Clinical trial NCT01926509: Study to Assess the Safety, Tolerability and Pharmacokinetics (PK) of MK-8892 in Participants With Pulmonary Arterial Hypertension (PAH) (MK-8892-005)
Official title: A 28-Day Multiple-Dose Titration Study to Assess the Effects of MK-8892 on Safety, Tolerability and Pharmacokinetics in Subjects With Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2013-08-21
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 at Day 1 and Day 28
timeFrame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24 hours postdose on Days 1 and 28
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to 42 days
measure: Number of Participants Who Had Study Drug Discontinued Due to an Adverse Event
timeFrame: Up to 28 days
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: