Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Study Of PF-06291874 As Oral Monotherapy To Treat Adults With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This study is going to assess the safety and tolerability of PF-06291874 in adults with Type 2 Diabetes Mellitus as monotherapy, to evaluate the significance of overall glycemic control in these subjects.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial To Assess The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Oral Doses Of Pf-06291874 Given As Monotherapy To Adults With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type II

Intervention / Treatment
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* Drug: Placebo
* Drug: PF-06291874
* Drug: PF-06291874
* Drug: PF-06291874
* Drug: PF-06291874


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects and non-childbearing potential female subjects between the ages of 18 and 70 years old. Body Mass Index of 18.0 to 45.4 kg/m2; and a total body weight of >50 kg HbA1c value at the screening visit meeting once of the following criteria: Currently taking acceptable oral antiglycemic drug therapy within 6.5 to 9.5% Not currently taking any oral antiglycemic drug therapy within 7 to 10.5% Fasting plasma glucose concentrations<270mg/dL at the screening and run-in visit, confirmed by a single repeat, if deemed necessary. Subjects must be willing and able to perform self-tests of blood glucose at least 4 times per day, and maintain a diary for the duration of participation in the study; and therefore, subjects must be literate. Exclusion Criteria: History of Type 1 diabetes mellitus or secondary forms of diabetes One or more self-reported hypoglycemic episodes of sever intensity within 3 months of screening; or 2 or more self-reported hypoglycemic episodes of severe intensity within the previous 6 months. History of myocardial infarction, unstable angina, arterial revascularization, stroke, New York Heart Association Functional Class II-IV heart failure, or transient ischemic attach within 6 months of screening. History or evidence of diabetic complications with significant end organ damage, such as Proliferative retinopathy and/or macular edema; Diabetic neuropathy complicated by neuropathic ulcers; Screening seated systolic blood pressure >160 mm Hg and/or diastolic blood pressure >100 mm Hg after at least a 5 minute seated rest. If the blood pressure exceeds this limit, the blood pressure may be repeated 2 more times following approximately 2 minutes of rest between measurements and the median of the 3 values should be used to determine subject eligibility; Male subjects with partners currently pregnant; or male subjects capable of conceiving children who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Treatment A- Placebo<br> | Drug: Placebo<br>* Tablet, once daily for 28 days<br>|
| Experimental: Treatment B- PF-06291874<br> | Drug: PF-06291874<br>* Tablet, 15 mg, once daily for 28 days<br>|
| Experimental: Treatment C- PF-06291874<br> | Drug: PF-06291874<br>* Tablet, 35 mg, once daily for 28 days<br>|
| Experimental: Treatment D- PF-06291874<br> | Drug: PF-06291874<br>* Tablet, 75 mg, once daily for 28 days<br>|
| Experimental: Treatment E- PF-06291874<br> | Drug: PF-06291874<br>* Tablet, 150 mg, once daily for 28 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 (TEAEs), or Serious Adverse Events (SAEs), or Hypoglycemic Adverse Events (HAE) or Withdrawals Due to Adverse Events (AEs) | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. An HAE was identified by characteristic symptoms or blood glucose levels. TEAEs are events between first dose of study drug and up to 10-14 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. | Baseline up to 10-14 days after last dose of study drug, up to 42 days | 
| Number of Participants With Laboratory Test Abnormalities | The total number of participants with laboratory test abnormalities (without regard to baseline abnormality) was assessed. Clinical laboratory tests included hematology, chemistry, urinalysis, and some other tests. | Baseline up to 10-14 days after last dose of study drug, up to 42 days | 
| Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Criteria of Potential Clinical Concern | Vital Signs included seated supine systolic and diastolic blood pressure (BP) and pulse rate. Vital signs criteria of potential clinical concern were 1), BP: systolic (SBP) greater than or equal to (>=) 30 millimeters of mercury (mm Hg) change from baseline, systolic less than (<) 90 mm Hg; diastolic BP (DBP) >=20 mm Hg change from baseline, diastolic <50 mm Hg; 2), pulse rate <40 or greater than (>) 120 beats per minute (bpm). | Baseline up to 10-14 days after last dose of study drug, up to 42 days | 
