| Eligibility |
Inclusion Criteria:
1. Subject is male or female between 18 and 80 years of age, inclusive.
2. Subject is available for clinical follow-up for the duration of the study.
3. Women of childbearing potential have a negative beta human chorionic gonadotropin
pregnancy test (serum) at the screening visit and a confirmatory negative pregnancy
test on Day 1 or Day -1 (PK subset) before receipt of study drug, and meet one of the
following criteria:
1. Subject or their partner has undergone surgical sterilization.
2. Subject is postmenopausal, defined as 12 consecutive months with no menses
without an alternative medical cause and has a documented plasma follicle
stimulating hormone level >40 IU/mL.
3. Subject agrees to be abstinent (ie, heterosexually inactive) for the duration of
the study.
4. Subject agrees to consistently use 1 of the following methods of contraception
from the beginning of screening (which they had been consistently using for at
least 30 days before the first dose of study drug) through 30 days after the last
dose of study drug:
i. Condoms, male or female, with a spermicide NOTE: For male subjects, condoms must be
used for 90 days after the last dose of study drug. Male and female condoms should not
be used together, as this can reduce their effectiveness.
ii. Diaphragm or cervical cap with spermicide iii. Intrauterine device with spermicide
iv. Oral contraceptives or other hormonal methods NOTE: Another nonhormonal method of
contraception must be used in conjunction with oral contraceptives.
v. Male sexual partner who had undergone a vasectomy at least 3 months before
screening
4. Male subjects must agree to not donate sperm from the first dose of study drug through
90 days after the last dose of study drug.
5. Subject is considered by the investigator to be in good general health as determined
by medical history (no hospitalizations for chronic medical conditions in the previous
2 years), clinical laboratory test results, vital sign measurements, 12-lead ECG
results, and physical examination findings at screening.
6. Subject agrees not to use nicotine products, including electronic vapor cigarettes,
nicotine patches, or nicotine gum, for at least 30 days before the Day 1 randomization
visit through completion of the Day 29 dosing complete/ET visit.
7. Subject agrees to comply with the study dietary requirements throughout the study drug
dosing period.
8. Subject agrees not to consume caffeine- or xanthine-containing products during all
study visits, including overnight stays (PK subset); sodas, coffee, and tea designated
as caffeine free or noncaffeinated may be consumed on study days; caffeine may be
consumed while at home and between study visits.
9. Subject agrees to comply with all protocol requirements.
10. Subject has adequate venous access if participating in the PK subset.
11. Subject is able and willing to provide written informed consent.
Exclusion Criteria:
1. Subject is a female who is pregnant or breastfeeding or planning to become pregnant
within 3 months after the last dose of study drug.
2. Subject has a history of any clinically significant conditions including:
- Asthma treated with oral systemic steroids within the past 6 months
- Diabetes mellitus (type 1 or 2), with the exception of gestational diabetes
- Hypertension that is poorly controlled (repeat readings >140 mm Hg systolic
and/or >90 mmHg diastolic)
- Thyroidectomy or thyroid disease that required medication within the past 12
months
- Serious angioedema episodes within the previous 3 years or requiring medication
in the previous 2 years
- History of head trauma resulting in a diagnosis of traumatic brain injury other
than concussion
- Frequent episodes of headache
3. Subject has received any vaccination within 28 days prior to Day 1 or plans to receive
a vaccination at any time during the treatment period or within 28 days after study
Day 28.
4. Subject has received treatment in another clinical study of an investigational drug
(or medical device) or investigational vaccine within 30 days or 5 half-lives
(whichever is longer) before the first dose of study drug.
5. Subject has a history of relevant drug and/or food allergies (ie, allergy to TPOXX or
excipients, or any significant food allergy that could preclude a standard diet in the
clinical investigative site).
6. Subject has any condition possibly affecting drug absorption (eg, previous surgery on
the gastrointestinal tract, including removal of parts of the stomach, bowel, liver,
gallbladder, or pancreas, with the exception of appendectomy).
7. Subject has evidence or history of clinically significant allergic (except for
untreated, asymptomatic, seasonal allergies at time of the first dose of study drug),
hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic,
psychiatric, or neurological disease. Exceptions to these criteria (eg, stable, mild
joint disease unassociated with collagen vascular disease) may be made following
discussions with the medical monitor.
8. Subject has a history of cardiac disease, symptomatic or asymptomatic arrhythmias,
syncopal episodes, or risk factors for torsades de pointes (eg, heart failure,
hypokalemia).
9. Subject has a family history of sudden cardiac death not clearly due to acute
myocardial infarction.
10. Subject is 20 years of age or older and has a =10% risk of developing a myocardial
infarction or coronary death within the next 10 years using the National Cholesterol
Education Program's Risk Assessment Tool:
https://www.mcw.edu/calculators/ldl-cholesterol-goal-level.
11. Subject has a seizure disorder or history of seizures (does not include childhood
febrile seizures) or a past history that increases seizure risks such as significant
head injury that caused loss of consciousness or other changes in the subject's daily
function, concussion, stroke, central nervous system infection or disease, or alcohol
or drug abuse or family history of idiopathic seizures.
