Patients With Pulmonary Arterial Hypertension to Psychometrically Validate the French, Italian and Spanish Versions of the PAH-SYMPACT™
Actual Study Start Date : March 1, 2014
Primary Completion Date : October 1, 2015
Study Completion Date : November 1, 2015


Arm Intervention/treatment
Experimental: Macitentan
Macitentan tablet, dose of 10 mg, once daily
Drug: Macitentan
Macitentan tablet, dose of 10 mg, once daily



Primary Outcome Measures :
  1. Evaluation of the Reliability and the Construct Validity of the Cardiopulmonary Symptoms Domain of the PAH-SYMPACT [ Time Frame: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16) ]
    The Cardiopulmonary Symptoms domain consists of 6 items reported on a 5-point Likert scale (from 0 to 4). The value 0 means "no symptom" and value 4 corresponds to "very severe symptoms".The symptoms part of the PAH-SYMPACT was administered daily over a 7 day period. The recall period of symptom items is the last 24 hours. An average Cardiopulmonary Symptoms domain score is determined based on the daily scores of the 6 items. It was administered two times (daily during 7 days each time) prior to administration of Macitentan (Visit 2, Baseline) and daily during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).

  2. Evaluation of the Reliability and the Construct Validity of the Cardiovascular Symptoms Domain of the PAH-SYMPACT [ Time Frame: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16) ]
    The Cardiovascular Symptoms domain consists of 5 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "no symptoms" and value 4 corresponds to "very severe symptoms". The symptoms part of the PAH-SYMPACT was administered daily over a 7 day period. The recall period of symptom items is the last 24 hours. An average Cardiovascular Symptoms domain score is determined based on the daily scores of the 5 items. It was administered two times (daily during 7 days each time) prior to administration of Macitentan (Visit 2, Baseline) and daily during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).

  3. Evaluation of the Reliability and the Construct Validity of the Physical Impacts Domain of the PAH-SYMPACT [ Time Frame: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16) ]
    The Physical Impacts domain consists of 7 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "not at all"/"with no difficulty at all" and value 4 corresponds to "very much"/"extremely"/ "not able at all". The impacts part of the PAH-SYMACT was administered on Day 7 of the symptoms part administration. Items in the impact part have a 7 day recall period. An average Physical Impacts domain score is determined based on the 7 items in the domain. It was administered two times prior to administration of Macitentan (Visit 2, Baseline) and during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16).

  4. Evaluation of the Reliability and the Construct Validity of the Cognitive/Emotional Impacts Domain of the PAH-SYMPACT [ Time Frame: From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16) ]
    The Cognitive/Emotional Impacts domain consists of 4 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "not at all"/"with no difficulty at all" and value 4 corresponds to "very much"/"extremely"/ "not able at all". The impacts part of the PAH-SYMACT was administered on Day 7 of the symptoms part administration. Items in the impact part have a 7 day recall period. An average Cognitive/Emotional Impacts domain score is determined based on the 4 items in the domain. It was administered two times prior to administration of Macitentan (Visit 2, Baseline) and during the 7-day period in the treatment period prior to Visit 3 (Week 8) and Visit 4 (Week 16)."



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent prior to initiation of any study-mandated procedure.
  2. Patients with symptomatic PAH in WHO Functional Class (FC) II or III.
  3. Patients with PAH belonging to one of the following subgroups of the Dana Point Clinical Classification Group 1:

    1. Idiopathic, or,
    2. Heritable, or,
    3. Drug or toxin induced, or,
    4. Associated with one of the following:

    i. Connective tissue disease, ii. Congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair, iii. HIV infection.

  4. Documented hemodynamic diagnosis of PAH by right heart catheterization - performed at any time prior to Screening showing:

    1. Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and,
    2. Resting pulmonary vascular resitance (PVR) > 240 dyn.s.cm-5 and,
    3. Pulmonary capillary wede pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg.
  5. 6-minute walk distance (6MWD) ≥ 150 m at Screening.
  6. Able to fluently speak and read the local language.
  7. Men or women aged 18-80; women of childbearing potential (as defined below) must:

    1. Have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline and agree to perform monthly serum pregnancy tests, and,
    2. Agree to use two reliable methods of contraception in parallel, from Screening Visit 1 until 1 month after study drug discontinuation (see details below).

      • A female is considered to have childbearing potential unless she meets at least one of the following criteria:

        • Previous bilateral salpingo and/or oophorectomy, or hysterectomy.
        • Premature ovarian failure confirmed by a specialist.
        • Pre-pubescence, XY genotype, Turner syndrome, uterine agenesis.
        • Postmenopausal, defined as 12 consecutive months with no menses without an alternative medical cause.
      • Of the two contraceptive methods that must be used, one must be from Group 1, and one must be from Group 2, defined as follows:

        • Group 1: Oral, implantable, transdermal or injectable hormonal contraceptives, intrauterine devices, female sterilization (tubal ligation or non surgical sterilization, e.g., permanent contraception with Essure procedure), or partner's sterilization (vasectomy). If a hormonal contraceptive is chosen from this group, it must be taken for at least 1 month prior to enrollment. Alternatively, if the Essure procedure is chosen as a contraceptive method, a hysterosalpingogram must have been performed to confirm correct location of the microinserts and tubal occlusion (as per manufacturer's recommendations).
        • Group 2: Female or male condoms, diaphragm or cervical cap, any of them in combination with a spermicide.
      • Sexual abstinence, rhythm methods, or contraception by the partner alone are not considered as acceptable methods of contraception for this study.

