Type 2 Diabetes Mellitus
Conditions
Keywords
Phase 1, type 2 diabetes, monotherapy, PF-04937319
Brief summary
Study B1621018 will assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Two Dose Levels of Pf-04937319 in Japanese Subjects with Type 2 Diabetes Mellitus As Monotherapy
Interventions
DRUGPF-04937319 high dose
tablets, 150 mg with breakfast plus 100 mg with lunch, 7 days
DRUGPF-04937319 low dose
tablets, 50 mg with breakfast plus 50 mg with lunch, 7 days
DRUGPlacebo
tablets, breakfast plus lunch, 7 days
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 64 Years
Healthy volunteers
No
Inclusion criteria
* Patients with type 2 diabetes, on diet/exercise therapy only or background therapy with 1 oral anti-diabetic agent (excluding Actos)
Exclusion criteria
* Patients with cardiovascular event * Patients with diabetic complications * Female subjects who are pregnant or planning to become pregnant * Subjects with unstable medical conditions (eg, hypertension)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Baseline up to 14 days after the last dose of study drug (minimum 8 weeks to maximum of 17 weeks) | 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; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 14 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. |
| Number of Participants With Protocol Defined Hypoglycaemic Adverse Events (HAEs) | Baseline up to 14 days after the last dose of study drug (minimum 8 weeks to maximum of 17 weeks) | A hypoglycemic event (HAE) was identified by characteristic symptoms or blood glucose levels. HAE was defined as 1 of the given definitions: 1) Characteristic symptoms of HAE with no home glucose monitoring performed where clinical picture included prompt resolution with food intake, subcutaneous glucagon, or intravenous glucose; 2) Characteristic symptoms of HAE with home glucose monitoring measurement of less than or equal to (=\<) 70 milligram per deciliter (mg/dL) using sponsor-provided, plasma-referenced, home glucometers (or central laboratory); 3) any glucose value =\<49 mg/dL using sponsor-provided, plasma-referenced, home glucometers (or central laboratory) with or without accompanying symptoms. |
| Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 | — |
| Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 1 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post-dose on Day 1 | AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). |
| Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7 | — |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7 | — |
| Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 7 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). |
| Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF-04937319 | 0 hour (pre-dose) on Day 7 | Ctrough is the concentration prior to study drug administration. |
| Average Plasma Concentration (Cav) on Day 7 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | Cav is the average plasma concentration during the 0 to 24 hour time period. |
| Apparent Oral Clearance on Day 7 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | 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 oral bioavailability. It is calculated as the total oral daily dose divided by AUC24, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours. |
| Terminal Half-Life (t1/2) on Day 7 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7 | Terminal half-life is the time measured for the plasma concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) multiplied by (\*) 2/k el, where 'k el' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. |
| Apparent Volume of Distribution on Day 7 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the oral bioavailability. It is calculated as the total oral daily dose divided by AUC24\* k el, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours and terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Accumulation Ratio (Rac) on Day 7 for PF-04937319 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | Rac is based on AUC24. It is the ratio of AUC24 of Day 7 and AUC24 of Day 1, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-morning meal (pre-breakfast), 5 hours (pre-lunch), 11 hours (pre-dinner) after morning meal on Day 0 (Baseline); pre-morning dose (pre-breakfast), 5 hours (pre-lunch), 11 hours (pre-dinner) post-morning dose on Day 7 | Time-matched change from baseline in pre-meal serum insulin on Day 7 of each period was analyzed. Pre-meal insulin levels therefore, pre-breakfast, pre-lunch, and pre-dinner were analyzed. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 | PF-06455349 is a metabolite of PF-04937319. |
| Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-morning meal (pre-breakfast), 5 hours (pre-lunch), 11 hours (pre-dinner) after morning meal on Day 0 (Baseline); pre-morning dose (pre-breakfast), 5 hours (pre-lunch), 11 hours (pre-dinner) post-morning dose on Day 7 | Time-matched change from baseline in pre-meal serum C-peptide on Day 7 of each period was analyzed. Pre-meal C-peptide levels therefore, pre-breakfast, pre-lunch, and pre-dinner were analyzed. |
| Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 | PF-06455349 is a metabolite of PF-04937319. |
| Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 1 for PF--06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 | AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). PF-06455349 is a metabolite of PF-04937319. |
| Metabolite to Parent Ratio for AUC24 (MRAUC24) on Day 1 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 | MRAUC24 is the ratio of AUC24 of PF-06455349 (metabolite) to AUC24 of PF-04937319 (parent drug) \* ratio of molecular weight of PF-04937319 to molecular weight of PF-06455349, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours. |
| Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF--06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7 | PF-06455349 is a metabolite of PF-04937319. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7 | PF-06455349 is a metabolite of PF-04937319. |
| Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 7 for PF--06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). PF-06455349 is a metabolite of PF-04937319. |
| Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF--06455349 | 0 hour (pre-dose) on Day 7 | Ctrough is the concentration prior to study drug administration. PF-06455349 is a metabolite of PF-04937319. |
| Average Plasma Concentration (Cav) on Day 7 for PF--06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | Cav is the average plasma concentration during the 0 to 24 hour time period. PF-06455349 is a metabolite of PF-04937319. |
| Terminal Half-Life (t1/2) on Day 7 for PF-06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7 | Terminal half-life is the time measured for the plasma concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) \* 2/k el, where 'k el' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. PF-06455349 is a metabolite of PF-04937319. |
| Accumulation Ratio (Rac) on Day 7 for PF-06455349 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | Rac is based on AUC24. It is the ratio of AUC24 of Day 7 and AUC24 of Day 1, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours. PF-06455349 is a metabolite of PF-04937319. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Last Day of Treatment | Pre-morning meal on Day 0, pre-morning dose on Day 1, pre-morning dose on Day 7, pre-morning meal on Day 8 | FPG was defined as plasma glucose measurements taken pre-breakfast, in the fasted state, and prior to dosing with study drug. Baseline was defined as the average of Hour 0 measurements taken on Day 0 and Day 1 in each intervention period. The measurement on the last day of treatment was defined as the average of Hour 0 measurements taken on Day 7 and Day 8 in each period. |
| Metabolite to Parent Ratio for AUC24 (MRAUC24) on Day 7 | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 | MRAUC24 is the ratio of AUC24 of PF-06455349 (metabolite) to AUC24 of PF-04937319 (parent drug) \* ratio of molecular weight of PF-04937319 to molecular weight of PF-06455349, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours. PF-06455349 is a metabolite of PF-04937319. |
| Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 7 | Pre-morning meal, 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 16 and 20 hours post- morning meal on Day 0; pre-morning dose, 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 16, 20 hours post-morning dose on Day 7 | WMDG was defined as time-weighted mean daily glucose. WMDG was calculated by as the time-weighted mean of glucose levels at actual time points for glucose sampling, for Day 0 (Baseline) and Day 7. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-04937319 100 mg Then PF-04937319 250 mg Then Placebo Participants received PF-04937319 100 milligram (mg) orally per day in 2 divided doses (split dose regimen of 50 mg with morning meal and 50 mg with afternoon meal at approximately 5 hours of interval) for 7 days in the first intervention period followed by PF-04937319 250 mg orally per day in 2 divided doses (split dose regimen of 150 mg with morning meal and 100 mg with afternoon meal at approximately 5 hours of interval) for 7 days in the second intervention period, and then placebo matched to PF-04937319 administered orally with morning and afternoon meals for 7 days in the third intervention period. A washout period of 7 to 14 days was maintained between each intervention. | 4 |
| PF-04937319 100 mg Then Placebo Then PF-04937319 250 mg Participants received PF-04937319 100 mg orally per day in 2 divided doses (split dose regimen of 50 mg with morning meal and 50 mg with afternoon meal at approximately 5 hours of interval) for 7 days in the first intervention period followed by placebo matched to PF-04937319 administered orally with morning and afternoon meals for 7 days in the second intervention period, and then PF-04937319 250 mg orally per day in 2 divided doses (split dose regimen of 150 mg with morning meal and 100 mg with afternoon meal at approximately 5 hours of interval) for 7 days in the third intervention period. A washout period of 7 to 14 days was maintained between each intervention. | 4 |
| Placebo Then PF-04937319 100 mg Then PF-04937319 250 mg Participants received placebo matched to PF-04937319 administered orally with morning and afternoon meals for 7 days in the first intervention period followed by PF-04937319 100 mg orally per day in 2 divided doses (split dose regimen of 50 mg with morning meal and 50 mg with afternoon meal at approximately 5 hours of interval) for 7 days in the second intervention period, and then PF-04937319 250 mg orally per day in 2 divided doses (split dose regimen of 150 mg with morning meal and 100 mg with afternoon meal at approximately 5 hours of interval) for 7 days in the third intervention period. A washout period of 7 to 14 days was maintained between each intervention. | 4 |
