Diabetes Mellitus, Type 2
Conditions
Keywords
inpatient, diabetes, phase 1
Brief summary
This will be a 2-week oral dose study of PF 04991532, performed in patients with type 2 diabetes. Safety, pharmacokinetics (how the drug is distributed in the body), and pharmacodynamics (how the drug works in the body) will be studied. Patients may be asked to wash off their diabetes medication for 4-6 prior to study drug administration, and they will remain in the clinical research unit for a total of 20 days for baseline tests, 2 weeks of dosing, and some follow up tests.
Interventions
DRUGPF-04991532
Oral administration of PF-04991532; 25 mg given twice a day (BID) for 14 days
DRUGPF-0499132
Oral administration of PF-04991532; 300 mg given twice a day (BID) for 14 days
DRUGPlacebo
Oral administration of PF-04991532 Matching Placebo; given twice a day (BID) for 14 days
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with type 2 diabetes mellitus who are taking either no medication for the treatment of diabetes (diet/exercise therapy only), or who are taking only a single oral anti-diabetic drug (OAD) that can be temporarily discontinued for approximately 8-10 weeks. For those taking a single OAD, treatment should be stable, where this is defined as no change in the treatment, including dose, over the past 3 months prior to Screening. OAD medications that are acceptable to be discontinued include: a sulfonylurea (SU), a meglitinide, a biguanide (eg, metformin), a dipeptidyl peptidase 4 inhibitor (DPP-4i), or an alpha glucosidase inhibitor. * Body Mass Index (BMI) of 18.5 to 45.0 kg/m2; and a total body weight \>50 kg (110 lbs). * HbA1c \>/=7% and \</=10% if the patient is on diet/exercise therapy only and does not require any OAD discontinuation. HbA1c \>/=6.5% and \</=9% if the patient requires to be washed off an OAD.
Exclusion criteria
* Evidence or history of diabetic complications with significant end organ damage. * History of stroke or transient ischemic attack. * History of myocardial infarction. * History of coronary artery bypass graft or stent implantation. * Clinically significant peripheral vascular disease. * Any history or clinical evidence of congestive heart failure, NYHA Classes II IV. * Current history of angina/unstable angina. * One or more episodes of hypoglycemia within the last 3 months, or two or more episodes of hypoglycemia within the last 6 months. * A positive urine drug screen. * Use of tobacco or nicotine-containing products in excess of the equivalent of 10 cigarettes per day. * Blood pressure \>/=160 mm Hg (systolic) or \>/=100 mm Hg (diastolic), following at least 5 minutes of rest. * Pregnant or nursing females; females of childbearing potential.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Baseline: hours -46, -44, -42, -40, -38, -36, -33, -and -30 on Day -1 (Day 1 morning dose was hour 0); Day 14: 2, 4, 6, 8, 10, 12, 15, and 18 hours after Day 14 morning dose | Mean daily glucose (MDG) was calculated based on the mean of 8 glucose measurements at pre-specified time points throughout the day on Day -1 and Day 14. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14 | Area under the plasma concentration versus time curve (AUC) from time zero to 10 hours post morning dose. |
| Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning | — |
| Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | 10 (before evening dose), 10.5, 11, 12, 13, 15, 18, and 24 hours after morning dose on Day 1 and Day 14 | — |
| Minimum Observed Plasma Trough Concentration (Cmin) of PF-04991532 | Day 14 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | 0 (predose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | 10 (before evening dose), 10.5, 11, 12, 13, 15, 18, and 24 hours after morning dose on Day 1 and Day 14 | Time was computed as post morning dose. |
| Apparent Oral Clearance (CL/F) of PF-04991532 | Day 1 and Day 14: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, 10 (before evening dose), 10.5, 11, 12, 13, 15, 18 and 24 hours after morning dose | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Observed Accumulation Ratio of Area Under the Curve From Time Zero to 10 Hours Postdose of PF-04991532 (Rac) | 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14 | Area under the curve from time zero to 10 hours postdose of PF-04991532 (AUC10) of Day 14 divided by AUC10 of Day 1 |
| Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, 10, 10.5, 11, 12, 13, 15, 18, and 24 hours after morning dose on Day 1 and Day 14 | Area under the plasma concentration versus time curve (AUC) from time zero to 24 hours post morning dose |
| Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, 10, 10.5, 11, 12, 13, 15, 18, and 24 hours after morning dose on Day 1 and Day 14 | Area under the curve from time zero to 24 Hours Postdose (AUC24) divided by total daily dose |
| Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14 | Maximum Observed Plasma Concentration of PF-04991532 after Morning Dose Administration (Cmax(AM)) divided by dose |
| Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Baseline: hours -72, -70, -68, -66, -62, -60, -57, and -54 on Day -2 (Day 1 morning dose was hour 0); Day 13: 0 (before morning dose), 2, 4, 6, 10, 12, 15 and 18 hours after Day 13 morning dose | Mean daily glucose (MDG) was calculated based on the mean of 8 glucose measurements at pre-specified time points throughout the day. |
| Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline: hours -46, -45.75, -45.5, -45, -44.5, -44, -43, -and -42 on Day -1 (Day 1 morning dose was hour 0); Day 14: 2, 2.25, 2.5, 3, 3.5, 4, 5, and 6 hours after Day 14 morning dose | Area under the curve of glucose from time 2 to 6 hours post morning dose (Glucose AUC(2-6)) was calculated based on 8 glucose measurements at prespecified time points using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT). |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Baseline: hour -48 on Day -1, hour -24 on Day 0, and hour 0 (before morning dose) on Day 1; hour 0 (before morning dose of each day) on Days 1, 2, 3, 6, and 10; and 24 hours after Day 14 morning dose on Day 15 | The average of the Day -1 (hour -48), Day 0 (hour -24) and Day 1 pre-dose (hour 0) measurements was the baseline for fasting plasma glucose (FPG) analyses. |
| Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline: hours -46, -45.75, -45.5, -45, -44.5, -44, -43, -and -42 on Day -1 (Day 1 morning dose was hour 0); Day 14: 2, 2.25, 2.5, 3, 3.5, 4, 5, and 6 hours after Day 14 morning dose | Area Under the Curve of Insulin from Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) was calculated based on 8 insulin measurements at prespecified time points using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT). |
| Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline: hours -46, -45.75, -45.5, -45, -44.5, -44, -43, -and -42 on Day -1 (Day 1 morning dose was hour 0); Day 14: 2, 2.25, 2.5, 3, 3.5, 4, 5, and 6 hours after Day 14 morning dose | Area Under the Curve of C-peptide from Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) was calculated based on 8 C-peptide measurements at prespecified timepoints using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT). |
| Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Baseline: hour -48 on Day -1, hour -24 on Day 0, and hour 0 on Day 1 for TG and Hour 0 (before morning dose) on Day 1 for TC, HDL, and LDL; 48 hours after morning dose on Day 16 for TG and Hour 0 (before morning dose) on Day14 for TC, HDL, and LDL | Baseline for fasting triglycerides (TG) was defined as the average of the Day -1 (hour -48), Day 0 (hour -24), and Day 1 pre-dose (hour 0) measurements. Baseline for fasting total cholesterol (TC), cholesterol (high-density lipoprotein (HDL)), and cholesterol (low-density lipoprotein (LDL)) was defined as the Day 1 pre-dose (hour 0) measurement. |
| Observed Accumulation Ratio of Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Rac, Cmax(AM)) | 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14 | Maximum observed plasma concentration of PF-04991532 after morning dose administration (Cmax(AM)) of Day 14 divided by Cmax(AM) of Day 1 |
Countries
Japan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo PF-04991532 matching placebo orally twice daily for 2 weeks. | 16 |
| PF-04991532 25 mg PF-04991532 25 milligram (mg) tablet orally twice daily for 2 weeks. | 17 |
| PF-04991532 75 mg PF-04991532 75 mg tablet orally twice daily for 2 weeks. | 16 |
| PF-04991532 150 mg PF-04991532 150 mg tablet orally twice daily for 2 weeks. | 16 |
| PF-04991532 300 mg PF-04991532 300 mg tablet orally twice daily for 2 weeks. | 17 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | PF-04991532 25 mg | PF-04991532 75 mg | PF-04991532 150 mg | PF-04991532 300 mg | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 59.2 years STANDARD_DEVIATION 8.2 | 56.4 years STANDARD_DEVIATION 9 | 57.4 years STANDARD_DEVIATION 10.7 | 57.0 years STANDARD_DEVIATION 9.4 | 56.1 years STANDARD_DEVIATION 8 | 57.2 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 5 Participants | 2 Participants | 5 Participants | 20 Participants |
| Sex: Female, Male Male | 12 Participants | 13 Participants | 11 Participants | 14 Participants | 12 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 16 | 3 / 17 | 7 / 16 | 5 / 16 | 4 / 17 |
| serious Total, serious adverse events | 0 / 16 | 0 / 17 | 0 / 16 | 0 / 16 | 0 / 17 |
Outcome results
Primary
Change From Baseline (Day -1) in Mean Daily Glucose at Day 14
Mean daily glucose (MDG) was calculated based on the mean of 8 glucose measurements at pre-specified time points throughout the day on Day -1 and Day 14.
