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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04732221




Registration number
NCT04732221
Ethics application status
Date submitted
27/01/2021
Date registered
1/02/2021
Date last updated
6/06/2024

Titles & IDs
Public title
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)
Scientific 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
Secondary ID [1] 0 0
MK-5475-007
Secondary ID [2] 0 0
5475-007
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 0 0
Hypertension, Pulmonary 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - MK-5475
Treatment: Drugs - Placebo to MK-5475

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.

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.

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.

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.

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

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.


Treatment: Drugs: MK-5475
MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation

Treatment: Drugs: Placebo to MK-5475
Placebo administered as dry powder inhalation
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 2 Cohort: Change from Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks
Timepoint [1] 0 0
At baseline and 12 weeks
Primary outcome [2] 0 0
Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
Timepoint [2] 0 0
At baseline and 12 weeks
Secondary outcome [1] 0 0
Phase 2 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
Timepoint [1] 0 0
At baseline and 12 weeks
Secondary outcome [2] 0 0
Phase 2 Cohort: Change from Baseline in Mean Right Arterial Pressure (mRAP) at 12 Weeks
Timepoint [2] 0 0
At baseline and 12 weeks
Secondary outcome [3] 0 0
Phase 2 Cohort: Change from Baseline in Cardiac Index (CI) at 12 weeks
Timepoint [3] 0 0
At baseline and 12 weeks
Secondary outcome [4] 0 0
Phase 2 Cohort: Change from Baseline in Stroke Volume Index (SVI) at 12 weeks
Timepoint [4] 0 0
At baseline and 12 weeks
Secondary outcome [5] 0 0
Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
Timepoint [5] 0 0
At baseline and 24 weeks
Secondary outcome [6] 0 0
Phase 3 Cohort: Change from Baseline in World Health Organization Functional Class (WHO-FC) at 12 Weeks
Timepoint [6] 0 0
At baseline and 12 weeks
Secondary outcome [7] 0 0
Phase 2 Cohort: Number of Participants Who Experience an Adverse Event
Timepoint [7] 0 0
Up to approximately 2.25 years
Secondary outcome [8] 0 0
Phase 2 Cohort: Number of Participants Who Discontinue Study Drug Due to an Adverse Event
Timepoint [8] 0 0
Up to approximately 2.25 years
Secondary outcome [9] 0 0
Phase 3 Cohort: Number of Participants who Experience an Adverse Event
Timepoint [9] 0 0
Up to approximately 5.5 years
Secondary outcome [10] 0 0
Phase 3 Cohort: Number of Participants who Discontinue Study Drug Due to an Adverse Event
Timepoint [10] 0 0
Up to approximately 5.5 years

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2/Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
19/05/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
15/07/2024
Actual
Sample size
Target
Accrual to date
Final
168
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Nepean Hospital ( Site 0184) - Kingswood
Recruitment hospital [2] 0 0
Macquarie University ( Site 0180) - Macquarie University
Recruitment hospital [3] 0 0
John Hunter Hospital ( Site 0185) - Newcastle
Recruitment postcode(s) [1] 0 0
2747 - Kingswood
Recruitment postcode(s) [2] 0 0
2109 - Macquarie University
Recruitment postcode(s) [3] 0 0
2305 - Newcastle
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
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State/province [2] 0 0
Colorado
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District of Columbia
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United States of America
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Florida
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Indiana
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Iowa
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Kansas
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United States of America
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Kentucky
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Maryland
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Missouri
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Nebraska
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New Mexico
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North Carolina
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South Carolina
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Tennessee
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Texas
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Virginia
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West Virginia
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Argentina
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Buenos Aires
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Argentina
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Caba
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Argentina
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Santa Fe
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Argentina
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Cordoba
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Belgium
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Bruxelles-Capitale, Region De
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Belgium
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Vlaams-Brabant
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Canada
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Alberta
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Canada
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Ontario
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Canada
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Quebec
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Colombia
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Antioquia
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Colombia
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Distrito Capital De Bogota
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Colombia
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Santander
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France
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Finistere
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France
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Seine-Maritime
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France
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Germany
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Baden-Wurttemberg
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Germany
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Bayern
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Germany
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Hessen
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Germany
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Niedersachsen
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Germany
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Sachsen
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Greece
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Thessaloniki
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Israel
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Beer Sheva
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Israel
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Haifa
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Israel
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Holon
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Israel
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Jerusalem
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Israel
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Petah Tikva
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Italy
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Campania
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Italy
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Lazio
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Italy
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Monza E Brianza
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Italy
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Milano
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Italy
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Pavia
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Veracruz
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Mexico D.F
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New Zealand
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Canterbury
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New Zealand
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Auckland
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Poland
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Dolnoslaskie
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Poland
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Lubelskie
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Poland
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Malopolskie
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Russian Federation
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Kemerovskaya Oblast
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Russian Federation
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Sankt-Peterburg
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Sweden
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Uppsala Lan
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Sweden
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Vastra Gotalands Lan
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Izmir
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Ankara
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Antalya
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Eskisehir
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Turkey
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Istanbul
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United Kingdom
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Glasgow City
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United Kingdom
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London, City Of
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United Kingdom
State/province [71] 0 0
Newcastle Upon Tyne

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04732221
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04732221