Single-Dose And Multiple-Dose Safety And Tolerability Study Of PF-04856883 In Type 2 Diabetic Adult Females

Phase 1

Completed

Conditions: Glucose Metabolism Disorders
Diabetes Mellitus
Diabetes Mellitus, Type 2
Metabolic Diseases
Endocrine System Diseases

Interventions: Biological: PF-04856883
Biological: Placebo

Registration Number: NCT01301456

Lead Sponsor: Pfizer

Brief Summary: The primary objective of this study is to evaluate the safety and tolerability of PF-04856883 (CVX-096) in adult female subjects with Type 2 diabetes mellitus on high dose of metformin.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 84

Inclusion Criteria

History of Type 2 diabetes and currently being treated with high dose metformin
BMI between 22.0 and 40.0 kg/m2
HbA1c between 7.0-10.0%
Fasting C-peptide >1.21 ng/mL

Exclusion Criteria

History of clinically significant chronic conditions other than Type 2 diabetes not well controlled by either diet or medications
Treatment with anti-diabetic therapies other than metformin
History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody
Males or women of childbearing potential

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment Arm 6 (Stage 1B)	PF-04856883	-
Treatment Arm 10 (Stage 2)	PF-04856883	-
Treatment Arm 5 (Stage 1B)	Placebo	-
Treatment Arm 4 (Stage 1A)	PF-04856883	-
Treatment Arm 7 (Stage 1B)	PF-04856883	-
Treatment Arm 8 (Stage 1B)	PF-04856883	-
Treatment Arm 3 (Stage 1A)	PF-04856883	-
Treatment Arm 9 (Stage 2)	Placebo	-
Treatment Arm 11 (Stage 2)	PF-04856883	-
Treatment Arm 1 (Stage 1A)	Placebo	-
Treatment Arm 2 (Stage 1A)	PF-04856883	-
Treatment Arm 12 (Stage 2)	PF-04856883	-
Treatment Arm 13 (Stage 2)	PF-04856883	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiograms (ECG)	Stage 1: Baseline up to Day 29; Stage 2: Baseline up to Day 50	ECG parameters included pulse rate (PR) interval, QRS interval, corrected QT interval using Bazett's formula (QTcB) and corrected QT interval using Fridericia's formula (QTcF). ECG criteria of clinically significant concern were 1) PR interval: greater than equal to (\>=) 25 percent (%) increase when baseline greater than (\>)200 milliseconds (msec); or increase \>=50% when baseline less than or equal to (\<=200) msec; 2) QRS interval: \>=25% increase when baseline \>100 msec; \>=50% increase when baseline \<= 100 msec; 3) QTCF interval: QTc interval using Fridericia's formula (QTcF interval) and Bazett's formula (QTcB interval): absolute value 450 - \<480 msec, 480 - \<500 msec \>=500; absolute change 30 - \<60, \>=60 msec. The number of participants with potentially clinically significant ECG findings at any visit were reported. IFB = increase from baseline.
Number of Participants With Clinically Significant Physical Examination Findings	Stage 1: Baseline up to Day 29; Stage 2: Baseline up to Day 50	Physical examination included examination of general appearance, head, ears, eyes (including fundoscopy), nose, mouth, throat, neck (including thyroid), skin, breast (optional), cardiac, respiratory, gastrointestinal, musculoskeletal and neurological systems.
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	Stage 1: Baseline up to Day 29; Stage 2: Baseline up to Day 50	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 28 days after last dose (Day 50) that were absent before treatment or that worsened relative to pretreatment state.
Number of Participants With Clinically Significant Abnormalities in Laboratory Measurements	Stage 1: Baseline up to Day 29; Stage 2: Baseline up to Day 50	Following parameters were analyzed for laboratory examination: Hematology: hemoglobin, hematocrit, red blood cell (RBC) \<0.8\lower limit of the reference range (LLRR); leukocytes \<0.6\LLRR or \>1.5\ULRR; platelet count \<0.5\LLRR or \>1.75\upper limit of the reference range (ULRR); total neutrophils (absolute \[abs\]), lymphocytes (abs) \<0.8\LLRR or \>1.2\ULRR; eosinophils (abs), basophils (abs), monocytes (abs) \>1.2\ULRR; chemistry (total bilirubin, direct bilirubin, indirect bilirubin \>1.5\ULRR; aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase \>3\ULRR, albumin, total protein \<0.8\LLRR or \>1.2\ULRR; blood urea nitrogen (BUN), creatinine \>1.3\ULRR; glucose (fasting) \<0.6\LLRR or \>1.5\ULRR; uric acid \>1.2\ ULRR; sodium \<0.95\LLRR or \>1.05\ULRR; potassium, chloride, bicarbonate, calcium \<0.9\LLRR or \>1.1\ULRR. Urinalysis: Urine white blood cell (WBC), Urine RBC =\>20/ high-power field (HPF).
Number of Participants With Vital Sign Abnormalities	Stage 1: Baseline up to Day 29; Stage 2 : Baseline up to Day 50	Criteria for vital signs abnormalities: sitting/supine systolic pulse rate less than (\<) 40 beats per minute (bpm) or greater than (\>) 120 bpm, standing/supine systolic pulse \< 40 bpm or \> 140 bpm, systolic blood pressure of \>=30 millimeters of mercury (mmHg) change from baseline and systolic blood pressure \<90 mmHg, diastolic blood pressure \>=20 mmHg change from baseline and diastolic blood pressure \<50 mm Hg.

