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)
- Conditions
- Pulmonary Arterial HypertensionHypertension, Pulmonary
- Interventions
- Drug: Placebo to MK-5475Drug: MK-5475
- Registration Number
- NCT04732221
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 168
-
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.
-
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 3 Cohort Placebo Placebo to MK-5475 Participants receive placebo via oral inhalation once daily for 12 week base period and up to 60 months in the extension period. Phase 2 Cohort MK-5475 100 µg MK-5475 Participants receive MK-5475 100 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period. Phase 2 Cohort Placebo Placebo to MK-5475 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. Phase 2 Cohort MK-5475 32 µg MK-5475 Participants receive MK-5475 32 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period. Phase 3 Cohort MK-5475 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 Phase 2 Cohort MK-5475 380 µg MK-5475 Participants receive MK-5475 380 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period.
- Primary Outcome Measures
Name Time Method Phase 2 Cohort: Change from Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks At baseline and 12 weeks PVR is assessed by right heart catheterization (RHC).
Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks At baseline and 12 weeks 6MWD is assessed using the 6-minute walk test (6MWT).
- Secondary Outcome Measures
Name Time Method Phase 2 Cohort: Change from Baseline in Stroke Volume Index (SVI) at 12 weeks At baseline and 12 weeks SVI is assessed by right heart catheterization (RHC).
Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks At baseline and 24 weeks 6MWD is assessed using the 6-minute walk test (6MWT).
Phase 2 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks At baseline and 12 weeks 6MWD is assessed using the 6-minute walk test (6MWT).
Phase 2 Cohort: Change from Baseline in Mean Right Arterial Pressure (mRAP) at 12 Weeks At baseline and 12 weeks mRAP is assessed by right heart catheterization (RHC).
Phase 2 Cohort: Change from Baseline in Cardiac Index (CI) at 12 weeks At baseline and 12 weeks Cardiac index is assessed by right heart catheterization (RHC).
Phase 3 Cohort: Change from Baseline in World Health Organization Functional Class (WHO-FC) at 12 Weeks At baseline and 12 weeks Participants are assigned one of four WHO-FC, dependent on limits of physical activity. As WHO-FC increases from I to IV, limits of physical activity increase.
Phase 3 Cohort: Number of Participants who Discontinue Study Drug Due to an Adverse Event Up to approximately 5.5 years An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Phase 2 Cohort: Number of Participants Who Discontinue Study Drug Due to an Adverse Event Up to approximately 2.25 years An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Phase 3 Cohort: Number of Participants who Experience an Adverse Event Up to approximately 5.5 years An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Phase 2 Cohort: Number of Participants Who Experience an Adverse Event Up to approximately 2.25 years An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Trial Locations
- Locations (91)
University Health Network - Toronto General Hospital ( Site 0104)
🇨🇦Toronto, Ontario, Canada
Hospital Universitario Austral ( Site 0138)
🇦🇷Pilar, Buenos Aires, Argentina
Thoraxklinik Heidelberg gGmbH am Universitaetsklinikum Heidelberg ( Site 0276)
🇩🇪Heidelberg, Baden-Wurttemberg, Germany
Universitaetsklinikum Leipzig ( Site 0285)
🇩🇪Leipzig, Sachsen, Germany
Shaare Zedek Medical Center ( Site 0331)
🇮🇱Jerusalem, Israel
Institut Coeur Poumon - CHRU de Lille ( Site 0252)
🇫🇷Lille Cedex, Nord-Pas-de-Calais, France
Golden Jubilee National Hospital ( Site 0556)
🇬🇧Glasgow, Glasgow City, United Kingdom
Royal Brompton and Harefield NHS Trust ( Site 0553)
🇬🇧London, London, City Of, United Kingdom
Houston Methodist Research Institute ( Site 0036)
🇺🇸Houston, Texas, United States
Indiana University Health Methodist Hospital ( Site 0045)
🇺🇸Indianapolis, Indiana, United States
Almazov National Medical Research Centre of the Ministry of Health ( Site 0402)
🇷🇺Saint Petersburg, Sankt-Peterburg, Russian Federation
Centro Cardiologico Monzino IRCCS ( Site 0306)
🇮🇹Milano, Italy
Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie ( Site 0352)
🇵🇱Lublin, Lubelskie, Poland
Eskisehir Osmangazi Uni. Tip Fakultesi Hastanesi ( Site 0506)
🇹🇷Eskisehir, Turkey
Christchurch Hospital ( Site 0201)
🇳🇿Christchurch, Canterbury, New Zealand
Consultorio 1020 Hospital Angeles Xalapa ( Site 0654)
🇲🇽Xalapa, Veracruz, Mexico
Dokuz Eylul University Faculty of Medicine ( Site 0505)
🇹🇷Izmir, Turkey
Akademiska sjukhuset ( Site 0453)
🇸🇪Uppsala, Uppsala Lan, Sweden
Operadora de Hospitales Angeles. S.A. de C.V. -Sucursal Lomas ( Site 0653)
🇲🇽Huixquilucan, Mexico
Scientific Research Institute Complex Problems Cardiovascular Disease ( Site 0403)
🇷🇺Kemerovo, Kemerovskaya Oblast, Russian Federation
Greenlane Clinical Centre ( Site 0203)
🇳🇿Auckland, New Zealand
Instituto Nacional de Cardiología -Ignacio Chavez ( Site 0651)
🇲🇽Mexico D.F, Mexico
Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 0510)
🇹🇷Ankara, Turkey
Specjalistyczny Szpital im. Dr Alfreda Sokolowskiego w Walbrzychu ( Site 0351)
🇵🇱Walbrzych, Dolnoslaskie, Poland
Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi ( Site 0501)
🇹🇷Istanbul, Turkey
Sahlgrenska Universitetssjukhuset-Cardiology Research Unit ( Site 0452)
🇸🇪Gothenburg, Vastra Gotalands Lan, Sweden
Akdeniz Uni.Tip Fakultesi Saglik Uygulama ve Arastirma Merkezi ( Site 0508)
🇹🇷Antalya, Turkey
University of Kansas Medical Center ( Site 0038)
🇺🇸Kansas City, Kansas, United States
Ege Universitesi Hastanesi-Cardilogy Department ( Site 0504)
🇹🇷Bornova, Izmir, Turkey
The Freeman Hosp.Newcastle upon Tyne Hosp NHS Trust ( Site 0552)
🇬🇧Newcastle-upon-Tyne, Newcastle Upon Tyne, United Kingdom
Ospedale San Gerardo - ASST Monza ( Site 0304)
🇮🇹Monza, Monza E Brianza, Italy
Fondazione IRCCS Policlinico San Matteo ( Site 0302)
🇮🇹Pavia, Italy
Istanbul Uni. Kardiyoloji Enstitusu ( Site 0502)
🇹🇷Istanbul, Turkey
UCSF Helen Diller Medical Center at Parnassus Heights ( Site 0063)
🇺🇸San Francisco, California, United States
University of Colorado - Denver ( Site 0003)
🇺🇸Aurora, Colorado, United States
Tampa General Hospital ( Site 0058)
🇺🇸Tampa, Florida, United States
University of California San Diego Health-Pulmonary Critical Care ( Site 0061)
🇺🇸La Jolla, California, United States
Georgetown University Hospital ( Site 0025)
🇺🇸Washington, District of Columbia, United States
Cardiovascular Institute of North Colorado - Banner Health ( Site 0013)
🇺🇸Greeley, Colorado, United States
University of Miami Hospital-Division of Pulmonary & Critical Care ( Site 0053)
🇺🇸Miami, Florida, United States
University of Kentucky ( Site 0006)
🇺🇸Lexington, Kentucky, United States
University of Iowa Hospital and Clinics ( Site 0009)
🇺🇸Iowa City, Iowa, United States
Washington University School of Medicine ( Site 0066)
🇺🇸Saint Louis, Missouri, United States
University of New Mexico, Health Sciences Center ( Site 0028)
🇺🇸Albuquerque, New Mexico, United States
University of Texas Southwestern Medical Center at Dallas ( Site 0012)
🇺🇸Dallas, Texas, United States
Statcare Pulmonary Consultants ( Site 0067)
🇺🇸Knoxville, Tennessee, United States
