Effect Of Single-Dose PF-05175157 On Metabolic And Cardiopulmonary Parameters

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01819922
First received: February 24, 2013
Last updated: March 30, 2016
Last verified: March 2016
  Purpose
This study is designed to assess the effect of one single dose of PF-05175157 on metabolic and cardiopulmonary parameters before, during and after treadmill exercise in healthy volunteers.

Condition Intervention Phase
Healthy
Drug: PF-05175157
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: A Phase 1 Randomized, Double-blind, Placebo-controlled, Two-way Crossover Study To Assess The Effect Of Pf-05175157 As A Single Oral Dose On Metabolic And Cardiopulmonary Parameters During Steady State And Graded Exercise In Healthy Subjects

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 20 Minutes Pre-dose [ Time Frame: 20 minutes pre-dose ] [ Designated as safety issue: No ]
    Global longitudinal left ventricular strain was defined as the percent change in left ventricular longitudinal dimension in comparison to its original dimension. Global longitudinal LV strain was assessed by echocardiography using speckled tracking analysis.

  • Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 1 Hour 30 Minutes Post-dose [ Time Frame: 1 hour 30 minutes post-dose ] [ Designated as safety issue: No ]
    Global longitudinal left ventricular strain was defined as the percent change in left ventricular longitudinal dimension in comparison to its original dimension. Global longitudinal LV strain was assessed by echocardiography using speckled tracking analysis.

  • Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 2 Hours 5 Minutes Post-dose [ Time Frame: 2 hours 5 minutes post-dose ] [ Designated as safety issue: No ]
    Global longitudinal left ventricular strain was defined as the percent change in left ventricular longitudinal dimension in comparison to its original dimension. Global longitudinal LV strain was assessed by echocardiography using speckled tracking analysis.

  • Cardiopulmonary Exercise Test: Oxygen Uptake Efficiency Slope (OUES): 1 Hour 40 Minute Post-dose [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    OUES was defined as an index of cardiopulmonary functional reserve that was based upon a submaximal exercise effort. OUES relates oxygen uptake to total ventilation during exercise.


Secondary Outcome Measures:
  • Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 5-10 days after last dose of study drug (up to 25 days) ] [ Designated as safety issue: Yes ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. Treatment-emergent were events between first dose of study drug and up to 5-10 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Adverse events included both serious and non-serious adverse events.

  • Number of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: Baseline up-to 3 hours post-dose ] [ Designated as safety issue: Yes ]
    Criteria for clinically significant:Hematology (hemoglobin,hematocrit,red blood corpuscles [RBC] count:less than [<]0.8*lower limit of normal [LLN];platelets:<0.5*LLN/greater than [>]1.75*upper limit of normal [ULN];white blood corpuscles [WBC]:<0.6*LLN or >1.5*ULN;lymphocytes, total neutrophils:<0.8*LLN or >1.2*ULN;basophils,eosinophil, monocytes:>1.2*ULN);Liver Function(aspartate aminotransferase, alanine aminotransferase,alkaline phosphatase:>0.3*ULN;total protein,albumin:<0.8*LLN or >1.2*ULN;total bilirubin:>1.5*ULN);Renal Function (blood urea nitrogen,creatinine:>1.3*ULN; uric acid:>1.2*ULN);Electrolytes (sodium:<0.95*LLN or >1.05*ULN,potassium,chloride, calcium,bicarbonate:<0.9*LLN or >1.1*ULN; glucose fasting:<0.6*LLN or >1.5*ULN);Urinalysis (urine pH:>1.5*ULN or >4.5;urine glucose,ketones,proteins, nitrites, leukocyte esterase,blood/hemoglobin:greater than or equal to (>=)1;urine WBC and RBC,urine bacteria:>=20/High Power Field [HPF];epithelial cells:>=6/HPF).

  • Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data [ Time Frame: Baseline up-to 3 hours post-dose ] [ Designated as safety issue: Yes ]
    Participants who met the pre-defined criteria for clinically significant cardiovascular events were reported. Criteria for clinically significant cardiovascular events: Blood pressure (BP) [supine systolic and sitting systolic BP (SBP): <90 millimeter of mercury (mm Hg), >=30 mmHg maximum increase and decrease from baseline in same posture; supine diastolic and sitting diastolic BP (DBP): <50 mm Hg, >=20 mmHg maximum increase and >=30 mmHg maximum decrease from baseline in same posture]; pulse rate: supine and sitting: <40 or >120 bpm.

  • Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters [ Time Frame: Baseline up-to 3 hour post-dose ] [ Designated as safety issue: Yes ]
    Criteria for clinically significant ECG values included: maximum PR interval >=300 millisecond (msec) and maximum increase of >=25 percent (%) from baseline value of >200 msec and >=50 % for baseline value of <=200 msec, maximum QRS interval >=140 msec or maximum increase of >=50% for baseline value of >100 msec; QT interval corrected using the Fridericia formula (QTcF) 450-<480 msec, 480-<500, >=500 msec or increase of >45 msec or maximum increase of >=30 to <60 and >=60 msec for QT interval where, PR interval: interval between the start of the P wave and the start of the QRS complex corresponding to the time between the onset of atrial depolarization and onset of ventricular depolarization; QRS interval: time from electrocardiogram Q wave to the end of the T wave corresponding to ventricle depolarization, QTcF interval: time corresponding to the beginning of depolarization to repolarization of the ventricles.

  • Cardiopulmonary Exercise Test: Peak Volume of Oxygen (VO2) [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    VO2 was the maximum rate of oxygen consumption as measured during incremental or prolonged, sub-maximal exercise. It reflects the aerobic physical fitness of the individual. It was assessed during indirect measure of heat production (calorimetry). The unit of measure is milliliter per kilogram per minute (mL/kg/min).

  • Cardiopulmonary Exercise Test: Respiratory Exchange Ratio (RER) [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    RER was defined as the ratio between the amount of oxygen (O2) consumed and carbon dioxide (CO2) produced in one breath. The parameter was assessed during indirect measure of heat production (calorimetry).

  • Cardiopulmonary Exercise Test: Minute Ventilation and Carbon Dioxide Production (VE/VCO2 Slope) [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    VE/VCO2 slope was also termed as ventilator efficiency. It was defined as the amount of minute ventilation required to eliminate 1 liter of carbon dioxide. The determinants of VE/VCO2 included fractional dead space and partial pressure of carbon dioxide. The parameter was assessed during indirect calorimetry.

  • Cardiopulmonary Exercise Test: Volume of Oxygen (VO2) at Anaerobic Threshold (AT) [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    VO2 at anaerobic threshold was widely recognized as a sub-max indicator of fitness. The parameter was assessed during indirect calorimetry.

  • Cardiopulmonary Exercise Test: Oxygen (O2) Pulse [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    Oxygen Pulse (VO2 /Heart Rate) was equal to stroke volume multiplied by oxygen extraction. This parameter was assessed during cardiopulmonary exercise test.

  • Cardiopulmonary Exercise Test: Oxygen (O2) Kinetics [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    Oxygen kinetics describes the dependence of respiration of isolated cells on oxygen partial pressure. The characteristics of oxygen uptake kinetics differ with intensity of exercise.

  • Cardiopulmonary Exercise Test: Aerobic Efficiency [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    Aerobic efficiency was defined as volume of oxygen divided by work. This parameter was assessed during cardiovascular exercise test.

  • Cardiopulmonary Exercise Test: Physical Work Capacity at a Heart Rate of 130 Beats Per Minute (PWC 130) [ Time Frame: 1 hour 40 minutes post-dose ] [ Designated as safety issue: No ]
    Physical work capacity evaluates the capacity of an individual to perform physically demanding work tasks. PWC 130 was a simple sub-max exercise parameter that can be used as surrogate for fitness that was independent of metabolic cart measurements. Interventions that improve fitness improve the PWC 130.

  • Cardiac Structure: Left Ventricular Volume [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Left ventricular volume was defined as volume of blood pumped from the left ventricle to the heart per beat. It was calculated using measurements of ventricle volumes from an echocardiogram and subtracting the volume of the blood in the ventricle at the end of a beat (called end-systolic volume) from the volume of blood just prior to the beat (called end-diastolic volume). Left ventricular volume was reported using modified Simpson's technique.

  • Change From Baseline in the Left Ventricular Volume [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Left ventricular volume was defined as volume of blood pumped from the left ventricle to the heart per beat. It was calculated using measurements of ventricle volumes from an echocardiogram and subtracting the volume of the blood in the ventricle at the end of a beat (called end-systolic volume) from the volume of blood just prior to the beat (called end-diastolic volume). Change from baseline in left ventricular volume was reported using modified Simpson's technique.

