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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: PF-05231023
* Drug: PF-05231023
* Drug: PF-05231023
* Drug: PF-05231023
* Drug: PF-05231023
* Drug: PF-05231023
* Drug: PF-05231023
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 diabetes, intravenous, single dose