Secondary Outcome Measures

Name	Time	Method
Maximum Observed Plasma Concentration (Cmax) of PF-04856883: Stage 1	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 1
Maximum Observed Plasma Concentration (Cmax) of PF-04856883: Stage 2	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168, 336 hours postdose on Day 1; predose (0 hour), 1, 2, 6, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 22
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0 - ∞]) of PF-04856883: Stage 1	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 1	AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
Terminal Elimination Half- Life (t1/2) of PF-04856883: Stage 1	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 1
Change From Baseline in Post-prandial Glucose Area Under the Curve (AUC) After Mixed Meal Tolerance Test (MMTT) at Day 3, 15, 24, 29 and 50: Stage 2	Baseline, Day 3, 15, 24, 29 and 50	Change from baseline in post-prandial area under the plasma glucose concentration time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04856883: Stage 1	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 1
Area Under the Concentration Time Curve From Time Zero to Time Tau (AUCtau) of PF-04856883: Stage 2	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168 hours postdose Day 1; predose (0 hour), 1, 2, 6, 24, 48, 72, 120, 168 hours postdose Day 22	Area under the serum concentration-time curve from time 0 to tau (AUCtau), where tau was the dosing interval of 168 hours.
Apparent Volume of Distribution (Vz/F) of PF-04856883: Stage 1	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 1
Change From Baseline in Post-prandial Glucose Area Under the Curve (AUC) After Mixed Meal Tolerance Test (MMTT) at Day 3 and 8: Stage 1	Baseline, Day 3 and 8	Change from baseline in post-prandial area under the plasma glucose concentration time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04856883: Stage 2	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168, 336 hours postdose on Day 1; predose (0 hour), 1, 2, 6, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 22
Apparent Clearance (CL/F) of PF-04856883: Stage 2	predose (0 hour), 1, 2, 6, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 22	It was calculated by dividing dose with AUC (0 - ∞) where AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). Outcome measure was planned to be analyzed in Stage 2 only. Data was not estimable if values were below the limit of quantification.
Apparent Volume of Distribution (Vz/F) of PF-04856883: Stage 2	predose (0 hour), 1, 2, 6, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 22
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 2, 4, 6, 15, 22 and 29: Stage 1	Baseline, Day 2, 4, 6, 15, 22 and 29
Change From Baseline in 24 Hours Glucose Normalized Area Under the Curve (NAUC) Profile at Day 30: Stage 2	Baseline, Day 30	A normalized area under the curve (NAUC) were computed by dividing the AUC by the amount of time between the last time point captured and the first time point captured.
