| Eligibility |
Inclusion Criteria:
1. Healthy male and female subjects, 18 to 55 years of age at the time of signing of
informed consent.
2. Body mass index (BMI, Quetelet index, calculated as weight in kg/height in m2) between
18.0 and 30.0 kg/m2 (both inclusive) and weigh at least 50 kg and no more than 95 kg
inclusive at Screening.
3. Healthy subjects, defined as individuals who are free from clinically significant
illness or disease as determined by their medical/surgical history, normal vital
signs, normal physical examination, normal standard 12-lead electrocardiogram (ECG),
and laboratory investigations.
4. At the Screening visit, supine vital signs must be within the following ranges:
- Systolic blood pressure (SBP) between 90 and 139 mmHg
- Diastolic blood pressure (DBP) between 60 and 89 mmHg
- Pulse between 50 and 90 beats per minute (bpm)
- Tympanic temperature between 35.0 and 37.5°C Note: These will be measured after
resting for 10 min.
5. Able to understand and communicate in German/or native language of the site with the
Investigator and research staff and to comply with the requirements of the entire
study. Provision of written informed consent to participate in the study.
6. Female subjects, if:
o Not of childbearing potential, e.g., have a documentation of irreversible surgical
sterilization by hysterectomy and/or bilateral oophorectomy and/or bilateral
salpingectomy and/or bilateral tubal ligation, at least 6 weeks before the Screening
visit, amenorrhea for = 12 months and follicle stimulating hormone (FSH) in the post
menopausal range according to local laboratory ranges.
o Of childbearing potential (for inclusion in Cohort 1, BE Study only), the following
conditions are to be met: i. Negative pregnancy test: If this test is positive, the
subject will be excluded from the study. In the rare circumstance that a pregnancy is
discovered after the subject received zoliflodacin, the IMP, every attempt must be
made to follow her to term and the newborn(s) up to 2 years of age.
ii. Not lactating iii. The female subject must agree to use, with their partner, an
approved method of highly effective contraception in combination with a barrier method
from at least 1 month before the Screening visit until 1 month after last dosing of
IMP. Female subjects must agree not to attempt to become pregnant, must not donate ova
from the Screening visit until at least 1 month after last dosing of IMP.
The following are considered to be highly effective methods of birth control:
1. Hormonal contraception (i.e., combined oral contraceptives, injectable or
implantable hormonal contraceptives
2. Hormonal or non-hormonal intrauterine device/system with a proven failure rate
<1%
3. The subject's male partner has undergone confirmed effective surgical
sterilization before the female subject entered the clinical study and he is the
sole sexual partner of the female subject during the clinical study
4. True abstinence: When this is in line with the preferred and usual lifestyle of
the subject. (Periodic abstinence [e.g., calendar, ovulation symptothermal, post
ovulation methods], declaration of abstinence for the duration of the study and
withdrawal are not acceptable methods of contraception).
Barrier methods of contraception include:
1. Condom (with or without spermicidal foam/gel/film/cream/ suppository but not use
of fat/oil containing lubricants).
2. Occlusive cap (diaphragm or cervical/vault caps) with spermicidal
gel/film/cream/suppository.
3. Other methods, if considered by the Investigator as reliable, will be accepted.
7. Male subjects who agree to use appropriate contraception methods to prevent pregnancy
in their female partner(s) from the time of first dose until one month after last dose
of IMP administration, i.e., condoms with or without spermicide. A male subject should
be instructed that, unless his female partner(s) has had a tubal ligation,
hysterectomy, or bilateral oophorectomy or is post-menopausal, his female partner(s)
should use another form of contraception from the time of first dosing until one month
after last dose of IMP administration - such other forms of contraception include an
intrauterine device, condom, diaphragm with spermicide, oral contraceptive, injectable
progesterone, or subdermal implant; male subjects who have been vasectomized at least
6 months before the first dose of IMP are exempt from the use of condom, and his
female partner(s) do(es) not need any additional form of contraception.
8. Provision of written informed consent to participate in the study.
9. Subjects in the BE cohort must be willing to consume the meal prescribed with
administration of the IMP in full and within the required time under fed conditions.
Exclusion Criteria:
1. For Cohort 2, DDI Study only: Female subjects of childbearing potential.
2. Subject has a positive RT PCR test for SARS-CoV-2 prior to randomization.
3. Subject has clinical signs and symptoms consistent with SARS-CoV-2 infection, e.g.,
fever, dry cough, dyspnea, sore throat, fatigue, or positive SARS-CoV-2 test result
within 4 weeks prior to Screening.
4. Subject had severe course of COVID-19 (i.e., hospitalization, extracorporeal membrane
oxygenation [ECMO], or mechanically ventilated) less than 3 months prior to Screening.
5. Subject received or is planning to receive a COVID-19 vaccine within 3 weeks prior to
the first IMP administration until Post-study visit.
6. Recent (within previous 14 days) exposure to someone who has COVID-19 symptoms or
positive test result.
