Intravenous Zotatifin in Adults With Mild or Moderate COVID-19
Intravenous Zotatifin in Adults With Mild or Moderate COVID-19
To evaluate the safety and tolerability, the antiviral activity, and plasma pharmacokinetics
 (PK) of zotatifin administered intravenously (IV) to adults with mild or moderate COVID-19.
This randomized, double-blind, placebo-controlled, dose-escalating study will evaluate the
 safety and efficacy of zotatifin administered IV to adults with mild or moderate COVID 19.

 Patients will be randomized to receive zotatifin or placebo in 3 cohorts of 12 patients each.
 Cohorts will be sequentially enrolled at progressively higher zotatifin dose levels. Study
 drug will not be administered to patients who are hospitalized. The second dose of study drug
 will not be administered should a patient progress from mild or moderate COVID-19 to severe
 COVID-19 prior to or on Day 8. Patients will assess and record their symptoms daily through
 Day 22 and at follow up (30 days after last infusion) (or at the early termination visit [if
 conducted]) in a paper patient diary using the WHO 9-point ordinal scale for clinical
 improvement. Other safety and efficacy measures will be assessed according to the Schedule of
 Procedures on Days 1, 4, 8, 10, 15 (end of treatment visit), and 22, and at follow up (30
 days after last infusion). On non-dosing days, study visits will be conducted as home health
 visits, except for the follow-up visit, which will be conducted as a telephone visit.
Inclusion Criteria:

 1. Has provided informed consent and any authorizations required by local law;

 2. Is a male or female patient ≥18 and <65 years of age;

 3. Has a laboratory-documented positive test for SARS CoV 2 infection as determined by
 local laboratory using a standard, Food and Drug Administration (FDA)-approved viral
 RNA or viral antigen assay from any oral or respiratory sample collected within 48
 hours of randomization;

 4. Has at least 2 symptoms associated with COVID-19 (fever or chills, cough, shortness of
 breath or difficulty breathing on exertion, fatigue, muscle or body aches, headache,
 new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting,
 or diarrhea) starting no more than 5 days prior to randomization and has mild or
 moderate disease at screening and at time of randomization, defined as the following:

 -  Mild COVID-19

 -  Positive testing by standard reverse transcriptase polymerase chain reaction
 (RT-PCR) assay or equivalent test;

 -  Symptoms of mild illness with COVID-19 that could include fever, cough, sore
 throat, malaise, headache, muscle pain, gastrointestinal symptoms, without
 shortness of breath or dyspnea; and

 -  No clinical signs indicative of moderate, severe, or critical severity;

 -  Moderate COVID-19

 -  Positive testing by standard RT-PCR assay or equivalent testing;

 -  Symptoms of moderate illness with COVID-19, which could include any symptom
 of mild illness or shortness of breath with exertion;

 -  Clinical signs suggestive of moderate illness with COVID-19, such as
 respiratory rate ≥20 breaths per minute, saturation of oxygen (SpO2) >93% on
 room air at sea level, heart rate ≥90 beats per minute; and

 -  No clinical signs indicative of severe or critical severity;

 5. Has adequate hepatic function during screening, defined as the following:

 -  Serum alanine aminotransferase ≤3 × upper limit of normal (ULN);

 -  Serum aspartate aminotransferase ≤3 × ULN; and

 -  Serum bilirubin (total) ≤1.5 × ULN (unless due to Gilbert's syndrome or
 hemolysis);

 6. Has adequate bone marrow function during screening, defined as the following:

 -  Absolute neutrophil count ≥1.0 × 10 9/L;

 -  Platelet count ≥75 × 109/L; and

 -  Hemoglobin ≥90 g/L (9.0 g/dL or 5.6 mmol/L);

 7. Has adequate renal function during screening, defined as measured or estimated
 glomerular filtration rate ≥60 mL/min, calculated by the Cockcroft-Gault formula using
 actual body weight;

 8. Female patients of childbearing potential must meet all of the following criteria:

 -  Is not pregnant (confirmed via a negative urine pregnancy test);

 -  Is not breastfeeding; and

 -  Is willing to use a protocol-recommended method of contraception or willing to
 abstain from heterosexual intercourse from the start of blinded study drug until
 at least 90 days after the last dose of blinded study drug; Note: A female
 patient is considered to be of childbearing potential unless she has had a
 hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically
 documented ovarian failure (with serum estradiol and follicle-stimulating hormone
 levels within the institutional laboratory postmenopausal range and a negative
 serum or urine β-human chorionic gonadotropin); or is menopausal (age ≥55 years
 with amenorrhea for ≥6 months).

