A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH



Sponsor:   United Therapeutics


Sommario: Study ROR-PH-302, ADVANCE CAPACITY, is designed to evaluate the effects of ralinepag
therapy on exercise capacity as assessed by change in peak oxygen consumption (VO2)
derived from cardiopulmonary exercise testing (CPET) after 28 weeks of treatment




TIPOLOGIA STUDIO

 
Interventistico



FASE

 
Fase 3




TRATTAMENTO

  
    
  
  • Ralinepag
  • Placebo
    • 






OBIETTIVO PRIMARIO


  
  • Misura: Change from Baseline in peak VO2 assessed by CPET
  • Tempo: Baseline to Week 28
  • Descrizione: Peak VO2 by CPET was measured at Baseline (prior to starting study drug) and Week 28




OBIETTIVO SECONDARIO


  
  • Misura: Change from Baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP)
  • Tempo: Baseline to Week 28
  • Descrizione: NT-proBNP was measured at Baseline (prior to starting study drug) and Weeks 4, 8, 12, 16,
20, 24 and 28
  • Misura: Change from Baseline in Minute Ventilation (VE)/Carbon Dioxide output (VCO2) slope
  • Tempo: Baseline to Week 28
  • Descrizione: VE/VCO2 slope (from CPET) was calculated at Baseline (prior to starting study drug) and
Week 28
  • Misura: Change from Baseline in health-related quality of life measured by the Short Form Health Survey (SF-36) Scores
  • Tempo: Baseline to Week 28
  • Descrizione: SF-36 was assessed at Baseline (prior to starting study drug) and Weeks 16 and 28. The
SF-36 consisted of 36 questions in 8 health categories (Vitality, Physical Functioning,
Bodily Pain, General Health Perception, Role Physical, Role Emotional, Social
Functioning, and Mental Health). Responses to the questions were graded on a numerical
scale, with 1 as the best score and higher numbers as worse scores. The raw scores from
the subscales were converted and summed by the Investigator to a total score between 0
and 100 to measure functional health and well-being from the patient's point of view. The
final score range was 0 (representing the lowest possible score; worst health state) to
100 (representing the highest possible score; best health state).
  • Misura: Time to First All-cause Non-elective Hospitalization
  • Tempo: Baseline to Week 28
  • Descrizione: The time to first all-cause nonelective hospitalization during the study period will be
assessed.




CRITERI DI ELIGIBILITA'


    
             
  • 
        Criteri di inclusione e esclusione
        
    Inclusion Criteria:

  1. Signed informed consent form.

  2. At least 18 years of age.

  3. Primary diagnosis of PAH.

  4. Has had a diagnostic RHC performed at or within 3 years before Screening (or at
     Screening if one is not available) that is consistent with the diagnosis of PAH.

  5. Has World Health Organization (WHO)/New York Heart Association (NYHA) Functional
     Class (FC) II to III symptoms

  6. Must be on a stable dose of PAH-specific oral therapy, defined as no change in dose
     or regimen for at least 90 days prior to randomization. Allowable PAH-specific
     therapy is an endothelin receptor antagonist and/or a phosphodiesterase type 5
     inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator. Subjects may be
     on a stable dose of either a PDE5-I or a sGC stimulator, not both.

  7. Has a 6-minute walk distance (6MWD) of ≥150 meters at Screening.

  8. Has a peak VO2 of ≥9 to <18 mL/min/kg during the Screening CPET, as assessed by the
     CPET core laboratory.

  9. If the subject is taking concomitant medications that may affect the clinical
     manifestations of PAH, the subject must be on a stable dose for at least 30 days
     prior to randomization. The exception is that the dose of diuretics must be stable
     for at least the 10 days prior to randomization.

 10. Both male and female subjects agree to use a highly effective method of birth
     control throughout the entire study period from informed consent through to the Week
     28 Visit/28-day Follow-up Visit, if the possibility of conception exists. Eligible
     male and female subjects must also agree not to participate in a conception process
     during the study and for 30 days after the final dose of study drug. Eligible male
     subjects must agree not to participate in sperm donation for 90 days after the final
     dose of study drug. Women who are surgically sterile or postmenopausal are not
     considered to be of childbearing potential. If of childbearing potential, female
     partners of male study participants should agree to utilize medically acceptable
     methods of contraception for the duration of study participation.

