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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)

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

Tracking Information
First Submitted Date  ICMJE January 27, 2021
First Posted Date  ICMJE February 1, 2021
Last Update Posted Date January 20, 2023
Actual Study Start Date  ICMJE May 19, 2021
Estimated Primary Completion Date February 9, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE 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  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE 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  ICMJE
  • Pulmonary Arterial Hypertension
  • Hypertension, Pulmonary
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 27, 2021)
450
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 19, 2028
Estimated Primary Completion Date February 9, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Canada,   Colombia,   France,   Germany,   Greece,   Israel,   Italy,   Mexico,   New Zealand,   Poland,   Russian Federation,   Sweden,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04732221
Other Study ID Numbers  ICMJE 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  ICMJE
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  ICMJE Merck Sharp & Dohme LLC
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme LLC
PRS Account Merck Sharp & Dohme LLC
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP