AGILE (Early Phase Platform Trial for COVID-19)

AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 Treatment

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Covid19
• Intervention / Treatment: Drug: CST-2: EIDD-2801; Drug: CST-2: Placebo; Drug: Nitazoxanide; Drug: VIR-7832; Drug: VIR-7831; Drug: CST-5: Placebo; Drug: Favipiravir; Drug: Molnupiravir; Drug: Paxlovid

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Helen E Reynolds; Phone Number: +44 (0)1517945553; Email: livagile@liv.ac.uk

Study Locations

• South Africa
  • Cape Town, South Africa
    • Desmond Tutu Health Foundation
  • Johannesburg, South Africa
    • Ezintsha
• United Kingdom
  • Liverpool, United Kingdom, L7 8XP
    • Liverpool University Hospitals NHS Foundation Trust
  • London, United Kingdom
    • Kings College Hospital NHS Foundation Trust
  • Manchester, United Kingdom
    • Manchester University NHS Foundation Trust
  • Southampton, United Kingdom, SO16 6YD
    • University Hospital Southampton NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

16

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: CST-2 Control; Phase 1b only (standard of care)
Placebo Comparator: CST-2 Placebo; Phase II placebo blinded controlled	Drug: CST-2: Placebo; CST-2 Phase II: Placebo will be administered orally, twice daily (BID) for 10 doses (5 or 6 days).; Other Names: Placebo
Experimental: CST-3A Nitazoxanide; 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	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.
No Intervention: CST3B Control; Standard of care
Experimental: CST6 IV Favipiravir; 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.	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).
No Intervention: CST6 Control; Standard of care
Experimental: CST-2 EIDD-2801 Phase Ib; 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.	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 Names: MK-4482; Molnupiravir
Experimental: CST-5 VIR-7832 Phase I; 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.	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.
Active Comparator: CST-5 VIR-7831 Phase II; Phase II: 500 mg dose of VIR-7831 will be given by IV infusion.	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 Names: Sotrovimab
Placebo Comparator: CST-5 Placebo Phase I; Phase I: placebo blinded controlled	Drug: CST-5: Placebo; CST-5 Phase 1, Phase II: Placebo given by intravenous infusion over 1 hour; Other Names: Placebo
Experimental: CST3B Nitazoxanide; Phase II experimental arm.	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.
Experimental: CST-2 EIDD-2801 Phase II; EIDD-2801 (also known as MK-4482, molnupiravir). Phase II: As per Phase Ib, with the dose determined by the recommended phase II dose.	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 Names: MK-4482; Molnupiravir
Experimental: CST-8 Phase I Molnupiravir + Paxlovid®; 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.	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 Names: 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 Names: nirmatrelvir and ritonavir
No Intervention: CST-8 Phase I Molnupiravir + Paxlovid® Control; Standard of care
Active Comparator: CST-5 VIR-7832; Phase II: 500 mg dose of VIR-7832 will be given by IV infusion.	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.
Placebo Comparator: CST-5 Placebo Phase II; Phase II: placebo blinded controlled	Drug: CST-5: Placebo; CST-5 Phase 1, Phase II: Placebo given by intravenous infusion over 1 hour; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Master Protocol: Dose-finding/Phase I	Determination of a dose(s) for efficacy evaluation. Dose limiting toxicities (Safety and Tolerability of drug under study - CTCAE v5 Grade ≥3 adverse events)	29 days from randomisation
Master Protocol: Efficacy evaluation/Phase II - Severe patients (Group A)	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.	29 days from randomisation
Master Protocol: Efficacy evaluation/Phase II - Mild to moderate patients (Group B)	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.	15 days from 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	7 days from randomisation
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	29 days from randomisation
CST6 Phase I: To determine the safety and tolerability of multiple doses of IV Favipiravir in patients with COVID-19	Adverse events and serious adverse events	29 days from randomisation
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)	8 days from randomisation
CST-8 Phase I: Dose Limiting Toxicities up to and including Day 11	Dose limiting toxicities (Safety and Tolerability of molnupiravir and Paxlovid® combination - CTCAE v5 Grade ≥3 adverse events) up to and including Day 11	11 days from randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Master Protocol: Safety assessed by rate of adverse events	Adverse event rate according to CTCAE v5	Up to 29 days from randomisation
Master Protocol: To evaluate clinical improvement	Proportion of patients with clinical improvement (as defined above) at day 8, 15 and day 29.	From randomisation to day 29
Master Protocol: To evaluate clinical improvement using WHO clinical progression scale	Change at day 8 and 15 from randomisation in the WHO Clinical Progression Scale	From randomisation to day 15
Master Protocol: To evaluate clinical improvement using WHO clinical progression scale	Time to a one point change on the WHO Clinical Progression Scale	From randomisation to day 29
Master Protocol: To evaluate clinical improvement using SpO2/FiO2	The ratio of the oxygen saturation to fractional inspired oxygen concentration (SpO2/FiO2)	From randomisation to day 29
