Safety And Tolerability Of Escalating Intravenous Doses Of PF-05231023 In Adult Subjects With Type 2 Diabetes

A Phase 1, Placebo-controlled, Randomized Study To Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Following Single, Escalating Intravenous Doses Of Pf-05231023 In Adult Subjects With Type 2 Diabetes

This is a trial in subjects with Type 2 diabetes mellitus to study the safety, tolerability and pharmacokinetics and pharmacodynamics of single escalating doses of PF-05231023.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: PF-05231023; Drug: PF-05231023; Drug: PF-05231023; Drug: PF-05231023; Drug: PF-05231023; Drug: PF-05231023; Drug: PF-05231023; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Chula Vista, California, United States, 91911
      • Profil Institute for Clinical Research, Inc.
  • Florida
    • Ft. Meyers, Florida, United States, 33901
      • Comprehensive Phase One (A Division of Comprehensive NeuroScience, Inc.)
    • Miami, Florida, United States, 33169
      • Elite Research Institute
    • Miramar, Florida, United States, 33025
      • Comprehensive Phase One (A Division of Comprehensive NeuroScience, Inc.)
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cetero Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female subjects between the ages of 30 and 65 years, inclusive, with a historical diagnosis of type 2 diabetes mellitus, diagnosed according to the American Diabetes Association guidelines.
• Body Mass Index (BMI) of 25 to 35.5 kg/m2, and a total body weight >50 kg (110 lbs).
• HbA1c >7% and not to exceed 10.5%.

