Overview

A Thorough QT/QTc Study to Evaluate the Effects of an Intravenous Infusion of Eravacycline (TP-434) on Cardiac Repolarization

Status:
Completed
Trial end date:
2013-07-01
Target enrollment:
0
Participant gender:
All
Summary
This is a randomized, placebo- and positive-controlled (moxifloxacin), 3-period, 3-way crossover thorough QT study, which includes a Screening Period, Treatment Periods (1 through 3), and a Follow-up Visit. Subjects will be confined to the investigational site for 4 nights/3 days during Period 1 and for 3 nights/2 days during Periods 2 and 3. There will be a minimum of a 14 day washout between treatments.
Phase:
Phase 1
Accepts Healthy Volunteers?
Accepts Healthy Volunteers
Details
Lead Sponsor:
Tetraphase Pharmaceuticals, Inc.
Treatments:
Fluoroquinolones
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Criteria
Inclusion Criteria:

1. Healthy male and female subjects of 18 to 55 years of age;

2. Females must be surgically sterile (hysterectomy and/or bilateral oophorectomy),
post-menopausal for 1 year (with follicle-stimulating hormone [FSH] in menopausal
range), or agree to use 2 medically accepted, effective methods of birth control
(e.g., hormonal contraception, including oral, implant/patch, or injection, or latex
condom with spermicide, diaphragm with intravaginal spermicide, cervical cap with
spermicide, or indwelling intrauterine device) from the time of signing informed
consent until 2 weeks after the Follow-Up Visit. One of the birth control methods must
be a barrier method;

3. Male subjects with sexual partners of childbearing potential must agree to use 2
medically accepted, effective methods of birth control (e.g., hormonal contraception,
including oral, implant/patch, or injection, or latex condom with spermicide,
diaphragm with intravaginal spermicide, cervical cap with spermicide, or indwelling
intrauterine device) for the duration of the study and for 90 days after the Follow-up
Visit. Male subjects who have had a vasectomy >6 months prior to the first dose of
study drug must agree to use 1 medically accepted barrier method for the duration of
the study and for 90 days after the Follow-up Visit;

4. Male subjects (including those who have had vasectomies >6 months prior to the first
dose of study drug) whose partners are currently pregnant must agree to use a barrier
method (without spermicide) for the duration of the study and for 2 weeks after the
Follow-up Visit;

5. Body mass index of 18 kg/m2 to 33 kg/m2, inclusive;

6. Non-smokers must have quit smoking >3 months prior to the Screening Visit;

7. Have negative alcohol and drug screens;

8. Have a quantitative urine cotinine screen <3;

9. Willing and able to be confined to the investigational site as required by the
protocol; and

10. Able to comprehend and willing to provide written informed consent in accordance with
institutional and regulatory guidelines.

Exclusion Criteria:

1. Evidence of clinically significant hematologic, renal, endocrine, pulmonary, cardiac,
gastrointestinal, hepatic, psychiatric, neurologic, or allergic disease (including
multiple or clinically significant drug allergies), cancer, or any other condition
that, in the opinion of the Investigator, might significantly interfere with the
absorption, distribution, metabolism, or excretion of study drug, interfere with the
integrity of electrophysiologic data, or place the subject at an unacceptable risk as
a participant in this study;

2. A personal or family history of long QT syndrome, Torsades de pointes, or other
complex ventricular arrhythmias or family history of sudden death;

3. Mean QTcF interval >450 msec on screening ECG, performed in triplicate. The mean QTcF
of these tracings will be used by the Investigator;

4. Cardiac conduction abnormalities denoted by any of the following at the Screening
Visit: evidence of second-degree (Mobitz type II) or third-degree atrioventricular
block, evidence of ventricular pre-excitation, complete left bundle branch block,
right bundle branch block, intraventricular conduction delay with QRS duration >120
msec, atrial fibrillation, or presence of cardiac pacemaker; PR interval >220 msec or
<120 msec; heart rate <45 bpm or >90 bpm; other clinically-significant ECG
abnormalities (measured as a mean value from triplicate ECGs);

