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

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.

Time frame: 1 hour 40 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 30 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 20 minutes pre-dose

Population: Full analysis set (FAS) was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 pharmacodynamic (PD) measurement.

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.

Time frame: 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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).

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: Data was not collected for this outcome measure as per study team's decision since single dose was not considered to be sufficient to analyze this specific parameter.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: Data was not collected for this outcome measure as per study team's decision since single dose was not considered to be sufficient to analyze this specific parameter.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

Aerobic efficiency was defined as volume of oxygen divided by work. This parameter was assessed during cardiovascular exercise test.

Time frame: 1 hour 40 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 40 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 40 minutes post-dose

Population: Data was not collected for this outcome measure as per study team's decision since single dose was not considered to be sufficient to analyze this specific parameter.

Oxygen Pulse (VO2 /Heart Rate) was equal to stroke volume multiplied by oxygen extraction. This parameter was assessed during cardiopulmonary exercise test.

Time frame: 1 hour 40 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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).

Time frame: 1 hour 40 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 40 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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).

Time frame: 1 hour 40 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

VO2 at anaerobic threshold was widely recognized as a sub-max indicator of fitness. The parameter was assessed during indirect calorimetry.

Time frame: 1 hour 40 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement. Here, n specified the number of participants who were evaluable for the specified time-point.

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.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

It was assessed by echocardiography using Tissue Doppler Imaging (Color Post-Processing). Change from baseline in peak contractile velocity was reported.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement. Here, n specified the number of participants who were evaluable for the specified time-point.

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.

Time frame: 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement. Here, n specified the number of participants who were evaluable for the specified time-point.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: Data was not collected for this outcome measure as per study team's decision since single dose was not considered to be sufficient to analyze this specific parameter.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement. Here, n specified the number of participants who were evaluable for the specified time-point.

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.

Time frame: Baseline up-to 3 hours post-dose

Population: Safety analysis set was defined as all participants who performed the peak aerobic capacity test, were randomized and who had received at least 1 dose of randomized treatment. Here, n specified the number of participants who were evaluable for the specified criteria.

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.

Time frame: Baseline up-to 3 hour post-dose

Population: Safety analysis set was defined as all participants who performed the peak aerobic capacity test, were randomized and who had received at least 1 dose of randomized treatment.

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).

Time frame: Baseline up-to 3 hours post-dose

Population: Safety analysis set was defined as all participants who performed the peak aerobic capacity test, were randomized and who had received at least 1 dose of randomized treatment.

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.

Time frame: Baseline up to 5-10 days after last dose of study drug (up to 25 days)

Population: Safety analysis set was defined as all participants who performed the peak aerobic capacity test, were randomized and who had received at least 1 dose of randomized treatment.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: Data was not collected for this outcome measure as per study team's decision since single dose was not considered to be sufficient to analyze this specific parameter.

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.

Time frame: 1 hour pre-dose, 1 hour 20 minutes and 2 hours 10 minutes post-dose

Population: Data was not collected for this outcome measure as per study team's decision since single dose was not considered to be sufficient to analyze this specific parameter.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

It was assessed by echocardiography using Tissue Doppler Imaging (Color Post-Processing).

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement.

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 .

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: Data was not collected for this outcome measure as per study team's decision since single dose was not considered to be sufficient to analyze this specific parameter.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement. Here, n specified the number of participants who were evaluable for the specified time-point.

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.

Time frame: 20 minutes pre-dose, 1 hour 30 minutes and 2 hours 5 minutes post-dose

Population: FAS was defined as all participants who performed the peak aerobic capacity test, were randomized and received at least 1 dose of randomized treatment, and had at least 1 PD measurement. Here, n specified the number of participants who were evaluable for the specified time-point.