| Total | 12 |
Baseline characteristics
| Characteristic | PF-04937319 100 mg Then PF-04937319 250 mg Then Placebo | PF-04937319 100 mg Then Placebo Then PF-04937319 250 mg | Placebo Then PF-04937319 100 mg Then PF-04937319 250 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 49.3 years STANDARD_DEVIATION 6.6 | 52.5 years STANDARD_DEVIATION 10.5 | 53.8 years STANDARD_DEVIATION 6.2 | 51.8 years STANDARD_DEVIATION 7.5 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 12 | 6 / 12 | 1 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Accumulation Ratio (Rac) on Day 7 for PF-04937319
Rac is based on AUC24. It is the ratio of AUC24 of Day 7 and AUC24 of Day 1, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Accumulation Ratio (Rac) on Day 7 for PF-04937319 | 1.159 ratio | Geometric Coefficient of Variation 16 |
| PF--04937319 250 mg | Accumulation Ratio (Rac) on Day 7 for PF-04937319 | 1.244 ratio | Geometric Coefficient of Variation 19 |
Primary
Apparent Oral Clearance on Day 7 for PF-04937319
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 oral bioavailability. It is calculated as the total oral daily dose divided by AUC24, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Apparent Oral Clearance on Day 7 for PF-04937319 | 434.0 milliliter per minute (mL/min) | Geometric Coefficient of Variation 21 |
| PF--04937319 250 mg | Apparent Oral Clearance on Day 7 for PF-04937319 | 525.0 milliliter per minute (mL/min) | Geometric Coefficient of Variation 27 |
Primary
Apparent Volume of Distribution on Day 7 for PF-04937319
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the oral bioavailability. It is calculated as the total oral daily dose divided by AUC24\* k el, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours and terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Apparent Volume of Distribution on Day 7 for PF-04937319 | 280.5 liter | Geometric Coefficient of Variation 48 |
| PF--04937319 250 mg | Apparent Volume of Distribution on Day 7 for PF-04937319 | 414.6 liter | Geometric Coefficient of Variation 40 |
Primary
Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 1 for PF-04937319
AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24).
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post-dose on Day 1
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 1 for PF-04937319 | 3308 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 16 |
| PF--04937319 250 mg | Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 1 for PF-04937319 | 6379 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 22 |
Primary
Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 7 for PF-04937319
AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24).
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 7 for PF-04937319 | 3840 ng*hr/mL | Geometric Coefficient of Variation 21 |
| PF--04937319 250 mg | Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 7 for PF-04937319 | 7937 ng*hr/mL | Geometric Coefficient of Variation 27 |
Primary
Average Plasma Concentration (Cav) on Day 7 for PF-04937319
Cav is the average plasma concentration during the 0 to 24 hour time period.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Average Plasma Concentration (Cav) on Day 7 for PF-04937319 | 159.9 ng/mL | Geometric Coefficient of Variation 21 |
| PF--04937319 250 mg | Average Plasma Concentration (Cav) on Day 7 for PF-04937319 | 330.6 ng/mL | Geometric Coefficient of Variation 27 |
Primary
Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-04937319
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1
Population: Pharmacokinetic (PK) parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-04937319 | 345.8 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 13 |
| PF--04937319 250 mg | Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-04937319 | 614.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 20 |
Primary
Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF-04937319
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF-04937319 | 361.3 ng/mL | Geometric Coefficient of Variation 16 |
| PF--04937319 250 mg | Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF-04937319 | 692.0 ng/mL | Geometric Coefficient of Variation 22 |
Primary
Number of Participants With Protocol Defined Hypoglycaemic Adverse Events (HAEs)
A hypoglycemic event (HAE) was identified by characteristic symptoms or blood glucose levels. HAE was defined as 1 of the given definitions: 1) Characteristic symptoms of HAE with no home glucose monitoring performed where clinical picture included prompt resolution with food intake, subcutaneous glucagon, or intravenous glucose; 2) Characteristic symptoms of HAE with home glucose monitoring measurement of less than or equal to (=\<) 70 milligram per deciliter (mg/dL) using sponsor-provided, plasma-referenced, home glucometers (or central laboratory); 3) any glucose value =\<49 mg/dL using sponsor-provided, plasma-referenced, home glucometers (or central laboratory) with or without accompanying symptoms.
