Trial Outcomes & Findings for Effect Of Single-Dose PF-05175157 On Metabolic And Cardiopulmonary Parameters (NCT NCT01819922)

NCT ID: NCT01819922

Last Updated: 2016-05-02

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 12 participants
• Primary outcome timeframe: 1 hour 40 minutes post-dose
• Results posted on: 2016-05-02

Participant Flow

Participant milestones

Measure	PF-05175157 Then Placebo Participants who met the pre-defined cardiopulmonary exercise test (CPET) criteria, received single dose of PF-05175157 600 milligram (mg) capsule orally in first intervention period then single dose of placebo matched to PF-05175157 capsule, 600 mg orally in second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo Then PF-05175157 Participants who met the pre-defined CPET criteria, received single dose of placebo matched to PF-05175157, 600 mg capsule orally in first intervention period then single dose of PF-05175157 600 mg capsule orally in second intervention period. A washout period at least of 7-10 days was maintained between each intervention period.
First Intervention Period (1 Day) STARTED	6	6
First Intervention Period (1 Day) COMPLETED	6	6
First Intervention Period (1 Day) NOT COMPLETED	0	0
Washout Period (at Least 7-10 Days) STARTED	6	6
Washout Period (at Least 7-10 Days) COMPLETED	6	6
Washout Period (at Least 7-10 Days) NOT COMPLETED	0	0
Second Intervention Period (1 Day) STARTED	6	6
Second Intervention Period (1 Day) COMPLETED	6	6
Second Intervention Period (1 Day) NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Overall Participants n=12 Participants All randomized participants who received single dose of PF-05175157 600 mg capsule or single dose of placebo matched to PF-05175157 600 mg capsule in either first or second intervention period.
Age, Continuous	23.8 years STANDARD_DEVIATION 2.5 • n=93 Participants
Sex: Female, Male Female	0 Participants n=93 Participants
Sex: Female, Male Male	12 Participants n=93 Participants
Oxygen Uptake Efficiency Slope (OUES)	3163.333 milliliter per log10*liter [mL/log10(L)] STANDARD_DEVIATION 3200.000 • n=93 Participants
Volume of oxygen	41.033 milliliter per kilogram per minute STANDARD_DEVIATION 3.6084 • n=93 Participants
Respiratory Exchange Ratio	1.313 ratio STANDARD_DEVIATION 0.0881 • n=93 Participants
Minute Ventilation and Carbon Dioxide Production (VE/VCO2 slope)	20.800 unitless STANDARD_DEVIATION 3.5545 • n=93 Participants
Volume of Oxygen (VO2) at Anaerobic Threshold	19.467 milliliter (mL) STANDARD_DEVIATION 2.6800 • n=93 Participants
Oxygen pulse	16.808 milliliter per beat (mL/beat) STANDARD_DEVIATION 2.0518 • n=93 Participants
Aerobic Efficiency	10.442 milliliter per watt (mL/watt) STANDARD_DEVIATION 0.8544 • n=93 Participants
Physical Work Capacity	154.750 beats per minute (bpm) STANDARD_DEVIATION 25.3094 • n=93 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 20 Minutes Pre-dose	-19.779 percent change Standard Deviation 1.9682	-20.483 percent change Standard Deviation 2.0050

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 1 Hour 30 Minutes Post-dose	-19.728 percent change Standard Deviation 2.0187	-20.183 percent change Standard Deviation 2.0058

PRIMARY outcome

Timeframe: 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 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Systolic Function: Global Longitudinal Left Ventricular (LV) Strain: 2 Hours 5 Minutes Post-dose	-24.058 percent change Standard Deviation 2.9330	-24.587 percent change Standard Deviation 3.5740

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiopulmonary Exercise Test: Oxygen Uptake Efficiency Slope (OUES): 1 Hour 40 Minute Post-dose	3192.500 mL/log10(L) Standard Deviation 458.6170	3165.833 mL/log10(L) Standard Deviation 439.0373

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Adverse events	0 participants	2 participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Serious adverse events	0 participants	0 participants

