Healthy Volunteers
Conditions
Keywords
QT/QTc
Brief summary
To assess the effect of immediate-release guanfacine hydrochloride, administered at therapeutic and supratherapeutic doses, on QT/QTc in healthy normal males and females
Interventions
DRUGimmediate release guanfacine hydrochloride
Subjects will receive 2x2mg immediate-release guanfacine on day 1. Subjects will receive 4x2mg immediate-release guanfacine on day 6.
DRUGmoxifloxacin
Subjects will receive 400mg of moxifloxacin on day 1. Subjects will receive 400mg of moxifloxacin on day 6.
DRUGPlacebo
Subjects will receive placebo on Day 1. Subjects will receive placebo on Day 6.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy Normal Subjects
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 6 | Baseline and Tmax (time of subject-specific maximum plasma concentration) | QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). |
| Change From Baseline in Electrocardiogram Results (QTcNi) at Time of Maximum Plasma Concentration (Tmax) on Day 1 | Baseline, Tmax (time of subject-specific maximum plasma concentration) | QTcNi is the QT interval using a subject-specific correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation. |
| Change From Baseline in Electrocardiogram Results (QTcNi) at Tmax on Day 6 | Baseline and Tmax (time of subject-specific maximum plasma concentration) | QTcNi is the QT interval using a subject-specific correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation. |
| Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 1 | Baseline and Tmax (time of subject-specific maximum plasma concentration) | QTcF is the QT interval using Fridericia's correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation. |
| Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 6 | Baseline and Tmax (time of subject-specific maximum plasma concentration) | QTcF is the QT interval using Fridericia's correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation. |
| Change From Baseline in Heart Rate (HR) at Tmax on Day 1 | Baseline and Tmax (time of subject-specific maximum plasma concentration) | — |
| Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 1 | Baseline and Tmax (time of subject-specific maximum plasma concentration) | QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). |
| Change From Baseline in Heart Rate (HR) at Tmax on Day 6 | Baseline and Tmax (time of subject-specific maximum plasma concentration) | — |
Secondary
| Measure | Time frame |
|---|---|
| Maximum Plasma Concentration (Cmax) of Guanfacine and Moxifloxacin on Day 6 | pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose |
| Time of Maximum Plasma Concentration (Tmax) of Guanfacine and Moxifloxacin on Day 1 | pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose |
| Time of Maximum Plasma Concentration (Tmax) of Guanfacine and Moxifloxacin on Day 6 | pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose |
| Area Under the Steady-state Plasma Concentration-time Curve (AUC) for Guanfacine and Moxifloxacin on Day 1 | pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose |
| Area Under the Steady-state Plasma Concentration-time Curve (AUC) for Guanfacine and Moxifloxacin on Day 6 | pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose |
| Maximum Plasma Concentration (Cmax) of Guanfacine and Moxifloxacin on Day 1 | pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose |
Countries
United States
Participant flow
Pre-assignment details
This is a three period crossover trial.