 9. Male patients who can father a child must meet all of the following criteria:

 -  Is willing to use a protocol-recommended method of contraception or willing to
 abstain from heterosexual intercourse with females of childbearing potential from
 the start of blinded study drug until at least 90 days after the last dose of
 blinded study drug; and

 -  Is willing to refrain from sperm donation from the start of blinded study drug
 until at least 90 days after the last dose of blinded study drug; Note: A male
 patient is considered able to father a child unless he has had a bilateral
 vasectomy with documented aspermia or a bilateral orchiectomy.

 10. Is willing to comply with the scheduled visits, drug administration plan,
 protocol-specified laboratory tests, other study procedures, and study restrictions;
 and Note: Psychological, social, familial, or geographical factors that may preclude
 adequate study participation should be considered.

 11. In the judgment of the Investigator, participation in the protocol offers an
 acceptable benefit to risk ratio when considering current disease status, medical
 condition, and the potential benefits and risks of alternative treatments for the
 patient's disease.

 Exclusion Criteria:

 1. Is hospitalized for COVID-19;

 2. Has dyspnea at rest or while talking, or has signs and symptoms of overt or impending
 respiratory failure;

 3. Has significant cardiovascular disease, defined by myocardial infarction, arterial
 thromboembolism, or cerebrovascular thromboembolism, within 3 months prior to
 randomization; symptomatic dysrhythmias or unstable dysrhythmias requiring medical
 therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York
 Heart Association Class 3 or 4 congestive heart failure; ≥Grade 3 hypertension
 (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg); or history
 of congenital prolonged QT syndrome;

 4. Has a history of chronic obstructive pulmonary disease or bronchial asthma requiring
 continuous treatment and/or intermittent or continuous oxygen within the 90 days prior
 to screening; Note: Intermittent use of a β2-agonist inhaler is allowed.

 5. Has evidence of an ongoing or systemic bacterial, fungal, or viral infection
 (including upper respiratory tract infections) other than SARS-CoV-2 infection,
 recurrent or repeat SARS CoV 2 infection, or history of incompletely treated
 tuberculosis (TB) and/or suspected or known extrapulmonary TB; Note: Patients with
 localized fungal infections of the skin or nails are eligible. Patients may be
 receiving topical antifungals. Systemic administration of azole antifungals is
 prohibited (see Section 5.6).

 6. Has significant infiltrates (involving >50% of lung parenchyma) on an optional
 standard of care chest X-ray or other lung imaging exam within 1 week of screening;

 7. Has known significant electrocardiogram abnormalities at screening, including unstable
 cardiac arrhythmia requiring medication, left bundle branch block, second-degree
 atrioventricular (AV) block type II, third-degree AV block, ≥Grade 2 bradycardia, or
 QTcF >450 msec for men or >470 msec for women;

 8. Has type 1 diabetes mellitus or type 2 diabetes mellitus;

 9. Has a body mass index (BMI) >30 kg/m2;

 10. Has received a live vaccine within 30 days prior to randomization;

 11. Has had major surgery within 4 weeks (inclusive) prior to randomization;

 12. Has had prior solid organ or bone marrow progenitor cell transplantation;

 13. Has a malignant tumor (excluding a malignant tumor cured with no recurrence in the
 past 2 years, completely resected basal cell and squamous cell carcinoma of the skin,
 and completely resected carcinoma in situ of any type);

 14. Has had prior high-dose chemotherapy requiring stem cell rescue;

 15. Has a history of or active uncontrolled systemic or local autoimmune disorders or
 other conditions that might impair or compromise the immune system;

 16. Has ongoing immunosuppressive therapy, including systemic corticosteroids; Note: At
 screening and during study participation, patients may be using systemic
 corticosteroids (doses ≤10 mg of prednisone or equivalent) or topical or inhaled
 corticosteroids.

 17. Has ongoing use of a therapeutic anticoagulant or history of bleeding disorder;

 18. Has ongoing use or plans to use antivirals against COVID-19;

 19. Has used a moderate or strong inhibitor or inducer of CYP3A4 within 7 days prior to
 randomization or is expected to require use of a moderate or strong CYP3A4 inhibitor
 or inducer during study participation;

 20. Has previously received investigational product in a clinical study within 30 days or
 within 5 elimination half-lives (whichever is shorter) prior to randomization or is
 planning to take part in another therapeutic clinical study while participating in
 this study; Note: Participation in observational studies is allowed.

 21. Has a known history of HIV or hepatitis B virus, or active hepatitis C virus
 infection;

 22. Has a known serious allergic reaction or hypersensitivity to components of zotatifin
 or placebo;

 23. Has a history of drug abuse or use of narcotics in the past 2 years that in the
 opinion of the Investigator will preclude study compliance; or

 24. Has any illness, medical condition, organ system dysfunction, or social situation,
 including mental illness or substance abuse, deemed by the Investigator to be likely
 to interfere with a patient's ability to provide informed consent, adversely affect
 the patient's ability to cooperate and participate in the study, or compromise the
 interpretation of study results.