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NCT Number: NCT04732221

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)

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.

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Key information

Conditions

Pulmonary Arterial Hypertension Cardiovascular Diseases Hypertension Hypertension, Pulmonary Lung Diseases Respiratory Tract Diseases Vascular Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Cardiologia Palermo ( Site 0140), Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Frespaciguat

Drug

Frespaciguat (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation

Placebo to Frespaciguat

Drug

Placebo administered as dry powder inhalation

Primary outcomes

  1. Phase 2 Cohort: Mean Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks

    Time frame: At baseline and 12 weeks

    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.

  2. Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks

    Time frame: At baseline and 12 weeks

    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.

Secondary outcomes

  1. Phase 2 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks

    Time frame: At baseline and 12 weeks

    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.

  2. Phase 2 Cohort: Mean Change From Baseline in Mean Right Atrial Pressure (mRAP) at 12 Weeks

    Time frame: At baseline and 12 weeks

    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.

  3. Phase 2 Cohort: Mean Change From Baseline in Cardiac Index (CI) at 12 Weeks

    Time frame: At baseline and 12 weeks

    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.

  4. Phase 2 Cohort: Mean Change From Baseline in Stroke Volume Index (SVI) at 12 Weeks

    Time frame: At baseline and 12 weeks

    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.

  5. Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks

    Time frame: At baseline and 24 weeks

    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.

  6. Phase 3 Cohort: Proportion of Participants Whose World Health Organization Functional Class (WHO-FC) is Not Worse at 12 Week Relative to Baseline

    Time frame: At baseline and 12 weeks

    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.

  7. Phase 2 Cohort: Number of Participants Who Experienced an Adverse Event

    Time frame: Up to approximately 2.25 years

    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.

  8. Phase 2 Cohort: Number of Participants Who Discontinued Study Drug Due to an Adverse Event

    Time frame: Up to approximately 2.25 years

    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.

  9. Phase 3 Cohort: Number of Participants Who Experienced an Adverse Event

    Time frame: Up to approximately 2.25 years

    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.

  10. Phase 3 Cohort: Number of Participants Who Discontinued Study Drug Due to an AE

    Time frame: Up to approximately 2.25 years

    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.

Sponsors and collaborators

Lead sponsor

Merck Sharp & Dohme LLC

Industry

Registry information

Official study title

A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-Controlled, Adaptive Design Study to Evaluate the Efficacy and Safety of MK-5475 in Adults With Pulmonary Arterial Hypertension

Important dates

Study start
2021
Primary completion
2024
Study completion
2024
First posted
Feb 1, 2021
Registry last updated
May 25, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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