Study to Evaluate the Efficacy and Safety of MK-5475 in Adults with Pulmonary Arterial Hypertensio

Phase 1

Conditions: Pulmonary arterial hypertension
MedDRA version: 20.0Level: LLTClassification code 10065150Term: Associated with pulmonary arterial hypertensionSystem Organ Class: 100000004855
Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Registration Number: EUCTR2020-001108-40-PL

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 450

Inclusion Criteria

1. Has the following PAH groups, as defined by the Updated Clinical Classification of Pulmonary Hypertension:
a) Group 1.1 Idiopathic PAH
b) Group 1.2 Heritable PAH
c) Group 1.3 Drug and toxin-induced PAH
d) Group 1.4 PAH associated with:
? Connective tissue disease
? HIV infection
? Simple repaired congenital systemic-to-pulmonary shunt with persistent PH =1 year after surgical repair and with no clinically significant residual shunt
2. Has a diagnosis of PAH performed as standard of care, per scientific guidelines, and documented by historical RHC at any time prior to Screening; if participant is postsurgical repair of systemic-to pulmonary shunt, diagnostic RHC must have been performed at least 1 year after surgery
3. Has an eligibility RHC, meeting all the following criteria:
? mean pulmonary artery pressure (mPAP) =25 mmHg
? PVR of =3 Wood units
? PCWP or LVEDP =15 mmHg
For the Phase 2 Cohort, the eligibility RHC should be performed during Screening and will be centrally reviewed. A participant with RHC performed within 30 days prior to Visit 1/Screening may have the RHC results submitted for central review and, if deemed adequate, the RHC may count as baseline. In each case, the RHC should be performed after at least 90 days of stable PAH-specific therapy. For the Phase 3 Cohort, an RHC performed within 365 days prior to Visit 1/Screening may count for eligibility assessment. An RHC will be performed during Screening if an RHC performed within 365 days prior to Visit 1/Screening is not available
4. Has WHO-FC symptoms Class II to IV
5. Has two 6MWD measurements between 150 and 500 meters, 1 at Screening and 1 at Randomization. The relative difference between the 2 measurements must be =15%. If the relative difference between the two 6MWD measurements is >15%, the Randomization 6MWT may be repeated after at least 4 hours. If the relative difference between the 2 Randomization 6MWD measurements is =15%, the participant can be randomized and the last 6MWD will be considered the baseline value
6. Has stable concomitant background PAH-specific therapy with any of the following agents:
? an ERA and/or
? a PDE5i and/or
? an oral prostacyclin analogue or oral prostacyclin receptor agonist, an intravenous prostacyclin analogue or a subcutaneous prostacyclin
analogue
7. If on vasodilators other than PAH-specific therapy, has stable concomitant use
8. If on calcium channel blockers, a participant from Groups 1.1, 1.2, and 1.3 must have a history of being a nonresponder to acute pulmonary vasoreactivity testing
9. If on anticoagulants, has stable concomitant use for at least 30 days prior to and over the duration of Screening
10. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the informed consent
11. Has a BMI between 18.5 kg/m2 and 40 kg/m2
12. Is willing to comply with scheduled visits, treatment plan, laboratory tests, and/or other study procedures and study restrictions
13. Agrees to allowing site contact via phone or email for follow-up purposes
14. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 14 days after the last dose of study intervention:
? Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR
? Must agree to use contraception unless confirmed to be azoospermic as detailed below:
- Agree to use a male condom plus partner use of an additional contracepti

Exclusion Criteria

1. Has Group 2 PH, Group 3 PH, Group 4 PH, or Group 5 PH according to the Updated Clinical Classification of Pulmonary Hypertension.
2. Has Group 1.5 PAH, long-term responders to calcium channel blockers, defined by sustained clinical improvement to WHO-FC I or II and sustained hemodynamic improvement after at least 1 year on CCBs only
3. Has Group 1.6 PAH, with overt features of venous/capillary (PVOD/PCH) involvement
4. For participants with Group 1.4 HIV-associated PAH, has any of the following within 90 days prior to and for the duration of Screening:
? concomitant active opportunistic infections
? plasma HIV-1 RNA=50 copies/mL or CD4+ T-cell count<200/mm3
? changes in antiretroviral regimen
5. Has evidence of more-than-mild obstructive lung disease on PFT at Screening: FEV1/FVC <70%; and FEV1 <60% of predicted value after bronchodilator administration
6. Has evidence of more-than-mild parenchymal lung disease, based on medical history and chest imaging , and/or restrictive lung disease with Total Lung Capacity <60% of predicted on PFT at Screening
7. Has evidence of more-than-mild OSA that is untreated. Participants with well-controlled, treated OSA are eligible
8. Has evidence or history of left heart disease, including any of the following:
? left ventricular ejection fraction =45%
? moderate or severe left-sided valvular disease
? Grade 3 and 4 left ventricular diastolic function on echocardiographic evaluation
9. Has 3 or more of the following risk factors for heart failure with preserved ejection fraction:
? BMI >30 kg/m2
? history of essential systemic hypertension
? diabetes mellitus of any type
? history of coronary artery disease
10. Has oxygen saturation measured by pulse oximetry <90%, despite supplemental oxygen therapy
11. Had clinically unstable or acutely decompensated right heart failure within 30 days prior to and over the duration of Screening including, but not limited to, hospitalization or emergency room visit for acute decompensated heart failure
12. Has stated systolic BP >160 mmHg or <90 mmHg or stated diastolic BP >100 mmHg
13. Has significant chronic renal insufficiency, as defined by eGFR <30 mL/min/1.73 m2 or by ongoing dialytic support
14. Has evidence of chronic liver disease, portal hypertension,
cirrhosis, or hepatic laboratory abnormalities
15. Is included in a cardiopulmonary rehabilitation program initiated within 90 days prior to Screening or is planning to initiate cardiopulmonary rehabilitation during the study
16. Has acute or chronic impairment(s), limiting the ability to perform 6MWT
17. Is a current smoker or currently uses electronic cigarettes
18. Is unable to correctly use the DPI prior to randomization due to, but not limited to, cognitive impairment or physical limitations
19. Has other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation
20. Has a history of cancer. Exceptions:1) Adequately treated
nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or;2) Other malignancies which have been successfully treated, with appropriate follow up, and therefore unlikely to recur for the duration of the study, in the opinion of the investigator
21. Has a known hypersensitivity to any of the ingredients or excipients of the IMP
22. At the time of signing the informed consent, is a user of illicit drugs or has had a recent history o

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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