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Number of Participants With Clinically Significant Laboratory Abnormalities	4 participants	6 participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Supine SBP: Maximum decrease from baseline (n=12)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Supine SBP (n=12)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Supine DBP: Maximum decrease from baseline (n=12)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Supine DBP (n=12)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Supine pulse rate (n=12)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Sitting pulse rate (n=1)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Sitting SBP (n=1)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Sitting DBP (n=1)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Supine SBP: Maximum Increase from Baseline (n=12)	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data Supine DBP: Maximum increase from baseline (n=12)	0 participants	1 participants

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters Maximum QTCF interval >=500 msec	0 participants	1 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters Maximum PR interval >=300 msec	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters Maximum QRS complex >=140 msec	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters Maximum QTCF interval 450-<480 msec	1 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters Maximum QTCF interval 480-<500 msec	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters PR interval increase from baseline >=25/50%	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters QRS complex increase from baseline >=50%	0 participants	0 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters QTCF interval increase from baseline>=30 to<60msec	0 participants	3 participants
Number of Participants With Categorical Post-dose Cardiovascular Monitoring Data: Electrocardiogram (ECG) Parameters QTCF interval increase from baseline >=60 msec	1 participants	1 participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiopulmonary Exercise Test: Peak Volume of Oxygen (VO2)	41.325 mL/kg/min Standard Deviation 3.9857	42.092 mL/kg/min Standard Deviation 4.4663

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiopulmonary Exercise Test: Respiratory Exchange Ratio (RER)	0.984 ratio Standard Deviation 0.1289	1.013 ratio Standard Deviation 0.1462

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiopulmonary Exercise Test: Minute Ventilation and Carbon Dioxide Production (VE/VCO2 Slope)	22.325 unitless Standard Deviation 4.0815	21.375 unitless Standard Deviation 3.3759

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiopulmonary Exercise Test: Volume of Oxygen (VO2) at Anaerobic Threshold (AT)	19.008 mL Standard Deviation 3.5279	18.633 mL Standard Deviation 4.0130

SECONDARY outcome

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

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiopulmonary Exercise Test: Oxygen (O2) Pulse	16.692 mL/beat Standard Deviation 2.2342	16.850 mL/beat Standard Deviation 2.3781

SECONDARY outcome

Timeframe: 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 kinetics describes the dependence of respiration of isolated cells on oxygen partial pressure. The characteristics of oxygen uptake kinetics differ with intensity of exercise.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiopulmonary Exercise Test: Aerobic Efficiency	10.358 mL/watt Standard Deviation 0.6201	10.483 mL/watt Standard Deviation 0.7638

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiopulmonary Exercise Test: Physical Work Capacity at a Heart Rate of 130 Beats Per Minute (PWC 130)	156.583 bpm Standard Deviation 31.4078	156.667 bpm Standard Deviation 26.7185

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiac Structure: Left Ventricular Volume 20 minutes pre-dose	76.750 mL Standard Deviation 10.9555	76.333 mL Standard Deviation 11.8117
Cardiac Structure: Left Ventricular Volume 1 hour 30 minutes post-dose	77.167 mL Standard Deviation 12.2610	77.333 mL Standard Deviation 11.9494
Cardiac Structure: Left Ventricular Volume 2 hours 5 minutes post-dose	85.250 mL Standard Deviation 15.2442	85.000 mL Standard Deviation 13.6980

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in the Left Ventricular Volume Change at 2 hours 5 minutes post-dose	8.500 mL Standard Deviation 8.5546	8.667 mL Standard Deviation 8.0265
Change From Baseline in the Left Ventricular Volume Change at 1 hour 30 minutes post-dose	0.417 mL Standard Deviation 3.6546	1.000 mL Standard Deviation 3.1909

