AGILE (Early Phase Platform Trial for COVID-19)

Master Protocol Inclusion Criteria:

1. Adults (≥18 years) with laboratory-confirmed* SARS-CoV-2 infection (PCR)

2. Ability to provide informed consent signed by study patient or legally acceptable
representative

3. Women of childbearing potential (WOCBP) and male patients who are sexually active
with WOCBP must agree to use a highly effective method of contraception (as outlined
in the protocol) from the first administration of trial treatment, throughout trial
treatment and for the duration outlined in the candidate-specific trial protocol
after the last dose of trial treatment

- If any CSTs are included in the community setting, the CST protocol will
clarify whether patients with suspected SARS-CoV-2 infection are also eligible.

Standard additional criteria that may be applied per CST protocol:

Group A (severe disease) 4a. Patients with clinical status of Grades 4 (hospitalised,
oxygen by mask or nasal prongs), 5 (hospitalised, on non-invasive ventilation, or high
flow oxygen), 6 (hospitalised, intubation and mechanical ventilation) or 7 (ventilation
and additional organ support - pressors, renal replacement therapy (RRT), extracorporeal
membrane oxygenation (ECMO)), as defined by the WHO clinical severity score, 9-point
ordinal scale.

Group B (mild-moderate disease) 4b. Ambulant or hospitalised patients with the following
characteristics peripheral capillary oxygen saturation (SpO2) >94% RA N.B. The CST
protocol inclusion criteria will take precedence over the master protocol inclusion
criteria.

CST-2 Inclusion Criteria:

For the purpose of the EIDD-2801 candidate-specific trial the following inclusion
criteria have been amended from the Master protocol to:

1. Male or female ≥ 60 years old or ≥50 years old with at least one well controlled
comorbidity: cardiovascular disease, chronic lung disease (e.g. COPD, or pulmonary
hypertension), immune deficiency (taking the equivalent of 20 mg prednisone daily,
chemotherapy, or immune modulating biologic therapies), diabetes (treated with
insulin or oral medications), BMI≥30, or hypertension requiring medication with
laboratory confirmed SARS-CoV-2 infection (PCR) .

3. Women of childbearing potential (WOCBP) and male patients who are sexually active
with WOCBP must agree to use two effective methods of contraception, one of which
should be highly effective (as outlined in the protocol). For women, from the first
administration of trial treatment, throughout trial and up to 50 days after the last
follow up visit (50 days after day 29) and for men with female partners of child
bearing potential, from the first administration until 100 days after last follow up
visit (100 days after day 29).

4. Group B (mild-moderate disease): Ambulant with the following characteristics
peripheral capillary oxygen saturation (SpO2) >94% RA (NB this differs to the Master
Protocol which also includes hospitalised patients in this group).

Additional criteria specific to this candidate are:

5. Has signs or symptoms of COVID-19 that began within 5 days of the planned first dose
of study drug.

6. Is in generally good health (except for current respiratory infection) and is free
of uncontrolled chronic conditions.

7. Is willing and able to comply with all study procedures and attending clinic visits
through the 4th week.

8. Has someone, aged ≥ 16 living in the same household during the dosing period.

CST-6 Additional inclusion criteria:

1. Group A (severe disease). Patients with clinical status of Grades 5 (hospitalised,
oxygen by mask or nasal prongs), 6 (hospitalised, on non-invasive ventilation, or
high flow oxygen as defined by the WHO Clinical Progression Scale (WHO, 2020)).

2. Less than or equal to 14 days from onset of COVID-19 symptoms

CST-8 Inclusion Criteria:

1. For the purpose of CST-8, criteria 1 has been amended from the Master Protocol to:

Adults (≥18 years) outpatients positive lateral flow test at screening or baseline
Day 1, who are within 5 days of symptom onset prior to the planned first dose of
study drug.

2. Criteria 3 has been amended from the Master Protocol to:

Women of childbearing potential (WOCBP) and male participants who are sexually active
with WOCBP must agree to use a highly effective method of contraception (as outlined in
section 5.5 of the Master Protocol) for the duration of the treatment and for six weeks
following the last dose.

Additional criteria specific to CST-8 are:

- Initial onset of COVID-19 signs/symptoms within 5 days prior to the day of
randomisation and at least 1 of the current specified COVID-19 signs/symptoms
(listed on the NHS website) present on the day of randomisation

- Is willing and able to comply with all study procedures and attending clinic visits

CST-9a Inclusion Criteria:

For the purpose of CST-9a, criteria 1 has been amended from the Master Protocol to:

1. Adults (>/= 18 years of age) with a positive SARS-CoV-2 lateral flow test on
screening or Day 1, who are at high risk (as defined in UK DHSC criteria) of
progressing to severe COVID-19 disease, within 3 days of symptom onset, with at
least one symptom of COVID-19 infection present on the day of randomization and are
with mild- moderate disease severity at enrolment.

