Atovaquone for Treatment of COVID-19

Design of the ATaQ COVID-19 Trial:

The purpose of the current study is to accelerate the use of a clinically available
therapeutic already FDA-approved for other indications in the setting of pandemic COVID-19
addressing a serious and emergent unmet medical need. In consideration of the information
included in this protocol, the overall risks to participants are outweighed by the potential
benefits of atovaquone experimental therapy for the treatment of COVID-19. The benefit-risk
balance for this study is considered positive.

Inclusion Criteria:

1. Diagnosis of COVID-19 by positive RT-PCR requiring hospitalization within 72 hours

2. Age ≥18 years old

3. Able to provide informed consent, or (as allowed by IRB), immediate availability of
designated legally authorized representative to provide consent by proxy

4. Anticipated hospitalization for >48 hours

Exclusion Criteria

Patients who meet any of the following exclusion criteria are not to be enrolled in this
study:

1. Participation in any other clinical trial with antiviral activity against COVID-19

2. Breastfeeding women

3. Known hypersensitivity to atovaquone or formulation excipient

4. Active treatment with rifampin

5. HIV patients with AIDS requiring treatment for Pneumocystis jirovecii or Toxoplasma
gondii

6. Not expected to survive for 72 hours.

7. >14 days from symptom onset

Randomization:

Patients who meet eligibility criteria and volunteer to participate will be randomized
in a 2:1 ratio to atovaquone or placebo on Day 1 using computerized randomization. An
unblinded investigational pharmacist not otherwise involved in the trial will know
treatment assignment and dispense investigational product. As GI absorption of
atovaquone increased when taken with food, so we will administer with a meal or snack.

Blinding:

Double blinding of treatment assignments will be performed in this study, with the study
team and patients blinded to treatment assignment.

The list of concomitant medications will be assessed only from Day 1 prior to enrollment
to Day 15 or discharge, whichever is earlier.

Patient Enrollment and Treatment Assignment:

Entry into screening does not guarantee enrollment into the study. In order to manage
the total study enrollment, the study researchers may suspend screening and/or
enrollment at any at any time.

Pretreatment Assessments:

Screening Visit

Patients will be screened within 2 days before randomization and dosing to determine
eligibility for participation in the study. Screening will occur under approved HIPAA
waiver for research to identify and screen all hospitalized COVID-19 positive patients
on a daily basis.

Obtain informed consent.

After informed consent has been negotiated and the form signed, the following
assessments will be performed to determine eligibility requirements as specified in the
inclusion and exclusion criteria:

- Review of focused medical history including the following information (e.g., date
of first symptoms, overall symptoms, exposure source, demographics, baseline
characteristics), allergies and past medical history.

- Review and record medications and therapies for the current illness

- Recording of vital signs (heart rate, temperature, blood pressure), body weight,
and height

- Documentation of respiratory support: Respiratory Rate, Oxygen supplementation:
room air, nasal canula, face mask, non-rebreather, high-flow device, mechanical
ventilation; and FiO2

- SpO2 at rest or PaO2

- Radiographic findings

Study patients who qualify and volunteer to participate should be immediately consented
and randomized. Randomization and initiation of dosing should occur on the same day if
possible.

Baseline/Day 1 Assessments

The following evaluations are to be completed at the Day 1 visit. The investigator must
have confirmed eligibility and signing of consent before proceeding with randomization
on the Day 1 visit, followed immediately by first dose of investigational product. The
assessments can be completed by the patient care team and do not need to be repeated by
research personnel. The following assessments must be documented before administering
investigational product, using the most recent data available at the time of
randomization:

Recording of vital signs (heart rate, temperature, blood pressure, body weight, height)

Documentation of respiratory status:

Respiratory rate

Oxygen supplementation and FiO2: room air, nasal canula, face mask, non-rebreather,
noninvasive ventilation or high flow oxygen devices, mechanical ventilation, or ECMO

Oxygenation: (SpO2 or PaO2)

Radiographic findings (if available)

Review AEs and document concomitant medications

Document Ordinal Scale at baseline

Obtain saliva sample and nasopharyngeal swab sample for viral load quantification at day
1 prior to initial dose

Obtain blood for research sample

Daily Study Assessments (Days 2-15):

The following evaluations are to be documented daily from Days 2 - 15 or until discharge
whichever comes earlier, using the data recorded at or closest to 12:00 noon each day:

- Vital signs (heart rate, temperature, blood pressure), body weight (if available).

- Documentation of respiratory status: Respiratory rate, Oxygen supplementation and
FiO2: room air, nasal canula, face mask, non-rebreather, noninvasive ventilation or
high flow oxygen devices, mechanical ventilation, or ECMO

- Oxygenation: (SpO2 or PaO2)

- Radiographic findings (if available)

- Review of AEs and document concomitant medications

- Saliva sample for COVID-19 RT-PCR every 12 hours (Days 2-8)

- Saliva sample for COVID-19 RT-PCR once daily (Days 9-15)

- Additional blood draws for biobanking (Day 3, and 5 only)

Clinical Laboratory Assessments:

Clinical laboratory assessments will be conducted as clinically indicated and all
laboratory testing will be completed by local laboratories. Clinical laboratory data to
be captured in the trial database will include serum chemistries, liver function tests,
complete blood counts including absolute neutrophil count, hs-CRP, D-dimer, ferritin,
IL-6, troponin, NTpBNP.

SARS-CoV-2 testing will include RT-qPCR to detect or quantify SARS-CoV-2 or virus
sequencing results from saliva (baseline and daily until discharge or death, and 8 days
and last day of hospitalization or Day 15 if still hospitalized.

Pretreatment and posttreatment samples with detectable SARS-CoV-2 may be sequenced for
resistance monitoring of the viral polymerase gene. For all clinical laboratory tests,
except those at Day 1, when more than 1 result is available in a calendar day, the value
closest to 12:00 noon should be captured in the eCRF. For Day 1 tests, the most recent
result before dosing should be used.

Physical Examination:

No physical examination is mandated by the study protocol beyond the capture of vital
signs (heart rate, respiratory rate, temperature, blood pressure, SpO2 at rest or PaO2)
as documented clinically.

Post-treatment Assessments:

Treatment will continue to complete a 10 Day course or until viral clearance is
documented, whichever occurs first.

Telephone call on Day 15 and 29 for those discharged. The phone call will include a
brief survey on symptoms and information on any re-hospitalizations.

Final review of AEs and concomitant medication.

Vital signs will be captured if still inpatient and the ordinal scale will be assessed.