A 12-week Study To Evaluate PF-06291874 Once a Day in Adults With T2DM Inadequately Controlled On Metformin

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether PF-06291874 is effective in the treatment T2DM

Detailed Description
-----------------
This will be a randomized, double blind, stratified, placebo controlled, parallel group study conducted in T2DM subjects receiving background metformin therapy. Subjects will complete screening procedures to determine eligibility, followed by an 8 week metformin stabilization period prior to randomization. In addition, subjects taking other OADs, in combination with metformin, will undergo a washout during this period, in which non metformin OAD medications will be temporarily discontinued for the duration of the trial. Following confirmation of study eligibility criteria at randomization, subjects will be stratified into 2 groups based on the use of concomitant statin therapy. Each stratum will be randomized across treatment groups, such that the number of subjects taking concomitant statin therapy and those not taking statin therapy will be approximately balanced across treatment groups.

Official Title
-----------------
A 12-week, Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel Group Study To Evaluate The Efficacy And Safety Of Once Daily Pf-06291874 Administration In Adults With Type 2 Diabetes Mellitus Inadequately Controlled On Metformin

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or non-childbearing potential females between the ages of 18 (or the minimum country specific age of consent if >18) and 70 years, inclusive, at the screening visit (V1) with the diagnosis of T2DM;Female subjects who are not of childbearing potential Subjects who have been on a stable dose of metformin either alone or in combination with one additional acceptable OAD HbA1c at the Screen Visit (V1), as assessed by study specific central laboratory, is 7-11% if on metformin monotherapy; is 6.5-9.5% if on dual combination therapy (metformin plus 1) Exclusion Criteria: Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes; Fasting plasma glucose levels >270 mg/dL (15.0 mmol/L) at the screening and run in visit, (as assessed by study specific central laboratory) confirmed by a single repeat, if deemed necessary History of myocardial infarction, unstable angina, arterial revascularization, stroke, New York Heart Association Functional Class III IV heart failure, or transient ischemic attack within 6 months of screening; Any medical condition possibly affecting study drug absorption (eg, gastrectomy or any area of intestinal resection, active inflammatory bowel disease or pancreatic insufficiency Subjects with a creatinine clearance <60 mL/min as determined by the Cockcroft Gault equation (listed below) using serum creatinine measured at screening, confirmed via a single repeat, if deemed necessary Subject with a positive result for hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (HBc Ab) or hepatitis C virus (HCV) antibodies Screening seated systolic blood pressure >160 mm Hg and/or diastolic blood pressure >105 mm Hg after at least a 5 minute rest. Blood pressure determined as the mean of triplicate measurements collected with approximately 2 minutes of rest between measurements Screening supine 12 lead ECG demonstrating a corrected QT (QTc) >470 msec; or a QRS interval >120 msec. If QTc exceeds 470 msec or QRS exceeds 120 msec, the ECG may be repeated 2 more times with an interval of 2-4 minutes between each measurement and the mean of the 3 values used to determine the subject's eligibility Subjects with an arm circumference >52 cm measured at the midpoint of the length of the upper arm; History (within the last 6 months) of regular alcohol consumption exceeding 14 drinks per week for men and 7 drinks a week for women. (1 drink = 5 ounces of wine (150 mL) or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor); Treatment with thiazolidinediones (TZDs), or subcutaneously administered anti diabetic agents (eg, insulin, exenatide, liraglutide, pramlintide) within 6 weeks prior to V1; Subjects with a known hypersensitivity or intolerance to a glucagon receptor antagonist, or known prior participation in a trial involving PF 06291874;

