A 6-Week Study Of PF-05175157 In Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This study is designed to assess the safety, tolerability and pharmacodynamics of 6 weeks of oral doses of PF-05175157 provided as monotherapy in subjects with type 2 diabetes mellitus.

Official Title
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A 6-week Phase 2a Randomized, Double-blind, Placebo-controlled, Parallel Group Study To Assess Safety, Tolerability And Pharmacodynamics Of Oral Pf-05175157 As Monotherapy In Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: PF-05175157
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who have been diagnosed with type 2 diabetes mellitus by a medical professional according to the American Diabetes Association guidelines. Hemoglobin A1c of ≥7 and ≤10.0% in subjects who are metformin-naive or have not taken metformin for 2 months or Hemoglobin A1c of ≥6.5 and ≤9.5% in subjects who are metformin-naïve and are taking SU or DPP-IVi which is washed off or taking metformin and are willing to discontinue metformin in a 8-week washout period. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine (other than T2DM and hypothyroidism), gastrointestinal, cardiovascular, pulmonary, hepatic, psychiatric or neurologic disease. A waist circumference which makes fitting imto the bore of the MR scanner impossible. Subjects with history of dry eye, known ocular or systemic disease that affect the sclera or cornea.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Part A (Pilot Study)<br> | |
| Experimental: Monotherapy (Part B)<br> | Drug: PF-05175157<br>* PF-05175157 will be administered at 200 mg twice a day for 43 days.<br>Drug: Placebo<br>* Placebo tablets matched to PF-05175157 will be administered twice a day for 43 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose Infusion Rates (GIR) in Part A | GIR obtained averaging respectively the last 30 minutes of glucose infusion at steady state on Step 1 (ie 150 to 180 min) and Step 2 (ie 330 to 360 min) insulin infusion. Whole-body insulin sensitivity was assessed with the euglycemic hyperinsulinemic clamp procedure; the use of 2 stepped insulin infusions and labeled glucose allowed the differentiation between hepatic and peripheral insulin sensitivity. Assessment of whole body insulin sensitivity was performed during the steady states of the low insulin infusion rate (ie, Step 1) and during the steady state of the high insulin infusion rate (ie, Step 2). These indices were called GIR1 and GIR2, respectively. | 1 day | 
| Endogenous Gucose Production (EGP) in Part A | EGP measured by means of euglycemic hyperinsulinemic clamp preceding insulin infusion (EGP0), on Step 1 insulin infusion (EGP1) and on Step 2 insulin infusion (EGP2). Whole-body insulin sensitivity was assessed with the euglycemic hyperinsulinemic clamp procedure; the use of 2 stepped insulin infusions and labeled glucose allowed the differentiation between hepatic and peripheral insulin sensitivity. EGP was measured under basal conditions; then during the low dose insulin infusion EGP was partially suppressed (hepatic insulin sensitivity), while during the high dose insulin infusion, EGP was almost completely suppressed and peripheral glucose uptake was maximally stimulated (peripheral insulin sensitivity). | 1 day | 
| [6,6-2H2] Plasma Glucose Enrichment (PGE) in Part A | [6,6-2H2] PGE was the molar fraction of labeled glucose measured in plasma. Whole-body insulin sensitivity was assessed with the euglycemic hyperinsulinemic clamp procedure; the use of 2 stepped insulin infusions and labeled glucose allowed the differentiation between hepatic and peripheral insulin sensitivity. | 1 day | 
| Rate of Appearance of Glucose (Ra) in Part A | Rate of appearance of glucose (Ra) in fasting state and during insulin infusions (Step 1 and Step 2). | 1 day | 
| Whole-body Glucose Uptake in Part A | Whole-body glucose uptake (Rate of glucose disappearance, Rd) during the Step 2 Clamp | 1 day | 
| Whole-body Glucose Uptake in Part B in Placebo Group | Whole-body glucose uptake (Rate of glucose disappearance, Rd) during the Step 2 Clamp | 6 weeks | 
