A Study of the Efficacy and Safety of MK-5475 in Participants with Pulmonary Arterial Hypertension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

25 Jun 2021 → 2 Jul 2024

Decision date (initial)

2023-06-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-500877-15-00

EudraCT number

2020-001108-40

WHO UTN

U1111-1278-4977

ClinicalTrials.gov

NCT04732221

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Pharmacogenomic, Efficacy, Pharmacodynamic, Pharmacogenetic, Dose response, Safety, Diagnosis

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

Secondary objectives 5

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 in the Phase 2 and Phase 3 Cohorts (independently)

Conditions and MedDRA coding

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

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 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
2. Diagnosis of PAH documented by right heart catheterization (RHC).
3. Eligibility RHC meeting all of the following criteria: Mean pulmonary artery pressure (mPAP) ≥25 mmHg, pulmonary vascular resistance (PVR) of ≥3 Wood units, and pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤15 mmHg.
4. World Health Organization functional class (WHO-FC) symptoms between Class II and IV.
5. Two 6-Minute walk distance (6MWD) measurements between 150 and 500 meters, one at screening and one at randomization.
6. Stable concomitant background PAH-specific therapy.
7. Body Mass Index (BMI) between 18.5 kg/m² and 40 kg/m².

Exclusion criteria 11

1. Group 2 to 5 pulmonary hypertension
2. PAH in one of the following groups: Long term responders to calcium channel blockers, or overt features of venous/capillary involvement
3. Evidence of more-than-mild obstructive lung disease or parenchymal lung disease.
4. Evidence of more-than-mild obstructive sleep apnea (OSA) that is untreated.
5. 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), or significant left ventricular diastolic dysfunction on echocardiographic evaluation.
6. 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.
7. Oxygen saturation measured by pulse oximetry (SpO₂) <90%, despite supplemental oxygen therapy.
8. Chronic renal insufficiency (eGFR <30 mL/min)
9. Chronic liver disease (i.e., Child-Pugh B or C), portal hypertension, cirrhosis, or significant hepatic laboratory abnormalities.
10. Current smoker or currently uses electronic cigarettes (vapes).
11. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

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 endpoints 8

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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Maria Jose Loureiro

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Maria Jose Loureiro

Third parties 7

Locations

7 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications