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)

• ClinicalTrials.gov Identifier: NCT04732221
• Recruitment Status: Recruiting
• First Posted: February 1, 2021
• Last Update Posted: January 20, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: January 27, 2021
• First Posted Date: February 1, 2021
• Last Update Posted Date: January 20, 2023
• Actual Study Start Date: May 19, 2021
• Estimated Primary Completion Date: February 9, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 27, 2021)

• Phase 2 Cohort: Change from Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks [ Time Frame: 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 [ Time Frame: At baseline and 12 weeks ]
  6MWD is assessed using the 6-minute walk test (6MWT).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 7, 2022)

• Phase 2 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: January 27, 2021)

• Phase 2 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 14 weeks ]
  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 [ Time Frame: Up to 14 weeks ]
  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 [ Time Frame: 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 [ Time Frame: 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief 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)
• 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

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 Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

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.

Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

Condition

• Pulmonary Arterial Hypertension
• Hypertension, Pulmonary

Intervention

• Drug: MK-5475
  MK-5475 (soluble guanylate cyclase stimulator) 380 µg, 100 µg or 32 µg administered as dry powder inhalation
• Drug: Placebo to MK-5475
  Placebo administered as dry powder inhalation

Study Arms

• 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.
  Intervention: Drug: MK-5475
• 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.
  Intervention: Drug: MK-5475
• 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.
  Intervention: Drug: MK-5475
• 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.
  Intervention: Drug: Placebo to MK-5475
• 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
  Intervention: Drug: MK-5475
• 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.
  Intervention: Drug: Placebo to MK-5475

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 27, 2021): 450
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 19, 2028
• Estimated Primary Completion Date: February 9, 2026 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Argentina, Australia, Belgium, Canada, Colombia, France, Germany, Greece, Israel, Italy, Mexico, New Zealand, Poland, Russian Federation, Sweden, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04732221
• Other Study ID Numbers: 5475-007; MK-5475-007 ( Other Identifier: Merck ); 2020-001108-40 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: January 2023