| Eligibility |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment
into the study:
1. Be able and willing to provide written Informed Consent indicating that the subject
has been informed of all pertinent aspects of the study.
2. Healthy female subjects and male subjects who, at the time of screening, are between
the ages of 18 and 45 years, inclusive.
Healthy is defined as no clinically relevant abnormalities identified by a detailed
medical history, full physical examination, including blood pressure (BP) and pulse
rate measurement, 12-lead electrocardiogram (ECG), and clinical laboratory tests.
3. Female subjects of nonchildbearing potential must meet at least one of the following
criteria:
- Achieved postmenopausal status, defined as follows: cessation of regular menses
for at least 12 consecutive months with no alternative pathological or
physiological cause; post-menopausal status will be confirmed by a serum
follicle-stimulating hormone level;
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure. All other female subjects (including
females with tubal ligations) will be considered to be of childbearing potential
and may be enrolled if they have negative pregnancy tests at screening and
admission day and agree to use a highly effective method of contraception for 14
days before study drug administration and 28 days after study drug
administration. Female subjects of childbearing potential must agree to undergo
repeated pregnancy tests. For highly effective methods of contraception include
see Section 6.5.1.
4. Male subjects must be willing to use an effective method of contraception. They must
agree to use a condom consistently and correctly, during the course of the study until
28 days after study drug administration.
5. Not using any prescription medication and dietary supplements within 30 days or 5
half-lives (whichever is longer) prior to the administration of study drug
administration, except for contraceptives - nor be taking any over-the-counter (OTC)
herbal or medicinal products. As an exception, acetaminophen/paracetamol may be used
at doses of = 2 g/day. Aspirin and non steroidal anti inflammatory drugs (NSAIDs)
should not be administered within 1 week of study dose.
6. Non-smoking and no use of any tobacco or nicotine products (by declaration) for a
period of at least 6 months prior to screening visit.
7. Be on no medication with potential to impair renal function (e.g., NSAIDs) or with
ototoxic potential (e.g., quinine, salicylates, aminoglycosides).
8. Normal renal function (glomular filtration rate >60 mL/min) based on creatinine plasma
concentration and the Modification of Diet in Renal Disease equation for estimated
glomular filtration rate. Subjects with lower Modification of Diet in Renal Disease
(MDRD) clearance can be included on the condition that they have a normal 24h
creatinine clearance (determined by a 24h urine collection).
9. Negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg),
hepatitis C virus antibody (HCV Ab) serology tests at screening.
10. No history of alcohol or drug of abuse (DOA). Negative urine test for DOA and alcohol
breath test at screening and Day -1.
11. No personal history (or current) or hereditary hearing loss, persistent tinnitus,
persistent vertigo, persistent imbalance, and persistent unsteadiness.
12. Body Mass Index (BMI) of 19.0 to 30.0 kg/m2 (inclusive); and a total body weight >50.0
kg (110 lbs) and <100.0 kg.
Subjects with any of the following characteristics/conditions will not be included in the
study:
1. Subjects who are investigational site staff members directly involved in the conduct
of the study and their family members, site staff members otherwise supervised by the
Investigator, or subjects who are the Sponsor employees directly involved in the
conduct of the study.
2. Concurrent participation or participation in another clinical trial within at least 5
tissue half-lives prior to dosing (calculated from the previous study's last dosing
day). If the previous trial involved agents with delayed effects or prolonged
metabolism, a 12 months interval is required.
3. Evidence or history of clinically relevant hematological, renal, endocrine, pulmonary,
gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic
disease (including drug allergies). This includes any acute or chronic medical or
psychiatric condition or laboratory abnormality that may increase the risk associated
with study participation or investigational drug administration or may interfere with
the interpretation of study results and, in the judgment of the Investigator, would
make the subject inappropriate for entry into this study.
4. Presence of mitochondrial mutations making subject susceptible to aminoglycoside
toxicity (A1555G, C1494T, T1095C, A827G, 1-BP DEL, 961T, C INS).
5. Subjects with any history of ear disease or surgeries, persistent dizziness or
persistent tinnitus.
6. Subjects with any abnormality at screening, that indicates the presence of a
vestibular pathology, conductive hearing loss or balance problem (by an ENT).
Subjects with abnormalities in audiometry results at screening as follows: any pure
tone threshold >55 dB and inter-ear difference in any frequency of >20 dB.
Dizziness Handicap Inventory (DHI)-H score>16. Tinnitus Handicap Inventory (THI) H
score >14.
7. History of regular alcohol consumption exceeding 14 drinks/week for females or 21
drinks/week for males (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard
liquor) within 6 months of screening.
8. Screening supine blood pressure (BP) =140 mm Hg (systolic) or =90 mm Hg (diastolic),
following at least 5 min of supine rest. If BP is =140 mm Hg (systolic) or =90 mm Hg
(diastolic), the BP should be repeated two more times and the average of the three BP
values should be used to determine the subject's eligibility.
9. Screening supine 12-lead ECG demonstrating QTc >450 msec for men and >470 msec for
women, or a QRS interval >120 msec. If QTc or QRS exceed these limits, the ECG should
be repeated two more times and the average of the three QTc or QRS values should be
used to determine the subject's eligibility.
10. Subjects with ANY abnormalities in clinical laboratory tests at screening, considered
by the study physician as clinically relevant. In particular, subjects with alanine
aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine and total
bilirubin =1.5 upper limit of normal will be excluded.
11. Pregnant or breastfeeding female subjects.
12. Subjects who donated blood or received blood or plasma derivatives in the three months
preceding study drug administration.
13. Unwilling or unable to comply with all scheduled visits, treatment plan, laboratory
tests and other study procedures and the restrictions described in this protocol.
14. Known relevant allergy to any drug and/or aminoglycosides.
15. Subjects with an inability to communicate well with the Investigators and CPU staff
(e.g., language problem, poor mental development).
16. Subjects with visual impairment or inability to read and comprehend the DHI and THI
scales.
17. Subjects with any acute medical situation (e.g., acute infection) within 48 hours of
study start, which is considered of significance by the Investigator.
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