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

Phase 1

Terminated

Conditions: Healthy

Interventions: Drug: PF-06282999
Drug: Placebo
Other: LPS

Registration Number: NCT01965600

Lead Sponsor: Pfizer

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 23

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Cohort 1	LPS	-
Cohort 1	Placebo	-
Cohort 2	Placebo	-
Cohort 2	LPS	-
Cohort 1	PF-06282999	-
Cohort 2	PF-06282999	-

Primary Outcome Measures

Name	Time	Method
Peak Myeloperoxidase (MPO) Activity Following Inflammatory Stimulus	Days 1, 3-5	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.
MPO Activity (Area Under the Concentration-time Profile From 0.5 to 2 Hours [AUC0.5-2hrs]) Following Inflammatory Stimulus	Days 1, 3-5	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.
MPO Activity (Area Under the Concentration-time Profile From 0 to 2 Hours [AUC0-2hrs]) Following Inflammatory Stimulus	Days 1, 3-5	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.
Number of Participants With Laboratory Test Abnormalities	Baseline up to 7-10 days following the last dose of PF-06282999/Placebo in Period 2	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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs	From Day 0 till approximately 7-10 days following the last dose of PF-06282999/Placebo in Period 2 (up to approximately 2 months)	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.
Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria	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	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.
Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria	Screening; Days 1-5 and approximately 7-10 days following the last dose of PF-06282999/Placebo in Period 2	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.
Number of Participants With Abnormal Urinary Biomarker Values	Days 1-3 prior to dosing with PF-06282999/Placebo; and Days 4-5	Urinary biomarkers included albumin, neutrophil gelatinase-associated lipocalin (NGAL) and Cystatin-C.

Secondary Outcome Measures

Name	Time	Method
Concentrations of TNF-alpha, IL-1 Beta, IL-6, IL-8, and hsCRP	Days 1, 3, and 4	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).
Peak (AUC0.5-2hours and AUC0-2hours) of MPO Activity/MPO Mass	Days 1, 3-5	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.
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

Trial Locations

Locations (2): (Drug Shipment Address ONLY) Duke University Health Systems (DUHS) Investigational Drug Services
🇺🇸
Durham, North Carolina, United States
Duke Clinical Research Unit
🇺🇸
Durham, North Carolina, United States