CP-690,550 Thorough QTc Study

Study Overview
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Brief Summary
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ICH E14 recommends that a thorough QT/QTc (TQT) study should be performed to determine whether intensive monitoring of QT interval in target patient populations is required during later stages of development. The current study is designed to ascertain whether CP-690,550 is associated with QTc prolongation.

Detailed Description
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The current study is designed to ascertain whether CP-690,550 is associated with QTc prolongation

Official Title
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A PHASE 1, RANDOMIZED, PLACEBO- AND POSITIVE-CONTROLLED CROSS-OVER STUDY TO DETERMINE THE EFFECT OF SINGLE-DOSE CP-690,550 ON QTC INTERVAL IN HEALTHY VOLUNTEERS

Conditions
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Healthy

Intervention / Treatment
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* Drug: CP-690,550
* Drug: Placebo
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and/or female subjects between ages of 18 and 55 years, inclusive. Body Mass Index (BMI) of approximately 18 to 30 kg/m2; and a total body weight >50 kg (110 lbs). Exclusion Criteria: Use of tobacco- or nicotine-containing products in excess of equivalent of 5 cigarettes per day. 12-lead ECG demonstrating QTc >450 msec or other clinically significant abnormalities at Screening. History of risk factors for QT prolongation or torsades de pointes. Pregnant or nursing women; women of childbearing potential unwilling or unable to use an acceptable method of nonhormonal contraception from at least 14 days prior to first dose until completion of follow-up. Use of prescription or nonprescription drugs, vitamins and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to first dose of trial medication. Any clinically significant infections within past 3 months or evidence of infection in past 7 days.

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CP-690,550 100 mg<br> | Drug: CP-690,550<br>* Single dose 100 mg (5 x 20 mg tablets)<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Single dose placebo tablets (5 tablets)<br>|
| Active Comparator: Moxifloxacin hydrochloride<br> | Drug: Moxifloxacin<br>* Single dose Avelox 400 mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 0.25 Hour Post-Dose | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to the beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as Least Squares (LS) mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 0.25 hour post-dose | 
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 0.5 Hour Post-Dose | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 0.5 hour post-dose | 
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 1 Hour Post-Dose | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 1 hour post-dose | 
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 2 Hours Post-Dose | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 2 hours post-dose | 
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 4 Hours Post-Dose | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 4 hours post-dose | 
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 8 Hours Post-Dose | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 8 hours post-dose | 
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 12 Hours Post-Dose | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 12 hours post-dose | 
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 16 Hours Post-Dose | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 16 hours post-dose | 
| Mean Time-Matched Difference in QTcF Intervals Between CP-690,550 Compared to Placebo at 24 Hours Post-Dose | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Time-Matched Difference in QTcF Intervals Between Moxifloxacin Compared to Placebo | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Data is reported as LS mean difference (moxifloxacin minus Placebo, baseline-adjusted). | 2 hours post-dose | 
| Mean Time-Matched Difference in QTcB Intervals Between CP-690,550 Compared to Placebo | Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The QT interval was adjusted for RR interval using the QT and RR from each ECG by Bazett's formula (QTcB = QT divided by square root of RR). Data is reported as LS mean difference (CP-690,550 minus Placebo, baseline-adjusted). | 0.25, 0.5, 1, 2, 4, 8, 12, 16, and 24 hours post-dose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] for CP-690,550 | AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for CP-690,550 | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of CP-690,550 |  | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for CP-690,550 |  | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Plasma Decay Half-Life (t1/2) of CP-690,550 | Plasma decay half-life is the time measured for the plasma concentration of drug to decrease by one half. | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of CP-690,550 by Cytochrome P450 2C19 (CYP2C19) Genotype | AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). Variation in CYP2C19 gene affected the pharmacokinetics of CP-690,550. AUC (0 - ∞) categorized by genotype into poor metabolizer, extensive metabolizer and ultra extensive metabolizer of CYP2C19. | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of CP-690,550 by CYP2C19 Genotype | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Variation in CYP2C19 gene affected the pharmacokinetics of CP-690,550. AUClast categorized by genotype as poor metabolizer, extensive metabolizer and ultra extensive metabolizer of CYP2C19. | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of CP-690,550 by CYP2C19 Genotype | Variation in CYP2C19 gene affected the pharmacokinetics of CP-690,550. Cmax categorized by genotype as poor metabolizer, extensive metabolizer and ultra extensive metabolizer of CYP2C19. | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of CP-690,550 by CYP2C19 Genotype | Variation in CYP2C19 gene affected the pharmacokinetics of CP-690,550. Tmax categorized by genotype as poor metabolizer, extensive metabolizer and ultra extensive metabolizer of CYP2C19. | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 
| Plasma Decay Half-Life (t1/2) of CP-690,550 by CYP2C19 Genotype | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Variation in CYP2C19 gene affected the pharmacokinetics of CP-690,550. t1/2 categorized by genotype as poor metabolizer, extensive metabolizer and ultra extensive metabolizer of CYP2C19. | 0 (pre-dose), and 0.25, 0.5, 1, 2, 4, 8, 12, 16 and 24 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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550, CP-690, TQT study