A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension



Sponsor:   Actelion


Sommario: The purpose of the study is to evaluate the effect of macitentan 75 mg versus placebo on
exercise capacity at Week 28 in participants with chronic thromboembolic pulmonary
hypertension (CTEPH).




TIPOLOGIA STUDIO

 
Interventistico



FASE

 
Fase 3




TRATTAMENTO

  
    
  
  • Macitentan
  • Placebo
    • 






OBIETTIVO PRIMARIO


  
  • Misura: Change From Baseline in 6-minute Walk Distance (6MWD) at Week 28
  • Tempo: Baseline (Day 1), Week 28
  • Descrizione: Change from baseline in 6MWD as measured by 6-minute walk test (6MWT) at Week 28 was
reported. The purpose of the 6MWT was to quantify exercise tolerance and capacity. This
standardized test measured the distance an individual was able to walk over a total of
six minutes on a hard, flat surface with no obstacles. The goal was for the individual to
walk as far as possible in 6 minutes.




OBIETTIVO SECONDARIO


  
  • Misura: Time to First Clinical Event Committee (CEC) Confirmed Clinical Worsening up to End-of Double-blind-treatment (EODBT) Period
  • Tempo: From Baseline (Day 1) up to EODBT: median 24.5 weeks (min 3.9 weeks; max 160.4 weeks) for macitentan, median 44 weeks (min 4 weeks; max 147.9 weeks) for placebo
  • Descrizione: Time (months) to first CEC-confirmed clinical worsening up to EODBT were reported.
Clinical worsening was defined as the occurrence of at least one of the following events:
1) All-cause death; 2) Heart and/or lung transplantation; 3) Unplanned pulmonary
hypertension (PH)-related hospitalization; 4) PH-related deterioration from baseline
identified by at least one of the following: a) Persistent increase in World Health
Organization functional class (WHO FC) that could not be explained by another cause (for
example, viral infection); b) Persistent deterioration by at least 15 percent (%) in
exercise capacity; as measured by the 6MWD; c) New or worsened signs or symptoms of right
heart failure; 5) Rescue pulmonary endarterectomy (PEA) and/or balloon pulmonary
angioplasty (BPA) procedure due to worsening of PH.
  • Misura: Number of Participants With Improvement in World Health Organization Functional Class (WHO FC) From Baseline to Week 28
  • Tempo: From Baseline (Day 1) up to Week 28
  • Descrizione: Number of participants with improvement in WHO FC from baseline to Week 28 were reported.
Improvement (decrease) in WHO FC from baseline to Week 28 was calculated for each
participant. WHO FC test was used to assess disease severity. Four functional classes
(FC) were defined from FC I (no limitation of physical activity) to FC IV (inability to
carry out any physical activity without symptoms). For the analysis purpose, these WHO FC
class values were transformed to a scale with scores ranged from 1 to 4; where a score of
1 corresponded to WHO FC Class I and a score of 4 corresponded to WHO FC Class IV. The
higher scores indicate greater symptom severity or worse impact. Improvement was
considered when a participant changed from a higher class to a lower class.
  • Misura: Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score
  • Tempo: From Baseline (Day 1) up to Week 28
  • Descrizione: The cardiopulmonary symptoms domain consisted of 6 items: shortness of breath, fatigue,
lack of energy, swelling in ankles or legs, swelling in stomach area and cough and were
reported on a 5-point Likert scale from 0 (no symptom at all) to 4 (very severe
symptoms), with higher score indicating more symptom. The symptoms part of the
PAH-SYMPACT was administered daily over a 7-day period. The recall period of symptom
items was the last 24 hours. The mean individual symptom item score was determined for
each of the 6 items and a domain score was calculated by summing the mean individual
symptom item scores and dividing by the number of items, ranged from 0=no cardiopulmonary
symptoms to 4=severe cardiopulmonary symptoms. A higher score indicated more severe
symptoms experienced.
  • Misura: Change From Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score
  • Tempo: From Baseline (Day 1) up to Week 28
  • Descrizione: The cardiovascular symptoms domain consisted of 5 items: heart palpitations (fluttering),
rapid heartbeat, chest pain, chest tightness, and lightheadedness and were reported on a
5-point Likert scale ranged from 0 (no symptoms at al) to 4 (very severe symptoms), with
high score indicating more symptom. The symptoms part of PAH-SYMPACT was administered
daily over a 7-day period. The recall period of symptom items was the last 24 hours. An
average Cardiovascular Symptoms domain score was determined based on the daily scores of
the 5 items. The mean individual symptom item score was determined for each of the 5
items and a domain score was calculated by summing the mean individual symptom item
scores and dividing by the number of items, ranged from 0=no cardiovascular symptoms to
4=severe cardiovascular symptoms. Higher score indicated more severe symptoms
experienced.
  • Misura: Change From Baseline to Week 28 in Euro Quality of Life-5-Dimension-5-Level (EQ-5D-5L) Utility Score and Visual Analog Scale (VAS) Score
  • Tempo: From Baseline (Day 1) up to Week 28
  • Descrizione: The EQ-5D-5L was a generic measure of health status. The EQ-5D-5L consisted of 2 parts:
EQ-5D-5L utility score (descriptive system) and VAS score. EQ-5D-5L descriptive system
consisted of 5-item questionnaire that assessed 5 domains including mobility, self-care,
usual activities, pain/discomfort and anxiety/depression. Each questionnaire had 5
response levels: 1 =no problems, 2 =slight problems, 3 =moderate problems, 4 =severe
problems and 5 =extreme problems. The scores for the 5 questionnaires were used to
compute a single utility score which ranged from 0 to 1, where higher score indicated
better health state and lower score indicated worse health state. EQ-5D-5L VAS rated
current health state on a vertical scale with a score ranged from 0 (worst imaginable
health state) to 100 (best imaginable health state), higher scores indicated a better
health state.
  • Misura: Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity
  • Tempo: From Baseline (Day 1) up to Week 28
  • Descrizione: Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in
moderate to vigorous physical activity were assessed. Daily life physical activity of
participant was assessed using accelerometer which was provided to the participant at
screening and was worn daily during waking hours up to Week 28. For each scheduled visit,
the 14 days prior to the visit were considered as the assessment period for physical
activity. To be considered evaluable for a given timepoint, actigraphy variables should
have been measured for at least 7 complete days (consecutive or not). A complete day is
defined as a record of at least 7 waking hours of data. Proportion of time spent in
moderate to vigorous physical activity was the estimated number of minutes spent in
moderate or higher physical activity as calculated using the Staudenmayer '15 technique
as proportion of the total minutes of algorithmically detected wear time and excluding
the minutes that fall within a sleep period.




