A Multiple Dose Titration Study of MK-8892 in Participants With Pulmonary Hypertension and Left Heart Disease (MK-8892-007)
Condition: Pulmonary Hypertension; Left Heart Disease
MeSH terms: Hypertension, Pulmonary; Hypertension; Heart Diseases
Intervention: MK-8892
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      This study will assess multiple doses of MK-8892 administered to participants with pulmonary
      hypertension "out of proportion" (PHOOP) and heart failure with reduced left ventricular
      ejection fraction (rEF). It is hypothesized that generally safe and well tolerated multiple
      doses of MK-8892 will achieve a true reduction from baseline in pulmonary vascular resistance
      (PVR) greater than 12%.

      Sixteen participants with PHOOP/rEF were to receive multiple doses of MK-8892 titrated to the
      highest tolerated dose for each participant (up to 4 mg daily), and to undergo evaluation for
      safety and systemic hemodynamics and cardiac function. Only 4 participants were enrolled and
      completed the study due to a strategic business decision by the sponsor to terminate the
      clinical conduct of all MK-8892 ongoing trials including this trial.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Pulmonary hypertension (out of proportion, PHOOP) and heart failure with reduced left
             ventricular ejection fraction (PHOOP/rEF)

          -  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) <=35 kg/m^2 and and <=18 kg/m^2

          -  Has World Health Organization (WHO) Group 2 pulmonary hypertension (PAH)

          -  Stable heart failure on optimal medical therapy with no hospitalizations for
             congestion due to heart failure within the previous 3 months

        Exclusion Criteria:

          -  Primary pulmonary arterial hypertension or veno-occlusive disease (WHO Group 1), or
             pulmonary hypertension secondary to other causes (WHO Groups 3 -5) including but not
             limited to autoimmune disease, connective tissue disease, and Eisenmenger syndrome

          -  Currently treatment with or anticipates use of nitrate, phosphodiesterase type 5
             (PDE5) inhibitor, or medications known to induce or inhibit cytochrome P450 3A4
             (CYP3A4) metabolism, and cannot be transitioned off of this therapy for >=7 days prior
             to dosing and through completion of this study

          -  Symptoms of coronary artery disease requiring therapy with nitrates, within the past 3
             months

          -  Severe aortic or mitral stenosis, or severe aortic, mitral, or tricuspid
             insufficiency.

          -  Significant carotid artery disease

          -  Restrictive, infiltrative (e.g., amyloidosis) or hypertrophic cardiomyopathy

          -  Mentally or legally institutionalized or incapacitated, has significant emotional
             problems at the time of pre study (screening) visit or expected during the conduct of
             the study or has a history of a clinically significant psychiatric disorder over the
             last 5 years. Subjects who have had situational depression may be enrolled in the
             study at the discretion of the investigator.

          -  History of stroke, chronic seizures, or major neurological disorder

          -  History of clinically significant endocrine (not including diabetes mellitus),
             gastrointestinal, hematological, hepatic (not including chronic Hepatitis C),
             immunological (not including chronic human immunodeficiency virus [HIV]), respiratory,
             or genitourinary abnormalities or diseases. Participants with a history of childhood
             asthma may be enrolled in the study at the discretion of the investigator.
             Participants with controlled hypertension are allowed to be enrolled.

          -  Unable to refrain from or anticipates the use of any medication, including
             prescription and non-prescription drugs or herbal remedies (such as St. John's Wort
             [hypericum perforatum]) beginning approximately 2 weeks (or 5 half-lives) prior to
             administration of the dose of study drug, throughout the study (including washout
             intervals between treatment periods), until the post study visit. There may be certain
             medications that will be permitted.

          -  Consumes excessive amounts of alcohol, defined as greater than 5 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 8 weeks prior to the pre study (screening) visit

          -  Participated in another investigational study within 4 weeks prior to the pre study
             (screening) visit

          -  History of significant multiple and/or severe allergies (including latex allergy), or
             has had an anaphylactic reaction or significant intolerability to prescription or
             nonprescription drugs or food

          -  Uses illicit drugs or has a history of drug (including alcohol) abuse within the past
             6 months