Study Of Two Dosing Regimens Of PF-04937319 Compared To An Approved Agent (Sitagliptin) In Patients With Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
Study B1621019 will assess efficacy and safety of two different dosing regimens of an investigational agent (PF-04937319) compared to an approved drug (sitagliptin) in patients with type 2 diabetes

Official Title
-----------------
A Phase 1b, Randomized, Double-blind, Active Comparator Controlled, 3-period, Cross-over Study To Characterize The Pharmacodynamics And Tolerability Of Two Dosing Regimens Of Pf-04937319 In Adults With Type 2 Diabetes Mellitus Inadequately Controlled On Metformin

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: PF-04937319 once-daily
* Drug: PF-04937319 split-dose
* Drug: Sitagliptin once-daily


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with type 2 diabetes, on background metformin therapy either alone or with 1 other oral anti-diabetic agent (excluding Actos) Exclusion Criteria: Patients with cardiovascular event within 6-months of screening 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
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04937319 once-daily<br> | Drug: PF-04937319 once-daily<br>* Tablets, 300 mg once-daily with breakfast, 14-days<br>|
| Experimental: PF-04937319 split-dose<br> | Drug: PF-04937319 split-dose<br>* tablets, 150 mg with breakfast plus 100 mg with lunch, 14-days<br>|
| Active Comparator: Sitagliptin once-daily<br> | Drug: Sitagliptin once-daily<br>* tablets, 100 mg once-daily with breakfast, 14-days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weighted Mean Daily Glucose (WMDG) at Day 14 | Plasma glucose concentration was determined predose (Hour 0) and at 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 16, 20, and 24 hours postdose on Days 0 (baseline) and 14. WMDG was calculated as the area under the curve (AUC) of the 12-point plasma glucose concentration-time profile divided by 24 hours. | Prior to morning dose (Hour 0) and at 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 16, 20, and 24 hours post morning dose on Days 0 (baseline) and Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Day 14 | Blood samples for measurement of glucose to permit derivation of pre-meal collections at the pre-specified nominal timepoints of each period: predose (ie, time 0), 1.5, 3, 5, 6.5, 8, 11, 12.5, 14, 16 and 20 hours on Day 0 (baseline) and Day 14; and predose on Days 1 and 15. | Day 14 | 
| Change From Baseline in Pre-meal C-Peptide on Day 14 | Blood samples for measurement of glucose to permit derivation of pre-meal collections of blood samples for C-peptide at the pre-specified nominal timepoints at predose, 5 and 11 hours on Day 0 (baseline) and Day 14. | Day 14 | 
| Change From Baseline in Pre-meal Insulin on Day 14 | Blood samples for measurement of glucose to permit derivation of pre-meal collections of blood samples for insulin at 0, 5 and 11 hours on Day 0 (baseline) and Day 14. | Day 14 | 
| Incidence of All Causality Treatment-Emergent Adverse Event by Preferred Term (Frequency Rate >5%) |  | Day 1 up to Day 14 | 
| Frequency of Laboratory Test Abnormalities Reported in Any Treatment Group | The total number of participants with laboratory test abnormalities (without regard to baseline abnormality) was assessed. | Day 1 up to Day 14 | 
| Change From Baseline in Body Weight (kg) |  | Day 1 up to Day 14 | 
| Number of Participants With Vital Signs Data Met Criteria of Potential Clinical Concern | Vital signs included blood pressure (BP; supine, sitting and standing) and pulse rate. Vital signs criteria of potential clinical concern were 1), BP: sitting systolic BP (SBP) greater than or equal to (>=) 30 millimeters of mercury (mm Hg) change from baseline, sitting SBP =<20 mmHg change from baseline, supine/sitting/standing SBP less than (<) 90 mm Hg; sitting diastolic BP (DBP) >=20 mm Hg change from baseline, sitting SBP =<20 mmHg change from baseline, supine/sitting/standing DBP <50 mm Hg; 2), pulse rate (supine): <40 or greater than (>) 120 beats per minute (bpm). | Day 1 up to Day 14 | 
| Number of Participants With Post-baseline Electrocardiograms (ECGs) Data Met Criteria of Potential Clinical Concern | ECG criteria of potential clinical concern were 1), PR interval: >=300 milliseconds (msec); >=25% increase when baseline >200 msec; or increase >=50% when baseline <=200 msec; 2), QRS interval: >=140 msec; >=50% increase from baseline; 3), QTc interval using Fridericia's formula (QTcF interval): absolute value >=450 - <480 msec, >=480-<500 msec, >500 msec; absolute change 30 - <60, >=60 msec. | Day 1 up to Day 14 | 
| Plasma PF-04937319 Area Under the Concentration Time Curve From Time 0 to 24 Hours (AUC24) of PF-04937319 at Day 14 | The PK parameters were summarized descriptively by treatment as appropriate. Two (2) PK parameters specified in the protocol and SAP were not reported: AUClast was not reported since it was the same as AUC24 in this study, and apparent volume of distribution (Vz/F) was not reported since the log-linear terminal phase of the concentration-time profiles was not consistently well characterized in the 24-hour sampling period. | Predose, 1.5, 3, 5, 6.5, 8, 11, 12.5, and 14 hours on Days 0 and 14; and predose on Days 7 and 15. | 
| Plasma PF-04937319 Apparent Clearance (CL/F) on Day 14 | The PK parameters were summarized descriptively by treatment as appropriate. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Predose, 1.5, 3, 5, 6.5, 8, 11, 12.5, and 14 hours on Days 0 and 14; and predose on Days 7 and 15. | 
| Plasma PF-04937319 Average Concentration Over the 24-hour Period (Cav) on Day 14 | Cav was average concentration over the 24-hour period. The PK parameters were summarized descriptively by treatment as appropriate. | Predose, 1.5, 3, 5, 6.5, 8, 11, 12.5, and 14 hours on Days 0 and 14; and predose on Days 7 and 15. | 
| Plasma PF-04937319 Highest Observed Concentration (Cmax) on Day 14 | Cmax was highest observed concentration. The PK parameters were summarized descriptively by treatment as appropriate. | Predose, 1.5, 3, 5, 6.5, 8, 11, 12.5, and 14 hours on Days 0 and 14; and predose on Days 7 and 15. | 
| Plasma PF-04937319 Lowest Observed Concentration During the 24-hour Period (Cmin) on Day 14 | Cmin lowest observed concentration during the 24-hour period. The PK parameters were summarized descriptively by treatment as appropriate. | Predose, 1.5, 3, 5, 6.5, 8, 11, 12.5, and 14 hours on Days 0 and 14; and predose on Days 7 and 15. | 
| Plasma PF-04937319 Time for Cmax (Tmax) on Day 14 | Tmax was time of maximum concentration. The PK parameters were summarized descriptively by treatment as appropriate. | Predose, 1.5, 3, 5, 6.5, 8, 11, 12.5, and 14 hours on Days 0 and 14; and predose on Days 7 and 15. | 

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