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)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04732221

Collaborator

(none)

450

Enrollment

Locations

Arms

65.3

Anticipated Duration (Months)

5.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension Hypertension, Pulmonary	Drug: MK-5475 Drug: Placebo to MK-5475	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

450 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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.

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 19, 2021

Anticipated Primary Completion Date :

Dec 2, 2024

Anticipated Study Completion Date :

Oct 29, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 2 Cohort MK-5475 380 µg Participants receive MK-5475 380 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period.	Drug: MK-5475 MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation
Experimental: Phase 2 Cohort MK-5475 100 µg Participants receive MK-5475 100 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period.	Drug: MK-5475 MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation
Experimental: Phase 2 Cohort MK-5475 32 µg Participants receive MK-5475 32 µg via oral inhalation once daily for 12 week base period and for optional 24 month extension period.	Drug: MK-5475 MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation
Placebo Comparator: Phase 2 Cohort Placebo 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.	Drug: Placebo to MK-5475 Placebo administered as dry powder inhalation
Experimental: Phase 3 Cohort 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	Drug: MK-5475 MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation
Placebo Comparator: Phase 3 Cohort Placebo Participants receive placebo via oral inhalation once daily for 12 week base period and up to 60 months in the extension period.	Drug: Placebo to MK-5475 Placebo administered as dry powder inhalation

