Pulmonary Arterial Hypertension
Conditions
Brief summary
This clinical trial will study the safety, tolerability, and pharmacodynamics of single doses of MK-8892 in participants with pulmonary arterial hypertension (PAH). The primary objective is to estimate the measured peak effect of the highest acutely tolerated (HAT) single oral dose of MK-8892 on pulmonary vascular resistance (PVR).
Interventions
DRUGMK-8892
Single oral capsule with 1 mg, 4 mg, or 8 mg of MK-8892
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* postmenopausal female or if female of reproductive potential, remains abstinent or uses two acceptable methods of birth control during 14 days after dosing with MK-8892 * has suspected PAH classified in one of the following sub-groups: idiopathic, heritable, drug- or toxin-induced, or associated with connective tissue disease, as defined by the Dana Point 2008 Clinical Classification * has a clinical indication for right heart catheterization * PAH classified as World Health Organization (WHO) functional class II or III
Exclusion criteria
* has a medical history indicating a secondary cause of Pulmonary Hypertension (PH) or a non-included etiology of PAH including the following tests within 6 months of Visit 1: Echo indicating significant left heart disease, valvular disease, or structural defects; function test indicating significant pulmonary disease; imaging test indicating veno-occlusive disease; perfusion scan indicating thromboembolic disease; abdominal ultrasound indicating cirrhosis; positive test for human immunodeficiency virus (HIV) * has persistent or permanent atrial fibrillation, significantly impaired gas exchange, history of radiation of the lung or mediastinum, hepatic or hepatobiliary disease, immunodeficiencies or latent bleeding risk * has estimated Glomerular Filtration Rate (GFR) \<45 mL/min * has alanine aminotransferase test (ALT) serum glutamic pyruvic transaminase (SGPT) or aspartate aminotransferase test (AST) serum glutamic oxaloacetic transaminase (SGOT) \>= 3 x upper limit of normal (ULN) at Visit 1 * has a systolic blood pressure (BP) \<105 mmHg, or heart rate (HR) \> 100 beats/min at Visit 1 (Day -7 to -1) * has previously received specific therapy for PAH within 4 weeks prior to Visit 1 * has taken sildenafil, valdenafil or a nitrate within 24 hours prior to Visit 2 date * has taken tadalafil within 7 days prior to Visit 2 date * has taken 2 or more specific PAH medications concomitantly within 4 weeks of anticipated Visit 2 date. Only treatment naïve subjects or subjects on stable PAH-specific monotherapy with an endothelin receptor antagonist (\[ERA\]; bosentan, ambrisentan, or macitentan) or a prostacyclin analog (\[PCA\]; treprostinil, epoprostenol, or iloprost) are eligible. PAH monotherapy with one of these medications may continue without interruption during this study * has taken a soluble guanylate cyclase (sGC) activator (riociguat) within 24 hours of anticipated Visit 2 date. * has taken diltiazem immediate release within 1 day or diltiazem extended release within 2 days prior to Visit 2 date * is currently taking potent inhibitors or inducers of Cytochrome P450 3A4 (CYPA4), or is consuming \>1 liter of grapefruit juice per day * is pregnant or breastfeeding or expecting to conceive during study or post study follow-up period * has donated 500 mL of blood within prior 60 days * is currently participating in or has within the prior three months participated in a study with an investigational compound or device
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at the Highest Acutely Tolerated (HAT) Dose of MK-8892 | Baseline and up to 5 hours post-dose | PVR assessments were performed throughout the right heart catheterization (RHC). Peak PVR reduction was determined to occur if 2 consecutive PVR measurements were at least 20% greater than the nadir PVR measurement. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1 mg MK-8892 Participants received a single oral dose of 1 mg MK-8892. | 2 |
| 4 mg MK-8892 Participants received a single oral dose of 4 mg MK-8892. | 2 |
| 8 mg MK-8892 Participants received a single oral dose of 8 mg MK-8892. | 3 |
| Total | 7 |
Baseline characteristics
| Characteristic | 1 mg MK-8892 | 4 mg MK-8892 | 8 mg MK-8892 | Total |
|---|---|---|---|---|
| Age, Continuous | 34.5 Years STANDARD_DEVIATION 17.7 | 52.0 Years STANDARD_DEVIATION 1.4 | 61.3 Years STANDARD_DEVIATION 11 | 51 Years STANDARD_DEVIATION 15.4 |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 3 |
| other Total, other adverse events | 1 / 2 | 1 / 2 | 0 / 3 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 0 / 3 |
Outcome results
Primary
Peak Percent Change From Baseline in Pulmonary Vascular Resistance (PVR) at the Highest Acutely Tolerated (HAT) Dose of MK-8892
PVR assessments were performed throughout the right heart catheterization (RHC). Peak PVR reduction was determined to occur if 2 consecutive PVR measurements were at least 20% greater than the nadir PVR measurement.
Time frame: Baseline and up to 5 hours post-dose
Population: Planned efficacy analysis could not be performed due to early study termination.