Phase 1 Thorough QT Study in Young Healthy Volunteers

Inclusion Criteria

• •1. Healthy adult Caucasian men or non-pregnant, non-lactating women between 18 and 40 years of age, inclusive.
• •2. Healthy as judged by responsible physician with no clinically significant abnormality identified on the medical and laboratory evaluation, including 12-lead ECG and vital signs.
• •3. Non-smoker in the previous 3 months.
• •4. Body weight greater than or equal to 50 kg and BMI within the range 19-29 kg/m2, inclusive.
• •5. At screening and Run-in period each ECG should have:
• •* Consistent sinus rhythm, (i.e. if greater than or equal to 2 ECGs are not sinusal at different time points the volunteer should not be included),
• •* No clinically significant conduction disorder,
• •* PR between 120 and 230 ms,
• •* HR less than or equal to 100 beats/min and greater than or equal to 40 beats/min,
• •* QRS \< 120 ms,
• •* QT intervals that can be consistently analysed,
• •* QTcB less than or equal to 430 ms for males,
• •* QTcB less than or equal to 450 ms for females
• •If there are outlying values in the ECGs, the consistency of these values should be confirmed as follows:
• •* If HR is between 40 and 44 bpm (inclusive) in 2 ECGs (of one triplicate) on more than one time point during Run-in, subject should not be selected. Conversely, this means that if HR is between 40 and 44 bpm at screening and/or on just one time-point-triplicate during Run-in, the volunteer can be selected.
• •* If HR \< 40 bpm on a single occasion at screening or in Run-in period, subject should not be selected,
• •* If PR interval is consistently out-of-range (\< 120 or \> 230 ms) during Run-in period, i.e. in 2 out of 3 ECGs at one time point or in one ECG at more than one time point, the cardiologist needs to perform a manual measurement of this value. If the manual measurement confirms that PR is out-of-range, the volunteer must not be selected.
• •* If QRS is consistently \>120 ms during run-in period, i.e. in 2 ECGs of a triplicate or in 2 ECGs from 2 different time-points, the cardiologist needs to perform a manual measurement of this value. If the manual measurement confirms the QRS is out-of-range, the volunteer must not be selected.
• •* If QTcB is out of range (QTcB \>430 ms for males or \>450 ms for females, or repeated demonstration of a QTcB interval \>440 ms for females) even on a single occasion, it should be checked whether the heart rate is constant. If the HR is not constant and if the increase in QTcB is clearly due to hysteresis (e.g. on the immediate repeated ECG with consistent HR the QTcB is back to normal), then the volunteer can be selected. If the HR is constant and the QTcB is still out-of-range, the cardiologist needs to perform a manual measurement and calculation of the QTcB. If the QTcB is normal on manual measurement, the volunteer can be selected. If the QTcB is abnormal on manual measurement without acceptable cause, the volunteer must not be selected, even if the QTcB is outlying on one single ECG.
• •The final decision to include / not include a volunteer based on protocol ECG criteria lies with the cardiologist assessing the Run-in ECGs.
• •6. Signed and dated written informed consent prior to admission to the study.
• •7. The subject is able to understand and comply with protocol requirements, instructions, and protocol-stated restrictions.
• •8. A female subject may be entered into the study if she is:
• •* Post-menopausal female defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. appropriate age and history of vasomotor symptoms. However; if indicated, this should be confirmed by estradiol and FSH levels consistent with menopause (according to local laboratory ranges).
• •* Pre-menopausal females with a documented hysterectomy (medical report verification) and/or bilateral oophorectomy. In the case of oophorectomy alone, only acceptable when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• •* Females of childbearing potential must use one of the following methods of contraception:
• •* Abstinence
• •* Surgical sterilisation (tubal ligation)
• •* use oral contraceptives, injectable progesterone, or subdermal implants
• •* use double barrier method consisting of spermicide in addition to using a condom, or having another form of contraception such as an intrauterine device, diaphragm, or cervical cap.