Clinical trial NCT04732221: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Pulmonary Arterial Hypertension
Hypertension, Pulmonary
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2021-02-01
Enrollment: 168
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Phase 2 Cohort: Mean Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks
timeFrame: At baseline and 12 weeks
measure: Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
timeFrame: At baseline and 12 weeks
Secondary outcomes:
measure: Phase 2 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
timeFrame: At baseline and 12 weeks
measure: Phase 2 Cohort: Mean Change From Baseline in Mean Right Atrial Pressure (mRAP) at 12 Weeks
timeFrame: At baseline and 12 weeks
measure: Phase 2 Cohort: Mean Change From Baseline in Cardiac Index (CI) at 12 Weeks
timeFrame: At baseline and 12 weeks
measure: Phase 2 Cohort: Mean Change From Baseline in Stroke Volume Index (SVI) at 12 Weeks
timeFrame: At baseline and 12 weeks
measure: Phase 3 Cohort: Mean Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
timeFrame: At baseline and 24 weeks
measure: Phase 3 Cohort: Proportion of Participants Whose World Health Organization Functional Class (WHO-FC) is Not Worse at 12 Week Relative to Baseline
timeFrame: At baseline and 12 weeks
measure: Phase 2 Cohort: Number of Participants Who Experienced an Adverse Event
timeFrame: Up to approximately 2.25 years
measure: Phase 2 Cohort: Number of Participants Who Discontinued Study Drug Due to an Adverse Event
timeFrame: Up to approximately 2.25 years
measure: Phase 3 Cohort: Number of Participants Who Experienced an Adverse Event
timeFrame: Up to approximately 2.25 years
measure: Phase 3 Cohort: Number of Participants Who Discontinued Study Drug Due to an AE
timeFrame: Up to approximately 2.25 years
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego Health-Pulmonary Critical Care ( Site 0061)
state: California
city: Sacramento
country: United States
facility: University of California Davis Health-Internal Medicine: Pulmonary, Critical Care and Sleep Medicine
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Medical Center at Parnassus Heights ( Site 0063)
state: California
city: Aurora
country: United States
facility: University of Colorado - Denver ( Site 0003)
state: Colorado
city: Greeley
country: United States
facility: Cardiovascular Institute of North Colorado - Banner Health ( Site 0013)
state: Colorado
city: Washington
country: United States
facility: Georgetown University Hospital ( Site 0025)
state: District of Columbia
city: Miami
country: United States
facility: University of Miami Hospital-Division of Pulmonary & Critical Care ( Site 0053)
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando ( Site 0040)
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital ( Site 0058)
state: Florida
city: Indianapolis
country: United States
facility: Indiana University Health Methodist Hospital ( Site 0045)
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics ( Site 0009)
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center ( Site 0038)
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky ( Site 0006)
state: Kentucky
city: Louisville
country: United States
facility: Norton Pulmonary Specialists ( Site 0048)
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland ( Site 0032)
state: Maryland
city: Saint Louis
country: United States
facility: Washington University School of Medicine ( Site 0066)
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center ( Site 0041)
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico, Health Sciences Center ( Site 0028)
state: New Mexico
city: Chapel Hill
country: United States
facility: Clinical Trials Unit at Eastowne Medical Office Building ( Site 0019)
state: North Carolina
city: Anderson
country: United States
facility: AnMed Health ( Site 0033)
state: South Carolina
city: Knoxville
country: United States
facility: Statcare Pulmonary Consultants ( Site 0067)
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas ( Site 0012)
state: Texas
city: Houston
country: United States
facility: Houston Methodist Research Institute ( Site 0036)
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston ( Site 0054)
state: Texas
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital ( Site 0014)
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University-WVU Heart and Vascular Institute ( Site 0051)
state: West Virginia
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Cardiologia Palermo ( Site 0140)
state: Buenos Aires
city: Florencio Varela
country: Argentina
facility: Hospital El Cruce Nestor Carlos Kirchner ( Site 0132)
state: Buenos Aires
city: La Plata
country: Argentina
facility: Centro Medico Capital ( Site 0131)
state: Buenos Aires
city: Pilar
country: Argentina
facility: Hospital Universitario Austral ( Site 0138)
state: Buenos Aires
city: Quilmes
country: Argentina
facility: Instituto de Investigaciones Clinicas Quilmes ( Site 0141)
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Sanatorio de la Trinidad Mitre ( Site 0130)
state: Caba
city: Rosario
country: Argentina
facility: Instituto Cardiovascular de Rosario ( Site 0128)
state: Santa Fe
city: Cordoba
country: Argentina
facility: Hospital Privado Universitario de Córdoba ( Site 0137)
city: Kingswood
country: Australia
facility: Nepean Hospital ( Site 0184)
state: New South Wales
city: Macquarie University
country: Australia
facility: Macquarie University ( Site 0180)
state: New South Wales
city: Newcastle
country: Australia
facility: John Hunter Hospital ( Site 0185)
state: New South Wales
city: Brussels
country: Belgium
facility: Université Libre de Bruxelles - Hôpital Erasme ( Site 0601)
