CiPA Phase 1 ECG Biomarker Validation Study

This study will assess whether exposure response analysis of the electrocardiographic QTc
and J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that
"balanced ion channel" drugs do not cause J-Tpeakc prolongation and that "predominant hERG"
drugs cause QTc prolongation. This clinical study consists of 2 parts: a 50-subject parallel
part (Part 1) and a 10-subject crossover part (Part 2). Up to 74 healthy subjects will be
enrolled (including 14 potential replacement subjects).

Part 1 will be a double-blind, randomized, placebo-controlled, 1 period parallel design to
assess the effect of 4 marketed drugs and 1 placebo on the QTc and J-Tpeakc intervals in 50
healthy subjects. A parallel design similar to a single or multiple ascending dose (SAD/MAD)
Phase 1 study will be used that will result in each study drug being administered to 10
subjects, and placebo to 10 subjects, in 1 period of 3 consecutive days to achieve low and
high drug exposure.

Part 2 will be a double-blind, randomized, 2-period crossover design to assess the effect of
hERG block (dofetilide) versus calcium block (diltiazem) on the QTc and J-Tpeakc intervals
in 10 healthy subjects on Days 1, 2, and 3 (Period 1) and Days 8, 9, and 10 (Period 2).

Inclusion criteria:

1. Subject signs an institutional review board (IRB) approved written informed consent
and privacy language as per national regulations (e.g., Health Insurance Portability
and Accountability Act [HIPAA] authorization) before any study related procedures are
performed.

2. Subject is a healthy man or woman, 18 to 50 years of age, inclusive, who weighs at
least 50 kg (110 pounds) and has a body mass index of 18 to 30 kg/m2, inclusive, at
Screening.

3. Subject has normal medical history findings, clinical laboratory results, vital sign
measurements, 12 lead ECG results, and physical examination findings at Screening or,
if abnormal, the abnormality is not considered clinically significant (as determined
and documented by the investigator or designee).

4. Female subjects will be at least 2 years postmenopausal, surgically sterile, or
practicing 2 highly effective methods of birth control (as determined by the
investigator or designee; one of the methods must be a barrier technique).

5. Female subjects must not be pregnant or lactating before enrollment in the study.

6. Male or female subjects must agree to practice 2 highly effective methods of birth
control (as determined by the investigator or designee; one of the methods must be a
barrier technique) from Screening until 30 days after the last dose of study drug.

7. Subject is highly likely (as determined by the investigator) to comply with the
protocol defined procedures and to complete the study.

Exclusion criteria:

1. Subject has a safety 12 lead ECG result at Screening or Check in with evidence of any
of the following abnormalities:

- QTc using Fridericia correction (QTcF) >430 msec

- PR interval >220 msec or <120 msec

- QRS duration >110 msec

- Second- or third-degree atrioventricular block

- Complete left or right bundle branch block or incomplete right bundle branch
block

- Heart rate <50 or >90 beats per minute

- Pathological Q-waves (defined as Q wave >40 msec)

- Ventricular pre-excitation

2. Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening.

3. Subject has a history of unexplained syncope, structural heart disease, long QT
syndrome, heart failure, myocardial infarction, angina, unexplained cardiac
arrhythmia, torsade de pointes, ventricular tachycardia, or placement of a pacemaker
or implantable defibrillator. Subjects will also be excluded if there is a family
history of long QT syndrome (genetically proven or suggested by sudden death of a
close relative due to cardiac causes at a young age) or Brugada syndrome.

4. Subject has a history or current evidence of any clinically significant (as
determined by the investigator) cardiovascular, dermatologic, endocrine,
gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurologic,
psychiatric, pulmonary, renal, urologic, and/or other major disease or malignancy
(excluding nonmelanoma skin cancer). The investigator may allow exceptions to these
criteria (e.g., cholecystectomy, childhood asthma) following discussion with the
medical monitor.

5. Subject has a history of thoracic surgery.

6. Subject has any condition possibly affecting study drug absorption (e.g.,
gastrectomy, Crohn's disease, irritable bowel syndrome).

7. Subject has a skin condition likely to compromise ECG electrode placement.

8. Subject is a female with breast implants.

9. Subject's laboratory test results at Screening or Check in are outside the reference
ranges provided by the clinical laboratory and considered clinically significant (as
determined and documented by the investigator or designee).

10. Subject's laboratory test results at Screening or Check in indicate hypokalemia,
hypocalcemia, or hypomagnesemia according to lower limits of the reference ranges
provided by the clinical laboratory.

11. Subject's laboratory test results at Screening or Check in are >2 × the upper limit
of normal (ULN) for alanine aminotransferase or aspartate aminotransferase, >1.5 ×
ULN for bilirubin, or >1.5 × ULN for creatinine.

12. Subject has a positive test result at Screening for human immunodeficiency virus I or
II antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.

13. Subject has a mean systolic blood pressure <100 or >140 mmHg or a mean diastolic
blood pressure <50 or >90 mmHg at either Screening or Check in. Blood pressure will
be measured in triplicate after the subject has been resting in a supine position for
a minimum of 5 minutes.

14. Subject has a known hypersensitivity to any of the study drugs or related compounds.

15. Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee,
chocolate, cola), caffeine, grapefruit, or grapefruit juice within 48 hours before
dosing or anticipates an inability to abstain from these products throughout the
duration of the study.

16. Subject has used nicotine containing products (e.g., cigarettes, cigars, chewing
tobacco, snuff) within 6 weeks before Screening (self reported).

17. Subject is unable to tolerate a controlled, quiet, study conduct environment,
including avoidance of music, television, movies, games, and activities that may
cause excitement, emotional tension, or arousal during the prespecified time points
(e.g., before and during ECG extraction windows).

18. Subject is unwilling to comply with study rules, including the study-specific diet,
attempting to void at specified times (e.g., before ECG extraction windows),
remaining quiet, awake, undistracted, motionless, and supine during specified times,
and avoiding vigorous exercise as directed.

19. Subject has a history of consuming more than 14 units of alcoholic beverages per week
within 6 months before Screening, has a history of alcoholism or
drug/chemical/substance abuse within 2 years before Screening (Note: 1 unit = 12
ounces of beer, 4 ounces of wine, or 1 ounce of spirits/hard liquor), or has a
positive test result for alcohol or drugs of abuse at Screening or Check in.

20. Subject has used any prescription or nonprescription drugs (including aspirin or
nonsteroidal anti inflammatory drugs [NSAIDs] and excluding oral contraceptives and
acetaminophen) within 14 days or 5 half lives (whichever is longer), or complementary
and alternative medicines within 28 days before the first dose of study drug.

21. Subject is currently participating in another clinical study of an investigational
drug or has been treated with any investigational drug within 30 days or 5 half-lives
(whichever is longer) of the compound.

22. Subject has had any significant blood loss, donated 1 unit (450 mL) of blood or more,
or received a transfusion of any blood or blood products within 60 days, or donated
plasma within 7 days before Check in.

23. Subject has any other condition that precludes his or her participation in the study
(as determined by the investigator).

24. Subject is unwilling to have genetic analysis performed or a blood sample collected
for isolating peripheral blood mononuclear cells (PBMCs).