Time frame: Baseline up to 14 days after the last dose of study drug (minimum 8 weeks to maximum of 17 weeks)
Population: Safety analysis set included all participants who received at least 1 dose of study medication (including placebo) in at least 1 period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF--04937319 100 mg | Number of Participants With Protocol Defined Hypoglycaemic Adverse Events (HAEs) | 1 participants |
| PF--04937319 250 mg | Number of Participants With Protocol Defined Hypoglycaemic Adverse Events (HAEs) | 4 participants |
| Placebo | Number of Participants With Protocol Defined Hypoglycaemic Adverse Events (HAEs) | 0 participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 14 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.
Time frame: Baseline up to 14 days after the last dose of study drug (minimum 8 weeks to maximum of 17 weeks)
Population: Safety analysis set included all participants who received at least 1 dose of study medication (including placebo) in at least 1 period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF--04937319 100 mg | Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 1 participants |
| PF--04937319 100 mg | Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| PF--04937319 250 mg | Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 6 participants |
| PF--04937319 250 mg | Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 1 participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
Primary
Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF-04937319
Ctrough is the concentration prior to study drug administration.
Time frame: 0 hour (pre-dose) on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF-04937319 | 44.82 ng/mL | Geometric Coefficient of Variation 30 |
| PF--04937319 250 mg | Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF-04937319 | 106.3 ng/mL | Geometric Coefficient of Variation 29 |
Primary
Terminal Half-Life (t1/2) on Day 7 for PF-04937319
Terminal half-life is the time measured for the plasma concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) multiplied by (\*) 2/k el, where 'k el' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Terminal Half-Life (t1/2) on Day 7 for PF-04937319 | 8.006 hour | Standard Deviation 3.5291 |
| PF--04937319 250 mg | Terminal Half-Life (t1/2) on Day 7 for PF-04937319 | 10.01 hour | Standard Deviation 4.5216 |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-04937319
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-04937319 | 6.50 hour | Full Range 13 |
| PF--04937319 250 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-04937319 | 6.50 hour | Full Range 20 |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-04937319
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-04937319 | 6.50 hour | Full Range 13 |
| PF--04937319 250 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-04937319 | 6.50 hour | Full Range 20 |
Secondary
Accumulation Ratio (Rac) on Day 7 for PF-06455349
Rac is based on AUC24. It is the ratio of AUC24 of Day 7 and AUC24 of Day 1, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours. PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Accumulation Ratio (Rac) on Day 7 for PF-06455349 | 1.756 ratio | Geometric Coefficient of Variation 14 |
| PF--04937319 250 mg | Accumulation Ratio (Rac) on Day 7 for PF-06455349 | 1.903 ratio | Geometric Coefficient of Variation 16 |
Secondary
Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 1 for PF--06455349
AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 1 for PF--06455349 | 5326 ng*hr/mL | Geometric Coefficient of Variation 18 |
| PF--04937319 250 mg | Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 1 for PF--06455349 | 10180 ng*hr/mL | Geometric Coefficient of Variation 19 |
Secondary
Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 7 for PF--06455349
AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 7 for PF--06455349 | 9346 ng*hr/mL | Geometric Coefficient of Variation 11 |
| PF--04937319 250 mg | Area Under the Concentration-Time Curve (AUC24) From Time Zero to 24 Hour on Day 7 for PF--06455349 | 19380 ng*hr/mL | Geometric Coefficient of Variation 15 |
Secondary
Average Plasma Concentration (Cav) on Day 7 for PF--06455349
Cav is the average plasma concentration during the 0 to 24 hour time period. PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Average Plasma Concentration (Cav) on Day 7 for PF--06455349 | 389.5 ng/mL | Geometric Coefficient of Variation 11 |
| PF--04937319 250 mg | Average Plasma Concentration (Cav) on Day 7 for PF--06455349 | 807.0 ng/mL | Geometric Coefficient of Variation 15 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Last Day of Treatment
FPG was defined as plasma glucose measurements taken pre-breakfast, in the fasted state, and prior to dosing with study drug. Baseline was defined as the average of Hour 0 measurements taken on Day 0 and Day 1 in each intervention period. The measurement on the last day of treatment was defined as the average of Hour 0 measurements taken on Day 7 and Day 8 in each period.