  • Cardiac Structure: Left Ventricular Wall Thickness [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Left ventricle is the chamber in the heart responsible for pumping blood to the rest of the body. Thickening of the lower chambers of left ventricular wall is also termed as ventricular hypertrophy. It was assessed by echocardiography using 2-dimensional gray-scale imaging; M-mode.

  • Cardiac Structure: Left Ventricular Geometry [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Left ventricular geometry was assessed by echocardiography using 2-dimensional gray-scale imaging. Relative wall thickness was the index of left ventricular geometry and defined as the sum of interventricular septal thickness (mm) and posterior wall thickness (mm) divided by LV internal end-diastolic diameter (mm).

  • Cardiac Structure: Right Ventricular Dimension [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Right ventricle is the chamber in the heart responsible for pumping blood to the lungs. Right ventricular dimensions included end-diastole area (EDA) and end-systole area (ESA). It was assessed by echocardiography using 2-dimensional gray-scale imaging.

  • Change From Baseline in Right Ventricular Dimension [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Right ventricle is the chamber in the heart responsible for pumping blood to the lungs. Right ventricular dimensions included end-diastole area and end-systole area. It was assessed by echocardiography using 2-dimensional gray-scale imaging. Change from baseline in right ventricular dimension was reported.

  • Cardiac Structure: Atrial Volume [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Atrial volumes were assessed by echocardiography using 2-dimensional gray-scale imaging and were calculated using the bi-plane area-length method. Both end-systole volumes (ESV) and end-diastole volumes (EDV) were reported.

  • Change From Baseline in Atrial Volumes [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Atrial volumes were assessed by echocardiography using 2-dimensional gray-scale imaging and were calculated using the bi-plane area-length method. Both end-systole volumes and end-diastole volumes were reported. Change from baseline in atrial volume was reported.

  • Systolic Function: Ejection Fraction [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Systolic ejection fraction was the fraction of the end-diastolic volume (EDV) that was ejected out of left ventricle with each contraction, estimated by echocardiography. EDV was the volume of blood within a ventricle immediately before a contraction. Ejection fraction served as a general measure of the cardiac function of a participant.

  • Change From Baseline in Ejection Fraction [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Systolic ejection fraction was the fraction of the end-diastolic volume that was ejected out of left ventricle with each contraction, estimated by echocardiography. EDV was the volume of blood within a ventricle immediately before a contraction. Ejection fraction served as a general measure of the cardiac function of a participant. Change from baseline in ejection fraction was reported.

  • Systolic Function: Peak Contractile Velocity [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    It was assessed by echocardiography using Tissue Doppler Imaging (Color Post-Processing).

  • Change From Baseline in Peak Contractile Velocity [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    It was assessed by echocardiography using Tissue Doppler Imaging (Color Post-Processing). Change from baseline in peak contractile velocity was reported.

  • Systolic Function: Rotation/Torsion [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Torsion is the twisting of an object due to an applied torque. It is expressed in newton metres. The left ventricle twists in systole storing potential energy and untwists (recoils) in diastole releasing the energy. Twist aids left ventricular ejection and untwist aids relaxation and ventricular filling. Therefore, rotation and torsion are important in cardiac mechanics. It was assessed by echocardiography using speckled tracking analysis .

  • Systolic Function: Global Strain Rate [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes ] [ Designated as safety issue: Yes ]
    Global longitudinal left ventricular strain rate was defined as the rate of percent change in left ventricular longitudinal dimension in comparison to its original dimension. Global strain rate was assessed by echocardiography using speckled tracking analysis.

  • Change From Baseline in Systolic Global Strain Rate [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Global longitudinal left ventricular strain rate was defined as the rate of percent change in left ventricular longitudinal dimension in comparison to its original dimension. Global strain rate was assessed by echocardiography using speckled tracking analysis. Change from baseline in systolic global strain rate was reported.

  • Trans-mitral Doppler: Ratio [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes ] [ Designated as safety issue: Yes ]
    Trans-mitral doppler ratio was Transmitral E wave peak velocity divided by transmitral A wave peak velocity. The E/A ratio was defined the ratio of the early (E) to late (A) ventricular filling velocities and was marker of the function of the left ventricle of the heart. It was determined on spectral doppler echocardiography.

