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)

NCT04732221 | Completed Phase 2 Results DMC FDA Drug

• 5 other identifiers: 5475-007MK-5475-0072022-500877-15-00U1111-1278-49772020-001108-40
• Study Type: interventional
• Target: 168
• Locations: 18 countries
• Sites: 91

Brief 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.

Conditions

Pulmonary Arterial Hypertension; Hypertension, Pulmonary

Outcome Measures

Primary Outcomes (2)

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

  At baseline and 12 weeks

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

  At baseline and 12 weeks

Secondary Outcomes (10)

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

  At baseline and 12 weeks

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

  At baseline and 12 weeks

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

  At baseline and 12 weeks

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

  At baseline and 12 weeks

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

  At baseline and 24 weeks

Study Arms (6)

Phase 2 Cohort Frespaciguat 380 µg

EXPERIMENTAL

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

Drug: Frespaciguat

Phase 2 Cohort Frespaciguat 100 µg

EXPERIMENTAL

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

Drug: Frespaciguat

Phase 2 Cohort Frespaciguat 32 µg

EXPERIMENTAL

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

Drug: Frespaciguat

Phase 2 Cohort Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo to Frespaciguat

Phase 3 Cohort Frespaciguat

EXPERIMENTAL

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

Drug: Frespaciguat

Phase 3 Cohort Placebo

PLACEBO COMPARATOR

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

Drug: Placebo to Frespaciguat

Interventions

Frespaciguat DRUG

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

Phase 2 Cohort Frespaciguat 100 µg; Phase 2 Cohort Frespaciguat 32 µg; Phase 2 Cohort Frespaciguat 380 µg; Phase 3 Cohort Frespaciguat

Placebo to Frespaciguat DRUG

Placebo administered as dry powder inhalation

Phase 2 Cohort Placebo; Phase 3 Cohort Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (91)

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

La Jolla, California, 92037-7381, United States

Location

University of California Davis Health-Internal Medicine: Pulmonary, Critical Care and Sleep Medicine

Sacramento, California, 95817, United States

Location

UCSF Helen Diller Medical Center at Parnassus Heights ( Site 0063)

San Francisco, California, 94143, United States

Location

University of Colorado - Denver ( Site 0003)

Aurora, Colorado, 80045, United States

Location

Cardiovascular Institute of North Colorado - Banner Health ( Site 0013)

Greeley, Colorado, 80631, United States

Location

Georgetown University Hospital ( Site 0025)

Washington D.C., District of Columbia, 20007, United States

Location

University of Miami Hospital-Division of Pulmonary & Critical Care ( Site 0053)

Miami, Florida, 33136, United States

Location

AdventHealth Orlando ( Site 0040)

Orlando, Florida, 32803, United States

Location

Tampa General Hospital ( Site 0058)

Tampa, Florida, 33606, United States

Location

Indiana University Health Methodist Hospital ( Site 0045)

Indianapolis, Indiana, 46202-1239, United States

Location

University of Iowa Hospital and Clinics ( Site 0009)

Iowa City, Iowa, 52242, United States

Location

University of Kansas Medical Center ( Site 0038)

Kansas City, Kansas, 66160, United States

Location

University of Kentucky ( Site 0006)

Lexington, Kentucky, 40536, United States

Location

Norton Pulmonary Specialists ( Site 0048)

Louisville, Kentucky, 40202, United States

Location

University of Maryland ( Site 0032)

Baltimore, Maryland, 21201, United States

Location

Washington University School of Medicine ( Site 0066)

St Louis, Missouri, 63110, United States

Location

University of Nebraska Medical Center ( Site 0041)

Omaha, Nebraska, 68198, United States

Location

University of New Mexico, Health Sciences Center ( Site 0028)

Albuquerque, New Mexico, 87131, United States

Location

Clinical Trials Unit at Eastowne Medical Office Building ( Site 0019)

Chapel Hill, North Carolina, 27514, United States

Location

AnMed Health ( Site 0033)

Anderson, South Carolina, 29621, United States

Location

Statcare Pulmonary Consultants ( Site 0067)

Knoxville, Tennessee, 37934, United States

Location

University of Texas Southwestern Medical Center at Dallas ( Site 0012)

Dallas, Texas, 75390, United States

Location

Houston Methodist Research Institute ( Site 0036)

Houston, Texas, 77030, United States

Location

The University of Texas Health Science Center at Houston ( Site 0054)

Houston, Texas, 77030, United States

Location

Sentara Norfolk General Hospital ( Site 0014)

Norfolk, Virginia, 23507, United States

Location

West Virginia University-WVU Heart and Vascular Institute ( Site 0051)