Master Protocol: To evaluate discharge	Proportion of patient discharged at days 8, 15 and 29	From randomisation to day 29
Master Protocol: To evaluate admission to ICU	Admission rate to ICU	From randomisation to day 29
Master Protocol: To evaluate safety further (WCC)	White cell count on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29	From randomisation to day 29
Master Protocol: To evaluate safety further (Hg)	Haemoglobin on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29	From randomisation to day 29
Master Protocol: To evaluate safety further (platelets)	Platelets on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29	From randomisation to day 29
Master Protocol: To evaluate safety further (creatinine)	Creatinine on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29	From randomisation to day 29
Master Protocol: To evaluate safety further (ALT)	ALT on day 1, 3, 5, 8, 11 (while hospitalised); and Day 15 and 29	From randomisation to day 29
Master Protocol: To evaluate overall mortality	Mortality at Days 8, 15 and 29. Time to death from randomisation	From randomisation to day 29
Master Protocol: To evaluate the number of oxygen-free days	Duration (days) of oxygen use and oxygen-free days	From randomisation to day 29
Master Protocol: To evaluate ventilator-free days	Duration (days) of mechanical ventilation and mechanical ventilation-free days	From randomisation to day 29
Master Protocol: To evaluate incidence of new mechanical ventilation use	Incidence of new mechanical ventilation use	From randomisation to day 29
Master Protocol: To evaluate National Early Warning Score (NEWS)2/qSOFA	NEWS2/qSOFA assessed daily while hospitalised	From randomisation to day 29
Master Protocol: To evaluate translational outcomes (Viral Load)	Change in viral load over time	From randomisation to day 29
Master Protocol: To evaluate translational outcomes (Baseline SARS-COV-2)	Change in viral load over time	From randomisation to day 29
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.	Concentrations of EIDD-2801 and -1931 in plasma	Samples collected on Day 1 and Day 5 post-randomisation
CST-2 Additional: Virologic Objective: To assess the difference in viral clearance (time to negative PCR) between EIDD-2801 and control.	Qualitative (and quantitative when possible) PCR for SARS-CoV-2 by nasal swab.	Swabs taken on Day 1 (day of randomisation), 3, 5, 8, 11, 15, 22 and 29
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)	Patient Reported Outcome Measures (FLU-PRO).	From randomisation to Day 29
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).	WHO Progression Scale at day 15 and 29	From randomisation to Day 29
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)	NEWS2 (National Early Warning Score2) assessed during study clinic visit on days 15 and 29.	From randomisation to Day 29
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)	Mortality at Days 15 and 29	From randomisation to Day 29
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)	Time from randomisation to death	From randomisation to Day 29
CST-6 Additional: To characterise the pharmacokinetics (PK) of multiple doses of IV Favipiravir	Plasma PK parameters of IV Favipiravir	From randomisation to Day 8
CST-6 Additional: To investigate the ability of IV Favipiravir to reduce the duration of signs and symptoms of COVID-19 in-patients	WHO Progression Scale (WHO, 2020)	Randomisation to Day 15 and Day 29
CST-6 Additional: To investigate the effect of IV Favipiravir on SARS-CoV-2 viral load	Viral load change from baseline over time	From randomisation to Day 29
CST-8: Assess feasibility for late phase study by reviewing any recorded AEs and SAEs	Review of any adverse events	From randomisation to Day 29
CST-8: Assess feasibility for late phase study by reviewing hospitalisation or death up to Day 29	Death and hospitalisation up to Day 29	From randomisation to Day 29
CST-8: Measure concentrations of IMP re evidence of virological efficacy	PK concentrations of both IMPs and their circulating metabolites in plasma.	From randomisation to Day 11
CST-8: Measure PK of each drug within the combination	PK concentrations of both IMPs and their circulating metabolites in plasma.	From randomisation to Day 11
CST8: Review evidence of virological efficacy via viral elimination slopes	Qualitative (and quantitative when possible) PCR for SARS-CoV-2 by nose and throat swab	From baseline to Day 11
CST8: Vital signs (Heart Rate) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11	Vital sign measure 1 heart rate (beats/min) - to be part of aggregated review of pt vitals to assess safety and tolerability.	From randomisation to Day 11
CST-8: Vital signs (Blood Pressure) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11	Vital sign measure 2 Blood Pressure (mmHG) - to be part of aggregated review of pt vitals to assess safety and tolerability.	From randomisation to Day 11
CST-8: Vital signs (Respiratory Rate) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11	Vital sign measure 3 respiratory rate (breaths/min) - to be part of aggregated review of pt vitals to assess safety and tolerability.	From randomisation to Day 11
CST-8: Vital signs (Temperature) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11	Vital sign measure 4 temperature (degrees c) - to be part of aggregated review of pt vitals to assess safety and tolerability.	From randomisation to Day 11
CST-8: Vital signs (Oxygen Saturation) at Screening, Baseline/Day 1, Day 3, Day 5 and Day 11	Vital sign measure 5 oxygen saturation (FiO2 as %) - to be part of aggregated review of pt vitals to assess safety and tolerability.	From randomisation to Day 11

