A Study of the Efficacy and Safety of Frespaciguat (MK-5475) in Participants With Pulmonary Arterial Hypertension (INSIGNIA-PAH: Phase 2/3 Study of an Inhaled sGC Stimulator in PAH) (MK-5475-007)



Sponsor:   Merck Sharp & Dohme LLC


Sommario: This is a two-part (Phase 2/Phase 3) study of frespaciguat, an inhaled soluble guanylate
cyclase stimulator, in participants with pulmonary arterial hypertension (PAH).

The first part (Phase 2) will assess three different doses of frespaciguat compared to
placebo in a base period of 12 weeks, followed by comparison of three different doses of
frespaciguat during an optional 40 month extension period. The treatment dose with the
best efficacy and safety profile in the phase 2 cohort base period will be selected for
use in the second part (Phase 3) of the study. The primary hypothesis of Phase 2 is that
at least one frespaciguat dose is superior to placebo in reducing pulmonary vascular
resistance (PVR) from baseline at week 12.

The purpose of the second part (Phase 3) of the study is to confirm the efficacy, safety,
and tolerability of frespaciguat at the selected dose compared to placebo during a 12
week base period followed by an extension period of up to 5 years. The primary hypothesis
of Phase 3 is that frespaciguat is superior to placebo in increasing 6-minute walk
distance (6MWD) from baseline at week 12. Due to sponsor's decision this phase/part was
not conducted.




TIPOLOGIA STUDIO

 
Interventistico



FASE

 




TRATTAMENTO

  
    
  
  • Frespaciguat
  • Placebo to Frespaciguat
    • 






OBIETTIVO PRIMARIO


  
  • Misura: Phase 2 Cohort: Mean Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks
  • Tempo: At baseline and 12 weeks
  • Descrizione: PVR was calculated in participants after MK-5475 dosing at baseline and Week 12. PVR is
assessed by right heart catheterization (RHC). Based on the variables obtained by right
heart catheterization (RHC), the percentage change from baseline PVR was calculated. Per
protocol, this outcome measure was assessed only for base period and was not assessed
during extension period.
  • Misura: Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
  • Tempo: At baseline and 12 weeks
  • Descrizione: 6MWD is measured by an exercise test known as 6-Minute Walk Test (6MWT) that assesses
functional capacity. It measures the distance covered over a time of 6 minutes and is
intended to be used as an outcome measure by which to compare changes in excercise
capacity. Each participant's 6MWD is to be measured at baseline and at 12 weeks. An
increase in the distance walked during the 6MWT indicates improvement in functional
exercise capacity.




OBIETTIVO SECONDARIO


  
  • Misura: Phase 2 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
  • Tempo: At baseline and 12 weeks
  • Descrizione: 6MWD is measured by an exercise test known as 6-Minute Walk Test (6MWT) that assesses
functional capacity. It measures the distance covered over a time of 6 minutes and is
used as an outcome measure by which to compare changes in exercise capacity. Each
participant's 6MWD was measured at baseline and at 12 weeks. An increase in the distance
walked during the 6MWT indicates improvement in functional exercise capacity.
  • Misura: Phase 2 Cohort: Mean Change From Baseline in Mean Right Atrial Pressure (mRAP) at 12 Weeks
  • Tempo: At baseline and 12 weeks
  • Descrizione: mRAP is the blood pressure in the right atrium of the heart. mRAP was assessed by right
heart catheterization (RHC).A decrease in mRAP indicates improvement in right ventricular
function, reduction of PAH related morbidity.
  • Misura: Phase 2 Cohort: Mean Change From Baseline in Cardiac Index (CI) at 12 Weeks
  • Tempo: At baseline and 12 weeks
  • Descrizione: The cardiac index (CI) is a hemodynamic measure that represents the cardiac output (CO)
of an individual divided by their body surface area (BSA). Cardiac index is assessed by
right heart catheterization (RHC). An increase in CI is indicates better right
ventricular function and is associated with a reduction of PAH related morbidity and
mortality.
  • Misura: Phase 2 Cohort: Mean Change From Baseline in Stroke Volume Index (SVI) at 12 Weeks
  • Tempo: At baseline and 12 weeks
  • Descrizione: The stroke volume index represents the amount of blood in mL, per square meter of body
surface area, that is mobilized with each heart beat. SVI is assessed by RHC. An increase
in SVI indicates better right ventricular function and is associated with a reduction of
PAH related morbidity and mortality.
  • Misura: Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
  • Tempo: At baseline and 24 weeks
  • Descrizione: 6MWD is measured by an exercise test known as 6-Minute Walk Test (6MWT) that assesses
functional capacity. It measures the distance covered over a time of 6 minutes and is
intended to be used as an outcome measure by which to compare changes in exercise
capacity. Each participant's 6MWD is to be measured at baseline and at 24 weeks. An
increase in the distance walked during the 6MWT indicates improvement in functional
exercise capacity.
  • Misura: Phase 3 Cohort: Proportion of Participants Whose World Health Organization Functional Class (WHO-FC) is Not Worse at 12 Week Relative to Baseline
  • Tempo: At baseline and 12 weeks
  • Descrizione: The World Health Organization (WHO) classification of functional status is a measure of
disease severity, based on a patient's description of their level of functioning and
symptoms of disease in relation to their everyday activity. Patients were to be assigned
1 of 4 WHO-FC, dependent on limits of physical activity. As WHO-FC increases from I to
IV, limits of physical activity were to increase.
  • Misura: Phase 2 Cohort: Number of Participants Who Experienced an Adverse Event
  • Tempo: Up to approximately 2.25 years
  • Descrizione: An adverse event (AE) is any untoward medical occurrence in a clinical study participant,
temporally associated with the use of study intervention, whether or not considered
related to the study intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated)
temporally associated with the use of a study intervention.
  • Misura: Phase 2 Cohort: Number of Participants Who Discontinued Study Drug Due to an Adverse Event
  • Tempo: Up to approximately 2.25 years
  • Descrizione: An adverse event (AE) is any untoward medical occurrence in a clinical study participant,
temporally associated with the use of study intervention, whether or not considered
related to the study intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated)
temporally associated with the use of a study intervention. The number of participants
who discontinued treatment due to an AE was assessed.
  • Misura: Phase 3 Cohort: Number of Participants Who Experienced an Adverse Event
  • Tempo: Up to approximately 2.25 years
  • Descrizione: An adverse event (AE) is any untoward medical occurrence in a clinical study participant,
temporally associated with the use of study intervention, whether or not considered
related to the study intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated)
temporally associated with the use of a study intervention.
  • Misura: Phase 3 Cohort: Number of Participants Who Discontinued Study Drug Due to an AE
  • Tempo: Up to approximately 2.25 years
  • Descrizione: An adverse event (AE) is any untoward medical occurrence in a clinical study participant,
temporally associated with the use of study intervention, whether or not considered
related to the study intervention. An AE can therefore be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated)
temporally associated with the use of a study intervention. The number of participants
who discontinued treatment due to an AE was assessed.