Time frame: Baseline: hours -46, -44, -42, -40, -38, -36, -33, -and -30 on Day -1 (Day 1 morning dose was hour 0); Day 14: 2, 4, 6, 8, 10, 12, 15, and 18 hours after Day 14 morning dose
Population: The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Change from Baseline (Day 14) | 24.98 milligram/deciliter (mg/dL) | Standard Deviation 40.48 |
| Placebo | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Baseline (Day -1) | 228.67 milligram/deciliter (mg/dL) | Standard Deviation 36.26 |
| PF-04991532 25 mg | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Baseline (Day -1) | 233.20 milligram/deciliter (mg/dL) | Standard Deviation 41.01 |
| PF-04991532 25 mg | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Change from Baseline (Day 14) | -17.55 milligram/deciliter (mg/dL) | Standard Deviation 25.4 |
| PF-04991532 75 mg | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Baseline (Day -1) | 219.13 milligram/deciliter (mg/dL) | Standard Deviation 38.16 |
| PF-04991532 75 mg | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Change from Baseline (Day 14) | -3.67 milligram/deciliter (mg/dL) | Standard Deviation 33.79 |
| PF-04991532 150 mg | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Baseline (Day -1) | 229.92 milligram/deciliter (mg/dL) | Standard Deviation 52.93 |
| PF-04991532 150 mg | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Change from Baseline (Day 14) | -9.73 milligram/deciliter (mg/dL) | Standard Deviation 21.52 |
| PF-04991532 300 mg | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Baseline (Day -1) | 218.20 milligram/deciliter (mg/dL) | Standard Deviation 53.01 |
| PF-04991532 300 mg | Change From Baseline (Day -1) in Mean Daily Glucose at Day 14 | Change from Baseline (Day 14) | -29.23 milligram/deciliter (mg/dL) | Standard Deviation 32.8 |
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test. Formal statistical inference was not performed thus p value was not reported.90% CI: [78.16, 92.15]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [82.69, 97.53]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [80.27, 94.63]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [72.06, 85.03]
Secondary
Apparent Oral Clearance (CL/F) of PF-04991532
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Day 1 and Day 14: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, 10 (before evening dose), 10.5, 11, 12, 13, 15, 18 and 24 hours after morning dose
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Apparent Oral Clearance (CL/F) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 1886 milliliter/minute (mL/min) | Standard Deviation 1112 |
| Placebo | Apparent Oral Clearance (CL/F) of PF-04991532 | D14 (n=16, 16, 16, 16) | 1710 milliliter/minute (mL/min) | Standard Deviation 1200 |
| PF-04991532 25 mg | Apparent Oral Clearance (CL/F) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 1434 milliliter/minute (mL/min) | Standard Deviation 844.7 |
| PF-04991532 25 mg | Apparent Oral Clearance (CL/F) of PF-04991532 | D14 (n=16, 16, 16, 16) | 1322 milliliter/minute (mL/min) | Standard Deviation 937.9 |
| PF-04991532 75 mg | Apparent Oral Clearance (CL/F) of PF-04991532 | D14 (n=16, 16, 16, 16) | 1292 milliliter/minute (mL/min) | Standard Deviation 624.5 |
| PF-04991532 75 mg | Apparent Oral Clearance (CL/F) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 1282 milliliter/minute (mL/min) | Standard Deviation 431.5 |
| PF-04991532 150 mg | Apparent Oral Clearance (CL/F) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 1440 milliliter/minute (mL/min) | Standard Deviation 607.7 |
| PF-04991532 150 mg | Apparent Oral Clearance (CL/F) of PF-04991532 | D14 (n=16, 16, 16, 16) | 1327 milliliter/minute (mL/min) | Standard Deviation 537.1 |
Secondary
Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532
Area under the plasma concentration versus time curve (AUC) from time zero to 10 hours post morning dose.
Time frame: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 372.1 ng*hr/mL | Standard Deviation 146.7 |
| Placebo | Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 384.7 ng*hr/mL | Standard Deviation 181.9 |
| PF-04991532 25 mg | Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 1508 ng*hr/mL | Standard Deviation 920.7 |
| PF-04991532 25 mg | Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 1447 ng*hr/mL | Standard Deviation 749.3 |
| PF-04991532 75 mg | Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 3329 ng*hr/mL | Standard Deviation 1153 |
| PF-04991532 75 mg | Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 2882 ng*hr/mL | Standard Deviation 1128 |
| PF-04991532 150 mg | Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 5661 ng*hr/mL | Standard Deviation 2595 |
| PF-04991532 150 mg | Area Under the Curve From Time Zero to 10 Hours Postdose (AUC10) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 5551 ng*hr/mL | Standard Deviation 2633 |
Secondary
Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532
Area under the plasma concentration versus time curve (AUC) from time zero to 24 hours post morning dose
Time frame: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, 10, 10.5, 11, 12, 13, 15, 18, and 24 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 441.6 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 172.3 |
| Placebo | Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 487.4 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 227.1 |
| PF-04991532 25 mg | Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 1745 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 757.1 |
| PF-04991532 25 mg | Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 1892 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 930.1 |
| PF-04991532 75 mg | Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 3899 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 1549 |
| PF-04991532 75 mg | Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 3870 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 1369 |
| PF-04991532 150 mg | Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 7531 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 3084 |
| PF-04991532 150 mg | Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 6943 nanogram*hour/milliliter (ng*hr/mL) | Standard Deviation 3053 |
Secondary
Change From Baseline (Day -2) in Mean Daily Glucose at Day 13
Mean daily glucose (MDG) was calculated based on the mean of 8 glucose measurements at pre-specified time points throughout the day.
Time frame: Baseline: hours -72, -70, -68, -66, -62, -60, -57, and -54 on Day -2 (Day 1 morning dose was hour 0); Day 13: 0 (before morning dose), 2, 4, 6, 10, 12, 15 and 18 hours after Day 13 morning dose
Population: The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Change from Baseline (Day 13) | 18.78 mg/dL | Standard Deviation 39.66 |
| Placebo | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Baseline (Day -2) | 214.31 mg/dL | Standard Deviation 42.39 |
| PF-04991532 25 mg | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Baseline (Day -2) | 230.70 mg/dL | Standard Deviation 37.88 |
| PF-04991532 25 mg | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Change from Baseline (Day 13) | -27.22 mg/dL | Standard Deviation 25.34 |
| PF-04991532 75 mg | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Baseline (Day -2) | 207.98 mg/dL | Standard Deviation 35.1 |
| PF-04991532 75 mg | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Change from Baseline (Day 13) | -15.78 mg/dL | Standard Deviation 31.99 |
| PF-04991532 150 mg | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Baseline (Day -2) | 219.59 mg/dL | Standard Deviation 43.78 |
| PF-04991532 150 mg | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Change from Baseline (Day 13) | -17.29 mg/dL | Standard Deviation 17.75 |
| PF-04991532 300 mg | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Baseline (Day -2) | 204.68 mg/dL | Standard Deviation 45.07 |
| PF-04991532 300 mg | Change From Baseline (Day -2) in Mean Daily Glucose at Day 13 | Change from Baseline (Day 13) | -33.58 mg/dL | Standard Deviation 37.06 |
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 13) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [76.06, 89.9]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 13) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [78.6, 92.77]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 13) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [78.59, 92.76]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in MDG (Day 13) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [69.78, 82.39]
Comparison: Treatment difference and 90% confidence interval (CI) were based on adjusted geometric mean.90% CI: [-52.89, -18.78]
Secondary
Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14
Area Under the Curve of C-peptide from Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) was calculated based on 8 C-peptide measurements at prespecified timepoints using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).
