Healthy
Conditions
Keywords
Endotoxin challenge
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.
Interventions
DRUGPF-06282999
Tablet, 125 mg, TID, 3 days, 1 of 2 periods
DRUGPlacebo
Tablet, 0 mg, TID, 3 days, 1 of 2 periods
OTHERLPS
IV bolus, 4 ng/kg, 1 day, QD, 2 of 2 periods
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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 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 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received PF-06282999 125 mg TID or 500 mg BID or matching placebo orally in tablet form from Days 1 to 3. On Day 3, participants received a dose of LPS as an IV bolus at a dose of 4 ng/kg over 45-60 secs 2 hours after the morning dose of PF-06282999 or matching placebo. A final dose of PF-06282999 or matching placebo was administered on the evening of Day 3. Period 2 started after a washout period of approximately 15 days with at least 21 days in between administration of LPS. Participants who took active treatment (PF-06282999) in Period 1 received placebo in Period 2 and vice versa. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Second Intervention | Study terminated by Sponsor | 0 | 0 | 2 | 2 |
| Washout Period of Approximately 15 Days | Adverse Event | 0 | 0 | 0 | 1 |
| Washout Period of Approximately 15 Days | Did not meet entrance criteria | 1 | 0 | 0 | 0 |
| Washout Period of Approximately 15 Days | Study terminated by Sponsor | 1 | 3 | 2 | 1 |
| Washout Period of Approximately 15 Days | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 32.2 years STANDARD_DEVIATION 5.3 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 17 / 19 | 5 / 7 |
| serious Total, serious adverse events | 0 / 10 | 0 / 19 | 0 / 7 |
Outcome results
Primary
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.
Time frame: Days 1, 3-5
Population: Due to early termination of the study, there was not enough participants to perform meaningful analysis on this endpoint. As such, no analysis was done.
Primary
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.
Time frame: Days 1, 3-5
Population: Due to early termination of the study, there was not enough participants to perform meaningful analysis on this endpoint. As such, no analysis was done.
Primary
Number of Participants With Abnormal Urinary Biomarker Values
Urinary biomarkers included albumin, neutrophil gelatinase-associated lipocalin (NGAL) and Cystatin-C.
Time frame: Days 1-3 prior to dosing with PF-06282999/Placebo; and Days 4-5
Population: Analysis not done due to early termination of study.
Primary
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.
Time frame: 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
Population: All participants who received at least 1 dose of study medication (including LPS) were included in the safety analyses and listings. n=number of participants evaluable for that parameter
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine PR >120 bpm (n=10,18,7) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth supine DBP >=20 mm Hg (n=10,18,7) | 1 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth supine DBP >=20 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting PR <40 bpm (n=1,0,0) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting SBP <90 mm Hg (n=1,0,0) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth standing SBP >=30 mm Hg (n=10,17,6) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing PR <40 bpm (n=10,17,6) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in supine SBP >=30 mm Hg (n=10,17,5) | 1 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Increase in orth supine SBP >=30 mm Hg (n=10,18,7) | 1 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing PR >140 bpm (n=10,17,6) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth standing SBP >=30 mm Hg (n=10,17,6) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine PR >120 bpm (n=10,17,5) | 1 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine SBP <90 mm Hg (n=10,17,5) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing SBP <90 mm Hg (n=10,17,6) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine PR <40 bpm (n=10,17,5) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine DBP <50 mm Hg (n=10,17,5) | 1 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic PR <40 bpm (n=0,1,0) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth supine SBP >=30 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine DBP <50 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic DBP <50 mm Hg (n=0,1,0) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in supine DBP >=20 mm Hg (n=10,17,5) | 1 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting DBP <50 mm Hg (n=1,0,0) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth standing DBP >=20 mm Hg (n=10,17,6) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic SBP <90 mm Hg (n=0,1,0) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing DBP <50 mm Hg (n=10,17,6) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine SBP <90 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in supine SBP >=30 mm Hg (n=10,17,5) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine PR <40 bpm (n=10,18,7) | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in supine DBP >=20 mm Hg (n=10,17,5) | 1 participants |
| PF-06282999 125 mg TID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth standing DBP >=20 mm Hg (n=10,17,6) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in supine SBP >=30 mm Hg (n=10,17,5) | 4 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic SBP <90 mm Hg (n=0,1,0) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic DBP <50 mm Hg (n=0,1,0) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic PR <40 bpm (n=0,1,0) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine SBP <90 mm Hg (n=10,18,7) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting SBP <90 mm Hg (n=1,0,0) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing SBP <90 mm Hg (n=10,17,6) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine DBP <50 mm Hg (n=10,18,7) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting DBP <50 mm Hg (n=1,0,0) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing DBP <50 mm Hg (n=10,17,6) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine PR <40 bpm (n=10,18,7) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine PR >120 bpm (n=10,18,7) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting PR <40 bpm (n=1,0,0) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing PR <40 bpm (n=10,17,6) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing PR >140 bpm (n=10,17,6) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine SBP <90 mm Hg (n=10,17,5) | 2 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine DBP <50 mm Hg (n=10,17,5) | 2 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine PR <40 bpm (n=10,17,5) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine PR >120 bpm (n=10,17,5) | 4 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Increase in orth supine SBP >=30 mm Hg (n=10,18,7) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth standing SBP >=30 mm Hg (n=10,17,6) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth supine DBP >=20 mm Hg (n=10,18,7) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth standing DBP >=20 mm Hg (n=10,17,6) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in supine DBP >=20 mm Hg (n=10,17,5) | 3 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth supine SBP >=30 mm Hg (n=10,18,7) | 1 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth standing SBP >=30 mm Hg (n=10,17,6) | 2 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth supine DBP >=20 mm Hg (n=10,18,7) | 0 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth standing DBP >=20 mm Hg (n=10,17,6) | 1 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in supine SBP >=30 mm Hg (n=10,17,5) | 1 participants |
| Placebo | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in supine DBP >=20 mm Hg (n=10,17,5) | 4 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine PR >120 bpm (n=10,18,7) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic PR <40 bpm (n=0,1,0) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth supine DBP >=20 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine PR <40 bpm (n=10,18,7) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic SBP <90 mm Hg (n=0,1,0) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth standing DBP >=20 mm Hg (n=10,17,6) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing DBP <50 mm Hg (n=10,17,6) | 1 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting DBP <50 mm Hg (n=1,0,0) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in supine SBP >=30 mm Hg (n=10,17,5) | 1 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine DBP <50 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth standing DBP >=20 mm Hg (n=10,17,6) | 1 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in supine DBP >=20 mm Hg (n=10,17,5) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing SBP <90 mm Hg (n=10,17,6) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic DBP <50 mm Hg (n=0,1,0) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth supine SBP >=30 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting SBP <90 mm Hg (n=1,0,0) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in supine DBP >=20 mm Hg (n=10,17,5) | 2 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine DBP <50 mm Hg (n=10,17,5) | 1 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine SBP <90 mm Hg (n=10,17,5) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth standing SBP >=30 mm Hg (n=10,17,6) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine PR <40 bpm (n=10,17,5) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing PR >140 bpm (n=10,17,6) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic supine SBP <90 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Supine PR >120 bpm (n=10,17,5) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic standing PR <40 bpm (n=10,17,6) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in supine SBP >=30 mm Hg (n=10,17,5) | 1 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Increase in orth supine SBP >=30 mm Hg (n=10,18,7) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Orthostatic sitting PR <40 bpm (n=1,0,0) | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Dec in orth supine DBP >=20 mm Hg (n=10,18,7) | 1 participants |
| PF-06282999 500 mg BID | Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Inc in orth standing SBP >=30 mm Hg (n=10,17,6) | 0 participants |
Primary
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.
Time frame: Screening; Days 1-5 and approximately 7-10 days following the last dose of PF-06282999/Placebo in Period 2
Population: All participants who received at least 1 dose of study medication (including LPS) were included in the safety analyses and listings.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QRS increase >=50% | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | PR interval >=300 msec | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF 480 to <500 msec | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QT >=500 msec | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QRS >=140 msec | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF >=500 msec | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF increase >=60 msec | 1 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF increase 30 to <60 msec | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | PR interval increase >=25/50% | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF 450 to <480 msec | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | PR interval increase >=25/50% | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QRS increase >=50% | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF increase 30 to <60 msec | 3 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QT >=500 msec | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF increase >=60 msec | 2 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF 450 to <480 msec | 2 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF 480 to <500 msec | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF >=500 msec | 2 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QRS >=140 msec | 0 participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | PR interval >=300 msec | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF increase >=60 msec | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | PR interval >=300 msec | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QRS >=140 msec | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF 450 to <480 msec | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF 480 to <500 msec | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF >=500 msec | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | PR interval increase >=25/50% | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QRS increase >=50% | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QTcF increase 30 to <60 msec | 1 participants |
| PF-06282999 500 mg BID | Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | QT >=500 msec | 0 participants |
Primary
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.
Time frame: Baseline up to 7-10 days following the last dose of PF-06282999/Placebo in Period 2
Population: All participants who received at least 1 dose of study medication (including LPS) were included in the safety analyses and listings.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-06282999 125 mg TID | Number of Participants With Laboratory Test Abnormalities | 5 participants |
| Placebo | Number of Participants With Laboratory Test Abnormalities | 8 participants |
| PF-06282999 500 mg BID | Number of Participants With Laboratory Test Abnormalities | 5 participants |
Primary
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.
Time frame: From Day 0 till approximately 7-10 days following the last dose of PF-06282999/Placebo in Period 2 (up to approximately 2 months)
Population: All participants who received at least 1 dose of study medication (including LPS) were included in the safety analyses and listings.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-06282999 125 mg TID | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants with SAEs | 0 participants |
| PF-06282999 125 mg TID | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants with TEAEs | 10 participants |
| PF-06282999 125 mg TID | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants discontinued permanently due to TEAEs | 0 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants with SAEs | 0 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants with TEAEs | 17 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants discontinued permanently due to TEAEs | 1 participants |
| PF-06282999 500 mg BID | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants with TEAEs | 5 participants |
| PF-06282999 500 mg BID | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants discontinued permanently due to TEAEs | 0 participants |
| PF-06282999 500 mg BID | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs | Participants with SAEs | 0 participants |
Primary
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.
Time frame: Days 1, 3-5
Population: Due to early termination of the study, there was not enough participants to perform meaningful analysis on this endpoint. As such, no analysis was done.
Secondary
Area Under the Concentration-time Profile From Time 0 to End of Dosing Interval, Tau (AUCtau) of PF-06282999
Time frame: Day 3
Population: Due to early termination of the study, no data was collected for this endpoint.
Secondary
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).
Time frame: Days 1, 3, and 4
Population: Due to early termination of the study, there was not enough participants to perform meaningful analysis on this endpoint. As such, no analysis was done.
Secondary
Maximum Plasma Concentration (Cmax) of PF-06282999
Time frame: Day 3
Population: Due to early termination of the study, there was not enough participants to perform meaningful analysis on this endpoint. As such, no analysis was done.
Secondary
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.
Time frame: Days 1, 3-5
Population: Due to early termination of the study, there was not enough participants to perform meaningful analysis on this endpoint. As such, no analysis was done.
Secondary
Time to Cmax (Tmax) of PF-06282999
Time frame: Day 3
Population: Due to early termination of the study, no data was collected for this endpoint.