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

Merck Sharp & Dohme (MSD)

Status and phase: Terminated; Phase 1

Conditions: Pulmonary Arterial Hypertension

Treatments: Drug: MK-8892

Study type: Interventional

Funder types: Industry

Identifiers

NCT01934647

2013-001680-23 (EudraCT Number)

8892-003

MK-8892-003 (Other Identifier)

Details and patient eligibility

About

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).

Enrollment: 7 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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7 participants in 3 patient groups

1 mg MK-8892

Experimental group

Description:

Participants will receive a single oral dose of 1 mg MK-8892.

Treatment:

Drug: MK-8892

4 mg MK-8892

Experimental group

Description:

Participants will receive a single oral dose of 4 mg MK-8892.

Treatment:

Drug: MK-8892

8 mg MK-8892

Experimental group

Description:

Participants will receive a single oral dose of 8 mg MK-8892.

Treatment:

Drug: MK-8892