Phase 1, Randomized, Double-Blind, Placebo-Controlled Exploratory Study That Will Assess the Safety, Tolerability, Pharmacokinetics and Hemodynamic Response to a Single 30 Minute Intravenous Infusion of Vasomera™ (PB1046) in Adult Subjects With Stage 1 or 2 Essential Hypertension

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
PhaseBio Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:
NCT01873885
First received: June 6, 2013
Last updated: April 8, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Essential Hypertension
Drug: Placebo Single IV (Intravenous) Infusion
Drug: Experimental: Single IV Infusion Vasomera (PB1046)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Phase 1, Randomized, Double-Blind, Placebo-Controlled Exploratory Study That Will Assess the Safety, Tolerability, Pharmacokinetics and Hemodynamic Response to a Single 30 Minute Intravenous Infusion of Vasomera™ (PB1046) in Adult Subjects With Stage 1 or 2 Essential Hypertension

Resource links provided by NLM:


Further study details as provided by PhaseBio Pharmaceuticals Inc.:

Primary Outcome Measures:
  • Safety and Tolerability [ 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) ] [ Designated as safety issue: Yes ]

    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

  • Pharmacokinetic Profile [ Time Frame: Days 0, 1, 2, 3, and 4 ] [ Designated as safety issue: No ]

    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.


Secondary Outcome Measures:
  • Hemodynamic Parameters [ Time Frame: Days -14, 0, 1, 2, 3, 4, 7, 14 and 28 ] [ Designated as safety issue: Yes ]

    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'.

  • Immunogenicity Assessment [ Time Frame: Days 0, 14 and 28 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 20
Study Start Date: June 2013
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1: Single IV Infusion Vasomera (PB1046) or Placebo
Cohort 1 - Single 30 minute infusion Vasomera (PB1046) at 0.01 mg/kg diluted in 0.9% Sodium Chloride or Placebo (0.9% Sodium Chloride)
Drug: Placebo Single IV (Intravenous) Infusion
0.9% Sodium Chloride - 30 minute IV infusion
Drug: Experimental: Single IV Infusion Vasomera (PB1046)
Experimental: Cohort 2: Single IV Infusion Vasomera (PB1046) or Placebo
Cohort 2 - Single 30 minute infusion Vasomera (PB1046) at 0.005mg/kg in 0.9% Sodium Chloride or Placebo (0.9% Sodium Chloride)
Drug: Placebo Single IV (Intravenous) Infusion
0.9% Sodium Chloride - 30 minute IV infusion
Drug: Experimental: Single IV Infusion Vasomera (PB1046)
Experimental: Cohort 3: Single IV Infusion Vasomera (PB1046) or Placebo
Cohort 3 - Single 30 minute infusion Vasomera (PB1046) at 0.02mg/kg 0.9% Sodium Chloride or Placebo (0.9% Sodium Chloride)
Drug: Placebo Single IV (Intravenous) Infusion
0.9% Sodium Chloride - 30 minute IV infusion
Drug: Experimental: Single IV Infusion Vasomera (PB1046)

Detailed Description:

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).

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Willing and able to sign a written informed consent and follow all study related procedures.
  • Males or females age 18 - 80 years of age inclusive.
  • Male and female subjects of childbearing potential must be willing and able to practice effective contraception during the study, and be willing and able to continue contraception for 1 month (30 days) after their last dose of study drug.
  • BMI ≥ 20 but ≤ 40 kg/m2
  • Diagnosed with essential hypertension and are currently taking one or more antihypertensive medications to control their blood pressure and, who in the opinion of the investigator, could be safely withdrawn from antihypertensive therapy.

Exclusion Criteria:

  • Known allergy to the study drug or any of its components, or who have previously received Vasomera (PB1046).
  • Inadequate "imaging window" by echocardiography as determined by screening echocardiography (core assessment), or cardiac abnormalities that may confound echocardiography readings (i.e., mitral regurgitation, "floppy-valve" syndrome) for evaluation of secondary study endpoints.
  • Seated systolic blood pressure <120 mmHg or diastolic blood pressure < 80 mmHg (confirmed in triplicate) at randomization (Day -1) or prior to the first dose of study drug (V3 Day 0) will exclude the subject from participation.
  • Evidence of sustained elevation in systolic blood pressure >169 mmHg or diastolic blood pressure >109 mmHg prior to dosing (Day 0) during the washout period which in the opinion of the investigator would place the subject at risk for continued study participation (i.e., can not be safely withdrawn from antihypertensive therapy).
  • Clinically significant changes in health status or concomitant prescription medications within 2 weeks prior to dosing (V3 Day 0) that could place the subject at risk for dosing with study drug or confound the primary or secondary outcome measures as assessed by the Investigator.
  • Unstable/underlying cardiovascular disease defined as: a. Congestive heart failure (NYHA class III-IV), stroke, transient ischemic attack, unstable angina pectoris, or myocardial infarction within the 6 months prior to screening (V1) b. Mean triplicate 12-lead ECG demonstrating a QT interval (corrected using Fridericia's formula (QTcF)) >450 msec in males and >470 msec in females at Screening, (V1) or a history or evidence of long QT syndrome. c. Sustained heart rate >100 beats per minute (BPM) (at rest) at screening (V1), prior to randomization (V3 Day -1), or prior to dosing (V3 Day 0). d. Any episode of atrial fibrillation, ventricular tachycardia (defined as ten (10) or more beats with heart rate greater than 130 beats per minute), ventricular fibrillation, firing of an implantable cardiac defibrillator (ICD) for documented ventricular ectopy, or other clinically significant documented arrhythmias within 3 months prior to administration of study drug (V3 Day 0).
  • Uncontrolled diabetes defined as a Hemoglobin A1c > 10.0%. Note: only applicable for subjects with a known or suspected history of diabetes.
  • Clinically significant renal and/or hepatic dysfunction at Screening (V1) or at baseline (V3 Day -1).
  • Pregnant or lactating females.
  • Known history of or active drug or alcohol abuse within the 12 months prior to screening (V1) and/or positive drug screen (for illicit drugs) or detection of alcohol at baseline.
  • Positive for Human Immunodeficiency Virus (HIV) antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies.
  • Participation in any other study and have received any other investigational drug or device within 30 days prior to the Screening visit or are taking part in a non-drug study which in the opinion of the Investigator would interfere with the outcome of the study.
  • Major surgery, donated or lost > or = 1 unit of blood (approximately 500 mL) within 30 days prior to Screening (V1) or display evidence of volume depletion (i.e., postural hypotension) prior to randomization (V3 Day -1) or dosing (V3 Day 0).
  • Other medical or psychiatric condition which in the opinion of the Investigator would place the subject at increased risk, would preclude obtaining voluntary consent, or would confound the results of the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01873885

Locations
United States, Tennessee
New Orleans Center for Clinical Research - Knoxville
Knoxville, Tennessee, United States, 37920
Sponsors and Collaborators
PhaseBio Pharmaceuticals Inc.
Investigators
Principal Investigator: William B. Smith, MD New Orleans Center for Clinical Research- Knoxville
  More Information

No publications provided

Responsible Party: PhaseBio Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT01873885     History of Changes
Other Study ID Numbers: PB1046-PT-CL-0002
Study First Received: June 6, 2013
Last Updated: April 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by PhaseBio Pharmaceuticals Inc.:
PB1046, VIP, Essential Hypertension, Vasomera

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on August 28, 2014