Participants by arm
| Arm | Count |
|---|---|
| Guanfacine First Single 4 mg dose of immediate-release Guanfacine HCl on Day 1, 4 mg of immediate-release Guanfacine HCl bid on Days 2 and 3, 6 mg of immediate-release Guanfacine HCl bid on Days 4 and 5, and a single 8 mg dose of immediate-release Guanfacine HCl on Day 6 in first intervention period; single 400 mg dose of Moxifloxacin on Day 1, placebo bid on Days 2, 3, 4, and 5, and single 400 mg dose of Moxifloxacin on Day 6 in second intervention period (after washout period); single dose of placebo on Day 1, placebo bid on Days 2, 3, 4, and 5, and single dose of placebo on Day 6 in third intervention period (after washout period). | 31 |
| Moxifloxacin First Single 400 mg dose of Moxifloxacin on Day 1, placebo bid on Days 2, 3, 4, and 5, and single 400 mg dose of Moxifloxacin on Day 6 in first intervention period; single dose of placebo on Day 1, placebo bid on Days 2, 3, 4, and 5, and single dose of placebo on Day 6 in second intervention period (after washout period); single 4 mg dose of immediate-release Guanfacine HCl on Day 1, 4 mg of immediate-release Guanfacine HCl bid on Days 2 and 3, 6 mg of immediate-release Guanfacine HCl bid on Days 4 and 5, and a single 8 mg dose of immediate-release Guanfacine HCl on Day 6 in third intervention period (after washout period). | 25 |
| Placebo First Single dose of placebo on Day 1, placebo bid on Days 2, 3, 4, and 5, and single dose of placebo on Day 6 in first intervention period; single 4 mg dose of immediate-release Guanfacine HCl on Day 1, 4 mg of immediate-release Guanfacine HCl bid on Days 2 and 3, 6 mg of immediate-release Guanfacine HCl bid on Days 4 and 5, and a single 8 mg dose of immediate-release Guanfacine HCl on Day 6 in second intervention period (after washout period); single 400 mg dose of Moxifloxacin on Day 1, placebo bid on Days 2, 3, 4, and 5, and single 400 mg dose of Moxifloxacin on Day 6 in third intervention period (after washout period). | 27 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| First Intervention | Adverse Event | 5 | 0 | 0 |
| First Intervention | Sponsor decision | 3 | 0 | 0 |
| First Intervention | Withdrawal by Subject | 1 | 2 | 2 |
| Second Intervention | Non-compliance with facility policies | 0 | 2 | 0 |
| Second Intervention | Protocol Violation | 0 | 1 | 1 |
| Second Intervention | Withdrawal by Subject | 0 | 3 | 0 |
| Third Intervention | Adverse Event | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Guanfacine First | Moxifloxacin First | Placebo First |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 83 Participants | 31 Participants | 25 Participants | 27 Participants |
| Age, Continuous | 29.4 years STANDARD_DEVIATION 8.61 | 27.7 years STANDARD_DEVIATION 7.55 | 30.8 years STANDARD_DEVIATION 10.02 | 30.2 years STANDARD_DEVIATION 8.71 |
| Region of Enrollment United States | 83 Participants | 31 Participants | 25 Participants | 27 Participants |
| Sex: Female, Male Female | 43 Participants | 16 Participants | 13 Participants | 14 Participants |
| Sex: Female, Male Male | 40 Participants | 15 Participants | 12 Participants | 13 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 | 76 / 76 | 46 / 72 | 39 / 68 |
| serious Total, serious adverse events | 5 / 76 | 0 / 72 | 0 / 68 |
Outcome results
Primary
Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 1
QTcF is the QT interval using Fridericia's correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation.
Time frame: Baseline and Tmax (time of subject-specific maximum plasma concentration)
Population: PD population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 1 | 0.15 msec | Standard Error 0.96 |
| Moxifloxacin | Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 1 | 9.96 msec | Standard Error 0.92 |
| Placebo (Guanfacine) | Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 1 | -0.83 msec | Standard Error 0.97 |
| Placebo (Moxifloxacin) | Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 1 | -1.14 msec | Standard Error 0.92 |
90% CI: [-1.07, 3.03]
90% CI: [8.97, 13.24]
Primary
Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 6
QTcF is the QT interval using Fridericia's correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation.
Time frame: Baseline and Tmax (time of subject-specific maximum plasma concentration)
Population: PD population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 6 | -2.67 msec | Standard Error 1.24 |
| Moxifloxacin | Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 6 | 6.44 msec | Standard Error 1.65 |
| Placebo (Guanfacine) | Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 6 | -4.31 msec | Standard Error 1.25 |
| Placebo (Moxifloxacin) | Change From Baseline in Electrocardiogram Results (QTcF) at Tmax on Day 6 | -4.35 msec | Standard Error 1.68 |
90% CI: [-0.99, 4.27]
90% CI: [7.63, 13.97]
Primary
Change From Baseline in Electrocardiogram Results (QTcNi) at Time of Maximum Plasma Concentration (Tmax) on Day 1
QTcNi is the QT interval using a subject-specific correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation.
