This study is an exploratory Phase 1 randomized, double-blind (Investigator and study subject and 2-D echo endpoint assessor), placebo-controlled single IV infusion dose escalation study that will enroll up to approximately 32 subjects with stage 1 or 2 essential hypertension.
The study will be conducted in two parts. Part 1: For the initial evaluation of safety, pharmacokinetic exposure and pharmacodynamic response, subjects will be tapered off antihypertensive background therapy.The initial starting dose will be a sub-therapeutic dose. Dose escalation will continue with a maximum of a doubling of the previous dose until either 1) a maximum tolerated dose (MTD) is identified or 2) modeling of the pharmacokinetic (PK) data indicate that maximum exposure (Cmax) at the next planned dose level would exceed a maximum drug concentration (Cmax) which was the maximum observed drug concentration following a single subcutaneous administration in Study PB1046-PT-CL-0001. Part 2: The dose group which is capable of providing a Cmax exposure which is capable of eliciting a clinically relevant hemodynamic response, will be expanded to enroll an additional 12 subjects (6 active and 6 placebo).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
20
0.9% Sodium Chloride - 30 minute IV infusion
New Orleans Center for Clinical Research - Knoxville
Knoxville, Tennessee, United States
Safety and Tolerability
To evaluate the safety and tolerability of single ascending doses of Vasomera administered as a 30 minute intravenous (IV) infusion to subjects with stage 1 or stage 2 essential hypertension. * Incidence and severity of adverse events (AEs) and their relationship to Vasomera (including AEs of interest, i.e., incidence and severity of gastrointestinal effects, and infusion site reactions) * Changes in vital signs, ECGs, safety laboratory parameters, heart rhythm via telemetry monitor from baseline
Time frame: Days -45 to 28: Vital signs (Days -45, -14, -1, 0, 1, 2, 3, 4, 7, 14 and 28), ECGs (Days -45, -1, 0, 1 and 2), Safety Labs (Days -45, -1, 1, 7 and 28), and Telemetry (Days -1, 0 and 1)
Pharmacokinetic Profile
To evaluate the pharmacokinetic profile of single ascending doses of Vasomera administered as a 30 minute intravenous (IV) infusion to subjects with stage 1 or stage 2 essential hypertension. * Elimination Half-life (t½) * Area under the concentration curve from time 0 to infinity (AUC0-inf) * Area under the curve to the final sample * Time to maximum concentration (Tmax) * Maximum serum concentration (Cmax) * Elimination rate constant (Lambda-z) * Clearance (CL) * Distribution (Vz) * Compartmental modeling - If the graphical presentations of the individual subject serum concentrations vs. time suggest that a compartmental model may be consistent with the data, then an appropriate compartmental model will be fit to the data.
Time frame: Days 0, 1, 2, 3, and 4
Hemodynamic Parameters
Compare changes in hemodynamic parameters as measured by serial systolic and diastolic blood pressure (BP) measurements and echocardiography compared to placebo. Change from baseline in systolic and diastolic BP and heart rate (HR). Change from baseline in two-dimensional echocardiography parameters which may include: * BP and HR * Left ventricular (LV) internal diameter in diastole and in systole, wall thickness in diastole, outflow tract diameter in mid-systole, volumes in end-diastole and end-systole, and outflow tract flow-time velocity integral * Ascending aorta peak flow velocity * Transmitral flow velocity pattern * Doppler tissue imaging of tricuspid, septal and mitral annulus * Left atrial volume * Derivation of: LV Ejection Fraction, LV Stroke Volume and Index, LV Cardiac Output and Index, Ejection Time, Systemic Vascular Resistance, Mitral E and A velocities, LV and index, Myocardial tissue velocities S' and e'.
Time frame: Days -14, 0, 1, 2, 3, 4, 7, 14 and 28
Immunogenicity Assessment
Evaluate if subjects elicit an immune response to study drug and if that response cross reacts with related endogenous compounds following a single 30 minute IV infusion.
Time frame: Days 0, 14 and 28
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