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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 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).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiac Structure: Right Ventricular Dimension End-diastole area: 1 hour 30 minutes post-dose	24.408 millimetre (mm) Standard Deviation 2.4247	23.975 millimetre (mm) Standard Deviation 2.7877
Cardiac Structure: Right Ventricular Dimension End-diastole area: 20 minutes pre-dose	24.250 millimetre (mm) Standard Deviation 2.4693	23.704 millimetre (mm) Standard Deviation 2.8601
Cardiac Structure: Right Ventricular Dimension End-diastole area: 2 hours 5 minutes post-dose	24.203 millimetre (mm) Standard Deviation 2.0097	23.642 millimetre (mm) Standard Deviation 2.1318
Cardiac Structure: Right Ventricular Dimension End-systole area: 20 minutes pre-dose	14.675 millimetre (mm) Standard Deviation 2.4643	13.992 millimetre (mm) Standard Deviation 2.3971
Cardiac Structure: Right Ventricular Dimension End-systole area: 1 hour 30 minutes post-dose	14.350 millimetre (mm) Standard Deviation 2.2841	14.342 millimetre (mm) Standard Deviation 2.1923
Cardiac Structure: Right Ventricular Dimension End-systole area: 2 hours 5 minutes post-dose	10.783 millimetre (mm) Standard Deviation 2.0395	10.208 millimetre (mm) Standard Deviation 1.8569

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in Right Ventricular Dimension EDA: change at 1hour 30 minutes post-dose	0.158 mm Standard Deviation 0.8350	0.271 mm Standard Deviation 1.0015
Change From Baseline in Right Ventricular Dimension EDA: change at 2 hours 5 minutes post-dose	-0.047 mm Standard Deviation 1.2544	-0.062 mm Standard Deviation 2.1118
Change From Baseline in Right Ventricular Dimension ESA: change at 1 hour 30 minutes post-dose	-0.325 mm Standard Deviation 0.7533	0.350 mm Standard Deviation 0.4622
Change From Baseline in Right Ventricular Dimension ESA: change at 2 hours 5 minutes post-dose	-3.892 mm Standard Deviation 1.9351	-3.783 mm Standard Deviation 1.7497

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Cardiac Structure: Atrial Volume End-diastole: 20 minutes pre-dose	47.000 mL Standard Deviation 12.7422	50.750 mL Standard Deviation 10.4544
Cardiac Structure: Atrial Volume End-diastole:1 hour 30 minutes post-dose	47.000 mL Standard Deviation 11.2896	49.833 mL Standard Deviation 10.0890
Cardiac Structure: Atrial Volume End-diastole: 2 hours 5 minutes post-dose	42.917 mL Standard Deviation 9.9312	44.917 mL Standard Deviation 9.7650
Cardiac Structure: Atrial Volume End-systole: 20 minutes pre-dose post-dose	19.917 mL Standard Deviation 6.7347	20.083 mL Standard Deviation 4.8328
Cardiac Structure: Atrial Volume End-systole:1 hour 30 minutes post-dose	21.333 mL Standard Deviation 6.8667	21.417 mL Standard Deviation 4.6993
Cardiac Structure: Atrial Volume End-systole: 2 hours 5 minutes post-dose	16.417 mL Standard Deviation 5.6642	16.083 mL Standard Deviation 3.3428

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in Atrial Volumes ESV: change at 1 hour 30 minute post-dose	1.417 mL Standard Deviation 1.8809	1.333 mL Standard Deviation 1.5570
Change From Baseline in Atrial Volumes EDV: change at 1 hour 30 minute post-dose	0.000 mL Standard Deviation 2.7303	-0.917 mL Standard Deviation 1.6214
Change From Baseline in Atrial Volumes EDV: change at 2 hours 5 minute post-dose	-4.083 mL Standard Deviation 4.7950	-5.833 mL Standard Deviation 5.2886
Change From Baseline in Atrial Volumes ESV: change at 2 hours 5 minutes post-dose	-3.500 mL Standard Deviation 2.3160	-4.000 mL Standard Deviation 3.9312