Criterion 2 has been amended from the Master Protocol to:

2. Ability to provide informed consent signed by trial participant or legally
acceptable representative and are willing and able to comply with all trial
procedures and attending clinic visits

Criterion 3 has been amended from the Master Protocol to:

3. Women of childbearing potential (WOCBP) and male participants who are sexually
active with WOCBP must agree to use two effective methods of contraception, one of
which must be highly effective for the duration of the treatment and for 90 Days
following the last dose

Master Protocol Exclusion Criteria:

1. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >5 times the
upper limit of normal (ULN)

2. Stage 4 severe chronic kidney disease or requiring dialysis (i.e., estimated
glomerular filtration rate <30 mL/min/1.73 m^2)

3. Pregnant or breast feeding

4. Anticipated transfer to another hospital which is not a study site within 72 hours

5. Allergy to any study medication

6. Patients taking other prohibited drugs (as outline in CST protocol) within 30 days
or 5 times the half-life (whichever is longer) of enrolment

7. Patients participating in another CTIMP trial

N.B. The CST protocol exclusion criteria will take precedence over the master
protocol exclusion criteria.

CST-2 Exclusion Criteria:

Additional criteria specific to this candidate are:

8. Has a febrile respiratory illness that includes signs of pneumonia, or requires
hospitalization, oxygenation, mechanical ventilation, or other supportive
modalities.

9. Has a platelet count less than 50x10^9/L, or lymphocytes less than 0.2x10^9/L,
haemoglobin less than 10 g/dL, or has a disorder of the hematologic system including
anaemic disorder or other blood dyscrasia, cancer of the hematologic system, history
of bone marrow transplant, or other significant hematologic disease at screening.

10. Is experiencing adverse events or laboratory abnormalities that are Grade 3 or above
based on the CTCAE scale.

11. Has clinically significant liver dysfunction or renal impairment.

12. Has history of Hepatitis C infection or concurrent bacterial pneumonia.

13. Has received an experimental agent (vaccine, drug, biologic, device, blood product,
or medication) within 30 days prior to the first dose of study drug.

14. In the opinion of the investigator, has significant end-organ disease as a result of
relevant comorbidities: chronic kidney disease, congestive heart failure, peripheral
vascular disease including diabetic ulcers.

15. Has a SaO2<95% by oximetry or has lung disease that requires supplemental oxygen.

16. Has any condition that would, in the opinion of the investigator, put the patient at
increased risk for participation in a clinical study.

CST-8 Exclusion Criteria:

For the purpose of the combination CST8 candidate-specific trial the following exclusion
criteria also apply:

1. Swallowing difficulties

2. Known medical history of active liver disease

3. Receiving dialysis or have known moderate to severe renal impairments (defined as
CKD stage 4 or 5 or current acute kidney injury or most recent eGFR in the past 6
months <30 ml/min/1.73m2)

4. Currently taking Paxlovid® or molnupiravir at time of screening

5. Oxygen saturation of <92% on room air, or on their standard home oxygen
supplementation

6. Taking a drug which would put subject at unacceptable risk due to interaction or is
contraindicated as per SPC for each IMP

CST-9a Exclusion Criteria:

Exclusion criteria has been amended from master protocol as:

1. Prior SARS-CoV-2 infection <90 days before enrolment and/or received any COVID-19
vaccine dose <90 days before enrolment

2. Alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) or Active
Liver disease

3. History or current evidence of cirrhosis

4. Receiving dialysis or have known moderate to severe renal impairment (defined as CKD
stage 4 or 5) or current acute kidney injury on most recent eGFR in the past 6
months

5. Pregnant or breast feeding

6. Anticipated transfer to another hospital which is not a trial site within 72 hours

7. Known allergy to any trial medication

8. Swallowing difficulties

9. Currently receiving ALG-097558, Paxlovid, molnupiravir or remdesivir or any SoC
therapy for COVID-19 at the time of screening

10. Received sotrovimab at any point during the current SARS-CoV-2 infection

11. Oxygen saturations <94% on room air

12. Urgent or expected need for nasal high-flow oxygen therapy or positive pressure
ventilation, invasive mechanical ventilation or ECMO.

13. Participants who have taken or require treatment with a comedication that is a
strong CYP450 3A4 inhibitor (atazanavir, clarithromycin, itraconazole, posaconazole,
voriconazole, nefazodone, nelfinavir, grapefruit juice, HIV protease inhibitors),
strong CYP450 3A4 inducers (rifampin, phenytoin, carbamazepine, St. John's Wort) or
sensitive substrates of CYP450 2C8 and 2B6 (repaglinide, rosiglitazone, paclitaxel,
bupropion) within at least 2 weeks or 5 half-lives (whichever is longer) before the
planned first dose of study drug.

14. Participating in another CTIMP trial