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

• Register: EUCTR
• Last refreshed on: 26 February 2024
• Main ID: EUCTR2020-001108-40-GR
• Date of registration: 13/07/2021
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck &Co.,Inc
• Public title: Study to Evaluate the Efficacy and Safety of MK-5475 in Adults with Pulmonary Arterial Hypertension
• 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 - Phase 2/3 Study of MK-5475 in Adults with Pulmonary Arterial Hypertension
• Date of first enrolment: 04/10/2021
• Target sample size: 450
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-001108-40
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Adaptive Design; Phase 2: 4 groups, Phase 3: 2 groups If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 6
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Key inclusion & exclusion criteria

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 450 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 contraceptive
Exclusion criteria:
1. Has Group 2 to 5 Pulmonary Hypertension in 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 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 sitting systolic BP >160 mmHg or <90 mmHg or sitting diastolic BP >100 mmHg
13. Has significant chronic renal insufficiency, as defined by eGFR <30 mL/min 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 of drug or alcohol abuse or dependence
23. Has a

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary arterial hypertension
MedDRA version: 20.0 Level: LLT Classification code 10065150 Term: Associated with pulmonary arterial hypertension System Organ Class: 100000004855

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Product Name: MK-5475
Product Code: MK-5475
Pharmaceutical Form: Inhalation powder
INN or Proposed INN: MK-5475
Other descriptive name: MK-5475
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 32-
Pharmaceutical form of the placebo: Inhalation powder
Route of administration of the placebo: Inhalation use

Product Name: MK-5475
Product Code: MK-5475
Pharmaceutical Form: Inhalation powder
INN or Proposed INN: MK-5475
Other descriptive name: MK-5475
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Inhalation powder
Route of administration of the placebo: Inhalation use

Product Name: MK-5475
Product Code: MK-5475
Pharmaceutical Form: Inhalation powder
INN or Proposed INN: MK-5475
Other descriptive name: MK-5475
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 380-
Pharmaceutical form of the placebo: Inhalation powder
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Primary end point(s): 1. Phase 2 Cohort: Change from Baseline in Pulmonary Vascular Resistance (PVR) at 12 Weeks
2. Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks

Secondary Objective: 1. To evaluate the effect of MK-5475 versus placebo on 6-minute walk distance (6MWD) at Week 12 in the Phase 2 Cohort
2. To evaluate the effect of MK-5475 versus placebo on hemodynamic parameters other than pulmonary vascular resistance (PVR) at Week 12 in the Phase 2 Cohort
3. To evaluate the effect of MK-5475 versus placebo on 6-minute walk distance (6MWD) at Week 24 in the Phase 3 Cohort
4. To evaluate the effect of MK-5475 versus placebo on the World Health Organization (WHO) functional pulmonary arterial hypertension (PAH) class at week 12 in the Phase 3 Cohort
5. To evaluate the safety and tolerability of MK-5475 compared to placebo in the Phase 2 and Phase 3 Cohorts (independently)

Main Objective: 1. To evaluate the effect of MK-5475 versus placebo on the pulmonary vascular resistance (PVR) at Week 12 in the Phase 2 Cohort
2. To evaluate the effect of MK-5475 versus placebo on 6-minute walk distance (6MWD) at Week 12 in the Phase 3 Cohort

Timepoint(s) of evaluation of this end point: 1. At baseline and 12 weeks
2. At baseline and 12 weeks

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. At baseline and 12 weeks
2. At baseline and 12 weeks
3. At baseline and 12 weeks
4. At baseline and 12 weeks
5. At baseline and 24 weeks
6. At baseline and 12 weeks
7. Phase 2 Cohort: Up to 14 weeks, Phase 3 Cohort: Up to approximately 5.5 years
8. Phase 2 Cohort: Up to 14 weeks, Phase 3 Cohort: Up to approximately 5.5 years

Secondary end point(s): 1. Phase 2 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 12 Weeks
2. Phase 2 Cohort: Change from Baseline in Mean Right Arterial Pressure (mRAP) at 12 Weeks
3. Phase 2 Cohort: Change from Baseline in Cardiac Index (CI) at 12 weeks
4. Phase 2 Cohort: Change from Baseline in Stroke Volume Index (SVI) at 12 weeks
5. Phase 3 Cohort: Change from Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
6. Phase 3 Cohort: Change from Baseline in World Health Organization Functional Class (WHO-FC) at 12 Weeks
7. Phase 2 and 3 Cohorts: Number of Participants Who Experience an Adverse Event
8. Phase 2 and 3 Cohorts: Number of Participants Who Discontinue Study Drug Due to an Adverse Event

Secondary ID(s)

149503

2020-001108-40-DE

MK-5475-007

Source(s) of Monetary Support

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc

Ethics review

Status: Approved
Approval date: 16/09/2021
Contact: