The AGILE platform master protocol allows incorporation of a range of identified and yet-to-be-identified candidates as potential treatments for adults with COVID-19 into the trial. Candidates will be added into the trial via candidate-specific trial (CST) protocols of this master protocol as appendices. Having one master protocol ensures different candidates are evaluated in the same consistent manor and opening up new trials for new candidates is more efficient. Inclusion of new candidates will be determined by the AGILE Scientific Advisory Board based on pre-clinical data, evidence in the clinical setting and GMP capabilities.
AGILE is a multicentre, multi-arm, multi-dose, multi-stage open-label, adaptive, seamless
phase I/II Bayesian randomised platform trial to determine the optimal dose, activity and
safety of multiple candidate agents for the treatment of COVID-19.
This study allows for the assessment of many candidates at different doses, with the ability
to add candidates as they are identified or drop them as their evaluation is completed.
Promising candidates will move to the an external trial for further evaluation in the phase
II/III setting.
Each candidate will be evaluated in its own trial, randomising between candidate and control
with 2:1 allocation in favour of the candidate. Each dose will be assessed for safety
sequentially in cohorts of 6 patients. Once a phase II dose has been identified we will
assess efficacy by seamlessly expanding into a larger cohort.
AGILE is completely flexible in that the core design in the master protocol (as has been
explained above) can be adapted for each candidate based on prior knowledge of the candidate
- i.e. population, primary endpoint and sample size can be amended. This will be detailed in
each candidate-specific trial protocol of the master protocol.
Candidate-Specific Trial 2 (CST-2): Open-label 2:1 randomised controlled phase I of EIDD-2801
versus standard of care followed by a 1:1 blinded controlled parallel group Phase II trial of
EIDD-2801 versus placebo. A phase I will be carried out to confirm the optimal dose in this
group. Following a safety review, EIDD-2801 will be tested for efficacy in a blinded placebo
controlled randomised phase II trial.
Candidate-Specific Trial 3 (CST-3A): Multicentre, Adaptive, Phase I trial to Determine the
optimal dose, Safety and Efficacy of Nitazoxanide for the Treatment of COVID-19
Candidate-Specific Trial 3 (CST-3B): A Randomized, Multicentre, Seamless, Adaptive, Phase
I/II trial to Determine the optimal dose, Safety and Efficacy of Nitazoxanide for the
Treatment of COVID-19
Candidate-Specific Trial 5 (CST-5): Randomized, Multicentre, Seamless, Adaptive, Phase I/II
Platform Study to Determine the Phase II dose of VIR-7832, and Evaluate the Safety and
Efficacy of VIR-7831 and VIR-7832 for the Treatment of COVID-19
Candidate-Specific Trial 6 (CST-6): A Randomized, Multicentre, Seamless, Adaptive, Phase I/II
Platform Study to Determine the Phase II dose and to Evaluate the Safety and Efficacy of
intravenous Favipiravir for the Treatment of COVID-19
Candidate-Specific Trial 8 (CST-8): A Randomised, Multicentre, Seamless, Adaptive, Phase I
Platform Study to Determine the recommended Phase II dose and Evaluate the Safety and
Efficacy of antiviral combination of Molnupiravir and Paxlovid® for the Treatment of COVID-19
Drug: CST-2: EIDD-2801
CST-2 Phase Ib: EIDD-2801 will be administered orally, twice daily (BID) for 10 doses (5 or 6 days). The starting dose will be established based on safety and pharmacokinetics from the EIDD-2801-1001-US/UK study, and dose escalations may occur as described in this CST.
Phase II: As per Phase Ib, with the dose determined by the recommended phase II dose.
Other Name: Array
Drug: CST-2: Placebo
CST-2 Phase II: Placebo will be administered orally, twice daily (BID) for 10 doses (5 or 6 days).
Other Name: Placebo
Drug: Nitazoxanide
CST3A & CST3B Phase I: Nitazoxanide will be administered orally, initially twice daily (BID) for 14 doses (7 days). The starting dose will be 1500mg BID based on existing dose information, but dose adaptations may occur.
Phase II: As per Phase Ib, with the dose determined by the recommended phase II dose.
Drug: VIR-7832
CST-5: Phase I, Single doses of VIR-7832 will be administered by intravenous (IV) infusion over 1 hour. The starting dose will be 50 mg, and dose escalations of 150 and 500 mg are anticipated, with escalation guided by emerging safety data and decision by the SRC.
Phase II: As per Phase I, with the dose determined by the recommended phase II dose.
Drug: VIR-7831
CST-5 Phase II: A 500 mg dose of VIR-7831 will also be given by IV infusion over 1 hour.
Other Name: Sotrovimab
Drug: CST-5: Placebo
CST-5 Phase 1, Phase II: Placebo given by intravenous infusion over 1 hour
Other Name: Placebo
Drug: Favipiravir
CST-6: Multiple doses of IV Favipiravir will be administered by intravenous (IV) infusion over 1 hour. Dosing regimen will be every 12 hours for 7 days duration. The starting dose will be 600mg (BID), and dose escalations to 1200mg (BID), 1800mg (BID) and 2400mg (BID) are anticipated as well as a de-escalation dose of 300mg (BID) if necessary, with de-escalation and escalation guided by emerging safety data and decision by the Safety Review Committee (SRC).
Drug: Molnupiravir
Molnupiravir 800mg Twice a day (BD) for 5 days as starting dose, with a de-escalation protocol reducing in increments of molnupiravir to 600mg BD, then 400mg BD if required.
Other Name: Lagevrio
Drug: Paxlovid
Paxlovid® (300mg nirmatrelvir + ritonavir 100mg) twice a day (BD) for 5 days. The dose of Paxlovid® will be fixed for all cohorts.
Other Name: nirmatrelvir and ritonavir
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
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
Desmond Tutu Health Foundation
Cape Town, South Africa
Ezintsha
Johannesburg, South Africa
Liverpool University Hospitals NHS Foundation Trust
Liverpool, United Kingdom
Kings College Hospital NHS Foundation Trust
London, United Kingdom
Manchester University NHS Foundation Trust
Manchester, United Kingdom
University Hospital Southampton NHS Foundation Trust
Southampton, United Kingdom
Saye Khoo, Principal Investigator
University of Liverpool