A Study To Evaluate The Safety And Effects On The Body Of An Investigational Drug Using An Endotoxin-Induced Inflammatory Response Model (POM)

A Phase 1, Randomized, Double Blind, Placebo Controlled, Multiple Dose, 2 Way Crossover Study To Evaluate The Safety And Pharmacodynamic Effects Of Pf 06282999 Using An Endotoxin (Lipopolysaccharide) Induced Inflammatory Response Model In Healthy Adult Subjects

An endotoxin challenge will be administered to healthy subjects to induce production of inflammatory markers. An investigational drug or placebo will be administered prior to the endotoxin challenge to assess the effect of the investigational drug on the markers of inflammation. Safety and tolerability will also be assessed.

Study Overview

• Status: Terminated
• Conditions: Healthy
• Intervention / Treatment: Drug: PF-06282999; Drug: Placebo; Other: LPS; Drug: PF-06282999; Drug: Placebo

Detailed Description

The trial was terminated on 25 March 2015 due to safety concerns regarding the administration of endotoxin and because of the uncertain availability of future endotoxin lots.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Clinical Research Unit
    • Durham, North Carolina, United States, 27710
      • (Drug Shipment Address ONLY) Duke University Health Systems (DUHS) Investigational Drug Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy men or women (non-childbearing potential) between the ages of 18-40 years.
• Body Mass Index (BMI) 18-30 kg/m2 and a total body weight >50 kg (110 lbs).

Exclusion Criteria:

• History or evidence of habitual use of tobacco- or nicotine-containing products within 3 months of screening.
• History of frequent headaches or migraines (>3 per month), or headaches from an absence of caffeine.
• Caffeine consumption in excess of 3 cups per day.
• Subjects who have experienced cold/flu symptoms (ie, runny nose, cough, and/or fever) within 2 weeks of the first administration of study drug/placebo of each period.
• History of recurrent or chronic infections of any type such as tuberculosis, sinusitis, urinary tract infection, respiratory tract or dental (abscess) infection, etc. Also excluded are subjects with recurrent oral or genital herpes, recurrent herpes zoster, or any infection otherwise judged by the investigator to have the potential for worsening if enrolled in this study.
• Treatment with LPS in the past 12 months and/or a history of an allergic type reaction or known hypersensitivity to endotoxin at any time.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1	Drug: PF-06282999; Tablet, 125 mg, TID, 3 days, 1 of 2 periods; Drug: Placebo; Tablet, 0 mg, TID, 3 days, 1 of 2 periods; Other: LPS; IV bolus, 4 ng/kg, 1 day, QD, 2 of 2 periods; Other Names: Endotoxin; Drug: PF-06282999; Tablet, 500 mg, BID, 3 days, 1 of 2 periods; Drug: Placebo; Tablet, 0 mg, BID, 3 days, 1 of 2 periods
Experimental: Cohort 2	Drug: PF-06282999; Tablet, 125 mg, TID, 3 days, 1 of 2 periods; Drug: Placebo; Tablet, 0 mg, TID, 3 days, 1 of 2 periods; Other: LPS; IV bolus, 4 ng/kg, 1 day, QD, 2 of 2 periods; Other Names: Endotoxin; Drug: PF-06282999; Tablet, 500 mg, BID, 3 days, 1 of 2 periods; Drug: Placebo; Tablet, 0 mg, BID, 3 days, 1 of 2 periods