Morgantown, West Virginia, 26506, United States

Location

Cardiologia Palermo ( Site 0140)

Ciudad Autonoma de Buenos Aires, Buenos Aires, C1425BNG, Argentina

Location

Centro Medico Capital ( Site 0131)

La Plata, Buenos Aires, B1904AAW, Argentina

Location

Hospital Universitario Austral ( Site 0138)

Pilar, Buenos Aires, B1629ODT, Argentina

Location

Instituto de Investigaciones Clinicas Quilmes ( Site 0141)

Quilmes, Buenos Aires, B1878GEG, Argentina

Location

Hospital El Cruce Nestor Carlos Kirchner ( Site 0132)

San Juan Bautista, Buenos Aires, 1888, Argentina

Location

Sanatorio de la Trinidad Mitre ( Site 0130)

Buenos Aires, Buenos Aires F.D., 1039, Argentina

Location

Instituto Cardiovascular de Rosario ( Site 0128)

Rosario, Santa Fe Province, S2000DSR, Argentina

Location

Hospital Privado Universitario de Córdoba ( Site 0137)

Córdoba, X5016KEH, Argentina

Location

Nepean Hospital ( Site 0184)

Kingswood, New South Wales, 2747, Australia

Location

Macquarie University ( Site 0180)

Macquarie University, New South Wales, 2109, Australia

Location

John Hunter Hospital ( Site 0185)

Newcastle, New South Wales, 2305, Australia

Location

Université Libre de Bruxelles - Hôpital Erasme ( Site 0601)

Brussels, Bruxelles-Capitale, Region de, 1070, Belgium

Location

UZ Leuven ( Site 0600)

Leuven, Vlaams-Brabant, 3000, Belgium

Location

Peter Lougheed Centre ( Site 0107)

Calgary, Alberta, T1Y 6J4, Canada

Location

University Health Network - Toronto General Hospital ( Site 0104)

Toronto, Ontario, M5G 2N2, Canada

Location

IUCPQ ( Site 0111)

Québec, Quebec, G1V 4G5, Canada

Location

Centro Cardiovascular Colombiano Clínica Santa María ( Site 0154)

Medellín, Antioquia, 050034, Colombia

Location

Hospital Universitario San Ignacio ( Site 0152)

Bogotá, Bogota D.C., 110231, Colombia

Location

Fundacion Cardiovascular de Colombia ( Site 0155)

Piedecuesta, Santander Department, 681017, Colombia

Location

CHRU Brest - Hopital Cavale Blanche ( Site 0254)

Brest, Finistere, 29609, France

Location

CHU de Toulouse - Hopital Larrey ( Site 0258)

Toulouse, Haute-Garonne, 31059, France

Location

Institut Coeur Poumon - CHRU de Lille ( Site 0252)

Lille, Hauts-de-France, 59037, France

Location

Centre Hospitalier Universitaire de Rouen ( Site 0253)

Rouen, Seine-Maritime, 76031, France

Location

CHU - Hopital de Bicetre ( Site 0251)

Le Kremlin-Bicêtre, Val-de-Marne, 94275, France

Location

Thoraxklinik Heidelberg gGmbH am Universitaetsklinikum Heidelberg ( Site 0276)

Heidelberg, Baden-Wurttemberg, 69126, Germany

Location

Klinikum Würzburg Mitte-Medizinische Klinik - Schwerpunkt Pneumologie & Beatmungsmedizin ( Site 0280

Würzburg, Bavaria, 97074, Germany

Location

UKGM Gießen/Marburg ( Site 0279)

Giessen, Hesse, 35392, Germany

Location

Medizinische Hochschule Hannover ( Site 0284)

Hanover, Lower Saxony, 30625, Germany

Location

Uniklinikum Dresden ( Site 0283)

Dresden, Saxony, 01307, Germany

Location

Universitaetsklinikum Leipzig ( Site 0285)

Leipzig, Saxony, 04103, Germany

Location

AHEPA University General Hospital of Thessaloniki ( Site 0577)

Thessaloniki, 54636, Greece

Location

Soroka Medical Center ( Site 0330)

Beersheba, 8410101, Israel

Location

Rambam Medical Center ( Site 0335)

Haifa, 3109601, Israel

Location

Wolfson Medical Center [Holon, Israel] ( Site 0333)

Holon, 5810000, Israel

Location

Shaare Zedek Medical Center ( Site 0331)

Jerusalem, 9103102, Israel

Location

Rabin Medical Center ( Site 0327)

Petah Tikva, 4941492, Israel

Location

University of Naples Federico II ( Site 0308)

Naples, Campania, 80100, Italy

Location

Azienda Ospedaliera Policlinico Umberto I ( Site 0301)

