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

Study Overview
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Brief Summary
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This is a two-part (Phase 2/Phase 3) study of MK-5475, an inhaled soluble guanylate cyclase stimulator, in participants with pulmonary arterial hypertension (PAH). The first part (Phase 2) will assess three different doses of MK-5475 compared to placebo in a base period of 12 weeks, followed by comparison of three different doses of MK-5475 during an optional 24 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 MK-5475 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 MK-5475 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 MK-5475 is superior to placebo in increasing 6-minute walk distance (6MWD) from baseline at week 12.

Official Title
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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

Conditions
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Pulmonary Arterial Hypertension, Hypertension, Pulmonary

Intervention / Treatment
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* Drug: MK-5475
* Drug: Placebo to MK-5475


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A total of approximately 450 participants will be randomized in this operationally seamless adaptive Phase 2/3 study. Phase 2 of the study will randomize approximately 164 participants into 4 arms, and Phase 3 of the study will randomize approximately 286 participants into 2 arms.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2 Cohort MK-5475 380 µg<br>Participants receive MK-5475 380 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period. | Drug: MK-5475<br>* MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation<br>|
| Experimental: Phase 2 Cohort MK-5475 100 µg<br>Participants receive MK-5475 100 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period. | Drug: MK-5475<br>* MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation<br>|
| Experimental: Phase 2 Cohort MK-5475 32 µg<br>Participants receive MK-5475 32 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period. | Drug: MK-5475<br>* MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation<br>|
| Placebo Comparator: Phase 2 Cohort Placebo<br>Participants receive placebo via oral inhalation once daily for 12 week base period, and one of the MK-5475 doses (380, 100, or 32 µg) for the optional 24 month extension period. | Drug: Placebo to MK-5475<br>* Placebo administered as dry powder inhalation<br>|
| Experimental: Phase 3 Cohort MK-5475<br>Participants receive one of 3 MK-5475 doses (380, 100 or 32 µg) to be selected at end of the Phase 2 Cohort, administered via oral inhalation once daily for 12-week base period and up to 60 months in the extension period | Drug: MK-5475<br>* MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation<br>|
| Placebo Comparator: Phase 3 Cohort Placebo<br>Participants receive placebo via oral inhalation once daily for 12 week base period and up to 60 months in the extension period. | Drug: Placebo to MK-5475<br>* Placebo administered as dry powder inhalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 Cohort: Change from Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks | PVR is assessed by right heart catheterization (RHC). | At baseline and 12 weeks | 
| Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks | 6MWD is assessed using the 6-minute walk test (6MWT). | At baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks | 6MWD is assessed using the 6-minute walk test (6MWT). | At baseline and 12 weeks | 
| Phase 2 Cohort: Change from Baseline in Mean Right Arterial Pressure (mRAP) at 12 Weeks | mRAP is assessed by right heart catheterization (RHC). | At baseline and 12 weeks | 
| Phase 2 Cohort: Change from Baseline in Cardiac Index (CI) at 12 weeks | Cardiac index is assessed by right heart catheterization (RHC). | At baseline and 12 weeks | 
| Phase 2 Cohort: Change from Baseline in Stroke Volume Index (SVI) at 12 weeks | SVI is assessed by right heart catheterization (RHC). | At baseline and 12 weeks | 
| Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks | 6MWD is assessed using the 6-minute walk test (6MWT). | At baseline and 24 weeks | 
| Phase 3 Cohort: Change from Baseline in World Health Organization Functional Class (WHO-FC) at 12 Weeks | Participants are assigned one of four WHO-FC, dependent on limits of physical activity. As WHO-FC increases from I to IV, limits of physical activity increase. | At baseline and 12 weeks | 
| Phase 2 Cohort: Number of Participants Who Experience an Adverse Event | 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. | Up to approximately 2.25 years | 
| Phase 2 Cohort: Number of Participants Who Discontinue Study Drug Due to an Adverse Event | 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. | Up to approximately 2.25 years | 
| Phase 3 Cohort: Number of Participants who Experience an Adverse Event | 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. | Up to approximately 5.5 years | 
| Phase 3 Cohort: Number of Participants who Discontinue Study Drug Due to an Adverse Event | 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. | Up to approximately 5.5 years |