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment	Drug: PF-05231023; 0.5 mg QD IV x 1 day; Drug: PF-05231023; 1.5 mg QD IV x 1 day; Drug: PF-05231023; 5 mg QD IV x 1 day; Drug: PF-05231023; 15 mg QD IV x 1 day; Drug: PF-05231023; 50 mg QD IV x 1 day; Drug: PF-05231023; 100 mg QD IV x 1 day; Drug: PF-05231023; 200 mg QD IV x 1 day
Placebo Comparator: Placebo; 0.9% w/v sodium chloride injection, USP	Other: Placebo; 0.9% w/v sodium chloride injection, USP QD IVx 1 day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Abnormal Physical Examination Findings	Physical examination included assessment of height, weight, blood pressure and pulse rate. Criteria for abnormal physical findings was based on investigator's discretion and were reported as adverse event (AE), as planned.	Day -1 up to Day 22
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)	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 22 days after last dose that were absent before treatment or that worsened relative to pretreatment state.	Day 1 up to Day 22
Number of Participants With Abnormal Laboratory Values	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/>1.75*ULN); neutrophils, lymphocytes (<0.8*LLN/>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/>1.2*ULN); creatinine, urea (>1.3*ULN); glucose (<0.6*LLN/>1.5*ULN); uric acid (>1.2*ULN); sodium, potassium, chloride, calcium, bicarbonate (<0.9*LLN/>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 was reported.	Day -1 up to Day 15
Number of Participants With Vital Signs Abnormalities	Criteria for vital signs abnormalities: supine systolic blood pressure (SBP) <90 millimeter of mercury (mmHg), supine diastolic BP (DBP) <50 mmHg, supine pulse rate <40 beats per minute (bpm). Maximum increase or decrease from baseline in supine SBP >=30 mmHg and maximum increase or decrease from baseline in supine DBP >=20 mmHg.	Day 1 up to Day 15
Number of Participants With Electrocardiogram (ECG) Abnormalities	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 for PR interval and maximum increase of >=50% for baseline value of less than or equal to (<=) 200 msec 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).	Screening up to Day 15
Number of Participants With Hypoglycemic Adverse Event Based on Capillary Glucose Levels	Capillary blood glucose levels were collected to observe any hypoglycemic adverse events. Hypoglycemia was assessed as following categories; Severe hypoglycemia (1. Participant was unable to treat himself/herself, requiring assistance of another person to actively administer carbohydrate, glucagon 2. Exhibited one of following neurological symptoms memory loss, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure or loss of consciousness, 3. Glucose <50 mg/dL confirmed on repeat measure); Documented symptomatic hypoglycemia (1. Symptoms of hypoglycaemia accompanied by a measured glucose concentration <=70 mg/dL); asymptomatic hypoglycemia (not accompanied by typical symptoms of hypoglycaemia but with a measured glucose concentration <=70 mg/dL), and probable hypoglycemia (typical symptoms of hypoglycaemia are not accompanied by a glucose determination, but was presumably caused by a plasma glucose concentration <=70 mg/dL).	Day 0 up to Day 22
Number of Participants With Blood Glucose Abnormalities	Criteria for blood glucose abnormality: Blood glucose levels <0.6*lower limit of normal (LLN) or >1.5*upper limit of normal (ULN).	Day -1 up to Day 15
Number of Participants With Anti-Drug Antibodies (ADA): Day 1	Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.	Day 1
Number of Participants With Anti-Drug Antibodies (ADA): Day 8	Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.	Day 8
Number of Participants With Anti-Drug Antibodies (ADA): Day 15	Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.	Day 15
Number of Participants With Anti-Drug Antibodies (ADA): Day 22	Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.	Day 22
Number of Participants With Anti-Drug Antibodies (ADA): Day 34	Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.	Day 34
Insulin-like Growth Factor - 1 (IGF-1), Insulin-like Growth Factor Binding Protein-1 (IGFBP-1), Insulin-like Growth Factor Binding Protein-2 (IGFBP-2), Growth Hormone (GH) Levels: Day 1	Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich (enzyme-linked immunosorbent assay) ELISA method.	Day 1
Insulin-like Growth Factor - 1 (IGF-1), Insulin-like Growth Factor Binding Protein-1 (IGFBP-1), Insulin-like Growth Factor Binding Protein-2 (IGFBP-2), Growth Hormone (GH) Levels: Day 2	Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.	Day 2
Insulin-like Growth Factor - 1 (IGF-1), Insulin-like Growth Factor Binding Protein-1 (IGFBP-1), Insulin-like Growth Factor Binding Protein-2 (IGFBP-2), Growth Hormone (GH) Levels: Day 3	Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.	Day 3
Insulin-like Growth Factor - 1 (IGF-1), Insulin-like Growth Factor Binding Protein-1 (IGFBP-1), Insulin-like Growth Factor Binding Protein-2 (IGFBP-2), Growth Hormone (GH) Levels: Day 5	Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.	Day 5
Insulin-like Growth Factor - 1 (IGF-1), Insulin-like Growth Factor Binding Protein-1 (IGFBP-1), Insulin-like Growth Factor Binding Protein-2 (IGFBP-2), Growth Hormone (GH) Levels: Day 7	Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.	Day 7
Insulin-like Growth Factor - 1 (IGF-1), Insulin-like Growth Factor Binding Protein-1 (IGFBP-1), Insulin-like Growth Factor Binding Protein-2 (IGFBP-2), Growth Hormone (GH) Levels: Day 15	Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.	Day 15
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 1	Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.	Day 1
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 2	Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.	Day 2
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 3	Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.	Day 3
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 5	Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.	Day 5
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 7	Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.	Day 7
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 15	Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.	Day 15
Number of Participants With Abnormal Cardiac Rhythms Recorded by Telemetry	Criteria for abnormal cardiac rhythms was based on investigator's discretion and were reported as adverse event (AE), as planned.	From 2 hours (H) pre-dose for intravenous bolus or 2 H prior to the start of infusion on Day 1 up to 8 H post-dose for bolus or 8 H following the end of the infusion on Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve From Time Zero to Time of Last Quantifiable Plasma Concentration (AUClast) of PF-05231023	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Participants who received PF-05231023 with C-terminal and N-terminal AUClast were reported.	Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023	Participants who received PF-05231023 with C-terminal and N-terminal Tmax were reported.	Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22
Maximum Observed Plasma Concentration (Cmax) of PF-05231023	Participants who received PF-05231023 with C-terminal and N-terminal Cmax were reported.	Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22
Plasma Terminal Half-Life (t1/2) of PF-05231023	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 were reported.	Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22
Apparent Clearance (CL) of PF-05231023 for Intravenous Bolus Dosing	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 were reported.	Hour (H)-1 (1 H pre-dose to bolus [Bo]),H-0.5(0.5 H pre-dose to Bo),H 0 (prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22
Apparent Volume of Distribution (Vz) of PF-05231023	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. PF-05231023 with C-terminal and N-terminal Vz were reported.	Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of PF-05231023	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 - ∞). PF-05231023 with C-terminal and N-terminal AUC (0 - ∞) were reported.	Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22
Back-extrapolated Concentration at Time Zero (C0) of PF-05231023	C0 was estimated by back-extrapolating from the first 2 concentration values using the log-linear regression on the first 2 data points (where second concentration was less than [<] first concentration) to back-extrapolate C0. PF-05231023 with C-terminal and N-terminal C0 were reported.	0.25 H post-dose to Bo on Day 1
Volume of Distribution at Steady State (Vss) of PF-05231023	Vss was calculated by dividing the area under the first moment curve from time zero to infinity [AUMC(0-∞)] with the product of area under the curve from time zero to extrapolated infinite time [AUC (0 - ∞)] and apparent clearance (CL). PF-05231023 with C-terminal and N-terminal Vss were reported.	Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: January 26, 2011
• First Submitted That Met QC Criteria: January 26, 2011
• First Posted (Estimate): January 28, 2011

Study Record Updates

• Last Update Posted (Estimate): November 18, 2016
• Last Update Submitted That Met QC Criteria: September 27, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Type 2 diabetes; intravenous; single dose
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: B2901001