AGILE (Early Phase Platform Trial for COVID-19)

University of Southampton, Liverpool School of Tropical Medicine, Liverpool University Hospitals NHS Foundation Trust, University of Cambridge

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

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. CST-3A: single arm, open-label phase Ia to confirm the optimum dose, safety and tolerability of Nitazoxanide in healthy volunteers CST-3B: Open-label 1:1 randomised controlled phase Ib of Nitazoxanide versus standard of care (SOC) to confirm the safety and tolerability of Nitazoxanide in participants with COVID-19 followed by a 1:1 blinded parallel group Phase II trial of Nitzaoxanide versus standard of care. CST-5: 3:1 randomised, blinded, placebo-controlled phase I of VIR-7832, followed by a 2:2:1 blinded, parallel group Phase II trial of VIR-7832 versus VIR-7831 versus placebo. CST-6: 2:1 randomised open-label standard of care controlled phase I IV favipiravir CST-8: Open-label 2:1 randomised controlled Phase I de-escalation study of molnupiravir + Paxlovid® versus standard of care alone.

CST-2: Phase I, open-label EIDD-2801 vs standard of care. Phase II, blinded controlled parallel group of EIDD-2801 vs placebo CST-3A: Phase Ia, open-label nitazoxanide CST-3B: Phase Ib, II, open label nitazoxanide vs standard of care CST-5: Phase I, blinded VIR-7832 vs placebo, Phase II, blinded VIR-7832 vs VIR-7831 vs placebo CST-6: Open label IV favipiravir vs standard of care CST-8: Open label Molnupiravir and Paxlovid® versus standard of care

EIDD-2801 (also known as MK-4482, molnupiravir). 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 Ia 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 I: Single doses of VIR-7832 will be administered by intravenous (IV) infusion. The starting dose will be 50 mg, and dose escalations of 150 and 500 mg are anticipated.

IV Favipiravir twice daily for 7 days. Starting dose 600 mg twice daily. Dose escalation to 1200 mg twice daily, 1800 twice daily, 2400 twice daily.

EIDD-2801 (also known as MK-4482, molnupiravir). Phase II: As per Phase Ib, with the dose determined by the recommended phase II dose.

Molnupiravir 800mg Twice a day (BD) in combination with Paxlovid® (300mg nirmatrelvir + ritonavir 100mg) 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. The dose of Paxlovid® will be fixed for all cohorts.

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.

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.

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.

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).

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.

Paxlovid® (300mg nirmatrelvir + ritonavir 100mg) twice a day (BD) for 5 days. The dose of Paxlovid® will be fixed for all cohorts.

Determination of a dose(s) for efficacy evaluation. Dose limiting toxicities (Safety and Tolerability of drug under study - CTCAE v5 Grade ≥3 adverse events)

Determination of activity and safety. In severe patients (Group A): time to clinical improvement. Improvement will be determined according to the WHO Clinical Progression Scale; improvement is defined as a minimum 2-step change from randomisation in the scale up to day 29 post-randomisation.

Determination of activity and safety. In mild to moderate patients (Group B): pharmacodynamics of drug under study, defined as time to negative viral titres in nose and/or throat swab, measured up to 15 days post-randomisation.

CST-2 Phase I: To determine the safety and tolerability of multiple ascending doses of EIDD-2801 to recommend dose for phase II.

Dose limiting toxicity (DLT) using CTCAE version 5 (grades 3 and above) over 7 days. CTCAE grading related to platelets and/or lymphocytes

CST-2 Phase II: To determine the ability of EIDD-2801 to reduce serious complications of COVID-19 including hospitalization, reduction in SAO2<92%, or death.

Progression of disease (SpO2<92% based on at least 2 consecutive recordings on the same day) or hospitalization or death up to day 29

CST6 Phase I: To determine the safety and tolerability of multiple doses of IV Favipiravir in patients with COVID-19

CST6 Phase I: To determine the maximum safe dose of IV Favipiravir for efficacy evaluation in phase II

Dose limiting toxicities (Safety and Tolerability of IV Favipiravir- CTCAE v5 Grade ≥3 adverse events)

Dose limiting toxicities (Safety and Tolerability of molnupiravir and Paxlovid® combination - CTCAE v5 Grade ≥3 adverse events) up to and including Day 11

CST-2 Additional: Pharmacokinetic Objective: To define PK of EIDD-2801 and EIDD-1931 in plasma following multiple doses administered to patients with COVID-19.

CST-2 Additional: Virologic Objective: To assess the difference in viral clearance (time to negative PCR) between EIDD-2801 and control.

CST-2 Additional: Clinical Objective: To determine the ability of EIDD-2801 to reduce the duration of signs and symptoms of COVID-19 in patients (FLU-PRO)

CST-2 Additional: Clinical Objective: To determine the ability of EIDD-2801 to reduce the duration of signs and symptoms of COVID-19 in patients (WHO Scale).

CST-2 Additional: Clinical Objective: To determine the ability of EIDD-2801 to reduce the duration of signs and symptoms of COVID-19 in patients (NEWS2)

CST-2 Additional: Clinical Objective: To determine the ability of EIDD-2801 to reduce the duration of signs and symptoms of COVID-19 in patients (mortality)

CST-2 Additional: Clinical Objective: To determine the ability of EIDD-2801 to reduce the duration of signs and symptoms of COVID-19 in patients (death)

CST-6 Additional: To investigate the ability of IV Favipiravir to reduce the duration of signs and symptoms of COVID-19 in-patients

Vital sign measure 1 heart rate (beats/min) - to be part of aggregated review of pt vitals to assess safety and tolerability.

