Acute Dosing of MK-8892 in Participants With Pulmonary Arterial Hypertension (PAH) (MK-8892-003)

A Non-randomized, Single-Panel, Open-Label Trial to Study the Safety, Tolerability and Pharmacodynamics of MK-8892 Acute Dosing in Subjects With Moderate to Severe Pulmonary Arterial Hypertension

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).

Study Overview

• Status: Terminated
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: MK-8892

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1 mg MK-8892; Participants will receive a single oral dose of 1 mg MK-8892.	Drug: MK-8892; Single oral capsule with 1 mg, 4 mg, or 8 mg of MK-8892
EXPERIMENTAL: 4 mg MK-8892; Participants will receive a single oral dose of 4 mg MK-8892.	Drug: MK-8892; Single oral capsule with 1 mg, 4 mg, or 8 mg of MK-8892
EXPERIMENTAL: 8 mg MK-8892; Participants will receive a single oral dose of 8 mg MK-8892.	Drug: MK-8892; Single oral capsule with 1 mg, 4 mg, or 8 mg of MK-8892

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and up to 5 hours post-dose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 22, 2013
• Primary Completion (ACTUAL): September 8, 2014
• Study Completion (ACTUAL): September 8, 2014

Study Registration Dates

• First Submitted: August 30, 2013
• First Submitted That Met QC Criteria: August 30, 2013
• First Posted (ESTIMATE): September 4, 2013

Study Record Updates

• Last Update Posted (ACTUAL): October 22, 2018
• Last Update Submitted That Met QC Criteria: March 27, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: 8892-003; 2013-001680-23 (EUDRACT_NUMBER); MK-8892-003 (OTHER: Merck Protocol Number)