Time frame: Baseline: hours -46, -45.75, -45.5, -45, -44.5, -44, -43, -and -42 on Day -1 (Day 1 morning dose was hour 0); Day 14: 2, 2.25, 2.5, 3, 3.5, 4, 5, and 6 hours after Day 14 morning dose
Population: The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 15.79 ng*hr/mL | Standard Deviation 6.08 |
| Placebo | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | 0.09 ng*hr/mL | Standard Deviation 2.15 |
| PF-04991532 25 mg | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 17.04 ng*hr/mL | Standard Deviation 6.73 |
| PF-04991532 25 mg | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | 1.34 ng*hr/mL | Standard Deviation 2.64 |
| PF-04991532 75 mg | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 17.20 ng*hr/mL | Standard Deviation 5.89 |
| PF-04991532 75 mg | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -1.53 ng*hr/mL | Standard Deviation 2.88 |
| PF-04991532 150 mg | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -0.55 ng*hr/mL | Standard Deviation 1.63 |
| PF-04991532 150 mg | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 15.23 ng*hr/mL | Standard Deviation 4.51 |
| PF-04991532 300 mg | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 19.21 ng*hr/mL | Standard Deviation 7.61 |
| PF-04991532 300 mg | Change From Baseline in Area Under the Curve of C-peptide From Time 2 to 6 Hours Post Morning Dose (C-peptide AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -2.12 ng*hr/mL | Standard Deviation 2.97 |
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in C-peptide AUC(2-6) (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [98.69, 116.3]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in C-peptide AUC(2-6) (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [85.26, 100.5]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in C-peptide AUC(2-6) (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [88.51, 104.27]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in C-peptide AUC(2-6) (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [84.38, 99.65]
Secondary
Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14
Area under the curve of glucose from time 2 to 6 hours post morning dose (Glucose AUC(2-6)) was calculated based on 8 glucose measurements at prespecified time points using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).
Time frame: Baseline: hours -46, -45.75, -45.5, -45, -44.5, -44, -43, -and -42 on Day -1 (Day 1 morning dose was hour 0); Day 14: 2, 2.25, 2.5, 3, 3.5, 4, 5, and 6 hours after Day 14 morning dose
Population: The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 1091.23 mg*hr/dL | Standard Deviation 163.3 |
| Placebo | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | 86.05 mg*hr/dL | Standard Deviation 148.94 |
| PF-04991532 25 mg | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 1126.34 mg*hr/dL | Standard Deviation 119.26 |
| PF-04991532 25 mg | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -84.44 mg*hr/dL | Standard Deviation 99.91 |
| PF-04991532 75 mg | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 1029.76 mg*hr/dL | Standard Deviation 154.84 |
| PF-04991532 75 mg | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -12.65 mg*hr/dL | Standard Deviation 114.19 |
| PF-04991532 150 mg | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -60.55 mg*hr/dL | Standard Deviation 89.36 |
| PF-04991532 150 mg | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 1085.84 mg*hr/dL | Standard Deviation 245.64 |
| PF-04991532 300 mg | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 1050.69 mg*hr/dL | Standard Deviation 241.7 |
| PF-04991532 300 mg | Change From Baseline in Area Under the Curve of Glucose From Time 2 to 6 Hours Post Morning Dose (Glucose AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -158.93 mg*hr/dL | Standard Deviation 152.09 |
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Glucose AUC(2-6) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [81.13, 92.7]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Glucose AUC(2-6) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [85.24, 97.44]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Glucose AUC(2-6) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [81.44, 93.04]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Glucose AUC(2-6) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [72.91, 83.34]
Secondary
Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14
Area Under the Curve of Insulin from Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) was calculated based on 8 insulin measurements at prespecified time points using the linear trapezoidal method. Nominal times were used in the calculation. Liquid meal was administered 2 hours post morning dose of PF-04991532 for mixed meal tolerance test (MMTT).