Outcome Measures

Primary Outcome Measures

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

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 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 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 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.
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 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Davis Health-Internal Medicine: Pulmonary, Critical Care and Sleep Medicine	Sacramento	California	United States	95817
2	University of Colorado - Denver ( Site 0003)	Aurora	Colorado	United States	80045
3	Cardiovascular Institute of North Colorado - Banner Health ( Site 0013)	Greeley	Colorado	United States	80631
4	Georgetown University Hospital ( Site 0025)	Washington	District of Columbia	United States	20007
5	AdventHealth Orlando ( Site 0040)	Orlando	Florida	United States	32803
6	Methodist Hospital [Indianapolis, IN] ( Site 0045)	Indianapolis	Indiana	United States	46202
7	University of Iowa Hospital and Clinics ( Site 0009)	Iowa City	Iowa	United States	52242
8	University of Kansas Medical Center ( Site 0038)	Kansas City	Kansas	United States	66160
9	University of Kentucky ( Site 0006)	Lexington	Kentucky	United States	40536
10	Norton Pulmonary Specialists ( Site 0048)	Louisville	Kentucky	United States	40202
11	University of Maryland ( Site 0032)	Baltimore	Maryland	United States	21201
12	University of Nebraska Medical Center ( Site 0041)	Omaha	Nebraska	United States	68198-7680
13	University of New Mexico, Health Sciences Center ( Site 0028)	Albuquerque	New Mexico	United States	87131
14	Clinical Trials Unit at Eastowne Medical Office Building ( Site 0019)	Chapel Hill	North Carolina	United States	27514
15	AnMed Health ( Site 0033)	Anderson	South Carolina	United States	29621
16	University of Texas Southwestern Medical Center at Dallas ( Site 0012)	Dallas	Texas	United States	75390
17	Houston Methodist Research Institute ( Site 0036)	Houston	Texas	United States	77030
18	Sentara Norfolk General Hospital ( Site 0014)	Norfolk	Virginia	United States	23507
19	West Virginia University-WVU Heart and Vascular Institute ( Site 0051)	Morgantown	West Virginia	United States	26506
20	Cardiologia Palermo ( Site 0140)	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1425BNG
21	Hospital El Cruce Nestor Carlos Kirchner ( Site 0132)	Florencio Varela	Buenos Aires	Argentina	1888
22	Centro Medico Capital ( Site 0131)	La Plata	Buenos Aires	Argentina	B1904AAW
23	Hospital Universitario Austral ( Site 0138)	Pilar	Buenos Aires	Argentina	B1629ODT
24	Instituto de Investigaciones Clinicas Quilmes ( Site 0141)	Quilmes	Buenos Aires	Argentina	B1878GEG
25	Sanatorio de la Trinidad Mitre ( Site 0130)	Buenos Aires	Caba	Argentina	1039
26	Instituto Cardiovascular de Rosario ( Site 0128)	Rosario	Santa Fe	Argentina	S2000DSR
27	Hospital Privado Universitario de Córdoba ( Site 0137)	Cordoba		Argentina	X5016KEH
28	Nepean Hospital ( Site 0184)	Kingswood	New South Wales	Australia	2747
29	Macquarie University ( Site 0180)	Macquarie University	New South Wales	Australia	2109
30	Peter Lougheed Centre ( Site 0107)	Calgary	Alberta	Canada	T1Y 6J4
31	Centro Cardiovascular Colombiano Clínica Santa María ( Site 0154)	Medellín	Antioquia	Colombia	050034
32	Hospital Universitario San Ignacio ( Site 0152)	Bogota	Distrito Capital De Bogota	Colombia	110231
33	Fundacion Cardiovascular de Colombia ( Site 0155)	Piedecuesta	Santander	Colombia	681017
34	CHRU Brest - Hopital Cavale Blanche ( Site 0254)	Brest	Finistere	France	29609
35	CHU de Toulouse - Hopital Larrey ( Site 0258)	Toulouse	Haute-Garonne	France	31059
36	Institut Coeur Poumon - CHRU de Lille ( Site 0252)	Lille Cedex	Nord-Pas-de-Calais	France	59037
37	Centre Hospitalier Universitaire de Rouen ( Site 0253)	Rouen	Seine-Maritime	France	76031
38	CHU - Hopital de Bicetre ( Site 0251)	Le Kremlin-Bicetre	Val-de-Marne	France	94275
39	Thoraxklinik Heidelberg gGmbH am Universitaetsklinikum Heidelberg ( Site 0276)	Heidelberg	Baden-Wurttemberg	Germany	69126
40	Klinikum Würzburg Mitte-Medizinische Klinik - Schwerpunkt Pneumologie & Beatmungsmedizin ( Site 0280	Wuerzburg	Bayern	Germany	97074
41	Universitaetsklinikum Giessen und Marburg GmbH ( Site 0279)	Giessen	Hessen	Germany	35392
42	Medizinische Hochschule Hannover ( Site 0284)	Hannover	Niedersachsen	Germany	30625
43	Uniklinikum Dresden ( Site 0283)	Dresden	Sachsen	Germany	01307
44	Universitaetsklinikum Leipzig ( Site 0285)	Leipzig	Sachsen	Germany	04103
45	AHEPA University General Hospital of Thessaloniki ( Site 0577)	Thessaloniki		Greece	54636
46	Soroka Medical Center ( Site 0330)	Beer Sheva		Israel	8410101
47	Rambam Medical Center ( Site 0335)	Haifa		Israel	3109601
48	Wolfson Medical Center [Holon, Israel] ( Site 0333)	Holon		Israel	5810000
49	Shaare Zedek Medical Center ( Site 0331)	Jerusalem		Israel	9103102
50	Rabin Medical Center ( Site 0327)	Petah Tikva		Israel	4941492
51	University of Naples Federico II ( Site 0308)	Naples	Campania	Italy	80100
52	Azienda Ospedaliera Policlinico Umberto I ( Site 0301)	Roma	Lazio	Italy	00161
53	Ospedale San Gerardo - ASST Monza ( Site 0304)	Monza	Monza E Brianza	Italy	20900
54	Centro Cardiologico Monzino IRCCS ( Site 0306)	Milano		Italy	20138
55	Fondazione IRCCS Policlinico San Matteo ( Site 0302)	Pavia		Italy	27100
56	Consultorio 1020 Hospital Angeles Xalapa ( Site 0654)	Xalapa	Veracruz	Mexico	91193
57	Operadora de Hospitales Angeles. S.A. de C.V. -Sucursal Lomas ( Site 0653)	Huixquilucan		Mexico	52763
58	Instituto Nacional de Cardiología -Ignacio Chavez ( Site 0651)	Mexico D.F		Mexico	14080
59	Christchurch Hospital ( Site 0201)	Christchurch	Canterbury	New Zealand	8011
60	Greenlane Clinical Centre ( Site 0203)	Auckland		New Zealand	1051
61	Specjalistyczny Szpital im. Dr Alfreda Sokolowskiego w Walbrzychu ( Site 0351)	Walbrzych	Dolnoslaskie	Poland	58-309
62	Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie ( Site 0352)	Lublin	Lubelskie	Poland	20-954
63	Scientific Research Institute Complex Problems Cardiovascular Disease ( Site 0403)	Kemerovo	Kemerovskaya Oblast	Russian Federation	650002
64	Almazov National Medical Research Centre of the Ministry of Health ( Site 0402)	Saint Petersburg	Sankt-Peterburg	Russian Federation	197341
65	Akademiska sjukhuset ( Site 0453)	Uppsala	Uppsala Lan	Sweden	751 85
66	Sahlgrenska Universitetssjukhuset-Cardiology Research Unit ( Site 0452)	Gothenburg	Vastra Gotalands Lan	Sweden	413 45
67	Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 0510)	Ankara		Turkey	06100
68	Akdeniz Uni.Tip Fakultesi Saglik Uygulama ve Arastirma Merkezi ( Site 0508)	Antalya		Turkey	07059
69	Eskisehir Osmangazi Uni. Tip Fakultesi Hastanesi ( Site 0506)	Eskisehir		Turkey	26040
70	Istanbul Uni. Kardiyoloji Enstitusu ( Site 0502)	Istanbul		Turkey	34096
71	Istanbul Universitesi Istanbul Tip Fakultesi ( Site 0509)	Istanbul		Turkey	34390
72	Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi ( Site 0501)	Istanbul		Turkey	34899
73	Ege Universitesi Tip Fakultesi Hastanesi ( Site 0504)	Izmir		Turkey	35100
74	Dokuz Eylul University Faculty of Medicine ( Site 0505)	Izmir		Turkey	35330
75	Golden Jubilee National Hospital ( Site 0556)	Glasgow	Glasgow City	United Kingdom	G81 4DY
76	Royal Brompton and Harefield NHS Trust ( Site 0553)	London	London, City Of	United Kingdom	SW3 6NP
77	Imperial College Healthcare NHS Trust - Hammersmith Hospital ( Site 0554)	London	London, City Of	United Kingdom	W12 0HS

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

Study Director: Medical Director, Merck Sharpe & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Merck Sharp & Dohme LLC

ClinicalTrials.gov Identifier:

NCT04732221

Other Study ID Numbers:

5475-007
MK-5475-007
2020-001108-40

First Posted:

Feb 1, 2021

Last Update Posted:

Aug 22, 2022

Last Verified:

Aug 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Pulmonary Arterial Hypertension

Familial Primary Pulmonary Hypertension

Hypertension, Pulmonary

Hypertension

Study Results

No Results Posted as of Aug 22, 2022