Safety and Tolerability of Ascending 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 of multiple ascending doses of PF-05231023.

Official Title
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A Phase 1, Placebo-Controlled Randomized Trial To Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Multiple Ascending Intravenous Doses Of PF-05231023 In Adult Subjects With Type 2 Diabetes Mellitus

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
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 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>* 5 mg IV twice a week for 4 weeks<br>Drug: PF-05231023<br>* 25 mg IV twice a week for 4 weeks<br>Drug: PF-05231023<br>* 100 mg IV twice a week for 4 weeks<br>Drug: PF-05231023<br>* 200 mg IV twice a week for 4 weeks<br>|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* 0.9% w/v sodium chloride injection, United States Pharmacopeia (USP), twice a week IV for 4 weeks<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, 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. | Baseline up to Day 42 | 
| 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 Day 77 which were absent before treatment or that worsened relative to pretreatment state. | Baseline up to Day 77 | 
| 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></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. | Baseline up to Day 42 | 
| Number of Participants With Vital Signs Abnormalities | 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. | Baseline up to Day 77 | 
| 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 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). | Baseline up to Day 77 | 
| Number of Participants With Blood Glucose Abnormalities | Criteria for blood glucose abnormality: Blood glucose levels <0.6* LLN or >1.5* ULN. | Baseline up to Day 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 After Single Dose | Participants who received PF-05231023 with C-terminal and N-terminal AUCtau were reported. | 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 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 After Single Dose | Participants who received PF-05231023 with C-terminal and N-terminal Tmax were reported. | 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 | 
| Maximum Observed Plasma Concentration (Cmax) of PF-05231023 After Single Dose | Participants who received PF 05231023 with C-terminal and N-terminal Cmax were reported. | 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 | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-05231023 at Steady State | Participants who received PF-05231023 with C-terminal and N-terminal AUCtau at steady state were reported. | 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 Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05231023 at Steady State | 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. | 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 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05231023 at Steady State | Participants who received PF-05231023 with C-terminal and N-terminal Tmax at steady state were reported. | 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 | 
| Maximum Observed Plasma Concentration (Cmax) of PF-05231023 at Steady State | Participants who received PF 05231023 with C-terminal and N-terminal Cmax at steady state were reported. | 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 | 
| Accumulation Ratio for Area Under the Curve From Time Zero to End of Dosing Interval of PF-05231023 (Rac) | 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. | 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 for Maximum Observed Plasma Concentration (Rac,Cmax) of PF- 05231023 | 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. | 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 | 
| Plasma Terminal Half-Life (t1/2) of PF-05231023 at Steady State | 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. | 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 | 
| Apparent Clearance (CL) of PF-05231023 at Steady State | 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. | 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 of PF-05231023 at Steady State (Vss) | 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. | 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 | 
| Minimum Observed Plasma Trough Concentration (Cmin) of PF-05231023 at Steady State | Participants who received PF 05231023 with C-terminal and N-terminal Cmax at steady state were reported. | 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 | 
| Average Plasma Concentration (Cav) of PF-05231023 at Steady State | Participants who received PF-05231023 with C-terminal and N-terminal Cmax at steady state were reported. | 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 | 

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