A Study of Single Doses of MK -5475 on Pulmonary Vascular Resistance (MK-5475-002)
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: MK-5475; Placebo
Intervention description: Single inhaled dose of MK-5475 120, 165, 240, 300, 360, or 480 ug depending upon randomization; Single inhaled dose of placebo to match MK-5475
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Part 1 of the study will evaluate safety, tolerability, and pharmacokinetics in this population using a sequential study design. Review of available safety data up to 24 hours post dose of at least the first 4 participants must occur prior to escalating to the next dose level. A break to review PK data from Periods 1 and 2 will occur after completion of Period 2. Review of safety will occur after completion of Period 3 in all participants from Panel A, prior to initiation of Part 2. An optional break to review rolling PK data from Panel A Period 3 will be dependent upon exposures observed in Periods 1 and 2.
Masking: Double (Participant, Investigator)
Masking description: In Part 1 (Panel A) of this study, a double-blinding technique will be used. MK-5475 and placebo will be packaged identically so that blind is maintained. The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in the study intervention administration or clinical evaluation of the participants are unaware of the intervention assignments.
Part 2 of this study is conducted as open label; therefore, the Sponsor, investigator, and participant will know the intervention administered.
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This study of MK-5475 in participants with Group 1 pulmonary arterial hypertension (PAH) will
      assess the safety, tolerability and pharmacokinetics (PK) of inhaled MK-5475. There is no
      formal hypothesis to be tested.
    

Eligibility 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
             equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits
             [29.5 mL/1 ounce]) per day

          -  Consumes excessive amounts, defined as greater than 6 servings (1 serving is
             approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks,
             or other caffeinated beverages per day

          -  Is a regular user of cannabis, any illicit drugs or has a history of drug (including
             alcohol) abuse within approximately 12 months. Participants must have a negative urine
             drug screen (UDS) prior to randomization