12. Subject has a history of a peptic ulcer or significant gastrointestinal bleeding.
13. Subject has a bleeding disorder diagnosed by a doctor (eg, factor deficiency,
coagulopathy, or platelet disorder requiring special precautions) or significant
bruising or bleeding difficulties with blood draws.
14. Subject has a malignancy that is active or treated malignancy for which there is not
reasonable assurance of sustained cure, or malignancy that is likely to recur during
the period of the study (subject should be in complete remission for at least 5
years).
15. Subject has neutropenia or other blood dyscrasia determined to be clinically
significant by the investigator.
16. Subject has used any of the following prohibited medications from within 7 days (or 5
half lives, whichever is longer) before the first dose of study drug: antidiabetic
medication; anticoagulants; anticonvulsants; substrates of the breast cancer
resistance protein transporter including methotrexate, mitoxantrone, imatinib,
irinotecan, lapatinib, rosuvastatin, sulfasalazine, and topotecan; substrates of
cytochromes (CYP)2C8 including repaglinide, paclitaxel, montelukast, pioglitazone,
rosiglitazone; and substrates of CYP2C19 including S-mephenytoin, clobazam, diazepam,
rabeprazole, voriconazole, lansoprazole, and omeprazole. Medications not listed here
that are known (or thought) to be CYP3A4 substrates may be allowed at the
investigator's discretion, after consultation with the medical monitor, if
administration poses little to no risk to the subject.
17. Subject has a history of drug or alcohol abuse or dependency within the last year
before screening.
18. Subject has a current or recent (<30 days before screening) history of clinically
significant bacterial, fungal, or mycobacterial infection.
19. Subject has a current clinically significant viral infection.
20. Subject has a known clinically significant chronic viral infection (eg, human T cell
lymphotropic virus I or II).
21. Subject demonstrates long-term use (=14 consecutive days) of glucocorticoids,
including oral or parenteral prednisone or equivalent (>20 mg total dose per day), or
high dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent)
within the preceding 1 month (low dose [=800 mcg/day of beclomethasone dipropionate or
equivalent] inhaled and topical steroids are allowed).
22. Subject has donated >450 mL blood or blood components within 30 days before the first
dose of study drug. The investigator should instruct subjects who participate in this
study to not donate blood or blood components for 4 weeks after the completion of the
study.
23. Subject reports participation in strenuous activity or contact sports within 24 hours
before the first dose of study drug.
24. Subject has known hepatitis B or C infection or positive test for hepatitis B surface
antigen, hepatitis C virus antibody, or human immunodeficiency virus type 1 or 2
antibodies at screening.
25. Subject has a positive test result for amphetamines (including methamphetamines and
ecstasy/methylenedioxymethamphetamine), barbiturates, benzodiazepines, cannabinoids
(including tetrahydrocannabinol), cocaine metabolites, opiates (including heroin,
codeine, and oxycodone), cotinine, or alcohol at screening or check-in.
26. Subject has any of the following laboratory test results within 28 days before the
first dose of study drug:
- Estimated serum creatinine clearance (Cockcroft Gault) <70 mL/min
- Creatinine in males >1.7 mg/dL and in females >1.4 mg/dL (1.3 times the upper
laboratory reference range)
- Hemoglobin =10% of the lower laboratory reference range
- White blood cell counts considered to be clinically significant by the
investigator
- Absolute neutrophil count <1000 cells/mm3
- Platelets not within ±10% of laboratory reference range
- Alanine aminotransferase >2 times above the upper laboratory reference range
- Aspartate aminotransferase >2 times above the upper laboratory reference range
- Alkaline phosphatase >20% above the upper laboratory reference range
- Hemoglobin A1c =7.0%
- Cholesterol =300 mg/dL and low density lipoprotein =190 mg/dL
27. Subject has a blood pressure considered to be clinically significant by the
investigator. Blood pressure may be retested twice in the sitting position at 5-minute
intervals.
28. Subject has a resting heart rate of <40 beats per minute or >110 beats per minute at
screening.
29. Subject has an abnormal ECG at screening that is determined by the investigator to be
clinically significant.
30. Male subject has a QT interval corrected using Fridericia's formula (QTcF) >450 ms or
female subject has a QTcF >470 ms at screening or Day 1, or Day -1 (PK subset).
31. Subject has used any prescription antiviral drugs with the intention of coronavirus
disease (COVID 19) prophylaxis, including those that are thought to be effective for
prevention of COVID 19 but have not been licensed for this indication, within 1 month
prior to study entry or during the study.
32. Subject is at a high risk of contracting SARS-CoV-2/COVID-19 infection, including, but
not limited to, individuals with known close contact with:
1. Anyone residing in, visiting, or working at a health care or long-term care
institution (ie, long-term care facilities, acute care hospitals, rehabilitation
hospitals, mental health hospitals, emergency departments)
2. Anyone with known history of COVID-19 within 2 weeks prior to study entry
3. Anyone who traveled outside the United States or has recently traveled outside of
the state and has returned from a state that is listed on a travel advisory list
requiring quarantine for any duration within 30 days before study entry
33. In the opinion of the investigator, the subject is not suitable for entry into the
study.
34. Subject is a member or family member of the investigator or study site personnel.
35. Subject has previously participated in this or any other clinical trial involving
TPOXX (tecovirimat).
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