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CST-8: Measure PK of nirmatrelvir and ritonavir in tears, saliva and nasal secretions	Concentration of nirmatrelvir and ritonavir in non-plasma	From randomisation to Day 5
CST-8:To characterise genetic variability in SARS-CoV-2 before and during treatment via PCR analysis	PCR analysis re Baseline and treatment emergent genetic mutations in SARS-CoV-2	From randomisation to Day 11

Collaborators and Investigators

• Sponsor: University of Liverpool
• Collaborators: University of Southampton; Liverpool University Hospitals NHS Foundation Trust; University of Cambridge; Liverpool School of Tropical Medicine
• Investigators: Principal Investigator: Saye Khoo, University of Liverpool

Publications and helpful links

General Publications

• 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.
• 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.
• Griffiths G, Fitzgerald R, Jaki T, Corkhill A, Marwood E, Reynolds H, Stanton L, Ewings S, Condie S, Wrixon E, Norton A, Radford M, Yeats S, Robertson J, Darby-Dowman R, Walker L, Khoo S; UK NIHR community. AGILE-ACCORD: A Randomized, Multicentre, Seamless, Adaptive Phase I/II Platform Study to Determine the Optimal Dose, Safety and Efficacy of Multiple Candidate Agents for the Treatment of COVID-19: A structured summary of a study protocol for a randomised platform trial. Trials. 2020 Jun 19;21(1):544. doi: 10.1186/s13063-020-04473-1.
• 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.
• Khoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R, Downs N, Walker L, Tansley-Hancock O, Greenhalf W, Woods C, Reynolds H, Marwood E, Mozgunov P, Adams E, Bullock K, Holman W, Bula MD, Gibney JL, Saunders G, Corkhill A, Hale C, Thorne K, Chiong J, Condie S, Pertinez H, Painter W, Wrixon E, Johnson L, Yeats S, Mallard K, Radford M, Fines K, Shaw V, Owen A, Lalloo DG, Jacobs M, Griffiths G. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study. J Antimicrob Chemother. 2021 Nov 12;76(12):3286-3295. doi: 10.1093/jac/dkab318.
• 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.
• 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.

Helpful Links

• The AGILE Clinical Trial Platform website

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2020
• Primary Completion (Estimated): December 18, 2023
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: October 13, 2020
• First Submitted That Met QC Criteria: February 8, 2021
• First Posted (Actual): February 9, 2021

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 21, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Phase I; Phase II; SARS coronavirus 2; Platform trial
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antiparasitic Agents; HIV Protease Inhibitors; Viral Protease Inhibitors; Favipiravir; Ritonavir; Nitazoxanide; Nirmatrelvir; Sotrovimab; Molnupiravir; Nirmatrelvir and ritonavir drug combination
• Other Study ID Numbers: UoL001542

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Master protocol publication. Data sets will be registered on CSDR
• IPD Sharing Time Frame: Master protocol published 19 June 2020
• IPD Sharing Access Criteria: Master protocol available from https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04473-1
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No