Time frame: Baseline: hours -46, -45.75, -45.5, -45, -44.5, -44, -43, -and -42 on Day -1 (Day 1 morning dose was hour 0); Day 14: 2, 2.25, 2.5, 3, 3.5, 4, 5, and 6 hours after Day 14 morning dose
Population: The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 149.12 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 117.08 |
| Placebo | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -3.96 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 18.09 |
| PF-04991532 25 mg | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 139.40 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 77.81 |
| PF-04991532 25 mg | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | 15.87 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 27.16 |
| PF-04991532 75 mg | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 166.87 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 132.39 |
| PF-04991532 75 mg | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -3.06 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 32.79 |
| PF-04991532 150 mg | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | 11.82 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 24.87 |
| PF-04991532 150 mg | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 111.13 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 69.16 |
| PF-04991532 300 mg | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Baseline (Day -1) | 276.61 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 313.03 |
| PF-04991532 300 mg | Change From Baseline in Area Under the Curve of Insulin From Time 2 to 6 Hours Post Morning Dose (Insulin AUC(2-6)) Following Mixed Meal Tolerance Test (MMTT) at Day 14 | Change from Baseline (Day 14) | -38.06 milliUnit*hour/liter (mU*hr/L) | Standard Deviation 73.89 |
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Insulin AUC(2-6) (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [99.84, 127.5]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Insulin AUC(2-6) (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [90.78, 114.85]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Insulin AUC(2-6) (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [98.5, 125.18]
Comparison: Test-to-Reference ratio and 90% confidence interval (CI) were based on adjusted geometric mean. Natural log-transformed change from baseline in Insulin AUC(2-6) (Day 14) was analyzed using ANCOVA with country and treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [85.46, 109.48]
Secondary
Change From Baseline in Fasting Lipid Parameters at Day 14 and 16
Baseline for fasting triglycerides (TG) was defined as the average of the Day -1 (hour -48), Day 0 (hour -24), and Day 1 pre-dose (hour 0) measurements. Baseline for fasting total cholesterol (TC), cholesterol (high-density lipoprotein (HDL)), and cholesterol (low-density lipoprotein (LDL)) was defined as the Day 1 pre-dose (hour 0) measurement.
Time frame: Baseline: hour -48 on Day -1, hour -24 on Day 0, and hour 0 on Day 1 for TG and Hour 0 (before morning dose) on Day 1 for TC, HDL, and LDL; 48 hours after morning dose on Day 16 for TG and Hour 0 (before morning dose) on Day14 for TC, HDL, and LDL
Population: The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Total Cholesterol (Day 14) (n=16, 16, 16, 15, 16) | 0.06 mg/dL | Standard Deviation 16.98 |
| Placebo | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol LDL (Day 14) (n=16, 16, 15, 14, 15) | 2.38 mg/dL | Standard Deviation 17.64 |
| Placebo | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol HDL (Day 14) (n=16, 16, 16, 16, 16) | 1.75 mg/dL | Standard Deviation 4.48 |
| Placebo | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Triglycerides (Day 16) (n=16, 16, 16, 16, 16) | -9.81 mg/dL | Standard Deviation 35.87 |
| PF-04991532 25 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol LDL (Day 14) (n=16, 16, 15, 14, 15) | -8.06 mg/dL | Standard Deviation 26.98 |
| PF-04991532 25 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol HDL (Day 14) (n=16, 16, 16, 16, 16) | -1.88 mg/dL | Standard Deviation 7.75 |
| PF-04991532 25 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Total Cholesterol (Day 14) (n=16, 16, 16, 15, 16) | -11.75 mg/dL | Standard Deviation 31.62 |
| PF-04991532 25 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Triglycerides (Day 16) (n=16, 16, 16, 16, 16) | 12.79 mg/dL | Standard Deviation 45.64 |
| PF-04991532 75 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol LDL (Day 14) (n=16, 16, 15, 14, 15) | 4.67 mg/dL | Standard Deviation 22.48 |
| PF-04991532 75 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Triglycerides (Day 16) (n=16, 16, 16, 16, 16) | 37.52 mg/dL | Standard Deviation 98.13 |
| PF-04991532 75 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol HDL (Day 14) (n=16, 16, 16, 16, 16) | 1.88 mg/dL | Standard Deviation 6.04 |
| PF-04991532 75 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Total Cholesterol (Day 14) (n=16, 16, 16, 15, 16) | 4.19 mg/dL | Standard Deviation 20.04 |
| PF-04991532 150 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Triglycerides (Day 16) (n=16, 16, 16, 16, 16) | 18.24 mg/dL | Standard Deviation 36.08 |
| PF-04991532 150 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Total Cholesterol (Day 14) (n=16, 16, 16, 15, 16) | 1.80 mg/dL | Standard Deviation 19.29 |
| PF-04991532 150 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol HDL (Day 14) (n=16, 16, 16, 16, 16) | 0.69 mg/dL | Standard Deviation 8.44 |
| PF-04991532 150 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol LDL (Day 14) (n=16, 16, 15, 14, 15) | -0.79 mg/dL | Standard Deviation 16.4 |
| PF-04991532 300 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol LDL (Day 14) (n=16, 16, 15, 14, 15) | 1.53 mg/dL | Standard Deviation 25.53 |
| PF-04991532 300 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Triglycerides (Day 16) (n=16, 16, 16, 16, 16) | 58.00 mg/dL | Standard Deviation 67.31 |
| PF-04991532 300 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Total Cholesterol (Day 14) (n=16, 16, 16, 15, 16) | 11.38 mg/dL | Standard Deviation 30.17 |
| PF-04991532 300 mg | Change From Baseline in Fasting Lipid Parameters at Day 14 and 16 | Cholesterol HDL (Day 14) (n=16, 16, 16, 16, 16) | 3.94 mg/dL | Standard Deviation 7.17 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
The average of the Day -1 (hour -48), Day 0 (hour -24) and Day 1 pre-dose (hour 0) measurements was the baseline for fasting plasma glucose (FPG) analyses.
