Study to Assess the Safety, Tolerability and Pharmacokinetics (PK) of MK-8892 in Participants With Pulmonary Arterial Hypertension (PAH) (MK-8892-005)
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: MK-8892; Placebo for MK-8892
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This study will evaluate the safety, tolerability, and PK of MK-8892 in participants with
      pulmonary arterial hypertension. The primary hypothesis is that the geometric mean of MK-8892
      area under the concentration time-curve from Hour 0 to 24 hours (AUC0-24hr) in participants
      with PAH, will be equal to or greater than the efficacious exposure in humans of 0.6 μM•hr.
    

Eligibility criteria:

        Inclusion Criteria:

          -  If female, cannot be pregnant or breastfeeding. Females of reproductive potential must
             agree to agree to use (and/or have their partner use) two (2) acceptable methods of
             birth control throughout the study and until 2 weeks after the last dose of study drug
             is administered

          -  Body mass index (BMI) ≤34 kg/m^2 and a total body weight >40 kg (>88 lbs)

          -  Has Group 1 pulmonary hypertension (PAH) as defined by the Dana Point 2008 Clinical
             Classification including: idiopathic PAH (IPAH), Heritable PAH, Drug and toxin-induced
             PAH, PAH associated with connective tissue disease or congenital heart disease
             (repaired simple cardiac defects at least 1 year status post corrective surgery, with
             no residual intracardiac or extracardiac shunt)

          -  On a stable regimen of background therapy for at least 3 months prior to starting
             study drug

          -  Have history of right heart catheterization within two years demonstrating pulmonary
             arterial hypertension

          -  Had pulmonary function testing within one year of starting study medication
             demonstrating total lung capacity (TLC) >70% predicted, forced expiratory volume in 1
             second (FEV1) >70% predicted

          -  Have hemoglobin >75% of the lower limit of the normal range

        Exclusion Criteria:

          -  Pulmonary hypertension subtypes including the following according to Dana Point 2008
             Clinical Classification: human immunodeficiency virus (HIV) infection, portal
             hypertension, schistosomiasis, chronic hemolytic anemia, persistent pulmonary
             hypertension of the newborn (PPHN), pulmonary hypertension due to left heart diseases
             such as systolic dysfunction, diastolic dysfunction or valvular disease, pulmonary
             hypertension due to lung diseases and/or hypoxia (e.g. 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, and developmental abnormalities),
             chronic thromboembolic pulmonary hypertension (CTEPH), hematologic disorder
             (myeloproliferative disorders, splenectomy), systemic disorders (sarcoidosis,
             pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis,
             vasculitis), metabolic disorders (glycogen storage disease, Gaucher disease, thyroid
             disorders) or other disorder (tumoral obstruction, fibrosing mediastinitis, chronic
             renal failure on dialysis)

          -  Have secondary forms of pulmonary hypertension due to pulmonary veno-occlusive disease
             (PVOD), or pulmonary capillary hemangiomatosis (PCH)

          -  Resting systolic blood pressure <105 mmHg, or resting heart rate ≥110/min

          -  Family history of Long QT Syndrome

          -  Uncorrected hypokalemia or hypomagnesemia

          -  Taking medications that are potent inhibitors or inducers of Cytochrome P450 3A4
             (CYP3A4) including but not limited to cyclosporine, systemic itraconazole or
             ketoconazole, glyburide, erythromycin, clarithromycin, or telithromycin, nefazodone,
             protease inhibitors, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin,
             rifampicin, St John's wort, diltiazem and verapamil) or has discontinued treatment <3
             weeks prior to the start of the study. Concomitant medications, including
             anticoagulants, angiotensin converting enzyme (ACE) -inhibitors, diuretics, bosentan,
             ambrisentan and selected calcium channel blockers (e.g., amlodipine) may be allowed at
             the discretion of the investigator with the concurrence of the Sponsor.

          -  Unable to refrain from or anticipates the use of organic nitrates (e.g. nitroglycerin,
             isosorbide mononitrate, isosorbide dinitrate, pentaerythritol) beginning approximately
             2 weeks before start of study and throughout the study

          -  Unable to refrain from or anticipates the use of prostanoid therapies beginning
             approximately 2 weeks before start of study and throughout the study

          -  Consume excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic
             beverages (1 glass is approximately equivalent to: beer [284 mL/10 ounces], wine [125
             mL/4 ounces], or distilled spirits [25 mL/1 ounce]) per day

          -  Major surgery or donated blood within previous 8 weeks

          -  Participated in another investigational study within 4 weeks

          -  History of significant multiple and/or severe allergies

          -  Regular user of illicit drugs, or has a history of drug (including alcohol) abuse,
             within approximately 6 months

          -  Pregnant or breast-feeding, or expecting to conceive

          -  Interstitial lung disease