| Whole-body Glucose Uptake in Part B in PF-05175157 200 mg BID Group | Whole-body glucose uptake (Rate of glucose disappearance, Rd) during the Step 2 Clamp | 6 weeks | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs), or Discontinuation Due to Adverse Events (AEs) in Part B | 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; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Baseline to follow-up (up to approximately 10 to 14 days after the last study drug administration) | 
| Number of Participants With Laboratory Test Abnormalities in Part B | Number of participants with laboratory test abnormalities without regard to baseline abnormality. The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, platelet count, white blood cell [WBC] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen [BUN], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, uric acid, albumin, total protein, and creatine phosphokinase); urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, and microscopy); others (follicle stimulating hormone [FSH], urine drug screen, lipid profile and very-low-density lipoproteins [VLDL], hemoglobin A1c [HbA1c], C-peptide, thyroid-stimulating hormone [TSH], Hepatitis B and C, human immunodeficiency virus [HIV], triglycerides, urine creatinine). | Screening up to follow-up (up to approximately 10 to 14 days after the last study drug administration) | 
| Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria in Part B | Criteria for potentially clinical important (PCI) change in vital signs included: sitting systolic blood pressure (SBP) of less than (<) 90 millimeters of mercury (mm Hg) or change in sitting SBP of greater or equal to (>=)30 mm Hg, sitting diastolic blood pressure (DBP) of <50 mm Hg or change in sitting DBP of >=20 mm Hg, sitting pulse rate of <40 or greater than (>) 120 beats per minute (bpm). | Screening up to follow-up (up to approximately 10 to 14 days after the last study drug administration) | 
| Number of Participants With Change From Baseline and Absolute Values in Electrocardiogram (ECG) Meeting Categorical Summarisation Criteria in Part B | Criteria for PCI changes in ECG (12-lead) were defined as: 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) and increase of >=25% from baseline when baseline >200 msec or increase of >=50% when baseline less than or equal to (<=) 200 msec; the time from the beginning of the electrocardiogram Q wave to the end of the S wave corresponding to ventricular depolarization (QRS interval) >=140 msec and increase of >=50% from baseline; the time corresponding to the beginning of depolarization to repolarization of the ventricles (QT), corrected for heart rate (QTc) using the Fridericia formula (QTcF) of 450 to < 480 msec and >=480 msec, or an increase from baseline of 30 to <60 msec or >=60 msec. | Screening up to follow-up (up to approximately 10 to 14 days after the last study drug administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GIR in Part B in Placebo Group | Glucose Infusion Rate rates obtained averaging respectively the last 30 minutes of glucose infusion at steady state on Step 1 (ie 150 to 180 min) and Step 2 (ie 330 to 360 min) insulin infusion. | 6 weeks | 
| GIR in Part B in PF-05175157 200 mg BID Group | Glucose Infusion Rate rates obtained averaging respectively the last 30 minutes of glucose infusion at steady state on Step 1 (ie 150 to 180 min) and Step 2 (ie 330 to 360 min) insulin infusion. | 6 weeks | 
| EGP in Part B in Placebo Group | EGP measured by means of euglycemic hyperinsulinemic clamp preceding insulin infusion (EGP0), on Step 1 insulin infusion (EGP1) and on Step 2 insulin infusion (EGP2) | 6 weeks | 
| EGP in Part B in PF-05175157 200 mg BID Group | EGP measured by means of euglycemic hyperinsulinemic clamp preceding insulin infusion (EGP0), on Step 1 insulin infusion (EGP1) and on Step 2 insulin infusion (EGP2) | 6 weeks | 
| Ra in Part B in Placebo Group | Ra in fasting state and during insulin infusions (Step 1 and Step 2). | 6 weeks | 
| Ra in Part B in PF-05175157 200 mg BID Group | Ra in fasting state and during insulin infusions (Step 1 and Step 2). | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Pharmacodynamics, Safety & Tolerability