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Systolic Function: Ejection Fraction 20 minutes pre-dose	63.190 percentage of EDV Standard Deviation 5.9675	63.058 percentage of EDV Standard Deviation 6.3917
Systolic Function: Ejection Fraction 1 hour 30 minutes post-dose	62.525 percentage of EDV Standard Deviation 5.6452	62.633 percentage of EDV Standard Deviation 6.5173
Systolic Function: Ejection Fraction 2 hours 5 minutes post-dose	72.462 percentage of EDV Standard Deviation 5.8507	72.949 percentage of EDV Standard Deviation 5.1819

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in Ejection Fraction Change at 1 hour 30 minutes post-dose	-0.665 percentage of EDV Standard Deviation 2.3178	-0.426 percentage of EDV Standard Deviation 1.7638
Change From Baseline in Ejection Fraction Change at 2 hours 5 minutes post-dose	9.272 percentage of EDV Standard Deviation 5.0915	9.891 percentage of EDV Standard Deviation 5.6629

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Systolic Function: Peak Contractile Velocity 20 minutes pre-dose	7.625 centimeter per second (cm/sec) Standard Deviation 1.0997	9.025 centimeter per second (cm/sec) Standard Deviation 2.0521
Systolic Function: Peak Contractile Velocity 1 hour 30 minutes post-dose	7.758 centimeter per second (cm/sec) Standard Deviation 1.4457	9.083 centimeter per second (cm/sec) Standard Deviation 1.8075
Systolic Function: Peak Contractile Velocity 2 hours 5 minutes post-dose	12.875 centimeter per second (cm/sec) Standard Deviation 1.4085	13.925 centimeter per second (cm/sec) Standard Deviation 1.3903

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in Peak Contractile Velocity Change at 2 hours 5 minutes post-dose	5.250 cm/sec Standard Deviation 1.6963	4.900 cm/sec Standard Deviation 2.0476
Change From Baseline in Peak Contractile Velocity Change at 1 hour 30 minutes post-dose	0.133 cm/sec Standard Deviation 0.6541	0.058 cm/sec Standard Deviation 0.4295

SECONDARY outcome

Timeframe: 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.

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 .

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Systolic Function: Global Strain Rate 20 minutes pre-dose	-1.043 percent change per second Standard Deviation 0.1449	-1.124 percent change per second Standard Deviation 0.1756
Systolic Function: Global Strain Rate 2 hours 5 minutes post-dose	-1.845 percent change per second Standard Deviation 0.5499	-1.916 percent change per second Standard Deviation 0.5786
Systolic Function: Global Strain Rate 1 hour 30 minutes post-dose	-1.047 percent change per second Standard Deviation 0.1462	-1.078 percent change per second Standard Deviation 0.1171

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in Systolic Global Strain Rate Change at 1 hour 30 minutes post-dose	-0.003 percent change per second Standard Deviation 0.1208	0.047 percent change per second Standard Deviation 0.1070
Change From Baseline in Systolic Global Strain Rate Change at 2 hours 5 minutes post-dose	-0.802 percent change per second Standard Deviation 0.5884	-0.792 percent change per second Standard Deviation 0.5934

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Trans-mitral Doppler: Ratio 20 minutes pre-dose (n=12, 12)	186.894 ratio Standard Deviation 53.0097	182.236 ratio Standard Deviation 39.8589
Trans-mitral Doppler: Ratio 1 hour 30 minutes post-dose (n=12, 12)	184.050 ratio Standard Deviation 40.4499	190.424 ratio Standard Deviation 36.1174
Trans-mitral Doppler: Ratio 2 hours 5 minutes post-dose (n=11, 11)	134.205 ratio Standard Deviation 52.0345	125.156 ratio Standard Deviation 34.6253

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in Trans-mitral Doppler Ratio Change at 1 hour 30 minutes post-dose (n=12,12)	-2.844 ratio Standard Deviation 17.6282	8.188 ratio Standard Deviation 19.7236
Change From Baseline in Trans-mitral Doppler Ratio Change at 2 hours 5 minutes post-dose (n=11,11)	-57.803 ratio Standard Deviation 62.4623	-61.330 ratio Standard Deviation 44.7622