5. Use of hormone replacement therapy;

6. Any major surgical procedure within 3 months prior to the first dose of study drug;

7. Gastrointestinal disorders or surgical procedures that could interfere significantly
with the absorption of orally administered drugs;

8. Use of another investigational drug or device within 30 days prior to receiving
eravacycline (TP-434), or within at least 5 half-lives of the previous investigational
drug, whichever is longer;

9. History of malignancy (other than basal cell or squamous cell skin cancer, in situ
carcinomas of the cervix, or in situ prostate cancer);

10. History or presence of hypertension (defined as systolic blood pressure >150 mmHg or
diastolic blood pressure >90 mmHg). If the subject's blood pressure is outside of the
acceptable range at the Screening Visit, the subject may be retested within 24 hours
at the discretion of the Investigator;

11. Known allergies to moxifloxacin, other quinolone or tetracycline antibiotics, or
related compounds or a history of multiple adverse drug allergies of any origin;

12. Inadequate venous access;

13. Obvious clinical signs or symptoms of liver disease, acute or chronic active
hepatitis, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2
the upper limit of normal (ULN). An abnormal ALT or AST test may not be repeated;

14. Total bilirubin >1.5 ULN with elevated direct bilirubin. An abnormal total or direct
bilirubin test may not be repeated;

15. Serum potassium, magnesium, or calcium levels that are outside of the laboratory's
reference range;

16. History of alcoholism or drug abuse within 2 years prior to dosing;

17. Typical weekly alcohol consumption of 14 alcoholic drinks. One drink is defined as 1
glass of beer (approximately 10 oz to 12 oz) or 1 can (12 oz) of beer, 1 glass of wine
(approximately 4 oz to 5 oz), or 1 glass of distilled spirits (hard liquor) containing
1 oz of the liquor (1 oz of liquid is approximately 30 mL);

18. Alcohol consumption within 48 hours prior to dosing;

19. Use of tobacco, nicotine, or nicotine-replacement products within the 3 months prior
to the first dose of study drug through the last study visit;

20. Unwillingness to refrain from caffeine and other xanthine-containing beverages,
including coffee and tea, as well as grapefruit juice, Seville oranges, or chocolate
within 24 hours prior to and after dosing;

21. History of human immunodeficiency virus (HIV) or hepatitis C virus or a positive test
at screening for HIV antibody, hepatitis C antibody, or hepatitis B surface antigen;

22. Cumulative blood donation of >500 mL within 2 months prior to the Screening Visit;

23. Use of any prescription or non-prescription medication, including vitamins or herbal
medications, within 7 days, or 5 half-lives (if known), whichever is longer, prior to
dosing in any of the 3 periods and within 24 hours after dosing in any period. The use
of acetaminophen, naproxen, and ibuprofen is permitted except for within 24 hours
prior to dosing;

24. Use of any prescription or non-prescription medication that may cause QT prolongation
within 14 days, or 5 half lives, whichever is longer, prior to dosing in Period 1
through 24 hours following dosing in Period 3;

25. Any known exposure to prescription or non prescription medications or other
substances, such as paint solvents or pesticides, known to induce or inhibit drug
metabolizing enzymes or transport system enzymes, within 30 days or 5 half-lives,
whichever is longer, prior to dosing in Period 1 through 24 hours following dosing in
Period 3, with the exception of hormonal contraception;

26. Unwillingness to abstain from strenuous exercise (e.g., heavy lifting, weight
training, calisthenics, aerobics) for at least 48 hours prior to admission to the
investigational site;

27. Investigational site personnel directly affiliated with this study;

28. Poor mental function or any other reason to expect subject difficulty in complying
with the requirements of the study in the judgment of the Investigator; or

29. Failure to comply with protocol requirements or whose further participation in the
study would be unsuitable to the subject, as determined by the Investigator.