Time frame: Baseline: hour -48 on Day -1, hour -24 on Day 0, and hour 0 (before morning dose) on Day 1; hour 0 (before morning dose of each day) on Days 1, 2, 3, 6, and 10; and 24 hours after Day 14 morning dose on Day 15
Population: The pharmacodynamic analysis population was defined as all randomized participants who received at least 1 dose of study medication (PF-04991532 or placebo) and had at least 1 of the pharmacodynamic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 14 (n=16, 16, 16, 16, 16) | 9.00 mg/dL | Standard Deviation 26.9 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 2 (n=16, 17, 16, 16, 17) | -4.19 mg/dL | Standard Deviation 17.77 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 10 (n=16, 16, 16, 16, 16) | -10.88 mg/dL | Standard Deviation 43.97 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 3 (n=16, 17, 16, 16, 17) | -0.63 mg/dL | Standard Deviation 15.76 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 6 (n=16, 16, 16, 16, 16) | 3.44 mg/dL | Standard Deviation 26.69 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 15 (n=16, 16, 16, 16, 15) | 12.63 mg/dL | Standard Deviation 44.47 |
| PF-04991532 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 15 (n=16, 16, 16, 16, 15) | -9.71 mg/dL | Standard Deviation 25.96 |
| PF-04991532 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 14 (n=16, 16, 16, 16, 16) | -17.83 mg/dL | Standard Deviation 25.71 |
| PF-04991532 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 6 (n=16, 16, 16, 16, 16) | -9.40 mg/dL | Standard Deviation 16.68 |
| PF-04991532 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 10 (n=16, 16, 16, 16, 16) | -17.21 mg/dL | Standard Deviation 24.08 |
| PF-04991532 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 3 (n=16, 17, 16, 16, 17) | -8.92 mg/dL | Standard Deviation 11.86 |
| PF-04991532 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 2 (n=16, 17, 16, 16, 17) | -5.04 mg/dL | Standard Deviation 10.43 |
| PF-04991532 75 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 10 (n=16, 16, 16, 16, 16) | -16.96 mg/dL | Standard Deviation 26.78 |
| PF-04991532 75 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 6 (n=16, 16, 16, 16, 16) | -9.90 mg/dL | Standard Deviation 18.13 |
| PF-04991532 75 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 15 (n=16, 16, 16, 16, 15) | -8.15 mg/dL | Standard Deviation 22.81 |
| PF-04991532 75 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 2 (n=16, 17, 16, 16, 17) | -4.33 mg/dL | Standard Deviation 18.15 |
| PF-04991532 75 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 14 (n=16, 16, 16, 16, 16) | -14.52 mg/dL | Standard Deviation 23.08 |
| PF-04991532 75 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 3 (n=16, 17, 16, 16, 17) | -2.15 mg/dL | Standard Deviation 15.25 |
| PF-04991532 150 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 14 (n=16, 16, 16, 16, 16) | -7.27 mg/dL | Standard Deviation 8.78 |
| PF-04991532 150 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 6 (n=16, 16, 16, 16, 16) | -6.33 mg/dL | Standard Deviation 12.24 |
| PF-04991532 150 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 10 (n=16, 16, 16, 16, 16) | -10.33 mg/dL | Standard Deviation 15.75 |
| PF-04991532 150 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 2 (n=16, 17, 16, 16, 17) | 0.29 mg/dL | Standard Deviation 14.93 |
| PF-04991532 150 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 3 (n=16, 17, 16, 16, 17) | 0.23 mg/dL | Standard Deviation 14.06 |
| PF-04991532 150 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 15 (n=16, 16, 16, 16, 15) | -0.58 mg/dL | Standard Deviation 16.71 |
| PF-04991532 300 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 15 (n=16, 16, 16, 16, 15) | -4.22 mg/dL | Standard Deviation 37.34 |
| PF-04991532 300 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 10 (n=16, 16, 16, 16, 16) | -17.40 mg/dL | Standard Deviation 30.99 |
| PF-04991532 300 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 6 (n=16, 16, 16, 16, 16) | -16.90 mg/dL | Standard Deviation 23.67 |
| PF-04991532 300 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 3 (n=16, 17, 16, 16, 17) | -7.78 mg/dL | Standard Deviation 16.4 |
| PF-04991532 300 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 2 (n=16, 17, 16, 16, 17) | -5.55 mg/dL | Standard Deviation 36.08 |
| PF-04991532 300 mg | Change From Baseline in Fasting Plasma Glucose (FPG) | Day 14 (n=16, 16, 16, 16, 16) | -11.40 mg/dL | Standard Deviation 19.12 |
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 2 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [92.7, 107.96]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 2 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [92.04, 107.43]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 2 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [94.1, 109.84]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 2 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [89.69, 104.52]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 3 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [88.82, 103.44]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 3 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [91.37, 106.64]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 3 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [92.3, 107.73]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 3 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [87.53, 102.1]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 6 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [86.5, 100.91]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 6 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [85.81, 100.15]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 6 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [87.08, 101.64]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 6 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [81.2, 