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* oral tablet<br>|
| Experimental: PF-06291874, 30 mg<br> | Drug: PF-06291874<br>* study drug to be given as an oral tablet at 30, 60 or 100 mg<br>|
| Experimental: PF-06291874, 60 mg<br> | Drug: PF-06291874<br>* study drug to be given as an oral tablet at 30, 60 or 100 mg<br>|
| Experimental: PF-06291874, 100 mg<br> | Drug: PF-06291874<br>* study drug to be given as an oral tablet at 30, 60 or 100 mg<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) (%) at Week 12 as Compared to Placebo | HbA1c was a form of hemoglobin which was measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Baseline was defined as the last pre-dose measurement prior to first double blind dosing for the study. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c (%) at Weeks 2, 4, and 8 | HbA1c was a form of hemoglobin which was measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Baseline was defined as the last pre-dose measurement prior to first double blind dosing for the study. n represented the available number of participants for analysis at post-baseline days. | Baseline, Weeks 2, 4, 8 | 
| Change From Baseline in Fasting Plasma Glucose at Weeks 2, 4, 8, and 12 | Fasting plasma glucose response changed from baseline at Weeks 2,4,8 and 12. Baseline was defined as the average of the measurements obtained during Day 14 visit window and Day 1 pre-dose measurement. n represented the available number of participants for analysis at post-baseline days. | Baseline, Weeks 2,4,8 and 12 | 
| Percentage of Participants Achieving Glycosylated Hemoglobin (HbA1c) <7% as Well as <6.5% at Week 12. | HbA1c was a form of hemoglobin which was measured primarily to identify the average plasma glucose concentration over prolonged periods of time. | Week 12 | 
| 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 98 days | 
| Number of Participants With Change From Baseline and Absolute Values in 12-lead Electrocardiograms (ECGs) Meeting Categorical Summarization Criteria | 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 milliseconds (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 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 Day 98 | 
| Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | 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 Day 98 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Hypoglycemic Adverse Events (HAEs). | An adverse event (AE) was any untoward medical occurrence in a participant administered a study drug; the event need not necessarily have a causal relationship with the treatment. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reasons: 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. Any events occurring following start of treatment (defined as blinded therapy, including single blind placebo administration on Day 14) or increasing in severity were counted as treatment emergent AE. | Baseline up to Day 119 | 
| Percent Changes From Baseline for Fasting Low Density Lipoprotein-Cholesterol (LDL-C) at Weeks 2, 4, 8 and 12 | Fasting low density lipoprotein-cholesterol (LDL-C) percent change from baseline (defined as the mean of Day 14 and Day 1 pre-dose) at Weeks 2,4,8 and 12. n represented the available number of participants for analysis at post-baseline days. | Baseline, Weeks 2, 4, 8 and 12 | 
| Percent Changes From Baseline for Triglycerides at Weeks 2, 4, 8 and 12 | Triglycerides percent change from baseline (defined as the mean of Day 14 and Day 1 pre-dose) at Weeks 2,4,8 and 12. n represented the available number of participants for analysis at post-baseline days. Triglycerides MMRM was not appropriate as the data were very skewed and not normally distributed, therefore per SAP non-parametric analysis were reported, presenting medians and CIs for medians, instead. If the data had many outliers even after the log transformation the following non parametric analysis was presented instead of the MMRM. An outlier was defined as any data point falling outside of 3.5 x standard deviations the median. | Baseline, Weeks 2, 4, 8 and 12 | 
| Percent Changes From Baseline for Total Cholesterol at Weeks 2, 4, 8 and 12 | Total cholesterol percent change from baseline (defined as the mean of Day 14 and Day 1 pre-dose) on Weeks 2,4,8 and 12. n represented the available number of participants for analysis at post-baseline days. | Baseline, Weeks 2, 4, 8 and 12 | 
| Percent Changes From Baseline for High Density Lipoprotein-Cholesterol (HDL-C) at Weeks 2, 4, 8 and 12 | High density lipoprotein-cholesterol (HDL-C) percent change from baseline (defined as the mean of Day 14 and Day 1 pre-dose) at Weeks 2,4,8 and 12. n represented the available number of participants for analysis at post-baseline days. | Baseline, Weeks 2, 4, 8 and 12 | 
| Percent Changes From Baseline for Non-High Density Lipoprotein (HDL) Cholesterol at Weeks 2, 4, 8 and 12 | Non-HDL-C percent change from baseline (defined as the mean of Day 14 and Day 1 pre-dose) on Weeks 2,4,8 and 12. n represented the available number of participants for analysis at post-baseline days. | Baseline, Weeks 2, 4, 8 and 12 | 
| Changes From Baseline in Body Weight at Weeks 2, 4, 8, and 12. | The body weight change from baseline (defined as the mean of Day 14 and Day 1 pre-dose) at Weeks 2,4,8 and 12. n represented the available number of participants for analysis at post-baseline days. | Baseline, Weeks 2, 4, 8 and 12 |