Trial Outcomes & Findings for PF-06291874 Multiple Ascending Dose Study In Type 2 Diabetes Mellitus Patients (NCT NCT01856595)

PF-06291874 Multiple Ascending Dose Study In Type 2 Diabetes Mellitus Patients

A hypoglycemic event (HAE) was identified by characteristic symptoms or blood glucose levels. Hypoglycaemia was assessed and reported in several categories: severe hypoglycaemia, documented symptomatic hypoglycaemia, asymptomatic hypoglycaemia, and probable hypoglycaemia.

A hypoglycemic event (HAE) was identified by characteristic symptoms or blood glucose levels. Hypoglycaemia was assessed and reported in several categories: severe hypoglycaemia, documented symptomatic hypoglycaemia, asymptomatic hypoglycaemia, and probable hypoglycaemia.

ECG criteria of potential clinical concern were 1), PR interval: greater than or equal to (\>=)300 milliseconds (msec); \>=25 percent (%) increase when baselinegreater than (\>)200 msec; or increase \>=50% when baseline less than or equal to (\<=)200 msec; 2), QRS interval: \>=140 msec; \>=50% increase from baseline; 3), QT interval: \>=500 msec, QTc interval using cridericia's formula (QTcF interval): absolute value \>=450 - \<480 msec, \>=480-\<500 msec, \>500 msec; absolute change 30 - \<60, \>=60 msec.

ECG criteria of potential clinical concern were 1), PR interval: \>=300 msec; \>=25% increase when baseline \>200 msec; or increase \>=50% when baseline \<=200 msec; 2), QRS interval: \>=140 msec; \>=50% increase from baseline; 3), QT interval: \>=500 msec, QTcF interval: absolute value \>=450 - \<480 msec, \>=480-\<500 msec, \>500 msec; absolute change 30 - \<60, \>=60 msec.

Vital signs included blood pressure (BP; supine, sitting and standing) and pulse rate. Vital signs criteria of potential clinical concern were 1), BP: systolic BP (SBP) greater than or equal to (\>=) 30 millimeters of mercury (mm Hg) change from grand baseline in same posture, systolic less than (\<) 90 mm Hg; diastolic BP (DBP) \>=20 mm Hg change from grand baseline in same posture, diastolic \<50 mm Hg; 2), pulse rate (supine): \<40 or greater than (\>) 120 beats per minute (bpm).

Vital signs included blood pressure (BP; supine, sitting and standing) and pulse rate. Vital signs criteria of potential clinical concern were 1), BP: SBP \>= 30 mm Hg change from grand baseline in same posture, SBP \< 90 mm Hg; DBP \>=20 mm Hg change from grand baseline in same posture, DBP\<50 mm Hg; 2), pulse rate (supine): \<40 or \> 120 bpm.

The laboratory test included: hematology (hemoglobin, hematocrit, red blood cell count, MCV, MCH, MCHC, platelets, white blood cell count, absolute lymphocytes, absolute total neutrophils, absolute basophils, absolute eosinophils and absolute monocytes), coagulation (PPT, prothrombin), liver function(total bilirubin, AST, ALT, alkaline phosphatase, total protein and albumin), renal function (blood urea nitrogen, creatinine, uric acid), Lipids (cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), Electrolytes (sodium, potassium, chloride, calcium, venous bicarbonate), clinical chemistry (glucose, glycosylated, hemoglobin, amylase, lipase), urinalysis dipstick (urine PH, urine glucose, urine ketones, urine protein, urine urobilinogen, urine bilirubin, urine nitrite, urine leukocyte, esterase), urinalysis microscopy (urine RBC, urine WBC, urine bacteria). Laboratory abnormality was determined by the investigator based on pre-defined criteria.

The laboratory test included: hematology (hemoglobin, hematocrit, red blood cell count, MCV, MCH, MCHC, platelets, white blood cell count, absolute lymphocytes, absolute total neutrophils, absolute basophils, absolute eosinophils and absolute monocytes), coagulation (PPT, prothrombin), liver function(total bilirubin, AST, ALT, alkaline phosphatase, total protein and albumin), renal function (blood urea nitrogen, creatinine, uric acid), Lipids (cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), Electrolytes (sodium, potassium, chloride, calcium, venous bicarbonate), clinical chemistry (glucose, glycosylated, hemoglobin, amylase, lipase), urinalysis dipstick (urine PH, urine glucose, urine ketones, urine protein, urine urobilinogen, urine bilirubin, urine nitrite, urine leukocyte, esterase), urinalysis microscopy (urine RBC, urine WBC, urine bacteria). Laboratory abnormality was determined by the investigator based on pre-defined criteria.