Exclusion Criteria:

  1. For subjects with known human immunodeficiency virus-associated PAH, a cluster of
     differentiation 4 T-cell count <200/mm3 at Screening.

  2. Has 3 or more left ventricular disease/dysfunction risk factors.

  3. Symptomatic coronary artery disease and/or myocardial infarction within past 6
     months.

  4. Current symptomatic aortic or mitral valve disease.

  5. Has evidence of more than mild lung disease on pulmonary function tests performed
     within 1 year prior to, or during, Screening.

  6. Has evidence of thromboembolic disease as determined by ventilation-perfusion lung
     scan or local standard of care diagnostic evaluation at or after diagnosis of PAH.

  7. Current diagnosis of ongoing and clinically significant sleep apnea as defined by
     the Investigator.

  8. Requires use of supplemental oxygen during CPET.

  9. Respiratory exchange ratio <1.0 at Screening CPET as determined by the CPET core
     laboratory.

 10. Acute non-cardiac disorder that may affect exercise performance or be aggravated by
     exercise (eg, infection, renal failure, thyrotoxicosis).

 11. Male subjects with a QTcF >450 msec and female subjects with a QTcF >470 msec on
     electrocardiogram (ECG) recorded at Screening and analyzed by the central ECG
     laboratory. Subjects with evidence of intraventricular conduction delay, defined as
     a QRS interval >110 msec, will be excluded if QTcF is >500 msec for both males and
     females.

 12. Severe chronic liver disease (ie, Child-Pugh Class C), portal hypertension,
     cirrhosis, or complications of cirrhosis/portal hypertension (eg, history of
     variceal hemorrhage, encephalopathy).

 13. Confirmed active infection with hepatitis B virus or hepatitis C virus.

 14. Subjects with alanine aminotransferase or aspartate aminotransferase ≥3 times the
     upper limit of normal or total bilirubin ≥2 times the upper limit of normal at
     Screening.

 15. Chronic renal insufficiency as defined by an estimated glomerular filtration rate
     using the Modification of Diet in Renal Disease Study equation of <30 mL/min/1.73 m2
     or requiring dialysis at Screening.

 16. Hemoglobin concentration <9 g/dL at Screening.

 17. Subjects treated with an intravenous, subcutaneous, inhaled, or oral prostacyclin
     pathway agent (eg, epoprostenol, treprostinil, iloprost, beraprost, or selexipag)
     for PAH within 90 days of randomization (use in vasoreactive testing is permitted).
     Subject is not eligible if previous prostacyclin therapy was stopped for a safety or
     tolerability issue related to systemic prostacyclin adverse effects.

 18. Subject has pulmonary veno-occlusive disease.

 19. Malignancy diagnosed and/or treated within 3 years of Screening, with the exception
     of localized non-metastatic basal cell or squamous cell carcinoma of the skin or
     in-situ carcinoma of the cervix excised with curative intent.

 20. Subject tests positive for amphetamine, cocaine, methamphetamine,
     methylenedioxymethamphetamine, or phencyclidine in urine drug screen performed at
     Screening, or has a recent history (6 months) of alcohol or drug abuse. Subjects
     will not be excluded due to a positive drug screen caused by prescribed medications.

 21. Initiation or discontinuation of a cardio-pulmonary rehabilitation program based
     upon exercise within 90 days prior to Screening and/or planned during study
     participation.

 22. Prior participation in any study of ralinepag or another interventional clinical
     study with medicinal products within 30 days prior to Screening. Concurrent
     participation in registry or observational studies is allowed, if the subject can
     fulfill all other entry criteria and comply with all study procedures.

 23. Any reason that, in the opinion of the Investigator, precludes the subject from
     participating in the study (eg, any previous or intercurrent medical condition) that
     may increase the risk associated with study participation or that would confound
     study analysis (eg, right-to-left shunt detected during CPET) or impair study
     participation or cooperation.

 24. Known hypersensitivity to ralinepag or any of the excipients.

 25. Life expectancy <12 months based on the Investigator's opinion.

 26. Women who are pregnant, lactating, or breast-feeding.
    
        
    • 
    




SESSO

  
Tutti




  


ETA' MINIMA



Età Minima: 18 Years

Età Massima: N/A






LUOGO


  
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan	6951411, 20122
Centro Cardiologico Monzino, IRCCS
Milan	6951411, 20138
AOU Policlinico Umberto I
Rome	3169070, 00161