Rome, Lazio, 00161, Italy

Location

Ospedale San Gerardo - ASST Monza ( Site 0304)

Monza, Monza E Brianza, 20900, Italy

Location

Centro Cardiologico Monzino IRCCS ( Site 0306)

Milan, 20138, Italy

Location

Fondazione IRCCS Policlinico San Matteo ( Site 0302)

Pavia, 27100, Italy

Location

Instituto Nacional de Cardiología -Ignacio Chavez ( Site 0651)

Mexico City, Mexico City, 14080, Mexico

Location

Consultorio 1020 Hospital Angeles Xalapa ( Site 0654)

Xalapa, Veracruz, 91193, Mexico

Location

Operadora de Hospitales Angeles. S.A. de C.V. -Sucursal Lomas ( Site 0653)

Huixquilucan, 52763, Mexico

Location

Christchurch Hospital ( Site 0201)

Christchurch, Canterbury, 8011, New Zealand

Location

Greenlane Clinical Centre ( Site 0203)

Auckland, 1051, New Zealand

Location

Krakowski Szpital Specjalistyczny im. Jana Pawa II-Oddzial Kliniczny Chorob Serca i Naczyn z Pododd

Krakow, Lesser Poland Voivodeship, 31-202, Poland

Location

Specjalistyczny Szpital im. Dr Alfreda Sokolowskiego w Walbrzychu ( Site 0351)

Wałbrzych, Lower Silesian Voivodeship, 58-309, Poland

Location

Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie ( Site 0352)

Lublin, Lublin Voivodeship, 20-954, Poland

Location

Scientific Research Institute Complex Problems Cardiovascular Disease ( Site 0403)

Kemerovo, Kemerovo Oblast, 650002, Russia

Location

Almazov National Medical Research Centre of the Ministry of Health ( Site 0402)

Saint Petersburg, Sankt-Peterburg, 197341, Russia

Location

Akademiska sjukhuset ( Site 0453)

Uppsala, Uppsala County, 751 85, Sweden

Location

Sahlgrenska Universitetssjukhuset-Cardiology Research Unit ( Site 0452)

Gothenburg, Västra Götaland County, 413 45, Sweden

Location

Ege Universitesi Hastanesi-Cardilogy Department ( Site 0504)

Bornova, İzmir, 35100, Turkey (Türkiye)

Location

Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 0510)

Ankara, 06100, Turkey (Türkiye)

Location

Akdeniz Uni.Tip Fakultesi Saglik Uygulama ve Arastirma Merkezi ( Site 0508)

Antalya, 07059, Turkey (Türkiye)

Location

Eskisehir Osmangazi Uni. Tip Fakultesi Hastanesi ( Site 0506)

Eskişehir, 26040, Turkey (Türkiye)

Location

Istanbul Uni. Kardiyoloji Enstitusu ( Site 0502)

Istanbul, 34096, Turkey (Türkiye)

Location

Istanbul Universitesi Istanbul Tip Fakultesi ( Site 0509)

Istanbul, 34390, Turkey (Türkiye)

Location

Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi ( Site 0501)

Istanbul, 34899, Turkey (Türkiye)

Location

Dokuz Eylul University Faculty of Medicine ( Site 0505)

Izmir, 35330, Turkey (Türkiye)

Location

Golden Jubilee National Hospital ( Site 0556)

Glasgow, Glasgow City, G81 4DY, United Kingdom

Location

Royal Brompton and Harefield NHS Trust ( Site 0553)

London, London, City of, SW3 6NP, United Kingdom

Location

Imperial College Healthcare NHS Trust - Hammersmith Hospital ( Site 0554)

London, London, City of, W12 0HS, United Kingdom

Location

The Freeman Hosp.Newcastle upon Tyne Hosp NHS Trust ( Site 0552)

Newcastle upon Tyne, Newcastle Upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (1)

• Humbert M, Hassoun PM, Chin KM, Bortman G, Patel MJ, La Rosa C, Fu W, Loureiro MJ, Hoeper MM. MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study. Eur Respir J. 2024 Nov 14;64(5):2401110. doi: 10.1183/13993003.01110-2024. Print 2024 Nov.

  PMID: 39255991 RESULT

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Hypertension, Pulmonary

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: MSD

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 27, 2021
• First Posted: February 1, 2021
• Study Start: May 19, 2021
• Primary Completion: January 4, 2024
• Study Completion: July 2, 2024
• Last Updated: May 25, 2025
• Results First Posted: February 21, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

DE (6); SE (2); AR (8); BE (2); NZ (2); RU (2); AU (3); CA (3); TU (8); GR (1); ME (3); CO (3); US (26); IL (5); IT (5); GB (4); FR (5); PL (3)