Phase 3 N=168 Randomized Triple-blind Treatment

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)

Pulmonary Arterial Hypertension · Hypertension, Pulmonary

Bottom Line

View on ClinicalTrials.gov: NCT04732221 ↗

Enrolled (actual)

168

Serious AEs

14.9%

Results posted

Feb 2025

Primary outcome: Primary: Phase 2 Cohort: Mean Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks — 4.3; -4.9; -17.6; -15.6 Percentage Change — p=0.068

Study Design & Population

Study type: Interventional
Phase: Phase 3
Interventions: Frespaciguat (Drug); Placebo to Frespaciguat (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: Merck Sharp & Dohme LLC
Primary completion: Jan 2024

Outcome Measures

Outcome	Result	p-value
PRIMARY Phase 2 Cohort: Mean Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks	4.3; -4.9; -17.6; -15.6	0.068
PRIMARY Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks	—	—
SECONDARY Phase 2 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks	24.6; 27.4; 10.8; 11.3	—
SECONDARY Phase 2 Cohort: Mean Change From Baseline in Mean Right Atrial Pressure (mRAP) at 12 Weeks	0.3; 0.3; -0.5; -0.1	—
SECONDARY Phase 2 Cohort: Mean Change From Baseline in Cardiac Index (CI) at 12 Weeks	0.1; 0.0; 0.2; 0.1	—
SECONDARY Phase 2 Cohort: Mean Change From Baseline in Stroke Volume Index (SVI) at 12 Weeks	2.9; 0.2; 3.2; 1.2	—
SECONDARY Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks	—	—
SECONDARY Phase 3 Cohort: Proportion of Participants Whose World Health Organization Functional Class (WHO-FC) is Not Worse at 12 Week Relative to Baseline	—	—
SECONDARY Phase 2 Cohort: Number of Participants Who Experienced an Adverse Event	27; 28; 28; 27; 33; 38	—
SECONDARY Phase 2 Cohort: Number of Participants Who Discontinued Study Drug Due to an Adverse Event	0; 1; 0; 0; 0; 1	—
SECONDARY Phase 3 Cohort: Number of Participants Who Experienced an Adverse Event	—	—
SECONDARY Phase 3 Cohort: Number of Participants Who Discontinued Study Drug Due to an AE	—	—

Summary

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.

Eligibility 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.

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Data sourced from ClinicalTrials.gov (NCT04732221). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.