state: Bruxelles-Capitale, Region De
city: Leuven
country: Belgium
facility: UZ Leuven ( Site 0600)
state: Vlaams-Brabant
city: Calgary
country: Canada
facility: Peter Lougheed Centre ( Site 0107)
state: Alberta
city: Toronto
country: Canada
facility: University Health Network - Toronto General Hospital ( Site 0104)
state: Ontario
city: Quebec
country: Canada
facility: IUCPQ ( Site 0111)
city: Medellín
country: Colombia
facility: Centro Cardiovascular Colombiano Clínica Santa María ( Site 0154)
state: Antioquia
city: Bogota
country: Colombia
facility: Hospital Universitario San Ignacio ( Site 0152)
state: Distrito Capital De Bogota
city: Piedecuesta
country: Colombia
facility: Fundacion Cardiovascular de Colombia ( Site 0155)
state: Santander
city: Brest
country: France
facility: CHRU Brest - Hopital Cavale Blanche ( Site 0254)
state: Finistere
city: Toulouse
country: France
facility: CHU de Toulouse - Hopital Larrey ( Site 0258)
state: Haute-Garonne
city: Lille Cedex
country: France
facility: Institut Coeur Poumon - CHRU de Lille ( Site 0252)
state: Nord-Pas-de-Calais
city: Rouen
country: France
facility: Centre Hospitalier Universitaire de Rouen ( Site 0253)
state: Seine-Maritime
city: Le Kremlin-Bicetre
country: France
facility: CHU - Hopital de Bicetre ( Site 0251)
state: Val-de-Marne
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg gGmbH am Universitaetsklinikum Heidelberg ( Site 0276)
state: Baden-Wurttemberg
city: Wuerzburg
country: Germany
facility: Klinikum Würzburg Mitte-Medizinische Klinik - Schwerpunkt Pneumologie & Beatmungsmedizin ( Site 0280
state: Bayern
city: Gießen
country: Germany
facility: UKGM Gießen/Marburg ( Site 0279)
state: Hessen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover ( Site 0284)
state: Niedersachsen
city: Dresden
country: Germany
facility: Uniklinikum Dresden ( Site 0283)
state: Sachsen
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig ( Site 0285)
state: Sachsen
city: Thessaloniki
country: Greece
facility: AHEPA University General Hospital of Thessaloniki ( Site 0577)
city: Beer Sheva
country: Israel
facility: Soroka Medical Center ( Site 0330)
city: Haifa
country: Israel
facility: Rambam Medical Center ( Site 0335)
city: Holon
country: Israel
facility: Wolfson Medical Center [Holon, Israel] ( Site 0333)
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center ( Site 0331)
city: Petah Tikva
country: Israel
facility: Rabin Medical Center ( Site 0327)
city: Naples
country: Italy
facility: University of Naples Federico II ( Site 0308)
state: Campania
city: Roma
country: Italy
facility: Azienda Ospedaliera Policlinico Umberto I ( Site 0301)
state: Lazio
city: Monza
country: Italy
facility: Ospedale San Gerardo - ASST Monza ( Site 0304)
state: Monza E Brianza
city: Milano
country: Italy
facility: Centro Cardiologico Monzino IRCCS ( Site 0306)
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo ( Site 0302)
city: Xalapa
country: Mexico
facility: Consultorio 1020 Hospital Angeles Xalapa ( Site 0654)
state: Veracruz
city: Huixquilucan
country: Mexico
facility: Operadora de Hospitales Angeles. S.A. de C.V. -Sucursal Lomas ( Site 0653)
city: Mexico D.F
country: Mexico
facility: Instituto Nacional de Cardiología -Ignacio Chavez ( Site 0651)
city: Christchurch
country: New Zealand
facility: Christchurch Hospital ( Site 0201)
state: Canterbury
city: Auckland
country: New Zealand
facility: Greenlane Clinical Centre ( Site 0203)
city: Walbrzych
country: Poland
facility: Specjalistyczny Szpital im. Dr Alfreda Sokolowskiego w Walbrzychu ( Site 0351)
state: Dolnoslaskie
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie ( Site 0352)
state: Lubelskie
city: Krakow
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawa II-Oddzial Kliniczny Chorob Serca i Naczyn z Pododd
state: Malopolskie
city: Kemerovo
country: Russian Federation
facility: Scientific Research Institute Complex Problems Cardiovascular Disease ( Site 0403)
state: Kemerovskaya Oblast
city: Saint Petersburg
country: Russian Federation
facility: Almazov National Medical Research Centre of the Ministry of Health ( Site 0402)
state: Sankt-Peterburg
city: Uppsala
country: Sweden
facility: Akademiska sjukhuset ( Site 0453)
state: Uppsala Lan
city: Gothenburg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset-Cardiology Research Unit ( Site 0452)
state: Vastra Gotalands Lan
city: Bornova
country: Turkey
facility: Ege Universitesi Hastanesi-Cardilogy Department ( Site 0504)
state: Izmir
city: Ankara
country: Turkey
facility: Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 0510)
city: Antalya
country: Turkey
facility: Akdeniz Uni.Tip Fakultesi Saglik Uygulama ve Arastirma Merkezi ( Site 0508)
city: Eskisehir
country: Turkey
facility: Eskisehir Osmangazi Uni. Tip Fakultesi Hastanesi ( Site 0506)
city: Istanbul
country: Turkey
facility: Istanbul Uni. Kardiyoloji Enstitusu ( Site 0502)
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi ( Site 0509)
city: Istanbul
country: Turkey
facility: Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi ( Site 0501)
city: Izmir
country: Turkey
facility: Dokuz Eylul University Faculty of Medicine ( Site 0505)
city: Glasgow
country: United Kingdom
facility: Golden Jubilee National Hospital ( Site 0556)
state: Glasgow City
city: London
country: United Kingdom
facility: Royal Brompton and Harefield NHS Trust ( Site 0553)
state: London, City Of
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust - Hammersmith Hospital ( Site 0554)
state: London, City Of
city: Newcastle-upon-Tyne
country: United Kingdom
facility: The Freeman Hosp.Newcastle upon Tyne Hosp NHS Trust ( Site 0552)
state: Newcastle Upon Tyne
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.