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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PF-04937319 | Experimental | PF-04937319 Split dose |
|
| Placebo | Placebo Comparator | Placebo split dose |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PF-04937319 high dose | Drug | tablets, 150 mg with breakfast plus 100 mg with lunch, 7 days |
| |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline up to 14 days after the last dose of study drug (minimum 8 weeks to maximum of 17 weeks) |
| 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. | Baseline up to 14 days after the last dose of study drug (minimum 8 weeks to maximum of 17 weeks) |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-06455349 | PF-06455349 is a metabolite of 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-06455349 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pfizer CT.gov Call Center | Pfizer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| P-one Clinic, Keikokai Medical Corporation | Hachioji-shi | Tokyo | 192-0071 | Japan |
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| Label | URL |
|---|---|
| To obtain contact information for a study center near you, click here. | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention Period (7 Days) |
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| First Washout Period (7 to 14 Days) |
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| Second Intervention Period (7 Days) |
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| Second Washout Period (7 to 14 Days) |
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| Third Intervention Period (7 Days) |
|
Safety analysis set included all participants who received at least 1 dose of study medication (including placebo) in at least 1 period.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Safety analysis set included all participants who received at least 1 dose of study medication (including placebo) in at least 1 period. | Posted | Number | participants | Baseline up to 14 days after the last dose of study drug (minimum 8 weeks to maximum of 17 weeks) |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | PF--04937319 100 mg | All participants who 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 either first or second intervention period. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA 17.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pfizer ClinicalTrials.gov Call Center | Pfizer, Inc. | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C000598526 | N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide |
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| PF-04937319 low dose |
| Drug |
tablets, 50 mg with breakfast plus 50 mg with lunch, 7 days |
|
| Placebo | Drug | tablets, breakfast plus lunch, 7 days |
|
| 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). | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post-dose on Day 1 |
| 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 | AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
| Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF-04937319 | Ctrough is the concentration prior to study drug administration. | 0 hour (pre-dose) on Day 7 |
| Average Plasma Concentration (Cav) on Day 7 for PF-04937319 | Cav is the average plasma concentration during the 0 to 24 hour time period. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
| 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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
| 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. | 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 |
| 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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
| 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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
PF-06455349 is a metabolite of 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--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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 |
| 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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 |
| Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF--06455349 | PF-06455349 is a metabolite of 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-06455349 | PF-06455349 is a metabolite of 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--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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
| 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. | 0 hour (pre-dose) on Day 7 |
| 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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
| 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. | 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 |
| 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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
| 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. | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
| 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. | 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 |
| 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. | Pre-morning meal on Day 0, pre-morning dose on Day 1, pre-morning dose on Day 7, pre-morning meal on Day 8 |
| 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. | 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 |
| 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. | 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 |
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| BG001 | 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. |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
All participants who 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 either first or second intervention period. |
| OG001 | PF--04937319 250 mg | All participants who received 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 at approximately 5 hours of interval) for 7 days in either second or third intervention period. |
| OG002 | Placebo | All participants who received placebo matched to PF-04937319 administered orally with morning meal and with afternoon meal for 7 days in either first, second or third intervention period. |
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| 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. | Safety analysis set included all participants who received at least 1 dose of study medication (including placebo) in at least 1 period. | Posted | Number | participants | Baseline up to 14 days after the last dose of study drug (minimum 8 weeks to maximum of 17 weeks) |
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| Primary | Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-04937319 | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram per milliliter (ng/mL) | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 |
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| Primary | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-04937319 | 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. | Posted | Median | Full Range | hour | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 |
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| 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram*hour per milliliter (ng*hr/mL) | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post-dose on Day 1 |
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| Primary | Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF-04937319 | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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 |
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| Primary | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-04937319 | 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. | Posted | Median | Full Range | hour | 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 |