Apparent Clearance (CL/F) of PF-04856883: Stage 1	predose (0 hour), 1, 6, 12, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 1	It was calculated by dividing dose with AUC (0 - ∞) where AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). Outcome measure was planned to be analyzed in Stage 1 only.
Terminal Elimination Half-life (t1/2) of PF-04856883: Stage 2	predose (0 hour), 1, 2, 6, 24, 48, 72, 120, 168, 336, 504, 672 hours postdose on Day 22
Change From Baseline in Insulin Area Under the Curve (AUC) After Mixed Meal Tolerance Test (MMTT) at Day 3, 15, 24, 29 and 50: Stage 2	Baseline, Day 3, 15, 24, 29 and 50	Change from baseline in post-prandial plasma insulin AUC under the plasma insulin concentration versus time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC.
Change From Baseline in C-Peptide Area Under the Curve (AUC) After Mixed Meal Tolerance Test (MMTT) at Day 3 and 8: Stage 1	Baseline, Day 3 and 8	Change from baseline in post-prandial area under the plasma C-peptide concentration time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC.
Percent Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Day 29 and 50: Stage 2	Baseline, Day 29 and 50	HbA1c is a measure of the glycosylated hemoglobin. Change (measured as percent): HbA1c at observation minus HbA1c at baseline. Outcome measure was planned to analyzed only for Stage 2.
Change From Baseline in Insulin Area Under the Curve (AUC) After Mixed Meal Tolerance Test (MMTT) at Day 3 and 8: Stage 1	Baseline, Day 3 and 8	Change from baseline in post-prandial plasma insulin AUC under the plasma insulin concentration versus time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC.
Change From Baseline in C-Peptide Area Under the Curve (AUC) After Mixed Meal Tolerance Test (MMTT) at Day 3, 15, 24, 29 and 50: Stage 2	Baseline, Day 3, 15, 24, 29 and 50	Change from baseline in post-prandial area under the plasma C-peptide concentration time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC.
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 2, 4, 6, 8, 22, 23, 25, 27, 30, 36 and 43: Stage 2	Baseline, Day 2, 4, 6, 8, 22, 23, 25, 27, 30, 36 and 43
Change From Baseline in Fructosamine Levels at Day 8, 15 and 29: Stage 1	Baseline, Day 8, 15 and 29
Change From Baseline in 1, 5 Anhydroglucitol at Day 8, 15, 22, 29 and 50: Stage 2	Baseline, Day 8, 15, 22, 29 and 50
Number of Participants With Anti-Drug Antibodies (ADA): Stage 1	Day 1 and 29
Change From Baseline in Fructosamine Levels at Day 8, 15, 22, 29 and 50: Stage 2	Baseline, Day 8, 15, 22, 29 and 50
Change From Baseline in 1, 5 Anhydroglucitol at Day 8, 15 and 29: Stage 1	Baseline, Day 8, 15 and 29
Number of Participant With Anti-Drug Antibodies (ADA): Stage 2	Day 1, 29 and 50

Trial Locations

Locations (7): ICON Clinical Pharmacology, LLC
🇺🇸
Omaha, Nebraska, United States
CRI Worldwide, LLC
🇺🇸
Philadelphia, Pennsylvania, United States
Comprehensive Phase One (A Division of Comprehensive NeuroScience, Inc.)
🇺🇸
Miramar, Florida, United States
Atlanta Center for Medical Research
🇺🇸
Atlanta, Georgia, United States
Elite Research Institute
🇺🇸
Miami, Florida, United States
Profil Institute for Clinical Research, Inc.
🇺🇸
Chula Vista, California, United States
Healthcare Discoveries LLC d/b/a ICON Development Solutions
🇺🇸
San Antonio, Texas, United States