7. Has a current occupation that involves routine exposure to potential COVID-19 patients
or sources of SARS-CoV-2 (e.g., healthcare worker).
8. History of orthostatic hypotension (drop of >20 mmHg at systolic blood pressure, drop
of > 10 at diastolic blood pressure, and/or heart rate increase of >30 bpm and >120
bpm after 3 minutes in standing position).
9. Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional
or intellectual problems likely to limit the validity of consent to participate in the
study or limit the ability to comply with protocol requirements.
10. History or presence of any clinically significant acute or chronic disease, including
known or suspected human immunodeficiency virus (HIV), hepatitis A virus (HAV), HBV,
or HCV infection (confirmed by positive laboratory test for anti-HAV IgM antibodies,
hepatitis B surface antigen (HbsAg), or anti-HIV1/2 or anti-HCV antibodies).
11. Receipt of zoliflodacin, vaccines, biologics, or any other investigational product
within 3 months prior to study start or during the study, or 5-times the half-life of
the drug tested in the previous clinical study, whichever is longer (time calculated
relative to the last dose in the previous clinical study). Influenza vaccination and
SARS-CoV-2 vaccination prior to Screening will be allowed.
12. Presence of clinically significant abnormality following review of pre-study
laboratory tests (i.e., aspartate aminotransferase [AST], alanine aminotransferase
[ALT], alkaline phosphatase [ALP], or creatinine > upper limit of normal [ULN]), vital
signs, full physical examination, and ECG.
13. History of serious allergy, allergic skin rash, history of drug allergy to
itraconazole or other azole antifungals or allergy/sensitivity to any drug.
14. Excessive intake of caffeine (more than 8 cups daily of beverage containing caffeine).
15. Current alcohol use >21 units of alcohol per week for males and >14 units of alcohol
per week for females (one unit = 8 g or about 10 mL of pure alcohol) and/or positive
urine alcohol test at Screening.
16. Known or suspected drug abuse or positive laboratory test for urine drug screening
(opiates, cocaine, amphetamine, cannabis, benzodiazepines).
17. Use of any medication, prescribed or over-the-counter (including antacid drug, except
for acetaminophen [paracetamol up to 4 g/day]), or herbal remedies, during the 28 days
before the first dose of IMP except if this will not affect the outcome of the study
in the opinion of the Investigator.
18. Use of any enzyme-modifying drugs and/or other products, including strong or moderate
inhibitors of cytochrome P450 (CYP) enzymes (e.g., cimetidine, fluoxetine, quinidine,
erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals)
and strong or moderate inducers of CYP enzymes (e.g., barbiturates, carbamazepine,
glucocorticoids, phenytoin, St. John´s Wort and rifampicin) in the previous 30 days
before first IMP administration until the last blood draw in the study.
19. Consumption of food or beverages containing grapefruit and/or pomelo within 14 days
prior to first IMP administration until the last blood draw in the study.
20. Consumption of food or beverages containing caffeine/methylxanthines, poppy seeds
and/or alcohol within 48 hours before dosing until the last blood draw in the study.
21. Treatment within the previous 3 months before the first administration of IMP with any
drug with a well defined potential for adversely affecting a major organ or system.
22. A major illness during the 3 months before commencement of the Screening period.
23. Presence of clinical condition or prior therapy which, in the opinion of the
Investigator, made the subject unsuitable for the study.
24. Subjects who had abdominal surgery (e.g., gastric, small intestine or colon resection
or bypass) or medical condition that might affect absorption of IMP taken orally.
25. History of gastrointestinal ulcer disease, inflammatory bowel disease, indigestion
symptoms >3 times a week, or blood in stool in previous 6 months not related to anal
trauma.
26. Who had febrile illness within 1 week before the start of the study.
27. Who has regular daily consumption of more than 1 L of xanthine containing beverages.
28. The subject has smoked, used tobacco products, e-cigarette or used nicotine
replacement products within the 3 months before the first dosing or has a positive
cotinine screen in urine.
29. Any clinically important abnormalities in heart rate, rhythm, conduction, or
morphology of resting ECG that in the opinion of the Investigator are clinically
significant or may interfere with the interpretation of QTc interval changes. QT
interval corrected using QTcF >450 ms for male subjects and 460 ms for female subjects
on Screening ECG. Clinically significant history or presence of myocardial infarction,
pulmonary congestion, cardiac arrhythmia, prolonged QT interval or conduction
abnormalities.
30. History of hypersensitivity or allergy to the IMP or its excipients or any related
medication.
31. Relevant history or laboratory or clinical findings indicative of acute or chronic
disease, likely to influence study outcome.
32. Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the
first administration of IMP or have donated plasma within 7 days of study dosing.
33. Clinically relevant abnormalities in the coagulation status or history of bleeding
disorders.
34. Vulnerable subjects, e.g., persons in detention, protected adult under
guardianship/trusteeship, soldier or committed to an institution by governmental or
juridical order.
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