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Myeloperoxidase (MPO) Activity Following Inflammatory Stimulus	MPO is a heme-containing peroxidase enzyme produced in the bone marrow and stored in the azurophilic granules of neutrophils, where it constitutes up to 5% of the cellular protein. Since PF-06282999 is a mechanism-based inactivator of MPO, it is of interest to evaluate the level of MPO activity in order to investigate the inhibition activity of PF-06282999.	Days 1, 3-5
MPO Activity (Area Under the Concentration-time Profile From 0.5 to 2 Hours [AUC0.5-2hrs]) Following Inflammatory Stimulus	MPO is a heme-containing peroxidase enzyme produced in the bone marrow and stored in the azurophilic granules of neutrophils, where it constitutes up to 5% of the cellular protein. Since PF-06282999 is a mechanism-based inactivator of MPO, it is of interest to evaluate the level of MPO activity in order to investigate the inhibition activity of PF-06282999.	Days 1, 3-5
MPO Activity (Area Under the Concentration-time Profile From 0 to 2 Hours [AUC0-2hrs]) Following Inflammatory Stimulus	MPO is a heme-containing peroxidase enzyme produced in the bone marrow and stored in the azurophilic granules of neutrophils, where it constitutes up to 5% of the cellular protein. Since PF-06282999 is a mechanism-based inactivator of MPO, it is of interest to evaluate the level of MPO activity in order to investigate the inhibition activity of PF-06282999.	Days 1, 3-5
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs	An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. AEs comprised both SAEs and non-SAEs. 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. TEAEs were defined as newly occurring AEs or those worsening after first dose. Due to early termination of the study, only AE data from partial enrollment are reflected and comparisons between treatment arms should not be attempted.	From Day 0 till approximately 7-10 days following the last dose of PF-06282999/Placebo in Period 2 (up to approximately 2 months)
Number of Participants With Laboratory Test Abnormalities	Number of participants with laboratory test abnormalities without regard to baseline abnormality. Laboratory test parameters included hematology, coagulation, liver function, renal function, electrolytes, clinical chemistry, and urinalysis (dipstick and microscopy). Due to early termination of the study, only laboratory data from partial enrollment are reflected and comparisons between treatment arms should not be attempted.	Baseline up to 7-10 days following the last dose of PF-06282999/Placebo in Period 2
Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria	Categorical summarization criteria in vital signs included: sitting, supine, and standing systolic blood pressure (SBP) of less than (<)90 millimeters of mercury (mm Hg) or change (increase [inc] or decrease [dec]) in sitting, supine and standing SBP of more than or equal to (>=)30 mm Hg; supine, sitting, and standing diastolic blood pressure (DBP) of <50 mm Hg or change (inc or dec) in sitting, supine, and standing DBP of >=20 mm Hg; supine and sitting pulse rate (PR) of <40 or more than (>)120 beats per minute (bpm); and standing PR of <40 or >140 bpm. Due to early termination of the study, only vital signs data from partial enrollment are reflected and comparisons between treatment arms should not be attempted.	Screening and Days 1-2, 4-5, and approximately 7-10 days following the last dose of PF-06282999/Placebo in Period 2 for orthostatic (orth) measurements; Day 3 for supine measurements
Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria	Criteria for ECG (12-lead) values meeting categorical summarization criteria were: the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization (PR interval >=300 milliseconds (msec) and increase from baseline >=25/50%; time from the beginning of the ECG Q wave to the end of the S wave corresponding to ventricular depolarization (QRS) interval >=140 msec and increase of >=50%; the beginning of the Q wave to the end of the T wave corresponding to electrical systole (QT) interval >=500 msec; QT corrected using the Fridericia formula (QTcF) of 450 to <480 msec, 480 to <500 msec, and >=500 msec, or an increase of 30 to <60 msec or >=60 msec. Due to early termination of the study, only ECG data from partial enrollment are reflected and comparisons between treatment arms should not be attempted.	Screening; Days 1-5 and approximately 7-10 days following the last dose of PF-06282999/Placebo in Period 2
Number of Participants With Abnormal Urinary Biomarker Values	Urinary biomarkers included albumin, neutrophil gelatinase-associated lipocalin (NGAL) and Cystatin-C.	Days 1-3 prior to dosing with PF-06282999/Placebo; and Days 4-5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentrations of TNF-alpha, IL-1 Beta, IL-6, IL-8, and hsCRP	The effect of multiple oral doses of PF-06282999 on inflammatory biomarkers was a secondary objective in this study. The biomarkers are tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-8, and high-sensitivity C-reactive protein (hsCRP).	Days 1, 3, and 4
Peak (AUC0.5-2hours and AUC0-2hours) of MPO Activity/MPO Mass	MPO is a heme-containing peroxidase enzyme produced in the bone marrow and stored in the azurophilic granules of neutrophils, where it constitutes up to 5% of the cellular protein. Since PF-06282999 is a mechanism-based inactivator of MPO, it is of interest to evaluate the level of MPO activity in order to investigate the inhibition activity of PF-06282999.	Days 1, 3-5
Maximum Plasma Concentration (Cmax) of PF-06282999		Day 3
Area Under the Concentration-time Profile From Time 0 to End of Dosing Interval, Tau (AUCtau) of PF-06282999		Day 3
Time to Cmax (Tmax) of PF-06282999		Day 3

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: March 1, 2014
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: October 15, 2013
• First Submitted That Met QC Criteria: October 15, 2013
• First Posted (Estimate): October 18, 2013

Study Record Updates

• Last Update Posted (Estimate): August 2, 2016
• Last Update Submitted That Met QC Criteria: June 21, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Endotoxin challenge
• Other Study ID Numbers: B5211007; 2013-001528-20 (EudraCT Number)