Cmax was maximum plasma concentration. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for pharmacokinetic (PK) analysis were collected at 0, 2, 4, 6, 8, 12, 19 and 24 hours post dose.

Cmax (dn) was dose normalized maximum plasma concentration. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for pharmacokinetic (PK) analysis were collected at 0, 2, 4, 6, 8, 12, 19 and 24 hours post dose.

Cmax was maximum plasma concentration. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19 and 24 hours post dose.

Cmax (dn) was dose normalized maximum plasma concentration. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19 and 24 hours post dose

Tmax was time at which Cmax occurred. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Tmax was time at which Cmax occurred. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

AUCtau was area under the concentration-time profile from time zero to time tau, the dosing interval, where tau = 24 hours. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

AUCtau was area under the concentration-time profile from time zero to time tau, the dosing interval, where tau = 24 hours. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Cmax was maximum plasma concentration. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Cmax was maximum plasma concentration. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Tmax was time at which Cmax occurred. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Tmax was time at which Cmax occurred. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

AUCtau was area under the concentration-time profile from time zero to time tau, the dosing interval, where tau = 24 hours. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

AUCtau was area under the concentration-time profile from time zero to time tau, the dosing interval, where tau = 24 hours. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Plasma half-life was the time measured for the plasma concentration to decrease by one half. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Cmin was the lowest plasma concentration observed during the dosing interval. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Cmin was the lowest plasma concentration observed during the dosing interval. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

CL/F was multiple dose apparent clearance. The 24-hour urine samples for PK analysis were collected on Day 14 over 2 collection periods (0-6 hours and 6-24 hours).

CL/F was multiple dose apparent clearance. The 24-hour urine samples for PK analysis were collected on Day 14 over 2 collection periods (0-6 hours and 6-24 hours).

Vz/F was apparent volume of distribution. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Rac was observed accumulation ratio. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Rac was observed accumulation ratio. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Rac,cmax was observed accumulation ratio for Cmax. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Rac,cmax was observed accumulation ratio for Cmax. Blood samples (3 mL) to provide a minimum of approximately 1.2 mL plasma for PK analysis were collected at 0, 2, 4, 6, 8, 12, 19, 24 hours post dose.

Aetau% was percent of cumulative amount of drug recovered unchanged in urine over the dosing interval τ. The 24-hour urine samples for PK analysis were collected on Day 14 over 2 collection periods (0-6 hours and 6-24 hours).

CLr was renal clearance. The 24 hour urine samples for PK analysis were collected on Day 14 over 2 collection periods (0-6 hours and 6-24 hours)

A MMTT was administered on Days -1 and 14 for all cohorts. Blood samples for analysis of glucose were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, 19 and 24 hours on Days -1 and 14 for all cohorts. MDG was computed by AUC24/24 hours of the glucose values measured.

A MMTT was administered on Days -1 and 14 for all cohorts. Blood samples for analysis of glucose were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, 19 and 24 hours on Days -1 and 14 for all cohorts. MDG was computed by AUC24/24 hours of the glucose values measured.

A MMTT was administered on Days -1 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. Blood samples for analysis of glucose were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, 19 and 24 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. MDG was computed by AUC24/24 hours of the glucose values measured.

Blood samples for analysis of glucose were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, and 4 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of glucose were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, and 4 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of glucose were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, and 4 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and glucagon-like peptide 1 (GLP-1) were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and glucagon-like peptide 1 (GLP-1) were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and GLP-1 were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and GLP-1 were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and GLP-1 were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and GLP-1 were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and GLP-1 were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and GLP-1 were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Blood samples for analysis of insulin, C-peptide, glucagon and GLP-1 were collected at nominal time 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B. AUC0-4 and natural log transformed AUC0-4 were calculated for each day.

Fasting blood glucose samples were also collected on Days 0, 2, 7, and 15 for all cohorts, and on Days 21 and 29 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.

Fasting blood glucose samples were also collected on Days 0, 2, 7, and 15 for all cohorts, and on Days 21 and 29 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.

Fasting blood insulin samples were collected on Days -1, 14 and 28 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A. Baseline was defined as the value on Day -1.

Fasting blood insulin samples were collected on Days -1, 14 and 28 for all cohorts, and on Day 28 for PF-06291874 30 mg Part B. Baseline was defined as the value on Day -1.

Blood samples (3.5 mL) for all lipids and 2 mL for ApoB100 were collected at Hour 0 Day 1, Day 7 prior to breakfast, Hour 0 Day 14 for all cohorts; Days 21 and 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.

Blood samples (3.5 mL) for all lipids and 2 mL for ApoB100 were collected at Hour 0 Day 1, Day 7 prior to breakfast, Hour 0 Day 14 for all cohorts; Days 21 and 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.