94.81]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 10 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [89.72, 104.67]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 10 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [88.9, 103.76]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 10 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [92.21, 107.64]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 10 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [87.46, 102.11]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 14 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [80.32, 93.69]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 14 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [81.34, 94.93]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 14 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [84.55, 98.7]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 14 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [82, 95.74]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 15 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [83.75, 97.69]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 15 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [84.03, 98.08]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 15 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [87.69, 102.34]
Comparison: Test-to-Reference ratio of log-transformed change from baseline and 90% confidence interval (CI) of log-transformed change from baseline at Day 15 were based on adjusted geometric mean. Natural log-transformed change from baseline in FPG was analyzed using mixed effects model with country, treatment as fixed effect and log-transformed baseline as covariate. Placebo is the reference; the active drug group is the test.90% CI: [86.17, 100.77]
Secondary
Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532
Area under the curve from time zero to 24 Hours Postdose (AUC24) divided by total daily dose
Time frame: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, 10, 10.5, 11, 12, 13, 15, 18, and 24 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 4.874 ng*hr/mL/mg | Standard Deviation 2.271 |
| Placebo | Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 4.416 ng*hr/mL/mg | Standard Deviation 1.723 |
| PF-04991532 25 mg | Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 6.307 ng*hr/mL/mg | Standard Deviation 3.107 |
| PF-04991532 25 mg | Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 5.810 ng*hr/mL/mg | Standard Deviation 2.52 |
| PF-04991532 75 mg | Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 6.497 ng*hr/mL/mg | Standard Deviation 2.578 |
| PF-04991532 75 mg | Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 6.449 ng*hr/mL/mg | Standard Deviation 2.279 |
| PF-04991532 150 mg | Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | Day 1 (n=16, 16, 16, 17) | 5.787 ng*hr/mL/mg | Standard Deviation 2.54 |
| PF-04991532 150 mg | Dose Normalized Area Under the Curve From Time Zero to 24 Hours Postdose (AUC24(dn)) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 6.275 ng*hr/mL/mg | Standard Deviation 2.558 |
Secondary
Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532
Maximum Observed Plasma Concentration of PF-04991532 after Morning Dose Administration (Cmax(AM)) divided by dose
Time frame: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | Day 1 (n=17, 16, 16, 17) | 2.754 ng/mL/mg | Standard Deviation 1.147 |
| Placebo | Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 2.964 ng/mL/mg | Standard Deviation 1.484 |
| PF-04991532 25 mg | Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 3.132 ng/mL/mg | Standard Deviation 3.296 |
| PF-04991532 25 mg | Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | Day 1 (n=17, 16, 16, 17) | 3.245 ng/mL/mg | Standard Deviation 2.431 |
| PF-04991532 75 mg | Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | Day 1 (n=17, 16, 16, 17) | 4.283 ng/mL/mg | Standard Deviation 1.947 |
| PF-04991532 75 mg | Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 3.009 ng/mL/mg | Standard Deviation 1.631 |
| PF-04991532 150 mg | Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | Day 1 (n=17, 16, 16, 17) | 3.252 ng/mL/mg | Standard Deviation 1.842 |
| PF-04991532 150 mg | Dose Normalized Maximum Plasma Concentration After Morning Dose Administration (Cmax(AM)(dn)) of PF-04991532 | Day 14 (n=16, 16, 16, 16) | 2.732 ng/mL/mg | Standard Deviation 1.53 |
Secondary
Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM))
Time frame: 10 (before evening dose), 10.5, 11, 12, 13, 15, 18, and 24 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | Day 1 (n=16, 16, 16, 17) | 97.10 ng/mL | Standard Deviation 67.45 |
| Placebo | Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | Day 14 (n=16, 16,16, 16) | 89.99 ng/mL | Standard Deviation 46.05 |
| PF-04991532 25 mg | Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | Day 14 (n=16, 16,16, 16) | 360.7 ng/mL | Standard Deviation 288.8 |
| PF-04991532 25 mg | Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | Day 1 (n=16, 16, 16, 17) | 336.0 ng/mL | Standard Deviation 219.7 |
| PF-04991532 75 mg | Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | Day 1 (n=16, 16, 16, 17) | 932.0 ng/mL | Standard Deviation 387.7 |
| PF-04991532 75 mg | Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | Day 14 (n=16, 16,16, 16) | 772.4 ng/mL | Standard Deviation 310.8 |
| PF-04991532 150 mg | Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | Day 1 (n=16, 16, 16, 17) | 1645 ng/mL | Standard Deviation 1132 |
| PF-04991532 150 mg | Maximum Observed Plasma Concentration of PF-04991532 After Evening Dose Administration (Cmax(PM)) | Day 14 (n=16, 16,16, 16) | 1687 ng/mL | Standard Deviation 914.9 |
Secondary
Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM))
Time frame: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | Day 1 (n=17, 16, 16, 17) | 137.7 ng/mL | Standard Deviation 57.36 |
