A Study To Evaluate The Effect Of PF-04447943 On Qtc Interval In Healthy Adult Subjects

Study Overview
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Brief Summary
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This is a study designed to ascertain the effect of PF-04447943 on QT interval in healthy adult subjects. This is conducted as part of standard drug development.

Official Title
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A Phase 1, Single-dose, Randomized, 4-treatment, 4-period Crossover, Placebo- And Positive-controlled, Double-blind (Open-label For Positive Control), Sponsor-open Study To Determine The Effect Of PF-04447943 On Qtc Interval In Healthy Adult Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: PF-04447943
* Drug: Placebo
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy female subjects of non childbearing potential and/or healthy male subjects, between the ages of 18 and 55 years. Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). History of cerebrovascular accident, transient ischemic attack (TIA), or traumatic brain injury. History of seizures or history or physical examination findings (eg localizing signs on neurologic examination) suggestive of structural central nervous system (CNS) abnormalities which may place patient at increased risk of seizures. History of orthostatic blood pressure changes or clinically significant orthostatic symptoms. Self reported history or risk factors for QT prolongation or torsades de pointes (eg, organic heart disease, congestive heart failure, hypokalemia, hypomagnesaemia, congenital long QT syndrome, myocardial ischemia or infarction), congenital deafness, family history of sudden death, and family history of long QT syndrome.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04447943 low dose<br>25 mg of PF-04447943 | Drug: PF-04447943<br>* Single oral dose of PF-04447943 administered as an extemporaneously prepared solution<br>|
| Experimental: PF-04447943 high dose<br>100 mg of PF-04447943 | Drug: PF-04447943<br>* Single oral dose of PF-04447943 administered as an extemporaneously prepared solution<br>|
| Placebo Comparator: Placebo<br>Matching placebo for PF-04447943 | Drug: Placebo<br>* Single oral dose of matching placebo for PF-04447943 administered as an extemporaneously prepared solution<br>|
| Active Comparator: Moxifloxacin<br>400 mg of moxifloxacin | Drug: Moxifloxacin<br>* Single oral dose of moxifloxacin administered as tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for PF-04447943 and Placebo at 0.5 Hour Post-Dose | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 0.5 hour post-dose | 
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for PF-04447943 and Placebo at 1 Hour Post-Dose | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 1 hour post-dose | 
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for PF-04447943 and Placebo at 2 Hours Post-Dose | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 2 hours post-dose | 
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for PF-04447943 and Placebo at 3 Hours Post-Dose | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 3 hours post-dose | 
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for PF-04447943 and Placebo at 4 Hours Post-Dose | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 4 hours post-dose | 
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for PF-04447943 and Placebo at 8 Hours Post-Dose | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 8 hours post-dose | 
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for PF-04447943 and Placebo at 12 Hours Post-Dose | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 12 hours post-dose | 
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for PF-04447943 and Placebo at 24 Hours Post-Dose | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-Matched Mean Difference in Corrected QT Interval Using Fridericia's Correction Method (QTcF) for Moxifloxacin and Placebo | Least square mean of QTcF measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across Moxifloxacin and placebo is reported in statistical analysis. | 0.5, 1 , 2, 3, 4, 8, 12 and 24 hours post-dose | 
| Time-Matched Mean Difference in Heart Rate for PF-04447943 and Placebo | Least square mean of heart rate measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 0.5, 1 , 2, 3, 4, 8, 12 and 24 hours post-dose | 
| Time-Matched Mean Difference in PR Interval for PF-04447943 and Placebo | Least square mean of PR interval measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose | 
| Time-Matched Mean Difference in QRS Interval for PF-04447943 and Placebo | Least square mean of QRS interval measure for each reporting arm has been reported in summary or descriptive statistics. Least square mean difference across PF-04447943 25 mg and placebo; PF-04447943 100 mg and placebo is reported in statistical analysis. | 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. | Baseline (Pre-dose) up to 28 days after last dose of study drug (56 days) | 
| Number of Participants With Physical Examination Abnormalities | Full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Physical examination abnormalities were judged by the investigator. | Baseline (Pre-dose) | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: maximum QTc corrected for heart rate using Bazett's formula (QTcB) and QTcF interval (450 to less than [<] 480 msec, 480 to <500 msec, greater than or equal to [>=] 500 msec; increase from baseline [IFB] >=30 msec and <60 msec, IFB >=60 msec). Baseline was defined as the average of the means obtained from the 3 sets of triplicate measurements taken at -1, -0.5 and 0 hours pre-dose on Day 1 within each intervention period. | Baseline up to 24 hours post-dose | 
| Number of Participants With Vital Sign Abnormalities | Criteria for vital sign abnormalities: supine and standing pulse rate <40 bpm or greater than (>) 120 bpm, supine and standing systolic blood pressure (SBP) <90 millimeter of mercury (mmHg), supine and standing diastolic blood pressure (DBP) <50 mmHg, maximum (max.) increase from baseline (IFB) and decrease from baseline (DFB) in supine and standing SBP of >=30 mmHg, maximum IFB and DFB in supine and Standing DBP of >=20 mmHg. | Baseline (Pre-dose) up to 24 hours post-dose | 
| Number of Participants With Laboratory Test Abnormalities | Hemoglobin(Hgb), hematocrit, red blood cell(RBC)<0.8*lower limit of normal(LLN), mean corpuscular(MC) Hgb, MC volume <0.9*LLN, >1.1*upper limit of normal(ULN), platelet<0.5*LLN,>1.75*ULN, lymphocyte, neutrophil<0.8*LLN, >1.2*ULN, basophil, eosinophil, monocyte>1.2*ULN, white blood cell(WBC)<0.6*LLN,>1.5*ULN, reticulocytes<0.5*LLN,>1.5*ULN; bilirubin>1.5*ULN, aspartate aminotransferase(AT), alanine AT, alkaline phosphatase>3.0*ULN, protein, albumin<0.8*LLN,>1.2*ULN; blood urea nitrogen, creatinine>1.3*ULN, uric acid>1.2*ULN; sodium<0.95*LLN,>1.05*ULN, potassium, chloride, calcium, bicarbonate<0.9*LLN,>1.1*ULN; glucose<0.6*LLN, >1.5*ULN, HbA1c>1.3*ULN, creatinine kinase>2*ULN; urine-specific gravity<1.003,>1.030, pH<4.5,>8, WBC, RBC>=20, bacteria>20, urobilinogen, glucose, ketone, protein, Hgb, nitrite, leukocyte esterase, bilirubin>=1; thyroid stimulating hormone<0.8*LLN,>1.2*ULN; cholesterol, triglycerides>1.3*ULN, high density lipoprotein cholesterol(DL-C) <0.8*LLN, low DL-C>1.2*ULN. | Baseline (Pre-dose) up to 24 hours post-dose | 
| Maximum Plasma Concentration (Cmax) of PF-04447943 |  | Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose | 
| Time of Observed Maximum Plasma Concentration (Tmax) of PF-04447943 |  | Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) of PF-04447943 | Area under the plasma concentration-time from time zero to time of last measurable concentration. Observed using the linear/log trapezoidal method. | Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose |