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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01285518
First received: January 26, 2011
Last updated: September 27, 2016
Last verified: September 2016
  Purpose
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.

Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: PF-05231023
Other: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: 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

Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Number of Participants With Abnormal Physical Examination Findings [ Time Frame: Day -1 up to Day 22 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to Day 22 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Abnormal Laboratory Values [ Time Frame: Day -1 up to Day 15 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Vital Signs Abnormalities [ Time Frame: Day 1 up to Day 15 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Electrocardiogram (ECG) Abnormalities [ Time Frame: Screening up to Day 15 ] [ Designated as safety issue: Yes ]
    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).

  • Number of Participants With Hypoglycemic Adverse Event Based on Capillary Glucose Levels [ Time Frame: Day 0 up to Day 22 ] [ Designated as safety issue: Yes ]
    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).

  • Number of Participants With Blood Glucose Abnormalities [ Time Frame: Day -1 up to Day 15 ] [ Designated as safety issue: Yes ]
    Criteria for blood glucose abnormality: Blood glucose levels <0.6*lower limit of normal (LLN) or >1.5*upper limit of normal (ULN).

  • Number of Participants With Anti-Drug Antibodies (ADA): Day 1 [ Time Frame: Day 1 ] [ Designated as safety issue: Yes ]
    Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

  • Number of Participants With Anti-Drug Antibodies (ADA): Day 8 [ Time Frame: Day 8 ] [ Designated as safety issue: Yes ]
    Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

  • Number of Participants With Anti-Drug Antibodies (ADA): Day 15 [ Time Frame: Day 15 ] [ Designated as safety issue: Yes ]
    Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

  • Number of Participants With Anti-Drug Antibodies (ADA): Day 22 [ Time Frame: Day 22 ] [ Designated as safety issue: Yes ]
    Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

  • Number of Participants With Anti-Drug Antibodies (ADA): Day 34 [ Time Frame: Day 34 ] [ Designated as safety issue: Yes ]
    Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

  • 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 [ Time Frame: Day 1 ] [ Designated as safety issue: Yes ]
    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.

  • 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 [ Time Frame: Day 2 ] [ Designated as safety issue: Yes ]
    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.

  • 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 [ Time Frame: Day 3 ] [ Designated as safety issue: Yes ]
    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.

  • 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 [ Time Frame: Day 5 ] [ Designated as safety issue: Yes ]
    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.

  • 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 [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]
    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.

  • 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 [ Time Frame: Day 15 ] [ Designated as safety issue: Yes ]
    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.

  • Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 1 [ Time Frame: Day 1 ] [ Designated as safety issue: Yes ]
    Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

  • Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 2 [ Time Frame: Day 2 ] [ Designated as safety issue: Yes ]
    Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

  • Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 3 [ Time Frame: Day 3 ] [ Designated as safety issue: Yes ]
    Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

  • Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 5 [ Time Frame: Day 5 ] [ Designated as safety issue: Yes ]
    Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

  • Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 7 [ Time Frame: Day 7 ] [ Designated as safety issue: Yes ]
    Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

  • Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels: Day 15 [ Time Frame: Day 15 ] [ Designated as safety issue: Yes ]
    Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

  • Number of Participants With Abnormal Cardiac Rhythms Recorded by Telemetry [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
    Criteria for abnormal cardiac rhythms was based on investigator's discretion and were reported as adverse event (AE), as planned.


Secondary Outcome Measures:
  • Area Under the Curve From Time Zero to Time of Last Quantifiable Plasma Concentration (AUClast) of PF-05231023 [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Participants who received PF-05231023 with C-terminal and N-terminal Tmax were reported.

  • Maximum Observed Plasma Concentration (Cmax) of PF-05231023 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Participants who received PF-05231023 with C-terminal and N-terminal Cmax were reported.

  • Plasma Terminal Half-Life (t1/2) of PF-05231023 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Apparent Clearance (CL) of PF-05231023 for Intravenous Bolus Dosing [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Apparent Volume of Distribution (Vz) of PF-05231023 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of PF-05231023 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Back-extrapolated Concentration at Time Zero (C0) of PF-05231023 [ Time Frame: 0.25 H post-dose to Bo on Day 1 ] [ Designated as safety issue: No ]
    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.

  • Volume of Distribution at Steady State (Vss) of PF-05231023 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 84
Study Start Date: February 2011
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   30 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01285518

Locations
United States, California
Profil Institute for Clinical Research, Inc.
Chula Vista, California, United States, 91911
United States, Florida
Comprehensive Phase One (A Division of Comprehensive NeuroScience, Inc.)
Ft. Meyers, Florida, United States, 33901
Elite Research Institute
Miami, Florida, United States, 33169
Comprehensive Phase One (A Division of Comprehensive NeuroScience, Inc.)
Miramar, Florida, United States, 33025
United States, Texas
Cetero Research
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01285518     History of Changes
Other Study ID Numbers: B2901001 
Study First Received: January 26, 2011
Results First Received: December 18, 2014
Last Updated: September 27, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Type 2 diabetes
intravenous
single dose

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on December 07, 2016