A Study of Single Doses of MK -5475 on Pulmonary Vascular Resistance (MK-5475-002)

• Register: ClinicalTrials.gov
• Last refreshed on: 7 March 2022
• Main ID: NCT03744637
• Date of registration: 13/11/2018
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp.
• Public title: A Study of Single Doses of MK -5475 on Pulmonary Vascular Resistance (MK-5475-002)
• Scientific title: A Study to Assess the Effect of Single Doses of MK -5475 on Pulmonary Vascular Resistance in Patients With Moderate to Severe Pulmonary Arterial Hypertension
• Date of first enrolment: January 18, 2019
• Target sample size: 25
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03744637
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 1

Countries of recruitment

Moldova, Republic of

Contacts

• Name: Medical Director
• Affiliation: Merck Sharp & Dohme Corp.

Key inclusion & exclusion criteria

Inclusion Criteria:

- Be or have suspected Group 1 pulmonary hypertension as defined by the Nice 2013
Clinical Classification, including: idiopathic PAH, heritable PAH, drug- or
toxin-induced PAH, or PAH associated with connective tissue disease or congenital
heart disease

- Have a Body Mass Index (BMI) =35 kg/m2,

- Female participant is eligible to participate if she is not pregnant or breastfeeding,
and at least one of the following conditions applies: She is a woman of
nonchildbearing potential (WONCBP) or is a WOCBP and using a contraceptive method that
is highly effective (with a failure rate of <1% per year), with low user dependency or
be abstinent from heterosexual intercourse as their preferred and usual lifestyle
(abstinent on a long term and persistent basis)

- Male participants are eligible to participate if they agree to the following during
the intervention period and for at least 14 days, corresponding to time needed to
eliminate study intervention(s) after the last dose of study intervention: Be
abstinent from heterosexual intercourse as their preferred and usual lifestyle
(abstinent on a long term and persistent basis) and agree to remain abstinent or must
agree to use contraception unless confirmed to be azoospermic (Vasectomized) or
secondary to medical cause.

- Have a clinical indication for right heart catheterization (RHC) as part of initial
work-up or ongoing medical management

- Panel A: Have history of RHC within 3 years of starting study medication demonstrating
mean pulmonary artery pressure of = 27 mmHg and pulmonary vascular resistance (PVR) of
= 300 dynes/sec/cm5

- Panels B/C/D: Have history of RHC within 3 years of starting study medication
demonstrating mean pulmonary artery pressure of = 27 mmHg and PVR of = 300
dynes/sec/cm5 OR have an echocardiogram performed by the investigator at screening or
within 1 year of screening demonstrating pulmonary artery systolic pressure = 50 mmHg
in conjunction with 1 or more of the following: tricuspid regurgitation velocity > 3.0
m/s and or significant right heart enlargement and or reduced right heart function.

Exclusion Criteria:

- Has pulmonary hypertension subtypes including the following according to Nice 2013
Clinical Classification: human immunodeficiency (HIV) infection, portal hypertension,
schistosomiasis, chronic hemolytic anemia, pulmonary veno-occlusive disease (PVOD) and
or pulmonary capillary hemangiomatosis (PCH), persistent pulmonary hypertension of the
newborn (PPHN), pulmonary hypertension owing to left heart diseases, left ventricular
systolic dysfunction, left ventricular diastolic dysfunction, valvular disease,
congenital/acquired left heart inflow/outflow tract obstruction and congenital
cardiomyopathies, pulmonary hypertension owing to lung diseases and/or hypoxia,
Chronic obstructive pulmonary disease, Interstitial lung disease, other pulmonary
diseases with mixed restrictive and obstructive pattern, sleep-disordered breathing,
alveolar hypoventilation disorders, chronic exposure to high altitude, developmental
abnormalities, pulmonary hypertension defined as chronic thromboembolic pulmonary
hypertension [CTEPH]), pulmonary hypertension with unclear multifactorial mechanisms,
hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders,
splenectomy, systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis,
lymphangioleiomyomatosis, neurofibromatosis, vasculitis, metabolic disorders: glycogen
storage disease, Gaucher disease, thyroid disorders, others: tumoral obstruction,
fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension

- Has a history of clinically significant endocrine (not including stable diabetes
mellitus), gastrointestinal, cardiovascular, hematological, hepatic (not including
chronic stable Hepatitis B and Hepatitis C), immunological, renal, respiratory,
genitourinary, or major neurological (including stroke and chronic seizures)
abnormalities or diseases