Time frame: Baseline, Tmax (time of subject-specific maximum plasma concentration)
Population: Pharmacodynamic (PD) population consists of all evaluable subjects with no major protocol deviations. Evaluable subjects were defined as subjects who received a Day 6 dose and had Day 6 data for the primary and secondary endpoints for all three periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Change From Baseline in Electrocardiogram Results (QTcNi) at Time of Maximum Plasma Concentration (Tmax) on Day 1 | -3.37 msec | Standard Error 1 |
| Moxifloxacin | Change From Baseline in Electrocardiogram Results (QTcNi) at Time of Maximum Plasma Concentration (Tmax) on Day 1 | 12.96 msec | Standard Error 1.03 |
| Placebo (Guanfacine) | Change From Baseline in Electrocardiogram Results (QTcNi) at Time of Maximum Plasma Concentration (Tmax) on Day 1 | -0.94 msec | Standard Error 1.02 |
| Placebo (Moxifloxacin) | Change From Baseline in Electrocardiogram Results (QTcNi) at Time of Maximum Plasma Concentration (Tmax) on Day 1 | -0.91 msec | Standard Error 1.04 |
90% CI: [-4.52, -0.34]
90% CI: [11.45, 16.29]
Primary
Change From Baseline in Electrocardiogram Results (QTcNi) at Tmax on Day 6
QTcNi is the QT interval using a subject-specific correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation.
Time frame: Baseline and Tmax (time of subject-specific maximum plasma concentration)
Population: PD population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Change From Baseline in Electrocardiogram Results (QTcNi) at Tmax on Day 6 | -12.45 msec | Standard Error 1.5 |
| Moxifloxacin | Change From Baseline in Electrocardiogram Results (QTcNi) at Tmax on Day 6 | 8.99 msec | Standard Error 1.79 |
| Placebo (Guanfacine) | Change From Baseline in Electrocardiogram Results (QTcNi) at Tmax on Day 6 | -4.37 msec | Standard Error 1.52 |
| Placebo (Moxifloxacin) | Change From Baseline in Electrocardiogram Results (QTcNi) at Tmax on Day 6 | -4.13 msec | Standard Error 1.84 |
90% CI: [-11.37, -4.78]
90% CI: [9.33, 16.93]
Primary
Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 1
QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval).
Time frame: Baseline and Tmax (time of subject-specific maximum plasma concentration)
Population: PD population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 1 | 15.88 msec | Standard Error 1.63 |
| Moxifloxacin | Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 1 | -1.27 msec | Standard Error 1.74 |
| Placebo (Guanfacine) | Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 1 | 0.56 msec | Standard Error 1.63 |
| Placebo (Moxifloxacin) | Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 1 | -2.20 msec | Standard Error 1.74 |
90% CI: [11.75, 18.89]
90% CI: [-2.77, 4.63]
Primary
Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 6
QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval).
Time frame: Baseline and Tmax (time of subject-specific maximum plasma concentration)
Population: PD population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 6 | 46.21 msec | Standard Error 2.4 |
| Moxifloxacin | Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 6 | -3.09 msec | Standard Error 2.15 |
| Placebo (Guanfacine) | Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 6 | -3.63 msec | Standard Error 2.4 |
| Placebo (Moxifloxacin) | Change From Baseline in Electrocardiogram Results (QT) Interval at Tmax on Day 6 | -6.71 msec | Standard Error 2.19 |
90% CI: [44.71, 54.98]
90% CI: [-0.41, 7.66]
Primary
Change From Baseline in Heart Rate (HR) at Tmax on Day 1
Time frame: Baseline and Tmax (time of subject-specific maximum plasma concentration)
Population: PD population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Change From Baseline in Heart Rate (HR) at Tmax on Day 1 | -7.18 bpm | Standard Error 0.58 |
| Moxifloxacin | Change From Baseline in Heart Rate (HR) at Tmax on Day 1 | 5.46 bpm | Standard Error 0.79 |
| Placebo (Guanfacine) | Change From Baseline in Heart Rate (HR) at Tmax on Day 1 | -0.42 bpm | Standard Error 0.58 |
| Placebo (Moxifloxacin) | Change From Baseline in Heart Rate (HR) at Tmax on Day 1 | 0.73 bpm | Standard Error 0.79 |
90% CI: [-8.01, -5.51]
90% CI: [3.08, 6.38]
Primary
Change From Baseline in Heart Rate (HR) at Tmax on Day 6
Time frame: Baseline and Tmax (time of subject-specific maximum plasma concentration)
Population: PD population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Change From Baseline in Heart Rate (HR) at Tmax on Day 6 | -19.74 bpm | Standard Error 0.89 |
| Moxifloxacin | Change From Baseline in Heart Rate (HR) at Tmax on Day 6 | 4.66 bpm | Standard Error 0.83 |
| Placebo (Guanfacine) | Change From Baseline in Heart Rate (HR) at Tmax on Day 6 | 0.11 bpm | Standard Error 0.89 |
| Placebo (Moxifloxacin) | Change From Baseline in Heart Rate (HR) at Tmax on Day 6 | 1.22 bpm | Standard Error 0.85 |
90% CI: [-21.92, -17.78]
90% CI: [1.77, 5.11]
Secondary
Area Under the Steady-state Plasma Concentration-time Curve (AUC) for Guanfacine and Moxifloxacin on Day 1
Time frame: pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Area Under the Steady-state Plasma Concentration-time Curve (AUC) for Guanfacine and Moxifloxacin on Day 1 | 110.8 ng.h/ml | Standard Deviation 24.4 |
| Moxifloxacin | Area Under the Steady-state Plasma Concentration-time Curve (AUC) for Guanfacine and Moxifloxacin on Day 1 | 19892 ng.h/ml | Standard Deviation 4670 |
Secondary
Area Under the Steady-state Plasma Concentration-time Curve (AUC) for Guanfacine and Moxifloxacin on Day 6
Time frame: pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Area Under the Steady-state Plasma Concentration-time Curve (AUC) for Guanfacine and Moxifloxacin on Day 6 | 370.3 ng.h/ml | Standard Deviation 101.3 |
| Moxifloxacin | Area Under the Steady-state Plasma Concentration-time Curve (AUC) for Guanfacine and Moxifloxacin on Day 6 | 20767 ng.h/ml | Standard Deviation 4396 |
Secondary
Maximum Plasma Concentration (Cmax) of Guanfacine and Moxifloxacin on Day 1
Time frame: pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose
Population: Pharmacokinetic (PK) population consists of all subjects in the safety population (subjects who had taken one dose of study medication and had one follow-up safety assessment completed) who had evaluable concentration-time profiles.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Maximum Plasma Concentration (Cmax) of Guanfacine and Moxifloxacin on Day 1 | 8.51 ng/ml | Standard Deviation 1.77 |
| Moxifloxacin | Maximum Plasma Concentration (Cmax) of Guanfacine and Moxifloxacin on Day 1 | 1943.1 ng/ml | Standard Deviation 463.8 |
Secondary
Maximum Plasma Concentration (Cmax) of Guanfacine and Moxifloxacin on Day 6
Time frame: pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Maximum Plasma Concentration (Cmax) of Guanfacine and Moxifloxacin on Day 6 | 24.70 ng/ml | Standard Deviation 6.1 |
| Moxifloxacin | Maximum Plasma Concentration (Cmax) of Guanfacine and Moxifloxacin on Day 6 | 2003.4 ng/ml | Standard Deviation 477.4 |
Secondary
Time of Maximum Plasma Concentration (Tmax) of Guanfacine and Moxifloxacin on Day 1
Time frame: pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Time of Maximum Plasma Concentration (Tmax) of Guanfacine and Moxifloxacin on Day 1 | 3.9 hours | Standard Deviation 1.9 |
| Moxifloxacin | Time of Maximum Plasma Concentration (Tmax) of Guanfacine and Moxifloxacin on Day 1 | 2.13 hours | Standard Deviation 1.08 |
Secondary
Time of Maximum Plasma Concentration (Tmax) of Guanfacine and Moxifloxacin on Day 6
Time frame: pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine 4 mg | Time of Maximum Plasma Concentration (Tmax) of Guanfacine and Moxifloxacin on Day 6 | 5.2 hours | Standard Deviation 2.3 |
| Moxifloxacin | Time of Maximum Plasma Concentration (Tmax) of Guanfacine and Moxifloxacin on Day 6 | 1.78 hours | Standard Deviation 0.89 |