Vital sign measure 2 Blood Pressure (mmHG) - to be part of aggregated review of pt vitals to assess safety and tolerability.

Vital sign measure 3 respiratory rate (breaths/min) - to be part of aggregated review of pt vitals to assess safety and tolerability.

Vital sign measure 4 temperature (degrees c) - to be part of aggregated review of pt vitals to assess safety and tolerability.

Vital sign measure 5 oxygen saturation (FiO2 as %) - to be part of aggregated review of pt vitals to assess safety and tolerability.

Master Protocol Inclusion Criteria: Adults (≥18 years) with laboratory-confirmed* SARS-CoV-2 infection (PCR) Ability to provide informed consent signed by study patient or legally acceptable representative 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: 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)). Less than or equal to 14 days from onset of COVID-19 symptoms CST-8 Inclusion Criteria: 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. 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: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >5 times the upper limit of normal (ULN) Stage 4 severe chronic kidney disease or requiring dialysis (i.e., estimated glomerular filtration rate <30 mL/min/1.73 m^2) Pregnant or breast feeding Anticipated transfer to another hospital which is not a study site within 72 hours Allergy to any study medication Patients taking other prohibited drugs (as outline in CST protocol) within 30 days or 5 times the half-life (whichever is longer) of enrolment 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: Has a febrile respiratory illness that includes signs of pneumonia, or requires hospitalization, oxygenation, mechanical ventilation, or other supportive modalities. 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. Is experiencing adverse events or laboratory abnormalities that are Grade 3 or above based on the CTCAE scale. Has clinically significant liver dysfunction or renal impairment. Has history of Hepatitis C infection or concurrent bacterial pneumonia. Has received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 30 days prior to the first dose of study drug. 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. Has a SaO2<95% by oximetry or has lung disease that requires supplemental oxygen. 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: Swallowing difficulties Known medical history of active liver disease 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) Currently taking Paxlovid® or molnupiravir at time of screening Oxygen saturation of <92% on room air, or on their standard home oxygen supplementation Taking a drug which would put subject at unacceptable risk due to interaction or is contraindicated as per SPC for each IMP

Master protocol available from https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04473-1

Khoo SH, FitzGerald R, Saunders G, Middleton C, Ahmad S, Edwards CJ, Hadjiyiannakis D, Walker L, Lyon R, Shaw V, Mozgunov P, Periselneris J, Woods C, Bullock K, Hale C, Reynolds H, Downs N, Ewings S, Buadi A, Cameron D, Edwards T, Knox E, Donovan-Banfield I, Greenhalf W, Chiong J, Lavelle-Langham L, Jacobs M, Northey J, Painter W, Holman W, Lalloo DG, Tetlow M, Hiscox JA, Jaki T, Fletcher T, Griffiths G; AGILE CST-2 Study Group. Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Infect Dis. 2023 Feb;23(2):183-195. doi: 10.1016/S1473-3099(22)00644-2. Epub 2022 Oct 19. Erratum In: Lancet Infect Dis. 2023 Jan;23(1):e1.

FitzGerald R, Dickinson L, Else L, Fletcher T, Hale C, Amara A, Walker L, Penchala SD, Lyon R, Shaw V, Greenhalf W, Bullock K, Lavelle-Langham L, Reynolds H, Painter W, Holman W, Ewings S, Griffiths G, Khoo S. Pharmacokinetics of ss-d-N4-Hydroxycytidine, the Parent Nucleoside of Prodrug Molnupiravir, in Nonplasma Compartments of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Clin Infect Dis. 2022 Aug 24;75(1):e525-e528. doi: 10.1093/cid/ciac199.

Walker LE, FitzGerald R, Saunders G, Lyon R, Fisher M, Martin K, Eberhart I, Woods C, Ewings S, Hale C, Rajoli RKR, Else L, Dilly-Penchala S, Amara A, Lalloo DG, Jacobs M, Pertinez H, Hatchard P, Waugh R, Lawrence M, Johnson L, Fines K, Reynolds H, Rowland T, Crook R, Okenyi E, Byrne K, Mozgunov P, Jaki T, Khoo S, Owen A, Griffiths G, Fletcher TE; AGILE platform. An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2. Clin Pharmacol Ther. 2022 Mar;111(3):585-594. doi: 10.1002/cpt.2463. Epub 2021 Nov 13.

Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Griffiths GO, FitzGerald R, Jaki T, Corkhill A, Reynolds H, Ewings S, Condie S, Tilt E, Johnson L, Radford M, Simpson C, Saunders G, Yeats S, Mozgunov P, Tansley-Hancock O, Martin K, Downs N, Eberhart I, Martin JWB, Goncalves C, Song A, Fletcher T, Byrne K, Lalloo DG, Owen A, Jacobs M, Walker L, Lyon R, Woods C, Gibney J, Chiong J, Chandiwana N, Jacob S, Lamorde M, Orrell C, Pirmohamed M, Khoo S; AGILE investigators. AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment: an update to the structured summary of a study protocol for a randomised platform trial letter. Trials. 2021 Jul 26;22(1):487. doi: 10.1186/s13063-021-05458-4.