Time frame: Pre-morning meal on Day 0, pre-morning dose on Day 1, pre-morning dose on Day 7, pre-morning meal on Day 8
Population: PD analysis population included all randomized participants who received at least 1 dose of study medication and had both a baseline and a post-baseline assessment for at least 1 PD parameter in at least 1 period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF--04937319 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Last Day of Treatment | Change at last day of treatment | -31.08 mg/dL | Standard Deviation 14.86 |
| PF--04937319 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Last Day of Treatment | Baseline | 164.42 mg/dL | Standard Deviation 32.389 |
| PF--04937319 250 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Last Day of Treatment | Baseline | 156.96 mg/dL | Standard Deviation 37.388 |
| PF--04937319 250 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Last Day of Treatment | Change at last day of treatment | -39.33 mg/dL | Standard Deviation 17.892 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Last Day of Treatment | Baseline | 159.25 mg/dL | Standard Deviation 30.716 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Last Day of Treatment | Change at last day of treatment | -13.92 mg/dL | Standard Deviation 17.142 |
Comparison: Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.000690% CI: [-17.16, -7.21]Mixed Models Analysis
Comparison: Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: <0.000190% CI: [-30.73, -20.88]Mixed Models Analysis
Secondary
Change From Baseline in Pre-Meal C-Peptide at Day 7
Time-matched change from baseline in pre-meal serum C-peptide on Day 7 of each period was analyzed. Pre-meal C-peptide levels therefore, pre-breakfast, pre-lunch, and pre-dinner were analyzed.
Time frame: Pre-morning meal (pre-breakfast), 5 hours (pre-lunch), 11 hours (pre-dinner) after morning meal on Day 0 (Baseline); pre-morning dose (pre-breakfast), 5 hours (pre-lunch), 11 hours (pre-dinner) post-morning dose on Day 7
Population: PD analysis population included all randomized participants who received at least 1 dose of study medication and had both a baseline and a post-baseline assessment for at least 1 PD parameter in at least 1 period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF--04937319 100 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-breakfast: Baseline | 1.68 ng/mL | Standard Deviation 0.432 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-breakfast: Change at Day 7 | -0.38 ng/mL | Standard Deviation 0.374 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-lunch: Baseline | 2.35 ng/mL | Standard Deviation 0.674 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-lunch: Change at Day 7 | 0.65 ng/mL | Standard Deviation 0.521 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-dinner: Baseline | 2.93 ng/mL | Standard Deviation 0.713 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-dinner: Change at Day 7 | -0.64 ng/mL | Standard Deviation 0.462 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-dinner: Change at Day 7 | -0.52 ng/mL | Standard Deviation 1.079 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-breakfast: Baseline | 1.90 ng/mL | Standard Deviation 0.663 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-lunch: Change at Day 7 | 0.97 ng/mL | Standard Deviation 0.676 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-dinner: Baseline | 2.93 ng/mL | Standard Deviation 0.936 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-breakfast: Change at Day 7 | -0.38 ng/mL | Standard Deviation 0.325 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-lunch: Baseline | 2.18 ng/mL | Standard Deviation 0.666 |
| Placebo | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-breakfast: Change at Day 7 | -0.14 ng/mL | Standard Deviation 0.358 |
| Placebo | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-lunch: Baseline | 2.28 ng/mL | Standard Deviation 0.845 |
| Placebo | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-dinner: Change at Day 7 | -0.16 ng/mL | Standard Deviation 0.608 |
| Placebo | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-lunch: Change at Day 7 | 0.84 ng/mL | Standard Deviation 0.904 |
| Placebo | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-breakfast: Baseline | 1.73 ng/mL | Standard Deviation 0.475 |
| Placebo | Change From Baseline in Pre-Meal C-Peptide at Day 7 | Pre-dinner: Baseline | 2.77 ng/mL | Standard Deviation 0.951 |
Comparison: Analysis for pre-breakfast. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.006790% CI: [-0.33, -0.09]Mixed Models Analysis
Comparison: Analysis for pre-breakfast. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.028290% CI: [-0.29, -0.05]Mixed Models Analysis
Comparison: Analysis for pre-lunch. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.787790% CI: [-0.18, 0.25]Mixed Models Analysis
Comparison: Analysis for pre-lunch. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.506490% CI: [-0.17, 0.39]Mixed Models Analysis
Comparison: Analysis for pre-dinner. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.407290% CI: [-0.75, 0.25]Mixed Models Analysis
Comparison: Analysis for pre-dinner. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.142290% CI: [-0.95, 0.06]Mixed Models Analysis
Secondary
Change From Baseline in Pre-Meal Insulin at Day 7
Time-matched change from baseline in pre-meal serum insulin on Day 7 of each period was analyzed. Pre-meal insulin levels therefore, pre-breakfast, pre-lunch, and pre-dinner were analyzed.
