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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: PF-05175157
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-05175157<br> | Drug: PF-05175157<br>* 600 mg as powder in capsule, one dose within 5 minutes prior to AM meal<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo powder in capsule, one dose within 5 minutes prior to AM meal<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 20 Minutes Pre-dose | 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. | 20 minutes pre-dose | 
| Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 1 Hour 30 Minutes Post-dose | 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. | 1 hour 30 minutes post-dose | 
| Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 2 Hours 5 Minutes Post-dose | 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. | 2 hours 5 minutes post-dose | 
| Cardiopulmonary Exercise Test: Oxygen Uptake Efficiency Slope (OUES): 1 Hour 40 Minute Post-dose | 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. | 1 hour 40 minutes post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Baseline up to 5-10 days after last dose of study drug (up to 25 days) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | 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). | Baseline up-to 3 hours post-dose | 
| Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data | 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. | Baseline up-to 3 hours post-dose | 
| Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters | 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. | Baseline up-to 3 hour post-dose | 
| Cardiopulmonary Exercise Test: Peak Volume of Oxygen (VO2) | 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). | 1 hour 40 minutes post-dose | 
| Cardiopulmonary Exercise Test: Respiratory Exchange Ratio (RER) | 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). | 1 hour 40 minutes post-dose | 
| Cardiopulmonary Exercise Test: Minute Ventilation and Carbon Dioxide Production (VE/VCO2 Slope) | 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. | 1 hour 40 minutes post-dose | 
| Cardiopulmonary Exercise Test: Volume of Oxygen (VO2) at Anaerobic Threshold (AT) | VO2 at anaerobic threshold was widely recognized as a sub-max indicator of fitness. The parameter was assessed during indirect calorimetry. | 1 hour 40 minutes post-dose | 
| Cardiopulmonary Exercise Test: Oxygen (O2) Pulse | Oxygen Pulse (VO2 /Heart Rate) was equal to stroke volume multiplied by oxygen extraction. This parameter was assessed during cardiopulmonary exercise test. | 1 hour 40 minutes post-dose | 
| Cardiopulmonary Exercise Test: Oxygen (O2) Kinetics | 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. | 1 hour 40 minutes post-dose | 
| Cardiopulmonary Exercise Test: Aerobic Efficiency | Aerobic efficiency was defined as volume of oxygen divided by work. This parameter was assessed during cardiovascular exercise test. | 1 hour 40 minutes post-dose | 
| Cardiopulmonary Exercise Test: Physical Work Capacity at a Heart Rate of 130 Beats Per Minute (PWC 130) | 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. | 1 hour 40 minutes post-dose | 
| Cardiac Structure: Left Ventricular Volume | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Change From Baseline in the Left Ventricular Volume | 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. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Cardiac Structure: Left Ventricular Wall Thickness | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Cardiac Structure: Left Ventricular Geometry | 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). | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Cardiac Structure: Right Ventricular Dimension | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Change From Baseline in Right Ventricular Dimension | 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. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Cardiac Structure: Atrial Volume | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Change From Baseline in Atrial Volumes | 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. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Systolic Function: Ejection Fraction | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Change From Baseline in Ejection Fraction | 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. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Systolic Function: Peak Contractile Velocity | It was assessed by echocardiography using Tissue Doppler Imaging (Color Post-Processing). | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Change From Baseline in Peak Contractile Velocity | It was assessed by echocardiography using Tissue Doppler Imaging (Color Post-Processing). Change from baseline in peak contractile velocity was reported. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Systolic Function: Rotation/Torsion | 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 . | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Systolic Function: Global Strain Rate | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes | 
| Change From Baseline in Systolic Global Strain Rate | 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. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Trans-mitral Doppler: Ratio | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes | 
| Change From Baseline in Trans-mitral Doppler Ratio | 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. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Trans-mitral Doppler: Time | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Change From Baseline in Trans-mitral Doppler Time | 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. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Early and Late Peak Tissue Velocity | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Change From Baseline in Early and Late Peak Velocity | 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. | 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Diastolic Strain Rate | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Peak Diastolic Untwisting Rate | 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. | 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose | 
| Plasma Metabolomic Profiles Before and Immediately Following Steady State and Incremental Exercise | 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. | 1 hour pre-dose, 1 hour 20 minutes and 2 hours 10 minutes post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiopulmonary exercise testing, metabolic parameters, Diabetes Mellitus Type 2