| Placebo | Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | Day 14 (n=16, 16, 16, 16) | 148.2 ng/mL | Standard Deviation 74.23 |
| PF-04991532 25 mg | Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | Day 14 (n=16, 16, 16, 16) | 469.8 ng/mL | Standard Deviation 495.3 |
| PF-04991532 25 mg | Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | Day 1 (n=17, 16, 16, 17) | 486.6 ng/mL | Standard Deviation 363.7 |
| PF-04991532 75 mg | Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | Day 1 (n=17, 16, 16, 17) | 1285 ng/mL | Standard Deviation 585.8 |
| PF-04991532 75 mg | Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | Day 14 (n=16, 16, 16, 16) | 902.4 ng/mL | Standard Deviation 489.1 |
| PF-04991532 150 mg | Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | Day 1 (n=17, 16, 16, 17) | 1951 ng/mL | Standard Deviation 1106 |
| PF-04991532 150 mg | Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Cmax(AM)) | Day 14 (n=16, 16, 16, 16) | 1639 ng/mL | Standard Deviation 917.8 |
Secondary
Minimum Observed Plasma Trough Concentration (Cmin) of PF-04991532
Time frame: Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Minimum Observed Plasma Trough Concentration (Cmin) of PF-04991532 | 0.1691 ng/mL | Standard Deviation 1.373 |
| PF-04991532 25 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-04991532 | 5.249 ng/mL | Standard Deviation 3.112 |
| PF-04991532 75 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-04991532 | 11.32 ng/mL | Standard Deviation 8.126 |
| PF-04991532 150 mg | Minimum Observed Plasma Trough Concentration (Cmin) of PF-04991532 | 21.15 ng/mL | Standard Deviation 12.73 |
Secondary
Observed Accumulation Ratio of Area Under the Curve From Time Zero to 10 Hours Postdose of PF-04991532 (Rac)
Area under the curve from time zero to 10 hours postdose of PF-04991532 (AUC10) of Day 14 divided by AUC10 of Day 1
Time frame: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Observed Accumulation Ratio of Area Under the Curve From Time Zero to 10 Hours Postdose of PF-04991532 (Rac) | 1.095 ratio | Standard Deviation 0.352 |
| PF-04991532 25 mg | Observed Accumulation Ratio of Area Under the Curve From Time Zero to 10 Hours Postdose of PF-04991532 (Rac) | 1.049 ratio | Standard Deviation 0.2995 |
| PF-04991532 75 mg | Observed Accumulation Ratio of Area Under the Curve From Time Zero to 10 Hours Postdose of PF-04991532 (Rac) | 0.9004 ratio | Standard Deviation 0.3353 |
| PF-04991532 150 mg | Observed Accumulation Ratio of Area Under the Curve From Time Zero to 10 Hours Postdose of PF-04991532 (Rac) | 1.017 ratio | Standard Deviation 0.2946 |
Secondary
Observed Accumulation Ratio of Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Rac, Cmax(AM))
Maximum observed plasma concentration of PF-04991532 after morning dose administration (Cmax(AM)) of Day 14 divided by Cmax(AM) of Day 1
Time frame: 0 (before morning dose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Observed Accumulation Ratio of Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Rac, Cmax(AM)) | 1.057 ratio | Standard Deviation 0.6267 |
| PF-04991532 25 mg | Observed Accumulation Ratio of Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Rac, Cmax(AM)) | 0.9655 ratio | Standard Deviation 0.5913 |
| PF-04991532 75 mg | Observed Accumulation Ratio of Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Rac, Cmax(AM)) | 0.7022 ratio | Standard Deviation 0.4744 |
| PF-04991532 150 mg | Observed Accumulation Ratio of Maximum Observed Plasma Concentration of PF-04991532 After Morning Dose Administration (Rac, Cmax(AM)) | 0.8663 ratio | Standard Deviation 0.3648 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM))
Time was computed as post morning dose.
Time frame: 10 (before evening dose), 10.5, 11, 12, 13, 15, 18, and 24 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | Day 1 (n=16, 16, 16, 17) | 11.0 hour |
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | Day 14 (n=16, 16, 16, 16) | 11.0 hour |
| PF-04991532 25 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | Day 14 (n=16, 16, 16, 16) | 11.0 hour |
| PF-04991532 25 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | Day 1 (n=16, 16, 16, 17) | 11.0 hour |
| PF-04991532 75 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | Day 1 (n=16, 16, 16, 17) | 11.0 hour |
| PF-04991532 75 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | Day 14 (n=16, 16, 16, 16) | 11.0 hour |
| PF-04991532 150 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | Day 1 (n=16, 16, 16, 17) | 11.0 hour |
| PF-04991532 150 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Evening Dose Administration (Tmax(PM)) | Day 14 (n=16, 16, 16, 16) | 11.0 hour |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM))
Time frame: 0 (predose), 0.5, 1, 2, 3, 4, 6, and 10 hours after morning dose on Day 1 and Day 14
Population: The pharmacokinetic parameter analysis population was defined as all randomized participants treated with PF-04991532 who had at least 1 of the pharmacokinetic parameters of interest; n is the number of participants analyzed for each day.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | Day 14 (n=16, 16, 16, 16) | 1.00 hour |
| Placebo | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | Day 1 (n=17, 16, 16, 17) | 1.00 hour |
| PF-04991532 25 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | Day 1 (n=17, 16, 16, 17) | 1.00 hour |
| PF-04991532 25 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | Day 14 (n=16, 16, 16, 16) | 1.00 hour |
| PF-04991532 75 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | Day 1 (n=17, 16, 16, 17) | 1.83 hour |
| PF-04991532 75 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | Day 14 (n=16, 16, 16, 16) | 1.83 hour |
| PF-04991532 150 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | Day 14 (n=16, 16, 16, 16) | 1.45 hour |
| PF-04991532 150 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04991532 After Morning Dose Administration (Tmax(AM)) | Day 1 (n=17, 16, 16, 17) | 1.00 hour |