- Is mentally or legally incapacitated, has significant emotional problems

- History of cancer (malignancy) except nonmelanomatous skin carcinoma or carcinoma in
situ of the cervix or other malignancies which have been successfully treated 10 years
prior to screening

- History of significant multiple and/or severe allergies

- Known hypersensitivity to iodine or iodine containing products

- Positive for HIV

- Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4
weeks of screening

- Has persistent or permanent atrial fibrillation with an uncontrolled ventricular rate

- Has significantly impaired gas exchange

- Has an active respiratory infection (e.g. common cold, bronchitis, influenza,
pneumonia) with lung function outside of the normal range

- Is currently on monotherapy calcium channel blockers as a specific treatment for
pulmonary hypertension

- Has taken nitrates within 24 hours of anticipated dosing

- Has taken inhaled prostacyclin within 24 hours of anticipated dosing (iloprost or
treprostinil)

- Has taken diltiazem immediate release taken within 24 hours or extended release taken
within 48 hours of anticipated dosing

- Has taken sildenafil or vardenafil within 24 hours or tadalafil within 7 days of
anticipated dosing

- Has taken soluble guanylate cyclase (sGC) activator for PAH within 24 hours of
anticipated dosing

- Is unable to refrain from or anticipates the use of any medication, including
prescription and nonprescription drugs or herbal remedies beginning approximately 2
weeks (or 5 half-lives) prior to administration of the initial dose of study drug,
throughout the study (including washout intervals between treatment periods), until
the poststudy visit

- Has participated in another investigational study within 4 weeks

- Does not agree to follow the smoking restrictions

- Part 2 only: Suffers from claustrophobia and would be unable to undergo computerized
tomography (CT) scan

- Part 2 only: Has participated in a positron-emission tomography (PET) research study
or other study involving administration of a radioactive substance or ionizing
radiation within 12 months prior to the screening visit, or has undergone or plans to
have extensive radiological examination within this period

- Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately



Age minimum: 18 Years
Age maximum: 70 Years
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension

Intervention(s)

Drug: MK-5475

Drug: Placebo

Primary Outcome(s)

Number of Participants Who Experienced at Least 1 Adverse Event (AE): All Parts [Time Frame: Up to ~14 days after last dose of treatment period (Up to ~32 weeks total)]

Number of Participants Who Discontinued From the Study Due to an AE: All Parts [Time Frame: Up to ~14 days after last dose of treatment period (Up to ~32 weeks total)]

Percentage Change From Baseline in Minimum Pulmonary Vascular Resistance (PVR): Part 2 Right Heart Catheterization (RHC) Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and up to 4.5 hours post-dose]

Secondary Outcome(s)

Change From Baseline in Diastolic Blood Pressure (DBP) at 4.5 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose]

Change From Baseline in Systolic Blood Pressure (SBP) at 0.5 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose]

Change From Baseline in Diastolic Blood Pressure (DBP) at 0.5 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose]

Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose]

Maximum Concentration (Cmax) of MK-5475: All Parts [Time Frame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)]

Apparent Terminal Half-life (t1/2) of MK-5475: All Parts [Time Frame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)]

Change From Baseline in Heart Rate (HR) at 0.5 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose]

Change From Baseline in Heart Rate (HR) at 24 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose]

Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose]

Change From Baseline in Systolic Blood Pressure (SBP) at 4.5 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose]

Time to Maximum Concentration (Tmax) of MK-5475: All Parts [Time Frame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)]

Change From Baseline in Heart Rate (HR) at 4.5 Hours Post-dose: Part 2 RHC Period [Time Frame: Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose]

Area Under the Concentration-Time Curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-5475: All Parts [Time Frame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)]

Area Under the Concentration-Time Curve From Hour 0 to Infinity (AUC0-inf) of MK-5475: All Parts [Time Frame: Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours)]

Concentration of MK-5475 at 24 Hours Postdose (C24): All Parts [Time Frame: 24 hours postdose]

Percentage Change From Baseline in Pulmonary Blood Volume (PBV) Over Time: Part 2 Functional Respiratory Imaging (FRI) Period [Time Frame: Baseline: Pre-dose on Day 1 of FRI Period (up to 227 days) and 1, 3, 8, and 24 hours post-dose]

Secondary ID(s)

5475-002

MK-5475-002

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 23/02/2022
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03744637