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

NCT01965600 | Terminated Phase 1 Results

• 2 other identifiers: B52110072013-001528-20
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 2

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.

Conditions

Healthy

Keywords

Endotoxin challenge

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (5)

• Concentrations of TNF-alpha, IL-1 Beta, IL-6, IL-8, and hsCRP

  Days 1, 3, and 4

• Peak (AUC0.5-2hours and AUC0-2hours) of MPO Activity/MPO Mass

  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

Study Arms (2)

Cohort 1

EXPERIMENTAL

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

Cohort 2

EXPERIMENTAL

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

Interventions

PF-06282999 DRUG

Tablet, 125 mg, TID, 3 days, 1 of 2 periods

Cohort 1

Placebo DRUG

Tablet, 0 mg, TID, 3 days, 1 of 2 periods

Cohort 1

LPS OTHER

IV bolus, 4 ng/kg, 1 day, QD, 2 of 2 periods

Also known as: Endotoxin

Cohort 1

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (2)

(Drug Shipment Address ONLY) Duke University Health Systems (DUHS) Investigational Drug Services

Durham, North Carolina, 27710, United States

Location

Duke Clinical Research Unit

Durham, North Carolina, 27710, United States

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Interventions

2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide; Endotoxins

Intervention Hierarchy (Ancestors)

Bacterial Toxins; Toxins, Biological; Biological Factors

Limitations and Caveats

Due to early study termination, PK, PD, or biomarker changes assessments were incomplete and there was only safety data from partial enrollment. As such, it was not possible to have meaningful interpretation and/or comparison of these data.

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc

ClinicalTrials.gov_Inquiries@pfizer.com

18007181021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 15, 2013
• First Posted: October 18, 2013
• Study Start: March 1, 2014
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: August 2, 2016
• Results First Posted: August 2, 2016

Record last verified: 2016-06

Locations

US (2)