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)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 3; Phase 2

Conditions: Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Treatments: Drug: Frespaciguat; Drug: Placebo to Frespaciguat

Study type: Interventional

Funder types: Industry

Identifiers

NCT04732221

2022-500877-15-00 (Registry Identifier)

5475-007

2020-001108-40 (EudraCT Number)

MK-5475-007 (Other Identifier)

U1111-1278-4977 (Registry Identifier)

Details and patient eligibility

About

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.

Enrollment: 168 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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 design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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168 participants in 6 patient groups, including a placebo group

Phase 2 Cohort Frespaciguat 380 µg

Experimental group

Description:

Participants receive frespaciguat 380 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period.

Treatment:

Drug: Frespaciguat

Phase 2 Cohort Frespaciguat 100 µg

Experimental group

Description:

Participants receive frespaciguat 100 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period.

Treatment:

Drug: Frespaciguat

Phase 2 Cohort Frespaciguat 32 µg

Experimental group

Description:

Participants receive frespaciguat 32 µg via oral inhalation once daily for 12 week base period and for optional 40 month extension period.

Treatment:

Drug: Frespaciguat

Phase 2 Cohort Placebo

Placebo Comparator group

Description:

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 40 month extension period.

Treatment:

Drug: Placebo to Frespaciguat

Phase 3 Cohort Frespaciguat

Experimental group

Description:

Participants receive one of 3 frespaciguat 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 40 months in the extension period

Treatment:

Drug: Frespaciguat

Phase 3 Cohort Placebo

Placebo Comparator group

Description:

Participants receive placebo via oral inhalation once daily for 12 week base period and up to 40 months in the extension period.

Treatment:

Drug: Placebo to Frespaciguat