Exclusion Criteria:

  1. Known moderate-to-severe obstructive lung disease (i.e., forced expiratory volume in one second [FEV1] < 80 % of predicted, with FEV1 / forced vital capacity [FVC] < 70%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).
  2. Known moderate-to-severe restrictive lung disease (i.e., total lung capacity [TLC] < 60% of predicted value).
  3. Hemoglobin < 100g/L at Screening.
  4. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 X upper limit of the normal range (ULN) at Screening.
  5. Patients undergoing dialysis.
  6. Systolic blood pressure (SBP) < 90 mmHg at Screening.
  7. Body weight < 40 kg at Screening.
  8. Known concomitant life-threatening diseases with a life expectancy of < 12 months.
  9. Treatment with ERAs within 3 months prior to Visit 2, or scheduled to receive any of these compounds, other than macitentan, during the trial.
  10. Treatment with intravenous or subcutaneous prostacyclin or prostacyclin analogs within 3 months prior to Visit 2, or scheduled to receive any of these compounds during the trial.
  11. Treatment with soluble guanylate cyclase stimulator (riociguat) within 3 months prior to Visit 2, or scheduled to receive riociguat during the trial.
  12. Patients who changed the dose of or discontinued phosphodiesterase type-5 inhibitor (PDE5i), inhaled prostacyclin analogues, or calcium channel blockers within 3 months prior to Visit 2.
  13. Initiation of diuretics within 1 week prior to the Baseline period.
  14. Patients on oral diuretics in whom the dose has not been stable for at least 1 week prior to the Baseline period.
  15. Treatment with cytochrome P4500 (CYP) 3A inducers within 4 weeks prior to Visit 2.
  16. Recently started (< 8 weeks prior to Visit 2) or planned cardio-pulmonary rehabilitation program based on exercise.
  17. Females who are lactating or pregnant (positive Screening or Baseline pregnancy test) or plan to become pregnant during the study.
  18. Known hypersensitivity to macitentan or its excipients or drugs of the same class.
  19. Treatment with another investigational drug within 3 months prior to Visit 2.
  20. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02081690


Locations
France
Hôpital de Haut Levêque
Bordeaux, France, 33604
Hôpital Côte de Nacre
Caen, France, 14033
Hôpital Albert Michallon
Grenoble, France, 38700
CHU de Bicêtre
Le Kremlin-Bicêtre, France, 94270
CHRU Lille - Hôpital Cardiologique
Lille, France, 59037
Hôpital Louis Pradel
Lyon, France, 69677
Hôpital Arnaud de Villeneuve
Montpellier, France, 34295
Hôpitaux de Brabois
Nancy, France, 54511
Hôpital Pontchaillou
Rennes, France, 35033
Hôpital Charles Nicolle
Rouen, France, 76031
Hôpital Nord
Saint-Etienne, France, 42227
Hôpital Civil
Strasbourg, France, 67091
Hôpital Larrey
Toulouse, France, 31059
Italy
Universita degli Studi di Bari
Bari, Italy, 70124
Ospedale di Venere
Bari, Italy, 70131
Ospedale Sant'Orsola
Bologna, Italy, 40138
A.O.U.C. Careggi
Firenze, Italy, 50124
Milan Sacco Hospital
Milan, Italy, 20157
AORN Azienda Ospedaliera dei Colli
Naples, Italy, 80131
Ambulatorio Scompenso Cardiaco e Trapiant
Pavia, Italy, 27100
Istituto di Fisiologia clinica - CNR
Pisa, Italy, 56126
Centro Per La Diagnosi E La Cura Dell'Ipertensione Polmonare
Roma, Italy, 00186
UOC Immunologia Clinica B-PGRM Centro di Riferimento per la Sclerosi Sistemica
Rome, Italy, 00161
Ospedale "S. Maria di Cà Foncello"
Treviso, Italy, 31100
Policlinico G.B. Rossi
Verona, Italy, 37134
Spain
Hospital Universitario Insular Gran Canarias
Las Palmas de Gran Canaria, Islas Canarias, Spain, 35016
Hospital General de Alicante
Alicante, Spain, 03010
Hospital Val Hebron
Barcelona, Spain, 08035
Hospital Clinic
Barcelona, Spain, 08036
Hospital de Cruces
Bilbao, Spain, 48903
Hospital Reina Sofia
Córdoba, Spain, 14004
Hospital Dr Negrin
Las Palmas de Gran Canaria, Spain, 35010
Hospital 12 Octubre
Madrid, Spain, 28041
Hospital La Paz
Madrid, Spain, 28046
Hospital Carlos Haya
Malaga, Spain, 29010
Hospital Son Espases
Palma de Mallorca, Spain, 7010
Hospital de Valdecilla
Santander, Spain, 39008
Hospital Virgen del Rocio
Sevilla, Spain, 41013
Hospita General U. Valencia
Valencia, Spain, 46014
Sponsors and Collaborators
Actelion
Investigators
Study Director: Loïc Perchene Actelion

Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT02081690     History of Changes
Other Study ID Numbers: AC-055-310
First Posted: March 7, 2014    Key Record Dates
Results First Posted: February 5, 2018
Last Update Posted: February 5, 2018
Last Verified: July 2017

Keywords provided by Actelion:
PAH-SYMPACT
psychometric instrument

Additional relevant MeSH terms:
Familial Primary Pulmonary Hypertension
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Macitentan
Endothelin A Receptor Antagonists
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Endothelin B Receptor Antagonists