| Number of Participants With Electrocardiogram (ECG) Data Meeting Criteria of Potential Clinical Concern | ECG criteria of potential clinical concern were 1), time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval): >=140 msec; >=50% increase from baseline; 2), the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization (PR interval): >=300 milliseconds (msec); >=25 percent (%) increase when baseline >200 msec; or increase >=50% when baseline less than or equal to (<=)200 msec; 3), time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula (QTcF interval): absolute value >=450 - <480 msec, >=480-<500 msec, >=500 msec; increase from baseline >=30 - <60, >=60 msec. | Baseline up to 10-14 days after last dose of study drug, up to 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Daily Glucose | The mean daily glucose was determined from the area under the concentration (AUC) of the glucose concentrations measured at nominal times 0, 0.5, 1, 1.5, 2, 4, 6, 10, 12, 15 and 24 hours post dose. Mean daily glucose change from baseline (defined as Day 0) on Day 28. | Baseline and Day 28 | 
| Change From Baseline in Fasting Plasma Glucose | Fasting plasma glucose response change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 14, and the mean of Days 28 and 29. | Baseline, Day 14 and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Triglycerides | Triglycerides percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 14, and the mean of Days 28 and 29. | Baseline, Day 14 and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Total Cholesterol | Total cholesterol percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 14, and the mean of Days 28 and 29. | Baseline, Day 14 and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Low Density Lipoprotein-Cholesterol (LDL-C) | LDL-C percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 14, and the mean of Days 28 and 29. | Baseline, Day 14 and the mean of Days 28 and 29 | 
| Percent Change From Baseline in High Density Lipoprotein-Cholesterol (HDL-C) | HDL-C percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 14, and the mean of Days 28 and 29. | Baseline, Day 14 and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Non-HDL-C | Non-HDL-C percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 14, and the mean of Days 28 and 29. | Baseline, Day 14 and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Oxidized LDL | Oxidized LDL percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 28 (the mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Large LDL Particles | Large LDL particles percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 28 (the mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Medium Small LDL Particles | Medium small LDL particles percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 28 (the mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Small LDL Particles | Small LDL particles percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 28 (the mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Very Small LDL Particles | Very small LDL particles percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 28 (the mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Total LDL Particles | Total LDL particles percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 28 (the mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Percent Change From Baseline in LDL Size | The LDL size percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 28 (the mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Apolipoprotein B100 | The Apolipoprotein B100 was calculated as the difference between total Apolipoprotein B and Apolipoprotein B48 and analyzed the percent change from baseline (defined as mean of Day 0 and Day 1) on Day 28 (mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Percent Change From Baseline in Lipoprotein A | The Lipoprotein A percent change from baseline (defined as the mean of Day 0 and Day 1 pre-dose) on Day 28 (mean of Days 28 and 29). | Baseline and the mean of Days 28 and 29 | 
| Maximum Plasma Concentration (Cmax) | Maximum PF-06291874 plasma concentration. | Day 28 (samples taken at 0, 2, 4, 8 and 24 hours after Day 28 dose) | 
| Time to Reach Cmax (Tmax) | Time to maximum PF-06291874 plasma concentration. | Day 28 (samples taken at 0, 2, 4, 8 and 24 hours after Day 28 dose) | 
| Area Under the Concentration-Time Profile From Zero to Time Tau (AUCtau) (Where Tau=24 Hours) | Area under the PF-06291874 plasma concentration-time profile from time zero to time tau, the dosing interval, where tau=24 hours. | Day 28 (samples taken at 0, 2, 4, 8 and 24 hours after Day 28 dose) | 
| Minimum Plasma Concentration (Cmin) | Minimum PF-06291874 plasma concentration. | Day 28 (samples taken at 0, 2, 4, 8 and 24 hours after Day 28 dose) | 
| Apparent Clearance (CL/F) | Apparent oral clearance of PF-06291874. | Day 28 (samples taken at 0, 2, 4, 8 and 24 hours after Day 28 dose) |