CRITERI DI ELIGIBILITA'


    
             
  • 
        Criteri di inclusione e esclusione
        
    Inclusion Criteria:

  -  Chronic thromboembolic pulmonary hypertension (CTEPH) (World Health Organization
     [WHO] Group 4) fulfilling one of the following criteria: a) inoperable due to the
     localization of the obstruction being surgically inaccessible (that is, distal
     disease), b) persistent/recurrent CTEPH after balloon pulmonary angioplasty (BPA),
     and deemed inoperable due to the localization of the obstruction being surgically
     inaccessible (that is, distal disease), c) persistent/recurrent CTEPH after rescue
     pulmonary endarterectomy (PEA)

  -  6-minute walk distance (6MWD) greater than or equal to (>=) 100 meter (m) and less
     than or equal to (<=) 450 meters (m), documented by an eligibility and a baseline
     6-minute walk test (6MWT). The baseline 6MWD must not differ by more than 15 percent
     (%) from the eligibility test

  -  World Health Organization functional class (WHO FC) >= II

  -  Participants are to receive riociguat as per local standard of care, unless it is
     contraindicated or unavailable

Exclusion Criteria:

  -  Acute pulmonary embolism within 3 months prior to or during Screening

  -  Planned balloon pulmonary angioplasty (BPA) during the fixed duration part of the
     double-blind period

  -  Significant obstructive and restrictive lung disease

  -  Acute or chronic conditions (other than dyspnea) that limit the ability to comply
     with study requirements, in particular with 6MWT (for example, intermittent
     claudication).

  -  Symptomatic coronary artery disease requiring an intervention within 3 months prior
     to or during Screening or anticipated during the fixed duration part of the study

  -  Decompensated cardiac failure if not under close supervision

  -  Known and documented life-threatening cardiac arrhythmias

  -  Acute myocardial infarction within 6 months prior to, or during Screening

  -  Cerebrovascular events (including transient ischemic attack) within 3 months prior
     to, or during Screening

  -  Known or suspicion of pulmonary veno-occlusive disease (PVOD)

  -  Administration of ERAs, intravenous prostacyclins / prostacyclin analogs, or
     investigational treatment within 90 days prior to Randomization

  -  Change in dose or initiation of Phosphodiesterase type-5 (PDE-5) inhibitors, oral,
     inhaled or subcutaneous (SC) prostacyclins / prostacyclin analogues, prostacyclin
     receptor agonists or riociguat, a) within 90 days prior to Randomization, or b)
     anticipated during the fixed duration part of the double-blind [DB] period

  -  Hypotension, that is, systolic blood pressure (SBP) less than (<) 90 millimeters of
     mercury (mmHg) or diastolic blood pressure (DBP) <50 mmHg at Screening.

  -  Severe renal dysfunction with an estimated Glomerular Filtration Rate <30
     milliliters per minute per 1.73 meter square (mL/min/1.73 m^2) using the Chronic
     Kidney Disease Epidemiology Collaboration formula at Screening

  -  Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C,
     based on records that confirm documented medical history

  -  Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater
     than or equal to (>=) 1.5*upper limit of normal (ULN) at Screening

  -  Hemoglobin <100 g/L (<10 gram per deciliter [g/dL]) at Screening
    
        
    • 
    




SESSO

  
Tutti




  


ETA' MINIMA



Età Minima: 18 Years

Età Massima: 80 Years






LUOGO


  
Ospedale SS. Annunziata
Chieti	3178796, 66100
Fondazione IRCCS Policlinico San Matteo
Pavia	3171366, 27100
Fondazione Toscana Gabriele Monasterio CNR
Pisa	3170647, 56124
Policlinico Gemelli Universita Cattolica
Roma	8957247, 00168
A.O.U. Città della Salute e della Scienza
Torino	8980539, 10126