The University of Texas Health Science Center at Houston ( Site 0054)
🇺🇸Houston, Texas, United States
AnMed Health ( Site 0033)
🇺🇸Anderson, South Carolina, United States
West Virginia University-WVU Heart and Vascular Institute ( Site 0051)
🇺🇸Morgantown, West Virginia, United States
Cardiologia Palermo ( Site 0140)
🇦🇷Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
Centro Medico Capital ( Site 0131)
🇦🇷La Plata, Buenos Aires, Argentina
Hospital El Cruce Nestor Carlos Kirchner ( Site 0132)
🇦🇷Florencio Varela, Buenos Aires, Argentina
Sentara Norfolk General Hospital ( Site 0014)
🇺🇸Norfolk, Virginia, United States
Sanatorio de la Trinidad Mitre ( Site 0130)
🇦🇷Buenos Aires, Caba, Argentina
Instituto de Investigaciones Clinicas Quilmes ( Site 0141)
🇦🇷Quilmes, Buenos Aires, Argentina
Instituto Cardiovascular de Rosario ( Site 0128)
🇦🇷Rosario, Santa Fe, Argentina
Nepean Hospital ( Site 0184)
🇦🇺Kingswood, New South Wales, Australia
Hospital Privado Universitario de Córdoba ( Site 0137)
🇦🇷Cordoba, Argentina
Macquarie University ( Site 0180)
🇦🇺Macquarie University, New South Wales, Australia
John Hunter Hospital ( Site 0185)
🇦🇺Newcastle, New South Wales, Australia
Université Libre de Bruxelles - Hôpital Erasme ( Site 0601)
🇧🇪Brussels, Bruxelles-Capitale, Region De, Belgium
Hospital Universitario San Ignacio ( Site 0152)
🇨🇴Bogota, Distrito Capital De Bogota, Colombia
IUCPQ ( Site 0111)
🇨🇦Quebec, Canada
Fundacion Cardiovascular de Colombia ( Site 0155)
🇨🇴Piedecuesta, Santander, Colombia
CHRU Brest - Hopital Cavale Blanche ( Site 0254)
🇫🇷Brest, Finistere, France
CHU de Toulouse - Hopital Larrey ( Site 0258)
🇫🇷Toulouse, Haute-Garonne, France
Centre Hospitalier Universitaire de Rouen ( Site 0253)
🇫🇷Rouen, Seine-Maritime, France
CHU - Hopital de Bicetre ( Site 0251)
🇫🇷Le Kremlin-Bicetre, Val-de-Marne, France
Klinikum Würzburg Mitte-Medizinische Klinik - Schwerpunkt Pneumologie & Beatmungsmedizin ( Site 0280
🇩🇪Wuerzburg, Bayern, Germany
UKGM Gießen/Marburg ( Site 0279)
🇩🇪Gießen, Hessen, Germany
Medizinische Hochschule Hannover ( Site 0284)
🇩🇪Hannover, Niedersachsen, Germany
AHEPA University General Hospital of Thessaloniki ( Site 0577)
🇬🇷Thessaloniki, Greece
Uniklinikum Dresden ( Site 0283)
🇩🇪Dresden, Sachsen, Germany
Soroka Medical Center ( Site 0330)
🇮🇱Beer Sheva, Israel
Rambam Medical Center ( Site 0335)
🇮🇱Haifa, Israel
Wolfson Medical Center [Holon, Israel] ( Site 0333)
🇮🇱Holon, Israel
Rabin Medical Center ( Site 0327)
🇮🇱Petah Tikva, Israel
Azienda Ospedaliera Policlinico Umberto I ( Site 0301)
🇮🇹Roma, Lazio, Italy
University of Naples Federico II ( Site 0308)
🇮🇹Naples, Campania, Italy
Istanbul Universitesi Istanbul Tip Fakultesi ( Site 0509)
🇹🇷Istanbul, Turkey
Imperial College Healthcare NHS Trust - Hammersmith Hospital ( Site 0554)
🇬🇧London, London, City Of, United Kingdom
University of California Davis Health-Internal Medicine: Pulmonary, Critical Care and Sleep Medicine
🇺🇸Sacramento, California, United States
Clinical Trials Unit at Eastowne Medical Office Building ( Site 0019)
🇺🇸Chapel Hill, North Carolina, United States
AdventHealth Orlando ( Site 0040)
🇺🇸Orlando, Florida, United States
Norton Pulmonary Specialists ( Site 0048)
🇺🇸Louisville, Kentucky, United States
University of Maryland ( Site 0032)
🇺🇸Baltimore, Maryland, United States
University of Nebraska Medical Center ( Site 0041)
🇺🇸Omaha, Nebraska, United States
UZ Leuven ( Site 0600)
🇧🇪Leuven, Vlaams-Brabant, Belgium
Peter Lougheed Centre ( Site 0107)
🇨🇦Calgary, Alberta, Canada
Krakowski Szpital Specjalistyczny im. Jana Pawa II-Oddzial Kliniczny Chorob Serca i Naczyn z Pododd
🇵🇱Krakow, Malopolskie, Poland
Centro Cardiovascular Colombiano Clínica Santa María ( Site 0154)
🇨🇴Medellín, Antioquia, Colombia