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 Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 75 Years
Gender	All

More Inclusion & Exclusion Criteria

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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04732221
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2/Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Merck Sharp & Dohme LLC
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Medical Director
Principal Investigator Affiliation	Merck Sharp & Dohme LLC
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Industry
Overall Status	Recruiting
Countries	Argentina, Australia, Belgium, Canada, Colombia, France, Germany, Greece, Israel, Italy, Mexico, New Zealand, Poland, Russian Federation, Sweden, Turkey, United Kingdom, United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Pulmonary Arterial Hypertension, Hypertension, Pulmonary
Study Website:	View Trial Website

Arms & Interventions

Arms

Experimental: Phase 2 Cohort MK-5475 380 µg

Participants receive MK-5475 380 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period.

Experimental: Phase 2 Cohort MK-5475 100 µg

Participants receive MK-5475 100 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period.

Experimental: Phase 2 Cohort MK-5475 32 µg

Participants receive MK-5475 32 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period.

Placebo Comparator: Phase 2 Cohort Placebo

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.

Experimental: Phase 3 Cohort MK-5475

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

Placebo Comparator: Phase 3 Cohort Placebo

Participants receive placebo via oral inhalation once daily for 12 week base period and up to 60 months in the extension period.

Interventions

Drug: - MK-5475

MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation

Drug: - Placebo to MK-5475

Placebo administered as dry powder inhalation

Contact a Trial Team

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La Jolla, California

Status

Active, not recruiting

Address

University of California San Diego Health-Pulmonary Critical Care ( Site 0061)

La Jolla, California, 92037-7381

Site Contact

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