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| 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). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| Primary | Pre-dose Plasma Concentration (Ctrough) on Day 7 for PF-04937319 | Ctrough is the concentration prior to study drug administration. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 0 hour (pre-dose) on Day 7 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | milliliter per minute (mL/min) | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| 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. | 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. | Posted | Mean | Standard Deviation | hour | 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 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | liter | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) on Day 1 for PF-06455349 | PF-06455349 is a metabolite of PF-04937319. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 |
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| Secondary | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 for PF-06455349 | PF-06455349 is a metabolite of PF-04937319. | 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. | Posted | Median | Full Range | hour | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 1 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) on Day 7 for PF--06455349 | PF-06455349 is a metabolite of PF-04937319. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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 |
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| Secondary | Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 7 for PF-06455349 | PF-06455349 is a metabolite of PF-04937319. | 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. | Posted | Median | Full Range | hour | 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 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 0 hour (pre-dose) on Day 7 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| 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. | 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. | Posted | Mean | Standard Deviation | hour | 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 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | 0 hour (pre-dose), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 24 hours post morning dose on Day 7 |
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| 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. | 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. | Posted | Mean | Standard Deviation | mg/dL | 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 |
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| 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. | 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. | Posted | Mean | Standard Deviation | mg/dL | Pre-morning meal on Day 0, pre-morning dose on Day 1, pre-morning dose on Day 7, pre-morning meal on Day 8 |
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| 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. | 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. | Posted | Mean | Standard Deviation | micro international unit per milliliter | 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 |
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| 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. | 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. | Posted | Mean | Standard Deviation | ng/mL | 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 |
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| 0 |
| 12 |
| 1 |
| 12 |
| EG001 | PF--04937319 250 mg | All participants who received 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 at approximately 5 hours of interval) for 7 days in either second or third intervention period. | 0 | 12 | 6 | 12 |
| EG002 | Placebo | All participants who received placebo matched to PF-04937319 administered orally with morning meal and with afternoon meal for 7 days in either first, second or third intervention period. | 0 | 12 | 1 | 12 |
| Blood uric acid increased | Investigations | MedDRA 17.1 | Non-systematic Assessment |
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| Haemoglobin decreased | Investigations | MedDRA 17.1 | Non-systematic Assessment |
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| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA 17.1 | Non-systematic Assessment |
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Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
| D004700 | Endocrine System Diseases |
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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. |
| Mixed Models Analysis |
| <0.0001 |
| LS Mean Difference |
| -41.06 |
| Standard Error of the Mean |
| 3.172 |
| 2-Sided |
| 90 |
| -46.77 |
| -35.35 |
| No |
| Superiority or Other |
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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. |
| Mixed Models Analysis |
| <0.0001 |
| LS Mean Difference |
| -25.81 |
| Standard Error of the Mean |
| 2.821 |
| 2-Sided |
| 90 |
| -30.73 |
| -20.88 |
| No |
| Superiority or Other |
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| Pre-lunch: Baseline |
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| Pre-lunch: Change at Day 7 |
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| Pre-dinner: Baseline |
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| Pre-dinner: Change at Day 7 |
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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. |
| Mixed Models Analysis |
| 0.0119 |
| LS Mean Difference |
| -1.949 |
| Standard Error of the Mean |
| 0.7249 |
| 2-Sided |
| 90 |
| -3.183 |
| -0.716 |
| No |
| Superiority or Other |
| 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. | Mixed Models Analysis | 0.6873 | LS Mean Difference | -0.967 | Standard Error of the Mean | 2.3324 | 2-Sided | 90 | -5.195 | 3.261 | No | Superiority or Other |
| 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. | Mixed Models Analysis | 0.0659 | LS Mean Difference | -2.439 | Standard Error of the Mean | 0.9533 | 2-Sided | 90 | -4.502 | -0.377 | No | Superiority or Other |
| 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. | Mixed Models Analysis | 0.4031 | LS Mean Difference | -1.358 | Standard Error of the Mean | 1.5994 | 2-Sided | 90 | -4.079 | 1.363 | No | Superiority or Other |
| 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. | Mixed Models Analysis | 0.0254 | LS Mean Difference | -3.766 | Standard Error of the Mean | 1.5951 | 2-Sided | 90 | -6.479 | -1.052 | No | Superiority or Other |
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| Pre-lunch: Baseline |
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| Pre-lunch: Change at Day 7 |
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| Pre-dinner: Baseline |
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| Pre-dinner: Change at Day 7 |
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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. |
| Mixed Models Analysis |
| 0.0282 |
| LS Mean Difference |
| -0.17 |
| Standard Error of the Mean |
| 0.071 |
| 2-Sided |
| 90 |
| -0.29 |
| -0.05 |
| No |
| Superiority or Other |
| 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. | Mixed Models Analysis | 0.7877 | LS Mean Difference | 0.03 | Standard Error of the Mean | 0.118 | 2-Sided | 90 | -0.18 | 0.25 | No | Superiority or Other |
| 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. | Mixed Models Analysis | 0.5064 | LS Mean Difference | 0.11 | Standard Error of the Mean | 0.156 | 2-Sided | 90 | -0.17 | 0.39 | No | Superiority or Other |
| 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. | Mixed Models Analysis | 0.4072 | LS Mean Difference | -0.25 | Standard Error of the Mean | 0.293 | 2-Sided | 90 | -0.75 | 0.25 | No | Superiority or Other |
| 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. | Mixed Models Analysis | 0.1422 | LS Mean Difference | -0.45 | Standard Error of the Mean | 0.295 | 2-Sided | 90 | -0.95 | 0.06 | No | Superiority or Other |