A Trial To Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Single Doses Of PF-04937319 In Subjects With Type 2 Diabetes Mellitus

Pfizer50 enrolled

Overview

The purpose of this study is to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-04937319 following single escalating oral doses in adult subjects with Type 2 Diabetes Mellitus (T2DM).

The purpose of this phase 1 study is to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF04937319 following single escalating oral doses in adult subjects with T2DM.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

TRIPLE

Enrollment

Conditions

Type 2 Diabetes Mellitus

Interventions

PlaceboDRUG

Placebo to match PF-04937319 will be provided.

PF-04937319DRUG

The initial planned dosing schedule is: 10, 30, 100, 200, and 400 mg, with one cohort to be determined. Doses shown may be adjusted upwards or downwards and may be adjusted to include intermediate doses. All doses will be administered as a single oral dose as a powder-in-capsule (PIC) formulation. PF-04937319 will be supplied as 10 mg and 80 mg (and potentially 1 mg) PIC.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients with type 2 diabetes mellitus who are taking stable doses of metformin only. Subjects treated with a sulfonylurea (SU) or a dipeptidyl peptidase-IV inhibitor (DPP-IVi) in combination with metformin may be eligible if washed off the SU or DPP-IVi to metformin only for a minimum of 4 weeks before dosing. * Male and/or female subjects (females will be women of non childbearing potential) between the ages of 18 and 65 years, inclusive, with a body mass index (BMI) of 18.5 to 45.0 kg/m2 and C-peptide \>0.8 ng/mL. * Screening and Day -2 troponin I concentration \</=0.05 ng/mL as measured by the Bayer Centaur Ultra assay. * HbA1c \>/=7% and \</=11%. If the patient requires to be washed off an SU or DPP-IVi, the HbA1c limits will be \>/=7% and \</=9.5%. 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). * Evidence or history of diabetic complications with significant end organ damage, eg, proliferative retinopathy and/or macular edema, creatinine clearance \</=60 mL/min based on the Cockcroft-Gault equation, diabetic neuropathy complicated by neuropathic ulcers. * History of stroke, transient ischemic attack, or myocardial infarction within the past 6 months. Additionally, history of coronary artery bypass graft or stent implantation, clinically significant peripheral vascular disease, or congestive heart failure (NYHA Classes II-IV). Furthermore, a current history of angina/unstable angina. Also, 12 lead electrocardiogram (ECG) demonstrating QTc \>450 msec at screening, ECG findings suggestive of asymptomatic myocardial ischemia, or supine blood pressure \>/=160 mm Hg (systolic) or \</=100 mm Hg (diastolic). * One or more self reported episodes of hypoglycemia within the last 3 months, or two or more self reported episodes of hypoglycemia within the last 6 months. * Screening or Day -2 fasting (\>/=8 hours) blood glucose, \</=70 or \>/=270 mg/dL, confirmed by a single repeat if deemed necessary.

Locations (3)

Dedicated Phase 1

Phoenix, Arizona, United States

West Coast Clinical Trials, LLC

Cypress, California, United States

Elite Research Institute

Miami, Florida, United States

Outcomes

Primary Outcomes

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 medication 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 medication and up to 10 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Time frame: Day 1 up to 10 days after last dose of study medication (up to 11 days)

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)

Area under the plasma concentration-time curve from zero to the last measured concentration (AUClast).

Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose

Maximum Observed Plasma Concentration (Cmax)

Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose

Apparent Oral Clearance (CL/F)

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours post-dose

Apparent Volume of Distribution (Vz/F)

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

Change From Baseline in Ratio of C-peptide Area Under Curve (C-peptide AUC) to Glucose Area Under Curve (Glucose AUC) After a Mixed Meal Tolerance Test (MMTT) on Day 1

Ratio of area under the plasma C-peptide concentration-time curve from time 2 to 6 hrs (in terms of nanogram\*deciliter\*hour \[ng\*dL\*hour\]) to area under the plasma glucose concentration-time curve from time 2 to 6 hrs (in terms of milligram\*milliliter\*hour \[mg\*mL\*hour\]) was calculated. Linear trapezoidal method was used to compute AUC. The change in ratio from baseline (Day -1) was calculated at Day 1.

Time frame: -46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hours pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hours post-dose on Day 1

Percent Change From Baseline in Post-Prandial Glucose Area Under the Curve From Time 2 to 6 Hours (AUC [2-6]) After a Mixed Meal Tolerance Test (MMTT) on Day 1

Percent 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. Baseline value was the AUC (2-6) calculated on Day -1.

Time frame: -46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hrs pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hrs post-dose on Day 1

Percent Change From Baseline in Post-Prandial Insulin Area Under the Curve From Time 2 to 6 Hours (AUC [2-6]) After a Mixed Meal Tolerance Test (MMTT) on Day 1

Percent change from baseline in post-prandial area under the plasma insulin concentration-time curve as determined by standardized MMTT. Linear trapezoidal method was used to compute AUC. Baseline value was the AUC (2-6) calculated on Day -1.

Time frame: -46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hrs pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hrs post-dose on Day 1

Percent Change From Baseline in Post-Prandial C-peptide Area Under the Curve From Time 2 to 6 Hours (AUC [2-6]) After a Mixed Meal Tolerance Test (MMTT) on Day 1

Percent 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. Baseline value was the AUC (2-6) calculated on Day -1.

Time frame: -46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hrs pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hrs post-dose on Day 1

Change From Baseline in Ratio of Insulin Delta C30 to Glucose Delta C30 After a Mixed Meal Tolerance Test (MMTT) on Day 1

Ratio of insulin delta C30 (in terms of milliunits\*deciliter \[mU\*dL\]) to glucose delta C30 (in terms of milligram\*liter \[mg\*liter\]) was calculated. The change in ratio from baseline (Day -1) was calculated at Day 1.

Time frame: -46, -45.5 hrs pre-dose on Day -1; 2, 2.5 hrs post-dose on Day 1

Change From Baseline in Ratio of C-peptide Delta C30 to Glucose Delta C30 After a Mixed Meal Tolerance Test (MMTT)

Ratio of C-peptide Delta C30 (in terms of nanogram\*deciliter \[ng\*dL\]) to glucose delta C30 (in terms of milligram\*milliliter \[mg\*mL\]) was calculated. The change in ratio from baseline (Day -1) was calculated at Day 1.

Time frame: -46, -45.5 hrs pre-dose on Day -1; 2, 2.5 hrs post-dose on Day 1

Change From Baseline in Ratio of Insulin Area Under Curve (Insulin AUC) to Glucose Area Under Curve (Glucose AUC) After a Mixed Meal Tolerance Test (MMTT) on Day 1

Ratio of area under the plasma insulin concentration-time curve from time 2 to 6 hrs (in terms of milliunit\*deciliter\*hour \[mU\*dL\*hour\]) to area under the plasma glucose concentration-time curve from time 2 to 6 hrs (in terms of milligram\*liter\*hour \[mg\*liter\*hour\]) was calculated. Linear trapezoidal method was used to compute AUC. The change in ratio from baseline (Day -1) was calculated at Day 1.

Time frame: -46, -45.75, -45.5, -45, -44.5, -44, -43, -42 hrs pre-dose on Day -1; 2, 2.25, 2.5, 3, 3.5, 4, 5, 6 hrs post-dose on Day 1