Safety and Tolerability of Ascending Intravenous Doses of PF-05231023 In Adult Subjects With Type 2 Diabetes

Phase 1

Completed

Conditions: Diabetes Mellitus, Type 2

Interventions: Drug: PF-05231023
Other: Placebo

Registration Number: NCT01396187

Lead Sponsor: Pfizer

Brief Summary: This is a trial in subjects with Type 2 diabetes mellitus to study the safety, tolerability and pharmacokinetics of multiple ascending doses of PF-05231023.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

Inclusion Criteria

Male subjects and female subjects of non-childbearing potential between the ages of 30 and 70 years, inclusive, with a historical diagnosis of type 2 diabetes mellitus, diagnosed according to the American Diabetes Association guidelines. Subjects who have other conditions but are well controlled by either diet or medications may be included as well (for example, a subject with high cholesterol level on appropriate treatment is eligible).
Body Mass Index (BMI) of 25 to 35.5 kg/m2, and a total body weight >50 kg (110 lbs).

Exclusion Criteria

Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
Diagnosis of Type 1 diabetes mellitus.
Evidence of diabetic complications with significant end organ damage

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment	PF-05231023	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Abnormal Physical Examination Findings	Baseline up to Day 42	Physical examination included assessment of height, weight, blood pressure, pulse rate and body temperature. Criteria for abnormal physical findings was based on investigator's discretion and were reported as adverse event (AE), as planned.
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	Baseline up to Day 77	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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. Treatment-emergent are events between first dose of study drug and up to Day 77 which were absent before treatment or that worsened relative to pretreatment state.
Number of Participants With Abnormal Laboratory Values	Baseline up to Day 42	Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (RBCs)(less than \[\<\] 0.8\lower limit of normal\[LLN\]); leucocytes (\<0.6/greater than \[\>\]1.5\upper limit of normal \[ULN\]); platelets (\<0.5\LLN\>\</0\>1.75\ULN); neutrophils, lymphocytes (\<0.8\LLN\>\</0\>1.2\ULN); eosinophils, basophils, monocytes (\>1.2\ULN); total bilirubin, direct bilirubin, indirect bilirubin (\>1.5\ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (\>3\ULN), total protein, albumin (\<0.8\LLN\>\</0\>1.2\ULN); creatinine, urea (\>1.3\ULN); glucose (\<0.6\LLN\>\</0\>1.5\ULN); uric acid (\>1.2\ULN); sodium, potassium, chloride, calcium, bicarbonate (\<0.9\LLN\>\</0\>1.1\*ULN); urine RBCs, urine white blood cells (WBCs) (\> or equal\[=\]20 high-powered field), urine bacteria \>20 high-powered field. Total number of participants with any laboratory abnormalities were reported.
Number of Participants With Vital Signs Abnormalities	Baseline up to Day 77	Criteria for vital signs abnormalities: supine systolic blood pressure (SBP) \<90 millimeter of mercury (mm Hg), supine diastolic BP (DBP) \<50 mm Hg, supine pulse rate \<40 beats per minute (bpm), \> 120 bpm. Maximum increase or decrease from baseline in supine SBP \>=30 mm Hg and maximum increase or decrease from baseline in supine DBP \>=20 mm Hg.
Number of Participants With Electrocardiogram (ECG) Abnormalities	Baseline up to Day 77	Criteria for potential clinical concern in ECG parameters: maximum PR interval of greater than or equal to (\>=) 300 milliseconds (msec), maximum QRS interval \>=140 msec, maximum QTCF interval (Fridericia's Correction) of 450 to \<480 msec, 480 to \<500 msec and \>=500 msec, maximum increase of \>=25 percent (%) for baseline value of \>200 msec and \>=50% for baseline value of less than or equal to (\<=) 200 msec for PR interval, maximum increase from baseline of \>=50% for QRS interval, maximum increase from baseline of \>=30 msec to \<60 msec and maximum increase from baseline of \>60 msec in QTCF interval (Fridericia's Correction).
Number of Participants With Blood Glucose Abnormalities	Baseline up to Day 32	Criteria for blood glucose abnormality: Blood glucose levels \<0.6\* LLN or \>1.5\* ULN.

Secondary Outcome Measures

Name	Time	Method
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose	0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3	Participants who received PF-05231023 with C-terminal and N-terminal AUCtau were reported.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose	0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3	Participants who received PF-05231023 with C-terminal and N-terminal Tmax were reported.
Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose	0 hour (pre-dose) on Day 1, 4; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1; Day 2, 3	Participants who received PF 05231023 with C-terminal and N-terminal Cmax were reported.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Participants who received PF-05231023 with C-terminal and N-terminal AUCtau at steady state were reported.
Apparent Clearance (CL) of PF-05231023 at Steady State	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Participants who received PF-05231023 with C-terminal and N-terminal CL at steady state were reported.
Volume of Distribution of PF-05231023 at Steady State (Vss)	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. PF-05231023 with C-terminal and N-terminal Vss at steady state were reported.
Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Participants who received PF 05231023 with C-terminal and N-terminal Cmax at steady state were reported.
Average Plasma Concentration (Cav) of PF-05231023 at Steady State	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Participants who received PF-05231023 with C-terminal and N-terminal Cmax at steady state were reported.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) at steady state. Participants who received PF-05231023 with C-terminal and N-terminal AUClast at steady state were reported.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Participants who received PF-05231023 with C-terminal and N-terminal Tmax at steady state were reported.
Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Participants who received PF 05231023 with C-terminal and N-terminal Cmax at steady state were reported.
Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac)	0 hour (pre-dose) on Day 1, 4, 25; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1, 25; Day 2, 3, 26, 29	Rac was obtained from AUCtau at steady state (Day 25) divided by AUCtau after single dose (Day 1). AUCtau was the area under the concentration-time profile from time zero to end of dosing interval, where tau = 72 hours for Day 1 and tau = 96 hours for Day 25. Participants who received PF-05231023 with C-terminal and N-terminal Rac at steady state were reported.
Accumulation Ratio for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023	0 hour (pre-dose) on Day 1, 4, 25; 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 1, 25; Day 2, 3, 26, 29	Accumulation ratio based on maximum plasma concentration (Cmax) was calculated as: Rac,Cmax = Cmax at steady state (Day 25) divided by Cmax at first dose (Day 1). Participants who received PF-05231023 with C-terminal and N-terminal Rac,Cmax at steady state were reported.
Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State	0 hour (pre-dose) 0.5, 1 (end of infusion), 1.5, 2, 3, 5, 9, 13 hours post-start of infusion on Day 25; Day 26, 29	Plasma terminal half-life is the time measured for the plasma concentration to decrease by one half at the terminal phase. Participants who received PF-05231023 with C-terminal and N-terminal t1/2 at steady state were reported.