Multiple Dose Study of PF-04991532 in Patients With Type 2 Diabetes

A Phase 1 Placebo-Controlled Trial to Assess The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Multiple Escalating Oral Doses of PF-04991532 in Adult Patients With Type 2 Diabetes Mellitus (T2DM)

The purpose of this study is to characterize the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-04991532 following multiple (14 days) escalating oral doses in patient wtih type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus
• Intervention / Treatment: Drug: PF-04991532; Drug: Placebo

Detailed Description

Safety/Tolerability, PK, and PD

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Chula Vista, California, United States, 91911
      • Pfizer Investigational Site
    • Fountain Valley, California, United States, 92708
      • Pfizer Investigational Site
  • Florida
    • Miami, Florida, United States, 33169
      • Pfizer Investigational Site
  • Texas
    • San Antonio, Texas, United States, 78229
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with type 2 diabetes mellitus who are taking metformin only. Treatment should be stable, where this is defined as no change in the treatment, including dose, over the past 2 months. Subjects treated with a sulfonylurea (SU) or a dipeptidyl peptidase-4 inhibitor (DPP-4i) in combination with metformin may be eligible if washed off the SU or DPP-4i to metformin only for a minimum of 4 weeks before dosing. Subjects being switched over from an SU and metformin or a DPP-4i and metformin to metformin only will still need to meet the fasting glucose requirements on Day -2 as defined in the protocol.
• Body Mass Index (BMI) of 18.5 to 45.0 kg/m2; and a total body weight >50 kg (110 lbs).
• Fasting C-peptide >0.8 ng/mL.
• HbA1c >/=7% and >/=10%. If the patient requires to be washed off an SU or DPP-4i, the HbA1c limits will be >/=6.5% and </=9%.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease. Subjects who have chronic conditions other than T2DM (for example, hypercholesterolemia or hypertension) but are controlled by either diet or stable (for the last 2 months) doses of medications may be included as well.
• Evidence or history of diabetic complications with significant end-organ damage.
• Any condition possibly affecting drug absorption (eg, gastrectomy).
• History of stroke, transient ischemic attack, or myocardial infarction within the past 6 months.
• History of coronary artery bypass graft or stent implantation.
• Clinically significant peripheral vascular disease.
• Any history or clinical evidence of congestive heart failure, NYHA Classes II-IV.
• Current history of angina/unstable angina.
• ECG findings suggestive of asymptomatic myocardial ischemia or QTc >470 msec at screening.
• 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) glucose, </=90 or >/=270 mg/dL, confirmed by a single repeat if deemed necessary.
• A positive urine drug screen.
• Use of tobacco or nicotine-containing products in excess of the equivalent of 10 cigarettes per day.
• History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of screening.
• Certain concomitant medications are excluded, as defined in the protocol.
• Screening supine blood pressure >/=160 mm Hg (systolic) or >/=100 mm Hg (diastolic).
• Certain laboratory values (for example, triglyceride and liver function test results).
• Pregnant or nursing females; females of childbearing potential.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo to match PF-04991532 will be provided. Subjects will be dosed for 14 days. In each cohort 9 subjects will receive PF-04991532 and 3 will receive placebo.
Experimental: PF-04991532	Drug: PF-04991532; Subjects will be dosed wtih PF-04991532 for 14 days. The tentative dosing schedule is 30, 100, 300, 1000, and 1500 mg QD, and 150 and 500 mg BID). Doses shown may be adjusted upwards or downwards and may be adjusted to include intermediate doses. All doses will be administered as tablets (10, 50, and 150 mg strengths). In each cohort 9 subjects will receive PF-04991532 and 3 will receive placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety Endpoints: Safety and tolerability of PF-04991532 will be assessed by physical examinations, adverse event monitoring, 12-lead ECGs, vital sign, and clinical safety laboratory measurements.	5 months
Single-Dose PK Endpoints for PF-04991352: Cmax, Tmax, and AUC(0-tau).	5 months
Multiple-Dose PK Endpoints for PF-04991532: Cmax(ss), Tmax(ss), AUC(0-tau,ss), AUC(0-last), half-life, Cmin(ss), Cav(ss), Ae%, CL/F, Vz/F, CLrenal; accumulation ratios AUC(0-tau,ss)/AUC(0-tau,sd) and Cmax(ss)/Cmax(sd), as the data permit.	5 months
PD Endpoint: glucose excursion (change from Day -1 baseline) in response to a liquid meal test (MMTT) on Days 1 and 14.	5 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Insulin and C-peptide (changes from Day -1 baseline) during an MMTT on Days 1 and 14.	5 months
Mean daily glucose (change from Day -1 baseline) on Days 1 and 14.	5 months
Fasting plasma glucose (change from Day -1 baseline) on Days 1, 3, 6, 10, and 14.	5 months
Lipids (change from Day -1 baseline), including: TG, TC, HDL-cholesterol, LDL-cholesterol, FFA, beta-OHB, and ACAC, at times specified in the SOA.	5 months
Lactate (change from Day -1 baseline), at times specified in the SOA.	5 months

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: June 1, 2010
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: May 21, 2010
• First Submitted That Met QC Criteria: May 21, 2010
• First Posted (Estimate): May 24, 2010

Study Record Updates

• Last Update Posted (Estimate): March 9, 2011
• Last Update Submitted That Met QC Criteria: March 8, 2011
• Last Verified: March 1, 2011

More Information

Terms related to this study

• Keywords: pharmacokinetics; PK; phase 1; type 2 diabetes mellitus; pharmacodynamics; PD; safety and tolerability
• Additional Relevant MeSH Terms: Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Metabolic Diseases; Glucose Metabolism Disorders; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid
• Other Study ID Numbers: B2611004