  • Change From Baseline in Trans-mitral Doppler Ratio [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Trans-mitral doppler ratio was Transmitral E wave peak velocity divided by transmitral A wave peak velocity. The E/A ratio was defined the ratio of the early (E) to late (A) ventricular filling velocities and was marker of the function of the left ventricle of the heart. It was determined on spectral doppler echocardiography. Change from baseline in trans-mitral ration was reported.

  • Trans-mitral Doppler: Time [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Trans-mitral doppler time was measured as the time between the closure of the aortic valve and the opening of the mitral valve. It was determined on spectral doppler echocardiography.

  • Change From Baseline in Trans-mitral Doppler Time [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Trans-mitral doppler time was measured as the time between the closure of the aortic valve and the opening of the mitral valve. It was determined on spectral doppler echocardiography. Change from baseline in trans-mitral doppler time was reported.

  • Early and Late Peak Tissue Velocity [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Tissue velocities were measured off-line from two dimensional (2D) color-coded tissue doppler images and reported as the average of 3 consecutive cardiac cycles. Tissue Doppler Imaging measured the velocity of the heart muscle or myocardium through the phases of one or more heartbeats by the Doppler effect (frequency shift) of the reflected ultrasound. Early and late peak tissue velocities (EPV and LPV) were reported.

  • Change From Baseline in Early and Late Peak Velocity [ Time Frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Tissue velocities were measured off-line from 2D color-coded tissue doppler images and reported as the average of 3 consecutive cardiac cycles. Tissue Doppler Imaging measured the velocity of the heart muscle or myocardium through the phases of one or more heartbeats by the Doppler effect (frequency shift) of the reflected ultrasound. Change from baseline in early and late peak tissue velocities were reported.

  • Diastolic Strain Rate [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Diastolic strain rate was defined as the rate of percent change in all segments of left ventricular dimension in comparison to its original dimension. It was assessed by echocardiography using speckled tracking analysis.

  • Peak Diastolic Untwisting Rate [ Time Frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose ] [ Designated as safety issue: Yes ]
    Diastolic untwisting is an important component of early diastolic left ventricular filling. Left ventricular diastolic function is determined by early diastolic relaxation and myocardial stiffness. Peak diastolic untwisting rate is defined as the rate of left ventricular relaxation. It was assessed by echocardiography using speckled tracking analysis.

  • Plasma Metabolomic Profiles Before and Immediately Following Steady State and Incremental Exercise [ Time Frame: 1 hour pre-dose, 1 hour 20 minutes and 2 hours 10 minutes post-dose ] [ Designated as safety issue: No ]
    Plasma metabolomic profiles before and immediately following steady state and incremental exercise were collected using vacutainer tube containing dipotassium ethylenediamine tetraacetic Acid (K2EDTA) were processed by the clinical site according to handling specifications.


Enrollment: 12
Study Start Date: April 2013
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PF-05175157 Drug: PF-05175157
600 mg as powder in capsule, one dose within 5 minutes prior to AM meal
Placebo Comparator: Placebo Drug: Placebo
Placebo powder in capsule, one dose within 5 minutes prior to AM meal

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male and/or female subjects of non child bearing potential only, between the ages of 18 and 40 years, inclusive (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests).
  • Body Mass Index (BMI) of 18 to 28 kg/m2; and a total body weight >50 kg (110 lbs).
  • Subjects with maximum effort studies (peak RER >1.05) and normal exercise capacity as defined by peak VO2 ≥80% and ≤120% of predicted and no evidence of inducible ischemia or significant arrhythmia at the time of peak aerobic capacity testing 3 (±1) days prior to initiation of the study.

Exclusion Criteria:

  • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
  • History of smoking in the past 5 years or history or evidence of habitual use of other (non smoked) tobacco or nicotine-containing products within 3 months of Screening or positive cotinine test at Screening or Day -3 (±1).
  • Dry eye symptoms
  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: NCT01819922

Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01819922     History of Changes
Other Study ID Numbers: B1731008 
Study First Received: February 24, 2013
Results First Received: February 29, 2016
Last Updated: March 30, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Cardiopulmonary exercise testing
metabolic parameters
Diabetes Mellitus Type 2

ClinicalTrials.gov processed this record on August 30, 2016