Time frame: Pre-morning meal (pre-breakfast), 5 hours (pre-lunch), 11 hours (pre-dinner) after morning meal on Day 0 (Baseline); pre-morning dose (pre-breakfast), 5 hours (pre-lunch), 11 hours (pre-dinner) post-morning dose on Day 7
Population: PD analysis population included all randomized participants who received at least 1 dose of study medication and had both a baseline and a post-baseline assessment for at least 1 PD parameter in at least 1 period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF--04937319 100 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-breakfast: Baseline | 8.577 micro international unit per milliliter | Standard Deviation 4.8132 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-breakfast: Change at Day 7 | -0.828 micro international unit per milliliter | Standard Deviation 1.297 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-lunch: Baseline | 10.548 micro international unit per milliliter | Standard Deviation 4.5632 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-lunch: Change at Day 7 | 4.258 micro international unit per milliliter | Standard Deviation 7.112 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-dinner: Baseline | 13.113 micro international unit per milliliter | Standard Deviation 6.1401 |
| PF--04937319 100 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-dinner: Change at Day 7 | -1.625 micro international unit per milliliter | Standard Deviation 3.0286 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-dinner: Change at Day 7 | -2.521 micro international unit per milliliter | Standard Deviation 2.8025 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-breakfast: Baseline | 9.038 micro international unit per milliliter | Standard Deviation 5.4983 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-lunch: Change at Day 7 | 2.640 micro international unit per milliliter | Standard Deviation 2.8358 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-dinner: Baseline | 13.031 micro international unit per milliliter | Standard Deviation 7.038 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-breakfast: Change at Day 7 | -1.439 micro international unit per milliliter | Standard Deviation 1.549 |
| PF--04937319 250 mg | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-lunch: Baseline | 9.093 micro international unit per milliliter | Standard Deviation 4.606 |
| Placebo | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-breakfast: Change at Day 7 | 0.594 micro international unit per milliliter | Standard Deviation 1.8753 |
| Placebo | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-lunch: Baseline | 9.781 micro international unit per milliliter | Standard Deviation 5.5415 |
| Placebo | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-dinner: Change at Day 7 | 0.449 micro international unit per milliliter | Standard Deviation 4.9616 |
| Placebo | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-lunch: Change at Day 7 | 5.416 micro international unit per milliliter | Standard Deviation 5.6758 |
| Placebo | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-breakfast: Baseline | 8.378 micro international unit per milliliter | Standard Deviation 5.1908 |
| Placebo | Change From Baseline in Pre-Meal Insulin at Day 7 | Pre-dinner: Baseline | 13.344 micro international unit per milliliter | Standard Deviation 9.6188 |
Comparison: Analysis for pre-breakfast. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.044790% CI: [-2.752, -0.29]Mixed Models Analysis
Comparison: Analysis for pre-breakfast. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.011990% CI: [-3.183, -0.716]Mixed Models Analysis
Comparison: Analysis for pre-lunch. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.687390% CI: [-5.195, 3.261]Mixed Models Analysis
Comparison: Analysis for pre-lunch. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.065990% CI: [-4.502, -0.377]Mixed Models Analysis
Comparison: Analysis for pre-dinner. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.403190% CI: [-4.079, 1.363]Mixed Models Analysis
Comparison: Analysis for pre-dinner. Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.025490% CI: [-6.479, -1.052]Mixed Models Analysis
Secondary
Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 7
WMDG was defined as time-weighted mean daily glucose. WMDG was calculated by as the time-weighted mean of glucose levels at actual time points for glucose sampling, for Day 0 (Baseline) and Day 7.