CRITERI DI ELIGIBILITA'


    
             
  • 
        Criteri di inclusione e esclusione
        
    Inclusion Criteria:

  -  Pulmonary arterial hypertension (PAH) in one of the following groups:

       -  Idiopathic PAH

       -  Heritable PAH

       -  Drug and toxin-induced PAH

       -  PAH associated with connective tissue disease, HIV infection, or congenital
          heart disease.

  -  Diagnosis of PAH documented by right heart catheterization (RHC).

  -  Eligibility RHC meeting all of the following criteria:

       -  Mean pulmonary artery pressure (mPAP) ≥25 mmHg

       -  Pulmonary vascular resistance (PVR) of ≥3 Wood units

       -  Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic
          pressure (LVEDP) ≤15 mmHg.

  -  World Health Organization functional class (WHO-FC) symptoms between Class II and
     IV.

  -  Two 6-Minute walk distance (6MWD) measurements between 150 and 500 meters, one at
     screening and one at randomization.

  -  Stable concomitant background PAH-specific therapy.

  -  Body Mass Index (BMI) between 18.5 kg/m² and 40 kg/m² .

  -  Agree to be abstinent from heterosexual intercourse or use contraception during the
     intervention period and for at least 14 days after the last dose of study
     intervention.

  -  Female participants may not be pregnant or breastfeeding.

Exclusion Criteria:

  -  Group 2 to 5 pulmonary hypertension.

  -  PAH in one of the following groups:

       -  Long term responders to calcium channel blockers

       -  Overt features of venous/capillary involvement

  -  Evidence of more-than-mild obstructive lung disease.

  -  Evidence of more-than-mild parenchymal lung disease.

  -  Evidence of more-than-mild obstructive sleep apnea (OSA) that is untreated.

  -  Evidence or history of left heart disease, including any of the following:

       -  Left ventricular ejection fraction (LVEF) ≤45%

       -  Moderate or severe left-sided valvular disease (aortic or mitral valve stenosis
          or regurgitation)

       -  Significant left ventricular diastolic dysfunction on echocardiographic
          evaluation

  -  Presence of 3 or more of the following risk factors for heart failure with preserved
     ejection fraction: BMI>30 kg/m², essential systemic hypertension, diabetes mellitus
     of any type, or coronary artery disease.

  -  Oxygen saturation measured by pulse oximetry (SpO₂) <90%, despite supplemental
     oxygen therapy.

  -  Chronic renal insufficiency (eGFR <30 mL/min)

  -  Chronic liver disease (i.e., Child-Pugh B or C), portal hypertension, cirrhosis, or
     significant hepatic laboratory abnormalities.

  -  Current smoker or currently uses electronic cigarettes (vapes).

  -  History of cancer, except: nonmelanomatous skin carcinoma or carcinoma in situ of
     the cervix or other malignancies which have been successfully treated, with
     appropriate follow up, and unlikely to recur for the duration of the study.
    
        
    • 
    




SESSO

  
Tutti




  


ETA' MINIMA



Età Minima: 18 Years

Età Massima: 75 Years






LUOGO


  
University of Naples Federico II ( Site 0308)
Naples	3172394, 80100
Azienda Ospedaliera Policlinico Umberto I ( Site 0301)
Rome	3169070, 00161
Ospedale San Gerardo - ASST Monza ( Site 0304)
Monza	3172629, 20900
Centro Cardiologico Monzino IRCCS ( Site 0306)
Milan	6951411, 20138
Fondazione IRCCS Policlinico San Matteo ( Site 0302)
Pavia	3171366, 27100