A Phase 1 Study In Japanese Subjects With Type 2 Diabetes Mellitus As Monotherapy

Study Overview
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Brief Summary
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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

Official Title
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A Phase 1, Randomized, Double-blind, Placebo-controlled, 3- Period, Crossover Study To Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Two Dose Levels of Pf-04937319 In Japanese Subjects With Type 2 Diabetes Mellitus as Monotherapy

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: PF-04937319 high dose
* Drug: PF-04937319 low dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04937319<br>PF-04937319 Split dose | Drug: PF-04937319 high dose<br>* tablets, 150 mg with breakfast plus 100 mg with lunch, 7 days<br>Drug: PF-04937319 low dose<br>* tablets, 50 mg with breakfast plus 50 mg with lunch, 7 days<br>|
| Placebo Comparator: Placebo<br>Placebo split dose | Drug: Placebo<br>* tablets, breakfast plus lunch, 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, type 2 diabetes, monotherapy, PF-04937319