Time frame: Pre-morning meal, 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 16 and 20 hours post- morning meal on Day 0; pre-morning dose, 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 16, 20 hours post-morning dose on Day 7
Population: The pharmacodynamic (PD) analysis population included all randomized participants who received at least 1 dose of study medication and had both a baseline and a post-baseline assessment for at least 1 PD parameter in at least 1 period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF--04937319 100 mg | Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 7 | Baseline | 201.31 mg/dL | Standard Deviation 49.204 |
| PF--04937319 100 mg | Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 7 | Change at Day 7 | -23.58 mg/dL | Standard Deviation 14.833 |
| PF--04937319 250 mg | Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 7 | Baseline | 184.38 mg/dL | Standard Deviation 51.844 |
| PF--04937319 250 mg | Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 7 | Change at Day 7 | -28.61 mg/dL | Standard Deviation 17.983 |
| Placebo | Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 7 | Baseline | 190.42 mg/dL | Standard Deviation 41.284 |
| Placebo | Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 7 | Change at Day 7 | 4.88 mg/dL | Standard Deviation 18.182 |
Comparison: Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: 0.003290% CI: [-28.93, -10.98]Mixed Models Analysis
Comparison: Analysis was done using a mixed effect model with sequence, period, dose, and baseline as fixed effects and participants within sequence as a random effect.p-value: <0.000190% CI: [-46.77, -35.35]Mixed Models Analysis
Secondary
Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-06455349
PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-06455349 | 310.5 ng/mL | Geometric Coefficient of Variation 21 |
| PF--04937319 250 mg | Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-06455349 | 583.7 ng/mL | Geometric Coefficient of Variation 22 |
Secondary
Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF--06455349
PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF--06455349 | 464.0 ng/mL | Geometric Coefficient of Variation 9 |
| PF--04937319 250 mg | Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF--06455349 | 978.6 ng/mL | Geometric Coefficient of Variation 17 |
Secondary
Metabolite to Parent Ratio for AUC24 (MRAUC24) on Day 1
MRAUC24 is the ratio of AUC24 of PF-06455349 (metabolite) to AUC24 of PF-04937319 (parent drug) \* ratio of molecular weight of PF-04937319 to molecular weight of PF-06455349, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Metabolite to Parent Ratio for AUC24 (MRAUC24) on Day 1 | 1.664 ratio | Geometric Coefficient of Variation 24 |
| PF--04937319 250 mg | Metabolite to Parent Ratio for AUC24 (MRAUC24) on Day 1 | 1.649 ratio | Geometric Coefficient of Variation 23 |
Secondary
Metabolite to Parent Ratio for AUC24 (MRAUC24) on Day 7
MRAUC24 is the ratio of AUC24 of PF-06455349 (metabolite) to AUC24 of PF-04937319 (parent drug) \* ratio of molecular weight of PF-04937319 to molecular weight of PF-06455349, where AUC24 is the area under the plasma concentration-time profile from time 0 to 24 hours. PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Metabolite to Parent Ratio for AUC24 (MRAUC24) on Day 7 | 2.516 ratio | Geometric Coefficient of Variation 22 |
| PF--04937319 250 mg | Metabolite to Parent Ratio for AUC24 (MRAUC24) on Day 7 | 2.523 ratio | Geometric Coefficient of Variation 27 |
Secondary
Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF--06455349
Ctrough is the concentration prior to study drug administration. PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose) on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF--06455349 | 321.8 ng/mL | Geometric Coefficient of Variation 15 |
| PF--04937319 250 mg | Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF--06455349 | 649.9 ng/mL | Geometric Coefficient of Variation 15 |
Secondary
Terminal Half-Life (t1/2) on Day 7 for PF-06455349
Terminal half-life is the time measured for the plasma concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) \* 2/k el, where 'k el' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline were used in the regression. PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Terminal Half-Life (t1/2) on Day 7 for PF-06455349 | 15.80 hour | Standard Deviation 1.9026 |
| PF--04937319 250 mg | Terminal Half-Life (t1/2) on Day 7 for PF-06455349 | NA hour | — |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-06455349
PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-06455349 | 11.0 hour | Full Range 13 |
| PF--04937319 250 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-06455349 | 11.0 hour | Full Range 20 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-06455349
PF-06455349 is a metabolite of PF-04937319.
Time frame: 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24, 36, 48 hours post morning dose on Day 7
Population: PK parameter analysis population included all randomized participants who received at least 1 dose of PF-04937319 and who had at least 1 of PK parameters of interest calculated and available in at least 1 period.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| PF--04937319 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-06455349 | 11.0 hour | Full Range 13 |
| PF--04937319 250 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-06455349 | 11.0 hour | Full Range 20 |