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Trans-mitral Doppler: Time 2 hours 5 minutes post-dose (n=11, 11)	179.091 msec Standard Deviation 25.8204	173.727 msec Standard Deviation 30.7542
Trans-mitral Doppler: Time 20 minutes pre-dose (n=12, 12)	168.333 msec Standard Deviation 24.6810	158.917 msec Standard Deviation 19.8470
Trans-mitral Doppler: Time 1 hour 30 minutes post-dose (n=12, 12)	166.417 msec Standard Deviation 19.0333	160.750 msec Standard Deviation 16.8799

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in Trans-mitral Doppler Time Change at 1 hour 30 minutes post-dose (n=12, 12)	-1.917 msec Standard Deviation 8.2513	1.833 msec Standard Deviation 6.1472
Change From Baseline in Trans-mitral Doppler Time Change at 2 hours 5 minutes post-dose (n=11, 11)	11.273 msec Standard Deviation 29.3465	14.273 msec Standard Deviation 44.1001

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Early and Late Peak Tissue Velocity EPV: 20 minutes pre-dose (n=12, 12)	9.892 cm/sec Standard Deviation 0.6934	10.375 cm/sec Standard Deviation 1.1663
Early and Late Peak Tissue Velocity EPV: 1 hour 30 minutes post-dose (n=12,12)	10.017 cm/sec Standard Deviation 0.6939	10.342 cm/sec Standard Deviation 1.2132
Early and Late Peak Tissue Velocity EPV: 2 hours 5 minutes post-dose (n=12,12)	11.600 cm/sec Standard Deviation 1.4635	11.825 cm/sec Standard Deviation 1.7889
Early and Late Peak Tissue Velocity LPV: 20 minutes pre-dose (n=12,12)	5.233 cm/sec Standard Deviation 1.0210	5.375 cm/sec Standard Deviation 0.5754
Early and Late Peak Tissue Velocity LPV: 1 hour 30 minutes post-dose(n=12,12)	4.933 cm/sec Standard Deviation 1.1555	5.500 cm/sec Standard Deviation 0.7058
Early and Late Peak Tissue Velocity LPV: 2 hours 5 minutes post-dose (n=8,9)	6.688 cm/sec Standard Deviation 2.2599	6.544 cm/sec Standard Deviation 1.4800

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	PF-05175157 600 mg n=12 Participants Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 Participants Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Change From Baseline in Early and Late Peak Velocity EPV:change at1 hour 30 minutes post-dose(n=12,12)	-0.300 cm/sec Standard Deviation 0.4045	0.125 cm/sec Standard Deviation 0.4288
Change From Baseline in Early and Late Peak Velocity EPV:change at 2 hours 5 minutes post-dose(n= 8,9)	1.713 cm/sec Standard Deviation 1.7008	1.144 cm/sec Standard Deviation 1.1780
Change From Baseline in Early and Late Peak Velocity LPV:change at1 hour 30 minute post-dose(n= 12,12)	0.125 cm/sec Standard Deviation 0.3494	-0.033 cm/sec Standard Deviation 0.2640
Change From Baseline in Early and Late Peak Velocity LPV:change at 2 hours 5 minutes post-dose(n=12,12)	1.708 cm/sec Standard Deviation 1.1611	1.450 cm/sec Standard Deviation 1.1213

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

Adverse Events

PF-05175157 600 mg

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	PF-05175157 600 mg n=12 participants at risk Participants who met the pre-defined CPET criteria received single dose of PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.	Placebo n=12 participants at risk Participants who met the pre-defined CPET criteria received single dose of placebo matched to PF-05175157 600 mg capsule orally in either first or second intervention period. A washout period of at least 7-10 days was maintained between each intervention period.
Nervous system disorders Dizziness	0.00% 0/12	8.3% 1/12
Gastrointestinal disorders Abdominal pain upper	0.00% 0/12	8.3% 1/12
Gastrointestinal disorders Vomiting	0.00% 0/12	8.3% 1/12

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: ClinicalTrials.gov_Inquiries@pfizer.com

Results disclosure agreements

• Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
• Publication restrictions are in place

Restriction type: OTHER